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Sample records for nonsyndromic x-linked sensorineural

  1. A new nonsyndromic X-linked sensorineural hearing impairment linked to Xp21.2

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    Lalwani, A.K.; Brister, J.R.; Fex, J.; Grundfast, K.M.; Pikus, A.T.; Ploplis, B.; San Agustin, T.; Skarka, H.; Wilcox, E.R. [National Institutes of Health, Bethesda, MD (United States)

    1994-10-01

    X-linked deafness is a rare cause of hereditary hearing impairment. We have identified a family with X-linked dominant sensorineural hearing impairment, characterized by incomplete penetrance and variable expressivity in carrier females, that is linked to the Xp21.2, which contains the Duchenne muscular dystrophy (DMD) locus. The auditory impairment in affected males was congenital, bilateral, profound, sensorineural, affecting all frequencies, and without evidence of radiographic abnormality of the temporal bone. Adult carrier females manifested bilateral, mild-to-moderate high-frequency sensorineural hearing impairment of delayed onset during adulthood. Eighteen commercially available polymorphic markers from the X chromosome, generating a 10-15-cM map, were initially used for identification of a candidate region. DXS997, located within the DMD gene, generated a two-point LOD score of 2.91 at {theta} = 0, with every carrier mother heterozygous at this locus. Recombination events at DXS992 (located within the DMD locus, 3{prime} to exon 50 of the dystrophin gene) and at DXS1068 (5{prime} to the brain promoter of the dystrophin gene) were observed. No recombination events were noted with the following markers within the DMD locus: 5{prime}DYS II, intron 44, DXS997, and intron 50. There was no clinical evidence of Duchenne or Becker muscular dystrophy in any family member. It is likely that this family represents a new locus on the X chromosome, which when mutated results in nonsyndromic sensorineural hearing loss and is distinct from the heterogeneous group of X-linked hearing losses that have been previously described. 57 refs., 6 figs., 1 tab.

  2. Refinement of the locus for non-syndromic sensorineural deafness ...

    Indian Academy of Sciences (India)

    Non-syndromic X-linked deafness is a rare form of genetic deafness in humans accounting for a small proportion of all hereditary hearing loss. Different clinical forms of non-syndromic X-linked deafness have been described, and most of these have been mapped. Here, we report a Chinese family affected by a congenital ...

  3. Non-syndromic posterior lenticonus a cause of childhood cataract: evidence for X-linked inheritance.

    Science.gov (United States)

    Russell-Eggitt, I M

    2000-12-01

    When an X-linked pedigree of posterior lenticonus with cataract was identified further evidence for X-linked inheritance of this condition was sought. Forty-three cases of posterior lenticonus were identified from a database of 354 children with cataract. Two children with the X-linked syndromes of Lowe and Nance-Horan and 3 children with Fanconi syndrome have been excluded from further analysis. None of the children was deaf. None of the non-syndromic cases had microcornea. There were 38 cases of non-syndromic posterior lenticonus (approximately 11%). There were 15 children from 13 pedigrees and 23 apparently sporadic cases. Of the 106 cases on the database with unilateral cataract 15 had posterior lenticonus (approximately 14%). Eleven of 13 pedigrees were compatible with X-linked inheritance or autosomal dominant inheritance with variable expression. However, in 2 pedigrees there was father to son transmission. Posterior lenticonus is a common cause of unilateral infantile cataract, but is thought to be a rare cause of bilateral cataracts. This study suggests that posterior lenticonus is responsible for a significant proportion of childhood cataracts (approximately 14% of unilateral and approximately 9% of bilateral cases). Posterior lenticonus is generally thought to occur as a sporadic condition. This study demonstrates that there is a family history of early-onset cataract in a significant number of bilateral cases (approximately 58%).

  4. A novel frameshift mutation of SMPX causes a rare form of X-linked nonsyndromic hearing loss in a Chinese family.

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    Zhijie Niu

    Full Text Available X-linked hearing impairment is the rarest form of genetic hearing loss (HL and represents only a minor fraction of all cases. The aim of this study was to investigate the cause of X-linked inherited sensorineural HL in a four-generation Chinese family. A novel duplication variant (c.217dupA, p.Ile73Asnfs*5 in SMPX was identified by whole-exome sequencing. The frameshift mutation predicted to result in the premature truncation of the SMPX protein was co-segregated with the HL phenotype and was absent in 295 normal controls. Subpopulation screening of the coding exons and flanking introns of SMPX was further performed for 338 Chinese patients with nonsydromic HL by Sanger sequencing, and another two potential causative substitutions (c.238C>A and c.55A>G in SMPX were identified in additional sporadic cases of congenital deafness. Collectively, this study is the first to report the role of SMPX in Chinese population and identify a novel frameshift mutation in SMPX that causes not only nonsyndromic late-onset progressive HL, but also congenital hearing impairment. Our findings extend the mutation and phenotypic spectrum of the SMPX gene.

  5. Loss-of-Function CNKSR2 Mutation Is a Likely Cause of Non-Syndromic X-Linked Intellectual Disability.

    Science.gov (United States)

    Houge, G; Rasmussen, I H; Hovland, R

    2012-01-01

    In a non-dysmorphic 5-year-old boy with developmental delay, well-controlled epilepsy, and microcephaly, a 234-kb deletion of Xp22.12 was detected by copy number analysis. The maternally inherited deletion removed the initial 15 of the 21 exons of the connector enhancer of KSR-2 gene called CNKSR2 or CNK2. Our finding suggests that loss of CNKSR2 is a novel cause of non-syndromic X-linked mental retardation, an assumption supported by high gene expression in the brain, localization to the post-synaptic density, and a role in RAS/MAPK-dependent signal transduction.

  6. Loss-of-Function CNKSR2 Mutation Is a Likely Cause of Non-Syndromic X-Linked Intellectual Disability

    OpenAIRE

    Houge, G.; Rasmussen, I.H.; Hovland, R.

    2011-01-01

    In a non-dysmorphic 5-year-old boy with developmental delay, well-controlled epilepsy, and microcephaly, a 234-kb deletion of Xp22.12 was detected by copy number analysis. The maternally inherited deletion removed the initial 15 of the 21 exons of the connector enhancer of KSR-2 gene called CNKSR2 or CNK2. Our finding suggests that loss of CNKSR2 is a novel cause of non-syndromic X-linked mental retardation, an assumption supported by high gene expression in the brain, localization to the pos...

  7. Prevalence of mitochondrial DNA mutations in sporadic patients with nonsyndromic sensorineural hearing loss.

    Science.gov (United States)

    Jiang, Hua; Chen, Jia; Li, Ying; Lin, Peng-Fang; He, Jian-Guo; Yang, Bei-Bei

    2016-01-01

    Several mitochondrial DNA mutations have been reported to be associated with nonsyndromic hearing loss in several families. However, little is known about the prevalence of these mutations in sporadic patients with nonsyndromic sensorineural hearing loss. The purpose of our study was to investigate the incidence of these mitochondrial DNA mutations in such population. A total of 178 sporadic patients with nonsyndromic sensorineural hearing loss were enrolled in this study. Genomic DNA was extracted from the peripheral blood sample. We employed the SNaPshot(®) sequencing method to detect five mitochondrial DNA mutations, including A1555G and A827G in 12S rRNA gene and A7445G, 7472insC, and T7511C in tRNA(Ser(UCN)) gene. Meanwhile, we used polymerase chain reaction and sequenced the products to screen GJB2 gene mutations in patients carrying mitochondrial DNA mutations. We failed to detect the presence of A1555G mutation in 12S rRNA gene, and of A7445G, 7472insC, T7511C mutations in tRNA(Ser(UCN)) gene in our population. However, we found that 6 patients (3.37%) were carriers of a homozygous A827G mutation and one of them also carried homozygous GJB2 235delC mutation. Our findings in the present study indicate that even in sporadic patients with nonsyndromic sensorineural hearing loss, mitochondrial DNA mutations might also contribute to the clinical phenotype. Copyright © 2015 Associação Brasileira de Otorrinolaringologia e Cirurgia Cérvico-Facial. Published by Elsevier Editora Ltda. All rights reserved.

  8. Mutations in the FTSJ1 gene coding for a novel S-adenosylmethionine-binding protein cause nonsyndromic X-linked mental retardation

    DEFF Research Database (Denmark)

    Freude, Kristine; Hoffmann, Kirsten; Jensen, Lars-Riff

    2004-01-01

    Nonsyndromic X-linked mental retardation (NSXLMR) is a very heterogeneous condition, and most of the underlying gene defects are still unknown. Recently, we have shown that approximately 30% of these genes cluster on the proximal Xp, which prompted us to perform systematic mutation screening in b...

  9. Mutations in the FTSJ1 gene coding for a novel S-adenosylmethionine-binding protein cause nonsyndromic X-linked mental retardation

    DEFF Research Database (Denmark)

    Freude, Kristine; Hoffmann, Kirsten; Jensen, Lars-Riff

    2004-01-01

    Nonsyndromic X-linked mental retardation (NSXLMR) is a very heterogeneous condition, and most of the underlying gene defects are still unknown. Recently, we have shown that approximately 30% of these genes cluster on the proximal Xp, which prompted us to perform systematic mutation screening...

  10. [Research progress of mutational spectrum and pathophysiology of WFS1 gene in Wolfram syndrome and nonsyndromic low frequency sensorineural hearing loss].

    Science.gov (United States)

    Shi, S M; Han, Y H; Wang, H B

    2016-09-07

    Compound homozygous or heterozygous mutations in WFS 1 can lead to autosomal recessive Wolfram syndrome (WS), and heterozygous mutations in WFS 1 can lead to autosomal dominant non-syndromic low frequency sensorineural hearing loss (LFSNHL). In addition, mutations in the WFS region has relationship with diabetes and psychiatric diseases. In this paper, we provide an overview of genetic research with different phenotypes, including WS and LFSNHL.

  11. Novel EDA or EDAR Mutations Identified in Patients with X-Linked Hypohidrotic Ectodermal Dysplasia or Non-Syndromic Tooth Agenesis

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    Binghui Zeng

    2017-10-01

    Full Text Available Abstract: Both X-linked hypohidrotic ectodermal dysplasia (XLHED and non-syndromic tooth agenesis (NSTA result in symptoms of congenital tooth loss. This study investigated genetic causes in two families with XLHED and four families with NSTA. We screened for mutations of WNT10A, EDA, EDAR, EDARADD, PAX9, MSX1, AXIN2, LRP6, and WNT10B through Sanger sequencing. Whole exome sequencing was performed for the proband of NSTA Family 4. Novel mutation c.1051G>T (p.Val351Phe and the known mutation c.467G>A (p.Arg156His of Ectodysplasin A (EDA were identified in families with XLHED. Novel EDA receptor (EDAR mutation c.73C>T (p.Arg25*, known EDA mutation c.491A>C (p.Glu164Ala, and known Wnt family member 10A (WNT10A mutations c.511C>T (p.Arg171Cys and c.742C>T (p.Arg248* were identified in families with NSTA. The novel EDA and EDAR mutations were predicted as being pathogenic through bioinformatics analyses and structural modeling. Two variants of WNT10A, c.374G>A (p.Arg125Lys and c.125A>G (p.Asn42Ser, were found in patients with NSTA. The two WNT10A variants were predicted to affect the splicing of message RNA, but minigene experiments showed normal splicing of mutated minigenes. This study uncovered the genetic foundations with respect to six families with XLHED or NSTA. We identified six mutations, of which two were novel mutations of EDA and EDAR. This is the first report of a nonsense EDAR mutation leading to NSTA.

  12. ZNF674: A New Kruppel-Associated Box-Containing Zinc-Finger Gene Involved in Nonsyndromic X-Linked Mental Retardation

    NARCIS (Netherlands)

    Lugtenberg, D.; Yntema, H.G.; Banning, M.J.G.; Oudakker, A.R.; Firth, H.; Willatt, L.; Raynaud, M.; Kleefstra, T.; Fryns, J.P.; Ropers, H.H.; Chelly, J.; Moraine, C.; Gecz, J.; Reeuwijk, J. van; Nabuurs, S.B.; Vries, L.B.A. de; Hamel, B.C.J.; Brouwer, A.P.M. de; Bokhoven, J.H.L.M. van

    2006-01-01

    Array-based comparative genomic hybridization has proven to be successful in the identification of genetic defects in disorders involving mental retardation. Here, we studied a patient with learning disabilities, retinal dystrophy, and short stature. The family history was suggestive of an X-linked

  13. Non-syndromic sensorineural prelingual deafness: the importance of genetic counseling in demystifying parents' beliefs about the cause of their children's deafness.

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    Rodrigues, Fidjy; Paneque, Milena; Reis, Cláudia; Venâncio, Margarida; Sequeiros, Jorge; Saraiva, Jorge

    2013-08-01

    Recent advances in molecular genetics have allowed the determination of the genetic cause of some childhood non-syndromic deafness. In Portugal only a small proportion of families are referred to a clinical genetics service in order to clarify the etiology of the deafness and to provide genetic counseling. Consequently, there are no published studies of the prior beliefs of parents about the causes of hereditary deafness of their children and their genetic knowledge after receipt of genetic counseling. In order to evaluate the impact of genetic counseling, 44 parents of 24 children with the diagnosis of non-syndromic sensorineural prelingual deafness due to mutations in the GJB2 (connexin 26), completed surveys before and after genetic counseling. Before counseling 13.6 % of the parents knew the cause of deafness; at a post-counseling setting this percentage was significantly higher, with 84.1 % of the parents accurately identifying the etiology. No significant differences were found between the answers of mothers and fathers either before or after genetic counseling. Parents' level of education was a significant factor in pre-test knowledge. After genetic counseling 95.5 % of the parents stated that the consultation had met their expectations, 70.5 % remembered correctly the inheritance pattern, and 93.2 % correctly recalled the chance of risk of deafness. These results underline the importance of genetic counseling in demystifying parents' beliefs about the etiology of their children's deafness.

  14. Whole Genome Sequencing Reveals Novel Non-Synonymous Mutation in Ectodysplasin A (EDA) Associated with Non-Syndromic X-Linked Dominant Congenital Tooth Agenesis

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    Sarkar, Tanmoy; Bansal, Rajesh; Das, Parimal

    2014-01-01

    Congenital tooth agenesis in human is characterized by failure of tooth development during tooth organogenesis. 300 genes in mouse and 30 genes in human so far have been known to regulate tooth development. However, candidature of only 5 genes viz. PAX9, MSX1, AXIN2, WNT10A and EDA have been experimentally established for congenitally missing teeth like hypodontia and oligodontia. In this study an Indian family with multiple congenital tooth agenesis was identified. Pattern of inheritance was apparently autosomal dominant type with a rare possibility to be X-linked. Whole genome sequencing of two affected individuals was carried out which revealed 119 novel non-synonymous single nucleotide variations (SNVs) distributed among 117 genes. Out of these only one variation (c.956G>T) located at exon 9 of X-linked EDA gene was considered as pathogenic and validated among all the affected and unaffected family members and unrelated controls. This variation leads to p.Ser319Ile change in the TNF homology domain of EDA (transcript variant 1) protein. In silico analysis predicts that this Ser319 is well conserved across different vertebrate species and a part of putative receptor binding site. Structure based homology modeling predicts that this amino acid residue along with four other amino acid residues nearby, those when mutated known to cause selective tooth agenesis, form a cluster that may have functional significance. Taken together these results suggest that c.956G>T (p.Ser319Ile) mutation plausibly reduces the receptor binding activity of EDA leading to distinct tooth agenesis in this family. PMID:25203534

  15. A Dutch family with progressive autosomal dominant non-syndromic sensorineural hearing impairment linked to DFNA13.

    NARCIS (Netherlands)

    Ensink, R.J.H.; Huygen, P.L.M.; Snoeckx, R.L.; Caethoven, G.; Camp, G. van; Cremers, C.W.R.J.

    2001-01-01

    We present a Dutch family with autosomal dominantly inherited mid-frequency and high-frequency sensorineural hearing impairment. Genetic linkage analysis in this family indicated linkage to DFNA13 with logarithm of the odds ratio (LOD) scores > +4. The majority of the affected persons presented

  16. Identification of two novel missense WFS1 mutations, H696Y and R703H, in patients with non-syndromic low-frequency sensorineural hearing loss.

    Science.gov (United States)

    Sun, Yi; Cheng, Jing; Lu, Yanping; Li, Jianzhong; Lu, Yu; Jin, Zhanguo; Dai, Pu; Wang, Rongguang; Yuan, Huijun

    2011-02-01

    Non-syndromic low-frequency sensorineural hearing loss (LFSNHL) is an unusual type of hearing loss in which frequencies ≤2000 Hz predominantly are affected. To date, different mutations in two genes, DIAPH1 and WFS1, have been found to be associated with LFSNHL. Here, we report a five-generation Chinese family with postlingual and progressive LFSNHL. We mapped the disease locus to a 2.5 Mb region on chromosome 4p16 between markers SNP_A-2167174 and D4S431, overlapping with the DFNA6/14/38 locus. Sequencing of candidate gene revealed a heterozygous c.2086C>T substitution in exon 8 of WFS1, leading to p.H696Y substitution at the C-terminus of Wolframin (WFS1). In addition, we performed mutational screening of WFS1 in 37 sporadic patients, 7-50 years of age, with LFSNHL. We detected a heterozygous c.2108G>A substitution in exon 8 of WFS1, leading to p.R703H substitution in a patient. The H696 and R703 in WFS1 are highly conserved across species, including human, orangutan, rat, mouse, and frog (Xenopus). Sequence analysis demonstrated the absence of c.2086C>T or c.2108G>A substitutions in the WFS1 genes among 200 unrelated control subjects of Chinese background, supporting the hypothesis that they represent causative mutations, and not rare polymorphisms. Our data provide additional molecular and clinical information for establishing a better genotype-phenotype correlation for LFSNHL. Copyright © 2011. Published by Elsevier Ltd.

  17. Generation of an induced pluripotent stem cell line from a 39-year-old female patient with severe-to-profound non-syndromic sensorineural hearing loss and a A1555G mutation in the mitochondrial MTRNR1 gene

    Directory of Open Access Journals (Sweden)

    Yu-Hung Hsu

    2017-12-01

    Full Text Available Sensorineural hearing loss (SNHL is a prevalent form of deafness commonly arising from damage to the cochlear sensory hair cells and degeneration of the spiral ganglion neurons. In this study, Sendai virus was used to generate an induced pluripotent stem cell (iPSC line from a 39-year-old female patient diagnosed with severe-to-profound, non-syndromic SNHL. The patient also carries a A1555G mutation in the mitochondrial 12S ribosome RNA gene (MTRNR1. This iPSC line was verified to express pluripotent markers, possess normal karyotype, harbor the specific mutation and demonstrated the capacity to differentiate into three germ layers.

  18. WFS1 and non-syndromic low-frequency sensorineural hearing loss: a novel mutation in a Portuguese case.

    Science.gov (United States)

    Gonçalves, A C; Matos, T D; Simões-Teixeira, H R; Pimenta Machado, M; Simão, M; Dias, O P; Andrea, M; Fialho, G; Caria, H

    2014-04-01

    Low-frequency sensorineural hearing loss (LFSNHL) is an unusual type of HL in which frequencies at 2,000 Hz and below are predominantly affected. Most of the families with LFSNHL carry missense mutations in WFS1 gene, coding for wolframin. A Portuguese patient aged 49, reporting HL since her third decade of life, and also referring tinnitus, was shown to display bilateral moderate LFSNHL after audiological evaluation. Molecular analysis led to the identification of a novel mutation, c.511G>A (p.Asp171Asn), found in heterozygosity in the exon 5 of the WFS1 gene, and changing the aspartic acid at position 171 to an asparagine, in the extracellular N-terminus domain of the wolframin protein. This novel mutation wasn't present either in 200 control chromosomes analyzed or in the hearing proband's half-brother, and it had not been reported in 1000 Genomes, Exome Variant Server, HGMD or dbSNP databases. No mutations were found in GJB2 and GJB6 genes. Multi-alignment of 27 wolframin sequences from mammalian species, against the human wolframin sequence in ConSurf, indicated a conservation score corresponding to 7 in a 1-9 color scale where 9 is conserved and 1 is variable. In addition, the mutation p.Asp171Asn was predicted to be damaging and possibly damaging by SIFT and Polyphen-2, respectively. The auditory phenotype of this patient could thus be due to the novel mutation p.Asp171Asn. Further functional characterization might enable to elucidate in which way the change in the residue 171, as other changes introduced by LFSNHL-associated mutations previously described, leads to this type of HL. Copyright © 2014 Elsevier B.V. All rights reserved.

  19. X-linked Agammaglobulinemia.

    Science.gov (United States)

    Suri, Deepti; Rawat, Amit; Singh, Surjit

    2016-04-01

    X-linked agammaglobulinemia (XLA) is one of the commonest primary immune deficiencies encountered in pediatric clinical practice. In adults, common variable immunodeficiency (CVID) is the most common primary immunodeficiency disease (PID). It is an X-linked disorder characterized by increased susceptibility to encapsulated bacteria, severe hypergammaglobulinemia and absent circulating B cells in the peripheral blood. Replacement immunoglobulin therapy is the main cornerstone of treatment. Aggressive management of intercurrent infections and prophylactic antimicrobials are needed. This review attempts to highlight varied clinical manifestations and management of XLA, especially in the context of developing country.

  20. Genotype-phenotype correlation for DFNA22: characterization of non-syndromic, autosomal dominant, progressive sensorineural hearing loss due to MYO6 mutations

    DEFF Research Database (Denmark)

    Topsakal, Vedat; Hilgert, Nele; van Dinther, Joost

    2010-01-01

    Clinical and audiological examination was done in 2 Belgian families with autosomal dominant sensorineural hearing loss (SNHL) linked to DFNA22. Nineteen subjects in family 1 had mild to moderate SNHL starting in the third decade. The hearing loss was characterized by a flat audiogram affecting all...... tested frequencies with statistically significant progression. In family 2 eleven subjects were affected with mild to moderate SNHL starting in the second decade. Most of them showed a flat audiogram, but some had mid-frequency hearing loss. Significant progression of thresholds was present at 4 and 8 k...

  1. Sensorineural deafness

    Science.gov (United States)

    Nerve deafness; Hearing loss - sensorineural; Acquired hearing loss; SNHL; Noise-induced hearing loss; NIHL; Presbycusis ... that carries the signals to the brain. Sensorineural deafness that is present at birth (congenital) is most ...

  2. The expanding spectrum of PRPS1-associated phenotypes: three novel mutations segregating with X-linked hearing loss and mild peripheral neuropathy

    Science.gov (United States)

    Robusto, Michela; Fang, Mingyan; Asselta, Rosanna; Castorina, Pierangela; Previtali, Stefano C; Caccia, Sonia; Benzoni, Elena; De Cristofaro, Raimondo; Yu, Cong; Cesarani, Antonio; Liu, Xuanzhu; Li, Wangsheng; Primignani, Paola; Ambrosetti, Umberto; Xu, Xun; Duga, Stefano; Soldà, Giulia

    2015-01-01

    Next-generation sequencing is currently the technology of choice for gene/mutation discovery in genetically-heterogeneous disorders, such as inherited sensorineural hearing loss (HL). Whole-exome sequencing of a single Italian proband affected by non-syndromic HL identified a novel missense variant within the PRPS1 gene (NM_002764.3:c.337G>T (p.A113S)) segregating with post-lingual, bilateral, progressive deafness in the proband's family. Defects in this gene, encoding the phosphoribosyl pyrophosphate synthetase 1 (PRS-I) enzyme, determine either X-linked syndromic conditions associated with hearing impairment (eg, Arts syndrome and Charcot-Marie-Tooth neuropathy type X-5) or non-syndromic HL (DFNX1). A subsequent screening of the entire PRPS1 gene in 16 unrelated probands from X-linked deaf families led to the discovery of two additional missense variants (c.343A>G (p.M115V) and c.925G>T (p.V309F)) segregating with hearing impairment, and associated with mildly-symptomatic peripheral neuropathy. All three variants result in a marked reduction (>60%) of the PRS-I activity in the patients' erythrocytes, with c.343A>G (p.M115V) and c.925G>T (p.V309F) affecting more severely the enzyme function. Our data significantly expand the current spectrum of pathogenic variants in PRPS1, confirming that they are associated with a continuum disease spectrum, thus stressing the importance of functional studies and detailed clinical investigations for genotype–phenotype correlation. PMID:25182139

  3. High prevalence of SLC6A8 deficiency in X-linked mental retardation

    NARCIS (Netherlands)

    Rosenberg, EH; Almeida, LS; Kleefstra, T; deGrauw, RS; Yntema, HG; Bahi, N; Moraine, C; Ropers, HH; Fryns, JP; deGrauw, TJ; Jakobs, C; Salomons, GS

    A novel X-linked mental retardation (XLMR) syndrome was recently identified, resulting from creatine deficiency in the brain caused by mutations in the creatine transporter gene, SLC6A8. We have studied the prevalence of SLC6A8 mutations in a panel of 290 patients with nonsyndromic XLMR archived by

  4. Mutations in the polyglutamine binding protein 1 gene cause X-linked mental retardation

    DEFF Research Database (Denmark)

    Kalscheuer, Vera M; Freude, Kristine; Musante, Luciana

    2003-01-01

    We found mutations in the gene PQBP1 in 5 of 29 families with nonsyndromic (MRX) and syndromic (MRXS) forms of X-linked mental retardation (XLMR). Clinical features in affected males include mental retardation, microcephaly, short stature, spastic paraplegia and midline defects. PQBP1 has previou...

  5. Genetics Home Reference: X-linked agammaglobulinemia

    Science.gov (United States)

    ... Home Health Conditions X-linked agammaglobulinemia X-linked agammaglobulinemia Printable PDF Open All Close All Enable Javascript ... view the expand/collapse boxes. Description X-linked agammaglobulinemia (XLA) is a condition that affects the immune ...

  6. X-linked Alport syndrome

    DEFF Research Database (Denmark)

    Jais, Jean Philippe; Knebelmann, Bertrand; Giatras, Iannis

    2003-01-01

    Alport syndrome (AS) is a type IV collagen hereditary disease characterized by progressive hematuric nephritis, hearing loss, and ocular changes. Mutations in the COL4A5 collagen gene are responsible for the more common X-linked dominant form of the disease characterized by much less severe disease...... in girls and women. A "European Community Alport Syndrome Concerted Action" (ECASCA) group was established to delineate the Alport syndrome phenotype in each gender and to determine genotype-phenotype correlations in a large number of families. Data concerning 329 families, 250 of them with an X...... to increase after the age of 60 yr in women. Because of the absence of genotype-phenotype correlation and the large intrafamilial phenotypic heterogeneity, early prognosis of the disease in X-linked Alport syndrome carriers remains moot. Risk factors for developing renal failure have been identified...

  7. X-linked Alport syndrome

    DEFF Research Database (Denmark)

    Jais, J P; Knebelmann, B; Giatras, I

    2000-01-01

    Alport syndrome (AS) is a type IV collagen hereditary disease characterized by the association of progressive hematuric nephritis, hearing loss, and, frequently, ocular changes. Mutations in the COL4A5 collagen gene are responsible for the more common X-linked dominant form of the disease....... Considerable allelic heterogeneity has been observed. A "European Community Alport Syndrome Concerted Action" has been established to delineate accurately the AS phenotype and to determine genotype-phenotype correlations in a large number of families. Data concerning 329 families, 250 of them with an X...

  8. Inherited ichthyosis: Non-syndromic forms.

    Science.gov (United States)

    Takeichi, Takuya; Akiyama, Masashi

    2016-03-01

    Inherited ichthyoses are a group of genetic disorders characterized by generalized dry skin, scaling and hyperkeratosis, and often associated with erythroderma. These manifestations are due to mutations in genes mostly involved in skin barrier formation. Inherited ichthyoses consist of non-syndromic ichthyoses and ichthyosis syndromes. Non-syndromic ichthyoses are characterized by the phenotypic expression of the disorder being seen only in the skin. Non-syndromic ichthyoses include ichthyosis vulgaris, recessive X-linked ichthyosis, autosomal recessive congenital ichthyosis, keratinopathic ichthyosis and other forms. This review focuses on updates for each type of non-syndromic ichthyosis, highlighting molecular mechanisms and phenotype/genotype correlations. Included in autosomal recessive congenital ichthyosis are three of the major phenotypes (harlequin ichthyosis, lamellar ichthyosis and congenital ichthyosiform erythroderma) and three of the minor subtypes (self-healing collodion baby, acral self-healing collodion baby and bathing suit ichthyosis). Keratinopathic ichthyosis is proposed as an umbrella term for ichthyoses caused by mutations in keratin genes. Next-generation sequencing technologies have become powerful tools for the diagnosis of inherited ichthyoses and the discovery of their genetic causes. This article reviews the current understanding of molecular pathomechanisms for non-syndromic ichthyoses and explores future perspectives. © 2016 Japanese Dermatological Association.

  9. X-linked mental deficiency.

    Science.gov (United States)

    des Portes, Vincent

    2013-01-01

    Ten percent of cases of intellectual deficiency in boys are caused by genes located on the X chromosome. X-linked mental retardation (XLMR) includes more than 200 syndromes and 80 genes identified to date. The fragile X syndrome is the most frequent syndrome, due to a dynamic mutation with a CGG triplet amplification. Mental retardation is virtually always present. Phonological and syntactic impairments are often combined with pragmatic language impairment and visuospatial reasoning difficulties. A minority fulfill the criteria for autism. In girls, the clinical expression of the complete mutation varies according to the X chromosome inactivation profile. Several XLMR occur as severe early onset encephalopathies: Lowe oculocerebrorenal syndrome, ATR-X syndrome (alpha thalassemia/mental retardation X-linked), Allan-Herdon-Dudley syndrome (MCT8 gene). Two genes, ARX (X-LAG; Partington syndrome) and MECP2 (Rett syndrome in females; mild MR with spastic diplegia/psychotic problems in males) are associated with various phenotypes, according to the mutation involved. Oligophrenine 1 (OPHN-1) gene mutations lead to vermal dysplasia. PQBP1 gene mutations (Renpenning syndrome) are responsible for moderate to severe mental deficiency, microcephaly, and small stature. Although some forms of XLMR are not very specific and the phenotype for each given gene is somewhat heterogeneous, a clinical diagnostic strategy is emerging. Copyright © 2013 Elsevier B.V. All rights reserved.

  10. Genetics Home Reference: X-linked adrenoleukodystrophy

    Science.gov (United States)

    ... particular ethnic groups? Genetic Changes Mutations in the ABCD1 gene cause X-linked adrenoleukodystrophy . The ABCD1 gene provides instructions for producing the adrenoleukodystrophy protein ( ...

  11. Genetic and audiologic study in elderly with sensorineural hearing loss.

    Science.gov (United States)

    Martins, Kelly; Fontenele, Marília; Câmara, Silva; Sartorato, Edi Lúcia

    2013-01-01

    This study aimed to correlate probable predisposing factors for sensorineural hearing loss in elderly by investigating the audiologic characteristics and frequency of mutations in genes considered responsible for non-syndromic hearing loss. Sixty elderly patients were separated into two groups: the Case Group, composed of 30 individuals, 21 females and nine males, all 60 years old or older and presenting diagnoses of sensorineural hearing loss, and the Control Group, composed of 30 elderly individuals matched to the experimental group by age and gender, presenting normal hearing. The patients underwent anamnesis and pure tone audiometry in frequencies of 250, 500, 1000, 2000, 3000, 4000 and 6000 Hz. Blood samples were collected from each patient for analysis of mutations in nuclear and mitochondrial genes related to non-syndromic sensorineural hearing loss. It was observed a greater tendency to noise exposure and consumption of alcohol in the Case Group. The statistically significant symptoms between the groups were tinnitus and hearing difficulty in several situations as: silent environment, telephone, television, sound location and in church. All the individuals of Case Group presented sensorineural and bilateral hearing loss. The symmetry and progression of the hearing impairment were also statistically significant between the groups. No genetic mutations were identified. The most reported symptoms were communication difficulties and tinnitus. The predominant auditory characteristics included sensorineural, bilateral, progressive and symmetrical hearing loss. It was not evidenced a relationship between sensorineural hearing loss in elderly and genes considered responsible for non-syndromic hearing loss as no genetic mutation was found in this study.

  12. Mapping the x-linked lymphoproliferative syndrome

    International Nuclear Information System (INIS)

    Skare, J.C.; Milunsky, A.; Byron, K.S.; Sullivan, J.L.

    1987-01-01

    The X-linked lymphoproliferative syndrome is triggered by Epstein-Barr virus infection and results in fatal mononucleosis, immunodeficiency, and lymphoproliferative disorders. This study shows that the mutation responsible for X-linked lymphoproliferative syndrome is genetically linked to a restriction fragment length polymorphism detected with the DXS42 probe (from Xq24-q27). The most likely recombination frequency between the loci is 4%, and the associated logarithm of the odds is 5.26. Haplotype analysis using flanking restriction fragment length polymorphism markers indicates that the locus for X-linked lymphoproliferative syndrome is distal to probe DXS42 but proximal to probe DXS99 (from Xq26-q27). It is now possible to predict which members of a family with X-linked lymphoproliferative syndrome are carrier females and to diagnose the syndrome prenatally

  13. Genetics Home Reference: X-linked intellectual disability, Siderius type

    Science.gov (United States)

    ... X-linked intellectual disability, Siderius type X-linked intellectual disability, Siderius type Printable PDF Open All Close All ... view the expand/collapse boxes. Description X-linked intellectual disability, Siderius type is a condition characterized by mild ...

  14. Genetics Home Reference: X-linked sideroblastic anemia

    Science.gov (United States)

    ... Conditions X-linked sideroblastic anemia X-linked sideroblastic anemia Printable PDF Open All Close All Enable Javascript ... the expand/collapse boxes. Description X-linked sideroblastic anemia is an inherited disorder that prevents developing red ...

  15. Progression of low-frequency sensorineural hearing loss (DFNA6/14-WFS1).

    NARCIS (Netherlands)

    Pennings, R.J.E.; Bom, S.J.H.; Cryns, K.; Flothmann, K.; Huygen, P.L.M.; Kremer, J.M.J.; Camp, G. van; Cremers, C.W.R.J.

    2003-01-01

    OBJECTIVE: To assess the audiometric profile and speech recognition characteristics in affected members of 2 families with DFNA6/14 harboring heterozygous mutations in the WFS1 gene that cause an autosomal dominant nonsyndromic sensorineural hearing impairment trait. DESIGN: Family study. SETTING:

  16. X-linked adrenoleukodystrophy: pathogenesis and treatment

    NARCIS (Netherlands)

    Engelen, Marc; Kemp, Stephan; Poll-The, Bwee-Tien

    2014-01-01

    X-linked adrenoleukodystrophy (X-ALD) is a puzzling inborn error of metabolism with a strikingly heterogeneous clinical spectrum. All patients have mutations in the ABCD1 gene and accumulate very long chain fatty acids in all tissues. Virtually all male X-ALD patients develop adrenocortical

  17. Prognosis of X-Linked Adrenoleukodystrophy

    Directory of Open Access Journals (Sweden)

    J Gordon Millichap

    2005-08-01

    Full Text Available The natural history of X-linked adrenoleukodystrophy (ALD was determined by questionnaire survey in a nation-wide retrospective study of 145 patients at Gifu University School of Medicine, and the Ministry of Health, Labor and Welfare, Japan.

  18. Late-onset Zellweger spectrum disorder caused by PEX6 mutations mimicking X-linked adrenoleukodystrophy.

    Science.gov (United States)

    Tran, Christel; Hewson, Stacy; Steinberg, Steven J; Mercimek-Mahmutoglu, Saadet

    2014-08-01

    Zellweger spectrum disorder is an autosomal recessively inherited multisystem disorder caused by one of the 13 different PEX gene defects resulting in defective peroxisomal assembly and multiple peroxisomal enzyme deficiencies. We report a new patient with late-onset Zellweger spectrum disorder mimicking X-linked adrenoleukodystrophy. This 8.5-year-old boy with normal development until 6.5 years of age presented with bilateral sensorineural hearing loss during a school hearing test. He then developed acute-onset diplopia, clumsiness, and cognitive dysfunction at age 7 years. Magnetic resonance imaging of the brain revealed symmetric leukodystrophy, although without gadolinium enhancement. Elevated plasma very long chain fatty acid levels were suggestive of X-linked adrenoleukodystrophy, but his ABCD1 gene had normal coding sequence and dosage. Additional studies of cultured skin fibroblasts were consistent with Zellweger spectrum disorder. Molecular testing identified disease-causing compound heterozygous mutations in the PEX6 gene supporting the Zellweger spectrum disorder diagnosis in this patient. We describe a new patient with late-onset Zellweger spectrum disorder caused by PEX6 mutations who presented with an acute neurodegenerative disease course mimicking X-linked adrenoleukodystrophy. This finding provides an additional reason that molecular confirmation is important for the genetic counseling and management of patients with a clinical and biochemical diagnosis of X-linked adrenoleukodystrophy. Copyright © 2014 Elsevier Inc. All rights reserved.

  19. Screening of Connexin 26 in Nonsyndromic Hearing Loss

    Directory of Open Access Journals (Sweden)

    Moreira, Danielle

    2014-04-01

    Full Text Available Introduction The first locus for nonsyndromic autosomal recessive hearing loss is on chromosome 13q11–22. The 35delG mutation is present in 80% of cases in which GJB2 is involved, which makes the study of this mutation very important. The viability and benefits of screening for mutations in the connexin 26 gene are now beginning to change the diagnostic evaluation and identification of the etiology of hearing loss. Objective To investigate the occurrence of the 35delG mutation in patients with nonsyndromic sensorineural hearing loss and their first degree relatives. Methods This transversal study included 72 patients from the local hospital. The patients were divided into three groups: group A, sensorineural hearing loss (n = 58; group B, first-degree relatives of group A with sensorineural hearing loss (n = 09; and group C, first-degree relatives of patients from group A without hearing loss (n = 05. All patients had audiological evaluation and genetic testing of the 35delG mutation. Results The 35delG mutation was found in four heterozygous mutations (three of them found in the same family. The other heterozygous mutation was found in a female patient with bilateral, moderate, prelingual, sensorineural hearing loss. A single homozygous mutation was found in a male patient, with severe sensorineural hearing loss in his right ear and profound hearing loss in the left ear. Conclusions The 35delG mutation was found in 7% of the cases. The test is easy to perform and inexpensive, but it is necessary to investigate other genes related to hearing loss.

  20. Screening of connexin 26 in nonsyndromic hearing loss.

    Science.gov (United States)

    Moreira, Danielle; Silva, Daniela da; Lopez, Priscila; Mantovani, Jair Cortez

    2015-01-01

    Introduction The first locus for nonsyndromic autosomal recessive hearing loss is on chromosome 13q11-22. The 35delG mutation is present in 80% of cases in which GJB2 is involved, which makes the study of this mutation very important. The viability and benefits of screening for mutations in the connexin 26 gene are now beginning to change the diagnostic evaluation and identification of the etiology of hearing loss. Objective To investigate the occurrence of the 35delG mutation in patients with nonsyndromic sensorineural hearing loss and their first degree relatives. Methods This transversal study included 72 patients from the local hospital. The patients were divided into three groups: group A, sensorineural hearing loss (n = 58); group B, first-degree relatives of group A with sensorineural hearing loss (n = 09); and group C, first-degree relatives of patients from group A without hearing loss (n = 05). All patients had audiological evaluation and genetic testing of the 35delG mutation. Results The 35delG mutation was found in four heterozygous mutations (three of them found in the same family). The other heterozygous mutation was found in a female patient with bilateral, moderate, prelingual, sensorineural hearing loss. A single homozygous mutation was found in a male patient, with severe sensorineural hearing loss in his right ear and profound hearing loss in the left ear. Conclusions The 35delG mutation was found in 7% of the cases. The test is easy to perform and inexpensive, but it is necessary to investigate other genes related to hearing loss.

  1. Refinement of the locus for non-syndromic sensorineural deafness ...

    Indian Academy of Sciences (India)

    Unknown

    2004-04-05

    Apr 5, 2004 ... 3.12 software (LI-COR Corp., USA). Linkage ready pedi- gree files were prepared using Gene Image 3.12 software. Linkage analysis. We conducted two-point linkage analyses using the LINK-. AGE v.5.10 software package (Lathrop et al. 1984). In the linkage analysis, we modelled the disease as having a.

  2. Refinement of the locus for non-syndromic sensorineural deafness ...

    Indian Academy of Sciences (India)

    Unknown

    2004-04-05

    Bergstrom et al. 1971). Several X- ... fied as a new syndrome, Mohr-Tranebjaerg syndrome (Tra- nebjaerg et al. 1995). Other studies have ... narrow down the candidate region as lying between mar- kers DXS6799 and GATA172D05.

  3. Arthritis and X-linked agammaglobulinemia.

    Science.gov (United States)

    Machado, Pedro; Santos, Alexandra; Faria, Emília; Silva, Jorge; Malcata, Armando; Chieira, Celso

    2008-01-01

    Primary immunodeficiencies are defined as genetically determined functional and/or quantitative abnormalities in one or more of the components of the immune system. Immunodeficiency and arthritis can be related, although the mechanisms are not always clear. Different causes for immunodeficiency can secondarily be found in patients with arthritis; on the other hand, arthritis can be a manifestation of primary immunodeficiency. Arthritis occurs chiefly in humoral primary immunodeficiencies, namely in X-linked agammaglobulinemia and common variable immunodeficiency, and may be one of the warning signs for primary immunodeficiency. We report a case of arthritis as the presenting feature of X-linked agammaglobulinemia. In X-linked agammaglobulinemia, arthritis may be a consequence of infection, most notably by Mycoplasma, or of immune dysfunction itself. In children, and occasionally in young adults, a combination of arthritis and hypogammaglobulinemia should suggest primary immunodeficiency, although other causes of hypogammaglobulinemia must be excluded. Physicians evaluating patients with arthritis should be aware of this fact so that an early diagnosis can be pursued as it is of extreme importance in the optimal management and prognosis of these patients.

  4. X-linked Adrenoleukodystrophy, The Tunisian Experience.

    Science.gov (United States)

    Nasrallah, Fahmi; Kraoua, Ichraf; Zidi, Wiem; Omar, Souheil; Sanhaji, Haifa; Feki, Moncef; Ben Youssef, Ilhem Turki; Kaabachi, Naziha

    2015-01-01

    X-linked adrenoleukodystrophy is a genetic disease affecting the degradation of very long chain fatty acids. This study aims to describe the clinical phenotype and biochemical feature of Tunisian patients; it also seeks to describe recognition of pattern analysis on the level of very long chain fatty acids in plasma for the visual discrimination of X-linked patients from a healthy group. During the last 21 years, 19 patients were diagnosed with X-linked adrenoleukodystrophy based on the clinical features combined with the area percentage of hexacosanoic acid (C26:0) as well as the ratio of C26:0 and lignoceric acid (C24:0) relative to behenic acid (C22:0) by gas chromatography. For the biochemical diagnosis of X-ALD with better accuracy, it has been desired to transform the numerical values of these biochemical markers into visually discriminating patterns. The clinical features of 19 patients aged between 4 to 47 years were classified into cerebral form (57.8%), adrenomyeloneuropathic (26.3%), and a few patients were asymptomatic. The ratio C24:0/C22:0 ranged from 1.12 to 2.41 (normal value: 0.46 - 0.9) and C26:0/C22:0 ratio ranged from 0.03 to 0.36 (normal value: 0.003 - 0.009). The concentration of fatty acids with 22 or more carbons in body fluid did not change with age in control subjects and patients. For the visual diagnostic of patients, the Scatter plot was a reliable method for the diagnostic patterns of very long chain fatty acids of patients with X-linked adrenoleukodystrophy disorders. The incidence of X-linked adrenoleukodystrophy disorders is under diagnosed in Tunisia. The diagnosis was confirmed by enzymatic activity study and molecular analysis but the analysis of very long chain fatty acids by gas chromatography remains a reliable tool for the diagnosis and early initiation of the treatment.

  5. Mutations in the Wolfram syndrome 1 gene (WFS1) are a common cause of low frequency sensorineural hearing loss.

    NARCIS (Netherlands)

    Bespalova, I.N.; Camp, G. van; Bom, S.J.H.; Brown, D.J.; Cryns, K.; Wan, A.T. de; Erson, A.E.; Flothmann, K.; Kunst, H.P.M.; Kurnool, P.; Sivakumaran, T.A.; Cremers, C.W.R.J.; Leal, S.M.; Burmeister, M.; Lesperance, M.M.

    2001-01-01

    Non-syndromic low frequency sensorineural hearing loss (LFSNHL) affecting only 2000 Hz and below is an unusual type of hearing loss that worsens over time without progressing to profound deafness. This type of LFSNHL may be associated with mild tinnitus but is not associated with vertigo. We have

  6. Genetics Home Reference: X-linked sideroblastic anemia and ataxia

    Science.gov (United States)

    ... linked sideroblastic anemia and ataxia X-linked sideroblastic anemia and ataxia Printable PDF Open All Close All ... the expand/collapse boxes. Description X-linked sideroblastic anemia and ataxia is a rare condition characterized by ...

  7. Gastrointestinal Manifestations in X-linked Agammaglobulinemia.

    Science.gov (United States)

    Barmettler, Sara; Otani, Iris M; Minhas, Jasmit; Abraham, Roshini S; Chang, Yenhui; Dorsey, Morna J; Ballas, Zuhair K; Bonilla, Francisco A; Ochs, Hans D; Walter, Jolan E

    2017-04-01

    X-linked agammaglobulinemia is a primary humoral immunodeficiency characterized by hypogammaglobulinemia and increased susceptibility to infection. Although there is increased awareness of autoimmune and inflammatory complications in X-linked agammaglobulinemia (XLA), the spectrum of gastrointestinal manifestations has not previously been fully explored. We present a case report of a family with two affected patients with XLA. Given the gastrointestinal involvement of the grandfather in this family, we performed a retrospective descriptive analysis of XLA patients with reported diagnoses of GI manifestations and inflammatory bowel disease (IBD) or enteritis registered at the United States Immunodeficiency Network, a national registry of primary immunodeficiencies. In this cohort of patients with XLA, we found that up to 35% had concurrent gastrointestinal manifestations, and 10% had reported diagnoses of IBD or enteritis. The most commonly reported mutations were missense, which have been associated with a less severe XLA phenotype in the literature. The severity of symptoms were wide ranging, and management strategies were diverse and mainly experimental. Patients with XLA may require close monitoring with particular attention for GI manifestations including IBD and infectious enteritis. Further studies are needed to improve diagnosis and management of GI conditions in XLA patients.

  8. Sagittal synostosis in X-linked hypophosphatemic rickets and related diseases

    Energy Technology Data Exchange (ETDEWEB)

    Currarino, Guido [Texas Scottish Rite Hospital, Department of Radiology, Dallas, TX (United States)

    2007-08-15

    The recent observations of two new cases of X-linked hypophosphatemic rickets associated with premature closure of the sagittal suture prompted a review of similar cases seen in this institution. To review the clinical records and skull radiographs of 28 children with hypophosphatemic rickets in order to investigate the frequency and type of craniosynostosis and other cranial vault changes seen in these conditions and to review the literature for relevant findings. Clinical and imaging records were reviewed on 28 patients with hypophosphatemic rickets, all younger than 18 years. Most patients had X-linked hypophosphatemic rickets and a few had autosomal-dominant hypophosphatemic rickets or were non-familial cases. Of the 28 patients, 13 had sagittal synostosis. Dolichocephaly was present in ten patients. The configuration of the cranial vault in some of these ten patients with dolichocephaly varied somewhat from that seen in nonsyndromic sagittal synostosis. In one patient, a Chiari I malformation was demonstrated by MRI. In another patient with increased intracranial pressure the sagittal suture closure was associated with lambdoidal synostosis. Dolichocephaly was not present in three patients, suggesting that the synostosis started later than in the other patients, probably in the second year of life, a period of slower brain growth than in the first year. The two patients in this group of three showed thickening and sclerosis of the cranial vault of uncertain etiology. There is an increased risk of sagittal synostosis in hypophosphatemic rickets and related diseases in children. The appearance of the cranial vault in this type of synostosis can vary from that seen in nonsyndromic synostosis. In this setting, careful clinical and imaging follow-up is warranted. (orig.)

  9. X-linked adrenoleukodystrophy: pathogenesis and treatment.

    Science.gov (United States)

    Engelen, Marc; Kemp, Stephan; Poll-The, Bwee-Tien

    2014-10-01

    X-linked adrenoleukodystrophy (X-ALD) is a puzzling inborn error of metabolism with a strikingly heterogeneous clinical spectrum. All patients have mutations in the ABCD1 gene and accumulate very long chain fatty acids in all tissues. Virtually all male X-ALD patients develop adrenocortical insufficiency in childhood and progressive myelopathy and peripheral neuropathy in adulthood. A subset of male patients, however, develops a fatal cerebral demyelinating disease, cerebral adrenoleukodystrophy. Female patients also develop progressive myelopathy and peripheral neuropathy, but generally at a later age than males. They only very rarely develop adrenocortical insufficiency or cerebral adrenoleukodystrophy. This review proposes to simplify the classification of the clinical spectrum of X-ALD and reviews the largely unresolved pathophysiological mechanisms and the current treatment options.

  10. X-linked cardiomyopathy is heterogeneous

    Energy Technology Data Exchange (ETDEWEB)

    Wilson, M.J.; Sillence, D.O.; Mulley, J.C. [and others

    1994-09-01

    Two major loci of X-linked cardiomyopathy have been mapped by linkage analysis. The gene for X-linked dilated cardiomyopathy (XLCM) is mapped to the dystrophin locus at Xp21, while Barth syndrome has been localised to distal Xq28. XLCM usually presents in juvenile males with no skeletal disease but decreased dystrophin in cardiac muscle. Barth syndrome most often presents in infants and is characterized by skeletal myopathy, short stature and neutropenia in association with cardiomyopathy of variable severity. Prior to carrier or prenatal diagnosis in a family, delineation of the cardiomyopathy locus involved is essential. We report the linkage mapping of a large kindred in which several male infants have died with hypertrophic cardiomyopathy. There is a family history of unexplained death of infant males less than 6 months old over 4 generations. Features of Barth syndrome such as short stature, skeletal myopathy and neutropenia have not been observed. Genotyping at 10 marker loci in Xq28 has revealed significant pairwise lod scores with the cardiomyopathy phenotype at DXS52 (Z=2.21 at {theta}=0.0), at markers p26 and p39 near DXS15 (Z=2.30 at {theta}=0.0) and at F8C (Z=2.24 at {theta}=0.0). A recombinant detected with DXS296 defines the proximal limit to the localization. No recombinants were detected at any of the loci distal to DXS296. The most distal marker in Xq28, DXS1108, is within 500 kb of the telomere. As the gene in this family is localized to Xq28, it is possible that this disorder is an allelic variant at the Barth syndrome locus.

  11. Congenital sensorineural hearing loss

    International Nuclear Information System (INIS)

    Mafee, M.F.; Selis, J.E.; Yannias, D.A.; Valvassori, G.E.; Pruzansky, S.; Applebaum, E.L.; Capek, V.

    1984-01-01

    The ears of 47 selected patients with congenital sensorineural hearing loss were examined with complex-motion tomography. The patients were divided into 3 general categories: those with a recognized syndrome, those with sensorineural hearing loss unrelated to any known syndrome, and those with microtia. A great variety of inner ear anomalies was detected, but rarely were these characteristic of a particular clinical entity. The most common finding was the Mondini malformation or one of its variants. Isolated dysplasia of the internal auditory canal or the vestibular aqueduct may be responsible for sensorineural hearing loss in some patients. Patients with microtia may also have severe inner ear abnormalities despite the fact that the outer and inner ears develop embryologically from completely separate systems

  12. Congenital sensorineural hearing loss

    Energy Technology Data Exchange (ETDEWEB)

    Mafee, M.F.; Selis, J.E.; Yannias, D.A.; Valvassori, G.E.; Pruzansky, S.; Applebaum, E.L.; Capek, V.

    1984-02-01

    The ears of 47 selected patients with congenital sensorineural hearing loss were examined with complex-motion tomography. The patients were divided into 3 general categories: those with a recognized syndrome, those with sensorineural hearing loss unrelated to any known syndrome, and those with microtia. A great variety of inner ear anomalies was detected, but rarely were these characteristic of a particular clinical entity. The most common finding was the Mondini malformation or one of its variants. Isolated dysplasia of the internal auditory canal or the vestibular aqueduct may be responsible for sensorineural hearing loss in some patients. Patients with microtia may also have severe inner ear abnormalities despite the fact that the outer and inner ears develop embryologically from completely separate systems.

  13. HOXA1 Mutations are Not Commonly Associated with Non-Syndromic Deafness.

    Science.gov (United States)

    Abu-Amero, Khaled K; Hagr, Abdulrahman al; Almomani, Murad O; Azad, Taif Anwar; Alorainy, Ibrahim A; Oystreck, Darren T; Bosley, Thomas M

    2014-07-01

    Homozygous homeobox A1 (HOXA1) mutations cause a spectrum of abnormalities in humans including bilateral profound deafness. This study evaluates the possible role of HOXA1 mutations in familial, non-syndromic sensorineural deafness. Forty-eight unrelated Middle Eastern families with either consanguinity or familial deafness were identified in a large deafness clinic, and the proband from each family was evaluated by chart review, audiogram, neuroimaging, and HOXA1 sequencing. All 48 probands had normal neuro-ophthalmologic and general medical examinations except for refractive errors. All had congenital non-syndromic sensorineural hearing loss that was symmetric bilaterally and profound (>90 dBHL) in 33 individuals and varied from 40 to 90 dBHL in the remainder. Thirty-nine of these individuals had neuroimaging studies, all documenting normal internal carotid arteries and normal 6th, 7th, and 8th cranial nerves bilaterally. Of these, 27 had normal internal ear structures with the remaining 12 having mild to modest developmental abnormalities of the cochlea, semicircular canals, and/or vestibular aqueduct. No patient had homozygous HOXA1 mutations. None of these patients with non-syndromic deafness had HOXA1 mutations. None had major inner ear anomalies, obvious cerebrovascular defects, or recognized congenital heart disease. HOXA1 is likely not a common cause of non-syndromic deafness in this Middle Eastern population.

  14. Newborn Screening for X-Linked Adrenoleukodystrophy

    Directory of Open Access Journals (Sweden)

    Ann B. Moser

    2016-12-01

    Full Text Available Early diagnosis of males with X-linked adrenoleukodystrophy (X-ALD is essential for preventing loss of life due to adrenal insufficiency and for timely therapy of the childhood cerebral form of X-ALD with hematopoietic cell transplantation. This article describes X-ALD, the current therapies, the history of the development of the newborn screening test, the approval by the Secretary of Health and Human Services for the addition of X-ALD newborn screening to the recommended uniform panel of disorders screened as newborns (RUSP and the successful implementation of X-ALD newborn screening in the state of New York beginning on 30 December 2013. Follow-up guidelines that have been established in New York are outlined. Based on the success of newborn screening in New York, and early results in Connecticut, where X-ALD newborn screening started in December 2015, and in California, where X-ALD newborn screening began in September 2016, we are confident and hopeful that X-ALD newborn screening will expand to include all US states and to countries that have established neonatal screening programs. The Minster of Health in the Netherlands has approved the addition of X-ALD to the newborn screening program with a start date expected in 2017. The states, such as Massachusetts, Illinois, Minnesota, New Jersey, Florida and Washington, that have legislative approval will commence screening as soon as budgetary resources, testing and follow-up procedures are in place.

  15. Bezafibrate for X-linked adrenoleukodystrophy.

    Directory of Open Access Journals (Sweden)

    Marc Engelen

    Full Text Available X-linked adrenoleukodystrophy (X-ALD is caused by mutations in the ABCD1 gene and is characterized by impaired beta-oxidation of very-long-chain fatty acids (VLCFA and subsequent VLCFA accumulation in tissues. In adulthood X-ALD most commonly manifests as a gradually progressive myelopathy, (adrenomyeloneuropathy; AMN without any curative or disease modifying treatments. We recently showed that bezafibrate (BF, a drug used for the treatment of hyperlipidaemia, reduces VLCFA accumulation in X-ALD fibroblasts by inhibiting ELOVL1, an enzyme involved in the VLCFA synthesis. We therefore designed a proof-of-principal clinical trial to determine whether BF reduces VLCFA levels in plasma and lymphocytes of X-ALD patients. Ten males with AMN were treated with BF for 12 weeks at a dose of 400 mg daily, followed by 12 weeks of 800 mg daily. Every 4 weeks patients were evaluated for side effects and blood samples were taken for analysis. Adherence was good as indicated by a clear reduction in triglycerides. There was no reduction in VLCFA in either plasma or lymphocytes. Plasma levels of BF did not exceed 25 µmol/L. We concluded that BF, at least in the dose given, is unable to lower VLCFA levels in plasma or lymphocytes in X-ALD patients. It is unclear whether this is due to the low levels of BF reached in plasma. Our future work is aimed at the identification of highly-specific inhibitors of ELOVL1 that act at much lower concentrations than BF and are well tolerated. BF appears to have no therapeutic utility in X-ALD.ClinicalTrials.gov NCT01165060.

  16. Pathophysiology of X-linked adrenoleukodystrophy.

    Science.gov (United States)

    Berger, J; Forss-Petter, S; Eichler, F S

    2014-03-01

    Currently the molecular basis for the clinical heterogeneity of X-linked adrenoleukodystrophy (X-ALD) is poorly understood. The genetic bases for all different phenotypic variants of X-ALD are mutations in the gene encoding the peroxisomal ATP-binding cassette (ABC) transporter, ABCD1 (formerly adrenoleukodystrophy protein, ALDP). ABCD1 transports CoA-activated very long-chain fatty acids from the cytosol into the peroxisome for degradation. The phenotypic variability is remarkable ranging from cerebral inflammatory demyelination of childhood onset, leading to death within a few years, to adults remaining pre-symptomatic through more than five decades. There is no general genotype-phenotype correlation in X-ALD. The default manifestation of mutations in ABCD1 is adrenomyeloneuropathy, a slowly progressive dying-back axonopathy affecting both ascending and descending spinal cord tracts as well as in some cases, a peripheral neuropathy. In about 60% of male X-ALD patients, either in childhood (35-40%) or in adulthood (20%), an initial, clinically silent, myelin destabilization results in conversion to a devastating, rapidly progressive form of cerebral inflammatory demyelination. Here, ABCD1 remains a susceptibility gene, necessary but not sufficient for inflammatory demyelination to occur. Although the accumulation of very long-chain fatty acids appears to be essential for the pathomechanism of all phenotypes, the molecular mechanisms underlying these phenotypes are fundamentally different. Cell autonomous processes such as oxidative stress and energy shortage in axons as well as non-cell autonomous processes involving axon-glial interactions seem pertinent to the dying-back axonopathy. Various dynamic mechanisms may underlie the initiation of inflammation, the altered immune reactivity, the propagation of inflammation, as well as the mechanisms leading to the arrest of inflammation after hematopoietic stem cell transplantation. An improved understanding of the

  17. Pathophysiology of X-linked adrenoleukodystrophy☆

    Science.gov (United States)

    Berger, J.; Forss-Petter, S.; Eichler, F.S.

    2014-01-01

    Currently the molecular basis for the clinical heterogeneity of X-linked adrenoleukodystrophy (X-ALD) is poorly understood. The genetic bases for all different phenotypic variants of X-ALD are mutations in the gene encoding the peroxisomal ATP-binding cassette (ABC) transporter, ABCD1 (formerly adrenoleukodystrophy protein, ALDP). ABCD1 transports CoA-activated very long-chain fatty acids from the cytosol into the peroxisome for degradation. The phenotypic variability is remarkable ranging from cerebral inflammatory demyelination of childhood onset, leading to death within a few years, to adults remaining pre-symptomatic through more than five decades. There is no general genotype–phenotype correlation in X-ALD. The default manifestation of mutations in ABCD1 is adrenomyeloneuropathy, a slowly progressive dying-back axonopathy affecting both ascending and descending spinal cord tracts as well as in some cases, a peripheral neuropathy. In about 60% of male X-ALD patients, either in childhood (35–40%) or in adulthood (20%), an initial, clinically silent, myelin destabilization results in conversion to a devastating, rapidly progressive form of cerebral inflammatory demyelination. Here, ABCD1 remains a susceptibility gene, necessary but not sufficient for inflammatory demyelination to occur. Although the accumulation of very long-chain fatty acids appears to be essential for the pathomechanism of all phenotypes, the molecular mechanisms underlying these phenotypes are fundamentally different. Cell autonomous processes such as oxidative stress and energy shortage in axons as well as non-cell autonomous processes involving axon–glial interactions seem pertinent to the dying-back axonopathy. Various dynamic mechanisms may underlie the initiation of inflammation, the altered immune reactivity, the propagation of inflammation, as well as the mechanisms leading to the arrest of inflammation after hematopoietic stem cell transplantation. An improved understanding of

  18. Molecular Investigation of Pediatric Portuguese Patients with Sensorineural Hearing Loss

    Directory of Open Access Journals (Sweden)

    Célia Nogueira

    2011-01-01

    Full Text Available The understanding of the molecular genetics in sensorineural hearing loss (SNHL has advanced rapidly during the last decade, but the molecular etiology of hearing impairment in the Portuguese population has not been investigated thoroughly. To provide appropriate genetic testing and counseling to families, we analyzed the whole mitochondrial genome in 95 unrelated children with SNHL (53 nonsyndromic and 42 syndromic and searched for variations in two frequent genes, GJB2 and GJB6, in the non-syndromic patients. Mutations in mtDNA were detected in 4.2% of the cases, including a hitherto undescribed change in the mtDNA-tRNATrp gene (namely, m.5558A>G. We also identified mono- or biallelic GJB2 mutations in 20 of 53 non-syndromic cases and also detected two novel mutations (p.P70R and p.R127QfsX84. Our data further reinforce the notion that genetic heterogeneity is paramount in children with SNHL.

  19. Whole saliva in X-linked hypohidrotic ectodermal dysplasia

    DEFF Research Database (Denmark)

    Lexner, Michala Oron; Bardow, Allan; Hertz, Jens Michael

    2007-01-01

    BACKGROUND: X-linked hypohidrotic ectodermal dysplasia (HED) is the most common type of ectodermal dysplasia. Identification of female carriers of X-linked HED can be difficult because of varying degrees of clinical symptoms due to the X-chromosome inactivation. This is the first study about whol...

  20. X-linked inhibitor of apoptosis (XIAP) deficiency

    DEFF Research Database (Denmark)

    Speckmann, C.; Lehmberg, K.; Albert, M.H.

    2013-01-01

    X-linked inhibitor of apoptosis (XIAP) deficiency caused by mutations in BIRC4 was initially described in patients with X-linked lymphoproliferative syndrome (XLP) who had no mutations in SH2D1A. In the initial reports, EBV-associated hemophagocytic lymphohistiocytosis (HLH) was the predominant...

  1. Sudden Sensorineural Hearing Loss

    Science.gov (United States)

    Kuhn, Maggie; Heman-Ackah, Selena E.; Shaikh, Jamil A.

    2011-01-01

    Sudden sensorineural hearing loss (SSNHL) is commonly encountered in audiologic and otolaryngologic practice. SSNHL is most commonly defined as sensorineural hearing loss of 30dB or greater over at least three contiguous audiometric frequencies occurring within a 72-hr period. Although the differential for SSNHL is vast, for the majority of patients an etiologic factor is not identified. Treatment for SSNHL of known etiology is directed toward that agent, with poor hearing outcomes characteristic for discoverable etiologies that cause inner ear hair cell loss. Steroid therapy is the current mainstay of treatment of idiopathic SSNHL in the United States. The prognosis for hearing recovery for idiopathic SSNHL is dependent on a number of factors including the severity of hearing loss, age, presence of vertigo, and shape of the audiogram. PMID:21606048

  2. Nonsyndromic types of ichthyoses - an update.

    Science.gov (United States)

    Traupe, Heiko; Fischer, Judith; Oji, Vinzenz

    2014-02-01

    Ichthyoses are genetically determined Mendelian disorders of cornification (MEDOC) that are characterized by universal scaling. Today we distinguish between non-syndromic and syndromic forms. Ichthyosis vulgaris is the most frequent type (prevalence 1:100) and is caused by autosomal semi-dominant filaggrin mutations. It is associated with a higher risk for the development of atopic diseases, such as atopic eczema and allergic rhinitis. Recessive X-linked ichthyosis (RXLI) occurs almost exclusively in boys; in Germany it has a prevalence of around 1:4,000. It is caused by steroid sulfatase deficiency and is often associated with further clinical problems, such as cryptorchidism (∼20%) or social communication deficits, such as attention deficit hyperactivity syndrome (40%) or autism (25%). Autosomal recessive congenital ichthyosis (ARCI) is genetically very heterogeneous and 8 different genes have been identified so far. The most frequent cause of ARCI is a transglutaminase 1 deficiency (prevalence 1:200, 000). Mutations in keratin genes are the cause of the keratinopathic ichthyoses, such as epidermolytic ichthyosis. They manifest at birth and often feature episodes of blistering. Most of these types are inherited as autosomal dominant traits, but autosomal recessive forms have also been described on occasion. © 2014 Deutsche Dermatologische Gesellschaft (DDG). Published by John Wiley & Sons Ltd.

  3. X-linked hypophosphatemic rickets without 'rickets'

    Energy Technology Data Exchange (ETDEWEB)

    Econs, M.J.; Feussner, J.R.; Quarles, L.D. (Duke Univ. Medical Center, Durham, NC (USA). Dept. of Medicine Veterans Administration Medical Center, Durham, NC (USA). Health Services Research Field Program); Samsa, G.P. (Duke Univ. Medical Center, Durham, NC (USA). Dept. of Biometry Veterans Administration Medical Center, Durham, NC (USA). Health Services Research Field Program); Effman, E.L.; Vogler, J.B.; Martinez, S. (Duke Univ. Medical Center, Durham, NC (USA). Dept. of Radiology Veterans Administration Medical Center, Durham, NC (USA). Health Services Research Field Program); Friedman, N.E. (Duke Univ. Medical Center, Durham, NC (USA). Dept. of Pediatrics Veterans Administration Medical Center, Durham, NC (USA). Health Services Research Field Program); Drezner, M.K. (Duke Univ. Medical Center, Durham, NC (USA). Dept. of Medicine Duke Univ. Medical Center, Durham, NC (USA). Dept. of Cell Biology Veterans Administration Medical Center, Durham, NC (USA). Health Services Research F

    1991-02-01

    Wrist and knee radiographs from children with X-linked hypophosphatemic rickets were analyzed and compared with those from normal children and children with established rickets to assess whether radiographically apparent rickets is a consistent abnormality in X-linked hypophosphatemia. The absence or presence of rickets was correctly identified in 94.8% of wrist and knee films from normal and positive controls. In contrast, patients with X-linked hypophosphatemia exhibited rachitic abnormalities in only 5 of 11 wrist and 13 of 15 knee radiographs. Our data indicate that radiographically detectable rickets is a variable abnormality of X-linked hypophosphatemia and does not provide an unambiguous index for the diagnosis of this disease. (orig./GDG).

  4. X-linked creatine transporter deficiency: clinical aspects and pathophysiology

    NARCIS (Netherlands)

    van de Kamp, J.M.; Mancini, G.M.; Salomons, G.S.

    2014-01-01

    Creatine transporter deficiency was discovered in 2001 as an X-linked cause of intellectual disability characterized by cerebral creatine deficiency. This review describes the current knowledge regarding creatine metabolism, the creatine transporter and the clinical aspects of creatine transporter

  5. Discovering the Unexpected with the Utilization of NGS in Diagnostics of Non-syndromic Hearing Loss Disorders: The Family Case ofILDR1-Dependent Hearing Loss Disorder.

    Science.gov (United States)

    Kovač, Jernej; Klančar, Gašper; Trebušak Podkrajšek, Katarina; Battelino, Saba

    2017-01-01

    Sensorineural hearing loss (SNHL) is a heterogeneous family of hearing disabilities with congenital (including genetic) as well as acquired etiology. Congenital SNHL of genetic etiology is further sub-divided into autosomal dominant, autosomal recessive and X-linked SNHL. More than 60 genes are involved in the etiology of autosomal recessive non-syndromic hearing loss (ARNSHL) commonly manifesting as heterogeneous pre-lingual profound to severe non-progressive clinical phenotype. ILDR1 -dependent ARNSHL (DFNB42, OMIM: # 609646) is a very rare sub-type of hearing disability, with unknown prevalence, caused by function-damaging genetic variants in ILDR1 gene reported in families of Middle-Eastern origin. ILDR1 (Immunoglobulin-Like Domain-containing Receptor 1) is involved in the development of semicircular canal, tricellular tight junction and auditory hair cells. An apparently non-consanguineous family of European ancestry with two affected siblings with profound progressive hearing loss characterized in their infancy and successfully treated with cochlear implants (CI) is presented. Genetic analysis of common ARNSHL genetic causes in the population of origin was negative, thus the next-generation sequencing (NGS) and family segregation analysis to identify underlying causative genetic variant was performed. Unexpectedly and atypical for the population of origin a homozygous non-sense variant ILDR1 c.942C > A (p.Cys314Ter) inherited from both heterozygous parents was identified in both patients. Contrary to the commonly reported phenotype, indices of a progressive hearing loss and potential compensatory mechanism of vestibular function were revealed with the analysis of clinical data. The utilization of NGS was demonstrated as an invaluable tool for the detection of atypical rare variants in diagnostics of unidentified hearing loss disorders.

  6. Discovering the Unexpected with the Utilization of NGS in Diagnostics of Non-syndromic Hearing Loss Disorders: The Family Case of ILDR1-Dependent Hearing Loss Disorder

    Directory of Open Access Journals (Sweden)

    Jernej Kovač

    2017-06-01

    Full Text Available Sensorineural hearing loss (SNHL is a heterogeneous family of hearing disabilities with congenital (including genetic as well as acquired etiology. Congenital SNHL of genetic etiology is further sub-divided into autosomal dominant, autosomal recessive and X-linked SNHL. More than 60 genes are involved in the etiology of autosomal recessive non-syndromic hearing loss (ARNSHL commonly manifesting as heterogeneous pre-lingual profound to severe non-progressive clinical phenotype. ILDR1-dependent ARNSHL (DFNB42, OMIM: # 609646 is a very rare sub-type of hearing disability, with unknown prevalence, caused by function-damaging genetic variants in ILDR1 gene reported in families of Middle-Eastern origin. ILDR1 (Immunoglobulin-Like Domain-containing Receptor 1 is involved in the development of semicircular canal, tricellular tight junction and auditory hair cells. An apparently non-consanguineous family of European ancestry with two affected siblings with profound progressive hearing loss characterized in their infancy and successfully treated with cochlear implants (CI is presented. Genetic analysis of common ARNSHL genetic causes in the population of origin was negative, thus the next-generation sequencing (NGS and family segregation analysis to identify underlying causative genetic variant was performed. Unexpectedly and atypical for the population of origin a homozygous non-sense variant ILDR1 c.942C > A (p.Cys314Ter inherited from both heterozygous parents was identified in both patients. Contrary to the commonly reported phenotype, indices of a progressive hearing loss and potential compensatory mechanism of vestibular function were revealed with the analysis of clinical data. The utilization of NGS was demonstrated as an invaluable tool for the detection of atypical rare variants in diagnostics of unidentified hearing loss disorders.

  7. [DIAGNOSTIC VARIATIONS OF X-LINKED MUSCULAR DYSTROPHY WITH CONTRACTURES].

    Science.gov (United States)

    Kvirkvelia, N; Shakarishvili, R; Gugutsidze, D; Khizanishvili, N

    2015-01-01

    Case report with review describes X-linked muscular dystrophy with contractures in 28 years old man and his cousin. The disease revealed itself in an early stage (age 5-10), the process was progressing with apparent tendons retraction and contraction, limited movement in the areas of the neck and back of spine, atrophy of shoulder and pelvic yard and back muscles. Intellect was intact. Cardyomyopathy was exhibited. CK was normal. EMG showed classic myopathic features. Muscle biopsy showed different caliber groups of muscle fibers, growth of endo-perimesial connective tissue. Clinical manifestations together with electrophysiological and histological data suggest consistency with Rotthauwe-Mortier-Bayer X-linked muscular dystrophy.

  8. Genetics Home Reference: nonsyndromic holoprosencephaly

    Science.gov (United States)

    ... with nonsyndromic holoprosencephaly often have a small head ( microcephaly ), although they can develop a buildup of fluid ... Overview ClinicalTrials.gov (1 link) ClinicalTrials.gov Scientific Articles on PubMed (1 link) PubMed OMIM (9 links) ...

  9. A family with severe X-linked arthrogryposis

    NARCIS (Netherlands)

    Hennekam, R. C.; Barth, P. G.; van Lookeren Campagne, W.; de Visser, M.; Dingemans, K. P.

    1991-01-01

    Five males are reported with severe X-linked arthrogryposis. Main findings are marked respiratory insufficiency and feeding problems, multiple contractures, deformities of chest and vertebral column, and typical facies. Most of these findings can be explained by a pronounced prenatal and postnatal

  10. X-linked adrenoleukodystrophy: Clinical, metabolic, genetic and pathophysiological aspects

    NARCIS (Netherlands)

    Kemp, Stephan; Berger, Johannes; Aubourg, Patrick

    2012-01-01

    X-linked adrenoleukodystrophy (X-ALD) is the most frequent peroxisomal disease. The two main clinical phenotypes of X-ALD are adrenomyeloneuropathy (AMN) and inflammatory cerebral ALD that manifests either in children or more rarely in adults. About 65% of heterozygote females develop symptoms by

  11. Biochemical and cell biological aspects of X-linked adrenoleukodystrophy

    NARCIS (Netherlands)

    Schackmann, M.J.A.

    2017-01-01

    X-linked adrenoleukodystrophy is a devastating peroxisomal disorder with only limited options for treatment. Recent findings however have pointed towards fatty acid elongation as a possible target for therapeutic intervention of X-ALD. Chapter 2 describes how bezafibrate reduces VLCFA levels in

  12. Methionine metabolism and phenotypic variability in X-linked adrenoleukodystrophy

    NARCIS (Netherlands)

    Linnebank, M.; Kemp, S.; Wanders, R. J. A.; Kleijer, W. J.; van der Sterre, M. L. T.; Gärtner, J.; Fliessbach, K.; Semmler, A.; Sokolowski, P.; Köhler, W.; Schlegel, U.; Schmidt, S.; Klockgether, T.; Wüllner, U.

    2006-01-01

    A combined genotype of polymorphisms of methionine metabolism has been associated with CNS demyelination in methotrexate-treated patients. Within a sample of 86 patients with X-linked adrenoleukodystrophy, this genotype was overrepresented in a subgroup of 15 patients with adrenomyeloneuropathy

  13. X-Linked agammaglobulinemia in a child with Klinefelter's syndrome.

    Science.gov (United States)

    Cochino, Alexis-Virgil; Janda, Ales; Ravcukova, Barbora; Plaiasu, Vasilica; Ochiana, Diana; Gherghina, Ioan; Freiberger, Tomas

    2014-02-01

    Bruton's agammaglobulinemia is a rare X-linked humoral immunodeficiency manifesting with recurrent bacterial infections early in life. Klinefelter's syndrome caused by an additional X chromosome is the most common sex chromosome disorder. A previously unreported association of these two conditions is described here.

  14. Multiple colorectal neoplasms in X-linked agammaglobulinemia

    NARCIS (Netherlands)

    Brosens, Lodewijk A. A.; Tytgat, Kristien M. A. J.; Morsink, Folkert H. M.; Sinke, Richard J.; ten Berge, Ineke J. M.; Giardiello, Francis M.; Offerhaus, G. Johan A.; Keller, Josbert J.

    2008-01-01

    X-linked agammaglobulinemia (XLA) is a primary immunodeficiency disorder caused by germline mutation of the Bruton tyrosine kinase (BTK) gene. It is characterized by disturbed B-cell development, decreased immunoglobulin levels, and increased patient susceptibility to infection. An increased risk of

  15. Multiple colorectal neoplasms in X-linked agammaglobulinemia

    NARCIS (Netherlands)

    Brosens, Lodewijk A. A.; Tytgat, Kristien M. A. J.; Viorsink, Folkert H. M.; Sinke, Richard J.; Ten Berge, Ineke J. N.; Giardiello, Francis M.; Offerhaus, G. Johan A.; Keller, Josbert J.

    X-linked agammaglobulinemia (XLA) is a primary immunodeficiency disorder caused by germline mutation of the Bruton tyrosine kinase (BTK) gene. It is characterized by disturbed B-cell development, decreased immunoglobulin levels, and increased patient susceptibility to infection. An increased risk of

  16. Genetics Home Reference: X-linked juvenile retinoschisis

    Science.gov (United States)

    ... Juvenile Retinoschisis ClinicalTrials.gov (1 link) ClinicalTrials.gov Scientific Articles on PubMed (1 link) PubMed OMIM (1 link) ... 42(6):e35. Citation on PubMed or Free article on PubMed ... Capone A Jr, Ciaccia S, Takada Y, Sieving PA, Trese MT. Congenital X-linked retinoschisis classification ...

  17. Pediatric Sudden Sensorineural Hearing Loss.

    Science.gov (United States)

    Kizilay, Ahmet; Koca, Çiğdem Firat

    2016-06-01

    Sudden sensorineural hearing loss is defined as sudden unilateral or bilateral sensorineural hearing loss with at least 30 dB decrease in threshold in 3 contiguous test frequencies occurring over 72 hours or less. It is rare among children. The mechanism of the process and prognosis of the disorder remains unclear. The current incidence of sudden sensorineural hearing loss among pediatric population is unknown. The authors carried out a retrospective chart analysis of patients under 15 years of age from 2004 to 2015, who consulted to the Otolaryngology Head and Neck Surgery Department of Inonu University Medical Faculty. Age, sex, number of affected ear and side, audiometric evaluations, medical follow-up, treatment method, duration of treatment recovery, associated complaints; tinnitus and/or vertigo, presence of mumps disease were recorded for each patient. A 4-frequency pure-tone average (500, 1000, 2000, and 4000 Hz) was calculated for each ear. Complete recovery, defined as some hearing level compared with the nonaffected ear, was observed in 3 patients (21.4 %) and there was no partial hearing recovery. The hearing loss of 11 patient remained unchanged after prednisolone treatment. Two of the 11 patients had bilaterally total sensorineural hearing loss and evaluated as appropriate for cochlear implantation. Sex of patient and laterality of hearing loss were not correlated with hearing recovery. Sensorineural hearing loss among pediatrics has been the issue of otolaryngologists. The incidence, etiology, and treatment methods should be more studied.

  18. [Disseminated BCG infection revealing X-linked severe combined immunodeficiency].

    Science.gov (United States)

    Marchand, I; Mahé, E; Clérici, T; Saiag, P; Chevallier, B

    2008-01-01

    Live attenuated Bacillus Calmette-Guérin (BCG) vaccine is rarely responsible for disseminated infection. We report a case of X-linked severe combined immunodeficiency (SCID) revealed by a disseminated skin infection. A 4-month-old baby was hospitalized for prolonged gastroenteritis. He was in poor general condition, with prolonged fever, oral and gluteal candidiasis and purple nodules associated with ulceration of the BCG scar. The absence of a thymus, T-cells and NK-cells, and the presence of nonfunctional B-lymphocytes led to a diagnosis of SCID. Biopsies of nodules revealed a dermal infiltrate without necrosis. A Ziehl-Neelson stain was highly positive and the culture grew Mycobacterium bovis. Treatment consisted of a four-drug antibiotic regimen directed against M. bovis combined with gamma interferon, immunoglobulins and antibiotic prophylaxis by cotrimoxazole and was followed by a haploid-identical bone marrow transplant without rejection at six months. The early death of the child's maternal uncle from sepsis suggested X-linked transmission, which was subsequently confirmed by genetic analysis. BCG vaccination can cause serious infections in immunocompromised subjects. Skin involvement is extremely rare but may be the first sign of SCID, of which the X-linked form is the most common and corresponds to a variety of mutations in the gene coding for the gamma chain common to several interleukin receptors. Genetic counselling is essential to identify female carriers and allow early antenatal diagnosis. Bone marrow transplantation is the only treatment.

  19. SOX2 nonsense mutation in a patient clinically diagnosed with non-syndromic hypogonadotropic hypogonadism.

    Science.gov (United States)

    Shima, Hirohito; Ishii, Akira; Wada, Yasunori; Kizawa, Junya; Yokoi, Tadashi; Azuma, Noriyuki; Matsubara, Yoichi; Suzuki, Erina; Nakamura, Akie; Narumi, Satoshi; Fukami, Maki

    2017-08-30

    Hypogonadotropic hypogonadism (HH) is a genetically heterogeneous condition that occurs either as an isolated disorder or as a component of congenital malformation syndromes. SOX2 is a causative gene of syndromic HH characterized by anophthalmia, microphthalmia, or coloboma and other neurological defects such as epilepsy. To date, the causal relationship between SOX2 abnormalities and non-syndromic HH remains speculative. Here, we identified a nonsense mutation of SOX2 in a male patient clinically diagnosed with non-syndromic HH. The patient had epilepsy but no additional clinical features. Ophthalmological examination revealed no abnormalities except for decreased thickness of the retinal nerve fiber layer. Audiometry showed mild sensorineural hearing impairment of both ears. Hormonal evaluation suggested isolated gonadotropin deficiency. Next-generation sequencing-based mutation screening of 13 major causative genes for HH identified a p.Lys35 ∗ mutation in SOX2 and excluded pathogenic mutations in other tested genes. The p.Lys35 ∗ mutation appeared to encode a non-functioning SOX2 protein that lacks 283 of 317 amino acids. The SOX2 mutation was absent in the maternal DNA sample, while a paternal sample was unavailable for sequence analysis. These results expand the clinical consequences of SOX2 haploinsufficiency to include non-syndromic HH. Systematic mutation screening using a next-generation sequencer and detailed evaluation of nonspecific ocular/neurological features may help identify SOX2 mutation-positive individuals among HH patients.

  20. X-linked ichthyosis along with epidermolysis bullosa

    Directory of Open Access Journals (Sweden)

    Shambulingappa Pallagatti

    2012-01-01

    Full Text Available Ichthyoses are a heterogenous group of hereditary keratinization disorders that share in common the accumulation & shedding of large amounts of hyperkeratotic epidermis.Early reports of ichthyosis in the Indian and Chinese literature date back to several hundred years. X-linked recessive ichthyosis (XLI is a common disorder of keratinization and affects males who inherit an X-chromosome having a steroid sulphatase genetic mutation.In the present communication we report a case of XLI and dystrophic epidermolysis bullosa in the same patient. To the best of our knowledge it has been reported only once before.

  1. Asymmetric Cerebral Lesion Pattern in X-linked Adrenoleukodystrophy

    Directory of Open Access Journals (Sweden)

    Shuang Wang

    2006-08-01

    Full Text Available X-linked adrenoleukodystrophy (X-ALD is an inherited disease caused by peroxisomal dysfunction. X-ALD usually involves the cerebral white matter in an approximately symmetric way. We report a 10-year-old boy with the cerebral form of X-ALD who presented with cognitive impairment and left spastic hemiparesis. Brain magnetic resonance imaging (MRI showed asymmetric lesions, and the lesions in the right hemisphere were predominant. In the late stage of the disease, bilateral limbs were involved. The cerebral lesions enlarged and appeared approximately symmetric on MRI. The purpose of our report is to highlight asymmetric demyelination in initial presentation of X-ALD.

  2. Evolving practice: X-linked agammaglobulinemia and lung transplantation.

    Science.gov (United States)

    Barnes, S; Kotecha, S; Douglass, J A; Paul, E; Hore-Lacy, F; Hore-Lacey, F; Stirling, R; Snell, G I; Westall, G P

    2015-04-01

    X-linked agammaglobulinemia (XLA) is a rare primary humoral immunodeficiency syndrome characterized by agammaglobulinemia, recurrent infections and bronchiectasis. Despite the association with end-stage bronchiectasis, the literature on XLA and lung transplantation is extremely limited. We report a series of 6 XLA patients with bronchiectasis who underwent lung transplantation. Short-term outcomes were excellent however long-term outcomes were disappointing with a high incidence of pulmonary sepsis and chronic lung allograft dysfunction (CLAD). © Copyright 2015 The American Society of Transplantation and the American Society of Transplant Surgeons.

  3. JOINT DISEASE IN CHILDREN WITH X-LINKED AGAMMAGLOBULINEMIA

    Directory of Open Access Journals (Sweden)

    Lidija Kareva

    2013-11-01

    Full Text Available Patients with X-linked agammaglobulinemia (XLA are prone to recurrent bacterial infections due to low levels of immunoglobulins. Clinical symptoms include recurrent bacterial otitis media, bronchitis, pneumonia, meningitis, skin infection and arthritis.In the majority of cases arthritis can be shown to be caused by infection, but also aseptic arthritis and autoimmune diseases may be present. Monoarthritis and oligoarthritis is usual pattern, although polyarthritis may occur. This paper presents diagnostic and therapeutic problems in our patients with agammaglobulinemia and arthritis.

  4. X-Linked and Autosomal Recessive Alport Syndrome

    DEFF Research Database (Denmark)

    Savige, Judith; Storey, Helen; Il Cheong, Hae

    2016-01-01

    Alport syndrome results from mutations in the COL4A5 (X-linked) or COL4A3/COL4A4 (recessive) genes. This study examined 754 previously- unpublished variants in these genes from individuals referred for genetic testing in 12 accredited diagnostic laboratories worldwide, in addition to all published...... COL4A5, COL4A3 and COL4A4 variants in the LOVD databases. It also determined genotype-phenotype correlations for variants where clinical data were available. Individuals were referred for genetic testing where Alport syndrome was suspected clinically or on biopsy (renal failure, hearing loss...

  5. Genetics Home Reference: alpha thalassemia X-linked intellectual disability syndrome

    Science.gov (United States)

    ... linked intellectual disability syndrome Alpha thalassemia X-linked intellectual disability syndrome Printable PDF Open All Close All Enable ... expand/collapse boxes. Description Alpha thalassemia X-linked intellectual disability syndrome is an inherited disorder that affects many ...

  6. Optical coherence tomography in x-linked adrenoleukodystrophy.

    Science.gov (United States)

    Aquino, Jannelle J; Sotirchos, Elias S; Saidha, Shiv; Raymond, Gerald V; Calabresi, Peter A

    2013-09-01

    X-linked adrenoleukodystrophy is a metabolic disease caused by mutations in the ABCD1 gene, which codes for a peroxisomal membrane protein, leading to the accumulation of very long-chain fatty acids. Thinning of the retinal nerve fiber layer and macula has been described in adult-onset adrenomyeloneuropathy; however, assessment of these structures in the presymptomatic stage remains largely unexplored. Optical coherence tomography is a high-resolution medical imaging technology that has been widely used to assess ophthalmological diseases and more recently in neurological disease states to quantify the axonal and neuronal injury in the retina that results from demyelination of the optic nerve. Fourteen boys with presymptomatic X-linked adrenoleukodystrophy and 14 age-matched healthy controls underwent retinal imaging with optical coherence tomography. Optical coherence tomography-derived retinal thickness measures did not differ between adrenoleukodystrophy subjects and healthy controls. Our results suggest that structural retinal abnormalities are not detectable before the development of neurological manifestations in adrenoleukodystrophy. Further investigation of the utility of optical coherence tomography scanning in individuals with symptomatic disease should be considered to determine if its measures could be used as a biomarker of disease progression. Copyright © 2013 Elsevier Inc. All rights reserved.

  7. Genetics Home Reference: X-linked hyper IgM syndrome

    Science.gov (United States)

    ... Conditions X-linked hyper IgM syndrome X-linked hyper IgM syndrome Printable PDF Open All Close All ... view the expand/collapse boxes. Description X-linked hyper IgM syndrome is a condition that affects the ...

  8. Methadone Induced Sensorineural Hearing Loss

    Directory of Open Access Journals (Sweden)

    Chadi Saifan

    2013-01-01

    Full Text Available Background. Sudden sensorineural hearing loss (SSHL caused by opiate abuse or overuse has been well documented in the medical literature. Most documented case reports have involved either heroin or hydrocodone/acetaminophen. Recently, case reposts of methadone induced SSHL have been published. Case Report. We present the case of a 31-year-old man who developed SSHL after a methadone overdose induced stupor. He was subsequently restarted on methadone at his regular dose. On follow-up audiometry exams, he displayed persistent moderately severe sensorineural hearing loss bilaterally. Discussion. This case is notable because unlike all but one previously reported case, the patient—who was restated on methadone—did not make a complete recovery. Conclusion. Methadone overuse in rare cases causes SSHL.

  9. Impaired αGDI Function in the X-Linked Intellectual Disability: The Impact on Astroglia Vesicle Dynamics.

    Science.gov (United States)

    Potokar, Maja; Jorgačevski, Jernej; Lacovich, Valentina; Kreft, Marko; Vardjan, Nina; Bianchi, Veronica; D'Adamo, Patrizia; Zorec, Robert

    2017-05-01

    X-linked non-syndromic intellectual disability (XLID) is a common mental disorder recognized by cognitive and behavioral deficits. Mutations in the brain-specific αGDI, shown to alter a subset of RAB GTPases redistribution in cells, are linked to XLID, likely via changes in vesicle traffic in neurons. Here, we show directly that isolated XLID mice astrocytes, devoid of pathologic tissue environment, exhibit vesicle mobility deficits. Contrary to previous studies, we show that astrocytes express two GDI proteins. The siRNA-mediated suppression of expression of αGDI especially affected vesicle dynamics. A similar defect was recorded in astrocytes from the Gdi1 -/Y mouse model of XLID and in astrocytes with recombinant mutated human XLID αGDI. Endolysosomal vesicles studied here are involved in the release of gliosignaling molecules as well as in regulating membrane receptor density; thus, the observed changes in astrocytic vesicle mobility may, over the long time-course, profoundly affect signaling capacity of these cells, which optimize neural activity.

  10. X-linked deafness with stapes gusher in females

    Energy Technology Data Exchange (ETDEWEB)

    Papadaki, E. [Department of Radiology, Faculty of Medicine, University Hospital of Heraklion, Medical School of Crete, 71110 Stavrakia, Heraklion, Crete (Greece); Prassopoulos, P. [Department of Radiology, Faculty of Medicine, University Hospital of Heraklion, Medical School of Crete, 71110 Stavrakia, Heraklion, Crete (Greece); Bizakis, J. [Department of Otolaryngology, University Hospital of Heraklion, Medical School of Crete, 71110 Stavrakia, Heraklion, Crete (Greece); Karampekios, S. [Department of Radiology, Faculty of Medicine, University Hospital of Heraklion, Medical School of Crete, 71110 Stavrakia, Heraklion, Crete (Greece); Papadakis, H. [Department of Otolaryngology, University Hospital of Heraklion, Medical School of Crete, 71110 Stavrakia, Heraklion, Crete (Greece); Gourtsoyiannis, N. [Department of Radiology, Faculty of Medicine, University Hospital of Heraklion, Medical School of Crete, 71110 Stavrakia, Heraklion, Crete (Greece)

    1998-11-01

    A 22-year-old woman presented with severe mixed hearing loss and a flow of cerebrospinal fluid in the middle ear during stapes surgery (stapes gusher). HRCT of the temporal bones showed characteristic abnormalities of the inner ear (bulbous dilatation of the lateral portion of the internal acoustic meatus with incomplete separation from the cochlea, and widening of the first part of the facial nerve canal) described in X-linked progressive mixed deafness with stapes gusher. The evaluation of the patient's family revealed a sister with the same clinical history and identical HRCT findings, and 11 normal male relatives. This is the first report with typical findings of this entity that affects only female members of a family, suggesting another type of inheritance.

  11. [Peroxisomal ABC transporters and X-linked adrenoleukodystrophy].

    Science.gov (United States)

    Geillon, Flore; Trompier, Doriane; Gondcaille, Catherine; Lizard, Gérard; Savary, Stéphane

    2012-12-01

    X-linked adrenoleukodystrophy (X-ALD) is a complex neurodegenerative disease associated with mutations in the ABCD1 gene, which encodes for a peroxisomal ABC transporter. Thanks to the efforts of the ELA foundation and to the recent successes of gene therapy published in Science in 2009, X-ALD is better known but still remains poorly understood. The exact role of ABCD1 and its homologs, as well as the exact link between the biochemical and metabolic peroxisomal defects and the clinical symptoms of the disease remain to be elucidated. This review summarizes the knowledge concerning the subfamily D of the ABC transporter family and concerning X-ALD, the most frequent peroxisomal disorder. © 2012 médecine/sciences – Inserm / SRMS.

  12. Localised proton magnetic resonance spectroscopy in X-linked adrenoleukodystrophy

    Energy Technology Data Exchange (ETDEWEB)

    Confort-Gouny, S. [Centre de Resonance Magnetique Biologique et Medicale (CRMBM), URA, CNRS, Faculte de Medicine, 13 - Marseille (France); Vion-Dury, J. [Centre de Resonance Magnetique Biologique et Medicale (CRMBM), URA, CNRS, Faculte de Medicine, 13 - Marseille (France); Cozzone, P.J. [Centre de Resonance Magnetique Biologique et Medicale (CRMBM), URA, CNRS, Faculte de Medicine, 13 - Marseille (France); Chabrol, B. [Service de Neuropediatrie, Hospital d`Enfants, Centre Hospitalo Universitaire, 13 - Marseille (France); Nicoli, F. [Service de Neurologie, Hopital Ste Margeurite, 13 - Marseille (France)

    1995-10-01

    We have performed localised proton magnetic resonance spectroscopy (MRS) of the brain on four patients with X-linked adrenoleukodystrophy (X-ALD). The spectrum is characterised at the beginning of the disease by a decrease in N-acetylaspartate and phosphocreatine-creatine content. Choline is strongly increased, and lactate can be detected in some cases. A proton signal from the CH{sub 2} groups borne by free intracellular very long chain fatty acids can also be observed. Later in the disease, the levels of all metabolites, in particular NAA, decrease significantly. The progression of neurometabolism documented by MRS correlates well with MRI and clinical progression on follow-up study. In one case, the metabolic profile recorded by proton MRS was abnormal before any change occurred on MRI. Proton MRS of the brain might be the method of choice for monitoring patients with X-ALD, to screen presumed cases and to study the effects of treatment. (orig.)

  13. X-linked deafness with stapes gusher in females

    International Nuclear Information System (INIS)

    Papadaki, E.; Prassopoulos, P.; Bizakis, J.; Karampekios, S.; Papadakis, H.; Gourtsoyiannis, N.

    1998-01-01

    A 22-year-old woman presented with severe mixed hearing loss and a flow of cerebrospinal fluid in the middle ear during stapes surgery (stapes gusher). HRCT of the temporal bones showed characteristic abnormalities of the inner ear (bulbous dilatation of the lateral portion of the internal acoustic meatus with incomplete separation from the cochlea, and widening of the first part of the facial nerve canal) described in X-linked progressive mixed deafness with stapes gusher. The evaluation of the patient's family revealed a sister with the same clinical history and identical HRCT findings, and 11 normal male relatives. This is the first report with typical findings of this entity that affects only female members of a family, suggesting another type of inheritance

  14. Membranoproliferative Glomerulonephritis and X-Linked Agammaglobulinemia: An Uncommon Association

    Directory of Open Access Journals (Sweden)

    Vasco Lavrador

    2014-01-01

    Full Text Available Introduction. X-linked agammaglobulinemia (XLA is a primary immunodeficiency characterized by agammaglobulinemia requiring replacement treatment with immunoglobulin. The association of XLA and membranoproliferative glomerulonephritis (MPGN is unexpected and, to our knowledge, only one case was previously published. Case Report. The authors report the case of a 10-year-old boy with family history and prenatal diagnosis of XLA, treated from birth with intravenous immunoglobulin replacement therapy. He presented with pneumonia, macroscopic hematuria, nephrotic proteinuria, hypoalbuminemia, and hypercholesterolemia with normal renal function and serum complement levels. Renal histology showed immune complex mediated MPGN. He was started on high dose prednisolone and ramipril and switched to weekly subcutaneous immunoglobulin. After a 4-month treatment, hematuria and proteinuria significantly improved and prednisolone was gradually tapered without relapse. Conclusion. The pathogenic process underlying MPGN development in this patient is unknown but residual humoral immunity might play an important role. Thus, this case highlights the risk of autoimmune disorders among patients with XLA.

  15. X linked agammaglobulinemia: a single centre experience from India.

    Science.gov (United States)

    Merchant, Rashid H; Parekh, Deep; Ahmad, Noor; Madkaikar, Manisha; Ahmed, Javed

    2014-01-01

    The authors report a series of seven cases of X-linked Agammaglobulinemia, diagnosed and receiving treatment at a tertiary care centre in Mumbai. The ages of the patients ranged from 15 mo to 15 y. After diagnosis at a mean age of 3 ½ y, all were advised intravenous immunoglobulin (IvIg) infusion therapy in doses of 400-600 mg/kg every 3-4 wk. They were followed up for an average duration of 9 y, throughout which the complications and overall response to immunoglobulin therapy have been observed. The clinical profiles of each of these cases were retrospectively analysed with respect to age at diagnosis, frequency and severity of infections before and after initiation of treatment, co-morbidities and response to therapy. The results demonstrate the importance of early diagnosis and its correlation with decreased complications.

  16. [Dermatomyositis-like syndrome in x-linked agammaglobulinemia].

    Science.gov (United States)

    Carvalho, P D; Costa, C; Rodrigues, M; Salvador, M J; Pereira da Silva, J A; Malcata, A

    2016-01-01

    Primary immunodeficiencies (PIDs) encompass more than 250 different pathological conditions. X-linked agammaglobulinemia (XLA) has been occasionally associated with cutaneous and muscular manifestations resembling dermatomyositis, often termed dermatomyositis-like syndrome (DLS). This syndrome has been associated with cutaneous, muscular and central nervous system manifestations, accompanying a persistent infection by an Echovirus. According to sixteen previously reported cases, this syndrome has a poor prognosis. We report the case of a 27-years old male, with XLA and DLS, successfully treated with 6 cycles of human immunoglobulin and methotrexate. Clinical symptoms improved dramatically with a complete resolution of the musculoskeletal manifestations. Despite this clinical response, prognosis should remain reserved. The evolution of this syndrome remains unpredictable and therapeutic options are limited. To the best of our knowledge, there are only a few reports of similar cases which have survived so many months after the diagnosis.

  17. Dermatomyositis-like syndrome in x-linked agammaglobulinemia

    Directory of Open Access Journals (Sweden)

    Pedro David Carvalho

    2016-01-01

    Full Text Available Primary immunodeficiencies (PIDs encompass more than 250 different pathological conditions. X-linked agammaglobulinemia (XLA has been occasionally associated with cutaneous and muscular manifestations resembling dermatomyositis, often termed dermatomyositis-like syndrome (DLS. This syndrome has been associated with cutaneous, muscular and central nervous system manifestations, accompanying a persistent infection by an Echovirus. According to sixteen previously reported cases, this syndrome has a poor prognosis. We report the case of a 27-years old male, with XLA and DLS, successfully treated with 6 cycles of human immunoglobulin and methotrexate. Clinical symptoms improved dramatically with a complete resolution of the musculoskeletal manifestations. Despite this clinical response, prognosis should remain reserved. The evolution of this syndrome remains unpredictable and therapeutic options are limited. To the best of our knowledge, there are only a few reports of similar cases which have survived so many months after the diagnosis.

  18. Molecular and genetic basis of X-linked immunodeficiency disorders

    Energy Technology Data Exchange (ETDEWEB)

    Puck, J.M. (National Center for Human Genome Research, Bethesda, MD (United States))

    1994-03-01

    Within a short time interval the specific gene defects causing three X-linked human immunodeficiencies, agammaglobulinemia (XLA), hyper-IgM syndrome (HIGM), and severe combined immunodeficiency (XSCID), have been identified. These represent the first human disease phenotypes associated with each of three gene families already recognized to be important in lymphocyte development and signaling: XLA is caused by mutations of a B cell-specific intracellular tyrosine kinase; HIGM, by mutations in the TNF-related CD40 ligand, through which T cells deliver helper signals by direct contact with B cell CD40; and XSCID, by mutations in the [gamma] chain of the lymphocyte receptor for IL-2. Each patient mutation analyzed to date has been unique, representing both a challenge for genetic diagnosis and management and an important resource for dissecting molecular domains and understanding the physiologic function of the gene products.

  19. Glutathione imbalance in patients with X-linked adrenoleukodystrophy☆

    Science.gov (United States)

    Petrillo, Sara; Piemonte, Fiorella; Pastore, Anna; Tozzi, Giulia; Aiello, Chiara; Pujol, Aurora; Cappa, Marco; Bertini, Enrico

    2013-01-01

    Background X-linked adrenoleukodystrophy (X-ALD) is a genetic disorder of X-linked inheritance caused by a mutation in the ABCD1 gene which determines an accumulation of long-chain fatty acids in plasma and tissues. Recent evidence shows that oxidative stress may be a hallmark in the pathogenesis of X-ALD and glutathione plays an important role in the defense against free radicals. In this study we have analyzed glutathione homeostasis in lymphocytes of 14 patients with X-ALD and evaluated the balance between oxidized and reduced forms of glutathione, in order to define the role of this crucial redox marker in this condition. Methods Lymphocytes, plasma and erythrocytes were obtained from the whole blood of 14 subjects with X-ALD and in 30 healthy subjects. Total, reduced and protein-bound glutathione levels were measured in lymphocytes by HPLC analysis. Erythrocyte free glutathione and antioxidant enzyme activities, plasma thiols and carbonyl content were determined by spectrophotometric assays. Results A significant decrease of total and reduced glutathione was found in lymphocytes of patients, associated to high levels of all oxidized glutathione forms. A decline of free glutathione was particularly significant in erythrocytes. The increased oxidative stress in X-ALD was additionally confirmed by the decrease of plasma thiols and the high level of carbonyls. Conclusion Our results strongly support a role for oxidative stress in the pathophysiology of X-ALD and strengthen the importance of the balance among glutathione forms as a hallmark and a potential biomarker of the disease. PMID:23768953

  20. Glutathione imbalance in patients with X-linked adrenoleukodystrophy.

    Science.gov (United States)

    Petrillo, Sara; Piemonte, Fiorella; Pastore, Anna; Tozzi, Giulia; Aiello, Chiara; Pujol, Aurora; Cappa, Marco; Bertini, Enrico

    2013-08-01

    X-linked adrenoleukodystrophy (X-ALD) is a genetic disorder of X-linked inheritance caused by a mutation in the ABCD1 gene which determines an accumulation of long-chain fatty acids in plasma and tissues. Recent evidence shows that oxidative stress may be a hallmark in the pathogenesis of X-ALD and glutathione plays an important role in the defense against free radicals. In this study we have analyzed glutathione homeostasis in lymphocytes of 14 patients with X-ALD and evaluated the balance between oxidized and reduced forms of glutathione, in order to define the role of this crucial redox marker in this condition. Lymphocytes, plasma and erythrocytes were obtained from the whole blood of 14 subjects with X-ALD and in 30 healthy subjects. Total, reduced and protein-bound glutathione levels were measured in lymphocytes by HPLC analysis. Erythrocyte free glutathione and antioxidant enzyme activities, plasma thiols and carbonyl content were determined by spectrophotometric assays. A significant decrease of total and reduced glutathione was found in lymphocytes of patients, associated to high levels of all oxidized glutathione forms. A decline of free glutathione was particularly significant in erythrocytes. The increased oxidative stress in X-ALD was additionally confirmed by the decrease of plasma thiols and the high level of carbonyls. Our results strongly support a role for oxidative stress in the pathophysiology of X-ALD and strengthen the importance of the balance among glutathione forms as a hallmark and a potential biomarker of the disease. Copyright © 2013 The Authors. Published by Elsevier Inc. All rights reserved.

  1. X-linked dominant protoporphyria: The first reported Japanese case.

    Science.gov (United States)

    Ninomiya, Yukiko; Kokunai, Yasuhito; Tanizaki, Hideaki; Akasaka, Eijiro; Nakano, Hajime; Moriwaki, Shinichi

    2016-04-01

    A 12-year-old boy with photosensitivity since 3 years of age presented with small concavities on both cheeks, the nasal root and the dorsal surface of both hands. According to the clinical features, erythropoietic protoporphyria (EPP) was suspected. Urine and blood samples were tested for porphyrin derivatives, which revealed a markedly elevated level of erythrocyte protoporphyrin (EP) and a diagnosis of EPP was made. The patient's mother had no photosensitivity, however, lesions appearing slightly as small scars were found on the dorsum of her right hand; his elder sister and father showed no rash. The EP levels were elevated in samples from his mother and mildly elevated in those from his elder sister and father. To obtain a definitive diagnosis, genetic analyses were performed using samples from all family members, which revealed no mutations in the ferrochelatase-encoding gene (FECH), which is responsible for EPP. Instead, a pathological mutation of the 5-aminolevulinic acid synthase-encoding gene (ALAS2) was identified in samples from the patient, his mother and his elder sister, confirming a definitive diagnosis of X-linked dominant protoporphyria (XLDPP). This is the first Japanese family reported to have XLDPP, demonstrating evidence of the condition in Japan. In addition, because XLDPP is very similar to EPP in its clinical aspects and laboratory findings, a genetic analysis is required for the differential diagnosis. © 2015 Japanese Dermatological Association.

  2. Dental management of patients with X-linked hypophosphatemia

    Directory of Open Access Journals (Sweden)

    Bin-Na Lee

    2017-05-01

    Full Text Available X-linked hypophosphatemia (XLH is a hereditary metabolic disease caused by the loss of phosphate through the renal tubules into the urine, and an associated decrease in serum calcium and potassium phosphate. Its dental features include spontaneous dental abscesses that occur in the absence of trauma or dental caries. The aim of this case report was to describe the dental problems of XLH patients and to evaluate limitations in their treatment. A 14 year old male and a 38 year old female with XLH were referred to the Department of Conservative Dentistry for endodontic treatment. The dental findings were periapical abscesses without obvious trauma or caries. Conservative endodontic treatment was performed in teeth with pulp necrosis and abscess. In case 1, the treated teeth showed improvements in bone healing, without clinical symptoms. However, in case 2, the implants and the treated tooth showed hypermobility, and the final restoration was therefore postponed. Early diagnosis, periodic examinations, and communication with the patient's pediatrician are important in the dental management of patients with XLH

  3. Clinical Manifest X-Linked Recessive Adrenoleukodystrophy in a Female

    Directory of Open Access Journals (Sweden)

    Gyda Hlin Skuladottir Jack

    2013-01-01

    Full Text Available Adrenoleukodystrophy (ALD is a rare X-linked inherited leukodystrophy with a reduced capacity for degradation of very long chain fatty acids (VLCFAs. The intracellular accumulation of VLCFA leads to demyelination in the central nervous system (CNS and cell destruction in the adrenal glands. ALD primarily affects males; however, females may develop milder symptoms that may be difficult to recognize. The present report describes a 35-year-old female who experienced a feeling of heaviness in the upper and lower limbs, pain in both knees, and difficulty climbing stairs, running, and jumping. Clinical examination revealed decreased sensitivity in the feet, particularly to touch. Deep tendon reflexes in the lower limbs were brisk, and Babinski's sign was present bilaterally. Multiple sclerosis (MS was excluded, and all clinical and biochemical tests were normal. After two years of progressing symptoms, the patient was reevaluated and plasma levels of VLCFA were found to be elevated. Seven years prior to this finding, the patient had been found to be heterozygous for the missense mutation c.1679C> T, p.Pro560Leu on the ABCD1 gene (ATP-Binding Cassette subfamily D1. In conclusion, the patient's symptoms could be attributed to ALD. The present case underlines the importance of reevaluating family history in women presenting with vague neurological symptoms.

  4. X-linked adrenoleukodystrophy: clinical, metabolic, genetic and pathophysiological aspects.

    Science.gov (United States)

    Kemp, Stephan; Berger, Johannes; Aubourg, Patrick

    2012-09-01

    X-linked adrenoleukodystrophy (X-ALD) is the most frequent peroxisomal disease. The two main clinical phenotypes of X-ALD are adrenomyeloneuropathy (AMN) and inflammatory cerebral ALD that manifests either in children or more rarely in adults. About 65% of heterozygote females develop symptoms by the age of 60years. Mutations in the ABCD1 gene affect the function of the encoded protein ALDP, an ATP-binding-cassette (ABC) transporter located in the peroxisomal membrane protein. ALDP deficiency impairs the peroxisomal beta-oxidation of very long-chain fatty acids (VLCFA) and facilitates their further chain elongation by ELOVL1 resulting in accumulation of VLCFA in plasma and tissues. While all patients have mutations in the ABCD1 gene, there is no general genotype-phenotype correlation. Environmental factors and a multitude of modifying genes appear to determine the clinical manifestation in this monogenetic but multifactorial disease. This review focuses on the clinical, biochemical, genetic and pathophysiological aspects of X-ALD. Copyright © 2012 Elsevier B.V. All rights reserved.

  5. Progression rate of myelopathy in X-linked adrenoleukodystrophy heterozygotes.

    Science.gov (United States)

    Habekost, Clarissa Troller; Pereira, Fernanda Santos; Vargas, Carmen Regla; Coelho, Daniella Moura; Torrez, Vitor; Oses, Jean Pierre; Portela, Luis Valmor; Schestatsky, Pedro; Felix, Vitor Torres; Matte, Ursula; Torman, Vanessa Leotti; Jardim, Laura Bannach

    2015-10-01

    X-linked adrenoleukodystrophy heterozygote women can present adult onset myeloneuropathy and little is known about its natural history. We aimed to describe the progression rate of the neurological impairment in the prospective follow-up of our cohort and to look for prognostic factors. The neurological scales Japanese Orthopaedic Association (JOA) and Severity Score System for Progressive Myelopathy (SSPROM) were applied at baseline in 29 symptomatic carriers and in follow-up visits. Age at onset, disease duration, X inactivation pattern, determination of the allele expressed, plasma levels of the very long chain fatty acids and of the neuron-specific enolase, and somato-sensory evoked potentials, were taken at baseline. The slope of the linear regression of both JOA and SSPROM versus disease duration since the first symptom was estimated using mixed modeling. JOA and SSPROM decreased 0.42 and 1.87 points per year, respectively (p < 0.001). None of the parameters under study influenced these rates. We estimated that the number of carriers per arm needed in a future 12 month trial with 80% power and a 50% reduction in disease progression would be 225 women for JOA and 750 for SSPROM. The progression rates of the studied neurological scales were small, did not depend on any modifier factor known, and reflected the characteristically slow worsening of symptoms in X-ALD heterozygotes. Better biomarkers are still necessary for future studies.

  6. X-linked adrenoleukodystrophy presenting as Addison’s disease

    Science.gov (United States)

    Morell, Bernhard Kaspar; Teichler, Jens; Budak, Kemal; Vollenweider, Jörg; Pavlicek, Vojtech

    2010-01-01

    We report the case of a young man with a history of attention deficit/hyperactivity disorder and mild cognitive impairment who presented with chronic fatigue, anorexia and progressive darkening of the skin. On laboratory testing, severely depressed concentrations of morning cortisol, along with highly elevated values of adrenocorticotropic hormone (ACTH) revealed primary adrenal insufficiency as the primary cause of the patient’s symptomatology. Imaging of the brain showed altered signal intensities in the parieto-occipital regions of the brain. The demonstration of increased very long chain fatty acids (VLCFA) established the diagnosis of adolescent X-linked adrenoleukodystrophy (X-ALD). Presenting at an advanced yet slowly progressive stage the patient was not a suitable candidate for haematopoietic stem cell transplantation (HSCT), and treatment focused on hormone replacement therapy, family counselling and supportive care. On follow-up visits within the following year, fatigue had diminished and there was no evidence of progressive neurological deficits. However, exacerbation of the psychiatric symptomatology resulted in admittance to a psychiatric ward. PMID:22753300

  7. Hypoperfusion predicts lesion progression in cerebral X-linked adrenoleukodystrophy.

    Science.gov (United States)

    Musolino, Patricia Leonor; Rapalino, Otto; Caruso, Paul; Caviness, Verne Strudwick; Eichler, Florian Sebald

    2012-09-01

    Magnetic resonance imaging sequences such as diffusion and spectroscopy have been well studied in X-linked adrenoleukodystrophy, but no data exist on magnetic resonance perfusion imaging. Since inflammation is known to modulate the microcirculation, we investigated the hypothesis that changes in the local perfusion might be one of the earliest signs of lesion development. Twenty patients with different phenotypes of adrenoleukodystrophy and seven age-matched controls were evaluated between 2006 and 2011. Fluid attenuated inversion recovery, post-contrast T(1)-weighted and normalized dynamic susceptibility contrast magnetic resonance perfusion cerebral blood volume maps were co-registered, segmented when cerebral lesion was present, and normalized cerebral blood volume values were analysed using a Food and Drug Association approved magnetic resonance perfusion software (NordicICE). Clinical and imaging data were reviewed to determine phenotype and status of progression. All eight patients with cerebral adrenoleukodystrophy had an average 80% decrease in normalized cerebral blood volume at the core of the lesion (P adrenoleukodystrophy lesions and follow-up imaging (2-24 month interval period), we found progression of contrast enhancement into the formerly hypoperfused perilesional zone. Asymptomatic, adrenomyeloneuropathy and female heterozygote patients had no significant changes in cerebral perfusion. Our data indicate that decreased brain magnetic resonance perfusion precedes leakage of the blood-brain barrier as demonstrated by contrast enhancement in cerebral adrenoleukodystrophy and is an early sign of lesion progression.

  8. Oxidative Stress in Patients with X-Linked Adrenoleukodystrophy.

    Science.gov (United States)

    Deon, Marion; Marchetti, Desirèe P; Donida, Bruna; Wajner, Moacir; Vargas, Carmen

    2016-05-01

    X-linked adrenoleukodystrophy (X-ALD) is the most frequent peroxisomal disorder that is characterized by progressive demyelination of the white matter, adrenal insufficiency, and accumulation of very long-chain fatty acids in body fluid and tissues. This disorder is clinically heterogeneous with seven different phenotypes in male patients and five phenotypes in female carriers. An ultimate treatment for X-ALD is not available. Depending on the rate of the disease progression and the degree of an individual handicap, special needs and challenges vary greatly. The exact mechanisms underlying the pathophysiology of this multifactorial neurodegenerative disorder remains obscure. Previous studies has been related oxidative stress with the pathogenesis of several disease that affecting the central nervous system, such as neurodegenerative disease, epilepsy, multiple sclerosis, Alzheimer, and Parkinson diseases. In addition, oxidative damage has been observed in various in vivo and in vitro studies with inborn errors of metabolism, including X-ALD. In this context, this review is focused on oxidative stress in X-ALD, with emphasis on studies using biological samples from patients affected by this disease.

  9. X-Linked Dystonia Parkinsonism: Clinical Phenotype, Genetics and Therapeutics

    Directory of Open Access Journals (Sweden)

    Raymond L. Rosales

    2010-10-01

    Full Text Available The clinical phenotype of X-Linked Dystonia Parkinsonism (XDP is typically one that involves a Filipino adult male whose ancestry is mostly traced in the Philippine island of Panay. Dystonia usually starts focally in the lower limbs or oromandibular regions, then spreads to become generalized eventually. Parkinsonism sets in later into the disease and usually in combination with dystonia. /DYT3/ and /TAF1/ are the two genes associated with XDP. An SVA retrotransposon insertion in an intron of /TAF1/ may reduce neuron-specific expression of the /TAF1/ isoform in the caudate nucleus, and subsequently interfere with the transcription of many neuronal genes. Polypharmacy with oral benzodiazepines, anticholinergic agents and muscle relaxants leaves much to be desired in terms of efficacy. The medications to date that may appear beneficial, especially in disabling dystonias, are zolpidem, muscle afferent block with lidocaine-ethanol and botulinum toxin type A. Despite the few cases undergoing deep brain stimulation, this functional surgery has shown the greatest promise in XDP. An illustrative case of XDP in a family depicts the variable course of illness, including a bout of “status dystonicus,” challenges in therapy, reckoning with the social impact of the disease, and eventual patient demise. Indeed, there remains some gaps in understanding some phenomenological, genetic and treatment aspects of XDP, the areas upon which future research directions may be worthwhile.

  10. Modeling X-linked ancestral origins in multiparental populations.

    Science.gov (United States)

    Zheng, Chaozhi

    2015-03-04

    The models for the mosaic structure of an individual's genome from multiparental populations have been developed primarily for autosomes, whereas X chromosomes receive very little attention. In this paper, we extend our previous approach to model ancestral origin processes along two X chromosomes in a mapping population, which is necessary for developing hidden Markov models in the reconstruction of ancestry blocks for X-linked quantitative trait locus mapping. The model accounts for the joint recombination pattern, the asymmetry between maternally and paternally derived X chromosomes, and the finiteness of population size. The model can be applied to various mapping populations such as the advanced intercross lines (AIL), the Collaborative Cross (CC), the heterogeneous stock (HS), the Diversity Outcross (DO), and the Drosophila synthetic population resource (DSPR). We further derive the map expansion, density (per Morgan) of recombination breakpoints, in advanced intercross populations with L inbred founders under the limit of an infinitely large population size. The analytic results show that for X chromosomes the genetic map expands linearly at a rate (per generation) of two-thirds times 1 - 10/(9L) for the AIL, and at a rate of two-thirds times 1 - 1/L for the DO and the HS, whereas for autosomes the map expands at a rate of 1 - 1/L for the AIL, the DO, and the HS. Copyright © 2015 Zheng.

  11. Shulman disease (eosinophilic fasciitis) in X-linked agammaglobulinemia.

    Science.gov (United States)

    Pituch-Noworolska, A; Mach-Tomalska, H; Szaflarska, A; Adamek, D

    2016-06-01

    X-linked agammaglobulinemia (XLA) diagnosed in the first year of life is an immunodeficiency with a life-long indication for substitution of immunoglobulins, due to lack of B lymphocytes in the periphery. The decrease of bacterial infection frequency and severity is an effect of immunoglobulin replacement. However, in the majority of patients bronchiectasis and chronic sinusitis with an overgrown mucous membrane develop despite regular substitution. Autoimmune diseases as co-existing diseases in XLA are noted in a few patients presenting symptoms associated with arthritis, scleroderma and myositis. Our patient was diagnosed with XLA in the first year of life, followed by regular substitution of immunoglobulins. The symptoms of pain, edema of muscles of the right shank with skin edema and discoloration after mild injury were noted in a 13-year-old boy. Shulman disease was diagnosed after 6 months of symptoms, based on histopathology of muscle and skin biopsy. Before the diagnosis, non-steroid anti-inflammatory drugs (NSAID) were used with a transient effect. After the diagnosis, therapy included steroids, immunoglobulins in a high dose and immunosuppression, with improvement of clinical symptoms. During methotrexate (MTX) therapy the patient developed two episodes of pneumonia, so mycophenolate mofetil (MMF) was used, with a similar effect. Now, with this therapy, the symptoms are mild and stable without progression.

  12. Tubulointerstitial nephritis complicating IVIG therapy for X-linked agammaglobulinemia.

    Science.gov (United States)

    Sugimoto, Keisuke; Nishi, Hitomi; Miyazawa, Tomoki; Wada, Norihisa; Izu, Akane; Enya, Takuji; Okada, Mitsuru; Takemura, Tsukasa

    2014-07-08

    Patients with X-linked agammaglobulinemia (XLA) develop immune-complex induced diseases such as nephropathy only rarely, presumably because their immunoglobulin (Ig) G concentration is low. We encountered a patient with XLA who developed tubulointerstitial nephritis during treatment with intravenous immunoglobulin (IVIG). A 20-year-old man was diagnosed with XLA 3 months after birth and subsequently received periodic γ-globulin replacement therapy. Renal dysfunction developed at 19 years of age in association with high urinary β2-microglobulin (MG) concentrations. A renal biopsy specimen showed dense CD3-positive lymphocytic infiltration in the tubulointerstitium and tubular atrophy, while no IgG4-bearing cell infiltration was found. Fibrosclerosis and crescent formation were evident in some glomeruli. Fluorescent antibody staining demonstrated deposition of IgG and complement component C3 in tubular basement membranes. After pulse steroid therapy was initiated, urinary β2-MG and serum creatinine concentrations improved. Neither drug reactions nor collagen disease were likely causes of tubular interstitial disorder in this patient. Although BK virus was ruled out, IgG in the γ-globulin preparation might have reacted with a pathogen present in the patient to form low-molecular-weight immune complexes that were deposited in the tubular basement membrane.

  13. [X-linked agammaglobulinemia in adults. Clinical evolution].

    Science.gov (United States)

    Giorgetti, Orlando B; Paolini, María V; Oleastro, Matías M; Fernández Romero, Diego S

    2016-01-01

    X-linked agammaglobulinemia (XLA) is characterized by absent or severely reduced B cells, low or undetectable immunoglobulin levels and clinically by extracellular bacterial infections which mainly compromise the respiratory tract as well as recurrent diarrheas. The mainstay of treatment is gammaglobulin replacement therapy, which allows most patients to reach adulthood with high quality of life. We analyzed the clinical features of 14 patients over 18 years of age with XLA diagnosis that received treatment in our unit from the year 2003, the date the first patient was derived, until 2015. The average age at which patients were referred was 20.4 years old; age at the last consult was 25.5. The average follow-up time was 59.8 months. Previously to being diagnosed all patients had suffered infections, most frequently respiratory. After diagnosis all were started on intravenous gammaglobulin replacement treatment and in spite of infections being reduced in severity and frequency, there were cases of severe disease with long term sequelae. At the beginning of our follow-up 35.7% presented impaired respiratory function with only one case being severe. In no cases during this period did the respiratory function worsen, nor were there severe clinical complications. Three patients were switched to subcutaneous immunoglobulin treatment with good tolerance. The number of XLA cases is increasing, as most reach the second decade of life without serious complications and remain free of severe infectious disease and further impairment of their respiratory functions with the treatment.

  14. Discordant phenotype in siblings with X-linked agammaglobulinemia

    Energy Technology Data Exchange (ETDEWEB)

    Bykowsky, M.J.; Veksler, K.S.; Sullivan, K.E. [Children`s Hospital, Philadelphia, PA (United States)] [and others

    1996-03-01

    X-linked agammaglobulinemia (XLA) is a congenital humoral immunodeficiency caused by a defect in a B-cell-specific signaling molecule, Btk. There has been little concordance of phenotype with genotype in this disorder, and defects in Btk cause immunodeficiencies that range from mild impairment to complete inability to produce antibodies. The factors modifying the phenotype of XLA are not understood. The current study is the first description of two male siblings with identical T{sup 134}{yields}C mutations in the translation initiation ATG of Btk who have different clinical phenotypes as well as different laboratory phenotypes. The proband lacks immunoglobulins and B cells and has recurrent infections, while the elder, affected brother has normal levels of IgG and IgM and very few infections. Both have undetectable levels of Btk kinase activity in circulating mononuclear cells. Complete sequencing of Btk gene transcripts in both brothers revealed no additional mutations to account for the discordant phenotypes. This description provides unequivocal evidence that the phenotype of XLA is influenced by factors additional to the Btk gene. 39 refs., 3 figs., 3 tabs.

  15. Ocular manifestations in the X-linked intellectual disability syndromes.

    Science.gov (United States)

    Couser, Natario L; Masood, Maheer M; Aylsworth, Arthur S; Stevenson, Roger E

    2017-01-01

    Intellectual disability (ID), a common neurodevelopmental disorder characterized by limitations of both intellectual functioning and adaptive behavior, affects an estimated 1-2% of children. Genetic causes of ID are often accompanied by recognizable syndromal patterns. The vision apparatus is a sensory extension of the brain, and individuals with intellectual disabilities frequently have coexisting abnormalities of ocular structures and the visual pathway system. About one-third of the X-linked intellectual disability (XLID) syndromes have significant eye or ocular adnexa abnormalities that provide important diagnostic clues. Some XLID syndromes (e.g. Aicardi, cerebrooculogenital, Graham anophthalmia, Lenz, Lowe, MIDAS) are widely known for their characteristic ocular manifestations. Nystagmus, optic atrophy, and strabismus are among the more common, nonspecific, ocular manifestations that contribute to neuro-ophthalmological morbidity. Common dysmorphic oculofacial findings include anophthalmia, microphthalmia, hypertelorism, and abnormalities in the configuration or orientation of the palpebral fissures. Four XLID syndromes with major ocular manifestations (incontinentia pigmenti, Goltz, MIDAS, and Aicardi syndromes) are notable because of male lethality and expression occurring predominantly in females. The majority of the genes associated with XLID and ocular manifestations have now been identified.

  16. Guillain Barré Syndrome in a Child With X-Linked Adrenoleukodystrophy

    Directory of Open Access Journals (Sweden)

    Ron Jacob MD

    2015-10-01

    Full Text Available X-Linked adrenoleukodystrophy is the most common peroxisomal disorder with different phenotypes among patients carrying the same ABCD1 mutation. There were previously reported associations of X-linked adrenoleukodystrophy with autoimmune disorders. The authors describe Guillain Barré syndrome in a child with X-linked adrenoleukodystrophy. The available evidence does not permit conclusion concerning etiological linkage between the 2 diseases, but it warrants further study.

  17. Guillain Barr? Syndrome in a Child With X-Linked Adrenoleukodystrophy

    OpenAIRE

    Jacob, Ron; Mandel, Hanna; Shehadeh, Naim

    2015-01-01

    X-Linked adrenoleukodystrophy is the most common peroxisomal disorder with different phenotypes among patients carrying the same ABCD1 mutation. There were previously reported associations of X-linked adrenoleukodystrophy with autoimmune disorders. The authors describe Guillain Barré syndrome in a child with X-linked adrenoleukodystrophy. The available evidence does not permit conclusion concerning etiological linkage between the 2 diseases, but it warrants further study.

  18. [X-linked agammaglobulinemia: experience in a Portuguese hospital].

    Science.gov (United States)

    Fernandes, A; Guedes, M; Vasconcelos, J; Neves, E; Fernandes, S; Marques, L

    2015-03-01

    X-Linked agammaglobulinemia (XLA) is characterized by an arrest of B cell differentiation, leading to recurrent bacterial infections. Lifelong immunoglobulin replacement therapy (IRT) is indicated to prevent infections and their complications. A retrospective study of patients with XLA followed in a level three hospital was performed; data was collected retrospectively by review of clinical files. XLA was diagnosed in 9 children. One (11%) had a positive family history with a prenatal diagnosis. Infection was the clinical presentation in all the others (89%), at an average age of 13 months; diagnosis was established at a mean age of 3.4 years. Acute otitis media (7/9) and pneumonia (5/9) were the most frequently observed. Seven (78%) presented serum immunoglobulin G (IgG) levels below 200mg/dL and all of them had CD19(+) B cells below 2%. Neutropenia was present at diagnosis in three patients (33%). Bruton tyrosine kinase (BTK) mutations were identified in all cases. Intravenous IRT was initiated, switched later to subcutaneous administration, in all. The mean time of follow-up was 10.7 years with cumulative time of 97 years. Eight children (89%) achieved IgG serum levels above 800 mg/dL. One presented lower values due to renal loss. No deaths occurred. After diagnosis the most frequent infections were acute otitis media (6/9). In spite of stable adequate IgG levels on IRT, two patients developed bronchiectasis. XLA overall prognosis is good, as long as patients have an early and adequate treatment. However, bronchiectasis can occur even on adequate immunoglobulin replacement therapy. Copyright © 2014 Asociación Española de Pediatría. Published by Elsevier España, S.L.U. All rights reserved.

  19. Altered expression of ALDP in X-linked adrenoleukodystrophy

    Energy Technology Data Exchange (ETDEWEB)

    Watkins, P.A.; Smith, M.A.; Moser, H.W. [John Hopkins Univ. School of Medicine, Baltimore MD (United States)] [and others

    1995-08-01

    X-linked adrenoleukodystrophy (ALD) is a neurodegenerative disorder with variable phenotypic expression that is characterized by elevated plasma and tissue levels of very long-chain fatty acids. However, the product of the gene defective in ALD (ALDP) is a membrane transporter of the ATP-binding cassette family of proteins and is not related to enzymes known to activate or oxidize fatty acids. We generated an antibody that specifically recognizes the C-terminal 18 amino acids of ALDP and can detect ALDP by indirect immunofluorecence. To better understand the mechanism by which mutations in ALDP lead to disease, we used this antibody to examine the subcellular distribution and relative abundance of ALDP in skin fibroblasts from normal individuals and ALD patients. Punctate immunoreactive material typical of fibroblast peroxisomes was observed in cells from seven normal controls and eight non-ALD patients. Of 35 ALD patients tested, 17 had the childhood-onset cerebral form of the disease, 13 had the milder adult phenotype adrenomyeloneuropathy, 3 had adrenal insufficiency only, and 2 were affected fetuses. More than two-thirds (69%) of all patients studied showed no punctate immunoreactive material. There was no correlation between the immunofluorescence pattern and clinical phenotype. We determined the mutation in the ALD gene in 15 of these patients. Patients with either a deletion or frameshift mutation lacked ALDP immunoreactivity, as expected. Four of 11 patients with misense mutations were also immunonegative, indicating that these mutations affected the stability or localization of ALDP. In the seven immunopositive patients with missense mutations, correlation of the location and nature of the amino acid substitution may provide new insights into the function of this peroxisomal membrane protein. Furthermore, the study of female relatives of immunonegative ALD probands may aid in the assessment of heterozygote status. 32 refs., 4 figs., 3 tabs.

  20. A novel deletion mutation in the TUSC3 gene in a consanguineous Pakistani family with autosomal recessive nonsyndromic intellectual disability

    Directory of Open Access Journals (Sweden)

    Ali Nadir

    2011-04-01

    Full Text Available Abstract Background Intellectual disability (ID is a serious disorder of the central nervous system with a prevalence of 1-3% in a general population. In the past decades, the research focus has been predominantly on X-linked ID (68 loci and 19 genes for non syndromic X linked ID while for autosomal recessive nonsyndromic ID (NSID only 30 loci and 6 genes have been reported to date. Methods Genome-wide homozygosity mapping with 500 K Nsp1 array (Affymetrix, CNV analysis, PCR based breakpoint mapping and DNA sequencing was performed to explore the genetic basis of autosomal recessive nonsyndromic ID in a large Pakistani family. Results Data analysis showed linkage at 8p23 locus with common homozygous region between SNPs rs6989820 and rs2237834, spanning a region of 12.494 Mb. The subsequent CNV analysis of the data revealed a homozygous deletion of 170.673 Kb which encompassed the TUSC3 gene. Conclusion We report a novel deletion mutation in TUSC3 gene which is the second gene after TRAPPC9 in which mutation has been identified in more than one family with autosomal recessive NSID. The study will aid in exploring the molecular pathway of cognition.

  1. Sensorineural hearing loss in children.

    LENUS (Irish Health Repository)

    Wormald, R

    2010-02-01

    The objective of the study was to examine the aetiology of sensorineural hearing loss (SNHL) in a paediatric population presenting to the National Centre of Medical Genetics. A retrospective chart review from 1998 to 2006. One hundred and twenty nine children were investigated for SNHL. The average age of diagnosis of hearing loss was 36 months. The degree of hearing loss was mild in 8 children, moderate in 33 children, severe in 31 children and profound in 57 children. Eighty-five children (66%) were diagnosed with a hereditary hearing loss, 11 (8%) children had an acquired hearing loss and no cause found in 33 (26%) children. This is the first report of the causes of hearing loss in Irish children. The mean age of diagnosis in our cohort is high and emphasises the need for a neonatal screening programme. There remains a number of children for whom the cause of hearing loss remains unknown.

  2. Concomitant imaging and genetic findings in children with unilateral sensorineural hearing loss.

    Science.gov (United States)

    Gruber, M; Brown, C; Mahadevan, M; Neeff, M

    2017-08-01

    To describe the concomitant imaging and genetic findings in children diagnosed with non-syndromic unilateral sensorineural hearing loss. A retrospective cohort study was conducted of 60 children diagnosed between January 2005 and December 2015 in a tertiary-level paediatric institution. Average age at diagnosis was 4.3 years. All children were considered non-syndromic. Hearing loss was categorised as mild (17 children), moderate (17 children), severe (7 children) or profound (19 children). Imaging was performed in 43 children (71.66 per cent). Nineteen patients (44.2 per cent) had positive computed tomography or magnetic resonance imaging findings. Genetic testing was performed in 51 children (85 per cent). Sixteen children (31 per cent) tested positive to connexin 26 (GJB2); 1 patient (2 per cent) had a homozygous mutation of GJB2 and 15 were heterozygous carriers. Amongst children who tested positive as heterozygous carriers of a GJB2 mutation, there was a high rate of positive imaging findings (47 per cent compared to 37.2 per cent in the total cohort). A genetic abnormality was confirmed in 50 per cent of children with positive imaging findings who underwent genetic testing. Rates of concomitant imaging and genetic findings suggest that both investigations are of value in the study of these patients.

  3. Refinement of the localization of the X-linked ocular albinism gene

    NARCIS (Netherlands)

    Bergen, A. A.; Zijp, P.; Schuurman, E. J.; Bleeker-Wagemakers, E. M.; Apkarian, P.; van Ommen, G. J.

    1993-01-01

    Although physical and genetic mapping studies assigned the X-linked ocular albinism gene to Xp22.3, the exact gene order in this region is still unclear. We present additional genetic mapping data concerning X-linked ocular albinism that suggests the consensus order Xpter-STS-DXS237-KAL-(OA1,

  4. X-linked hydrocephalus : A novel missense mutation in the L1CAM gene

    NARCIS (Netherlands)

    Sztriha, L; Vos, YJ; Verlind, E; Johansen, J; Berg, B

    2002-01-01

    X-linked hydrocephalus is associated with mutations in the L1 neuronal cell adhesion molecule gene. L1 protein plays a key role in neurite outgrowth, axonal guidance, and pathfinding during the development of the nervous system. A male is described with X-linked hydrocephalus who had multiple small

  5. Mutations in USP9X Are Associated with X-Linked Intellectual Disability and Disrupt Neuronal Cell Migration and Growth

    Science.gov (United States)

    Homan, Claire C.; Kumar, Raman; Nguyen, Lam Son; Haan, Eric; Raymond, F. Lucy; Abidi, Fatima; Raynaud, Martine; Schwartz, Charles E.; Wood, Stephen A.; Gecz, Jozef; Jolly, Lachlan A.

    2014-01-01

    With a wealth of disease-associated DNA variants being recently reported, the challenges of providing their functional characterization are mounting. Previously, as part of a large systematic resequencing of the X chromosome in 208 unrelated families with nonsyndromic X-linked intellectual disability, we identified three unique variants (two missense and one protein truncating) in USP9X. To assess the functional significance of these variants, we took advantage of the Usp9x knockout mouse we generated. Loss of Usp9x causes reduction in both axonal growth and neuronal cell migration. Although overexpression of wild-type human USP9X rescued these defects, all three USP9X variants failed to rescue axonal growth, caused reduced USP9X protein localization in axonal growth cones, and (in 2/3 variants) failed to rescue neuronal cell migration. Interestingly, in one of these families, the proband was subsequently identified to have a microdeletion encompassing ARID1B, a known ID gene. Given our findings it is plausible that loss of function of both genes contributes to the individual's phenotype. This case highlights the complexity of the interpretations of genetic findings from genome-wide investigations. We also performed proteomics analysis of neurons from both the wild-type and Usp9x knockout embryos and identified disruption of the cytoskeleton as the main underlying consequence of the loss of Usp9x. Detailed clinical assessment of all three families with USP9X variants identified hypotonia and behavioral and morphological defects as common features in addition to ID. Together our data support involvement of all three USP9X variants in ID in these families and provide likely cellular and molecular mechanisms involved. PMID:24607389

  6. Discovery of MYH14 as an important and unique deafness gene causing prelingually severe autosomal dominant nonsyndromic hearing loss.

    Science.gov (United States)

    Kim, Bong Jik; Kim, Ah Reum; Han, Jin Hee; Lee, Chung; Oh, Doo Yi; Choi, Byung Yoon

    2017-04-01

    Pathogenic variants of MYH14 are known to be associated (in either a syndromic or nonsyndromic manner) with hearing loss. Interestingly, all reported cases to date of MYH14-related nonsyndromic hearing loss with detailed phenotypes have demonstrated mild-to-moderate progressive hearing loss with postlingual onset. In the present study, targeted resequencing (TRS) of known deafness genes was performed to identify the causative variant in two multiplex families segregating autosomal dominant (AD) inherited hearing loss. TRS uncovered two novel variants of MYH14 (c.A572G: p.Asp191Gly in the myosin head domain and c.C73T:p.Gln25* in exon 2) from two multiplex deafness Korean families. Notably, both probands showed phenotypes of congenital or prelingual severe hearing loss. It is remarkably uncommon to encounter such a severe-to-profound, prelingual, AD hearing loss. Given that the first variant, p. Asp191Gly, was the first documented missense allele discovered in the myosin head domain of this gene related to either congenital or prelingual severe nonsyndromic hearing loss, and also that the second variant, p. Gln25*, lead to a null allele, more severe phenotypes from our probands may have been the result of either genotype-phenotype correlation or genetic backgrounds, or both. In the present study, we report that MYH14 can manifest as nonsyndromic prelingual severe sensorineural hearing loss in an AD fashion in Koreans. The results of the present study suggest that further genetic studies of similar patients should consider MYH14 as a causative gene, and cochlear implantation during infant or early childhood should be indicated for those patients with certain MYH14 pathogenic variants. Copyright © 2017 John Wiley & Sons, Ltd.

  7. Neuroradiological imaging in patients with sensorineural hearing loss prior to cochlear implantation; Neuroradiologische Diagnostik bei Patienten mit sensorineuralem Hoerverlust vor Cochlea-Implantation

    Energy Technology Data Exchange (ETDEWEB)

    Biller, A.; Bartsch, A.; Solymosi, L.; Bendszus, M. [Abteilung fuer Neuroradiologie, Universitaet Wuerzburg (Germany); Knaus, C.; Mueller, J. [Klinik und Poliklinik fuer Hals-, Nasen- und Ohrenkranke, Universitaet Wuerzburg (Germany)

    2007-09-15

    Cochlear implantation (CI) is an established technique for enabling speech perception in patients suffering from severe bilateral sensorineural hearing loss (SNHL). Thorough preoperative radiological assessment is essential for correctly evaluating the indication for surgery and safely performing cochlear implantation. CT and conventional and functional MRI are available for radiological assessment. Therefore, knowledge of the most frequent congenital syndromal, non-syndromal, and acquired malformations of inner ear structures is fundamental. This article provides information about imaging techniques prior to CI and relevant malformations of the inner ear. Safety aspects for patients with a cochlear implant undergoing MR imaging are also discussed. (orig.)

  8. Hearing Disorders and Sensorineural Aging

    Directory of Open Access Journals (Sweden)

    Alessandra Fioretti

    2014-01-01

    Full Text Available The physiological age-related hearing loss is defined as presbycusis and it is characterized by reduced hearing sensitivity and problems in understanding spoken language especially in a noisy environment. In elderly the reduced speech recognition is generally caused by a reduction of the cochlear cells in the organ of Corti and degeneration of the central auditory pathways. In order to have a complete management strategy of central and peripheral presbycusis the diagnostic evaluation should include clinical ENT examination, standard audiological tests, and tests of central auditory function. Treatment should include not only the appropriate instruments for peripheral compensation but also auditory rehabilitative training and counseling to prevent social isolation and loss of autonomy. Other common hearing disorders in elderly are tinnitus and hyperacusis which are often undervalued. Tinnitus is characterized by the perception of a “phantom” sound due to abnormal auditory perception. Hyperacusis is defined as a reduced tolerance to ordinary environmental sounds. Furthermore auditory, visual, nociceptive, and proprioceptive systems may be involved together in a possible context of “sensorineural aging.” The aim of this review is to underline the presence of hearing disorders like tinnitus and hyperacusis which in many cases coexist with hearing loss in elderly.

  9. Bilateral sudden sensorineural hearing loss: review.

    Science.gov (United States)

    Sara, S A; Teh, B M; Friedland, P

    2014-01-01

    Unilateral and bilateral sudden sensorineural hearing loss represent different disease entities. The unilateral condition is more common and predominantly idiopathic, and up to 65 per cent of patients spontaneously recover hearing. Conversely, the bilateral condition is rare, mostly associated with serious systemic conditions, and has a higher prevalence of morbidity and mortality. A literature search using the PubMed database was conducted using the MeSH terms 'sudden', 'bilateral' and 'sensorineural hearing loss'. One hundred and three reported cases of bilateral sudden sensorineural hearing loss were identified. The condition is most often associated with toxic, autoimmune, neoplastic and vascular conditions. A younger age of onset, with a bimodal age distribution, was seen for bilateral sudden sensorineural hearing loss, compared with the unilateral condition. Patients with the bilateral condition had more profound hearing loss, with poorer recovery and a 35 per cent mortality rate. Vestibular symptoms were also less common than in the unilateral condition. The presentation of bilateral sudden onset sensorineural hearing loss is a medical emergency requiring thorough and urgent investigation to exclude life-threatening and reversible conditions.

  10. X-linked adrenoleukodystrophy in women: a cross-sectional cohort study.

    Science.gov (United States)

    Engelen, Marc; Barbier, Mathieu; Dijkstra, Inge M E; Schür, Remmelt; de Bie, Rob M A; Verhamme, Camiel; Dijkgraaf, Marcel G W; Aubourg, Patrick A; Wanders, Ronald J A; van Geel, Bjorn M; de Visser, Marianne; Poll-The, Bwee T; Kemp, Stephan

    2014-03-01

    X-linked adrenoleukodystrophy is the most common peroxisomal disorder. The disease is caused by mutations in the ABCD1 gene that encodes the peroxisomal transporter of very long-chain fatty acids. A defect in the ABCD1 protein results in elevated levels of very long-chain fatty acids in plasma and tissues. The clinical spectrum in males with X-linked adrenoleukodystrophy has been well described and ranges from isolated adrenocortical insufficiency and slowly progressive myelopathy to devastating cerebral demyelination. As in many X-linked diseases, it was assumed that female carriers remain asymptomatic and only a few studies addressed the phenotype of X-linked adrenoleukodystrophy carriers. These studies, however, provided no information on the prevalence of neurological symptoms in the entire population of X-linked adrenoleukodystrophy carriers, since data were acquired in small groups and may be biased towards women with symptoms. Our primary goal was to investigate the symptoms and their frequency in X-linked adrenoleukodystrophy carriers. The secondary goal was to determine if the X-inactivation pattern of the ABCD1 gene was associated with symptomatic status. We included 46 X-linked adrenoleukodystrophy carriers in a prospective cross-sectional cohort study. Our data show that X-linked adrenoleukodystrophy carriers develop signs and symptoms of myelopathy (29/46, 63%) and/or peripheral neuropathy (26/46, 57%). Especially striking was the occurrence of faecal incontinence (13/46, 28%). The frequency of symptomatic women increased sharply with age (from 18% in women 60 years of age). Virtually all (44/45, 98%) X-linked adrenoleukodystrophy carriers had increased very long-chain fatty acids in plasma and/or fibroblasts, and/or decreased very long-chain fatty acids beta-oxidation in fibroblasts. We did not find an association between the X-inactivation pattern and symptomatic status. We conclude that X-linked adrenoleukodystrophy carriers develop an

  11. Bilateral macular holes in X-linked retinoschisis: Now the spectrum is wider

    Directory of Open Access Journals (Sweden)

    Manoj Gautam

    2011-01-01

    Full Text Available Bilateral occurrence of macular hole in X-linked retinoschisis is an extremely rare event. Spectral domain optical coherence tomography (OCT findings revealed that formation of a macular hole is secondary to the retinoschisis process alone. Bilateral macular holes should be added to the spectrum of X-linked retinoschisis variations and the retinoschisis process alone should be accounted for their formation.

  12. Supernumerary teeth in non-syndromic patients

    OpenAIRE

    Mali, Santosh; Karjodkar, Freny Rashmiraj; Sontakke, Subodh; Sansare, Kaustubh

    2012-01-01

    Hyperdontia or supernumerary teeth without associated syndrome is a rare phenomenon, as supernumerary teeth are usually associated with cleft lip and palate or other syndromes such as Gardner's syndrome, cleidocranial dysplasia, and so on. Five patients with supernumerary teeth visited our department. They had no familial history or other pathology, certain treatment protocols was modified due to the presence of supernumerary teeth. Non-syndromic supernumerary teeth, if asymptomatic, need to ...

  13. X-linked ichthyosis associated with psychosis and behavioral abnormalities: a case report.

    Science.gov (United States)

    Malik, Amna; Amer, Ahmed Bait; Salama, Mohammed; Haddad, Bander; Alrifai, Muhammad T; Balwi, Mohammed Al; Davies, William; Eyaid, Wafaa

    2017-09-22

    X-linked ichthyosis is a dermatological condition caused by deficiency for the enzyme steroid sulfatase. Previously, X-linked ichthyosis/steroid sulfatase deficiency has been associated with developmental and neurological phenotypes. Here, we show for the first time, that X-linked ichthyosis may be comorbid with an additional psychiatric phenotype (psychosis). We report the case of an 11-year-old Saudi Arabian boy with X-linked ichthyosis associated with psychosis, mental retardation, autism spectrum disorder, inattentive attention deficit hyperactivity disorder, and epilepsy. Genetic analysis revealed a 1.68 Mb deletion encompassing STS in 95% of cells while biochemical analysis revealed correspondingly low steroid sulfatase activity consistent with a diagnosis of X-linked ichthyosis. The psychotic symptoms could be reasonably well controlled by administration of an atypical antipsychotic. This report describes a case of comorbid X-linked ichthyosis and psychosis (most closely corresponding to early-onset schizophrenia) for the first time, and suggests that deficiency for steroid sulfatase and contiguous genes may increase vulnerability to psychosis as well as other psychological disorders.

  14. Mutation analysis of SLC26A4 for Pendred syndrome and nonsyndromic hearing loss by high-resolution melting

    DEFF Research Database (Denmark)

    Chen, Neng; Tranebjærg, Lisbeth; Rendtorff, Nanna Dahl

    2011-01-01

    Pendred syndrome and DFNB4 (autosomal recessive nonsyndromic congenital deafness, locus 4) are associated with autosomal recessive congenital sensorineural hearing loss and mutations in the SLC26A4 gene. Extensive allelic heterogeneity, however, necessitates analysis of all exons and splice sites...... to identify mutations for individual patients. Although Sanger sequencing is the gold standard for mutation detection, screening methods supplemented with targeted sequencing can provide a cost-effective alternative. One such method, denaturing high-performance liquid chromatography, was developed...... for clinical mutation detection in SLC26A4. However, this method inherently cannot distinguish homozygous changes from wild-type sequences. High-resolution melting (HRM), on the other hand, can detect heterozygous and homozygous changes cost-effectively, without any post-PCR modifications. We developed...

  15. Preliminary Evidence for Aortopathy and an X-Linked Parent-of-Origin Effect on Aortic Valve Malformation in a Mouse Model of Turner Syndrome

    Directory of Open Access Journals (Sweden)

    Robert B. Hinton

    2015-07-01

    Full Text Available Turner syndrome (TS, most frequently caused by X-monosomy (45,X, is characterized in part by cardiovascular abnormalities, including aortopathy and bicuspid aortic valve (BAV. There is a need for animal models that recapitulate the cardiovascular manifestations of TS. Extracellular matrix (ECM organization and morphometrics of the aortic valve and proximal aorta were examined in adult 39,XO mice (where the parental origin of the single X was paternal (39,XPO or maternal (39,XMO and 40,XX controls. Aortic valve morphology was normal (tricuspid in all of the 39,XPO and 40,XX mice studied, but abnormal (bicuspid or quadricuspid in 15% of 39,XMO mice. Smooth muscle cell orientation in the ascending aorta was abnormal in all 39,XPO and 39,XMO mice examined, but smooth muscle actin was decreased in 39,XMO mice only. Aortic dilation was present with reduced penetrance in 39,XO mice. The 39,XO mouse demonstrates aortopathy and an X-linked parent-of-origin effect on aortic valve malformation, and the candidate gene FAM9B is polymorphically expressed in control and diseased human aortic valves. The 39,XO mouse model may be valuable for examining the mechanisms underlying the cardiovascular findings in TS, and suggest there are important genetic modifiers on the X chromosome that modulate risk for nonsyndromic BAV and aortopathy.

  16. Genetic Determinants of Non-syndromic Hearing Impairment

    NARCIS (Netherlands)

    R.L.P. Santos (Regie)

    2006-01-01

    textabstractCongenital hearing impairment (HI) affects 1-2 per 1000 neonates, of which half would be genetic in etiology. Of the genetic cases, 70% would be non-syndromic in nature. To date ~120 non-syndromic (NS) HI loci have been mapped, for which 39 NSHI genes have been identified. For the

  17. Is the extracellular ATP a key in X-linked Charcot-Marie-Tooth disease and in inherited non-syndromic deafness?

    OpenAIRE

    Mas del Molino, Ezequiel

    2011-01-01

    [spa] El ATP es una molécula ampliamente conocida por su papel en muchas funciones como la homeostasis celular, el mantenimiento de gradientes iónicos, el mantenimiento del pH en gránulos secretores, el almacenamiento energético, regulador de la interacción actina-miosina, etc. Además, el ATP puede actuar como molécula señalizadora a través de los receptores purinérgicos P2. De receptores P2 hay de dos tipos, los P2X, que son ionotrópicos, y los P2Y que son metabotrópicos. Los primeros son un...

  18. IRF6 mutation screening in non-syndromic orofacial clefting

    DEFF Research Database (Denmark)

    Leslie, Elizabeth J; Koboldt, Daniel C; Kang, C. J.

    2016-01-01

    -syndromic OFCs. About 70% of causal VWS mutations occur in IRF6, a gene that is also associated with non-syndromic OFCs. Screening for IRF6 mutations in apparently non-syndromic cases has been performed in several modestly sized cohorts with mixed results. In this study, we screened 1521 trios with presumed non......-syndromic OFCs to determine the frequency of causal IRF6 mutations. We identified seven likely causal IRF6 mutations, although a posteriori review identified two misdiagnosed VWS families based on the presence of lip pits. We found no evidence for association between rare IRF6 polymorphisms and non......-syndromic OFCs. We combined our results with other similar studies (totaling 2472 families) and conclude that causal IRF6 mutations are found in 0.24–0.44% of apparently non-syndromic OFC families. We suggest that clinical mutation screening for IRF6 be considered for certain family patterns such as families...

  19. Sudden (reversible) sensorineural hearing loss in pregnancy.

    LENUS (Irish Health Repository)

    Kenny, R

    2011-03-01

    Sudden hearing loss directly associated with pregnancy or birth is a little known and rare occurrence. The temporary, unilateral, low-frequency sensorineural hearing loss in this case was reported after the birth of the patient\\'s first child, and again during the third trimester of her second pregnancy.

  20. XLPRA: A canine retinal degeneration inherited as an X-linked trait

    Energy Technology Data Exchange (ETDEWEB)

    Acland, G.M.; Blanton, S.H.; Hershfield, B.; Aguirre, G.D.

    1994-08-01

    Breeding studies are reported of a previously undescribed hereditary retinal degeneration identified in the Siberian Husky breed of dog. This disorder clinically resembles the previously reported autosomal recessive canine hereditary retinal degenerations collectively termed progressive retinal atrophy (PRA). However, the pedigree of the propositus, a male Siberian Husky, exhibited an X-linked pattern of transmission. This dog was outcrossed to three phenotypically normal female laboratory Beagles and two of their F1 daughters were bred to a phenotypically normal male Beagle, producing affected males in the F2 generation. Subsequent inbreedings produced further affected males and affected females as well. X-linked transmission was established by exclusion of alternative modes of inheritance and, consequently, the disease has been termed X-linked progressive retinal atrophy (XLPRA). This is the first reported X-linked retinal degeneration in an animal. Because of the many similarities of PRA in dogs to retinitis pigmentosa (RP) in humans, this new disease may not only represent the first animal model of X-linked RP (XLRP) but may well be a true homolog of one of the XLRP loci (RP2, RP3, RP6). It is the first retinal degeneration in dogs that can be assigned to an identified canine chromosome, and the first for which linkage mapping offers a realistic approach to proceed by positional cloning towards identifying the responsible gene. 58 refs., 1 fig., 3 tabs.

  1. A novel mutation of EYA4 in a large Chinese family with autosomal dominant middle-frequency sensorineural hearing loss by targeted exome sequencing.

    Science.gov (United States)

    Sun, Yi; Zhang, Zhao; Cheng, Jing; Lu, Yu; Yang, Chang-Liang; Luo, Yan-Yun; Yang, Guang; Yang, Hui; Zhu, Li; Zhou, Jia; Yao, Hang-Qi

    2015-06-01

    The middle-frequency sensorineural hearing loss (MFSNHL) is rare among hereditary non-syndromic hearing loss. To date, only three genes are reported to be associated with MFSNHL, including TECTA, EYA4 and COL11A2. In this report, we analyzed and explored the clinical audiological characteristics and the causative gene of a Chinese family named HG-Z087 with non-syndromic autosomal dominant inherited MFSNHL. Clinical audiological characteristics and inheritance pattern of a family were evaluated, and pedigree was drawn based on medical history investigation. Our results showed that the Chinese family was characterized by late onset, progressive, non-sydromic autosomal dominant MFSNHL. Targeted exome sequencing, conducted using DNA samples of an affected member in this family, revealed a novel heterozygous missense mutation c.1643C>G in exon 18 of EYA4, causing amino-acid (aa) substitution Arg for Thr at a conserved position aa-548. The p.T548R mutation related to hearing loss in the selected Chinese family was validated by Sanger sequencing. However, the mutation was absent in control group containing 100 DNA samples from normal Chinese families. In conclusion, we identified the pathogenic gene and found that the novel missense mutation c.1643C>G (p.T548R) in EYA4 might have caused autosomal dominant non-syndromic hearing impairment in the selected Chinese family.

  2. Discovery of CDH23 as a Significant Contributor to Progressive Postlingual Sensorineural Hearing Loss in Koreans.

    Directory of Open Access Journals (Sweden)

    Bong Jik Kim

    Full Text Available CDH23 mutations have mostly been associated with prelingual severe-to-profound sensorineural hearing loss (SNHL in either syndromic or nonsyndromic SNHL (DFNB12. Herein, we demonstrate the contribution of CDH23 mutations to postlingual nonsyndromic SNHL (NS-SNHL. We screened 32 Korean adult probands with postlingual NS-SNHL sporadically or in autosomal recessive fashion using targeted panel or whole exome sequencing. We identified four (12.5%, 4/32 potential postlingual DFNB12 families that segregated the recessive CDH23 variants, qualifying for our criteria along with rapidly progressive SNHL. Three of the four families carried one definite pathogenic CDH23 variant previously known as the prelingual DFNB12 variant in a trans configuration with rare CDH23 variants. To determine the contribution of rare CDH23 variants to the postlingual NS-SNHL, we checked the minor allele frequency (MAF of CDH23 variants detected from our postlingual NS-SNHL cohort and prelingual NS-SNHL cohort, among the 2040 normal control chromosomes. The allele frequency of these CDH23 variants in our postlingual cohort was 12.5%, which was significantly higher than that of the 2040 control chromosomes (5.53%, confirming the contribution of these rare CDH23 variants to postlingual NS-SNHL. Furthermore, MAF of rare CDH23 variants from the postlingual NS-SNHL group was significantly higher than that from the prelingual NS-SNHL group. This study demonstrates an important contribution of CDH23 mutations to poslingual NS-SNHL and shows that the phenotypic spectrum of DFNB12 can be broadened even into the presbycusis, depending on the pathogenic potential of variants. We also propose that pathogenic potential of CDH23 variants and the clinical fate of DFNB12 may be predicted by MAF.

  3. Drosophila X-Linked Genes Have Lower Translation Rates than Autosomal Genes.

    Science.gov (United States)

    Zhang, Zhenguo; Presgraves, Daven C

    2016-02-01

    In Drosophila, X-linked and autosomal genes achieve comparable expression at the mRNA level. Whether comparable X-autosome gene expression is realized at the translational and, ultimately, the protein levels is, however, unknown. Previous studies suggest the possibility of higher translation rates for X-linked genes owing to stronger usage of preferred codons. In this study, we use public ribosome profiling data from Drosophila melanogaster to infer translation rates on the X chromosome versus the autosomes. We find that X-linked genes have consistently lower ribosome densities than autosomal genes in S2 cells, early embryos, eggs, and mature oocytes. Surprisingly, the lower ribosome densities of X-linked genes are not consistent with faster translation elongation but instead imply slower translation initiation. In particular, X-linked genes have sequence features known to slow translation initiation such as stronger mRNA structure near start codons and longer 5'-UTRs. Comparison to outgroup species suggests that stronger mRNA structure is an evolved feature of Drosophila X chromosomes. Finally, we find that the magnitude of the X-autosome difference in ribosome densities is smaller for genes encoding members of protein complexes, suggesting that stoichiometry constrains the evolution of translation rates. In sum, our analyses suggest that Drosophila X-linked genes have evolved lower translation rates than autosomal genes despite stronger usage of preferred codons. © The Author 2015. Published by Oxford University Press on behalf of the Society for Molecular Biology and Evolution. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

  4. Screening for X-linked adrenoleukodystrophy among adult men with Addison's disease.

    Science.gov (United States)

    Horn, Morten A; Erichsen, Martina M; Wolff, Anette S B; Månsson, Jan-Eric; Husebye, Eystein S; Tallaksen, Chantal M E; Skjeldal, Ola H

    2013-09-01

    X-linked adrenoleukodystrophy is an important cause of Addison's disease in boys, but less is known about its contribution to Addison's disease in adult men. After surveying all known cases of X-linked adrenoleukodystrophy in Norway in a separate study, we aimed to look for any missed cases among the population of adult men with nonautoimmune Addison's disease. Among 153 adult men identified in a National Registry for Addison's Disease (75% of identified male cases of Addison's disease in Norway), those with negative indices for 21-hydroxylase autoantibodies were selected. Additionally, cases with low autoantibody indices (48-200) were selected. Sera from subjects included were analysed for levels of very long-chain fatty acids, which are diagnostic for X-linked adrenoleukodystrophy in men. Eighteen subjects had negative indices and 17 had low indices for 21-hydroxylase autoantibodies. None of those with low indices and only one of those with negative indices were found to have X-linked adrenoleukodystrophy; this subject had already been diagnosed because of the neurological symptoms. Cases of Addison's disease proved to be caused by X-linked adrenoleukodystrophy constitute 1·5% of all adult male cases in Norway; the proportion among nonautoimmune cases was 15%. We found X-linked adrenoleukodystrophy to be an uncommon cause of Addison's disease in adult men. However, this aetiological diagnosis has far-reaching consequences both for the patient and for his extended family. We therefore recommend that all adult men with nonautoimmune Addison's disease be analysed for levels of very long-chain fatty acids. © 2013 John Wiley & Sons Ltd.

  5. Oxidative stress modulates mitochondrial failure and cyclophilin D function in X-linked adrenoleukodystrophy.

    Science.gov (United States)

    López-Erauskin, Jone; Galino, Jorge; Bianchi, Patrizia; Fourcade, Stéphane; Andreu, Antoni L; Ferrer, Isidre; Muñoz-Pinedo, Cristina; Pujol, Aurora

    2012-12-01

    A common process associated with oxidative stress and severe mitochondrial impairment is the opening of the mitochondrial permeability transition pore, as described in many neurodegenerative diseases. Thus, inhibition of mitochondrial permeability transition pore opening represents a potential target for inhibiting mitochondrial-driven cell death. Among the mitochondrial permeability transition pore components, cyclophilin D is the most studied and has been found increased under pathological conditions. Here, we have used in vitro and in vivo models of X-linked adrenoleukodystrophy to investigate the relationship between the mitochondrial permeability transition pore opening and redox homeostasis. X-linked adrenoleukodystrophy is a neurodegenerative condition caused by loss of function of the peroxisomal ABCD1 transporter, in which oxidative stress plays a pivotal role. In this study, we provide evidence of impaired mitochondrial metabolism in a peroxisomal disease, as fibroblasts in patients with X-linked adrenoleukodystrophy cannot survive when forced to rely on mitochondrial energy production, i.e. on incubation in galactose. Oxidative stress induced under galactose conditions leads to mitochondrial damage in the form of mitochondrial inner membrane potential dissipation, ATP drop and necrotic cell death, together with increased levels of oxidative modifications in cyclophilin D protein. Moreover, we show increased expression levels of cyclophilin D in the affected zones of brains in patients with adrenomyeloneuropathy, in spinal cord of a mouse model of X-linked adrenoleukodystrophy (Abcd1-null mice) and in fibroblasts from patients with X-linked adrenoleukodystrophy. Notably, treatment with antioxidants rescues mitochondrial damage markers in fibroblasts from patients with X-linked adrenoleukodystrophy, including cyclophilin D oxidative modifications, and reverses cyclophilin D induction in vitro and in vivo. These findings provide mechanistic insight into the

  6. Functional assessment of allelic variants in the SLC26A4 gene involved in Pendred syndrome and nonsyndromic EVA

    Science.gov (United States)

    Pera, Alejandra; Dossena, Silvia; Rodighiero, Simona; Gandía, Marta; Bottà, Guido; Meyer, Giuliano; Moreno, Felipe; Nofziger, Charity; Hernández-Chico, Concepción; Paulmichl, Markus

    2008-01-01

    Pendred syndrome is an autosomal recessive disorder characterized by sensorineural hearing loss, with malformations of the inner ear, ranging from enlarged vestibular aqueduct (EVA) to Mondini malformation, and deficient iodide organification in the thyroid gland. Nonsyndromic EVA (ns-EVA) is a separate type of sensorineural hearing loss showing normal thyroid function. Both Pendred syndrome and ns-EVA seem to be linked to the malfunction of pendrin (SLC26A4), a membrane transporter able to exchange anions between the cytosol and extracellular fluid. In the past, the pathogenicity of SLC26A4 missense mutations were assumed if the mutations fulfilled two criteria: low incidence of the mutation in the control population and substitution of evolutionary conserved amino acids. Here we show that these criteria are insufficient to make meaningful predictions about the effect of these SLC26A4 variants on the pendrin-induced ion transport. Furthermore, we functionally characterized 10 missense mutations within the SLC26A4 ORF, and consistently found that on the protein level, an addition or omission of a proline or a charged amino acid in the SLC26A4 sequence is detrimental to its function. These types of changes may be adequate for predicting SLC26A4 functionality in the absence of direct functional tests. PMID:19017801

  7. Management of Red Teeth in an International Patient with X-Linked Adrenoleukodystrophy.

    Science.gov (United States)

    Petrova, Elena; Miller, Weston P; Myers, Sandra L; Karp, Jeffrey M

    2015-01-01

    Childhood cerebral X-linked adrenoleukodystrophy is a progressive, central nervous system, and endocrine disorder that typically leads to total neurologic disability and, eventually, death without appropriate, timely medical therapy. Hematopoietic stem cell transplantation has been found effective in slowing cerebral deterioration and improving long-term survival. The purpose of this case report was to describe the multidisciplinary management of red, discolored, pulpally treated primary molars identified in a nine-year-old Russian boy with childhood cerebral X-linked adrenoleukodystrophy preparing for myeloablative conditioning chemotherapy followed by hematopoietic stem cell transplantation.

  8. X-linked Agammaglobulinemia With Normal Immunoglobulin and Near-Normal Vaccine Seroconversion.

    Science.gov (United States)

    Preece, Kahn; Lear, Graeme

    2015-12-01

    We present a 22-month-old boy with X-linked agammaglobulinemia masked by normal immunoglobulin levels and vaccine seroconversion. Diagnosis was made after strong clinical suspicion of immune deficiency led to identification of markedly reduced B-cell numbers and confirmation with identification of a novel Bruton tyrosine kinase gene mutation. He was commenced on replacement immunoglobulin therapy with excellent clinical improvement. This case highlights the variability of phenotypic presentation and apparent disunity between routine immunologic investigations and severe disease in X-linked agammaglobulinemia, necessitating clinical acumen to make the diagnosis. Copyright © 2015 by the American Academy of Pediatrics.

  9. Signalling through FOXP3 as an X-linked Tumor Suppressor

    Science.gov (United States)

    Katoh, Hiroto; Zheng, Pan; Liu, Yang

    2010-01-01

    The FOXP3 (forkhead box P3) gene is a member of forkhead winged helix family transcription factors and functions as both a transcriptional activator and a repressor. FOXP3 dysfunction is responsible for an X-linked autoimmune syndrome: immune dysregulation, polyendopathy, enterophathy, X-linked syndrome. In addition to its role as an essential transcription factor in regulatory T cells, the FOXP3 gene is an epithelial cell-intrinsic tumor suppressor for breast and prostate cancers. We will focus on the FOXP3 signalling pathway in epithelial cells and discuss how genetic and/or epigenetic inactivation of the FOXP3 contributes to the malignant transformation of cells. PMID:20678582

  10. Gd enhanced MRI in sensorineural hearing loss

    Energy Technology Data Exchange (ETDEWEB)

    Takenaka, Mika; Tono, Tetsuya; Toyama, Katsuhiro; Kano, Kiyo; Morimitsu, Tamotsu [Miyazaki Medical Coll., Kiyotake (Japan)

    1996-09-01

    The enhanced MRI hearing findings of the inner ear in 124 patients with sensorineural hearing loss were evaluated. MR images were obtained before and after the intravenous administration of gadolinium (0.1 mmol/kg). In three out of seventy-nine patients with unilateral healing loss, cochlear and/or the vestibular enhancement was noted on the symptomatic side. The positive cases included those with Ramsay-Hunt syndrome, mumps and so-called sudden deafness. Forty-five patients with bilateral hearing loss showed no enhancement within the inner ear. Although positive gadolinium enhancement of the inner ear may detect inflammatory lesions due to a viral infection, its incidence in sensorineural hearing loss, including cases of sudden deafness. seems to be extremely rare. (author)

  11. Sudden Sensorineural Hearing Loss; Prognostic Factors

    OpenAIRE

    Arjun, Dass; Neha, Goel; Surinder K, Singhal; Ravi, Kapoor

    2015-01-01

    Introduction: Sudden sensorineural hearing loss (SSNHL) is a frightening and frustrating symptom for the patient as well as the physician. Prognosis is affected by multiple factors including duration of hearing loss, presence of associated vertigo and tinnitus, and co-morbidities such as hypertension and diabetes.   Materials and Methods: Forty subjects presenting to our department with features of sudden hearing loss were included in the study. Detailed otological history and examination, se...

  12. Complex Treatment of Sensorineural Hearing Loss

    OpenAIRE

    Aleksandruk, N. V.

    2014-01-01

    Recent data on use of Ginkgo Biloba extract in otorhinolaryngological practice were presented. The mechanism of the curative action of Ginkgo Biloba extract (vasoprotective, antioxidative, rheological, and edematous) was described. Effectiveness of Ginkgo Biloba as a part of complex treatment of sensorineural hearing loss in children was elucidated. Results of the research proved effectiveness of treatment with Ginkgo Biloba and showed perspectives of Ginkgo Biloba use in treatment programs f...

  13. Sensorineural hearing loss after magnetic resonance imaging

    DEFF Research Database (Denmark)

    Mollasadeghi, Abolfazl; Mehrparvar, Amir Houshang; Atighechi, Saeid

    2013-01-01

    Magnetic resonance imaging (MRI) devices produce noise, which may affect patient's or operators' hearing. Some cases of hearing impairment after MRI procedure have been reported with different patterns (temporary or permanent, unilateral or bilateral, with or without other symptoms like tinnitus......). In this report, a case of bilateral sensorineural hearing loss in an otherwise healthy patient underwent brain MRI was described. The patient's hearing loss was accompanied with tinnitus and was not improved after 3 months of followup....

  14. X-Linked Deafness in a South African Kindred | Thorpe | South ...

    African Journals Online (AJOL)

    The X-linked deafness of Nance is present in a South African kindred. Recognition of the familial pattern of the disorder, together with the characteristic clinical and audiometric features, permits diagnostic precision, thereby facilitating accurate genetic counselling and rational management. Linkage studies indicated that the ...

  15. Mutations in X-linked PORCN, a putative regulator of Wnt signaling, cause focal dermal hypoplasia

    Science.gov (United States)

    Focal dermal hypoplasia is an X-linked dominant disorder characterized by patchy hypoplastic skin and digital, ocular, and dental malformations. We used array comparative genomic hybridization to identify a 219-kb deletion in Xp11.23 in two affected females. We sequenced genes in this region and fou...

  16. X-Linked Lymphoproliferative Disease Presenting as Pancytopenia in a 10-Month-Old Boy

    Directory of Open Access Journals (Sweden)

    S. Nicole Chadha

    2010-01-01

    Full Text Available X-linked lymphoproliferative disease, also known as Duncan's syndrome, is a rare genetic disorder that causes exaggerated immune responses to Epstein-Barr virus (EBV infection and often leads to death. Patient presentation varies but can include signs and symptoms typical of EBV, pancytopenia, and fulminant hepatitis.

  17. Exonization of a LINE1 fragment implicated in X-linked hypohidrotic ectodermal dysplasia in cattle

    DEFF Research Database (Denmark)

    Karlskov-Mortensen, Peter; Cirera Salicio, Susanna; Nielsen, Ole Lerberg

    2011-01-01

    A case of X-linked hypohidrotic ectodermal dysplasia (XHED) was identified in a family of Danish Red Holstein cattle. The ectodysplasin-signalling protein (EDA) is known to be central in the normal development of ectodermal structures, and mutations in the ectodysplasin A (EDA) gene have been rep...

  18. X-linked hypomyelination with spondylometaphyseal dysplasia (H-SMD) associated with mutations in AIFM1

    NARCIS (Netherlands)

    Miyake, Noriko; Wolf, Nicole I.; Cayami, Ferdy K.; Crawford, Joanna; Bley, Annette; Bulas, Dorothy; Conant, Alex; Bent, Stephen J.; Gripp, Karen W.; Hahn, Andreas; Humphray, Sean; Kimura-Ohba, Shihoko; Kingsbury, Zoya; Lajoie, Bryan R.; Lal, Dennis; Micha, Dimitra; Pizzino, Amy; Sinke, Richard J.; Sival, Deborah; Stolte-Dijkstra, Irene; Superti-Furga, Andrea; Ulrick, Nicole; Taft, Ryan J.; Ogata, Tsutomu; Ozono, Keiichi; Matsumoto, Naomichi; Neubauer, Bernd A.; Simons, Cas; Vanderver, Adeline

    2017-01-01

    An X-linked condition characterized by the combination of hypomyelinating leukodystrophy and spondylometaphyseal dysplasia (H-SMD) has been observed in only four families, with linkage to Xq25-27, and recent genetic characterization in two families with a common AIFM1 mutation. In our study, 12

  19. Skin barrier properties in patients with recessive X-linked ichthyosis

    DEFF Research Database (Denmark)

    Johansen, J D; Ramsing, D; Vejlsgaard, G

    1995-01-01

    Patients with X-linked recessive ichthyosis (RXLI) were studied as a model of the effect of disturbed epidermal lipid composition on skin barrier function. Thirteen patients with RXLI and 15 age- and sex-matched controls were patch-tested with sodium lauryl sulphate (SLS) 0.5% for 24 h. Basal skin...

  20. Pioglitazone halts axonal degeneration in a mouse model of X-linked adrenoleukodystrophy

    Science.gov (United States)

    Morató, Laia; Galino, Jorge; Ruiz, Montserrat; Calingasan, Noel Ylagan; Starkov, Anatoly A.; Dumont, Magali; Naudí, Alba; Martínez, Juan José; Aubourg, Patrick; Portero-Otín, Manuel; Pamplona, Reinald; Galea, Elena; Beal, M. Flint; Ferrer, Isidre; Fourcade, Stéphane

    2013-01-01

    X-linked adrenoleukodystrophy is a neurometabolic disorder caused by inactivation of the peroxisomal ABCD1 transporter of very long-chain fatty acids. In mice, ABCD1 loss causes late onset axonal degeneration in the spinal cord in association with locomotor disability resembling the most common phenotype in patients, adrenomyeloneuropathy. Increasing evidence indicates that oxidative stress and bioenergetic failure play major roles in the pathogenesis of X-linked adrenoleukodystrophy. In this study, we aimed to evaluate whether mitochondrial biogenesis is affected in X-linked adrenoleukodystrophy. We demonstrated that Abcd1 null mice show reduced mitochondrial DNA concomitant with downregulation of mitochondrial biogenesis pathway driven by PGC-1α/PPARγ and reduced expression of mitochondrial proteins cytochrome c, NDUFB8 and VDAC. Moreover, we show that the oral administration of pioglitazone, an agonist of PPARγ, restored mitochondrial content and expression of master regulators of biogenesis, neutralized oxidative damage to proteins and DNA, and reversed bioenergetic failure in terms of ATP levels, NAD+/NADH ratios, pyruvate kinase and glutathione reductase activities. Most importantly, the treatment halted locomotor disability and axonal damage in X-linked adrenoleukodystrophy mice. These results lend support to the use of pioglitazone in clinical trials with patients with adrenomyeloneuropathy and reveal novel molecular mechanisms of action of pioglitazone in neurodegeneration. Future studies should address the effects of this anti-diabetic drug on other axonopathies in which oxidative stress and mitochondrial dysfunction are contributing factors. PMID:23794606

  1. X-linked adrenoleukodystrophy in women: a cross-sectional cohort study

    NARCIS (Netherlands)

    Engelen, Marc; Barbier, Mathieu; Dijkstra, Inge M. E.; Schür, Remmelt; de Bie, Rob M. A.; Verhamme, Camiel; Dijkgraaf, Marcel G. W.; Aubourg, Patrick A.; Wanders, Ronald J. A.; van Geel, Bjorn M.; de Visser, Marianne; Poll-The, Bwee T.; Kemp, Stephan

    2014-01-01

    X-linked adrenoleukodystrophy is the most common peroxisomal disorder. The disease is caused by mutations in the ABCD1 gene that encodes the peroxisomal transporter of very long-chain fatty acids. A defect in the ABCD1 protein results in elevated levels of very long-chain fatty acids in plasma and

  2. X-Linked Adrenoleukodystrophy: Molecular and Functional Analysis of the ABCD1 Gene in Argentinean Patients

    NARCIS (Netherlands)

    Amorosi, Cyntia Anabel; Myskóva, Helena; Monti, Mariela Roxana; Argaraña, Carlos Enrique; Morita, Masashi; Kemp, Stephan; Dodelson de Kremer, Raquel; Dvoráková, Lenka; Oller de Ramírez, Ana María

    2012-01-01

    X-linked adrenoleukodystrophy (X-ALD) is an inherited metabolic disease associated with mutations in the ABCD1 gene that encodes an ATP-binding cassette transporter protein, ALDP. The disease is characterized by increased concentrations of very long-chain fatty acids (VLCFAs) in plasma and in

  3. Rare novel variants in the ZIC3 gene cause X-linked heterotaxy

    NARCIS (Netherlands)

    Paulussen, Aimee D C; Steyls, Anja; Vanoevelen, Jo; Van Tienen, Florence H J; Krapels, Ingrid P C; Claes, Godelieve R F; Chocron, Sonja; Velter, Crool; Tan-Sindhunata, Gita M.; Lundin, Catarina; Valenzuela, Irene; Nagy, Balint; Bache, Iben; Maroun, Lisa Leth; Avela, Kristiina; Brunner, Han G.; Smeets, Hubert J M; Bakkers, Jeroen; Van Den Wijngaard, Arthur

    2016-01-01

    Variants in the ZIC3 gene are rare, but have demonstrated their profound clinical significance in X-linked heterotaxy, affecting in particular male patients with abnormal arrangement of thoracic and visceral organs. Several reports have shown relevance of ZIC3 gene variants in both familial and

  4. X-Linked Creatine Transporter Deficiency Presenting as a Mitochondrial Disorder

    NARCIS (Netherlands)

    Hathaway, S.C.; Friez, M.; Limbo, K.; Parker, C.; Salomons, G.S.; Vockley, J.; Wood, T.; Abdul-Rahman, O.A.

    2010-01-01

    X-linked creatine transporter defect is caused by mutations in SLC6A8 at Xq28, which encodes the sodium-dependent creatine transporter. Reduction in creatine uptake results in elevated urine creatine and CSF creatine deficiency, which can be detected on magnetic resonance spectroscopy. We report a

  5. Somatic mosaicism underlies X-linked acrogigantism syndrome in sporadic male subjects

    NARCIS (Netherlands)

    A.F. Daly (Adrian); B. Yuan (Bo); Fina, F. (Frederic); J.-H. Caberg (Jean-Hubert); G. Trivellin (Giampaolo); L. Rostomyan (Liliya); W.W. de Herder (Wouter); L.A. Naves (Lucianna); D. Metzger (Daniel); T. Cuny (Thomas); Rabl, W. (Wolfgang); N.S. Shah (Nalini Samir); M-L. Jaffrain-Rea (Marie-Lise); Chiara Zatelli, M. (Maria); F.R. Faucz (Fabio R.); E. Castermans (Emilie); Nanni-Metellus, I. (Isabelle); Lodish, M. (Maya); A. Muhammad (Ammar); Palmeira, L. (Leonor); Potorac, I. (Iulia); G. Mantovani (Giovanna); S.J.C.M.M. Neggers (Bas); Klein, M. (Marc); A. Barlier (Anne); P. Liu (Pengfei); Ouafik, L. (L'houcine); V. Bours (Vincent); Lupski, J.R. (James R.); C.A. Stratakis (Constantine); A. Beckers (Albert)

    2016-01-01

    textabstractSomatic mosaicism has been implicated as a causative mechanism in a number of genetic and genomic disorders. X-linked acrogigantism (XLAG)syndrome is a recently characterized genomic form of pediatric gigantism due to aggressive pituitary tumors that is caused by submicroscopic

  6. Clinical, biochemical, neuroimaging and molecular findings of X-linked Adrenoleukodystrophy patients in South China.

    Science.gov (United States)

    Jiang, Min-yan; Cai, Yan-na; Liang, Cui-li; Peng, Min-zhi; Sheng, Hui-ying; Fan, Li-ping; Lin, Rui-zhu; Jiang, Hua; Huang, Yonglan; Liu, Li

    2015-12-01

    X-linked adrenoleukodystrophy is a common X-linked recessive peroxisomal disorder caused by the mutations in the ABCD1 gene. In this study, we analyzed 19 male patients and 9 female carriers with X-linked adrenoleukodystrophy in South China. By sequencing the ABCD1 gene, 13 different mutations were identified, including 7 novel mutations, and 6 known mutations, and 1 reported polymorphism. Mutation c.1180delG was demonstrated to be de novo mutation. 26.3 % (5/19) patients carried the deletion c.1415_16delAG, which may be the mutational hot spot in South China population. In addition, 73.7 % (14/19) patients were type of childhood cerebral adrenoleukodystrophy, 26.3 %(5/19) were in Addison only. Half of the childhood cerebral adrenoleukodystrophy patients had the adrenocortical insufficiency preceded the onset of neurological symptoms. Furthermore, 5 of 19 cases underwent hematopoietic stem cell transplantation. Our data showed that hematopoietic stem cell transplantation performed at an advanced stage of the cerebral X- linked adrenoleukodystrophy would accelerate the progression of the disease. Good clinical outcome achieved when hematopoietic stem cell transplantation performed at the very early stage of the disease.

  7. Pioglitazone halts axonal degeneration in a mouse model of X-linked adrenoleukodystrophy.

    Science.gov (United States)

    Morató, Laia; Galino, Jorge; Ruiz, Montserrat; Calingasan, Noel Ylagan; Starkov, Anatoly A; Dumont, Magali; Naudí, Alba; Martínez, Juan José; Aubourg, Patrick; Portero-Otín, Manuel; Pamplona, Reinald; Galea, Elena; Beal, M Flint; Ferrer, Isidre; Fourcade, Stéphane; Pujol, Aurora

    2013-08-01

    X-linked adrenoleukodystrophy is a neurometabolic disorder caused by inactivation of the peroxisomal ABCD1 transporter of very long-chain fatty acids. In mice, ABCD1 loss causes late onset axonal degeneration in the spinal cord in association with locomotor disability resembling the most common phenotype in patients, adrenomyeloneuropathy. Increasing evidence indicates that oxidative stress and bioenergetic failure play major roles in the pathogenesis of X-linked adrenoleukodystrophy. In this study, we aimed to evaluate whether mitochondrial biogenesis is affected in X-linked adrenoleukodystrophy. We demonstrated that Abcd1 null mice show reduced mitochondrial DNA concomitant with downregulation of mitochondrial biogenesis pathway driven by PGC-1α/PPARγ and reduced expression of mitochondrial proteins cytochrome c, NDUFB8 and VDAC. Moreover, we show that the oral administration of pioglitazone, an agonist of PPARγ, restored mitochondrial content and expression of master regulators of biogenesis, neutralized oxidative damage to proteins and DNA, and reversed bioenergetic failure in terms of ATP levels, NAD+/NADH ratios, pyruvate kinase and glutathione reductase activities. Most importantly, the treatment halted locomotor disability and axonal damage in X-linked adrenoleukodystrophy mice. These results lend support to the use of pioglitazone in clinical trials with patients with adrenomyeloneuropathy and reveal novel molecular mechanisms of action of pioglitazone in neurodegeneration. Future studies should address the effects of this anti-diabetic drug on other axonopathies in which oxidative stress and mitochondrial dysfunction are contributing factors.

  8. MRI findings in an asymptomatic boy with X-linked adrenoleukodystrophy and his symptomatic mother

    Energy Technology Data Exchange (ETDEWEB)

    Bekiesinska-Figatowska, M. [Dept. of Diagnostic Imaging, Central Railway Hospital, Warsaw (Poland); Tylki-Szymanska, A.; Stradomska, T.J. [Dept. of Metabolic Diseases, Children' s Memorial Health Institute, Warsaw (Poland); Walecki, J. [Dept. of Radiology and Diagnostic Imaging, Medical Centre for Postgraduate Education, Warsaw (Poland)

    2001-11-01

    We report an asymptomatic 15-year-old boy with X-linked adrenoleukodystrophy and his symptomatic 38-year-old mother. MRI revealed similar, subtle high-signal lesions in the periventricular white matter of the parieto-occipital regions, without involvement of the corpus callosum, more pronounced in the mother. (orig.)

  9. Multipoint linkage analysis in X-linked ocular albinism of the Nettleship-Falls type

    NARCIS (Netherlands)

    Bergen, A. A.; Samanns, C.; Schuurman, E. J.; van Osch, L.; van Dorp, D. B.; Pinckers, A. J.; Bakker, E.; Gal, A.; van Ommen, G. J.; Bleeker-Wagemakers, E. M.

    1991-01-01

    An extensive linkage analysis was performed by studying ten Xp22 loci in ten families segregating for X-linked ocular albinism of the Nettleship-Falls type (XOA). Linkage was confirmed between the XOA locus (OA1) and both DXS16 (theta max = 0.10, zeta max = 4.09) and DXS237 (theta max = 0.12, zeta

  10. Successful approach to treatment of Helicobacter bilis infection in X-linked agammaglobulinemia.

    Science.gov (United States)

    Turvey, Stuart E; Leo, Sara H; Boos, Annette; Deans, Gregory D; Prendiville, Julie; Crawford, Richard I; Senger, Christof; Conley, Mary Ellen; Tilley, Peter; Junker, Anne; Janz, Loretta; Azana, Robert; Hoang, Linda; Morton, Tracy L

    2012-12-01

    Helicobacter bilis, an unusual cause of chronic infections in patients with X-linked agammaglobulinemia (XLA), is notoriously difficult to diagnose and eradicate. Based on the limited number of cases reported worldwide, we highlight the typical features of H. bilis infection in XLA and provide a rational and successful approach to diagnosis and treatment of this challenging infection.

  11. Splice-correcting oligonucleotides restore BTK function in X-linked agammaglobulinemia model

    DEFF Research Database (Denmark)

    Bestas, Burcu; Moreno, Pedro M D; Blomberg, K Emelie M

    2014-01-01

    X-linked agammaglobulinemia (XLA) is an inherited immunodeficiency that results from mutations within the gene encoding Bruton's tyrosine kinase (BTK). Many XLA-associated mutations affect splicing of BTK pre-mRNA and severely impair B cell development. Here, we assessed the potential of antisense...

  12. Frequency of fragile-x in x-linked mental retardation

    African Journals Online (AJOL)

    introduction: Fragile X syndrome (FXS) is the most common form of inher‑ ited mental retardation and accounts for about one third of all cases of X linked mental retardation (XLMR). It is inherited as an X‑linked dominant trait with a fragile site at Xq27.3 locus named fragile X mental retardation gene (FMR‑1). The FMR‑1 ...

  13. High-resolution genomic microarrays for X-linked mental retardation.

    NARCIS (Netherlands)

    Lugtenberg, D.; Veltman, J.A.; Bokhoven, J.H.L.M. van

    2007-01-01

    Developments in genomic microarray technology have revolutionized the study of human genomic copy number variation. This has significantly affected many areas in human genetics, including the field of X-linked mental retardation (XLMR). Chromosome X-specific bacterial artificial chromosomes

  14. Self-induced vomiting in X-linked {alpha}-thalassemia/mental retardation syndrome

    Energy Technology Data Exchange (ETDEWEB)

    Kurosawa, Kenji; Akatsuka, Akira; Ochiai, Yukikatsu [Jikei Univ. School of Medicine, Tokyo (Japan)] [and others

    1996-06-14

    This report poses the question of whether the vomiting observed in X-linked {alpha}-thalassemia/mental retardation syndrome could be self-induced. The authors present a case history which seems to support this hypothesis. 5 refs., 1 fig.

  15. Severe tracheobronchial stenosis and cervical vertebral subluxation in X-linked recessive chondrodysplasia punctata

    Energy Technology Data Exchange (ETDEWEB)

    Mundinger, Gerhard S. [Johns Hopkins Hospital, Division of Plastic, Reconstructive, and Maxillofacial Surgery, Baltimore, MD (United States); Weiss, Clifford; Fishman, Elliot K. [Johns Hopkins Hospital, Russell H. Morgan Department of Radiology and Radiological Science, Baltimore, MD (United States)

    2009-06-15

    Radiologic manifestations of X-linked chondrodysplasia punctata (CDPX1) typically include chondrodysplasia, epiphyseal stippling, punctate calcification of cartilage, distal phalangeal hypoplasia, and nasal/midface hypoplasia. We present an infant with CDPX1 demonstrating calcification and stenosis of the entire trachea and mainstem bronchi, as well as possible anterior C1 subluxation due to progression of congenital vertebral dysplasia. (orig.)

  16. X-linked NDUFA1 gene mutations associated with mitochondrial encephalomyopathy.

    NARCIS (Netherlands)

    Fernandez-Moreira, D.; Ugalde, C.; Smeets, R.; Rodenburg, R.J.T.; Lopez-Laso, E.; Ruiz-Falco, M.L.; Briones, P.; Martin, M.A.; Smeitink, J.A.M.; Arenas, J.

    2007-01-01

    OBJECTIVE: Mitochondrial complex I deficiency is the commonest diagnosed respiratory chain defect, being genetically heterogeneous. The male preponderance of previous patient cohorts suggested an X-linked underlying genetic defect. We investigated mutations in the X-chromosomal complex I structural

  17. DFNB79: reincarnation of a nonsyndromic deafness locus on chromosome 9q34.3.

    Science.gov (United States)

    Khan, Shahid Yar; Riazuddin, Saima; Shahzad, Mohsin; Ahmed, Nazir; Zafar, Ahmad Usman; Rehman, Atteeq Ur; Morell, Robert J; Griffith, Andrew J; Ahmed, Zubair M; Riazuddin, Sheikh; Friedman, Thomas B

    2010-01-01

    Genetic analysis of an inbred Pakistani family PKDF280, segregating prelingual severe to profound sensorineural hearing loss, provided evidence for a DFNB locus on human chromosome 9q34.3. Co-segregation of the deafness trait with marker D9SH159 was determined by a two-point linkage analysis (LOD score 9.43 at theta=0). Two additional large families, PKDF517 and PKDF741, co-segregate recessive deafness with markers linked to the same interval. Haplotype analyses of these three families refined the interval to 3.84 Mb defined by D9S1818 (centromeric) and D9SH6 (telomeric). This interval overlaps with the previously reported DFNB33 locus whose chromosomal map position has been recently revised and assigned to a new position on chromosome 10p11.23-q21.1. The nonsyndromic deafness locus on chromosome 9q segregating in family PKDF280 was designated DFNB79. We are currently screening the 113 candidate DFNB79 genes for mutations and have excluded CACNA1B, EDF1, PTGDS, EHMT1, QSOX2, NOTCH1, MIR126 and MIR602.

  18. Fine mapping of dominant X-linked incompatibility alleles in Drosophila hybrids.

    Science.gov (United States)

    Matute, Daniel R; Gavin-Smyth, Jackie

    2014-04-01

    Sex chromosomes have a large effect on reproductive isolation and play an important role in hybrid inviability. In Drosophila hybrids, X-linked genes have pronounced deleterious effects on fitness in male hybrids, which have only one X chromosome. Several studies have succeeded at locating and identifying recessive X-linked alleles involved in hybrid inviability. Nonetheless, the density of dominant X-linked alleles involved in interspecific hybrid viability remains largely unknown. In this report, we study the effects of a panel of small fragments of the D. melanogaster X-chromosome carried on the D. melanogaster Y-chromosome in three kinds of hybrid males: D. melanogaster/D. santomea, D. melanogaster/D. simulans and D. melanogaster/D. mauritiana. D. santomea and D. melanogaster diverged over 10 million years ago, while D. simulans (and D. mauritiana) diverged from D. melanogaster over 3 million years ago. We find that the X-chromosome from D. melanogaster carries dominant alleles that are lethal in mel/san, mel/sim, and mel/mau hybrids, and more of these alleles are revealed in the most divergent cross. We then compare these effects on hybrid viability with two D. melanogaster intraspecific crosses. Unlike the interspecific crosses, we found no X-linked alleles that cause lethality in intraspecific crosses. Our results reveal the existence of dominant alleles on the X-chromosome of D. melanogaster which cause lethality in three different interspecific hybrids. These alleles only cause inviability in hybrid males, yet have little effect in hybrid females. This suggests that X-linked elements that cause hybrid inviability in males might not do so in hybrid females due to differing sex chromosome interactions.

  19. Macrocytosis and sudden sensorineural hearing loss: a case report.

    Science.gov (United States)

    McMurran, A E L; Adair, R A

    2015-11-01

    Although other blood dyscrasias are known to cause sudden sensorineural hearing loss, macrocytosis has not previously been implicated in the absence of another causative agent. We present a case of bilateral sequential sudden sensorineural hearing loss in a patient with significant macrocytosis (mean corpuscular volume at presentation 124 fl) secondary to alcohol-induced liver dysfunction. A possible pathophysiological mechanism linking macrocytosis and sudden sensorineural hearing loss was identified, suggesting areas for further investigation.

  20. Hyperbaric oxygen therapy for sudden sensorineural hearing loss in divers.

    Science.gov (United States)

    Van Der Wal, A W; Van Ooij, P J A M; De Ru, J A

    2016-11-01

    Sudden sensorineural hearing loss in divers may be caused by either inner-ear barotrauma or inner-ear decompression sickness. There is no consensus on the best treatment option. This study aimed to evaluate the therapeutic value of hyperbaric oxygen therapy for sudden sensorineural hearing loss in divers. A literature review and three cases of divers with sudden sensorineural hearing loss treated with hyperbaric oxygen therapy are presented. Hyperbaric oxygen therapy resulted in hearing improvement in 80 per cent of patients: 39 per cent had hearing improvement and 41 per cent had full recovery. Hyperbaric oxygen therapy improved hearing in divers with sudden sensorineural hearing loss.

  1. Supernumerary teeth in non-syndromic patients.

    Science.gov (United States)

    Mali, Santosh; Karjodkar, Freny Rashmiraj; Sontakke, Subodh; Sansare, Kaustubh

    2012-03-01

    Hyperdontia or supernumerary teeth without associated syndrome is a rare phenomenon, as supernumerary teeth are usually associated with cleft lip and palate or other syndromes such as Gardner's syndrome, cleidocranial dysplasia, and so on. Five patients with supernumerary teeth visited our department. They had no familial history or other pathology, certain treatment protocols was modified due to the presence of supernumerary teeth. Non-syndromic supernumerary teeth, if asymptomatic, need to have periodical radiographic observation. If they showed no variation as they impacted in the jaw, careful examination is necessary because they may develop into pathological status such as dentigerous cysts. The importance of a precise clinical history and radiographic examination for patients with multiple supernumerary teeth should be emphasized.

  2. Supernumerary teeth in non-syndromic patients

    Energy Technology Data Exchange (ETDEWEB)

    Mali, Santosh; Karjodkar, Freny Rashmiraj; Sontakke, Subodh; Sansare, Kaustubh [Nair Hospital Dental College, Maharashtra (India)

    2012-03-15

    Hyperdontia or supernumerary teeth without associated syndrome is a rare phenomenon, as supernumerary teeth are usually associated with cleft lip and palate or other syndromes such as Gardner's syndrome, cleidocranial dysplasia, and so on. Five patients with supernumerary teeth visited our department. They had no familial history or other pathology, certain treatment protocols was modified due to the presence of supernumerary teeth. Non-syndromic supernumerary teeth, if asymptomatic, need to have periodical radiographic observation. If they showed no variation as they impacted in the jaw, careful examination is necessary because they may develop into pathological status such as dentigerous cysts. The importance of a precise clinical history and radiographic examination for patients with multiple supernumerary teeth should be emphasized.

  3. Supernumerary teeth in non-syndromic patients

    International Nuclear Information System (INIS)

    Mali, Santosh; Karjodkar, Freny Rashmiraj; Sontakke, Subodh; Sansare, Kaustubh

    2012-01-01

    Hyperdontia or supernumerary teeth without associated syndrome is a rare phenomenon, as supernumerary teeth are usually associated with cleft lip and palate or other syndromes such as Gardner's syndrome, cleidocranial dysplasia, and so on. Five patients with supernumerary teeth visited our department. They had no familial history or other pathology, certain treatment protocols was modified due to the presence of supernumerary teeth. Non-syndromic supernumerary teeth, if asymptomatic, need to have periodical radiographic observation. If they showed no variation as they impacted in the jaw, careful examination is necessary because they may develop into pathological status such as dentigerous cysts. The importance of a precise clinical history and radiographic examination for patients with multiple supernumerary teeth should be emphasized.

  4. Descriptive Epidemiology of Nonsyndromic Complete Atrioventricular Canal Defects

    Science.gov (United States)

    Agopian, A. J.; Moulik, Mousumi; Gupta-Malhotra, Monesha; Marengo, Lisa K.; Mitchell, Laura E.

    2012-01-01

    Background Complete atrioventricular canal defects (CAVC) are a common heart defect, but few epidemiologic studies have evaluated nonsyndromic CAVC. Risk factors for nonsyndromic CAVC have not been well established. Methods To assess the relationship between risk for nonsyndromic CAVC in offspring and several sociodemographic and reproductive parental factors, including maternal diabetes and obesity, we conducted Poisson regression analyses, using data ascertained through the Texas Birth Defects Registry, a large, population-based birth defects registry. Data were evaluated for 563 nonsyndromic cases with CAVC. Results Significant associations were observed between nonsyndromic CAVC in offspring and maternal pregestational diabetes (adjusted prevalence ratio (aPR): 6.74, 95% confidence interval (CI): 3.67–12.37), gestational diabetes [aPR: 1.69, 95% CI: 1.03, 2.79], and obesity [aPR: 1.69, 95% CI: 1.24, 2.30]. Comments Our findings add nonsyndromic CAVC to the growing list of birth defects that appear to be associated with maternal diabetes and obesity. PMID:23061687

  5. Descriptive epidemiology of non-syndromic complete atrioventricular canal defects.

    Science.gov (United States)

    Agopian, A J; Moulik, Mousumi; Gupta-Malhotra, Monesha; Marengo, Lisa K; Mitchell, Laura E

    2012-11-01

    Complete atrioventricular canal defects (CAVC) are a common heart defect, but few epidemiologic studies have evaluated non-syndromic CAVC. Risk factors for non-syndromic CAVC have not been well established. To assess the relationship between risk for non-syndromic CAVC in offspring and several sociodemographic and reproductive parental factors, including maternal diabetes and obesity, we conducted Poisson regression analyses, using data ascertained through the Texas Birth Defects Registry, a large, population-based birth defects registry. Data were evaluated for 563 non-syndromic cases with CAVC. Significant associations were observed between non-syndromic CAVC in offspring and maternal pregestational diabetes (adjusted prevalence ratio (aPR) 6.74; 95% confidence interval (CI) 3.67, 12.37), gestational diabetes (aPR 1.69; 95% CI 1.03, 2.79) and obesity (aPR 1.69; 95% CI 1.24, 2.30).  Our findings add non-syndromic CAVC to the growing list of birth defects that appear to be associated with maternal diabetes and obesity. © 2012 Blackwell Publishing Ltd.

  6. Detection of mutations in the COL4A5 gene by SSCP in X-linked Alport syndrome

    DEFF Research Database (Denmark)

    Hertz, Jens Michael; Juncker, I; Persson, U

    2001-01-01

    of type IV-collagen. We performed mutation analysis of the COL4A5 gene by PCR-SSCP analysis of each of the 51 exons with flanking intronic sequences in 81 patients suspected of X-linked Alport syndrome including 29 clear X-linked cases, 37 cases from families with a pedigree compatible with X...

  7. Genetics Home Reference: X-linked immunodeficiency with magnesium defect, Epstein-Barr virus infection, and neoplasia

    Science.gov (United States)

    ... Conditions XMEN X-linked immunodeficiency with magnesium defect, Epstein-Barr virus infection, and neoplasia Printable PDF Open All Close ... boxes. Description X-linked immunodeficiency with magnesium defect, Epstein-Barr virus infection, and neoplasia (typically known by the acronym ...

  8. X-linked ichthyosis without STS deficiency: Clinical, genetical, and molecular studies

    Energy Technology Data Exchange (ETDEWEB)

    Robledo, R.; Melis, P.; Schillinger, E.; Siniscalco, M. [Istituto di Genetica Molecolare del, Trieste (Italy)] [and others

    1995-11-06

    We report on a Sardinian pedigree with congenital ichthyosis associated with normal levels of steroid sulfatase and a normal molecular pattern, as detectable with a cDNA probe for the steroid sulfatase (STS) gene. Though the pattern of transmission of the disease is consistent with X-linked recessive inheritance, this form of ichthyosis was found to segregate independently of genetic polymorphisms detected by probes of the region Xp22.3, where the STS locus has been mapped. The search for close genetic linkages with other polymorphic markers scattered along the entire X chromosome has so far been fruitless. For the time being, the main conclusion derived from these data is that STS deficiency is not a sine qua non for X-linked ichthyosis which may also result from a mutational event at an X-chromosomal site genetically unlinked to the STS locus. 16 refs., 4 figs.

  9. X-linked adrenoleukodystrophy in heterozygous female patients: women are not just carriers

    Directory of Open Access Journals (Sweden)

    Charles Marques Lourenço

    2012-07-01

    Full Text Available X-linked adrenoleukodystrophy (X-ALD is a recessive X-linked disorder associated with marked phenotypic variability. Female carriers are commonly thought to be normal or only mildly affected, but their disease still needs to be better described and systematized. OBJECTIVES: To review and systematize the clinical features of heterozygous women followed in a Neurogenetics Clinic. METHODS: We reviewed the clinical, biochemical, and neuroradiological data of all women known to have X-ADL. RESULTS: The nine women identified were classified into three groups: with severe and aggressive diseases; with slowly progressive, spastic paraplegia; and with mildly decreased vibratory sensation, brisk reflexes, and no complaints. Many of these women did not have a known family history of X-ALD. CONCLUSIONS: Heterozygous women with X-ADL have a wide spectrum of clinical manifestations, ranging from mild to severe phenotypes.

  10. Convergence of Human Genetics and Animal Studies: Gene Therapy for X-Linked Retinoschisis

    Science.gov (United States)

    Bush, Ronald A.; Wei, Lisa L.; Sieving, Paul A.

    2015-01-01

    Retinoschisis is an X-linked recessive genetic disease that leads to vision loss in males. X-linked retinoschisis (XLRS) typically affects young males; however, progressive vision loss continues throughout life. Although discovered in 1898 by Haas in two brothers, the underlying biology leading to blindness has become apparent only in the last 15 years with the advancement of human genetic analyses, generation of XLRS animal models, and the development of ocular monitoring methods such as the electroretinogram and optical coherence tomography. It is now recognized that retinoschisis results from cyst formations within the retinal layers that interrupt normal visual neurosignaling and compromise structural integrity. Mutations in the human retinoschisin gene have been correlated with disease severity of the human XLRS phenotype. Introduction of a normal human retinoschisin cDNA into retinoschisin knockout mice restores retinal structure and improves neural function, providing proof-of-concept that gene replacement therapy is a plausible treatment for XLRS. PMID:26101206

  11. X-linked adrenoleukodystrophy in a 6-year-old boy initially presenting with psychiatric symptoms.

    Science.gov (United States)

    İncecik, Faruk; Hergüner, M Özlem; Mert, Gülen; Önenli-Mungan, Neslihan; Ceylaner, Serdar; Kör, Deniz; Altunbaşak, Şakir

    2014-01-01

    X-linked adrenoleukodystrophy (ALD) leads to demyelination of the nervous system, adrenal insufficiency and accumulation of long-chain fatty acids. Most young patients with X-linked ALD develop seizures and progressive neurologic deficits, and die within the first two decades of life. We present the case of a 6-year-old with childhood-onset ALD, first presenting with psychiatric symptoms and progressive gait difficulties, slurred speech and cognitive impairment. Genetic testing was performed and a p.R401Q (c.1202G>A) mutation detected in the ABCD1 gene. ALD should be considered in the differential diagnosis of patients presenting with behavior changes and white matter disease in neuroimaging.

  12. Sensorineural hearing loss in hemorrhagic dengue?

    Science.gov (United States)

    Ribeiro, Bruna Natália Freire; Guimarães, Alexandre Caixeta; Yazawa, Felipe; Takara, Tammy Fumiko Messias; de Carvalho, Guilherme Machado; Zappelini, Carlos Eduardo Monteiro

    2015-01-01

    Dengue is an acute febrile infectious disease, with high fever followed by symptoms flu-like. Dengue hemorrhagic fever (DHF) is a vascular leak syndrome and could present spontaneous bleeding and worsening of symptoms after some days. Dengue could have some ENT manifestations, however hearing loss is not one of them. Sudden hearing loss is considered as sensorineural or perceptual hearing loss with a sudden onset in a person without other prior otological history. The relation between infectious diseases and sudden hearing are been investigated, some viruses were already linked, but the relation between dengue virus and sudden hearing still remains unknown. This article has the goal of presenting a case of DHF that evolved with SSHL in his hospitalization process. We report a 60 years-male patient of with DHF who developed bilateral secretory otitis media and sensorineural hearing loss after the fifth day of onset of symptoms. His hearing loss remained even after 7 months and the patient was referred for hearing aid fitting. This is the first case report that brings together DHF and sudden hearing loss. In the development of this case no other cause to sudden hearing loss was found and the correlation between dengue and hearing loss was questioned. In the literature review was found that some viruses, as mumps virus, varicella-zoster virus and HSV-1 and HSV-2 are related to sudden hearing loss, all of them fit in the viral theory. Besides the viral theory of sudden hearing loss, there is the vascular theory that is the occlusion of the end artery that supplies the cochlea. DHF has a vascular commitment, and the hypothesis of a vascular cause could be elicited in this case. Many studies in this area are needed and this article has the objective of elicit the discussion about the subject. Could dengue be associated with sensorineural hearing loss? Copyright © 2015. Published by Elsevier Ltd.

  13. Genetic analysis of X-linked hybrid sterility in the house mouse

    Czech Academy of Sciences Publication Activity Database

    Storchová, Radka; Gregorová, Soňa; Buckiová, Daniela; Kyselová, Vendula; Divina, Petr; Forejt, Jiří

    2004-01-01

    Roč. 15, - (2004), s. 515-524 ISSN 0938-8990 R&D Projects: GA MŠk LN00A079; GA ČR GA204/02/1373 Grant - others:EU(XE) QLRI-2000-00233; HHMI(US) 555000306 Institutional research plan: CEZ:AV0Z5052915 Keywords : X-linked hybrid sterility * genetic analysis Subject RIV: EB - Genetics ; Molecular Biology Impact factor: 2.658, year: 2004

  14. Genetic study of a new X-linked recessive immunodeficiency syndrome.

    OpenAIRE

    de Saint-Basile, G; Le Deist, F; Caniglia, M; Lebranchu, Y; Griscelli, C; Fischer, A

    1992-01-01

    Seven forms of X-linked (XL) immunodeficiency have been described (XL agammaglobulinemia, XL severe combined immunodeficiency [SCID], Wiskott-Aldrich syndrome, XL chronic granulomatous disease, XL hyper-IgM syndrome with low IgG and IgA, and XL lymphoproliferative syndrome), and properdine deficiency. Although there are (some) phenotypic variants, diagnosis is relatively simple on the basis of clinical, immunological, and genetic characteristics. We studied a family in which several males wer...

  15. Cochlear implantation in X-linked deafness - How to manage the surgical challenges.

    Science.gov (United States)

    Saeed, Haroon; Powell, Harry R F; Saeed, Shakeel R

    2016-07-01

    In children with X-linked deafness, cochlear malformations challenge the implant surgeon to avoid electrode insertion into the internal auditory meatus and prevent a continuous cerebrospinal fluid (CSF) leak. We describe our experience of cochlear implantation (CI) in two children with profound hearing loss secondary to X-linked deafness, highlighting safer operative techniques to avoid potential complications. Descriptive cases of two children with X-linked deafness (patient 1 and patient 2) undergoing CI. Peri-operative imaging and work-up to surgery are discussed. Specific operative considerations, post-operative complications and subsequent audiological performance are highlighted. In each case, intra-operative fluoroscopic imaging ensured intra-cochlear insertion of electrodes. Expected CSF gusher was seen in each case which was initially controlled by packing around the cochleostomy and array with temporalis muscle and fascia. Patient 1 developed post-operative meningitis secondary to continuous CSF leak. We avoided further significant CSF leak by planning staged procedures for patient 2, with obliteration of the middle ear cleft and external ear canal (EAC) at the time of implantation. In both patients, bilateral implantation successfully provided hearing thresholds of less than 35 dB in both ears at routine follow up. When planning for CI in children with radiological features of X-linked deafness, intra-operative imaging should be utilized to ensure correct electrode positioning. Traditional methods of stopping a CSF gusher may not suffice. We therefore encourage additional surgical obliteration of the middle ear space and EAC to avoid persistent CSF leak and its associated complications.

  16. Genetic localization and phenotypic expression of X-linked cataract (Xcat) in Mus musculus.

    Science.gov (United States)

    Favor, J; Pretsch, W

    1990-01-01

    Linkage data relative to the markers tabby and glucose-6-phosphate dehydrogenase are presented to locate X-linked cataract (Xcat) in the distal portion of the mouse X-chromosome between jimpy and hypophosphatemia. The human X-linked cataract-dental syndrome, Nance-Horan Syndrome, also maps closely to human hypophosphatemia and would suggest homology between mouse Xcat and human Nance-Horan Syndrome genes. In hemizygous males and homozygous females penetrance is complete with only slight variation in the degree of expression. Phenotypic expression in Xcat heterozygous females ranges from totally clear to totally opaque lenses. The phenotypic expression between the two lenses of a heterozygous individual could also vary between totally clear and totally opaque lenses. However, a correlation in the degree of expression between the eyes of an individual was observed. A variegated pattern of lens opacity was evident in female heterozygotes. Based on these observations, the site of gene action for the Xcat locus is suggested to be endogenous to the lens cells and the precursor cell population of the lens is concluded to be small. The identification of an X-linked cataract locus is an important contribution to the estimate of the number of mutable loci resulting in cataract, an estimate required so that dominant cataract mutagenesis results may be expressed on a per locus basis. The Xcat mutation may be a useful marker for a distal region of the mouse X-chromosome which is relatively sparsely marked and the X-linked cataract mutation may be employed in gene expression and lens development studies.

  17. Acute monocytic leukemia in a dog with X-linked severe combined immunodeficiency.

    OpenAIRE

    Felsburg, P J; Somberg, R L; Krakowka, G S

    1994-01-01

    We describe the occurrence of acute monocytic leukemia in a dog with X-linked severe combined immunodeficiency (XSCID) that had been raised in a gnotobiotic environment for 20 months. This case represents the first reported instance of malignancy in canine XSCID, the first case of acute monocytic leukemia in any species with severe combined immunodeficiency, and the first documented malignancy in any species with XSCID that was not associated with immunotherapy.

  18. Neonatal Treatment with Recombinant Ectodysplasin Prevents Respiratory Disease in Dogs with X-Linked Ectodermal Dysplasia

    OpenAIRE

    Mauldin, Elizabeth A.; Gaide, Olivier; Schneider, Pascal; Casal, Margret L.

    2009-01-01

    Patients with defective ectodysplasin A (EDA) have X-linked hypohidrotic ectodermal dysplasia (XLHED; OMIM#305100), a condition comprising hypotrichosis, inability to sweat, abnormal teeth, and frequent pulmonary infections. The XLHED dogs show the same clinical signs as humans with the disorder, including frequent respiratory infections that can be fatal. The respiratory disease in humans and dogs is thought to be due to the absence of tracheal and bronchial glands which are a vital part of ...

  19. Mutation identification in a canine model of X-linked ectodermal dysplasia

    OpenAIRE

    Casal, Margret L.; Scheidt, Jennifer L.; Rhodes, James L.; Henthorn, Paula S.; Werner, Petra

    2005-01-01

    X-linked hypohidrotic ectodermal dysplasia (XHED), an inherited disease recognized in humans, mice, and cattle, is characterized by hypotrichosis, a reduced number or absence of sweat glands, and missing or malformed teeth. In a subset of affected individuals and animals, mutations in the EDA gene (formerly EDI), coding for ectodysplasin, have been found to cause this phenotype. Ectodysplasin is a homotrimeric transmembrane protein with an extracellular TNF-like domain, which has been shown t...

  20. Autoimmunity in X-linked agammaglobulinemia: Kawasaki disease and review of the literature.

    Science.gov (United States)

    Behniafard, Nasrin; Aghamohammadi, Asghar; Abolhassani, Hassan; Pourjabbar, Sarvenaz; Sabouni, Farah; Rezaei, Nima

    2012-02-01

    Although autoimmunity phenotype is surprisingly common in patients with different types of primary antibody deficiency, it is much less frequent in X-linked agammaglobulinemia (XLA). Herein, we report on a 15-month-old boy with XLA who also suffered from Kawasaki disease. The current case presentation is the first report of an association between Kawasaki disease and XLA. XLA could be considered as a special opportunity to understand autoimmunity in the near absence of immunoglobulins.

  1. Successful hematopoietic cell transplantation in a patient with X-linked agammaglobulinemia and acute myeloid leukemia.

    Science.gov (United States)

    Abu-Arja, Rolla F; Chernin, Leah R; Abusin, Ghada; Auletta, Jeffery; Cabral, Linda; Egler, Rachel; Ochs, Hans D; Torgerson, Troy R; Lopez-Guisa, Jesus; Hostoffer, Robert W; Tcheurekdjian, Haig; Cooke, Kenneth R

    2015-09-01

    X-linked agammaglobulinemia (XLA) is a primary immunodeficiency characterized by marked reduction in all classes of serum immunoglobulins and the near absence of mature CD19(+) B-cells. Although malignancy has been observed in patients with XLA, we present the first reported case of acute myeloid leukemia (AML) in a patient with XLA. We also demonstrate the complete correction of the XLA phenotype following allogeneic hematopoietic cell transplantation for treatment of the patient's leukemia. © 2015 Wiley Periodicals, Inc.

  2. Papilledema in the Setting of X-Linked Hypophosphatemic Rickets with Craniosynostosis

    Directory of Open Access Journals (Sweden)

    Lora R. Dagi Glass

    2011-12-01

    Full Text Available Purpose: Introduction to the ophthalmic literature of an unusual cause of papilledema and subsequent optic atrophy: X-linked hypophosphatemic rickets (XLH. Methods: Case report of a 3-year-old female presenting with papilledema resulting from craniosynostosis secondary to XLH. Results: Early intervention with craniofacial surgery prevented the development of optic atrophy. Conclusion: Children with XLH should be screened for ophthalmic evidence of elevated intracranial pressure to aid early intervention and prevention of permanent loss of vision.

  3. Nonspecific X-linked mental retardation with macrocephaly and obesity: A further family

    Energy Technology Data Exchange (ETDEWEB)

    Baraitser, M.; Reardon, W. [Hospital for Sick Children, London (United Kingdom); Vijeratnam, S. [Highlands Hospital, London (United Kingdom)

    1995-07-03

    The phenotypic nonspecificity of many forms of X-linked mental retardation has hampered attempts to classify them into clinically homogeneous groups. One such condition, described by Clark and Baraitser, has been the subject of a single pedigree report to date. We now describe a further pedigree whose affected members share many manifestations with those reported by Clark and Baraitser, and we consider the possible distinction between this condition and Atkin-Flaitz syndrome. 9 refs., 4 figs., 1 tab.

  4. CD1 Gene Polymorphisms and Phenotypic Variability in X-Linked Adrenoleukodystrophy

    OpenAIRE

    Barbier, Mathieu; Sabbagh, Audrey; Kasper, Edwige; Asheuer, Muriel; Ahouansou, Ornella; Pribill, Ingrid; Forss-Petter, Sonja; Vidaud, Michel; Berger, Johannes; Aubourg, Patrick

    2012-01-01

    X-linked adrenoleukodystrophy (X-ALD) is characterized by marked phenotypic variation ranging from adrenomyeloneuropathy (AMN) to childhood cerebral ALD (CCALD). X-ALD is caused by mutations in the ABCD1 gene, but no genotype-phenotype correlation has been established so far and modifier gene variants are suspected to modulate phenotypes. Specific classes of lipids, enriched in very long-chain fatty acids that accumulate in plasma and tissues from X-ALD patients are suspected to be involved i...

  5. CRISPR/Cas9 Promotes Functional Study of Testis Specific X-Linked Gene In Vivo.

    Directory of Open Access Journals (Sweden)

    Minyan Li

    Full Text Available Mammalian spermatogenesis is a highly regulated multistage process of sperm generation. It is hard to uncover the real function of a testis specific gene in vitro since the in vitro model is not yet mature. With the development of the CRISPR/Cas9 (Clustered Regularly Interspaced Short Palindromic Repeats/CRISPR-associated 9 system, we can now rapidly generate knockout mouse models of testis specific genes to study the process of spermatogenesis in vivo. SYCP3-like X-linked 2 (SLX2 is a germ cell specific component, which contains a Cor1 domain and belongs to the XLR (X-linked, lymphocyte regulated family. Previous studies suggested that SLX2 might play an important role in mouse spermatogenesis based on its subcellular localization and interacting proteins. However, the function of SLX2 in vivo is still elusive. Here, to investigate the functions of SLX2 in spermatogenesis, we disrupted the Slx2 gene by using the CRISPR/Cas9 system. Since Slx2 is a testis specific X-linked gene, we obtained knockout male mice in the first generation and accelerated the study process. Compared with wild-type mice, Slx2 knockout mice have normal testis and epididymis. Histological observation of testes sections showed that Slx2 knockout affected none of the three main stages of spermatogenesis: mitosis, meiosis and spermiogenesis. In addition, we further confirmed that disruption of Slx2 did not affect the number of spermatogonial stem cells, meiosis progression or XY body formation by immunofluorescence analysis. As spermatogenesis was normal in Slx2 knockout mice, these mice were fertile. Taken together, we showed that Slx2 itself is not an essential gene for mouse spermatogenesis and CRISPR/Cas9 technique could speed up the functional study of testis specific X-linked gene in vivo.

  6. Refined genetic mapping of X-linked Charcot-Marie-Tooth neuropathy

    Energy Technology Data Exchange (ETDEWEB)

    Fain, P.R.; Barker, D.F.; Chance, P.F. (Univ. of Utah, School of Medicine, Salt Lake City, UT (United States))

    1994-02-01

    Genetic linkage studies were conducted in four multigenerational families with X-linked Charcot-Marie-Tooth disease (CMTX), using 12 highly polymorphic short-tandem-repeat markers for the pericentromeric region of the X Chromosome. Pairwise linkage analysis with individual markers confirmed tight linkage of CMTX to the pericentromeric region in each family. Multipoint analyses strongly support the order DXS337-CMTX-DXS441-(DXS56, PGK1). 38 refs., 2 figs., 1 tab.

  7. Mobile phone induced sensorineural hearing loss

    International Nuclear Information System (INIS)

    Al-Dousary, Surayie H.

    2007-01-01

    The increased use of mobile phones worldwide has focused interest on the biological effects and possible health outcomes of exposure to radiofrequency fields from mobile phones, and their base stations. Various reports suggest that mobile phone use can cause health problems like fatigue, headache, dizziness, tension and sleep disturbances, however, only limited research data is available in medical literature regarding interaction between electromagnetic fields emitted by mobile phones and auditory function and the possible impact on hearing. We report a case of sensorineural hearing loss due to Global System for Mobile Communication mobile phone use in a 42-year-old male. (author)

  8. Sensorineural Hearing Loss after Magnetic Resonance Imaging

    Directory of Open Access Journals (Sweden)

    Abolfazl Mollasadeghi

    2013-01-01

    Full Text Available Magnetic resonance imaging (MRI devices produce noise, which may affect patient’s or operators’ hearing. Some cases of hearing impairment after MRI procedure have been reported with different patterns (temporary or permanent, unilateral or bilateral, with or without other symptoms like tinnitus. In this report, a case of bilateral sensorineural hearing loss in an otherwise healthy patient underwent brain MRI was described. The patient’s hearing loss was accompanied with tinnitus and was not improved after 3 months of followup.

  9. An algorithm for the diagnosis of X-linked intellectual disability in children

    Directory of Open Access Journals (Sweden)

    V. Yu. Voinova

    2016-01-01

    Full Text Available X-linked intellectual disability (XLID is a clinically and genetically heterogeneous group of hereditary diseases caused by mutations on the X chromosome, which lead to impaired intellectual development. The paper determines for the first time the proportion of X-linked diseases (6.54% in the pattern of intellectual disability in children. A system has been developed to quantify the clinical severity of fragile X mental retardation syndrome and Rett syndrome. A system has been scientifically justified to predict the clinical severity, which is based on an analysis of the impact of genetic and epigenetic factors (mutation type and location, X chromosome inactivation. The authors have determined the contribution of nonrandom X inactivation to the clinical polymorphism of various forms of XLID and established its role as an important diagnostic marker for pathology. It is shown that the study of X chromosome inactivation can identify asymptomatic female carriers of X-linked mutations to provide medical genetic counseling to families. An algorithm has been elaborated to diagnose XLID among the undifferentiated forms of mental developmental abnormalities in children. 

  10. X-linked cataract and Nance-Horan syndrome are allelic disorders.

    Science.gov (United States)

    Coccia, Margherita; Brooks, Simon P; Webb, Tom R; Christodoulou, Katja; Wozniak, Izabella O; Murday, Victoria; Balicki, Martha; Yee, Harris A; Wangensteen, Teresia; Riise, Ruth; Saggar, Anand K; Park, Soo-Mi; Kanuga, Naheed; Francis, Peter J; Maher, Eamonn R; Moore, Anthony T; Russell-Eggitt, Isabelle M; Hardcastle, Alison J

    2009-07-15

    Nance-Horan syndrome (NHS) is an X-linked developmental disorder characterized by congenital cataract, dental anomalies, facial dysmorphism and, in some cases, mental retardation. Protein truncation mutations in a novel gene (NHS) have been identified in patients with this syndrome. We previously mapped X-linked congenital cataract (CXN) in one family to an interval on chromosome Xp22.13 which encompasses the NHS locus; however, no mutations were identified in the NHS gene. In this study, we show that NHS and X-linked cataract are allelic diseases. Two CXN families, which were negative for mutations in the NHS gene, were further analysed using array comparative genomic hybridization. CXN was found to be caused by novel copy number variations: a complex duplication-triplication re-arrangement and an intragenic deletion, predicted to result in altered transcriptional regulation of the NHS gene. Furthermore, we also describe the clinical and molecular analysis of seven families diagnosed with NHS, identifying four novel protein truncation mutations and a novel large deletion encompassing the majority of the NHS gene, all leading to no functional protein. We therefore show that different mechanisms, aberrant transcription of the NHS gene or no functional NHS protein, lead to different diseases. Our data highlight the importance of copy number variation and non-recurrent re-arrangements leading to different severity of disease and describe the potential mechanisms involved.

  11. ABCD1 gene mutations in Chinese patients with X-linked adrenoleukodystrophy.

    Science.gov (United States)

    Pan, Hong; Xiong, Hui; Wu, Ye; Zhang, Yue-Hua; Bao, Xin-Hua; Jiang, Yu-Wu; Wu, Xi-Ru

    2005-08-01

    X-linked adrenoleukodystrophy is a neurodegenerative disorder caused by mutations in the adrenoleukodystrophy (ALD) protein gene ABCD1. This study used direct sequencing of genomic polymerase chain reaction products to perform mutational analysis of ABCD1 in 34 unrelated Chinese X-linked adrenoleukodystrophy patients and 27 of their maternal relatives. Thirty-two different mutations were identified in 34 patients. Most of the mutations (62.5%, 20/32) were missense mutations, six of which are novel. One novel single nucleotide polymorphism, c.1047 C>A, was also found in three patients and their mothers, which can also be observed in 1 of 120 normal control alleles. Two synonymous mutations (p.L516L and p.V349V) appeared in two unrelated patients, and no other mutations were evident after screening the gene's 10 exons. Seventeen of the probands' mothers were found to be heterozygous for the same mutations present in their sons' ABCD1 gene. Eight of the 10 screened sisters and cousins were identified as carriers. There were no hot spot mutations in the ABCD1 gene of Chinese patients with X-linked adrenoleukodystrophy. However, over half of the mutations (19/34) were located in exon 1 and exon 6, suggesting possible hot exons. No obvious relationship between genotype and phenotype was observed.

  12. Peroxisomal. beta. -oxidation enzyme proteins in adrenoleukodystrophy: distinction between x-linked adrenoleukodystrophy and neonatal adrenoleukodystrophy

    Energy Technology Data Exchange (ETDEWEB)

    Chen, W.W.; Watkins, P.A.; Osumi, T.; Hashimoto, T.; Moser, H.W.

    1987-03-01

    Very long chain fatty acids, which accumulate in plasma and tissues in x-linked adrenoleukodystrophy (ALD), neonatal ALD, and the Zellweger cerebrohepatorenal syndrome, are degraded by the peroxisomal ..beta..-oxidation pathway, consisting of acyl-CoA oxidase, the bifunctional enoyl-CoA hydratase/3-hydroxyacyl-CoA dehydrogenase, and ..beta..-ketothiolase. A marked deficiency of all three enzyme proteins was reported in livers from patients with the Zellweger syndrome, a disorder in which peroxisomes are decreased or absent. Peroxisomes are not as markedly decreased in neonatal ALD and appear normal in x-linked ALD. Immunoblot analysis of the peroxisomal ..beta..-oxidation enzymes revealed an almost complete lack of the bifunctional enzymes in neonatal ALD liver, similar to the finding in Zellweger tissues. In contrast, acyl-CoA oxidase and ..beta..-ketothiolase were present in neonatal ALD liver, although the thiolase appeared to be in precursor form (2-3 kDa larger than the mature enzyme) in neonatal ALD. Unlike either neonatal ALD or Zellweger syndrome, all three peroxisomal ..beta..-oxidation enzymes were present in x-linked ALD liver. Despite the absence in neonatal ALD liver of bifunctional enzyme protein, its mRNA was detected by RNA blot analysis in fibroblasts from these patients. These observations suggest that lack of bifunctional enzyme protein in neonatal ALD results from either abnormal translation of the mRNA or degradation of the enzyme prior to its entry into peroxisomes.

  13. Small nerve fiber involvement is frequent in X-linked adrenoleukodystrophy.

    Science.gov (United States)

    Horn, Morten A; Nilsen, Kristian B; Jørum, Ellen; Mellgren, Svein I; Tallaksen, Chantal M E

    2014-05-13

    To investigate the presence of small nerve fiber dysfunction in subjects with X-linked adrenoleukodystrophy. Cross-sectional study in which 11 Norwegian subjects (3 males, 8 females) with X-linked adrenoleukodystrophy, phenotypes ranging from asymptomatic to wheelchair-bound with adrenomyeloneuropathy, were investigated with neurophysiologic studies including EMG, nerve conduction velocities, quantitative sensory testing, tests of autonomic function, and skin biopsy for intraepidermal nerve fiber density measurements. We found small nerve fiber dysfunction in 10 of 11 subjects, increasing with age and more pronounced in males. Low intraepidermal nerve fiber densities were found in 5 of 11 subjects, indicating a loss of thin unmyelinated nerve fibers peripherally. Five of 11 subjects showed small nerve fiber dysfunction despite normal nerve fiber densities, suggesting possible involvement of the spinothalamic tracts. Two subjects showed moderate abnormalities in autonomic function tests. Evidence of small nerve fiber dysfunction was widespread in this cohort of subjects with X-linked adrenoleukodystrophy, with findings indicating loss of peripheral small nerve fibers and possibly also fibers of the spinothalamic tracts. The results support the theory of primary axonal degeneration in adrenomyeloneuropathy. Evidence of nervous system involvement was found in all heterozygotes, with severity increasing with age. Clinicians caring for these patients should be alert to signs of small nerve fiber involvement.

  14. X-linked agammaglobulinemia caused by new mutation in BTK gene: a case report.

    Science.gov (United States)

    Havlicekova, Zuzana; Jesenak, Milos; Freiberger, Tomas; Banovcin, Peter

    2014-09-01

    Primary immunodeficiencies (PID) are becoming a recognized public health problem worldwide. The most important subgroup of these disorders are the antibody deficiencies. X-linked agammaglobulinaemia was the first described entity of this group and is characterised by early onset of recurrent bacterial infections, profound deficiency of all immunoglobulin isotypes and markedly reduced number of peripheral B-lymphocytes. We report the case of a 10-year old boy with X-linked agammaglobulinaemia caused by a previously non-described mutation in BTK gene with typical clinical presentation but delayed diagnosis. Following diagnosis, substitution therapy with intravenous immunoglobulins was started and the clinical status of the patient improved. We reported a case of X-linked agammaglobulinaemia with delayed diagnosis despite the typical anamnestic signs for primary humoral immunodeficiency. The disease was caused by a previously non-reported mutation in the BTK gene. Measurement of serum immunoglobulins should be performed in all children with recurrent, complicated respiratory infections as a screening test for humoral immunodeficiencies.

  15. Frequency of CNKSR2 mutation in the X-linked epilepsy-aphasia spectrum.

    Science.gov (United States)

    Damiano, John A; Burgess, Rosemary; Kivity, Sara; Lerman-Sagie, Tally; Afawi, Zaid; Scheffer, Ingrid E; Berkovic, Samuel F; Hildebrand, Michael S

    2017-03-01

    Synaptic proteins are critical to neuronal function in the brain, and their deficiency can lead to seizures and cognitive impairments. CNKSR2 (connector enhancer of KSR2) is a synaptic protein involved in Ras signaling-mediated neuronal proliferation, migration and differentiation. Mutations in the X-linked gene CNKSR2 have been described in patients with seizures and neurodevelopmental deficits, especially those affecting language. In this study, we sequenced 112 patients with phenotypes within the epilepsy-aphasia spectrum (EAS) to determine the frequency of CNKSR2 mutation within this complex set of disorders. We detected a novel nonsense mutation (c.2314 C>T; p.Arg712*) in one Ashkenazi Jewish family, the male proband of which had a severe epileptic encephalopathy with continuous spike-waves in sleep (ECSWS). His affected brother also had ECSWS with better outcome, whereas the sister had childhood epilepsy with centrotemporal spikes. This mutation segregated in the three affected siblings in an X-linked manner, inherited from their mother who had febrile seizures. Although the frequency of point mutation is low, CNKSR2 sequencing should be considered in families with suspected X-linked EAS because of the specific genetic counseling implications. Wiley Periodicals, Inc. © 2017 International League Against Epilepsy.

  16. Preimplantation genetic diagnosis of X-linked Charcot-Marie-Tooth disease by indirect linkage analysis.

    Science.gov (United States)

    Borgulová, Irena; Putzová, Martina; Soldatova, Inna; Stejskal, David

    2018-03-23

    To present methodical approach of preimplantation genetic diagnosis (PGD) as an option for an unaffected pregnancy in reproductive-age couples who have a genetic risk of the X-linked dominant peripheral neuropathy Charcot-Marie-Tooth type 1 disease. We performed PGD of X-linked Charcot-Marie-Tooth type 1 disease using haplotyping/indirect linkage analysis, when during analysis we reach to exclude embryos that carry a high-risk haplotype linked to the causal mutation p.Leu9Phe in the GJB1 gene. Within the PGD cycle, we examined 4 blastomeres biopsied from cleavage-stage embryos and recommended 3 embryos for transfer. Two embryos were implanted into the uterus; however, it resulted in a singleton pregnancy with a male descendant. Three years later, the couple returned again with spontaneous gravidity. A chorionic biopsy examination of this gravidity ascertained the female sex and a pericentric inversion of chromosome 5 in 70% of the cultivated foetal cells. Using indirect linkage analysis, PGD may help to identify genetic X-linked defects within embryos during screening, thereby circumventing the potential problems with abortion. Copyright © 2017 Elsevier España, S.L.U. All rights reserved.

  17. Mutational studies in X-linked Charcot-Marie-Tooth disease (CMTX)

    Energy Technology Data Exchange (ETDEWEB)

    Cherryson, A.K.; Yeung, L.; Kennerson, M.L.; Nicholson, G.A. [Univ. of Syndey, Concord (Australia)

    1994-09-01

    Charcot-Marie-Tooth disease, also known as hereditary motor and sensory neuropathy (HMSN), is a heterogeneous group of slowly progressive disorders of the peripheral nerve. X-linked CMT (CMTX) is characterized by slow motor nerve conduction velocities in affected males and the presence of mildly affected or normal carrier females with intermediate or normal nerve conduction velocities. CMTX, which has an incidence of 3.1 per 100,000 and accounts for approximately 10% of CMT cases, has been mapped to Xq13. One of the genes lying in this region, connexin 32, has been found to contain alterations in individuals affected with X-linked CMT. We have identified our X-linked families from dominant type 1 CMT families using the clinical criteria given above. These families were screened for point mutations in connexin 32. We have identified three missense mutations, a G{r_arrow}A transition at amino acid 35 (valine to methionine), a C{r_arrow}G transition at amino acid 158 (proline to alanine) and a T{r_arrow}A transition at amino acid 182 (serine to threonine). Another family showed a 18 bp deletion, which removed the amino acid 111 to 116 inclusive (histidine, glycine, aspartic acid, proline, leucine, histidine).

  18. A honey bee can threat ear: Sudden sensorineural hearing loss.

    Science.gov (United States)

    Düzenli, Ufuk; Bozan, Nazım; Ayral, Abdurrahman; Yalınkılıç, Abdülaziz; Kıroğlu, Ahmet Faruk

    2017-11-01

    Sudden sensorineural hearing loss is an otologic emergency. Many etiological factors can lead to this pathology. Honey bee (Apis mellifera) sting may lead to local and systemic reactions due to sensitization of the patient. In this paper we described a sudden sensorineural hearing loss occurred after honey bee sting. Copyright © 2017 Elsevier Inc. All rights reserved.

  19. MR Imaging in Sudden Sensorineural Hearing Loss. Time to Talk.

    Science.gov (United States)

    Conte, G; Di Berardino, F; Sina, C; Zanetti, D; Scola, E; Gavagna, C; Gaini, L; Palumbo, G; Capaccio, P; Triulzi, F

    2017-08-01

    Sudden sensorineural hearing loss is defined as acute hearing loss of the sensorineural type of at least 30 dB over 3 contiguous frequencies that occurs within a 72-hour period. Although many different causative factors have been proposed, sudden sensorineural hearing loss is still considered "idiopathic" in 71%-85% of cases, and treatments are empiric, not based on etiology. MR imaging implemented with a 3D FLAIR sequence has provided new insights into the etiology of sudden sensorineural hearing loss. Herein, we review the current management trends for patients with sudden sensorineural hearing loss, from the initial clinical diagnosis to therapeutic strategies and diagnostic work-up. We focused primarily on MR imaging assessment and discuss the relevance that MR imaging findings might have for patient management, pointing out different perspectives for future clinical research. © 2017 by American Journal of Neuroradiology.

  20. Mobile phone usage does not affect sudden sensorineural hearing loss.

    Science.gov (United States)

    Sagiv, D; Migirov, L; Madgar, O; Nakache, G; Wolf, M; Shapira, Y

    2018-01-01

    Recent studies found that mobile phone users had a significantly greater risk of having elevated thresholds in speech frequencies. This study investigated the correlation between the laterality of sudden sensorineural hearing loss, handedness and the preferred ear for mobile phone use. The study included all patients who presented with sudden sensorineural hearing loss to the Department of Otolaryngology - Head and Neck Surgery in our tertiary referral medical centre between 2014 and 2016. Patients were asked to indicate their dominant hand and preferred ear for mobile phone use. The study comprised 160 patients. No correlation was found between the dominant hand or preferred ear for mobile phone use and the side of sudden sensorineural hearing loss. There was no correlation between the side of the sudden sensorineural hearing loss (preferable or non-preferable for mobile phone use) and audiometric characteristics. No correlation was found between the laterality of ears used for mobile phone and sudden sensorineural hearing loss.

  1. Recovery of Idiopathic Sudden Sensorineural Hearing Loss.

    Science.gov (United States)

    Edizer, Deniz Tuna; Çelebi, Özlem; Hamit, Bahtiyar; Baki, Ahmet; Yiğit, Özgür

    2015-08-01

    The objective was to identify and evaluate factors that may influence the recovery rate in patients with idiopathic sudden sensorineural hearing loss (ISSNHL). A retrospective analysis was performed for patients with sudden sensorineural hearing loss between 2009 and 2013. Those with an identified etiology were excluded. The patients were divided into four treatment groups: (i) systemic corticosteroids (SC) only, (ii) SC+low-molecular-weight heparin (LMWH), (iii) SC+hyperbaric oxygen (HBO), and (iv) SC+LMWH+HBO. Recovery was evaluated according to Siegel's criteria. Age, initial hearing level, onset, treatment and audiogram types, comorbidities, and associated tinnitus and vestibular symptoms were investigated for their impact on prognosis. Two hundred five patients with ISSNHL were included. Recovery was seen in 59% of the patients. The complete recovery rate was significantly lower in patients older than 60 years and in patients presenting with profound hearing loss. Different audiogram curves had no significant effect on recovery. Sudden hearing loss was accompanied by tinnitus in 107 (52.1%) patients and vestibular symptoms in 55 (26.8%); however, neither was noted to affect prognosis. Different treatment combinations did not significantly affect prognosis. However, hypertension and a delay in treatment by more than 10 days from the onset of hearing loss were associated with a worse prognosis. Profound hearing loss, older than 60 years, a delay in treatment by more than 10 days, and hypertension were negative prognostic factors in this study, whereas, the type of audiogram curve and addition of HBO to SC did not affect prognosis.

  2. Studying VEMP in Sudden Sensorineural Hearing Loss

    Directory of Open Access Journals (Sweden)

    Mohsen Rajati

    2011-03-01

    Full Text Available Introduction: Sudden sensorineural hearing loss (SSNHL has a prevalence of 10 in 100,000. Viral infections, vascular obstruction and rupture of the intracochlear membranes are supposed to be its most common etiologies. About 40% of patients experience vertigo or imbalance. The VEMP (vestibular evoked myogenic potentials test is a known approach for detailed study of the labyrinth. The advantage of this test in comparison to other tests is the selected study of sacculus and sacculocochlear pathways. Materials and Methods:  In this cross sectional study all patients with SSNHL diagnosis were admitted and underwent routine standard treatments and diagnostic tests. Clinical symptoms and paraclinic findings were recorded in especially designed forms and VEMP test was performed on admission. Results: Among the 43 cases with sudden sensorineural hearing loss, 14 (32.6% had vertigo. Thirteen patients (39.2% out of 43 had a negative (abnormal VEMP, 6 of which (42.9% had vertigo, while in the 30 VEMP positive (normal cases, vertigo was detected in 8 (26.6%. Discussion: Saccular dysfunction seems to be an important finding in SSNHL. Although it is more prevalent in the patients with vertigo, it can be found in the non-dizzy cases. VEMP disturbance in SSNHL shows more extensive pathological involvement. Conclusion: In SSNHL the pathology isn’t limited to the cochlea and even in patients with no vestibular symptoms sacculus might be involved.

  3. Homozygosity Mapping Reveals Mutations of GRXCR1 as a Cause of Autosomal-Recessive Nonsyndromic Hearing Impairment

    Science.gov (United States)

    Schraders, Margit; Lee, Kwanghyuk; Oostrik, Jaap; Huygen, Patrick L.M.; Ali, Ghazanfar; Hoefsloot, Lies H.; Veltman, Joris A.; Cremers, Frans P.M.; Basit, Sulman; Ansar, Muhammad; Cremers, Cor W.R.J.; Kunst, Henricus P.M.; Ahmad, Wasim; Admiraal, Ronald J.C.; Leal, Suzanne M.; Kremer, Hannie

    2010-01-01

    We identified overlapping homozygous regions within the DFNB25 locus in two Dutch and ten Pakistani families with sensorineural autosomal-recessive nonsyndromic hearing impairment (arNSHI). Only one of the families, W98-053, was not consanguineous, and its sibship pointed toward a reduced critical region of 0.9 Mb. This region contained the GRXCR1 gene, and the orthologous mouse gene was described to be mutated in the pirouette (pi) mutant with resulting hearing loss and circling behavior. Sequence analysis of the GRXCR1 gene in hearing-impaired family members revealed splice-site mutations in two Dutch families and a missense and nonsense mutation, respectively, in two Pakistani families. The splice-site mutations are predicted to cause frameshifts and premature stop codons. In family W98-053, this could be confirmed by cDNA analysis. GRXCR1 is predicted to contain a GRX-like domain. GRX domains are involved in reversible S-glutathionylation of proteins and thereby in the modulation of activity and/or localization of these proteins. The missense mutation is located in this domain, whereas the nonsense and splice-site mutations may result in complete or partial absence of the GRX-like domain or of the complete protein. Hearing loss in patients with GRXCR1 mutations is congenital and is moderate to profound. Progression of the hearing loss was observed in family W98-053. Vestibular dysfunction was observed in some but not all affected individuals. Quantitative analysis of GRXCR1 transcripts in fetal and adult human tissues revealed a preferential expression of the gene in fetal cochlea, which may explain the nonsyndromic nature of the hearing impairment. PMID:20137778

  4. Is X-linked methyl-CpG binding protein 2 a new target for the treatment of Parkinson's disease

    OpenAIRE

    Xie, Teng; Zhang, Jie; Yuan, Xianhou; Yang, Jing; Ding, Wei; Huang, Xin; Wu, Yong

    2013-01-01

    X-linked methyl-CpG binding protein 2 mutations can induce symptoms similar to those of Parkinson's disease and dopamine metabolism disorders, but the specific role of X-linked methyl-CpG binding protein 2 in the pathogenesis of Parkinson's disease remains unknown. In the present study, we used 6-hydroxydopamine-induced human neuroblastoma cell (SH-SY5Y cells) injury as a cell model of Parkinson's disease. The 6-hydroxydopamine (50 μmol/L) treatment decreased protein levels for both X-linked ...

  5. Meiotic drive impacts expression and evolution of x-linked genes in stalk-eyed flies.

    Directory of Open Access Journals (Sweden)

    Josephine A Reinhardt

    Full Text Available Although sex chromosome meiotic drive has been observed in a variety of species for over 50 years, the genes causing drive are only known in a few cases, and none of these cases cause distorted sex-ratios in nature. In stalk-eyed flies (Teleopsis dalmanni, driving X chromosomes are commonly found at frequencies approaching 30% in the wild, but the genetic basis of drive has remained elusive due to reduced recombination between driving and non-driving X chromosomes. Here, we used RNAseq to identify transcripts that are differentially expressed between males carrying either a driving X (XSR or a standard X chromosome (XST, and found hundreds of these, the majority of which are X-linked. Drive-associated transcripts show increased levels of sequence divergence (dN/dS compared to a control set, and are predominantly expressed either in testes or in the gonads of both sexes. Finally, we confirmed that XSR and XST are highly divergent by estimating sequence differentiation between the RNAseq pools. We found that X-linked transcripts were often strongly differentiated (whereas most autosomal transcripts were not, supporting the presence of a relatively large region of recombination suppression on XSR presumably caused by one or more inversions. We have identified a group of genes that are good candidates for further study into the causes and consequences of sex-chromosome drive, and demonstrated that meiotic drive has had a profound effect on sequence evolution and gene expression of X-linked genes in this species.

  6. X-linked adrenal hypoplasia congenita: a case report and ethical dilemma.

    Science.gov (United States)

    Ismail, Heba M; Rincon, Marielisa

    2014-07-01

    Our objective is to present the first case report of X-linked adrenal hypoplasia congenita in a child conceived by a donated egg and which also presented atypically, with initial mineralocorticoid deficiency. Case report with literature review. A late preterm fraternal twin male, conceived by in vitro fertilization of donated eggs, presented shortly after birth with feeding intolerance, hyponatremia, and hyperkalemia. Testing revealed a low aldosterone level, high plasma renin activity, normal cortisol level, and normal 17-hydroxyprogesterone level. He was diagnosed with 18-hydroxylase deficiency based on low 18-hydroxycorticosterone levels and was treated with mineralocorticoid successfully for 17 months. At age 18 months, he presented with dehydration secondary to herpetic gingivostomatitis and was found to be hypoglycemic, hyponatremic, hyperkalemic, and acidotic, with a low serum cortisol level. An adrenocorticotropic hormone (ACTH) stimulation test revealed low levels of all adrenal cortex products, with an elevated ACTH level. He was started on glucocorticoids. Genetic testing confirmed X-linked adrenal hypoplasia congenita (AHC). His asymptomatic fraternal twin underwent genetic testing and the results were negative. The fertility center records indicated that the mother had donated eggs to other families, but none of the children were known to have this disorder. The egg donor was informed but did not pursue genetic testing. We report a case of X-linked AHC presenting in the context of extraordinary ethical considerations. Our case raises a question unique to the era of assisted reproduction: should routine genetic screening of gamete donors be done for rare but potentially life-threatening conditions?

  7. X-Linked Dyskeratosis Congenita Is Predominantly Caused by Missense Mutations in the DKC1 Gene

    OpenAIRE

    Knight, S.W.; Heiss, N.S.; Vulliamy, T.J.; Greschner, S.; Stavrides, G.; Pai, G.S.; Lestringant, G.; Varma, N.; Mason, P.J.; Dokal, I.; Poustka, A.

    1999-01-01

    Dyskeratosis congenita is a rare inherited bone marrow-failure syndrome characterized by abnormal skin pigmentation, nail dystrophy, and mucosal leukoplakia. More than 80% of patients develop bone-marrow failure, and this is the major cause of premature death. The X-linked form of the disease (MIM 305000) has been shown to be caused by mutations in the DKC1 gene. The gene encodes a 514-amino-acid protein, dyskerin, that is homologous to Saccharomyces cerevisiae Cbf5p and rat Nap57 proteins. B...

  8. X-linked inhibitor of apoptosis regulates T cell effector function

    DEFF Research Database (Denmark)

    Zehntner, Simone P; Bourbonnière, Lyne; Moore, Craig S

    2007-01-01

    To understand how the balance between pro- and anti-apoptotic signals influences effector function in the immune system, we studied the X-linked inhibitor of apoptosis (XIAP), an endogenous regulator of cellular apoptosis. Real-time PCR showed increased XIAP expression in blood of mice...... and oligodendrocytes were not affected; neither did apoptosis increase in liver, where XIAP knockdown also occurred. ASO-XIAP increased susceptibility of T cells to activation-induced apoptosis in vitro. Our results identify XIAP as a critical controller of apoptotic susceptibility of effector T cell function...

  9. Phenotypic Conservation in Patients With X-Linked Retinitis Pigmentosa Caused by RPGR Mutations

    Science.gov (United States)

    Zahid, Sarwar; Khan, Naheed; Branham, Kari; Othman, Mohammad; Karoukis, Athanasios J.; Sharma, Nisha; Moncrief, Ashley; Mahmood, Mahdi N.; Sieving, Paul A.; Swaroop, Anand; Heckenlively, John R.; Jayasundera, Thiran

    2015-01-01

    IMPORTANCE For patients with X-linked retinitis pigmentosa and clinicians alike, phenotypic variability can be challenging because it complicates counseling regarding patients’ likely visual prognosis. OBJECTIVE To evaluate the clinical findings from patients with X-linked retinitis pigmentosa with 13 distinct RPGR mutations and assess for phenotypic concordance or variability. DESIGN Retrospective medical record review of data collected from 1985 to 2011. SETTING Kellogg Eye Center, University of Michigan. PATIENTS A total of 42 patients with X-linked retinitis pigmentosa with mutations in RPGR. Age at first visit ranged from 4 to 53 years, with follow-up ranging from 1 to 11 visits (median follow-up time, 5.5 years; range, 1.4-32.7 years, for 23 patients with >1 visit). MAIN OUTCOMES AND MEASURES Clinical data assessed for concordance included visual acuity (VA), Goldmann visual fields (GVFs), and full-field electroretinography (ERG). Electroretinography phenotype (cone-rod vs rod-cone dysfunction) was defined by the extent of photopic vs scotopic abnormality. Qualitative GVF phenotype was determined by the GVF pattern, where central or peripheral loss suggested cone or rod dysfunction, respectively. Goldmann visual fields were also quantified and compared among patients. RESULTS Each mutation was detected in 2 or more related or unrelated patients. Five mutations in 11 patients displayed strong concordance of VA, while 4 mutations in 16 patients revealed moderate concordance of VA. A definitive cone-rod or rod-cone ERG pattern consistent among patients was found in 6 of 13 mutations (46.2%); the remaining mutations were characterized by patients demonstrating both phenotypes or who had limited data or nonrecordable ERG values. Concordant GVF phenotypes (7 rod-cone pattern vs 4 cone-rod pattern) were seen in 11 of 13 mutations (84.6%). All 6 mutations displaying a constant ERG pattern within the mutation group revealed a GVF phenotype consistent with the ERG

  10. X-linked anhidrotic ectodermal dysplasia (ED1 in men, mice, and cattle

    Directory of Open Access Journals (Sweden)

    Drögemüller Cord

    2003-06-01

    Full Text Available Abstract Ectodermal dysplasias are a large group of rare genetic disorders characterized by impaired development of hair, teeth, and eccrine glands in humans, mice, and cattle. Here, we review the cloning, mutation analyses, and functional studies of the known causative genes for the X-chromosomal anhidrotic ectodermal dysplasia (ED1 in these species. Mutations in the ectodysplasin 1 (ED1 gene are responsible for X-linked anhidrotic ectodermal dysplasia. The ED1 gene encodes a signaling molecule of the tumor necrosis factor family that is involved in development of ectodermal appendages. The bovine disorder may serve as an animal model for human ED1.

  11. Adenoassociated Virus Serotype 9-Mediated Gene Therapy for X-Linked Adrenoleukodystrophy

    OpenAIRE

    Gong, Yi; Mu, Dakai; Prabhakar, Shilpa; Moser, Ann; Musolino, Patricia; Ren, JiaQian; Breakefield, Xandra O; Maguire, Casey A; Eichler, Florian S

    2015-01-01

    X-linked adrenoleukodystrophy (X-ALD) is a devastating neurological disorder caused by mutations in the ABCD1 gene that encodes a peroxisomal ATP-binding cassette transporter (ABCD1) responsible for transport of CoA-activated very long-chain fatty acids (VLCFA) into the peroxisome for degradation. We used recombinant adenoassociated virus serotype 9 (rAAV9) vector for delivery of the human ABCD1 gene (ABCD1) to mouse central nervous system (CNS). In vitro, efficient delivery of ABCD1 gene was...

  12. Newborn screening for X-linked adrenoleukodystrophy: further evidence high throughput screening is feasible.

    Science.gov (United States)

    Theda, Christiane; Gibbons, Katy; Defor, Todd E; Donohue, Pamela K; Golden, W Christopher; Kline, Antonie D; Gulamali-Majid, Fizza; Panny, Susan R; Hubbard, Walter C; Jones, Richard O; Liu, Anita K; Moser, Ann B; Raymond, Gerald V

    2014-01-01

    X-linked adrenoleukodystrophy (ALD) is characterized by adrenal insufficiency and neurologic involvement with onset at variable ages. Plasma very long chain fatty acids are elevated in ALD; even in asymptomatic patients. We demonstrated previously that liquid chromatography tandem mass spectrometry measuring C26:0 lysophosphatidylcholine reliably identifies affected males. We prospectively applied this method to 4689 newborn blood spot samples; no false positives were observed. We show that high throughput neonatal screening for ALD is methodologically feasible. Copyright © 2013 Elsevier Inc. All rights reserved.

  13. X-linked albinism-deafness syndrome and Waardenburg syndrome type II: A hypothesis

    Energy Technology Data Exchange (ETDEWEB)

    Zlotogora, J. [Hadassah Univ. Hospital, Jerusalem (Israel)

    1995-11-20

    Margolis reported on a large pedigree with a {open_quotes}new{close_quotes} X-linked syndrome of profound deafness and albinism (MIM 300700, albinism-deafness syndrome). The affected males presented with profound deafness and severe pigmentary abnormalities of the skin. At birth the skin appeared as almost albinotic except for areas of light pigmentation over the gluteal and scrotal areas, and thereafter pigmentation gradually increased over the body. Skin changes ultimately included areas of hypopigmentation and spots of hyperpigmentation. Some of the affected males also had blue irides, heterochromia, or segmental color iris changes. In carrier females, variable hearing impairment was documented without any pigmentary changes. 9 refs., 1 fig.

  14. A Child with X-Linked Agammaglobulinemia and Enthesitis-Related Arthritis

    Directory of Open Access Journals (Sweden)

    Sukesh Sukumaran

    2011-01-01

    Full Text Available X-linked agammaglobulinemia (XLA is a primary immune deficiency characterized by recurrent bacterial infections and profoundly depressed serum immunoglobulin levels and circulating mature B cells. We describe a 12-year-old boy with XLA and enthesitis-related arthritis (ERA. To date, there has been a paucity of reports of noninfectious inflammatory arthritis in children with XLA. This case illustrates that functional B cells and/or immunoglobulin are not required for ERA pathogenesis. In addition, this case suggests a possible link between immune deficiency, immune dysregulation, and rheumatic illness.

  15. Helicobacter cinaedi bacteremia resulting from antimicrobial resistance acquired during treatment for X-linked agammaglobulinemia.

    Science.gov (United States)

    Toyofuku, Meiwa; Tomida, Junko; Kawamura, Yoshiaki; Miyata, Ippei; Yuza, Yuki; Horikoshi, Yuho

    2016-10-01

    This is the first report of penicillin/cephalosporin-resistant Helicobacter cinaedi arising from prolonged treatment. H. cinaedi, common among immunocompromised patients, caused recurrent bacteremia and cellulitis in a 19-year-old Japanese man with X-linked agammaglobulinemia. The minimal inhibitory concentration of these drugs was raised, which subsequently resulted in clinical failure. Prolonged suboptimal treatment may cause bacterial resistance to β-lactam antibiotics in H. cinaedi. It is possible that this resistance may have contributed to the treatment failure. Copyright © 2016 Japanese Society of Chemotherapy and The Japanese Association for Infectious Diseases. Published by Elsevier Ltd. All rights reserved.

  16. Sudden Sensorineural Hearing Loss; Prognostic Factors

    Directory of Open Access Journals (Sweden)

    Arjun Dass

    2015-09-01

    Full Text Available Introduction: Sudden sensorineural hearing loss (SSNHL is a frightening and frustrating symptom for the patient as well as the physician. Prognosis is affected by multiple factors including duration of hearing loss, presence of associated vertigo and tinnitus, and co-morbidities such as hypertension and diabetes.   Materials and Methods: Forty subjects presenting to our department with features of sudden hearing loss were included in the study. Detailed otological history and examination, serial audiometric findings and course of disease were studied.   Results: Subjects presenting late (in older age, having associated vertigo, hypertension and diabetes had a significantly lower rate of recovery.   Conclusion:  Only 60–65% of patients experiencing SSNHL recover within a period of 1 month; this rate is further affected by presence of multiple prognostic indicators.

  17. Sensorineural hearing loss in hemorrhagic dengue?

    Directory of Open Access Journals (Sweden)

    Bruna Natália Freire Ribeiro

    2015-01-01

    Discussion and conclusion: This is the first case report that brings together DHF and sudden hearing loss. In the development of this case no other cause to sudden hearing loss was found and the correlation between dengue and hearing loss was questioned. In the literature review was found that some viruses, as mumps virus, varicella-zoster virus and HSV-1 and HSV-2 are related to sudden hearing loss, all of them fit in the viral theory. Besides the viral theory of sudden hearing loss, there is the vascular theory that is the occlusion of the end artery that supplies the cochlea. DHF has a vascular commitment, and the hypothesis of a vascular cause could be elicited in this case. Many studies in this area are needed and this article has the objective of elicit the discussion about the subject. Could dengue be associated with sensorineural hearing loss?

  18. Prevalence of TECTA mutation in patients with mid-frequency sensorineural hearing loss.

    Science.gov (United States)

    Yamamoto, Nobuko; Mutai, Hideki; Namba, Kazunori; Morita, Noriko; Masuda, Shin; Nishi, Yasuyuki; Nakano, Atsuko; Masuda, Sawako; Fujioka, Masato; Kaga, Kimitaka; Ogawa, Kaoru; Matsunaga, Tatsuo

    2017-09-25

    To date, 102 genes have been reported as responsible for non-syndromic hearing loss, some of which are associated with specific audiogram features. Four genes have been reported as causative for mid-frequency sensorineural hearing loss (MFSNHL), among which TECTA is the most frequently reported; however, the prevalence of TECTA mutations is unknown. To elucidate the prevalence of TECTA mutation in MFSNHL and clarify genotype-phenotype correlations, we analyzed the genetic and clinical features of patients with MFSNHL. Subjects with bilateral non-syndromic hearing loss were prescreened for GJB2 and m.1555A > G and m.3243A > G mitochondrial DNA mutations, and patients with inner ear malformations were excluded. We selected MFSNHL patients whose audiograms met the U-shaped criterion proposed by the GENDEAF study group, along with those with shallow U-shaped audiograms, for TECTA analysis. All TECTA exons were analyzed by Sanger sequencing. Novel missense variants were classified as possibly pathogenic, non-pathogenic, and variants of uncertain significance, based on genetic data. To evaluate novel possibly pathogenic variants, we predicted changes in protein structure by molecular modeling. Pathogenic and possibly pathogenic variants of TECTA were found in 4 (6.0%) of 67 patients with MFSNHL. In patients with U-shaped audiograms, none (0%) of 21 had pathogenic or possibly pathogenic variants. In patients with shallow U-shaped audiograms, four (8.7%) of 46 had pathogenic or possibly pathogenic variants. Two novel possibly pathogenic variants were identified and two previously reported mutations were considered as variant of unknown significance. The clinical features of patients with pathogenic and possibly pathogenic variants were consistent with those in previous studies. Pathogenic or possibly pathogenic variants were identified in 3 of 23 families (13.0%) which have the family histories compatible with autosomal dominant and 1 of 44 families (2.3%) which have

  19. Germline but macrophage-tropic CYBB mutations in kindreds with X-linked predisposition to tuberculous mycobacterial diseases

    OpenAIRE

    2011-01-01

    Abstract Germline mutations in the human CYBB gene, encoding the gp91phox subunit of the phagocyte NADPH oxidase, impair the respiratory burst of phagocytes and result in X-linked chronic granulomatous disease. We report two kindreds in which otherwise healthy male adults show X-linked recessive Mendelian susceptibility to mycobacterial diseases. These patients harbor mutations in CYBB that profoundly reduce the respiratory burst in monocyte-derived macrophages, but not in monocyte...

  20. X-linked hypomyelination with spondylometaphyseal dysplasia (H-SMD) associated with mutations in AIFM1.

    Science.gov (United States)

    Miyake, Noriko; Wolf, Nicole I; Cayami, Ferdy K; Crawford, Joanna; Bley, Annette; Bulas, Dorothy; Conant, Alex; Bent, Stephen J; Gripp, Karen W; Hahn, Andreas; Humphray, Sean; Kimura-Ohba, Shihoko; Kingsbury, Zoya; Lajoie, Bryan R; Lal, Dennis; Micha, Dimitra; Pizzino, Amy; Sinke, Richard J; Sival, Deborah; Stolte-Dijkstra, Irene; Superti-Furga, Andrea; Ulrick, Nicole; Taft, Ryan J; Ogata, Tsutomu; Ozono, Keiichi; Matsumoto, Naomichi; Neubauer, Bernd A; Simons, Cas; Vanderver, Adeline

    2017-12-01

    An X-linked condition characterized by the combination of hypomyelinating leukodystrophy and spondylometaphyseal dysplasia (H-SMD) has been observed in only four families, with linkage to Xq25-27, and recent genetic characterization in two families with a common AIFM1 mutation. In our study, 12 patients (6 families) with H-SMD were identified and underwent comprehensive assessment accompanied by whole-exome sequencing (WES). Pedigree analysis in all families was consistent with X-linked recessive inheritance. Presentation typically occurred between 12 and 36 months. In addition to the two disease-defining features of spondylometaphyseal dysplasia and hypomyelination on MRI, common clinical signs and symptoms included motor deterioration, spasticity, tremor, ataxia, dysarthria, cognitive defects, pulmonary hypertension, nystagmus, and vision loss due to retinopathy. The course of the disease was slowly progressive. All patients had maternally inherited or de novo mutations in or near exon 7 of AIFM1, within a region of 70 bp, including synonymous and intronic changes. AIFM1 mutations have previously been associated with neurologic presentations as varied as intellectual disability, hearing loss, neuropathy, and striatal necrosis, while AIFM1 mutations in this small region present with a distinct phenotype implicating bone. Analysis of cell lines derived from four patients identified significant reductions in AIFM1 mRNA and protein levels in osteoblasts. We hypothesize that AIFM1 functions in bone metabolism and myelination and is responsible for the unique phenotype in this condition.

  1. A rare variant in the FHL1 gene associated with X-linked recessive hypoparathyroidism.

    Science.gov (United States)

    Pillar, Nir; Pleniceanu, Oren; Fang, Mingyan; Ziv, Limor; Lahav, Einat; Botchan, Shay; Cheng, Le; Dekel, Benjamin; Shomron, Noam

    2017-07-01

    Isolated familial hypoparathyroidism is an extremely rare disorder, which to date has been linked to several loci including mutations in CASR, GCM2, and PTH, as well as a rare condition defined as X-linked recessive hypoparathyroidism, previously associated with a 1.5 Mb region on Xq26-q27. Here, we report a patient with hypocalcemia-induced seizures leading to the diagnosis of primary hypoparathyroidism. Mutations in CASR, GCM2, and PTH were ruled out, while whole exome sequencing of the family suggested FHL1, located on chromosome Xq26, as the most likely causative gene variant (FHL1, exon 4, c.C283T, p.R95W). Since FHL1 has not been linked to calcium regulation before, we provide evidence for its functional role in hypoparathyroidism by: (i) bioinformatics analysis coupling its action to known modulators of PTH function; (ii) observing strong expression of fhl1b in Corpuscles of Stannius, gland-like aggregates in zebrafish that function in calcium regulation similar to mammalian PTH; and (iii) implicating fhl1b and FHL1 as regulators of calcium homeostasis in zebrafish and human cells, respectively. Altogether, our data suggest that FHL1 is a novel regulator of calcium homeostasis and implicate it as the causative gene for X-linked recessive hypoparathyroidism.

  2. ABCD1 mutations and phenotype distribution in Chinese patients with X-linked adrenoleukodystrophy.

    Science.gov (United States)

    Niu, Yan-Fang; Ni, Wang; Wu, Zhi-Ying

    2013-06-10

    X-linked adrenoleukodystrophy (X-ALD) is a neurodegenerative disorder resulting from mutations within the ABCD1 gene. Adrenomyeloneuropathy (AMN) and childhood cerebral ALD (CCALD) are most common phenotypes in the Western ALD patients. Here we performed mutation analysis of ABCD1 in 10 Chinese ALD families and identified 8 mutations, including one novel deletion (c.1477_1488+11del23) and 7 known mutations. Mutations c.1772G>A and c.1816T>C were first reported in the Chinese patients. Mutations c.1661G>A and c.1679C>T were demonstrated to be de novo mutations. The dinucleotide deletion 1415_16delAG, described as a mutational hotspot in different ethnic groups, was identified in two families. In addition, we performed a retrospective nation-wide mutation study of X-linked ALD in China based on a literature review. The retrospective study further confirmed the hypothesis that exon 6 is a potential mutation cluster region in the Asian populations. Furthermore, it suggested that CCALD is the most common phenotype in China. Copyright © 2013 Elsevier B.V. All rights reserved.

  3. [Preliminary analysis of mutations in X-linked adrenoleukodystrophy gene(ABCD1) in Chinese patients].

    Science.gov (United States)

    Xiong, Hui; Pan, Hong; Zhang, Yue-hua; Wu, Xi-ru

    2003-10-01

    To detect the mutations in exon 6 of ABCD1 gene encoding adrenoleukodystrophy protein(ALDP) in Chinese X-linked adrenoleukodystrophy (ALD MIM 300100) patients. Genomic DNA from 14 unrelated patients and two patients' parents with X-linked ALD was extracted using standard procedures from the peripheral blood leukocytes. Polymerase chain reaction (PCR) and DNA direct sequencing were employed to analyze exon 6 of ABCD1 gene. Three mutations in exon 6 were identified in 3 of 14 patients. One mutation was deleted 1 base pair at splice acceptor-site (1489-6 del C). It was not clear what the effect of this mutation is on the ALD protein, maybe induce splicing error. One missense mutation: T1559A(L520Q). These two patients' mothers were heterozygous. The third patient had a mutation: G1548A (L516 L), which is a known polymorphism. It was not a disease causing mutation, so there should be another mutation in this patient. For the first time, mutations in ABCD1 are identified in Chinese ALD patients in the mainland of China. No major gene deletion or rearrangement is detected in exon 6. Despite many mutations having been identified in patients with these clinical phenotypes, the genotype-phenotype correlations have not been clarified, suggesting that other genetic or environmental factors may also be involved in determining phenotypic expression in ALD. Two carriers are also confirmed.

  4. Clinical characteristics and mutation analysis of X-linked severe combined immunodeficiency in China.

    Science.gov (United States)

    Zhang, Cui; Zhang, Zhi-Yong; Wu, Jun-Feng; Tang, Xue-Mei; Yang, Xi-Qiang; Jiang, Li-Ping; Zhao, Xiao-Dong

    2013-02-01

    X-linked severe combined immunodeficiency (X-SCID) is a rare, life-threatening immune disorder, caused by mutations of the gene for the γ-chain (γc) of the interleukin-2 receptor, IL2RG. We analyzed the clinical, immunologic, and molecular characteristics of children with X-SCID, attempting to improve the diagnosis and treatment of X-SCID in China. X-SCID was suspected in male infants with recurrent or persistent infections. Eleven male infants from ten unrelated Chinese families were included. The IL2RG gene was amplified and sequenced, followed by mutation analysis in these children and their female relatives. X-linked short tandem repeat (X-STR) typing was done to define the maternal lymphocyte engraftment. The 11 children exhibited recurrent infections and 10 of them had lymphopenia. B cells were present in all patients, T cells were markedly reduced in 10, and NK cells were markedly reduced in 9. Nine IL2RG gene mutations were identified in the 11 children, with 5 novel mutations. One patient was found to have the maternal lymphocyte engraftment. The clinical presentations and immunologic characteristics of the X-SCID patients were accordingly quite uniform despite the heterogeneity of mutations locating almost in the entire γc gene.

  5. Mutation of the BTK gene and clinical feature of X-linked agammaglobulinemia in mainland China.

    Science.gov (United States)

    Wang, Ying; Kanegane, Hirokazu; Wang, Xiaochuan; Han, Xiaohua; Zhang, Qian; Zhao, Shunying; Yu, Yeheng; Wang, Jingyi; Miyawaki, Toshio

    2009-05-01

    X-Linked agammaglobulinemia is a prototypical humoral immunodeficiency with the mutation of the Bruton's tyrosine kinase gene. We investigated the gene mutation and clinical features of 30 Chinese X-linked agammaglobulinemia (XLA) patients from 27 families. There were 26 mutations, including 11 novel and 15 recurrent mutations, distributing over the entire gene. The nucleotide and amino acid aberration, 1129C>T(H333Y) and 1196T>A(I355N), in SH2 have not been reported before. Five (I355N, W124R, R520X, I590F, G594E) of the 24 mutations not detected in the mothers receiving gene analysis were determined to be de novo. Two mutations occurred within intronic splice-site sequences (intron5(-2)A>G, intron17(-2)A>T). There are eight mutations in the PH domain, two mutations in the SH3 domain, three mutations in the SH2 domain, one mutation in the TH domain, and other 16 mutations in the TK domain. The mutations of protein domain is most common in TK (53%) domain and then in PH(8%) domain. Missense and nonsense mutations were found equal in 46% of the detected mutations. All of the patients are alive, but one died of liver cancer. Clinical features and serum Igs levels range variedly and were not correlated with genotypes. Our results demonstrated molecular genetic characteristics of XLA in mainland China.

  6. Treatment of Chronic Enterovirus Encephalitis With Fluoxetine in a Patient With X-Linked Agammaglobulinemia.

    Science.gov (United States)

    Gofshteyn, Jacqueline; Cárdenas, Ana María; Bearden, David

    2016-11-01

    Enterovirus may result in a devastating chronic encephalitis in immunocompromised patients, particularly in patients with X-linked agammaglobulinemia. Prognosis for patients with chronic enterovirus encephalitis is poor, almost invariably resulting in mortality without specific treatment. There are currently no approved antiviral agents for enterovirus, but the antidepressant drug fluoxetine has been identified through library-based compound screening as a potential anti-enteroviral agent in vitro. However, use of fluoxetine has not previously been studied in humans with enteroviral disease. A five year old boy with X-linked agammaglobulinemia presented with progressive neurological deterioration and was found to have chronic enterovirus encephalitis by brain biopsy. He failed to respond to standard treatment with high dose intravenous immunoglobulin, but showed stabilization and improvement following treatment with fluoxetine. This is the first report to describe the use of fluoxetine as a potential therapy for chronic enterovirus infection. Further investigation of fluoxetine as a treatment option for chronic enterovirus encephalitis is necessary. Copyright © 2016 Elsevier Inc. All rights reserved.

  7. Molecular genetic analysis of X-linked hypogammaglobulinemia and isolated growth hormone deficiency

    Energy Technology Data Exchange (ETDEWEB)

    Stewart, D.M.; Kurman, C.C.; Staudt, L.M. [Univ. of Brescia (Italy)] [and others

    1995-09-01

    In 1980 the clinical syndrome of X-linked hypogammaglobulinemia and isolated growth hormone deficiency (XLA/GHD) was described. XLA/GHD patients have reduced serum levels of Ig and normal cell-mediated immunity, and thus resemble patients with Bruton`s X-linked agammaglobulinemia (XLA). However, XLA/GHD patients also have isolated GHD. Mutations and deletions in the Bruton`s tyrosine kinase gene (BTK) are responsible for Bruton`s XLA. We investigated BTK gene expression in an XLA/GHD patient from the family originally described by Northern analysis, cDNA sequencing, and Western analysis of protein production using mAb to BTK. BTK mRNA was normal in size and abundance, and the mRNA sequence was normal over the coding region, except for a single silent mutation. BTK protein was present in normal amounts in PBMC of this patient. Thus, at the molecular level, XLA/GHD is a different disease entity from Bruton`s XLA. These results suggest that undescribed genes critical for B cell development and growth hormone production exist on the X chromosome. 17 refs., 4 figs.

  8. Linkage and candidate gene analysis of X-linked familial exudative vitreoretinopathy

    Energy Technology Data Exchange (ETDEWEB)

    Shastry, B.S.; Hartzer, M.K. [Oakland Univ., Rochester, MI (United States); Hejtmancik, J.F. [National Eye Institute, Bethesda, MD (United States)] [and others

    1995-05-20

    Familial exudative vitreoretinopathy (FEVR) is a hereditary eye disorder characterized by avascularity of the peripheral retina, retinal exudates, tractional detachment, and retinal folds. The disorder is most commonly transmitted as an autosomal dominant trait, but X-linked transmission also occurs. To initiate the process of identifying the gene responsible for the X-linked disorder, linkage analysis has been performed with three previously unreported three- or four-generation families. Two-point analysis showed linkage to MAOA (Z{sub max} = 2.1, {theta}{sub max} = 0) and DXS228 (Z{sub max} = 0.5, {theta}{sub max} = 0.11), and this was further confirmed by multipoint analysis with these same markers (Z{sub max} = 2.81 at MAOA), which both lie near the gene causing Norrie disease. Molecular genetic analysis further reveals a missense mutation (R121W) in the third exon of the Norrie`s disease gene that perfectly cosegregates with the disease through three generations in one family. This mutation was not detected in the unaffected family members and six normal unrelated controls, suggesting that it is likely to be the pathogenic mutation. Additionally, a polymorphic missense mutation (H127R) was detected in a severely affected patient. 21 refs., 3 figs., 1 tab.

  9. Long-term follow-up of a family with dominant X-linked retinitis pigmentosa

    Science.gov (United States)

    Wu, DM; Khanna, H; Atmaca-Sonmez, P; Sieving, PA; Branham, K; Othman, M; Swaroop, A; Daiger, SP; Heckenlively, JR

    2010-01-01

    Purpose To document the progression of disease in male and female members of a previously described family with X-linked dominant retinitis pigmentosa (RP) caused by a de novo insertion after nucleotide 173 in exon ORF15 of RPGR. Methods The clinical records of 19 members of family UTAD054 were reviewed. Their evaluations consisted of confirmation of family history, standardised electroretinograms (ERGs), Goldmann visual fields, and periodic ophthalmological examinations over a 23-year period. Results Male members of family UTAD054 had non-recordable to barely recordable ERGs from early childhood. The males showed contracted central fields and developed more severe retinopathy than the females. The female members showed a disease onset delayed to teenage years, recordable but diminishing photopic and scotopic ERG amplitudes in a cone-rod pattern, progressive loss and often asymmetric visual fields, and diffuse atrophic retinopathy with fewer pigment deposits compared with males. Conclusions This insertion mutation in the RPGR exon ORF15 is associated with a RP phenotype that severely affects males early and females by 30 years of age, and is highly penetrant in female members. Families with dominant-acting RPGR mutations may be mistaken to have an autosomal mode of inheritance resulting in an incorrect prediction of recurrence risk and prognosis. Broader recognition of X-linked RP forms with dominant inheritance is necessary to facilitate appropriate counselling of these patients. PMID:19893586

  10. Convergence of Human Genetics and Animal Studies: Gene Therapy for X-Linked Retinoschisis.

    Science.gov (United States)

    Bush, Ronald A; Wei, Lisa L; Sieving, Paul A

    2015-06-22

    Retinoschisis is an X-linked recessive genetic disease that leads to vision loss in males. X-linked retinoschisis (XLRS) typically affects young males; however, progressive vision loss continues throughout life. Although discovered in 1898 by Haas in two brothers, the underlying biology leading to blindness has become apparent only in the last 15 years with the advancement of human genetic analyses, generation of XLRS animal models, and the development of ocular monitoring methods such as the electroretinogram and optical coherence tomography. It is now recognized that retinoschisis results from cyst formations within the retinal layers that interrupt normal visual neurosignaling and compromise structural integrity. Mutations in the human retinoschisin gene have been correlated with disease severity of the human XLRS phenotype. Introduction of a normal human retinoschisin cDNA into retinoschisin knockout mice restores retinal structure and improves neural function, providing proof-of-concept that gene replacement therapy is a plausible treatment for XLRS. Copyright © 2015 Cold Spring Harbor Laboratory Press; all rights reserved.

  11. Test-Retest Intervisit Variability of Functional and Structural Parameters in X-Linked Retinoschisis.

    Science.gov (United States)

    Jeffrey, Brett G; Cukras, Catherine A; Vitale, Susan; Turriff, Amy; Bowles, Kristin; Sieving, Paul A

    2014-09-01

    To examine the variability of four outcome measures that could be used to address safety and efficacy in therapeutic trials with X-linked juvenile retinoschisis. Seven men with confirmed mutations in the RS1 gene were evaluated over four visits spanning 6 months. Assessments included visual acuity, full-field electroretinograms (ERG), microperimetric macular sensitivity, and retinal thickness measured by optical coherence tomography (OCT). Eyes were separated into Better or Worse Eye groups based on acuity at baseline. Repeatability coefficients were calculated for each parameter and jackknife resampling used to derive 95% confidence intervals (CIs). The threshold for statistically significant change in visual acuity ranged from three to eight letters. For ERG a-wave, an amplitude reduction greater than 56% would be considered significant. For other parameters, variabilities were lower in the Worse Eye group, likely a result of floor effects due to collapse of the schisis pockets and/or retinal atrophy. The criteria for significant change (Better/Worse Eye) for three important parameters were: ERG b/a-wave ratio (0.44/0.23), point wise sensitivity (10.4/7.0 dB), and central retinal thickness (31%/18%). The 95% CI range for visual acuity, ERG, retinal sensitivity, and central retinal thickness relative to baseline are described for this cohort of participants with X-linked juvenile retinoschisis (XLRS). A quantitative understanding of the variability of outcome measures is vital to establishing the safety and efficacy limits for therapeutic trials of XLRS patients.

  12. Genetic analysis of a kindred with X-linked mental handicap and retinitis pigmentosa

    Energy Technology Data Exchange (ETDEWEB)

    Aldred, M.A.; Dry, K.L.; Hardwick, L.J.; Teague, P.W.; Lester, D.H.; Brown, J.; Spowart, G.; Carothers, A.D.; Wright, A.F. [Western General Hospital, Edinburgh, Scotland (United Kingdom); Knight-Jones, E.B. [Univ. of Nottingham (United Kingdom)] [and others

    1994-11-01

    A kindred is described in which X-linked nonspecific mental handicap segregates together with retinitis pigmentosa. Carrier females are mentally normal but may show signs of the X-linked retinitis pigmentosa carrier state and become symptomatic in their later years. Analysis of polymorphic DNA markers at nine loci on the short arm of the X chromosome shows that no crossing-over occurs between the disease and Xp11 markers DXS255, TIMP, DXS426, MAOA, and DXS228. The 90% confidence limits show that the locus is in the Xp21-q21 region. Haplotype analysis is consistent with the causal gene being located proximal to the Xp21 loci DXS538 and 5{prime}-dystrophin on the short arm of the X chromosome. The posterior probability of linkage to the RP2 region of the X chromosome short arm (Xp11.4-p11.23) is .727, suggesting the possibility of a contiguous-gene-deletion syndrome. No cytogenetic abnormality has been identified. 33 refs., 2 figs., 2 tabs.

  13. Linkage localization of X-linked Charcot-Marie-Tooth disease

    Energy Technology Data Exchange (ETDEWEB)

    Bergoffen, J. (Children' s Hospital, Philadelphia, PA (United States) Univ. of Pennsylvania, Philadelphia (United States)); Trofatter, J.; Haines, J.L. (Massachusetts General Hospital, Boston (United States)); Pericak-Vance, M.A. (Duke Univ., Durham, NC (United States)); Chance, P.F. (Univ. of Utah, Salt Lake City (United States)); Fischbeck, K.H. (Univ. of Pennsylvania, Philadelphia (United States))

    1993-02-01

    Charcot-Marie-Tooth disease (CMT), also known as hereditary motor and sensory neuropathy, is a heterogeneous group of slowly progressive, degenerative disorders of peripheral nerve. X-linked CMT (CMTX) (McKusick 302800), a subdivision of type I, or demyelinating, CMT is an X-linked dominant condition with variable penetrance. Previous linkage analysis using RFLPs demonstrated linkage to markers on the proximal long and short arms of the X chromosome, with the more likely localization on the proximal long arm of the X chromosome. Available variable simple-sequence repeats (VSSRs) broaden the possibilities for linkage analysis. This paper presents new linkage data and recombination analysis derived from work with four VSSR markers - AR, PGKP1, DXS453, and DXYS1X - in addition to analysis using RFLP markers described elsewhere. These studies localize the CMTX gene to the proximal Xq segment between PGKP1 (Xq11.2-12) and DXS72 (Xq21.1), with a combined maximum multipoint lod score of 15.3 at DXS453 ([theta] = 0). 32 refs., 3 figs., 2 tabs.

  14. X-linked Charcot-Marie-Tooth disease predominates in a cohort of multiethnic Malaysian patients.

    Science.gov (United States)

    Shahrizaila, Nortina; Samulong, Sarimah; Tey, Shelisa; Suan, Liaw Chiew; Meng, Lao Kah; Goh, Khean Jin; Ahmad-Annuar, Azlina

    2014-02-01

    Data regarding Charcot-Marie-Tooth disease is lacking in Southeast Asian populations. We investigated the frequency of the common genetic mutations in a multiethnic Malaysian cohort. Patients with features of Charcot-Marie-Tooth disease or hereditary liability to pressure palsies were investigated for PMP22 duplication, deletion, and point mutations and GJB1, MPZ, and MFN2 point mutations. Over a period of 3 years, we identified 25 index patients. A genetic diagnosis was reached in 60%. The most common were point mutations in GJB1, accounting for X-linked Charcot-Marie-Tooth disease (24% of the total patient population), followed by PMP22 duplication causing Charcot-Marie-Tooth disease type 1A (20%). We also discovered 2 novel GJB1 mutations, c.521C>T (Proline174Leucine) and c.220G>A (Valine74Methionine). X-linked Charcot-Marie-Tooth disease was found to predominate in our patient cohort. We also found a better phenotype/genotype correlation when applying a more recently recommended genetic approach to Charcot-Marie-Tooth disease. Copyright © 2013 Wiley Periodicals, Inc.

  15. Prenatal growth restriction, retinal dystrophy, diabetes insipidus and white matter disease: expanding the spectrum of PRPS1-related disorders

    NARCIS (Netherlands)

    Al-Maawali, Almundher; Dupuis, Lucie; Blaser, Susan; Heon, Elise; Tarnopolsky, Mark; Al-Murshedi, Fathiya; Marshall, Christian R.; Paton, Tara; Scherer, Stephen W.; Roelofsen, Jeroen; van Kuilenburg, André B. P.; Mendoza-Londono, Roberto; Boycott, Kym; Friedman, Jan; Michaud, Jacques; Bernier, Francois; Brudno, Michael; Fernandez, Bridget; Knoppers, Bartha; Samuels, Mark; Scherer, Steve; Marcadier, Janet; Beaulieu, Chandree

    2015-01-01

    PRPS1 codes for the enzyme phosphoribosyl pyrophosphate synthetase-1 (PRS-1). The spectrum of PRPS1-related disorders associated with reduced activity includes Arts syndrome, Charcot-Marie-Tooth disease-5 (CMTX5) and X-linked non-syndromic sensorineural deafness (DFN2). We describe a novel phenotype

  16. Exome sequencing identifies a novel missense mutation of WFS1 as the cause of non-syndromic low-frequency hearing loss in a Chinese family.

    Science.gov (United States)

    Niu, Zhijie; Feng, Yong; Hu, Zhengmao; Li, Jiada; Sun, Jie; Chen, Hongsheng; He, Chufeng; Wang, Xueping; Jiang, Lu; Liu, Yalan; Cai, Xinzhang; Wang, Lili; Cai, Yuxiang; Liu, Xuezhong; Mei, Lingyun

    2017-09-01

    Autosomal dominant non-syndromic low-frequency sensorineural hearing loss (LFSNHL) DFNA6/14/38 is an uncommon type of hearing loss that classically affects low frequencies of 2000 Hz and below, demonstrating an ascending configuration. The current study aimed to investigate the cause of LFSNHL in a five-generation Chinese family. The phenotype of the Chinese family was characterized using audiologic testing and pedigree analysis. The combined approach of array screening and whole-exome sequencing was used to identify the disease-causing gene in this family. This pedigree, in which the affected subjects presented isolated low-frequency sensorineural hearing impairment with childhood onset, was associated with autosomal dominant inheritance of the c.2591A > G mutation in exon 8 of the Wolframin syndrome 1 (WFS1) gene which was not present in 286 unrelated controls with matched ancestry and is highly conserved across species. In addition, several mutations affecting the Glu864 residue have been previously identified in different populations, suggesting that this site is likely to be a mutational hot spot. We identified a novel substitution, Glu864Gly, of WFS1 as the causative variant for this pedigree. Our data extend the mutation spectrum of the WFS1 gene in Chinese individuals and may contribute to establishing a better genotype-phenotype correlation for LFSNHL. Copyright © 2017 Elsevier B.V. All rights reserved.

  17. A three-year-old boy with X-linked adrenoleukodystrophy and congenital pulmonary adenomatoid malformation: a case report

    Directory of Open Access Journals (Sweden)

    Cakan Nedim

    2009-12-01

    Full Text Available Abstract Introduction X-linked adrenoleukodystrophy leads to demyelination of the nervous system, adrenal insufficiency, and accumulation of long-chain fatty acids. Most young patients with X-linked adrenoleukodystrophy develop seizures and progressive neurologic deficits, and die within the first two decades of life. Congenital or acquired disorders of the respiratory system have not been previously described in patients with X-linked adrenoleukodystrophy. Case presentation A 3-year-old Arabic boy from Yemen presented with discoloration of the mucous membranes and nail beds, which were considered cyanoses due to methemoglobinemia. He also had shortness of breath, fatigue, emesis and dehydration episodes for which he was admitted to our hospital. Chest radiograph and chest computed tomography scans showed congenital pulmonary adenomatoid malformation. A few weeks before the removal of the malformation, he had a significant episode of hypotension and hypoglycemia. This development required further in-hospital evaluation that led to the diagnosis of adrenal insufficiency and the initiation of treatment with corticosteroids. One year later, he developed seizures and loss of consciousness. Magnetic resonance imaging of his head showed diffuse demyelination secondary to X-linked adrenoleukodystrophy. He was treated with anti-seizure and anti-oxidants, and was referred for bone marrow transplant evaluation. Conclusion The presence of adrenal insufficiency, neurologic deficits and seizures are common manifestations of X-linked adrenoleukodystrophy. The association of congenital lung disease with X-linked adrenoleukodystrophy or Addison's disease has not been described previously.

  18. Sensorineural Hearing Loss and Celiac Disease: A Coincidental Finding

    Directory of Open Access Journals (Sweden)

    Umberto Volta

    2009-01-01

    Full Text Available BACKGROUND: Celiac disease (CD can be associated with a variety of extraintestinal manifestations, including neurological diseases. A new neurological correlation has been found between CD and sensorineural hearing loss (SNHL.

  19. Concordance of MRI and EEG Focal Slowing in Nonsyndromic Epilepsy

    Directory of Open Access Journals (Sweden)

    J Gordon Millichap

    2013-04-01

    Full Text Available Investigators at the Kangwon National University, Korea, and The Epilepsy Center, Lurie Children’s Hospital of Chicago, USA studied the correlation and significance of EEG focal slowing and focal MRI abnormalities in 253 children with nonsyndromic epilepsy.

  20. Disacusia neurossensorial imunomediada Immunomediated sensorineural hearing loss

    Directory of Open Access Journals (Sweden)

    Norma de Oliveira Penido

    2002-10-01

    Full Text Available A disacusia neurossensorial imunomediada (DNSI é caracterizada geralmente por uma disacusia neurossensorial bilateral, progressiva e assimétrica, acompanhada ou não por outros sintomas da orelha interna. Três pacientes com DNSI cujo quadro clínico e audiométrico eram sugestivos de doença auto-imune, e apresentaram resposta positiva à terapia imunossupressora ou pesquisa positiva de anticorpo anti hsp-70 68kD, foram estudados com relação às características clínicas, testes diagnósticos, alternativas terapêuticas e evolução da doença. Dois pacientes apresentaram quadro de disacusia neurossensorial rapidamente progressiva, associado a quadro vestibular, e outro, quadro de surdez súbita unilateral. Nenhum paciente apresentou positividade às provas reumatológicas, e apenas um paciente apresentou aumento na velocidade de hemossedimentação. Nenhum paciente obteve resposta adequada sustentada à corticoterapia, mas dois deles melhoraram com outras terapias imunossupressoras. O diagnóstico da DNSI é clínico e baseado na resposta positiva ao teste terapêutico com imunossupressores. A pesquisa de anticorpo anti-hsp70 de 68 kD pelo Western Blot é o único exame laboratorial específico para seu diagnóstico, possuindo sensibilidade de 42% e especificidade de 90%. Apenas 1 paciente apresentou positividade para este teste e não respondeu à terapia imunossupressora. Os dois pacientes com teste negativo responderam satisfatoriamente ao tratamento. A baixa sensibilidade do Western Blot e seu alto custo dificultam sua difusa utilização em nosso meio. A introdução precoce do tratamento é de suma importância por auxiliar no diagnóstico e por proporcionar um melhor prognóstico auditivo.The immunomediated sensorineural hearing loss (ISHL is characterized as an asymmetric and progressive sensorineural hearing loss. Tree patients with ISHL were studied, regarding clinical aspects, diagnostic tests, treatment options and disease

  1. Nonsyndromic Craniosynostosis and Associated Abnormal Speech and Language Development.

    Science.gov (United States)

    Naran, Sanjay; Miller, Matthew; Shakir, Sameer; Ware, Benjamin; Camison, Liliana; Ford, Matthew; Goldstein, Jesse; Losee, Joseph E

    2017-07-01

    Although many metrics for neurodevelopment in children with nonsyndromic craniosynostosis have been analyzed, few have directly examined early language acquisition and speech development. The authors characterized language acquisition and speech development in children with nonsyndromic craniosynostosis. The authors' institutional database was queried for nonsyndromic craniosynostosis from 2000 to 2014. Patients with an identified syndrome were excluded. Specific data elements included age, gender, velopharyngeal adequacy by means of the Pittsburgh Weighted Speech Scale, evaluation for anatomical motor delay, language acquisition delay/disorder, articulation or speech sound production delays/disorders, and whether speech therapy was recommended. Diagnosis of a submucous cleft palate was noted. One hundred one patients met inclusion criteria, of which 57.4 percent were male. Average age at the time of the most recent speech evaluation was 6.1 years (range, 2.31 to 17.95 years); 43.6 percent had normal speech/language metrics and 56.4 percent had one or more abnormalities, including anatomical motor delay/disorder (29.7 percent), language acquisition delay/disorder (21.8 percent), articulation or speech production delay/disorder (4.0 percent), hypernasality (15.8 percent), and velopharyngeal insufficiency or borderline competency (23.8 percent). Average Pittsburgh Weighted Speech Scale score was 1.3 (range, 0 to 5), and 29.7 percent (n = 30) of patients were recommended to have speech therapy. In addition, 25.8 percent of patients were diagnosed with a submucous cleft palate. One in four patients with nonsyndromic craniosynostosis carried a diagnosis of submucous cleft palate. The authors found that abnormal speech and language development occurs in one in 1.7 patients with nonsyndromic craniosynostosis, and that speech therapy for such abnormal development is warranted in one in 3.4 of them-a prevalence two to five times higher compared with the general pediatric

  2. Role of cholesterol sulfate in epidermal structure and function: Lessons from X-linked ichthyosis☆

    Science.gov (United States)

    Elias, Peter M.; Williams, Mary L.; Choi, Eung-Ho; Feingold, Kenneth R.

    2014-01-01

    X-linked ichthyosis is a relatively common syndromic form of ichthyosis most often due to deletions in the gene encoding the microsomal enzyme, steroid sulfatase, located on the short area of the X chromosome. Syndromic features are mild or unapparent unless contiguous genes are affected. In normal epidermis, cholesterol sulfate is generated by cholesterol sulfotransferase (SULT2B1b), but desulfated in the outer epidermis, together forming a ‘cholesterol sulfate cycle’ that potently regulates epidermal differentiation, barrier function and desquamation. In XLI, cholesterol sulfate levels my exceed 10% of total lipid mass (≈1% of total weight). Multiple cellular and biochemical processes contribute to the pathogenesis of the barrier abnormality and scaling phenotype in XLI. This article is part of a Special Issue entitled The Important Role of Lipids in the Epidermis and their Role in the Formation and Maintenance of the Cutaneous Barrier. Guest Editors: Kenneth R. Feingold and Peter Elias. PMID:24291327

  3. MBTPS2 mutations cause defective regulated intramembrane proteolysis in X-linked osteogenesis imperfecta

    Science.gov (United States)

    Lindert, Uschi; Cabral, Wayne A.; Ausavarat, Surasawadee; Tongkobpetch, Siraprapa; Ludin, Katja; Barnes, Aileen M.; Yeetong, Patra; Weis, Maryann; Krabichler, Birgit; Srichomthong, Chalurmpon; Makareeva, Elena N.; Janecke, Andreas R.; Leikin, Sergey; Röthlisberger, Benno; Rohrbach, Marianne; Kennerknecht, Ingo; Eyre, David R.; Suphapeetiporn, Kanya; Giunta, Cecilia; Marini, Joan C.; Shotelersuk, Vorasuk

    2016-01-01

    Osteogenesis imperfecta (OI) is a collagen-related bone dysplasia. We identified an X-linked recessive form of OI caused by defects in MBTPS2, which encodes site-2 metalloprotease (S2P). MBTPS2 missense mutations in two independent kindreds with moderate/severe OI cause substitutions at highly conserved S2P residues. Mutant S2P has normal stability, but impaired functioning in regulated intramembrane proteolysis (RIP) of OASIS, ATF6 and SREBP transcription factors, consistent with decreased proband secretion of type I collagen. Further, hydroxylation of the collagen lysine residue (K87) critical for crosslinking is reduced in proband bone tissue, consistent with decreased lysyl hydroxylase 1 in proband osteoblasts. Reduced collagen crosslinks presumptively undermine bone strength. Also, proband osteoblasts have broadly defective differentiation. These mutations provide evidence that RIP plays a fundamental role in normal bone development. PMID:27380894

  4. High bone mineral apparent density in children with X-linked hypophosphatemia

    DEFF Research Database (Denmark)

    Beck-Nielsen, Signe; Brixen, K; Gram, J

    2013-01-01

    Bone mineral apparent density (BMAD) in children with X-linked hypophosphatemia (XLH) was evaluated, as they are unlikely to have extra-skeletal ossifications contributing to the elevated bone mineral density of the spine in adult patients. Children with XLH also had significantly higher BMAD...... of the spine compared to femoral neck. INTRODUCTION: BMAD obtained by dual-energy X-ray absorptiometry scans in children with XLH was evaluated, as they are unlikely to have the extra-skeletal ossifications contributing to the elevated bone mineral density of the spine in adult patients. METHODS: A total of 15...... children with biochemically and genetically verified XLH were recruited. Anthropometric measurements were performed, and to correct for the short stature (small bones), the BMAD of the spine and the femoral neck was evaluated. RESULTS: Z-scores of BMAD of the spine (mean (95 % CI); 2.0 (1.3-2.7); p ...

  5. Sustained virologic response following HCV eradication in two brothers with X-linked agammaglobulinaemia.

    LENUS (Irish Health Repository)

    Houlihan, Diarmaid D

    2009-08-21

    X-linked agammaglobulinaemia (XLA) is a humoral immunodeficiency syndrome characterized from childhood by the absence of circulating B lymphocytes, absent or reduced levels of serum immunoglobulin and recurrent bacterial infections. For many affected patients, regular treatment with immunoglobulin is life saving. Hepatitis C viral (HCV) infection acquired through contaminated blood products is widely described in this patient cohort. The natural history of HCV infection in patients with XLA tends to follow a more rapid and aggressive course compared to immunocompetent individuals. Furthermore, standard anti-viral therapy appears to be less efficacious in this patient cohort. Here we report the cases of two brothers with XLA who contracted HCV through contaminated blood products. They were treated with a six month course of Interferon alpha-2b and Ribavirin. We report a sustained virologic response five years after completing treatment.

  6. A novel ABCD1 gene mutation in a Chinese patient with X-linked adrenoleukodystrophy.

    Science.gov (United States)

    Cai, Yan-na; Jiang, Min-yan; Liang, Cui-li; Peng, Min-zhi; Cheng, Jing; Sheng, Hui-ying; Fan, Li-ping; Chen, Xi-qing; Liu, Li

    2015-05-01

    X-linked adrenoleukodystrophy (X-ALD) (OMIM: 300100) is a recessive neurodegenerative disorder caused by defects in the ABCD1 gene on chromosome Xq28. Childhood cerebral ALD (CCALD) is the most frequent phenotype. We describe an affected boy who developed normally until he was 8 years old then suffered progressive neurological deficits that ultimately led to death. Diagnosis was based on clinical symptoms, an abnormal very long chain fatty acid profile in plasma, typical CCALD MRI pattern, and molecular analysis. Direct sequencing of the ABCD1 gene in this patient identified a novel splicing mutation (IVS1+1G>A) in intron 1, which is considered to be the pathogenic mutation. We have identified a novel ABCD1 mutation as the likely cause of CCALD in a Chinese patient.

  7. Tremor in X-linked recessive spinal and bulbar muscular atrophy (Kennedy's disease

    Directory of Open Access Journals (Sweden)

    Francisco A. Dias

    2011-01-01

    Full Text Available OBJECTIVE: To study tremor in patients with X-linked recessive spinobulbar muscular atrophy or Kennedy's disease. METHODS: Ten patients (from 7 families with a genetic diagnosis of Kennedy's disease were screened for the presence of tremor using a standardized clinical protocol and followed up at a neurology outpatient clinic. All index patients were genotyped and showed an expanded allele in the androgen receptor gene. RESULTS: Mean patient age was 37.6 years and mean number of CAG repeats 47 (44-53. Tremor was present in 8 (80% patients and was predominantly postural hand tremor. Alcohol responsiveness was detected in 7 (88% patients with tremor, who all responded well to treatment with a β-blocker (propranolol. CONCLUSION: Tremor is a common feature in patients with Kennedy's disease and has characteristics similar to those of essential tremor.

  8. Acute Myeloid Leukemia in a Patient With X-linked Severe Combined Immunodeficiency.

    Science.gov (United States)

    Shigemura, Tomonari; Motobayashi, Mitsuo; Matsuda, Kazuyuki; Shimodaira, Takahiro; Kurata, Takashi; Kobayashi, Norimoto; Agematsu, Kazunaga; Nakazawa, Yozo

    2017-11-01

    Severe combined immunodeficiency (SCID) is a defect in the differentiation and function of T cells. An increased malignancy risk, mainly lymphatic malignancy, has been described in patients with SCID. We report a patient with X-linked SCID who developed acute myeloid leukemia, derived from the recipient with somatic NRAS mutation 4 months after cord blood transplantation (CBT). Loss of heterozygosity phenomenon of the recipient at 6q14 locus was observed at 2 months post-CBT and progressed to 6q deletion (6q-) chromosome abnormality. Somatic NRAS mutation was detected at 3 months post-CBT. Thus, 6q- and NRAS mutation were strongly associated with the leukemic transformation in our patient.

  9. Gene therapy studies in a canine model of X-linked severe combined immunodeficiency.

    Science.gov (United States)

    Felsburg, Peter J; De Ravin, Suk See; Malech, Harry L; Sorrentino, Brian P; Burtner, Christopher; Kiem, Hans-Peter

    2015-03-01

    Since the occurrence of T cell leukemias in the original human γ-retroviral gene therapy trials for X-linked severe combined immunodeficiency (XSCID), considerable effort has been devoted to developing safer vectors. This review summarizes gene therapy studies performed in a canine model of XSCID to evaluate the efficacy of γ-retroviral, lentiviral, and foamy viral vectors for treating XSCID and a novel method of vector delivery. These studies demonstrate that durable T cell reconstitution and thymopoiesis with no evidence of any serious adverse events and, in contrast to the human XSCID patients, sustained marking in myeloid cells and B cells with reconstitution of normal humoral immune function can be achieved for up to 5 years without any pretreatment conditioning. The presence of sustained levels of gene-marked T cells, B cells, and more importantly myeloid cells for almost 5 years is highly suggestive of transduction of either multipotent hematopoietic stem cells or very primitive committed progenitors.

  10. X-linked Myotubular Myopathy with a Novel MTM1 Mutation in a Taiwanese Child

    Directory of Open Access Journals (Sweden)

    Chia-Ying Chang

    2008-12-01

    Full Text Available We report a male, preterm newborn infant with X-linked myotubular myopathy, the most severe type of the disease. He presented at birth with generalized hypotonia, difficulty in swallowing, and respiratory distress with frequent episodes of atelectasis. The infant had a long thin face, generalized hypotonia, and arachnodactyly. Diagnosis was based on fetal history, muscle histopathology, electron microscopy and a genetic study. A base pair change was detected in exon 11 of the MTM1 gene: c.1160C > A, which caused an amino acid change, p.S387Y. The father's gene was normal but the mother had the same mutation as her son and was thus a carrier.

  11. Hematopoietic cell transplantation does not prevent myelopathy in X-linked adrenoleukodystrophy: a retrospective study.

    Science.gov (United States)

    van Geel, Björn M; Poll-The, Bwee Tien; Verrips, Aad; Boelens, Jaap-Jan; Kemp, Stephan; Engelen, Marc

    2015-03-01

    X-linked adrenoleukodystrophy (X-ALD) is a peroxisomal metabolic disorder. Male patients develop adrenocortical insufficiency (80 % before 18 years), a chronic myelopathy (adrenomyeloneuropathy (AMN); all in adulthood), or progressive cerebral demyelination (cerebral ALD; 40 % before 18 years). Cerebral ALD is treated with haematopoetic cell transplantation (HCT). It is unknown if AMN still develops in patients with X-ALD that underwent HCT for cerebral ALD in childhood. A retrospective observational study was performed by selecting all adult patients with X-ALD in our cohort that underwent HCT in childhood. This retrospective study found that three out of five patients in our cohort who underwent HCT in childhood developed signs of myelopathy in adulthood. These data suggest that HCT for cerebral ALD in childhood does not prevent the onset of AMN in X-ALD in adulthood.

  12. X-linked deafness, stapes gushers and a distinctive defect of the inner ear

    International Nuclear Information System (INIS)

    Phelps, P.D.; Reardon, W.; Pembrey, M.; Bellman, S.; Luxom, L.

    1991-01-01

    We have made genetic linkage studies in 7 pedigrees in whom deafness was inherited in an X-linked manner. All patients had a full range of audiometric and vestibular function tests. Thin section high resolution CT in two planes was used to assess the state of the middle and inner ears. We found a distinctive inner ear deformity in some of the deaf males. Moreover, some of the obligate feamle carriers seem to have a milder form of the same anomaly associated with slight hearing loss. Genetic studies on some of the deaf males with apparently normal inner ear anatomy suggest a different locus on the X chromosome and hence a different pathogenesis for the deafness. (orig./GDG)

  13. Bruton's tyrosine kinase: from X-linked agammaglobulinemia toward targeted therapy for B-cell malignancies.

    Science.gov (United States)

    Ponader, Sabine; Burger, Jan A

    2014-06-10

    Discovery of Bruton's tyrosine kinase (BTK) mutations as the cause for X-linked agammaglobulinemia was a milestone in understanding the genetic basis of primary immunodeficiencies. Since then, studies have highlighted the critical role of this enzyme in B-cell development and function, and particularly in B-cell receptor signaling. Because its deletion affects mostly B cells, BTK has become an attractive therapeutic target in autoimmune disorders and B-cell malignancies. Ibrutinib (PCI-32765) is the most advanced BTK inhibitor in clinical testing, with ongoing phase III clinical trials in patients with chronic lymphocytic leukemia and mantle-cell lymphoma. In this article, we discuss key discoveries related to BTK and clinically relevant aspects of BTK inhibitors, and we provide an outlook into clinical development and open questions regarding BTK inhibitor therapy. © 2014 by American Society of Clinical Oncology.

  14. Membranous glomerulopathy in an adult patient with X-linked agammaglobulinemia receiving intravenous gammaglobulin.

    Science.gov (United States)

    Endo, L M; Giannobile, J V; Dobbs, A K; Foote, J B; Szymanska, E; Warnock, D G; Cook, W J; Conley, M E; Schroeder, H W

    2011-01-01

    Immune complex deposition in the subepithelial zone of glomerular capillaries can lead to membranous glomerulopathy. To present the case of a 23-year-old man with X-linked agammaglobulinemia (XLA) who developed idiopathic membranous glomerulopathy while receiving intravenous immunoglobulin (IVIG). We performed an immunological workup, genetic testing, and a renal biopsy. XLA was confirmed with less than 0.02% CD19+ cells in the blood after sequence analysis revealed a nonfunctional BTK gene. The patient presented with microhematuria, which persisted for 3 years and spanned treatment with 5 different preparations of intravenous gammaglobulin. Immunohistochemistry revealed membranous glomerulopathy. Although endogenous serum immunoglobulin (Ig) production is severely impaired in XLA, rare B lymphocytes that have managed to mature can produce functional IgG antibodies. The pathogenic immune complexes could reflect IVIG reacting with polymorphic autoantigens, an endogenous IgG-producing clone reacting with a common idiotype present in the IVIG, or both.

  15. Application of carrier testing to genetic counseling for X-linked agammaglobulinemia

    Energy Technology Data Exchange (ETDEWEB)

    Allen, R.C.; Nachtman, R.G.; Belmont, J.W.; Rosenblatt, H.M.

    1994-01-01

    Bruton X-linked agammaglobulinemia (XLA) is a phenotypically recessive genetic disorder of B lymphocyte development. Female carriers of XLA, although asymptomatic, have a characteristic B cell lineage-specific skewing of the pattern of X inactivation. Skewing apparently results from defective growth and maturation of B cell precursors bearing a mutant active X chromosome. In this study, carrier status was tested in 58 women from 22 families referred with a history of agammaglobulinemia. Primary carrier analysis to examine patterns of X inactivation in CD19[sup +] peripheral blood cells (B lymphocytes) was conducted using quantitative PCR at the androgen-receptor locus. Obligate carriers of XLA demonstrated >95% skewing of X inactivation in peripheral blood CD19[sup +] cells but not in CD19[sup [minus

  16. X-linked agammaglobulinemia combined with juvenile idiopathic arthritis and invasive Klebsiella pneumoniae polyarticular septic arthritis.

    Science.gov (United States)

    Zhu, Zaihua; Kang, Yuli; Lin, Zhenlang; Huang, Yanjing; Lv, Huoyang; Li, Yasong

    2015-02-01

    X-linked agammaglobulinemia (XLA) is a primary immunodeficiency disease caused by mutations in the Bruton's tyrosine kinase (BTK) gene. XLA can also present in combination with juvenile idiopathic arthritis (JIA), the major chronic rheumatologic disease in children. We report herein the first known case of a juvenile patient diagnosed with XLA combined with JIA that later developed into invasive Klebsiella pneumoniae polyarticular septic polyarthritis. An additional comprehensive review of XLA combined with JIA and invasive K. pneumoniae septic arthritis is also presented. XLA was identified by the detection of BTK mutations while the diagnosis of JIA was established by clinical and laboratory assessments. Septic arthritis caused by invasive K. pneumoniae was confirmed by culturing of the synovia and gene detection of the isolates. Invasive K. pneumoniae infections can not only result in liver abscesses but also septic arthritis, although this is rare. XLA combined with JIA may contribute to invasive K. pneumoniae infection.

  17. Mutations of Bruton's tyrosine kinase gene in Brazilian patients with X-linked agammaglobulinemia

    Directory of Open Access Journals (Sweden)

    V.D. Ramalho

    2010-09-01

    Full Text Available Mutations in Bruton's tyrosine kinase (BTK gene are responsible for X-linked agammaglobulinemia (XLA, which is characterized by recurrent bacterial infections, profound hypogammaglobulinemia, and decreased numbers of mature B cells in peripheral blood. We evaluated 5 male Brazilian patients, ranging from 3 to 10 years of age, from unrelated families, whose diagnosis was based on recurrent infections, markedly reduced levels of IgM, IgG and IgA, and circulating B cell numbers <2%. BTK gene analysis was carried out using PCR-SSCP followed by sequencing. We detected three novel (Ala347fsX55, I355T, and Thr324fsX24 and two previously reported mutations (Q196X and E441X. Flow cytometry revealed a reduced expression of BTK protein in patients and a mosaic pattern of BTK expression was obtained from mothers, indicating that they were XLA carriers.

  18. X-linked agammaglobulinemia associated with B-precursor acute lymphoblastic leukemia.

    Science.gov (United States)

    Hoshino, Akihiro; Okuno, Yusuke; Migita, Masahiro; Ban, Hideki; Yang, Xi; Kiyokawa, Nobutaka; Adachi, Yuichi; Kojima, Seiji; Ohara, Osamu; Kanegane, Hirokazu

    2015-02-01

    X-linked agammaglobulinemia (XLA) is clinically characterized by reduced number of peripheral B cells and diminished levels of serum immunoglobulins, and caused by a mutation in the Bruton's tyrosine kinase (BTK) gene, which play a pivotal role in signal transduction of pre-B-cell receptor (BCR) and BCR. B-cell precursor acute lymphoblastic leukemia (BCP-ALL) is the most common malignancy in children, and it may be associated with gene alterations that regulate B-cell development. Here we described a first case of XLA associated BCP-ALL. The whole-exome sequencing revealed a somatic mutation in MLL2 in the sample from the onset of BCP-ALL. This study suggests that the alterations of BTK and MLL2 synergistically function as leukemogenesis.

  19. Helicobacter bilis-Associated Suppurative Cholangitis in a Patient with X-Linked Agammaglobulinemia.

    Science.gov (United States)

    Degand, Nicolas; Dautremer, Justine; Pilmis, Benoît; Ferroni, Agnès; Lanternier, Fanny; Bruneau, Julie; Hermine, Olivier; Blanche, Stéphane; Nassif, Xavier; Lortholary, Olivier; Lecuit, Marc

    2017-10-01

    ᅟ: Helicobacter bilis is a commensal bacterium causing chronic hepatitis and colitis in mice. In humans, enterohepatic Helicobacter spp. are associated with chronic hepatobiliary diseases. We aimed at understanding the microbial etiology in a patient with X-linked agammaglobulinemia presenting with suppurative cholangitis. 16S rDNA PCR directly performed on a liver biopsy retrieved DNA of H. bilis. Clinical outcome resulted in the normalization of clinical and biological parameters under antibiotic treatment by a combination of ceftriaxone, metronidazole, and doxycyclin followed by a 2-week treatment with moxifloxacin and a 2-month treatment with azithromycin. In conclusion, these data suggest a specific clinical and microbiological approach in patients with humoral deficiency in order to detect H. bilis hepatobiliary diseases.

  20. X-Linked Agammaglobulinemia Presenting with Secondary Hemophagocytic Syndrome: A Case Report

    Directory of Open Access Journals (Sweden)

    Can Ozturk

    2013-01-01

    Full Text Available Introduction. Coincidence of X-linked agammaglobulinemia (XLA and secondary hemophagocytic syndrome (sHS is atypical. Both diseases are rare and pathogenesis of the latter one is not clearly known. Case Presentation. A 5-year-old boy was diagnosed both with XLA and sHS. However, in his history, he did not have severe and recurrent infections. Bruton tyrosine kinase (BTK gene mutation was present (c.1581_1584delTTTG. To the best of the authors’ knowledge, coincidence of XLA and sHS had not been reported in the literature before. Conclusion. Patients with XLA are extremely vulnerable to recurrent bacterial infections. The diagnosis of XLA with sHS at any time of life is both an interesting and challenging situation without history of recurrent bacterial infections.

  1. Mutations of Bruton's tyrosine kinase gene in Brazilian patients with X-linked agammaglobulinemia.

    Science.gov (United States)

    Ramalho, V D; Oliveira Júnior, E B; Tani, S M; Roxo Júnior, P; Vilela, M M S

    2010-09-01

    Mutations in Bruton's tyrosine kinase (BTK) gene are responsible for X-linked agammaglobulinemia (XLA), which is characterized by recurrent bacterial infections, profound hypogammaglobulinemia, and decreased numbers of mature B cells in peripheral blood. We evaluated 5 male Brazilian patients, ranging from 3 to 10 years of age, from unrelated families, whose diagnosis was based on recurrent infections, markedly reduced levels of IgM, IgG and IgA, and circulating B cell numbers <2%. BTK gene analysis was carried out using PCR-SSCP followed by sequencing. We detected three novel (Ala347fsX55, I355T, and Thr324fsX24) and two previously reported mutations (Q196X and E441X). Flow cytometry revealed a reduced expression of BTK protein in patients and a mosaic pattern of BTK expression was obtained from mothers, indicating that they were XLA carriers.

  2. Urokinase mediates endothelial cell survival via induction of the X-linked inhibitor of apoptosis protein

    DEFF Research Database (Denmark)

    Prager, Gerald W; Mihaly, Judit; Brunner, Patrick M

    2008-01-01

    Urokinase-type plasminogen activator (uPA) additionally elicits a whole array of pro-angiogenic responses, such as differentiation, proliferation, and migration. In this study, we demonstrate that in endothelial cells uPA also protects against apoptosis by transcriptional up-regulation and partia......Urokinase-type plasminogen activator (uPA) additionally elicits a whole array of pro-angiogenic responses, such as differentiation, proliferation, and migration. In this study, we demonstrate that in endothelial cells uPA also protects against apoptosis by transcriptional up......-regulation and partially by mRNA stabilization of inhibitor of apoptosis proteins, most prominently the X-linked inhibitor of apoptosis protein (XIAP). The antiapoptotic activity of uPA was dependent on its protease activity, the presence of uPA receptor (uPAR) and low-density lipoprotein receptor-related protein (LRP...

  3. Neonatal estradiol stimulation prevents epilepsy in Arx model of X-linked infantile spasms syndrome.

    Science.gov (United States)

    Olivetti, Pedro R; Maheshwari, Atul; Noebels, Jeffrey L

    2014-01-22

    Infantile spasms are a catastrophic form of pediatric epilepsy with inadequate treatment. In patients, mutation of ARX, a transcription factor selectively expressed in neuronal precursors and adult inhibitory interneurons, impairs cell migration and causes a major inherited subtype of the disease X-linked infantile spasms syndrome. Using an animal model, the Arx((GCG)10+7) mouse, we determined that brief estradiol (E2) administration during early postnatal development prevented spasms in infancy and seizures in adult mutants. E2 was ineffective when delivered after puberty or 30 days after birth. Early E2 treatment altered mRNA levels of three downstream targets of Arx (Shox2, Ebf3, and Lgi1) and restored depleted interneuron populations without increasing GABAergic synaptic density. Postnatal E2 treatment may induce lasting transcriptional changes that lead to enduring disease modification and could potentially serve as a therapy for inherited interneuronopathies.

  4. A Review of X-linked Charcot-Marie-Tooth Disease.

    Science.gov (United States)

    Wang, Ying; Yin, Fei

    2016-05-01

    X-linked Charcot-Marie-Tooth disease (CMTX) is the second common genetic variant of CMT. CMTX type 1 causes 90% of CMTX. The most important clinical features of CMTX are similar with other types of CMT; however, a few patients get the central nervous system involved with or without white matter lesions; males are more severely and earlier affected than females. In this review, the authors focus on the origin and classification of CMTX, the central nervous system manifestations of CMTX1, the possible mechanism by which GJB1 mutations cause CMT1X, and the emerging therapeutic strategies for CMTX. Moreover, several cases are presented to illustrate the central nervous system manifestations. © The Author(s) 2015.

  5. Connexin mutations in X-linked Charcot-Marie-Tooth disease

    Energy Technology Data Exchange (ETDEWEB)

    Bergoffen, J. (Univ. of Pennsylvania Medical School, Philadelphia, PA (United States)); Scherer, S.S.; Wang, S.; Scott, M.; Bone, L.J.; Chen, K.; Lensch, M.W.; Fischbeck, K.H. (Univ. of Pennsylvania Medical School, PA (United States)); Paul, D.L. (Harvard Medical School, Boston, MA (United States)); Change, P.F. (Univ. of Pennsylvania Medical School and Neurology Division, Philadelphia, PA (United States))

    1993-12-24

    X-linked Charcot-Marie-Tooth disease (CMTX) is a form of hereditary neuropathy with demyelination. Recently, this disorder was mapped to chromosome Xq13.1. The gene for the gap junction protein connexin32 is located in the same chromosomal segment, which led to its consideration as a candidate gene for CMTX. With the use of Northern (RNA) blot and immunohistochemistry techniques, it was found that connexin32 is normally expressed in myelinated peripheral nerve. Direct sequencing of the connexin32 gene showed seven different mutations in affected persons from eight CMTX families. These findings, a demonstration of inherited defects in a gap junction protein, suggest that connexin32 plays an important role in peripheral nerve.

  6. Genetic analysis and clinical phenotype of two Indian families with X-linked choroideremia

    Directory of Open Access Journals (Sweden)

    Rajani Battu

    2016-01-01

    Full Text Available Purpose: This study aims to describe the phenotype and genotype of two Indian families affected with X-linked choroideremia (CHM. Materials and Methods: In these two families, the affected individuals and unaffected family members underwent a comprehensive ophthalmic examination including an optical coherence tomography (OCT and electroretinogram. Blood samples were collected from the families for genetic analysis. Next generation sequencing (NGS was done using a panel of 184 genes, which covered previously associated genes with retinal dystrophies. Sequencing data were analyzed for the CHM, RPGR, and RP2 genes that have been implicated in CHM and X-linked retinitis pigmentosa (XLRP, respectively. The identified variants were confirmed by Sanger sequencing in available individuals and unrelated controls. Results: In two unrelated male patients, NGS analysis revealed a previously reported 3'-splice site change c.820-1G>C in the CHM gene in the first family and hemizygous mutation c.653G>C (p.Ser218X in the second family. The asymptomatic family members were carriers for these mutations. Spectral domain-OCT showed loss of outer retina, preservation of the inner retina, and choroidal thinning in the affected males and retinal pigment epithelial changes in the asymptomatic carriers. The identified mutations were not present in 100 controls of Indian origin. There were no potential mutations found in XLRP-associated (RPGR and RP2 genes. Conclusion: This report describes the genotype and phenotype findings in patients with CHM from India. The identified genetic mutation leads to lack of Rab escort protein-1 (REP-1 or affects the production of a REP-1 protein that is likely to cause retinal abnormalities in patients.

  7. Test–Retest Intervisit Variability of Functional and Structural Parameters in X-Linked Retinoschisis

    Science.gov (United States)

    Jeffrey, Brett G.; Cukras, Catherine A.; Vitale, Susan; Turriff, Amy; Bowles, Kristin; Sieving, Paul A.

    2014-01-01

    Purpose To examine the variability of four outcome measures that could be used to address safety and efficacy in therapeutic trials with X-linked juvenile retinoschisis. Methods Seven men with confirmed mutations in the RS1 gene were evaluated over four visits spanning 6 months. Assessments included visual acuity, full-field electroretinograms (ERG), microperimetric macular sensitivity, and retinal thickness measured by optical coherence tomography (OCT). Eyes were separated into Better or Worse Eye groups based on acuity at baseline. Repeatability coefficients were calculated for each parameter and jackknife resampling used to derive 95% confidence intervals (CIs). Results The threshold for statistically significant change in visual acuity ranged from three to eight letters. For ERG a-wave, an amplitude reduction greater than 56% would be considered significant. For other parameters, variabilities were lower in the Worse Eye group, likely a result of floor effects due to collapse of the schisis pockets and/or retinal atrophy. The criteria for significant change (Better/Worse Eye) for three important parameters were: ERG b/a-wave ratio (0.44/0.23), point wise sensitivity (10.4/7.0 dB), and central retinal thickness (31%/18%). Conclusions The 95% CI range for visual acuity, ERG, retinal sensitivity, and central retinal thickness relative to baseline are described for this cohort of participants with X-linked juvenile retinoschisis (XLRS). Translational Relevance A quantitative understanding of the variability of outcome measures is vital to establishing the safety and efficacy limits for therapeutic trials of XLRS patients. PMID:25346871

  8. X-linked agammaglobulinemia: Twenty years of single-center experience from North West India.

    Science.gov (United States)

    Singh, Surjit; Rawat, Amit; Suri, Deepti; Gupta, Anju; Garg, Ravinder; Saikia, Biman; Minz, Ranjana Walker; Sehgal, Shobha; Chan, Koon-Wing; Lau, Yu Lung; Kamae, Chikako; Honma, Kenichi; Nakagawa, Noriko; Imai, Kohsuke; Nonoyama, Shigeaki; Oshima, Koichi; Mitsuiki, Noriko; Ohara, Osamu

    2016-10-01

    X-linked agammaglobulinemia (XLA) is an X-linked genetic defect in maturation of B lymphocytes that results in the absence of B lymphocytes in the peripheral blood and profound hypogammaglobulinemia. It is caused by a mutation in the BTK gene located on the X chromosome. There are no large series describing XLA from the developing world. To analyze the clinical features, immunologic and genetic characteristics, and outcomes of 36 patients with XLA diagnosed and managed for a period of 2 decades. Diagnosis of XLA was made on the basis of presence of BTK gene mutation or marked reduction of B lymphocytes in peripheral blood with a family history of an affected male relative. The diagnosis was confirmed by genetic mutation studies in 28 patients with 25 unique mutations in the BTK gene. There was a significant delay in diagnosis in most of the patients. The mean (SD) delay in the diagnosis was 4.2 (3.5) years. Point mutations were the most common mutations detected, accounting for 68% of all mutations. Deletions and insertions were also seen in a few cases. Four of the mutations are novel mutations that have not been previously reported. Seven of the 36 patients (19%) were dead at the time of analysis in the present cohort. The mean survival was 137 months (95% confidence interval, 13-163 months). The present study is perhaps the largest series of patients with XLA from any developing country so far. Copyright © 2016 American College of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.

  9. X-linked congenital adrenal hypoplasia associated with hypospadias in an Egyptian baby: a case report

    Directory of Open Access Journals (Sweden)

    Metwalley Kotb

    2012-12-01

    Full Text Available Abstract Introduction X-linked congenital adrenal hypoplasia is a rare developmental disorder of the human adrenal cortex and is caused by deletion or mutation of the dosage-sensitive sex reversal adrenal hypoplasia congenita critical region of the X chromosome, gene 1 (DAX-1 gene. Most affected children present with failure to thrive, salt wasting and hypoglycemic convulsions in the first months of life. Hypospadias affects approximately one in 250 live male births. Mutations in the mastermind-like domain-containing 1 (MAMLD1 gene have been implicated as one of the causes of hypospadias in children. To the best of our knowledge, an association between congenital adrenal hypoplasia due to a DAX-1 mutation and hypospadias due to mutation of the MAMLD1 gene has not previously been reported in the literature. Case presentation A 35-day-old male Egyptian baby was referred to our institution for the evaluation of a two-week history of recurrent vomiting associated with electrolyte imbalance. On examination, our patient was found to have hypotension and dehydration. A genital examination showed distal penile hypospadias with chordee and normal testes. He had hyponatremia, hyperkalemia, hypoglycemia and metabolic acidosis. Endocrinological investigations revealed low levels of cortisol, 17-hydroxyprogesterone and aldosterone, with a high level of adrenocorticotrophic hormone. A provisional diagnosis of congenital adrenal hypoplasia associated with hypospadias was made. A molecular genetics study confirmed the diagnosis of X-linked congenital adrenal hypoplasia due to DAX-1 mutations and hypospadias due to MAMLD1 mutation. He was started on hydrocortisone and fludrocortisone treatment. After three weeks of treatment, his symptoms improved and his blood sugar, sodium, potassium and cortisol levels normalized. Conclusions We report the case of an Egyptian baby with an association of congenital adrenal hypoplasia due to DAX-1 mutation and hypospadias due

  10. Analysis of mutations in Menkes and X-linked cutis laxa patients

    Energy Technology Data Exchange (ETDEWEB)

    Das, S.; Levinson, B.; Gitschier, J. [Univ. of California, San Francisco, CA (United States)] [and others

    1994-09-01

    Menkes disease is an X-linked disorder of copper metabolism. The complex clinical phenotype is attribute to a deficiency of copper-containing enzymes resulting from a defect in copper transport. X-linked cutis laxa (XLCL), a mild, connective tissues disease may also be an allele of Menkes disease. A gene for the Menkes disease locus (MNK) has been isolated and found to code for a copper-transportion ATPase. Deletions in this gene have been observed in only 15-20% of patients by Southern blot analysis. We have analysed the MNK gene for mutations by RT-PCR and chemical cleavage mismatch detection in a group of 12 patients with severe Menkes phenotype and who were normal by Southern analysis. Mutations were observed in ten patients, and in each case, a different, debilitating mutation was present. Mutations that resulted in splicing abnormalities, detected by RT-PCR alone, were observed in six patients and included two splice site changes, a nonsense mutation, a missense mutation, a small duplication and a small deletion. Chemical cleavage analysis of the remaining six patients revealed the presence of one nonsense mutation, two adjacent 5 bp deletions and one missense mutation. A valine/leucine polymorphism was also observed. These findings, combined with the prior observation of large deletions in {approx}15% of patients, suggest that Southern blot hybridization and RT-PCR will identify mutations in the majority of patients. To date, no mutations have been found in 4 XLCL patients in the MNK coding region by chemical cleavage. However in 2 patients Southern blot changes have been detected with a 5{prime} UTR probe, suggesting mutations affecting regulatory elements.

  11. Management of sudden sensorineural hearing loss.

    Science.gov (United States)

    Metrailer, Aaron M; Babu, Seilesh C

    2016-10-01

    Sudden sensorineural hearing loss (SNHL) is an otologic emergency and should be managed quickly and effectively. This review focuses on the management of sudden SNHL, primarily idiopathic sudden SNHL as it is the most common cause. Management options include observation, oral steroids, intratympanic steroids, or combined oral/intratympanic steroids. One-third to two-thirds of patients will achieve spontaneous recovery, most likely within the first 2 weeks. Despite the lack of randomized controlled trials on steroid therapy efficacy, all patients should be offered steroid treatment given low risk and possible significant benefits. All patients should undergo MRI with gadolinium to rule out retrocochlear disorder. Bilateral sudden hearing loss should alert the clinician to possible systemic disease. Sudden hearing loss is an otologic emergency. Appropriate counseling of patients is necessary to allow physician and patient to make a joint, educated decision. It is paramount to rule out retrocochlear disorder and to follow patients closely for improvement or need for future auditory rehabilitation.

  12. Sensorineural hearing loss in Kawasaki disease.

    Science.gov (United States)

    Aggarwal, Varun; Etinger, Veronica; Orjuela, Andres F

    2016-01-01

    Kawasaki disease is a common nonspecific vasculitis seen in childhood. The most significant long-term sequela is coronary artery aneurysm. However, the spectrum of complications involves not only the heart, but also other organs such as the eyes, skin, kidneys, gallbladder, liver, and central nervous system. Sensorineural hearing loss (SNHL) is a relatively unrecognized complication of the disease. Although most of the complications (except coronary artery aneurysm) are self-limiting, SNHL can be persistent. It is, especially important in infants and young children who might not be able to report the hearing deficits and are most likely to have cognitive and speech delays if this hearing loss is not addressed in a timely manner. We report a child with Kawasaki disease who had SNHL during the 2(nd) week of the illness. The aim of this article is to briefly review the pathophysiology behind this hearing loss and strongly emphasize the importance of universal hearing evaluation in all children diagnosed with Kawasaki disease. This screening in children with Kawasaki disease may provide some timely intervention if needed. Since most Kawasaki disease patients will be seen by cardiologists, we hope to create more awareness about this complication to the cardiology community as well.

  13. Weather conditions and sudden sensorineural hearing loss

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    Kateri Maria

    2002-07-01

    Full Text Available Abstract Background Climatic or meteorological condition changes have been implicated in the pathogenesis of Idiopathic Sudden Sensorineural Hearing Loss (ISSHL. We investigated the seasonal distribution of ISSHL and evaluated the influence of meteorological parameters (such as temperature, humidity, and atmospheric pressure, their variation and covariation on the incidence of the disease. Methods A total of 82 cases of ISSHL, admitted to our department over a five-year period, were enrolled in the study. Seasonal distribution of the disease was investigated by dividing the year in four seasons. Meteorological data included daily values of 13 distinct parameters recorded at the meteorological station of the University of Ioannina during this period. A relationship between each meteorological variable and the incidence of ISSHL was investigated by applying (χ2 test on data from 13 contingency tables as well as by using logistic regression and t-test approaches. In addition, the influence of different weather types on the incidence of ISSHL was investigated using Cluster Analysis in order to create eight clusters (weather types characteristic for the prefecture of Ioannina. Results The results of the study could not indicate any seasonal distribution of the disease. The incidence of ISSHL could not be significantly correlated either to any distinct meteorological parameter or to any specific weather type. Conclusions Meteorological conditions, such as those dominating in the Northwestern Greece, and/or their changes, have no proven effect on the incidence of ISSHL.

  14. Relation between Glaucoma and Sensorineural Hearing Loss

    Directory of Open Access Journals (Sweden)

    A Mollasadeghi

    2008-01-01

    Full Text Available Introduction: Glaucoma is one of the leading causes of blindness throughout the world. Some studies have suggested a relationship between glaucoma and sensorineural hearing loss, while others have found no evidence of an association. We performed a study to determine whether there is a significant difference in hearing of patients with glaucoma and a match control population. Methods: In this cross-sectional study, from February, 2005 till April, 2006, 44 patients with glaucoma were studied. The age range was between 15 to 60 years. After taking a complete medical history, those suffering from presbycusis, history of exposure to ototoxic drugs and substances and history of ear surgery were excluded from the study. All of the patients were cases of open-angle glaucoma, and were surveyed separately for normal-pressure glaucoma. Then complete audiometric tests (PTA, SDS, SRT, Impedance were conducted for all of them, and the results compared with a control group. Results: There was no statistically significant difference between the case group and control group in PTA, SDS, and SRT, except for Normal Tension Glaucoma (NTG. There wasn't any statistically significant difference between two groups with respect to age, gender, and history of diseases. In the NTG group, significant difference was seen only in high frequencies. Conclusion: As mentioned, there was a statistically significant difference between NTG group and control group. It is therefore recommended to conduct complete audiometric tests and histopathologic examinations in this group for early detection of hearing loss and application of rehabilitative measures.

  15. Phenotypic characterization of DFNA24: prelingual progressive sensorineural hearing impairment.

    NARCIS (Netherlands)

    Santos, R.L.; Hafner, F.M.; Huygen, P.L.M.; Linder, T.E.; Schinzel, A.; Spillmann, T.; Leal, S.M.

    2006-01-01

    This article describes the hearing impairment (HI) phenotype which segregates in a large multi-generation Swiss-German family with autosomal dominant nonsyndromic HI. The locus segregating within this pedigree is located on chromosome 4q35-qter and is designated as DFNA24. For this pedigree,

  16. Histopathology of the Human Inner Ear in a Patient With Sensorineural Hearing Loss Caused by a Variant in DFNA5.

    Science.gov (United States)

    Nadol, Joseph B; Handzel, Ophir; Amr, Sami

    2015-12-01

    Describe the histopathology of the inner ear in a patient with hearing loss caused by a pathogenic variant of the DFNA5 gene. Variants in DFNA5 have been described as causing an autosomal dominant nonsyndromic sensorineural hearing loss. To date, there has been no description of the histopathology of the inner ear in humans with hearing loss because of pathogenic variants in DFNA5. Temporal bone histopathology by light microscopy, next-generation sequencing (NGS) of DNA obtained from blood, and Sanger sequencing of DNA obtained from formalin fixed temporal bone sections. Both the temporal bone donor and her daughter were shown to have the same pathogenic variant in the DFNA5 gene. The principal histopathologic correlates of the hearing loss were loss of the inner and outer hair cells and severe degeneration of the stria vascularis and spiral ligament throughout the cochlea. In addition, there was severe degeneration of spiral ganglion cells, particularly in the basal turn, and degeneration of vestibular neuroepithelium and neurons. The donor had undergone unilateral cochlear implantation during life. Histopathology demonstrated that the cochlear implant was inserted into the scala vestibuli with considerable new bone formation around the track of the implanted electrode. This is the first report of the histopathology of the inner ear in a patient with hearing loss caused by a pathogenic variant in the DFNA5 gene.

  17. WFS1 variants in Finnish patients with diabetes mellitus, sensorineural hearing impairment or optic atrophy, and in suicide victims.

    Science.gov (United States)

    Kytövuori, Laura; Seppänen, Allan; Martikainen, Mika H; Moilanen, Jukka S; Kamppari, Seija; Särkioja, Terttu; Remes, Anne M; Räsänen, Pirkko; Rönnemaa, Tapani; Majamaa, Kari

    2013-08-01

    Mutations in the wolframin gene, WFS1, cause Wolfram syndrome, a rare recessive neurodegenerative disorder. The clinical features include early-onset bilateral optic atrophy (OA), diabetes mellitus (DM), diabetes insipidus, hearing impairment, urinary tract abnormalities and psychiatric illness, and, furthermore, WFS1 variants appear to be associated with non-syndromic DM and hearing impairment. Variation of WFS1 was investigated in Finnish subjects consisting 182 patients with DM, 117 patients with sensorineural hearing impairment (SNHI) and 44 patients with OA, and in 95 suicide victims. Twenty-two variants were found in the coding region of WFS1, including three novel nonsynonymous variants. The frequency of the p.[His456] allele was significantly higher in the patients with SNHI (11.5%; corrected P=0.00008), DM (6.6%; corrected P=0.036) or OA (9.1%; corrected P=0.043) than that in the 285 controls (3.3%). The frequency of the p.[His611] allele was 55.8% in the patients with DM being higher than that in the controls (47%; corrected P=0.039). The frequencies of p.[His456] and p.[His611] were similarly increased in an independent group of patients with DM (N=299). The results support previous findings that genetic variation of WFS1 contributes to the risk of DM and SNHI.

  18. Idiopathic sudden sensorineural hearing loss: vascular or viral?

    Science.gov (United States)

    Linthicum, Fred H; Doherty, Joni; Berliner, Karen I

    2013-12-01

    To demonstrate that sudden sensorineural hearing loss is possibly of viral origin rather than vascular. The histopathologic morphology in 7 temporal bones with known vascular impairment due to surgical interventions was compared with that of 11 bones with a history of idiopathic sudden sensorineural hearing loss (ISSNHL). Attention was paid to the spiral ligament, stria vascularis, organ of Corti hair cells, tectorial membrane, ganglion cell population, and degree of perilymph fibrosis and the auditory nerve. A temporal bone laboratory that has been in operation for more than 50 years and includes a database consisting of clinical and histopathological information that facilitates quantitative and qualitative analysis. Eight hundred forty-nine individuals who pledged their temporal bones for scientific study, of which 18 were selected for this study by means of the database criteria of sudden sensorineural hearing loss and postmiddle fossa and retro sigmoid sinus tumor removal or vestibular nerve section. Sudden sensorineural hearing loss bones exhibited no perilymph fibrosis compared with 6 of 7 vascular cases with fibrosis (P ≤ .001), exhibited less loss of ganglion cells (P ≤ .026), exhibited greater survival of spiral ligament (P ≤ .029), and averaged twice the survival of hair cells and more widespread tectorial membrane abnormalities. Analysis of human temporal bones from patients with a sudden sensorineural hearing loss does not support a vascular insufficiency but is more suggestive of a viral etiology.

  19. X-linked gene transcription patterns in female and male in vivo, in vitro and cloned porcine individual blastocysts.

    Directory of Open Access Journals (Sweden)

    Chi-Hun Park

    Full Text Available To determine the presence of sexual dimorphic transcription and how in vitro culture environments influence X-linked gene transcription patterns in preimplantation embryos, we analyzed mRNA expression levels in in vivo-derived, in vitro-fertilized (IVF, and cloned porcine blastocysts. Our results clearly show that sex-biased expression occurred between female and male in vivo blastocysts in X-linked genes. The expression levels of XIST, G6PD, HPRT1, PGK1, and BEX1 were significantly higher in female than in male blastocysts, but ZXDA displayed higher levels in male than in female blastocysts. Although we found aberrant expression patterns for several genes in IVF and cloned blastocysts, similar sex-biased expression patterns (on average were observed between the sexes. The transcript levels of BEX1 and XIST were upregulated and PGK1 was downregulated in both IVF and cloned blastocysts compared with in vivo counterparts. Moreover, a remarkable degree of expression heterogeneity was observed among individual cloned embryos (the level of heterogeneity was similar in both sexes but only a small proportion of female IVF embryos exhibited variability, indicating that this phenomenon may be primarily caused by faulty reprogramming by the somatic cell nuclear transfer (SCNT process rather than in vitro conditions. Aberrant expression patterns in cloned embryos of both sexes were not ameliorated by treatment with Scriptaid as a potent HDACi, although the blastocyst rate increased remarkably after this treatment. Taken together, these results indicate that female and male porcine blastocysts produced in vivo and in vitro transcriptional sexual dimorphisms in the selected X-linked genes and compensation of X-linked gene dosage may not occur at the blastocyst stage. Moreover, altered X-linked gene expression frequently occurred in porcine IVF and cloned embryos, indicating that X-linked gene regulation is susceptible to in vitro culture and the SCNT process

  20. Recurrent Anion Gap Acidosis: An Unusual Presentation of X-Linked Adrenoleukodystrophy in a Five-year-old Male.

    Science.gov (United States)

    Schwab, Joel; Pena, Loren; Sigman, Laura; Waggoner, Darrel

    2010-01-01

    We are presenting a five-year-old male with recurrent anion gap acidosis. During his last admission, it was detected that he had elevated VLCFA and the evaluation discovered that he had X-linked Adrenooleukodystrophy. He had the Addisonian only phenotype without any clinical or radiographic CNS findings. We were unable to find any other reports of this presentation of ALD. If the work-up of recurrent anion gap acidosis does not uncover an etiology, X-linked ALD should be considered in the differential diagnosis.

  1. Gastric adenocarcinoma in a patient with X-linked agammaglobulinemia and HIV: Case report and review of the literature

    Directory of Open Access Journals (Sweden)

    Joud Hajjar

    2016-09-01

    Full Text Available X-linked agammaglobulinemia (XLA is an X-linked inherited disease usually caused by a germline mutation in the BTK gene leading to Bruton’s tyrosine kinase deficiency, which results in the impaired development of B-lymphocytes and a subsequent lack of immunoglobulin production. Patients with XLA have an increased susceptibility to bacterial and viral infections, and multiple case reports have been published regarding an association between XLA and gastrointestinal (GI malignancy. Here, we describe a case of a 25-year-old man with XLA and HIV, who developed gastric adenocarcinoma. Previously reported cases of XLA and GI malignancy are also reviewed and summarized.

  2. An X-linked homologue of the autosomal inprinted gene ZNF127 escapes X inactivation

    Energy Technology Data Exchange (ETDEWEB)

    Longstreet, M.; Nicholls, R.D.; Willard, H.F. [Case Western Reserve Univ., Cleveland, OH (United States)] [and others

    1994-09-01

    The ZNF127 gene has been shown to be subject to parental imprinting in both humans and the mouse and maps to within the Prader-Willi/Angelman Syndrome critical region on chromosome 15. We have cloned two X-linked related loci, one of which, ZNFXp is a transcribed gene while the other, ZNFXq, is an untranscribed pseudogene. ZNFXp is 83.6% identical to ZNFXq and 65.4% identical to ZNF127 over 1.4 kb of open reading frame they share in common, Like ZNF127, the predicted protein sequence of ZNFXp contains a C{sub 3}HC{sub 4} zinc finger domain and C{sub 3}H zinc finger-like motifs. Whereas ZNF127 has three C{sub 3}H motifs, ZNFXp has four. A strong CpG island is located within 1 kb 5{prime} of the predicted amino terminus of ZNFXp. Expression of ZNFXp has been detected from mouse/human somatic cell hybrids containing either an active (n=2) or an inactive (n=4) chromosome, and thus escapes X inactivation. Probes made from the 3{prime} UTR of ZNFXp detect a number of related loci in both human and murine DNA, none of which is the ZNF127 locus on chromosome 15. None of the detectable murine bands shows dosage differences between males and females as would be expected for X-linked loci. This raises the possibility that ZNFXp inserted into the human X chromosome after its divergence from a common ancestor with the murine X. We have mapped ZNFXp to Xp11.4 by Southern blotting and PCR of hybrid DNAs and by fluorescence in situ hybridization (FISH). ZNFXq maps within the X Inactivation Center (XIC) region on Xq13.2, approximately 300 kb distal to the XIST gene. We find it intriguing, and perhaps significant, that two members of this gene family are subject to epigenetic regulation -- one autosomal imprinting, and the other escape from X inactivation. These results could imply an evolutionary and mechanistic relationship between these two processes.

  3. X-linked gene expression and X-chromosome inactivation: marsupials, mouse, and man compared.

    Science.gov (United States)

    VandeBerg, J L; Robinson, E S; Samollow, P B; Johnston, P G

    1987-01-01

    The existence of paternal X inactivation in Australian and American marsupial species suggests that this feature of X-chromosome dosage compensation is not a recent adaptation, but probably predates the evolutionary separation of the Australian and American marsupial lineages. Although it is theoretically possible that the marsupial system is one of random X inactivation with p greater than 0.99 and q less than 0.01 and dependent on parental source, no instance of random X inactivation (p = q or p not equal to q) has ever been verified in any tissue or cell type of any marsupial species. Therefore, we conclude that the most fundamental difference in X inactivation of marsupials and eutherians is whether the inactive X is the paternal one or is determined at random (with p = q in most but not all cases). The only other unequivocal difference between eutherians and marsupials is that both X chromosomes are active in mice and human oocytes, but not in kangaroo oocytes. Apparently, the inactive X is reactivated at a later meiotic stage or during early embryogenesis in kangaroos. X-chromosome inactivation takes place early in embryogenesis of eutherians and marsupials. Extraembryonic membranes of mice exhibit paternal X inactivation, whereas those of humans seem to exhibit random X inactivation with p greater than q (i.e., preferential paternal X inactivation). In general, extraembryonic membranes of marsupial exhibit paternal X inactivation, but the Gpd locus is active on both X chromosomes in at least some cells of kangaroo yolk sac. It is difficult to draw any general conclusion because of major differences in embryogeny of mice, humans, and marsupials, and uncertainties in interpreting the data from humans. Other differences between marsupials and eutherians in patterns of X-linked gene expression and X-chromosome inactivation seem to be quantitative rather than qualitative. Partial expression of some genes on the inactive X is characteristic of marsupials, with

  4. Sensorineural Hearing Loss due to Air Bag Deployment

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    Masafumi Ohki

    2012-01-01

    Full Text Available Deployment of the air bag in a passenger vehicle accident rarely causes otologic injuries. However, sensorineural hearing loss induced by air bag deployment is extremely rare, with only a few cases reported in the English literature. A 38-year-old man involved in a traffic accident while driving his car at 40 km/hour presented with right sensorineural hearing loss and tinnitus, without associated vertigo. Pure-tone audiometry demonstrated elevated thresholds of 30 dB and 25 dB at 4 kHz and 8 kHz, respectively, on the right side. Air bag deployment in car accidents is associated with the risk of development of sensorineural hearing loss.

  5. Resolution of Sudden Sensorineural Hearing Loss Following a Roller Coaster Ride

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    Kumar, Aman; Sinha, Amrita; Al-Waa, Ahmad M.

    2011-01-01

    We report a case of sudden unilateral sensorineural hearing loss of sudden onset during an aeroplane flight, which completely resolved during a roller coaster ride at Alton Towers theme park. A review of the literature concerning sudden idiopathic sensorineural hearing loss and spontaneous resolution are discussed. Initially, pure-tone audiometry showed a profound sensorineural hearing loss in the right ear and mild sensorineural hearing loss in the left ear (of note, the hearing was normal p...

  6. Very Early-Onset Inflammatory Manifestations of X-Linked Chronic Granulomatous Disease

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    Roxane Labrosse

    2017-09-01

    Full Text Available Chronic granulomatous disease (CGD is a rare primary immune deficiency caused by mutations in genes coding for components of the nicotinamide adenine dinucleotide phosphate oxidase, characterized by severe and recurrent bacterial and fungal infections, together with inflammatory complications. Dysregulation of inflammatory responses are often present in this disease and may lead to granulomatous lesions, most often affecting the gastrointestinal (GI and urinary tracts. Treatment of inflammatory complications usually includes corticosteroids, whereas antimicrobial prophylaxis is used for infection prevention. Curative treatment of both infectious susceptibility and inflammatory disease can be achieved by hematopoietic stem cell transplantation. We report herein three patients with the same mutation of the CYBB gene who presented with very early-onset and severe GI manifestations of X-linked CGD. The most severely affected patient had evidence of antenatal inflammatory involvement of the GI and urinary tracts. Extreme hyperleukocytosis with eosinophilia and high inflammatory markers were observed in all three patients. A Mycobacterium avium lung infection and an unidentified fungal lung infection occurred in two patients both during their first year of life, which is indicative of the severity of the disease. All three patients underwent bone marrow transplantation and recovered fully from their initial symptoms. To our knowledge, these are the first reports of patients with such an early-onset and severe inflammatory manifestations of CGD.

  7. 7 Tesla proton magnetic resonance spectroscopic imaging in adult X-linked adrenoleukodystrophy

    Science.gov (United States)

    Ratai, Eva; Kok, Trina; Wiggins, Christopher; Wiggins, Graham; Grant, Ellen; Gagoski, Borjan; O'Neill, Gilmore; Adalsteinsson, Elfar; Eichler, Florian

    2010-01-01

    Background Adult patients with X-linked adrenoleukodystrophy (X-ALD) remain at risk for progressive neurological deterioration. Phenotypes vary in their pathology, ranging from axonal degeneration to inflammatory demyelination. The severity of symptoms is poorly explained by conventional imaging. Objective To test the hypothesis that neurochemistry in normal appearing brain differs among adult phenotypes of X-ALD, and that neurochemical changes correlate with the severity of symptoms. Patients and Methods Using a 7 Tesla scanner we performed structural and proton MRSI in 13 adult patients with X-ALD, including 4 patients with adult cerebral ALD (ACALD), 5 with adrenomyeloneuropathy (AMN) and 4 female heterozygotes. Studies were also performed in nine healthy controls. Results Among adult X-ALD phenotypes, MI/Cr was 46% higher and Cho/Cr 21% higher in normal appearing white matter of ACALD compared to AMN (p Tesla proton MRSI reveals differences in the neurochemistry of ACALD but is unable to distinguish AMN from female heterozygotes. MI/Cr correlates with the severity of the symptoms and may be a meaningful biomarker in adult X-ALD. PMID:19001168

  8. Diagnosis of X-Linked Hypohidrotic Ectodermal Dysplasia by Meibography and Infrared Thermography of the Eye.

    Science.gov (United States)

    Kaercher, Thomas; Dietz, Jasna; Jacobi, Christina; Berz, Reinhold; Schneider, Holm

    2015-09-01

    X-linked hypohidrotic ectodermal dysplasia (XLHED) is the most common form of ectodermal dysplasia. Clinical characteristics include meibomian gland disorder and the resulting hyperevaporative dry eye. In this study, we evaluated meibography and ocular infrared thermography as novel methods to diagnose XLHED. Eight infants, 12 boys and 14 male adults with XLHED and 12 healthy control subjects were subjected to a panel of tests including the ocular surface disease index (OSDI), meibography and infrared thermography, non-invasive measurement of tear film break-up time (NIBUT) and osmolarity, Schirmer's test, lissamine green staining and fluorescein staining. Sensitivity and specificity were determined for single tests and selected test combinations. Meibography had 100% sensitivity and specificity for identifying XLHED. Infrared thermography, a completely non-invasive procedure, revealed a typical pattern for male subjects with XLHED. It was, however, less sensitive (86% for adults and 67% for children) than meibography or a combination of established routine tests. In adults, OSDI and NIBUT were the best single routine tests (sensitivity of 86% and 71%, respectively), whereas increased tear osmolarity appeared as a rather unspecific ophthalmic symptom. In children, NIBUT was the most convincing routine test (sensitivity of 91%). Meibography is the most reliable ophthalmic examination to establish a clinical diagnosis in individuals with suspected hypohidrotic ectodermal dysplasia, even before genetic test results are available. Tear film tests and ocular surface staining are less sensitive in children, but very helpful for estimating the severity of ocular surface disease in individuals with known XLHED.

  9. Dental abnormalities associated with X-linked hypohidrotic ectodermal dysplasia in dogs

    Science.gov (United States)

    Lewis, JR; Reiter, AM; Mauldin, EA; Casal, ML

    2009-01-01

    Objectives X-linked hypohidrotic ectodermal dysplasia (XLHED) occurs in several species, including humans, mice, cattle and dogs. The orofacial manifestations of ectodermal dysplasia in humans and mice have been extensively studied, but documentation of dental abnormalities in dogs is lacking. The current study describes the results of clinical and radiographic examinations of XLHED-affected dogs and demonstrates profound similarities to findings of XLHED-affected humans. Setting and sample population Section of Medical Genetics at the University of Pennsylvania, School of Veterinary Medicine. Clinical and radiographic oral examinations were performed on 17 dogs with XLHED, 3 normal dogs, and 2 dogs heterozygous for XLHED. Materials and methods The prevalence and severity of orofacial and dental abnormalities were evaluated by means of a sedated examination, photographs, and full-mouth intraoral radiographs. Results Crown and root abnormalities were common in dogs affected by XLHED, including hypodontia, oligodontia, conical crown shape, decreased number of cusps, decreased number of roots, and dilacerated roots. Persistent deciduous teeth were frequently encountered. Malocclusion was common, with Angle Class I mesioversion of the maxillary and/or mandibular canine teeth noted in 15 of 17 dogs. Angle Class III malocclusion (maxillary brachygnathism) was seen in one affected dog. Conclusion Dental abnormalities are common and severe in dogs with XLHED. Dental manifestations of canine XLHED share characteristics of brachyodont tooth type and diphyodont dentition, confirming this species to be an orthologous animal model for study of human disease. PMID:20078794

  10. X-linked adrenoleukodystrophy: correlation between Loes score and diffusion tensor imaging parameters.

    Science.gov (United States)

    Ono, Sergio Eiji; de Carvalho Neto, Arnolfo; Gasparetto, Emerson Leandro; Coelho, Luiz Otávio de Mattos; Escuissato, Dante Luiz; Bonfim, Carmem Maria Sales; Ribeiro, Lisandro Lima

    2014-01-01

    The present study was aimed at evaluating the correlation between diffusion tensor imaging parameters and Loes score as well as whether those parameters could indicate early structural alterations. Diffusion tensor imaging measurements were obtained in 30 studies of 14 patients with X-linked adrenoleukodystrophy and were correlated with Loes scores. A control group including 28 male patients was created to establish agematched diffusion tensor imaging measurements. Inter- and intraobserver statistical analyses were undertaken. Diffusion tensor imaging measurements presented strong Pearson correlation coefficients (r) of -0.86, 0.89, 0.89 and 0.84 for fractional anisotropy and mean, radial and axial diffusivities (p tensor measurements at early stage of the disease indicates that mean and radial diffusivities might be useful to predict the disease progression. Measurements of diffusion tensor parameters can be used as an adjunct to the Loes score, aiding in the monitoring of the disease and alerting for possible Loes score progression in the range of interest for therapeutic decisions.

  11. Clinical and biochemical findings in 7 patients with X-linked adrenoleukodystrophy treated with Lorenzo's Oil

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    Vargas Carmen R.

    2000-01-01

    Full Text Available X-Linked adrenoleukodystrophy (X-ALD is a hereditary disorder of the peroxisomal metabolism biochemically characterized by the accumulation of very long chain fatty acids (VLCFA in tissues and biological fluids. The major accumulated acids are hexacosanoic acid (C26:0 and tetracosanoic acid (C24:0. The disorder is characterized clinically by central and peripheral demyelination and adrenal insufficiency closely related to the accumulation of fatty acids. The incidence of X-ALD is estimated to be 1:25,000 males. At least six phenotypes can be distinguished. The most common phenotypes are childhood cerebral ALD and adrenomyeloneuropathy (AMN. The recommended therapy consists of the use of the glyceroltrioleate/glyceroltrierucate (GTO/GTE mixture, known as Lorenzo's Oil, combined with a VLCFA-poor diet. There are alternative treatments such as bone marrow transplantation and immunosuppression, as well as the use of lovastatin and sodium phenylacetate. In the present study we report the clinical and biochemical course of 7 male patients with X-ALD treated with Lorenzo's Oil and a VLCFA-restricted diet. Treatment produced 50% reduction in C26:0 and 42.8% reduction in the C26:0/C22:0 ratio. Most patients remained clinically well, although approximately 30% of them presented a rapid clinical deterioration. The results showed a poor biochemical-clinical correlation for treatment, indicating that new therapies for X-ALD are needed in order to obtain a better prognosis for patients.

  12. Increased insula-putamen connectivity in X-linked dystonia-parkinsonism

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    Anne J. Blood

    2018-01-01

    Full Text Available Preliminary evidence from postmortem studies of X-linked dystonia-parkinsonism (XDP suggests tissue loss may occur first and/or most severely in the striatal striosome compartment, followed later by cell loss in the matrix compartment. However, little is known about how this relates to pathogenesis and pathophysiology. While MRI cannot visualize these striatal compartments directly in humans, differences in relative gradients of afferent cortical connectivity across compartments (weighted toward paralimbic versus sensorimotor cortex, respectively can be used to infer potential selective loss in vivo. In the current study we evaluated relative connectivity of paralimbic versus sensorimotor cortex with the caudate and putamen in 17 individuals with XDP and 17 matched controls. Although caudate and putamen volumes were reduced in XDP, there were no significant reductions in either “matrix-weighted”, or “striosome-weighted” connectivity. In fact, paralimbic connectivity with the putamen was elevated, rather than reduced, in XDP. This was driven most strongly by elevated putamen connectivity with the anterior insula. There was no relationship of these findings to disease duration or striatal volume, suggesting insula and/or paralimbic connectivity in XDP may develop abnormally and/or increase in the years before symptom onset.

  13. X-linked Hyper IgM Syndrome Presenting as Pulmonary Alveolar Proteinosis.

    Science.gov (United States)

    Gallagher, Joel; Adams, Juan; Hintermeyer, Mary; Torgerson, Troy R; Lopez-Guisa, Jesus; Ochs, Hans D; Szabo, Sara; Salib, Mina; Verbsky, James; Routes, John

    2016-08-01

    X-linked hyper IgM syndrome (XHIGM) is a combined immunodeficiency caused by mutations in the CD40 ligand (CD40L) gene that typically results in decreased or absent CD40L expression on activated T cells, leading to defective class switching and somatic hypermutation. We describe an infant who presented with respiratory failure due to pulmonary alveolar proteinosis (PAP) with a novel damaging missense mutation in the CD40L gene. Whole exome sequencing (WES) was used to identify a mutation in the CD40L gene. CD40L expression and function were determined by flow cytometry. A 5-month-old previously-healthy male presented with respiratory failure and diffuse pulmonary ground glass opacities on CT scan of the chest. Laboratory evaluation revealed an undetectable IgG, normal IgA, and elevated IgM. A bronchoalveolar lavage demonstrated pulmonary alveolar proteinosis. WES demonstrated a c.608G > C mutation in the CD40L gene resulting in p.R203T. Flow cytometry demonstrated normal CD40L expression on activated T cells but absent binding of CD40-Ig to CD40L on activated patient T cells. The clinical manifestations of XHIGM in our patient had several unique features, including the presentation with PAP, normal serum IgA, and expression of non-functional CD40L on activated T cells. To our knowledge, this is the first published case of PAP in a patient with XHIGM.

  14. Early respiratory and ocular involvement in X-linked hypohidrotic ectodermal dysplasia.

    Science.gov (United States)

    Dietz, Jasna; Kaercher, Thomas; Schneider, Anne-Theres; Zimmermann, Theodor; Huttner, Kenneth; Johnson, Ramsey; Schneider, Holm

    2013-08-01

    X-linked hypohidrotic ectodermal dysplasia (XLHED; ectodysplasin deficiency) has been classically described as affecting hair, sweat glands, and dentition. What may be underappreciated is the effect ectodysplasin deficiency has on glands surrounding the airways and eyes and the resulting chronic health issues. In this study, 12 male children (age range 6-13 years) and 14 male adults with XLHED (18-58 years of age) were investigated by pulmonary function tests, measurement of fractional exhaled nitric oxide, and by ophthalmologic assessments. Twelve healthy individuals (six children, six adults) served as controls. Signs of airway constriction and inflammation were detected in eight children with XLHED, including the youngest subject, and in ten adult XLHED patients. Increased tear osmolarity, reduced tear film break-up time, and other ocular abnormalities were also present at an early age. Five of 12 XLHED subjects not reporting a history of asthma and 7 of the 12 patients not reporting a history of dry eye issues showed at least two abnormal test results in the respective organ system. The presence of residual sweat ducts, suggestive of partial ectodysplasin gene expression, correlated with milder disease in two XLHED subjects with mutations affecting the collagen-like domain of ectodysplasin. The high prevalence of asthma-like symptoms in XLHED patients as young as 6 years and a similar prevalence of dry eye problems indicate that screening evaluation, regular monitoring, and consideration of therapeutic intervention should begin in early childhood.

  15. Novel variants of RPGR in X-linked retinitis pigmentosa families and genotype-phenotype correlation.

    Science.gov (United States)

    Parmeggiani, Francesco; Barbaro, Vanessa; Migliorati, Angelo; Raffa, Paolo; Nespeca, Patrizia; De Nadai, Katia; Del Vecchio, Claudia; Palù, Giorgio; Parolin, Cristina; Di Iorio, Enzo

    2017-03-10

    To identify novel mutations in the retinitis pigmentosa GTPase regulator (RPGR) gene and retinitis pigmentosa 2 (RP2) gene underlying X-linked retinitis pigmentosa (XLRP) and assess genotype-phenotype correlations. The patient cohort, consisting of 13 individuals from 3 unrelated XLRP families, underwent comprehensive ophthalmologic examination. The open reading frames of RPGR and RP2 were analyzed with Sanger sequencing in each patient. The identified genetic variants were defined as mutations or polymorphisms on the basis of their pathological effect. We found 3 genetic variants: a novel mutation c.1591G>T in exon 14 and a novel polymorphism c.1105C>T in exon 10, resulting in p.Glu531* and p.Arg369Cys of RPGR gene, respectively, and one already known mutation c.413A>G in exon 2, resulting in a p.Glu138Gly of RP2 gene. Considering our XLRP probands, RPGR-related phenotypic damages were similar and less severe than those of the patient with the RP2 mutation. On the other hand, the female carriers of XLRP variants showed different RPGR-related consequences, ranging from rods hypofunctionality in c.1591G>T nonsense heterozygosity to no retinal changes in c.1105C>T polymorphic heterozygosity. These findings broaden the spectrum of RPGR mutations and phenotypic variability of the disease, which will be useful for genetic consultation and diagnosis in the future.

  16. CD1 gene polymorphisms and phenotypic variability in X-linked adrenoleukodystrophy.

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    Mathieu Barbier

    Full Text Available X-linked adrenoleukodystrophy (X-ALD is characterized by marked phenotypic variation ranging from adrenomyeloneuropathy (AMN to childhood cerebral ALD (CCALD. X-ALD is caused by mutations in the ABCD1 gene, but no genotype-phenotype correlation has been established so far and modifier gene variants are suspected to modulate phenotypes. Specific classes of lipids, enriched in very long-chain fatty acids that accumulate in plasma and tissues from X-ALD patients are suspected to be involved in the neuroinflammatory process of CCALD. CD1 proteins are lipid- antigen presenting molecules encoded by five CD1 genes in human (CD1A-E. Association studies with 23 tag SNPs covering the CD1 locus was performed in 52 patients with AMN and 87 patients with CCALD. The minor allele of rs973742 located 4-kb downstream from CD1D was significantly more frequent in AMN patients (χ² = 7.6; P = 0.006. However, this association was no longer significant after Bonferroni correction for multiple testing. The other polymorphisms of the CD1 locus did not reveal significant association. Further analysis of other CD1D polymorphisms did not detect stronger association with X-ALD phenotypes. Although the association with rs973742 warrants further investigations, these results indicate that the genetic variants of CD1 genes do not contribute markedly to the phenotypic variance of X-ALD.

  17. Role of ALDP (ABCD1) and mitochondria in X-linked adrenoleukodystrophy.

    Science.gov (United States)

    McGuinness, M C; Lu, J-F; Zhang, H-P; Dong, G-X; Heinzer, A K; Watkins, P A; Powers, J; Smith, K D

    2003-01-01

    Peroxisomal disorders have been associated with malfunction of peroxisomal metabolic pathways, but the pathogenesis of these disorders is largely unknown. X-linked adrenoleukodystrophy (X-ALD) is associated with elevated levels of very-long-chain fatty acids (VLCFA; C(>22:0)) that have been attributed to reduced peroxisomal VLCFA beta-oxidation activity. Previously, our laboratory and others have reported elevated VLCFA levels and reduced peroxisomal VLCFA beta-oxidation in human and mouse X-ALD fibroblasts. In this study, we found normal levels of peroxisomal VLCFA beta-oxidation in tissues from ALD mice with elevated VLCFA levels. Treatment of ALD mice with pharmacological agents resulted in decreased VLCFA levels without a change in VLCFA beta-oxidation activity. These data indicate that ALDP does not determine the rate of VLCFA beta-oxidation and that VLCFA levels are not determined by the rate of VLCFA beta-oxidation. The rate of peroxisomal VLCFA beta-oxidation in human and mouse fibroblasts in vitro is affected by the rate of mitochondrial long-chain fatty acid beta-oxidation. We hypothesize that ALDP facilitates the interaction between peroxisomes and mitochondria, resulting, when ALDP is deficient in X-ALD, in increased VLCFA accumulation despite normal peroxisomal VLCFA beta-oxidation in ALD mouse tissues. In support of this hypothesis, mitochondrial structural abnormalities were observed in adrenal cortical cells of ALD mice.

  18. Adenoassociated virus serotype 9-mediated gene therapy for x-linked adrenoleukodystrophy.

    Science.gov (United States)

    Gong, Yi; Mu, Dakai; Prabhakar, Shilpa; Moser, Ann; Musolino, Patricia; Ren, JiaQian; Breakefield, Xandra O; Maguire, Casey A; Eichler, Florian S

    2015-05-01

    X-linked adrenoleukodystrophy (X-ALD) is a devastating neurological disorder caused by mutations in the ABCD1 gene that encodes a peroxisomal ATP-binding cassette transporter (ABCD1) responsible for transport of CoA-activated very long-chain fatty acids (VLCFA) into the peroxisome for degradation. We used recombinant adenoassociated virus serotype 9 (rAAV9) vector for delivery of the human ABCD1 gene (ABCD1) to mouse central nervous system (CNS). In vitro, efficient delivery of ABCD1 gene was achieved in primary mixed brain glial cells from Abcd1-/- mice as well as X-ALD patient fibroblasts. Importantly, human ABCD1 localized to the peroxisome, and AAV-ABCD1 transduction showed a dose-dependent effect in reducing VLCFA. In vivo, AAV9-ABCD1 was delivered to Abcd1-/- mouse CNS by either stereotactic intracerebroventricular (ICV) or intravenous (IV) injections. Astrocytes, microglia and neurons were the major target cell types following ICV injection, while IV injection also delivered to microvascular endothelial cells and oligodendrocytes. IV injection also yielded high transduction of the adrenal gland. Importantly, IV injection of AAV9-ABCD1 reduced VLCFA in mouse brain and spinal cord. We conclude that AAV9-mediated ABCD1 gene transfer is able to reach target cells in the nervous system and adrenal gland as well as reduce VLCFA in culture and a mouse model of X-ALD.

  19. [X-linked adrenoleukodystrophy ABCD1 gene mutation analysis in China].

    Science.gov (United States)

    Pan, Hong; Xiong, Hui; Zhang, Yue-hua; Wu, Ye; Bao, Xin-hua; Jiang, Yu-wu; Wu, Xi-ru

    2004-02-01

    To investigate mutations of ABCD1 gene in X- linked adrenoleukodystrophy (ALD) patients in China. Polymerase chain reaction and DNA direct sequencing were employed to analyze the 10 exons of ABCD1 gene in 25 ALD patients. Seventeen mutations in different exons (except exons 4, 9 and 10) were identified in 18 of 25 patients. Most of the mutations were missense mutations, including R182P, G266R, H283D, S404P, N509I, R518G, L520Q, Q556R, S606L and R617C, four (H283D, S40 4P, N509I, R518G) of 10 missense mutations were novel. Also identified were 3 nonsense mutations (W132X, W242X, W595X), 1 dinucleotides deletion mutation (1414 del AG) resulting in frameshift, and 1 base pair deletion at splice acceptor site (IVS5-6 del C). Two synonymous mutations (L516L and V349V) appeared simultaneously in 2 unrelated patients, and no other mutations could be found with them in all 10 exons screened. There were no hot spot mutations in ABCD1 gene in China. Mutations in gene were found over 70% of patients with ALD in China. The ABCD1 gene mutations identified revealed no obvious correlation between the type of mutation and phenotype.

  20. Childhood cerebral X-linked adrenoleukodystrophy with atypical neuroimaging abnormalities and a novel mutation

    Directory of Open Access Journals (Sweden)

    M Muranjan

    2018-01-01

    Full Text Available Childhood cerebral X-linked adrenoleukodystrophy (XALD typically manifests with symptoms of adrenocortical insufficiency and a variety of neurocognitive and behavioral abnormalities. A major diagnostic clue is the characteristic neuroinflammatory parieto-occipital white matter lesions on magnetic resonance imaging. This study reports a 5-year 10-month old boy presenting with generalized skin hyperpigmentation since 3 years of age. Over the past 9 months, he had developed right-sided hemiparesis and speech and behavioral abnormalities, which had progressed over 5 months to bilateral hemiparesis. Retrospective analyses of serial brain magnetic resonance images revealed an unusual pattern of lesions involving the internal capsules, corticospinal tracts in the midbrain and brainstem, and cerebellar white matter. The clinical diagnosis of childhood cerebral adrenoleukodystrophy was confirmed by elevated basal levels of adrenocorticotropin hormone and plasma very long chain fatty acid levels. Additionally, sequencing of the ABCD1 gene revealed a novel mutation. The only specific palliative therapy that could be offered after diagnosis was dietary intervention. The patient died within 16 months of onset of neurological symptoms. Awareness that childhood cerebral XALD can present with atypical neuroimaging patterns early in its course may aid diagnosis at a stage when definitive treatment can be attempted and timely genetic counseling be offered to the family.

  1. S149R, a novel mutation in the ABCD1 gene causing X-linked adrenoleukodystrophy

    Science.gov (United States)

    Ying, Hui; Li, Hongyu; Chen, Jing; Xu, Chao

    2017-01-01

    X-linked adrenoleukodystrophy (X-ALD) is the most common peroxisomal disorder. It is a heterogeneous disorder caused by mutations in the ATP-binding cassette protein subfamily D1 (ABCD1) gene, encoding the peroxisomal membrane protein ALDP, which is involved in the transmembrane transport of very long-chain fatty acids. For the first time, we report a case of olivopontocerebellar X-ALD on the Chinese mainland. In this study, a novel mutation (c.447T>A; p.S149R) in ABCD1 was detected in a patient diagnosed with X-ALD. The mutant amino acid is well conserved among species. Bioinformatics analysis predicted the substitution to be deleterious and to cause structural changes in the adrenoleukodystrophy protein. Immunofluorescence showed an altered subcellular localization of the S149R mutant protein, which may lead to defects in the degradation of very long chain fatty acids in peroxisomes. We therefore suggest that the novel mutation, which alters ALDP structure, subcellular distribution and function, is responsible for X-ALD. PMID:29152099

  2. The genetic landscape of X-linked adrenoleukodystrophy: inheritance, mutations, modifier genes, and diagnosis

    Science.gov (United States)

    Wiesinger, Christoph; Eichler, Florian S; Berger, Johannes

    2015-01-01

    X-linked adrenoleukodystrophy (X-ALD) is caused by mutations in the ABCD1 gene encoding a peroxisomal ABC transporter. In this review, we compare estimates of incidence derived from different populations in order to provide an overview of the worldwide incidence of X-ALD. X-ALD presents with heterogeneous phenotypes ranging from adrenomyeloneuropathy (AMN) to inflammatory demyelinating cerebral ALD (CALD). A large number of different mutations has been described, providing a unique opportunity for analysis of functional domains within ABC transporters. Yet the molecular basis for the heterogeneity of clinical symptoms is still largely unresolved, as no correlation between genotype and phenotype exists in X-ALD. Beyond ABCD1, environmental triggers and other genetic factors have been suggested as modifiers of the disease course. Here, we summarize the findings of numerous reports that aimed at identifying modifier genes in X-ALD and discuss potential problems and future approaches to address this issue. Different options for prenatal diagnosis are summarized, and potential pitfalls when applying next-generation sequencing approaches are discussed. Recently, the measurement of very long-chain fatty acids in lysophosphatidylcholine for the identification of peroxisomal disorders was included in newborn screening programs. PMID:25999754

  3. Molecular analysis of ABCD1 gene in Indian patients with X-linked adrenoleukodystrophy.

    Science.gov (United States)

    Shukla, Pallavi; Gupta, Neerja; Gulati, Sheffali; Ghosh, Manju; Vasisht, Suman; Sharma, Raju; Gupta, Arun K; Kalra, Veena; Kabra, Madhulika

    2011-11-20

    X-linked Adrenoleukodystrophy (X-ALD), with an incidence of 1:14,000 is the most frequent monogenic demyelinating disorder worldwide. The principal biochemical abnormality in X-ALD is the increased levels of saturated, unbranched very long chain fatty acids (VLCFA). It is caused by mutations in ABCD1 gene. No molecular data on X-ALD is available in India and mutational spectrum in Indian patients is not known. We standardized conformation sensitive gel electrophoresis (CSGE) method to detect mutations in ABCD1 gene in twenty Indian patients with X-ALD. The results were confirmed by sequencing. Genotype-phenotype correlation was also attempted. Prenatal diagnosis (PND) in one family was done using chorionic villi (CV) sample at 12 weeks of gestation. Out of twenty, causative mutations could be identified in twelve patients (60%). Six reported and four novel mutations were identified. Three polymorphisms were also observed. No hot spot was found. No significant genotype-phenotype correlation could be established. The study identified the mutation spectrum of Indian X-ALD patients, which enabled us to offer accurate genetic counseling, carrier detection and prenatal diagnosis where needed. Copyright © 2011 Elsevier B.V. All rights reserved.

  4. Biochemical mechanisms of pallidal deep brain stimulation in X-linked dystonia parkinsonism.

    Science.gov (United States)

    Tronnier, V M; Domingo, A; Moll, C K; Rasche, D; Mohr, C; Rosales, R; Capetian, P; Jamora, R D; Lee, L V; Münchau, A; Diesta, C C; Tadic, V; Klein, C; Brüggemann, N; Moser, A

    2015-08-01

    Invasive techniques such as in-vivo microdialysis provide the opportunity to directly assess neurotransmitter levels in subcortical brain areas. Five male Filipino patients (mean age 42.4, range 34-52 years) with severe X-linked dystonia-parkinsonism underwent bilateral implantation of deep brain leads into the internal part of the globus pallidus (GPi). Intraoperative microdialysis and measurement of gamma aminobutyric acid and glutamate was performed in the GPi in three patients and globus pallidus externus (GPe) in two patients at baseline for 25/30 min and during 25/30 min of high-frequency GPi stimulation. While the gamma-aminobutyric acid concentration increased in the GPi during high frequency stimulation (231 ± 102% in comparison to baseline values), a decrease was observed in the GPe (22 ± 10%). Extracellular glutamate levels largely remained unchanged. Pallidal microdialysis is a promising intraoperative monitoring tool to better understand pathophysiological implications in movement disorders and therapeutic mechanisms of high frequency stimulation. The increased inhibitory tone of GPi neurons and the subsequent thalamic inhibition could be one of the key mechanisms of GPi deep brain stimulation in dystonia. Such a mechanism may explain how competing (dystonic) movements can be suppressed in GPi/thalamic circuits in favour of desired motor programs. Copyright © 2015 Elsevier Ltd. All rights reserved.

  5. Self-inactivating gammaretroviral vectors for gene therapy of X-linked severe combined immunodeficiency.

    Science.gov (United States)

    Thornhill, Susannah I; Schambach, Axel; Howe, Steven J; Ulaganathan, Meera; Grassman, Elke; Williams, David; Schiedlmeier, Bernhard; Sebire, Neil J; Gaspar, H Bobby; Kinnon, Christine; Baum, Christopher; Thrasher, Adrian J

    2008-03-01

    Gene therapy for X-linked severe combined immunodeficiency (SCID-X1) has proven highly effective for long-term restoration of immunity in human subjects. However, the development of lymphoproliferative complications due to dysregulated proto-oncogene expression has underlined the necessity for developing safer vector systems. To reduce the potential for insertional mutagenesis, we have evaluated the efficacy of self-inactivating (SIN) gammaretroviral vectors in cellular and in vivo models of SCID-X1. Vectors incorporating an internal human elongation factor-1alpha regulatory element were capable of fully restoring the lymphoid differentiation potential of gammac-deficient lineage negative cells. Multilineage lymphoid reconstitution of a murine model was achieved at a similar level to that achieved by a conventional long-terminal repeat (LTR)-regulated vector used in previous clinical trials. Functional proliferative responses to mitogenic stimuli were also restored, and serum immunoglobulin levels were normalized. The reduced mutagenic potential conferred by SIN vector configurations and alternative non-LTR-based regulatory elements, together with proven efficacy in correction of cellular defects provides an important platform for development of the next phase of clinical trials for SCID-X1.

  6. [Mutation analysis and prenatal diagnosis of a Chinese family with X-linked severe combined immunodeficiency].

    Science.gov (United States)

    Wu, Qing-hua; Shi, Hui-rong; Liu, Ning; Jiang, Miao; Lu, Ning; Zhao, Zhen-hua; Kong, Xiang-dong

    2012-11-01

    To analyze the mutation of IL2RG gene in a Chinese family with a birth history of a dead child suspected of X-linked severe combined immunodeficiency (X-SCID), and to perform prenatal diagnosis with DNA sequencing. Blood samples of the parents of the dead child and chorionic villi at gestational age 11 weeks were collected. Eight exons comprising the open reading frame as well as their exon/intron boundaries of IL2RG gene were analyzed by PCR and bi-directional sequencing. A heterozygous nucleotide substitution c.690C > T (R226C) in exon 5 was detected in the mother, but not in the father. In the second pregnancy of the mother, the mutation of R226C was not detected in the male fetus by prenatal diagnosis, and the heterozygous mutation was detected in the female fetus of the third pregnancy. The reliability of the prenatal genetic diagnosis was confirmed by the one-year follow-up after the neonates were born. The mutation of c.690C>T in IL2RG gene may be the pathologic cause of the proband with X-SCID. DNA sequencing combining sex determination is a valid strategy for prenatal diagnosis of X-SCID.

  7. The evolution of gene therapy in X-linked severe combined immunodeficiency.

    Science.gov (United States)

    Rans, Tonya S; England, Ronald

    2009-05-01

    To review the evolution of gene therapy in infants with X-linked severe combined immunodeficiency (XL-SCID) and to evaluate the current challenges facing this evolving field. The MEDLINE, OVID, CINAHL, and HealthSTAR databases were searched to identify pertinent articles using the following keywords: gene therapy, XL-SCID, bone marrow transplant, and viral vectors. Journal articles were selected for their relevance to human gene therapy in patients with XL-SCID. Gene therapy with a retrovirus-derived vector has been used to treat 20 patients with XL-SCID internationally. Although most patients derived improvements in T- and B-cell immune numbers and function, severe adverse effects have occurred. After gene therapy, 5 of the 20 patients developed leukemia. This outcome has been associated with insertion of the corrected gene near the T-cell proto-oncogene LMO2. One of the 5 patients subsequently died. Within the past decade, effective improvements in vectorology and cell culture conditions have resulted in clinical success in some infants with SCID and have revived interest after many years of setbacks. However, clinical success and significant adverse events have been reported in patients with XL-SCID who have undergone gene therapy using a retroviral vector. As extensive research into improving safety through vector development and monitoring of gene therapy continues, further progress in gene therapy development can be anticipated.

  8. Lentiviral hematopoietic stem cell gene therapy for X-linked severe combined immunodeficiency.

    Science.gov (United States)

    De Ravin, Suk See; Wu, Xiaolin; Moir, Susan; Anaya-O'Brien, Sandra; Kwatemaa, Nana; Littel, Patricia; Theobald, Narda; Choi, Uimook; Su, Ling; Marquesen, Martha; Hilligoss, Dianne; Lee, Janet; Buckner, Clarissa M; Zarember, Kol A; O'Connor, Geraldine; McVicar, Daniel; Kuhns, Douglas; Throm, Robert E; Zhou, Sheng; Notarangelo, Luigi D; Hanson, I Celine; Cowan, Mort J; Kang, Elizabeth; Hadigan, Coleen; Meagher, Michael; Gray, John T; Sorrentino, Brian P; Malech, Harry L; Kardava, Lela

    2016-04-20

    X-linked severe combined immunodeficiency (SCID-X1) is a profound deficiency of T, B, and natural killer (NK) cell immunity caused by mutations inIL2RGencoding the common chain (γc) of several interleukin receptors. Gamma-retroviral (γRV) gene therapy of SCID-X1 infants without conditioning restores T cell immunity without B or NK cell correction, but similar treatment fails in older SCID-X1 children. We used a lentiviral gene therapy approach to treat five SCID-X1 patients with persistent immune dysfunction despite haploidentical hematopoietic stem cell (HSC) transplant in infancy. Follow-up data from two older patients demonstrate that lentiviral vector γc transduced autologous HSC gene therapy after nonmyeloablative busulfan conditioning achieves selective expansion of gene-marked T, NK, and B cells, which is associated with sustained restoration of humoral responses to immunization and clinical improvement at 2 to 3 years after treatment. Similar gene marking levels have been achieved in three younger patients, albeit with only 6 to 9 months of follow-up. Lentiviral gene therapy with reduced-intensity conditioning appears safe and can restore humoral immune function to posthaploidentical transplant older patients with SCID-X1. Copyright © 2016, American Association for the Advancement of Science.

  9. Gene Therapy for X-Linked Severe Combined Immunodeficiency: Where Do We Stand?

    Science.gov (United States)

    Cavazzana, Marina; Six, Emmanuelle; Lagresle-Peyrou, Chantal; André-Schmutz, Isabelle; Hacein-Bey-Abina, Salima

    2016-02-01

    More than 20 years ago, X-linked severe combined immunodeficiency (SCID-X1) appeared to be the best condition to test the feasibility of hematopoietic stem cell gene therapy. The seminal SCID-X1 clinical studies, based on first-generation gammaretroviral vectors, demonstrated good long-term immune reconstitution in most treated patients despite the occurrence of vector-related leukemia in a few of them. This gene therapy has successfully enabled correction of the T cell defect. Natural killer and B cell defects were only partially restored, most likely due to the absence of a conditioning regimen. The success of these pioneering trials paved the way for the extension of gene-based treatment to many other diseases of the hematopoietic system, but the unfortunate serious adverse events led to extensive investigations to define the retrovirus integration profiles. This review puts into perspective the clinical experience of gene therapy for SCID-X1, with the development and implementation of new generations of safer vectors such as self-inactivating gammaretroviral or lentiviral vectors as well as major advances in integrome knowledge.

  10. Gene therapy model of X-linked severe combined immunodeficiency using a modified foamy virus vector.

    Science.gov (United States)

    Horino, Satoshi; Uchiyama, Toru; So, Takanori; Nagashima, Hiroyuki; Sun, Shu-Lan; Sato, Miki; Asao, Atsuko; Haji, Yoichi; Sasahara, Yoji; Candotti, Fabio; Tsuchiya, Shigeru; Kure, Shigeo; Sugamura, Kazuo; Ishii, Naoto

    2013-01-01

    X-linked severe combined immunodeficiency (SCID-X1) is an inherited genetic immunodeficiency associated with mutations in the common cytokine receptor γ chain (γc) gene, and characterized by a complete defect of T and natural killer (NK) cells. Gene therapy for SCID-X1 using conventional retroviral (RV) vectors carrying the γc gene results in the successful reconstitution of T cell immunity. However, the high incidence of vector-mediated T cell leukemia, caused by vector insertion near or within cancer-related genes has been a serious problem. In this study, we established a gene therapy model of mouse SCID-X1 using a modified foamy virus (FV) vector expressing human γc. Analysis of vector integration in a human T cell line demonstrated that the FV vector integration sites were significantly less likely to be located within or near transcriptional start sites than RV vector integration sites. To evaluate the therapeutic efficacy, bone marrow cells from γc-knockout (γc-KO) mice were infected with the FV vector and transplanted into γc-KO mice. Transplantation of the FV-treated cells resulted in the successful reconstitution of functionally active T and B cells. These data suggest that FV vectors can be effective and may be safer than conventional RV vectors for gene therapy for SCID-X1.

  11. Gene therapy model of X-linked severe combined immunodeficiency using a modified foamy virus vector.

    Directory of Open Access Journals (Sweden)

    Satoshi Horino

    Full Text Available X-linked severe combined immunodeficiency (SCID-X1 is an inherited genetic immunodeficiency associated with mutations in the common cytokine receptor γ chain (γc gene, and characterized by a complete defect of T and natural killer (NK cells. Gene therapy for SCID-X1 using conventional retroviral (RV vectors carrying the γc gene results in the successful reconstitution of T cell immunity. However, the high incidence of vector-mediated T cell leukemia, caused by vector insertion near or within cancer-related genes has been a serious problem. In this study, we established a gene therapy model of mouse SCID-X1 using a modified foamy virus (FV vector expressing human γc. Analysis of vector integration in a human T cell line demonstrated that the FV vector integration sites were significantly less likely to be located within or near transcriptional start sites than RV vector integration sites. To evaluate the therapeutic efficacy, bone marrow cells from γc-knockout (γc-KO mice were infected with the FV vector and transplanted into γc-KO mice. Transplantation of the FV-treated cells resulted in the successful reconstitution of functionally active T and B cells. These data suggest that FV vectors can be effective and may be safer than conventional RV vectors for gene therapy for SCID-X1.

  12. X-linked adrenoleukodystrophy: are signs of hypogonadism always due to testicular failure?

    Science.gov (United States)

    Karapanou, Olga; Vlassopoulou, Barbara; Tzanela, Marinella; Papadopoulos, Dimitrios; Angelidakis, Panagiotis; Michelakakis, Helen; Ioannidis, George; Mihalatos, Markos; Kamakari, Smaragda; Tsagarakis, Stylianos

    2014-01-01

    We present the clinical and hormonal findings of a young male with X-linked adrenoleukodystrophy (X-ALD), with special emphasis on the biochemical and clinical pattern of hypogonadism. A patient, with primary adrenal insufficiency since the age of 5 years, developed progressive neurological symptoms at the age of 29. Diagnosis of X-ALD was established by elevated serum very long chain fatty acids (VLCFAs) and genetic testing. His sexual body hair was sparse. Hormonal investigations revealed normal testosterone and inappropriately elevated LH levels. Androgen receptor gene analysis was negative for mutations or polymorphic variants associated with decreased receptor activity. Signs of hypogonadism in patients with confirmed X-ALD are not exclusively due to primary testicular failure. Tissue specific androgen resistance represents an alternative possibility. Since no loss-of-function mutations were detected in the androgen receptor, it is speculated that the patient's androgen resistance could be part of a functional defect mediated through VLCFA accumulation at the testosterone receptor and/or post-receptor levels.

  13. Newborn screening for X-linked adrenoleukodystrophy: evidence summary and advisory committee recommendation.

    Science.gov (United States)

    Kemper, Alex R; Brosco, Jeffrey; Comeau, Anne Marie; Green, Nancy S; Grosse, Scott D; Jones, Elizabeth; Kwon, Jennifer M; Lam, Wendy K K; Ojodu, Jelili; Prosser, Lisa A; Tanksley, Susan

    2017-01-01

    The secretary of the US Department of Health and Human Services in February 2016 recommended that X-linked adrenoleukodystrophy (X-ALD) be added to the recommended uniform screening panel for state newborn screening programs. This decision was informed by data presented on the accuracy of screening from New York, the only state that currently offers X-ALD newborn screening, and published and unpublished data showing health benefits of earlier treatment (hematopoietic stem cell transplantation and adrenal hormone replacement therapy) for the childhood cerebral form of X-ALD. X-ALD newborn screening also identifies individuals with later-onset disease, but poor genotype-phenotype correlation makes predicting health outcomes difficult and might increase the risk of unnecessary treatment. Few data are available regarding the harms of screening and presymptomatic identification. Significant challenges exist for implementing comprehensive X-ALD newborn screening, including incorporation of the test, coordinating follow-up diagnostic and treatment care, and coordination of extended family testing after case identification.Genet Med 19 1, 121-126.

  14. A Thyroid Hormone-Based Strategy for Correcting the Biochemical Abnormality in X-Linked Adrenoleukodystrophy.

    Science.gov (United States)

    Hartley, Meredith D; Kirkemo, Lisa L; Banerji, Tapasree; Scanlan, Thomas S

    2017-05-01

    X-linked adrenoleukodystrophy (X-ALD) is a rare, genetic disorder characterized by adrenal insufficiency and central nervous system (CNS) demyelination. All patients with X-ALD have the biochemical abnormality of elevated blood and tissue levels of very long chain fatty acids (VLCFAs), saturated fatty acids with 24 to 26 carbons. X-ALD results from loss of function mutations in the gene encoding the peroxisomal transporter ABCD1, which is responsible for uptake of VLCFAs into peroxisomes for degradation by oxidation. One proposed therapeutic strategy for genetic complementation of ABCD1 is pharmacologic upregulation of ABCD2, a gene encoding a homologous peroxisomal transporter. Here, we show that thyroid hormone or sobetirome, a clinical-stage selective thyroid hormone receptor agonist, increases cerebral Abcd2 and lowers VLCFAs in blood, peripheral organs, and brains of mice with defective Abcd1. These results support an approach to treating X-ALD that involves a thyromimetic agent that reactivates VLCFA disposal both in the periphery and the CNS. Copyright © 2017 Endocrine Society.

  15. Mitochondrial dysfunction and oxidative damage cooperatively fuel axonal degeneration in X-linked adrenoleukodystrophy.

    Science.gov (United States)

    Fourcade, Stéphane; López-Erauskin, Jone; Ruiz, Montserrat; Ferrer, Isidre; Pujol, Aurora

    2014-03-01

    X-linked adrenoleukodystrophy (X-ALD) is the most frequent inherited monogenic demyelinating disease (minimal incidence 1:17,000). It is often lethal and currently lacks a satisfactory therapy. The disease is caused by loss of function of the ABCD1 gene, a peroxisomal ATP-binding cassette transporter, resulting in the accumulation of VLCFA (very long-chain fatty acids) in organs and plasma. Understanding of the aetiopathogenesis is a prerequisite for the development of novel therapeutic strategies. Functional genomics analysis of an ABCD1 null mouse, a mouse model for adrenomyeloneuropathy, has revealed presymptomatic alterations in several metabolic pathways converging on redox and bioenergetic homeostasis, with failure of mitochondrial OXPHOS disruption and mitochondrial depletion. These defects could be major contributors to the neurodegenerative cascade, as has been reported in several neurodegenerative disorders. Drugs targeting the redox imbalance/mitochondria dysfunction interplay have shown efficacy at halting axonal degeneration and associated disability in the mouse, and thus offer therapeutic hope. Copyright © 2013 Elsevier Masson SAS. All rights reserved.

  16. Abnormal osteopontin and matrix extracellular phosphoglycoprotein localization, and odontoblast differentiation, in X-linked hypophosphatemic teeth.

    Science.gov (United States)

    Salmon, B; Bardet, C; Coyac, B R; Baroukh, B; Naji, J; Rowe, P S; Opsahl Vital, S; Linglart, A; Mckee, M D; Chaussain, C

    2014-08-01

    Mutations in phosphate-regulating gene (PHEX) lead to X-linked hypophosphatemic rickets (XLH), a genetic disease characterized by impaired mineralization in bones and teeth. In human XLH tooth dentin, calcospherites that would normally merge as part of the mineralization process are separated by unmineralized interglobular spaces where fragments of matrix proteins accumulate. Here, we immunolocalized osteopontin (OPN) in human XLH teeth, in a three-dimensional XLH human dental pulp stem cell-collagen scaffold culture model and in a rat tooth injury repair model treated with acidic serine- and aspartate-rich motif peptides (ASARM). In parallel, matrix extracellular phosphoglycoprotein (MEPE) immunolocalization and alkaline phosphatase (ALP) activity were assessed in XLH teeth. OPN was expressed by odontoblasts in the XLH models, and localized to the abnormal calcospherites of XLH tooth dentin. In addition, ALP activity and MEPE localization were abnormal in human XLH teeth, with MEPE showing an accumulation in the unmineralized interglobular spaces in dentin. Furthermore, XLH odontoblasts failed to form a well-polarized odontoblast layer. These data suggest that both MEPE and OPN are involved in impaired tooth mineralization associated with XLH, possibly through different effects on the mineralization process.

  17. Decremental responses to repetitive nerve stimulation in x-linked bulbospinal muscular atrophy.

    Science.gov (United States)

    Kim, Jee Young; Park, Kee Duk; Kim, Seung-Min; Sunwoo, Il Nam

    2013-01-01

    X-linked bulbospinal muscular atrophy (X-BSMA) is characterized by bulbar and spinal muscular weakness and fasciculations. Although X-BSMA is a motor neuronopathy, there are several reports of myasthenic symptoms or decremental responses to repetitive nerve stimulation (RNS). We report the results of applying the RNS test to 15 patients among 41 with genetically confirmed X-BSMA; these 15 patients complained of fatigue, ease of becoming tired, or early muscular exhaustion. The 3-Hz RNS test was performed on the trapezius, nasalis, orbicularis oculi, flexor carpi ulnaris, and abductor digiti quinti muscles. A decrement greater than 10% was considered abnormal. Additionally, a pharmacologic response to neostigmine was identified in three patients. A significant decrement was observed in 67% of patients, and was most common in the trapezius muscle (nine cases). The decrement of the trapezius muscle response ranged from 15.9% to 36.9%. The decrement was inversely correlated with the amplitude of compound muscle action potentials at rest. Neostigmine injection markedly improved the decrement in three patients, who showed noticeable decremental responses to 3-Hz RNS. This study shows that myasthenic symptoms and abnormal decremental responses to low-rate RNS are common in X-BSMA.

  18. X-linked Liver Glycogenosis in a Taiwanese Family: Transmission From Undiagnosed Males

    Directory of Open Access Journals (Sweden)

    Szu-Ta Chen

    2009-10-01

    Full Text Available X-linked liver glycogenosis (XLG, also known as glycogen storage disease type-IXa, is characterized by hepatomegaly, abnormal liver functions and growth retardation. It is caused by mutations in the PHKA2 gene that encodes the α-subunit of phosphorylase kinase (PHK. XLG can be divided into two subtypes: XLG-I, with a deficiency in PHK activity in peripheral blood cells and the liver; and XLG-II, with normal PHK activity in vitro. This report describes two boys who presented with hepatomegaly and abnormal liver function. Pedigree analysis revealed them to be fifth-degree relatives, with the disease transmitted through undiagnosed grandfathers. Liver histology confirmed GSD diagnosis, and both cases had a deficiency in PHK activity in red blood cells and liver tissues. This is the first report of XLG-I in the ethnic-Chinese population in Taiwan. This report indicates that XLG may be undiagnosed or underestimated. A correct diagnosis is necessary for proper management and genetic counseling.

  19. Mutations in PHKA2 are responsible for X-linked liver glycogen storage disease

    Energy Technology Data Exchange (ETDEWEB)

    Hendrickx, J.; Coucke, P.; Dams, E. [Univ. of Antwerp (Belgium)

    1994-09-01

    X-linked liver glycogenosis type I (XLG I) is due to a deficiency of phosphorylase kinase (PHK), a key enzyme in the control of glycogen breakdown. XLG I is the most common glycogen storage disease. Patients show hepatomegaly, growth retardation and elevation of liver enzymes as their main clinical symptoms. We assigned the XLG I gene to the chromosomal region Xp22 by linkage analysis in six XLG I families. As the liver {alpha}-subunit of PHK (PHKA2) was also localized to Xp22, PHKA2 was considered a candidate gene for XLG I. In this study, we searched for mutations in 6 exons of the PHDA2 gene of 9 unrelated XLG I patients by SSCP analysis. This revealed three point mutations present in three different patients. Two of these mutations introduce a premature stop codon leading to a truncated protein. The third mutation abolishes a 5{prime} splice site consensus sequence leading to exon skipping. All three mutations therefore result in a PHKA2 protein that lacks several amino acids, what most probably affects enzyme function or stability. These findings indicate that PHKA2 is the XLG I gene.

  20. Neonatal treatment with recombinant ectodysplasin prevents respiratory disease in dogs with X-linked ectodermal dysplasia.

    Science.gov (United States)

    Mauldin, Elizabeth A; Gaide, Olivier; Schneider, Pascal; Casal, Margret L

    2009-09-01

    Patients with defective ectodysplasin A (EDA) have X-linked hypohidrotic ectodermal dysplasia (XLHED; OMIM#305100), a condition comprising hypotrichosis, inability to sweat, abnormal teeth, and frequent pulmonary infections. The XLHED dogs show the same clinical signs as humans with the disorder, including frequent respiratory infections that can be fatal. The respiratory disease in humans and dogs is thought to be due to the absence of tracheal and bronchial glands which are a vital part of the mucociliary clearance mechanism. In our XLHED model, the genetically missing EDA was replaced by postnatal intravenous administration of recombinant EDA resulting in long-term, durable corrective effect on adult, permanent dentition. After treatment with EDA, significant correction of the missing tracheal and bronchial glands was achieved in those dogs that received higher doses of EDA. Moreover, successful treatment resulted in the presence of esophageal glands, improved mucociliary clearance, and the absence of respiratory infection. These results demonstrate that a short-term treatment at a neonatal age with a recombinant protein can reverse a developmental disease and result in vastly improved quality of life. (c) 2009 Wiley-Liss, Inc.

  1. Methylation state of the EDA gene promoter in Chinese X-linked hypohidrotic ectodermal dysplasia carriers.

    Directory of Open Access Journals (Sweden)

    Wei Yin

    Full Text Available Hypodontia, hypohidrosis, sparse hair and characteristic faces are the main characters of X-linked hypohidrotic ectodermal dysplasia (XLHED which is caused by genetic ectodysplasin A (EDA deficiency. Heterozygous female carriers tend to have mild to moderate XLHED phenotype, even though 30% of them present no obvious symptom.A large Chinese XLHED family was reported and the entire coding region and exon-intron boundaries of EDA gene were sequenced. To elucidate the mechanism for carriers' tempered phenotype, we analyzed the methylation level on four sites of the promoter of EDA by the pyrosequencing system.A known frameshift mutation (c.573-574 insT was found in this pedigree. Combined with the pedigrees we reported before, 120 samples comprised of 23 carrier females from 11 families and 97 healthy females were analyzed for the methylation state of EDA promoter. Within 95% confidence interval (CI, 18 (78.26% carriers were hypermethylated at these 4 sites.Chinese XLHED carriers often have a hypermethylated EDA promoter.

  2. Clinical and mutational features of Vietnamese children with X-linked agammaglobulinemia.

    Science.gov (United States)

    Vu, Quang Van; Wada, Taizo; Le, Huong Thi Minh; Le, Hai Thanh; Van Nguyen, Anh Thi; Osamu, Ohara; Yachie, Akihiro; Nguyen, Sang Ngoc

    2014-05-28

    X-linked agammaglobulinemia (XLA) is a primary immune deficiency characterized by recurrent bacterial infections and profoundly depressed serum immunoglobulin levels and circulating mature B cells. It is caused by mutations of the Bruton tyrosine kinase (BTK) gene and is the most common form of inherited antibody deficiency. To our knowledge, this is the first report of XLA from Vietnam. We investigated the BTK gene mutations and clinical features of four unrelated Vietnamese children. The mean ages at onset and at diagnosis were 2.5 and 8 years, respectively. All patients had a medical history of otitis media, pneumonia, and septicemia at the time of diagnosis. Other infections reported included sinusitis, bronchiectasis, arthritis, skin infections, meningitis, and recurrent diarrhea. We identified one previously reported mutation (c.441G >A) and three novel mutations: two frameshifts (c.1770delG and c.1742 delG), and one nonsense (c.1249A >T). The delayed diagnosis may be attributable to insufficient awareness of this rare disease on the background of frequent infections even in the immunocompetent pediatric population in Vietnam. Our results further support the importance of molecular genetic testing in diagnosis of XLA.

  3. Recurrent pneumonia with mild hypogammaglobulinemia diagnosed as X-linked agammaglobulinemia in adults

    Science.gov (United States)

    Usui, Kazuhiro; Sasahara, Yoji; Tazawa, Ryushi; Hagiwara, Koichi; Tsukada, Satoshi; Miyawaki, Toshio; Tsuchiya, Shigeru; Nukiwa, Toshihiro

    2001-01-01

    Background X-linked agammaglobulinemia (XLA) is a humoral immunodeficiency caused by disruption of the Bruton's tyrosine kinase (BTK) gene. Typical XLA patients suffer recurrent and severe bacterial infections in childhood. Methods Flow cytometric analysis of the peripheral monocytes using the anti-BTK antibody was used to characterize a 27 year old male patient with mild hypogammaglobulinemia (IgG, 635 mg/dl; IgM, 11 mg/dl; IgA, <5 mg/dl). He had suffered from frequent pneumonia since age 25 but had no history of frequent infections in his childhood or in adolescence. Sequencing of the BTK cDNA obtained from an Epstein–Barr virus-transformed B lymphoblastoid cell line derived from the bone marrow of the patient was performed to confirm a genetic defect. Results Flow cytometric analysis of cytoplasmic BTK protein in peripheral monocytes indicated that the patient presents a rare case of adult-onset XLA and that his mother is an XLA carrier. Sequencing of the BTK gene revealed a deletion of AG in the codon for Glu605 (AGT), resulting in an aberrant stop codon that truncates the BTK protein in its kinase domain. Conclusions This case suggests that some XLA cases may remain undiagnosed because they only show mild hypogammaglobulinemia and they lack repeated infections in childhood. Flow cytometric analysis is a powerful method to screen these patients. PMID:11686883

  4. Enteroviruses in X-Linked Agammaglobulinemia: Update on Epidemiology and Therapy.

    Science.gov (United States)

    Bearden, David; Collett, Marc; Quan, P Lan; Costa-Carvalho, Beatriz T; Sullivan, Kathleen E

    X-linked agammaglobulinemia (XLA) has been associated with a broad range of infections, but enteroviral disease represents one of the most damaging infections. The risk of enteroviral infection in XLA is lower now than in the setting of intramuscular immunoglobulin or in patients without immunoglobulin replacement, but the rate of infection has not declined significantly in the era of intravenous immunoglobulin replacement. Enteroviruses can cause inflammation of nearly every organ, but in XLA, infections often manifest as dermatomyositis or chronic meningoencephalitis. Difficulty and delay in recognizing symptoms and lack of specific therapy contribute to the poor outcomes. Furthermore, cerebrospinal fluid detection of enteroviruses is not very sensitive. Reluctance to perform brain biopsies can lead to significant delays. The other feature compromising outcomes is the lack of specific therapy. High-dose peripheral and intraventricular immunoglobulin have been used, but failure is still common. New antienteroviral drugs are in development and show promise for immunodeficient patients with life-threatening infections with enterovirus. Copyright © 2016 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.

  5. Females with a disorder phenotypically identical to X-linked agammaglobulinemia

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    Conley, M.E. (Univ. of Tennessee College of Medicine, Memphis (United States)); Sweinberg, S.K. (Children' s Hospital of Philadelphia, PA (United States))

    1992-03-01

    Clinical and laboratory findings in two girls with a disorder phenotypically indistinguishable from typical X-linked agammaglobulinemia (XLA) are described. To examine the possibility that subtle defects in the X chromosome might explain the findings, detailed genetic studies were performed on one of these patients. Cytogenetic studies showed a normal 46XX karyotype. Southern blot analysis of her DNA showed that she had inherited a maternal and a paternal allele at sites flanking the locus for typical XLA at Xq22, making a microdeletion or uniparental disomy unlikely. To determine whether both of her X chromosomes could function as the active X, somatic-cell hybrids that selectively retained the active X were produced from her activated T cells. A normal random pattern of X inactivation was seen. Of 21 T-cell hybrids, 3 retained both X chromosomes, 7 had one X as the active X, and 11 had the other X as the active X. The authors have interpreted these studies as indicating that there is an autosomal recessive disorder that is phenotypically identical to XLA.

  6. Splice-correcting oligonucleotides restore BTK function in X-linked agammaglobulinemia model.

    Science.gov (United States)

    Bestas, Burcu; Moreno, Pedro M D; Blomberg, K Emelie M; Mohammad, Dara K; Saleh, Amer F; Sutlu, Tolga; Nordin, Joel Z; Guterstam, Peter; Gustafsson, Manuela O; Kharazi, Shabnam; Piątosa, Barbara; Roberts, Thomas C; Behlke, Mark A; Wood, Matthew J A; Gait, Michael J; Lundin, Karin E; El Andaloussi, Samir; Månsson, Robert; Berglöf, Anna; Wengel, Jesper; Smith, C I Edvard

    2014-09-01

    X-linked agammaglobulinemia (XLA) is an inherited immunodeficiency that results from mutations within the gene encoding Bruton's tyrosine kinase (BTK). Many XLA-associated mutations affect splicing of BTK pre-mRNA and severely impair B cell development. Here, we assessed the potential of antisense, splice-correcting oligonucleotides (SCOs) targeting mutated BTK transcripts for treating XLA. Both the SCO structural design and chemical properties were optimized using 2'-O-methyl, locked nucleic acid, or phosphorodiamidate morpholino backbones. In order to have access to an animal model of XLA, we engineered a transgenic mouse that harbors a BAC with an authentic, mutated, splice-defective human BTK gene. BTK transgenic mice were bred onto a Btk knockout background to avoid interference of the orthologous mouse protein. Using this model, we determined that BTK-specific SCOs are able to correct aberrantly spliced BTK in B lymphocytes, including pro-B cells. Correction of BTK mRNA restored expression of functional protein, as shown both by enhanced lymphocyte survival and reestablished BTK activation upon B cell receptor stimulation. Furthermore, SCO treatment corrected splicing and restored BTK expression in primary cells from patients with XLA. Together, our data demonstrate that SCOs can restore BTK function and that BTK-targeting SCOs have potential as personalized medicine in patients with XLA.

  7. Splice-correction strategies for treatment of X-linked agammaglobulinemia.

    Science.gov (United States)

    Bestas, Burcu; Turunen, Janne J; Blomberg, K Emelie M; Wang, Qing; Månsson, Robert; El Andaloussi, Samir; Berglöf, Anna; Smith, C I Edvard

    2015-03-01

    X-linked agammaglobulinemia (XLA) is a primary immunodeficiency disease caused by mutations in the gene coding for Bruton's tyrosine kinase (BTK). Deficiency of BTK leads to a developmental block in B cell differentiation; hence, the patients essentially lack antibody-producing plasma cells and are susceptible to various infections. A substantial portion of the mutations in BTK results in splicing defects, consequently preventing the formation of protein-coding mRNA. Antisense oligonucleotides (ASOs) are therapeutic compounds that have the ability to modulate pre-mRNA splicing and alter gene expression. The potential of ASOs has been exploited for a few severe diseases, both in pre-clinical and clinical studies. Recently, advances have also been made in using ASOs as a personalized therapy for XLA. Splice-correction of BTK has been shown to be feasible for different mutations in vitro, and a recent proof-of-concept study demonstrated the feasibility of correcting splicing and restoring BTK both ex vivo and in vivo in a humanized bacterial artificial chromosome (BAC)-transgenic mouse model. This review summarizes the advances in splice correction, as a personalized medicine for XLA, and outlines the promises and challenges of using this technology as a curative long-term treatment option.

  8. High-throughput sequencing reveals an altered T cell repertoire in X-linked agammaglobulinemia.

    Science.gov (United States)

    Ramesh, Manish; Simchoni, Noa; Hamm, David; Cunningham-Rundles, Charlotte

    2015-12-01

    To examine the T cell receptor structure in the absence of B cells, the TCR β CDR3 was sequenced from DNA of 15 X-linked agammaglobulinemia (XLA) subjects and 18 male controls, using the Illumina HiSeq platform and the ImmunoSEQ analyzer. V gene usage and the V-J combinations, derived from both productive and non-productive sequences, were significantly different between XLA samples and controls. Although the CDR3 length was similar for XLA and control samples, the CDR3 region of the XLA T cell receptor contained significantly fewer deletions and insertions in V, D, and J gene segments, differences intrinsic to the V(D)J recombination process and not due to peripheral T cell selection. XLA CDR3s demonstrated fewer charged amino acid residues, more sharing of CDR3 sequences, and almost completely lacked a population of highly modified Vβ gene segments found in control DNA, suggesting both a skewed and contracted T cell repertoire in XLA. Copyright © 2015 Elsevier Inc. All rights reserved.

  9. Relapsing Campylobacter jejuni Systemic Infections in a Child with X-Linked Agammaglobulinemia

    Directory of Open Access Journals (Sweden)

    Paola Ariganello

    2013-01-01

    Full Text Available X-linked agammaglobulinemia (XLA is a primary immunodeficiency of the humoral compartment, due to a mutation in the Bruton tyrosine kinase (BTK gene, characterized by a severe defect of circulating B cells and serum immunoglobulins. Recurrent infections are the main clinical manifestations; although they are especially due to encapsulated bacteria, a specific association with Campylobacter species has been reported. Here, we report the case of a boy with XLA who presented with relapsing Campylobacter jejuni systemic infections. His clinical history supports the hypothesis of the persistence of C. jejuni in his intestinal tract. Indeed, as previously reported, XLA patients may become chronic intestinal carriers of Campylobacter, even in absence of symptoms, with an increased risk of relapsing bacteraemia. The humoral defect is considered to be crucial for this phenomenon, as well as the difficulties to eradicate the pathogen with an appropriate antibiotic therapy; drug resistance is raising in Campylobacter species, and the appropriate duration of treatment has not been established. C. jejuni should always be suspected in XLA patients with signs and symptoms of systemic infection, and treatment should be based on antibiogram to assure the eradication of the pathogen.

  10. Clinical characteristics and genetic profiles of 174 patients with X-linked agammaglobulinemia

    Science.gov (United States)

    Chen, Xia-Fang; Wang, Wei-Fan; Zhang, Yi-Dan; Zhao, Wei; Wu, Jing; Chen, Tong-Xin

    2016-01-01

    Abstract X-linked agammaglobulinemia (XLA) is a humoral primary immunodeficiency. XLA patients typically present with very low numbers of peripheral B cells and a profound deficiency of all immunoglobulin isotypes. Most XLA patients carry mutations in Bruton tyrosine kinase (BTK) gene. The genetic background and clinical features of 174 Chinese patients with XLA were investigated. The relationship between specific BTK gene mutations and severity of clinical manifestations was also examined. Mutations were graded from mild to severe based on structural and functional prediction through bioinformatics analysis. One hundred twenty-seven mutations were identified in 142 patients from 124 families, including 45 novel mutations and 82 recurrent mutations that were distributed over the entire BTK gene sequence. Variation in phenotypes was observed, and there was a tendency of association between genotype and age of disease onset. This report constitutes the largest group of patients with BTK mutations in China. A genotype–phenotype correlation was observed in this study. Early diagnosis of congenital agammaglobulinemia should be based on clinical symptoms, family history, and molecular analysis of the BTK gene. PMID:27512878

  11. Clinical and mutational features of X-linked agammaglobulinemia in Mexico.

    Science.gov (United States)

    García-García, E; Staines-Boone, A T; Vargas-Hernández, A; González-Serrano, M E; Carrillo-Tapia, E; Mogica-Martínez, D; Berrón-Ruíz, L; Segura-Mendez, N H; Espinosa-Rosales, F J; Yamazaki-Nakashimada, M A; Santos-Argumedo, L; López-Herrera, G

    2016-04-01

    X-linked agammaglobulinemia (XLA) is caused by BTK mutations, patients typically show <2% of peripheral B cells and reduced levels of all immunoglobulins; they suffer from recurrent infections of bacterial origin; however, viral infections, autoimmune-like diseases, and an increased risk of developing gastric cancer are also reported. In this work, we report the BTK mutations and clinical features of 12 patients diagnosed with XLA. Furthermore, a clinical revision is also presented for an additional cohort of previously reported patients with XLA. Four novel mutations were identified, one of these located in the previously reported mutation refractory SH3 domain. Clinical data support previous reports accounting for frequent respiratory, gastrointestinal tract infections and other symptoms such as the occurrence of reactive arthritis in 19.2% of the patients. An equal proportion of patients developed septic arthritis; missense mutations and mutations in SH1, SH2 and PH domains predominated in patients who developed arthritis. Copyright © 2016 Elsevier Inc. All rights reserved.

  12. The genomic structure of human BTK, the defective gene in X-linked agammaglobulinemia

    Energy Technology Data Exchange (ETDEWEB)

    Rohrer, J.; Parolini, O. [St. Jude Children`s Research Hospital, Memphis, TN (United States); Conley, M.E. [St. Jude Children`s Research Hospital, Memphis, TN (United States)]|[Univ. of Tennessee College of Medicine, Memphis, TN (United States); Belmont, J.W. [Baylor College of Medicine, Houston, TX (United States)

    1994-12-31

    It has recently been demonstrated that mutations in the gene for Bruton`s tyrosine kinase (BTK) are responsible for X-linked agammaglobulinemia. Southern blot analysis and sequencing of cDNA were used to document deletions, insertions, and single base pair substitutions. To facilitate analysis of BTK regulation and to permit the development of assays that could be used to screen genomic DNA for mutations in BTK, the authors determined the genomic organization of this gene. Subcloning of a cosmid and a yeast artificial chromosome showed that BTK is divided into 19 exons spanning 37 kilobases of genomic DNA. Analysis of the region 5{prime} to the first untranslated exon revealed no consensus TATAA or CAAT boxes; however, three retinoic acid binding sites were identified in this region. Comparison of the structure of BTK with that of other nonreceptor tyrosine kinases, including SRC, FES, and CSK, demonstrated a lack of conservation of exon borders. Information obtained in this study will contribute to understanding of the evolution of nonreceptor tyrosine kinases. It will also be useful in diagnostic studies, including carrier detection, and in studies directed towards gene therapy or gene replacement. 29 refs., 2 figs., 2 tabs.

  13. Recurrent pneumonia with mild hypogammaglobulinemia diagnosed as X-linked agammaglobulinemia in adults

    Directory of Open Access Journals (Sweden)

    Tsuchiya Shigeru

    2001-04-01

    Full Text Available Abstract Background X-linked agammaglobulinemia (XLA is a humoral immunodeficiency caused by disruption of the Bruton's tyrosine kinase (BTK gene. Typical XLA patients suffer recurrent and severe bacterial infections in childhood. Methods Flow cytometric analysis of the peripheral monocytes using the anti-BTK antibody was used to characterize a 27 year old male patient with mild hypogammaglobulinemia (IgG, 635 mg/dl; IgM, 11 mg/dl; IgA, Results Flow cytometric analysis of cytoplasmic BTK protein in peripheral monocytes indicated that the patient presents a rare case of adult-onset XLA and that his mother is an XLA carrier. Sequencing of the BTK gene revealed a deletion of AG in the codon for Glu605 (AGT, resulting in an aberrant stop codon that truncates the BTK protein in its kinase domain. Conclusions This case suggests that some XLA cases may remain undiagnosed because they only show mild hypogammaglobulinemia and they lack repeated infections in childhood. Flow cytometric analysis is a powerful method to screen these patients.

  14. A novel gene mutation in a family with X-linked retinoschisis.

    Science.gov (United States)

    Lai, Yu-Hung; Huang, Shun-Ping; Chen, Shee-Ping; Hu, Pei-Shin; Lin, Shu-Fung; Sheu, Min-Muh; Wang, Hwei-Zu; Tsai, Rong Kung

    2015-09-01

    To describe the clinical characteristics of a Taiwanese family with X-linked retinoschisis (XLRS) and to investigate the molecular genetics of a novel mutation in the retinoschisin 1 (RS1) gene. A total of 15 participants in this XLRS family were analyzed. Complete ophthalmic examinations and fundus photography were performed on 15 family members. These tests identified five affected males and two female carriers. Blood samples were collected, and genomic DNA was extracted. Best-corrected visual acuity, optical coherence tomography (OCT), electroretinogram (ERG), and direct DNA sequence analysis of the RS1 gene were performed on 15 family members. Five affected males, with visual acuity ranging from 0.2 to 0.7, had macular schisis and abnormal retinal pigment epithelium pigmentation. The mixed scotopic ERG "b" wave was more reduced than the "a" wave. OCT revealed typical microcystic schisis cavities within the macula area. Direct DNA sequence analysis revealed a single base pair deletion, 97delT, in all the affected individuals. This deletion resulted in a frameshift mutation of the RS1 gene, causing protein truncation. The affected males in this family showed moderately decreased visual acuity and dysfunction in both cone cells and phototransduction. We identified a novel RS1 (97delT) mutation in a Taiwanese family with XLRS. This finding expands the RS1 mutation spectrum and may help to further understand the molecular pathogenesis of XLRS. Copyright © 2014. Published by Elsevier B.V.

  15. Characterization of point mutations in patients with X-linked ichtyosis (XLI)

    Energy Technology Data Exchange (ETDEWEB)

    Alperin, E.S.; Shaprio, L.J. [UCSF, San Francisco, CA (United States)

    1994-09-01

    X-linked icthyosis is the result of steroid sulfatase (STS) deficiency and is one of the most prevalent inborn errors of metabolism. The gene for STS contains ten exons which encode a 561 aa membrane bound protein. Although the majority of patients with XLI have complete deletions of the STS gene, 10% show normal DNA hybridization patterns. The STS mutations in these patients are of interest since they may help to recognize domains important for post-translational processing, protein stability and enzyme activity. Basler et al. have identified point mutations in three patients with XLI. We have characterized an additional three mutations. All six patients have unique single base pair substitutions. The mutations in all six patients are located within 105 residues in the C-terminal half of the polypeptide. Site-directed mutagenesis has been used to replicate four of the six mutations in an expression vector containing the coding region of STS. These vectors are being used to study the effects of the mutations in vitro as well as in vivo. When transfected into A9 cells, none of these vectors produces STS activity. When the vectors are transcribed and translated in a rabbit reticulyte system, three of the four result in a polypeptide with the same mobility on SDS-PAGE as normal STS. As expected, the product from the vector encoding the splice junction mutation was smaller than normal. Current experiments are examining the processing and localization of these mutant polypeptides.

  16. X inactivation in females with X-linked Charcot-Marie-Tooth disease.

    LENUS (Irish Health Repository)

    Murphy, Sinéad M

    2012-07-01

    X-linked Charcot-Marie-Tooth disease (CMT1X) is the second most common inherited neuropathy, caused by mutations in gap junction beta-1 (GJB1). Males have a uniformly moderately severe phenotype while females have a variable phenotype, suggested to be due to X inactivation. We aimed to assess X inactivation pattern in females with CMT1X and correlate this with phenotype using the CMT examination score to determine whether the X inactivation pattern accounted for the variable phenotype in females with CMT1X. We determined X inactivation pattern in 67 females with CMT1X and 24 controls using the androgen receptor assay. We were able to determine which X chromosome carried the GJB1 mutation in 30 females. There was no difference in X inactivation pattern between patients and controls. In addition, there was no correlation between X inactivation pattern in blood and phenotype. A possible explanation for these findings is that the X inactivation pattern in Schwann cells rather than in blood may explain the variable phenotype in females with CMT1X.

  17. EIF2S3 Mutations Associated with Severe X-Linked Intellectual Disability Syndrome MEHMO.

    Science.gov (United States)

    Skopkova, Martina; Hennig, Friederike; Shin, Byung-Sik; Turner, Clesson E; Stanikova, Daniela; Brennerova, Katarina; Stanik, Juraj; Fischer, Ute; Henden, Lyndal; Müller, Ulrich; Steinberger, Daniela; Leshinsky-Silver, Esther; Bottani, Armand; Kurdiova, Timea; Ukropec, Jozef; Nyitrayova, Olga; Kolnikova, Miriam; Klimes, Iwar; Borck, Guntram; Bahlo, Melanie; Haas, Stefan A; Kim, Joo-Ran; Lotspeich-Cole, Leda E; Gasperikova, Daniela; Dever, Thomas E; Kalscheuer, Vera M

    2017-04-01

    Impairment of translation initiation and its regulation within the integrated stress response (ISR) and related unfolded-protein response has been identified as a cause of several multisystemic syndromes. Here, we link MEHMO syndrome, whose genetic etiology was unknown, to this group of disorders. MEHMO is a rare X-linked syndrome characterized by profound intellectual disability, epilepsy, hypogonadism and hypogenitalism, microcephaly, and obesity. We have identified a C-terminal frameshift mutation (Ile465Serfs) in the EIF2S3 gene in three families with MEHMO syndrome and a novel maternally inherited missense EIF2S3 variant (c.324T>A; p.Ser108Arg) in another male patient with less severe clinical symptoms. The EIF2S3 gene encodes the γ subunit of eukaryotic translation initiation factor 2 (eIF2), crucial for initiation of protein synthesis and regulation of the ISR. Studies in patient fibroblasts confirm increased ISR activation due to the Ile465Serfs mutation and functional assays in yeast demonstrate that the Ile465Serfs mutation impairs eIF2γ function to a greater extent than tested missense mutations, consistent with the more severe clinical phenotype of the Ile465Serfs male mutation carriers. Thus, we propose that more severe EIF2S3 mutations cause the full MEHMO phenotype, while less deleterious mutations cause a milder form of the syndrome with only a subset of the symptoms. © 2017 WILEY PERIODICALS, INC.

  18. Epilepsy and mental retardation restricted to females: X-linked epileptic infantile encephalopathy of unusual inheritance.

    Science.gov (United States)

    Duszyc, Kinga; Terczynska, Iwona; Hoffman-Zacharska, Dorota

    2015-02-01

    Epilepsy in females with mental retardation (EFMR) is a rare early infantile epileptic encephalopathy (EIEE), phenotypically resembling Dravet syndrome (DS). It is characterised by a variable degree of intellectual deficits and epilepsy. EFMR is caused by heterozygous mutations in the PCDH19 gene (locus Xq22.1) encoding protocadherin-19, a protein that is highly expressed during brain development. The protein is involved in cell adhesion and probably plays an important role in neuronal migration and formation of synaptic connections. EFMR is considered X-linked of variable mutations' penetrance. Mutations in the PCDH19 gene mainly arise de novo, but if inherited, they show a unique pattern of transmission. Females with heterozygous mutations are affected, while hemizygous males are not, regardless of mutation carriage. This singular mode might be explained by cell interference as a pathogenic molecular mechanism leading to neuronal dysfunction. Recently, PCDH19-related EIEE turned out to be more frequent than initially thought, contributing to around 16% of cases (25% in female groups) in the SCN1A-negative DS-like patients. Therefore, the PCDH19 gene is now estimated to be the second, after SCN1A, most clinically relevant gene in epilepsy.

  19. How do Mutations in GJB1 Cause X-linked Charcot-Marie-Tooth Disease?

    Science.gov (United States)

    Kleopa, Kleopas A.; Abrams, Charles K.; Scherer, Steven S.

    2012-01-01

    The X-linked form of Charcot-Marie-Tooth disease (CMT1X) is the second most common form of hereditary motor and sensory neuropathy. The clinical phenotype is characterized by progressive weakness, atrophy, and sensory abnormalities that are most pronounced in the distal extremities. Some patients have CNS manifestations. Affected males have moderate to severe symptoms, whereas heterozygous females are usually less affected. Neurophysiology shows intermediate slowing of conduction and length-dependent axonal loss. Nerve biopsies show more prominent axonal degeneration than de/remyelination. Mutations in GJB1, the gene that encodes the gap junction (GJ) protein connexin32 (Cx32) cause CMT1X; more than 400 different mutations have been described. Many Cx32 mutants fail to form functional GJs, or form GJs with abnormal biophysical properties. Schwann cells and oligodendrocytes express Cx32, and the GJs formed by Cx32 play an important role in the homeostasis of myelinated axons. Animal models of CMT1X demonstrate that loss of Cx32 in myelinating Schwann cells causes a demyelinating neuropathy. Effective therapies remain to be developed. PMID:22771394

  20. Nonsyndromic Familial Hyperdontia: Two Case Reports and Review of Literature

    Directory of Open Access Journals (Sweden)

    Pradhuman Verma

    2010-01-01

    Early clinical and radiographic examination of the supernumerary teeth allow for optimal yet minimal treatment. This article reports two rare cases of nonsyndromic hereditary hyperdontia both in the maxillary anterior region. First case report with bilateral mesiodentes palatal to the central incisors in sister and brother and second case report with presence of fused mesiodentes in father and conical mesiodens in son. Though the exact etiology of this dental anomaly remains unclear, genetics as key factor in development of supernumerary teeth is highlighted.

  1. Disrupted functional brain connectome in unilateral sudden sensorineural hearing loss.

    Science.gov (United States)

    Xu, Haibo; Fan, Wenliang; Zhao, Xueyan; Li, Jing; Zhang, Wenjuan; Lei, Ping; Liu, Yuan; Wang, Haha; Cheng, Huamao; Shi, Hong

    2016-05-01

    Sudden sensorineural hearing loss (SSNHL) is generally defined as sensorineural hearing loss of 30 dB or greater over at least three contiguous audiometric frequencies and within a three-day period. This hearing loss is usually unilateral and can be associated with tinnitus and vertigo. The pathogenesis of unilateral sudden sensorineural hearing loss is still unknown, and the alterations in the functional connectivity are suspected to involve one possible pathogenesis. Despite scarce findings with respect to alterations in brain functional networks in unilateral sudden sensorineural hearing loss, the alterations of the whole brain functional connectome and whether these alterations were already in existence in the acute period remains unknown. The aim of this study was to investigate the alterations of brain functional connectome in two large samples of unilateral sudden sensorineural hearing loss patients and to investigate the correlation between unilateral sudden sensorineural hearing loss characteristics and changes in the functional network properties. Pure tone audiometry was performed to assess hearing ability. Abnormal changes in the peripheral auditory system were examined using conventional magnetic resonance imaging. The graph theoretical network analysis method was used to detect brain connectome alterations in unilateral sudden sensorineural hearing loss. Compared with the control groups, both groups of unilateral SSNHL patients exhibited a significantly increased clustering coefficient, global efficiency, and local efficiency but a significantly decreased characteristic path length. In addition, the primary increased nodal strength (e.g., nodal betweenness, hubs) was observed in several regions primarily, including the limbic and paralimbic systems, and in the auditory network brain areas. These findings suggest that the alteration of network organization already exists in unilateral sudden sensorineural hearing loss patients within the acute period

  2. C26:0-Carnitine Is a New Biomarker for X-Linked Adrenoleukodystrophy in Mice and Man

    NARCIS (Netherlands)

    van de Beek, Malu-Clair; Dijkstra, Inge M. E.; van Lenthe, Henk; Ofman, Rob; Goldhaber-Pasillas, Dalia; Schauer, Nicolas; Schackmann, Martin; Engelen-Lee, Joo-Yeon; Vaz, Frédéric M.; Kulik, Wim; Wanders, Ronald J. A.; Engelen, Marc; Kemp, Stephan

    2016-01-01

    X-linked adrenoleukodystrophy (ALD), a progressive neurodegenerative disease, is caused by mutations in ABCD1 and characterized by very-long-chain fatty acids (VLCFA) accumulation. Virtually all males develop progressive myelopathy (AMN). A subset of patients, however, develops a fatal cerebral

  3. X-linked sideroblastic anaemia due to ALAS(2) mutations in the Netherlands: a disease in disguise

    NARCIS (Netherlands)

    Donker, A.E.; Raymakers, R.A.P.; Nieuwenhuis, H.K.; Coenen, M.J.H.; Janssen, M.C.H.; MacKenzie, M.A.; Brons, P.P.T.; Swinkels, D.W.

    2014-01-01

    BACKGROUND: X-linked sideroblastic anaemia (XLSA; OMIM#300751) is the most common inherited form of sideroblastic anaemia and is associated with several mutations in the erythroid specific 5-aminolevulinate synthase gene (ALAS(2)). This gene encodes for aminolevulinic acid synthase 2 (ALAS(2)), the

  4. Treatment of the X-linked lymphoproliferative, Griscelli and Chédiak-Higashi syndromes by HLH directed therapy

    DEFF Research Database (Denmark)

    Trottestam, Helena; Beutel, Karin; Meeths, Marie

    2009-01-01

    BACKGROUND: Griscelli syndrome type 2 (GS2), the X-linked lymphoproliferative (XLP) and the Chédiak-Higashi (CHS) syndromes are diseases that all may develop hemophagocytic syndromes. We wanted to investigate whether the treatment protocols for hemophagocytic lymphohistiocytosis (HLH) can also...

  5. ABCD1 mutations and the X-linked adrenoleukodystrophy mutation database: role in diagnosis and clinical correlations

    NARCIS (Netherlands)

    Kemp, S.; Pujol, A.; Waterham, H. R.; van Geel, B. M.; Boehm, C. D.; Raymond, G. V.; Cutting, G. R.; Wanders, R. J.; Moser, H. W.

    2001-01-01

    X-linked adrenoleukodystrophy (X-ALD) is caused by mutations in the ABCD1 gene, which encodes a peroxisomal ABC half-transporter (ALDP) involved in the import of very long-chain fatty acids (VLCFA) into the peroxisome. The disease is characterized by a striking and unpredictable variation in

  6. X-linked glycogen storage disease IXa manifested in a female carrier due to skewed X chromosome inactivation.

    Science.gov (United States)

    Cho, Sun Young; Lam, Ching-wan; Tong, Sui-Fan; Siu, Wai-Kwan

    2013-11-15

    Glycogen storage disease (GSD) is a group of inherited metabolic disorders due to enzymatic deficiency involved in glycogen breakdown. In various subtypes of GSD, GSD IXa is an X-linked recessive disorder, which only manifested in males. Here, we report a case of X-linked GSD IXa manifested in a female Chinese patient accompanying a skewed X-chromosome inactivation (XCI). A 29-y-old Chinese female was admitted to evaluate mild hepatomegaly, which was repeatedly observed in serial abdominal ultrasonographic examinations. GSDIXa was suspected. To identify the mutation and the disease mechanism, we performed sequencing analysis of the PHKA2 gene, XCI assay and cDNA expression analysis. Sequencing analysis revealed a heterozygous mutation in the PHKA2 gene (c.3614C>T; p.P1205L) of the patient. In XCI assay, the proband showed a skewed XCI pattern cDNA expression analysis showed a preferential expression of the mutant allele in leukocytes of the patient. This is a rare report of X-linked GSD IXa manifested in a female carrier with skewed XCI. Skewed XCI can play a key role in the manifestation of X-linked recessive disorders in female carriers. © 2013 Elsevier B.V. All rights reserved.

  7. Noninvasive prenatal diagnosis for X-linked disease by maternal plasma sequencing in a family of Hemophilia B

    Directory of Open Access Journals (Sweden)

    Ping Hu

    2017-10-01

    Conclusions: This study is the first report of a haplotype-based approach in NIPD of Hemophilia B. With further evaluation, this method might be useful for NIPD of Hemophilia B and for other X-linked single-gene disorders.

  8. Carrier detection in X-linked ocular albinism of the Nettleship-Falls type by DNA analysis

    NARCIS (Netherlands)

    Bergen, A. A.; Schuurman, E. J.; van den Born, L. I.; Samanns, C.; van Dorp, D. B.; Pinckers, A. J.; Bakker, E.; van Ommen, G. J.; Gal, A.; Bleeker-Wagemakers, E. M.

    1992-01-01

    X-linked ocular albinism (XOA) is characterized by anomalies of the eyes and hypopigmentation or absence of pigment in skin, hair and eyes due to a hereditary inborn error of metabolism affecting the pigment cells. The gene of XOA of the Nettleship-Falls type (OA1) has been mapped to Xp22.3, and

  9. Cone photoreceptor structure in patients with x-linked cone dysfunction and red-green color vision deficiency

    DEFF Research Database (Denmark)

    Patterson, Emily J.; Wilk, Melissa; Langlo, Christopher S.

    2016-01-01

    PURPOSE. Mutations in the coding sequence of the L and M opsin genes are often associated with X-linked cone dysfunction (such as Bornholm Eye Disease, BED), though the exact color vision phenotype associated with these disorders is variable. We examined individuals with L/ M opsin gene mutations...

  10. Mutation pattern in the Bruton's tyrosine kinase gene in 26 unrelated patients with X-linked agammaglobulinemia

    DEFF Research Database (Denmark)

    Vorechovský, I; Luo, L; Hertz, Jens Michael

    1997-01-01

    Mutation pattern was characterized in the Bruton's tyrosine kinase gene (BTK) in 26 patients with X-linked agammaglobulinemia, the first described immunoglobulin deficiency, and was related to BTK expression. A total of 24 different mutations were identified. Most BTK mutations were found to result...

  11. PROTECTIVE LEVELS OF VARICELLA-ZOSTER ANTIBODY DID NOT EFFECTIVELY PREVENT CHICKENPOX IN AN X-LINKED AGAMMAGLOBULINEMIA PATIENT.

    Science.gov (United States)

    Nobre, Fernanda Aimée; Gonzalez, Isabela Garrido da Silva; de Moraes-Pinto, Maria Isabel; Costa-Carvalho, Beatriz Tavares

    2015-01-01

    We describe the case of an eight-year-old boy with X-linked agammaglobulinemia who developed mild varicella despite regular intravenous immunoglobulin (IVIG) therapy. He maintained protective antibody levels against varicella and the previous batches of IVIG that he received had adequate varicella-specific IgG levels. The case illustrates that IVIG may not prevent VZV infection.

  12. FACL4, encoding fatty acid-CoA ligase 4, is mutated in nonspecific X-linked mental retardation.

    NARCIS (Netherlands)

    Meloni, I.; Muscettola, M.; Raynaud, M.; Longo, I.; Bruttini, M.; Moizard, M.P.; Gomot, M.; Chelly, J.; Portes, V. des; Fryns, J.P.; Ropers, H.H.; Magi, B.; Bellan, C.; Volpi, N.; Yntema, H.G.; Lewis, S.E.; Schaffer, J.E.; Renieri, A.

    2002-01-01

    X-linked mental retardation (XLMR) is an inherited condition that causes failure to develop cognitive abilities, owing to mutations in a gene on the X chromosome. The latest XLMR update lists up to 136 conditions leading to 'syndromic', or 'specific', mental retardation (MRXS) and 66 entries leading

  13. The first de novo mutation of the connexin 32 gene associated with X linked Charcot-Marie-Tooth disease

    NARCIS (Netherlands)

    Meggouh, F.; Benomar, A.; Rouger, H.; Tardieu, S.; Birouk, N.; Tassin, J.; Barhoumi, C.; Yahyaoui, M.; Chkili, T.; Brice, A.; LeGuern, E.

    1998-01-01

    X linked Charcot-Marie-Tooth disease (CMTX) is a hereditary motor and sensory neuropathy caused by mutations in the connexin 32 gene (Cx32). Using the SSCP technique and direct sequencing of PCR amplified genomic DNA fragments of the Cx32 gene from a Moroccan patient and her relatives, we identified

  14. Prognostic Factors in Sudden Sensorineural Hearing Loss

    Directory of Open Access Journals (Sweden)

    Gamze Atay

    2016-02-01

    Full Text Available Background: Sudden sensorineural hearing loss (SSNHL is still a complex and challenging process which requires clinical evidence regarding its etiology, treatment and prognostic factors. Therefore, determination of prognostic factors might aid in the selection of proper treatment modality. Aims: The aim of this study is to analyze whether there is correlation between SSNHL outcomes and (1 systemic steroid therapy, (2 time gap between onset of symptoms and initiation of therapy and (3 audiological pattern of hearing loss. Study Design: Retrospective chart review. Methods: Patients diagnosed at our clinic with SSNHL between May 2005 and December 2011were reviewed. A detailed history of demographic features, side of hearing loss, previous SSNHL and/or ear surgery, recent upper respiratory tract infection, season of admission, duration of symptoms before admission and the presence of co-morbid diseases was obtained. Radiological and audiological evaluations were recorded and treatment protocol was assessed to determine whether systemic steroids were administered or not. Treatment started ≤5 days was regarded as “early” and >5 days as “delayed”. Initial audiological configurations were grouped as “upward sloping”, “downward sloping”, “flat” and “profound” hearing loss. Significant recovery was defined as thresholds improved to the same level with the unaffected ear or improved ≥30 dB on average. Slight recovery was hearing improvement between 10-30dB on average. Hearing recovery less than 10 dB was accepted as unchanged. Results: Among the 181 patients who met the inclusion criteria, systemic steroid was administered to 122 patients (67.4%, whereas 59 (32.6% patients did not have steroids. It was found that steroid administration did not have any statistically significant effect in either recovered or unchanged hearing groups. Early treatment was achieved in 105 patients (58% and 76 patients (42% had delayed treatment

  15. Efficacy of vitreoretinal surgery in the treatment of X-linked retinoschisis with serious complications

    Directory of Open Access Journals (Sweden)

    Chen Zhao

    2013-10-01

    Full Text Available AIM: To evaluate the efficacy of vitreoretinal surgery in the treatment of X-linked retinoschisis(XLRSand its complications. METHODS: A retrospective study was made on all the XLRS patients with severe complications after operation in this hospital. All the 25 patients(31 eyespresent with macular abnormalities with/without peripheral retina split bypreoperative OCT examination. Among the 31 eyes, there were 7 eyes with vitreous hemorrhage, 8 eyes with retinal detachment and vitreous hemorrhage, and 16 eyes with rhegmatogenous retinal detachment. All the 31 eyes were divided into 2 groups: group A included 15 eyes which underwent photocoagulation before the surgery, while the other 16 eyes in group B didn't perform photocoagulation before the surgery. All the patients underwent a pars plana vitrectomy without lensectomy associated with internal limiting membrane peeling. Photocoagulation was done to the retinal holes and degeneration areas in group A. Gas or silicone oil was filled in group B after retinal photocoagulation treatment. Three years later, analysis was made on the results of the visual acuity, postoperative anatomical and functional outcome in these 2 groups. Statistical analysis was made on the results of average visual acuity before and after operation by SPSS software method, the difference was statistically significant(PRESULTS: Postoperative anatomical and functional outcome were satisfied at the last visit. A total of 23 eyes'(74.2%visual acuity were improved with the mean visual acuity increasing from 0.13±0.08 to 0.24±0.16, the difference was statistically significant(t=-5.354,P=0.000. The average visual acuity in group A was improved from 0.11±0.08 to 0.22±0.15 after operation(t=-4.391, P=0.000. While the average visual acuity in group B increased from 0.14±0.08 to 0.26±0.15(t=-4.488, P=0.000. The visual changes in two groups were statistical significance. But when compared the average changes of visual acuity before

  16. Spontaneous shaker rat mutant - a new model for X-linked tremor/ataxia.

    Science.gov (United States)

    Figueroa, Karla P; Paul, Sharan; Calì, Tito; Lopreiato, Raffaele; Karan, Sukanya; Frizzarin, Martina; Ames, Darren; Zanni, Ginevra; Brini, Marisa; Dansithong, Warunee; Milash, Brett; Scoles, Daniel R; Carafoli, Ernesto; Pulst, Stefan M

    2016-05-01

    The shaker rat is an X-linked recessive spontaneous model of progressive Purkinje cell (PC) degeneration exhibiting a shaking ataxia and wide stance. Generation of Wistar Furth (WF)/Brown Norwegian (BN) F1 hybrids and genetic mapping of F2 sib-sib offspring using polymorphic markers narrowed the candidate gene region to 26 Mbp denoted by the last recombinant genetic marker DXRat21 at 133 Mbp to qter (the end of the long arm). In the WF background, the shaker mutation has complete penetrance, results in a stereotypic phenotype and there is a narrow window for age of disease onset; by contrast, the F2 hybrid phenotype was more varied, with a later age of onset and likely non-penetrance of the mutation. By deep RNA-sequencing, five variants were found in the candidate region; four were novel without known annotation. One of the variants caused an arginine (R) to cysteine (C) change at codon 35 of the ATPase, Ca(2+) transporting, plasma membrane 3 (Atp2b3) gene encoding PMCA3 that has high expression in the cerebellum. The variant was well supported by hundreds of overlapping reads, and was found in 100% of all affected replicas and 0% of the wild-type (WT) replicas. The mutation segregated with disease in all affected animals and the amino acid change was found in an evolutionarily conserved region of PMCA3. Despite strong genetic evidence for pathogenicity, in vitro analyses of PMCA3(R35C) function did not show any differences to WT PMCA3. Because Atp2b3 mutation leads to congenital ataxia in humans, the identified Atp2b3 missense change in the shaker rat presents a good candidate for the shaker rat phenotype based on genetic criteria, but cannot yet be considered a definite pathogenic variant owing to lack of functional changes. © 2016. Published by The Company of Biologists Ltd.

  17. Spontaneous shaker rat mutant – a new model for X-linked tremor/ataxia

    Directory of Open Access Journals (Sweden)

    Karla P. Figueroa

    2016-05-01

    Full Text Available The shaker rat is an X-linked recessive spontaneous model of progressive Purkinje cell (PC degeneration exhibiting a shaking ataxia and wide stance. Generation of Wistar Furth (WF/Brown Norwegian (BN F1 hybrids and genetic mapping of F2 sib-sib offspring using polymorphic markers narrowed the candidate gene region to 26 Mbp denoted by the last recombinant genetic marker DXRat21 at 133 Mbp to qter (the end of the long arm. In the WF background, the shaker mutation has complete penetrance, results in a stereotypic phenotype and there is a narrow window for age of disease onset; by contrast, the F2 hybrid phenotype was more varied, with a later age of onset and likely non-penetrance of the mutation. By deep RNA-sequencing, five variants were found in the candidate region; four were novel without known annotation. One of the variants caused an arginine (R to cysteine (C change at codon 35 of the ATPase, Ca2+ transporting, plasma membrane 3 (Atp2b3 gene encoding PMCA3 that has high expression in the cerebellum. The variant was well supported by hundreds of overlapping reads, and was found in 100% of all affected replicas and 0% of the wild-type (WT replicas. The mutation segregated with disease in all affected animals and the amino acid change was found in an evolutionarily conserved region of PMCA3. Despite strong genetic evidence for pathogenicity, in vitro analyses of PMCA3R35C function did not show any differences to WT PMCA3. Because Atp2b3 mutation leads to congenital ataxia in humans, the identified Atp2b3 missense change in the shaker rat presents a good candidate for the shaker rat phenotype based on genetic criteria, but cannot yet be considered a definite pathogenic variant owing to lack of functional changes.

  18. Spontaneous shaker rat mutant – a new model for X-linked tremor/ataxia

    Science.gov (United States)

    Figueroa, Karla P.; Paul, Sharan; Calì, Tito; Lopreiato, Raffaele; Karan, Sukanya; Frizzarin, Martina; Ames, Darren; Zanni, Ginevra; Brini, Marisa; Dansithong, Warunee; Milash, Brett; Scoles, Daniel R.; Carafoli, Ernesto; Pulst, Stefan M.

    2016-01-01

    ABSTRACT The shaker rat is an X-linked recessive spontaneous model of progressive Purkinje cell (PC) degeneration exhibiting a shaking ataxia and wide stance. Generation of Wistar Furth (WF)/Brown Norwegian (BN) F1 hybrids and genetic mapping of F2 sib-sib offspring using polymorphic markers narrowed the candidate gene region to 26 Mbp denoted by the last recombinant genetic marker DXRat21 at 133 Mbp to qter (the end of the long arm). In the WF background, the shaker mutation has complete penetrance, results in a stereotypic phenotype and there is a narrow window for age of disease onset; by contrast, the F2 hybrid phenotype was more varied, with a later age of onset and likely non-penetrance of the mutation. By deep RNA-sequencing, five variants were found in the candidate region; four were novel without known annotation. One of the variants caused an arginine (R) to cysteine (C) change at codon 35 of the ATPase, Ca2+ transporting, plasma membrane 3 (Atp2b3) gene encoding PMCA3 that has high expression in the cerebellum. The variant was well supported by hundreds of overlapping reads, and was found in 100% of all affected replicas and 0% of the wild-type (WT) replicas. The mutation segregated with disease in all affected animals and the amino acid change was found in an evolutionarily conserved region of PMCA3. Despite strong genetic evidence for pathogenicity, in vitro analyses of PMCA3R35C function did not show any differences to WT PMCA3. Because Atp2b3 mutation leads to congenital ataxia in humans, the identified Atp2b3 missense change in the shaker rat presents a good candidate for the shaker rat phenotype based on genetic criteria, but cannot yet be considered a definite pathogenic variant owing to lack of functional changes. PMID:27013529

  19. Long-term outcome of patients with X-linked adrenoleukodystrophy: A retrospective cohort study.

    Science.gov (United States)

    Tran, Christel; Patel, Jaina; Stacy, Hewson; Mamak, Eva G; Faghfoury, Hanna; Raiman, Julian; Clarke, Joe T R; Blaser, Susan; Mercimek-Mahmutoglu, Saadet

    2017-07-01

    X-linked adrenoleukodystrophy (X-ALD) is a peroxisomal disorder associated with leukodystrophy, myeloneuropathy and adrenocortical insufficiency. We performed a retrospective cohort study to evaluate long-term outcome of patients with X-ALD. All patients with X-ALD diagnosed between 1989 and 2012 were included. Electronic patient charts were reviewed for clinical features, biochemical investigations, molecular genetic testing, neuroimaging, long-term outcome and treatment. Forty-eight patients from 18 unrelated families were included (15 females; 33 males). Seventeen patients were symptomatic at the time of the biochemical diagnosis including 14 with neurocognitive dysfunction and 3 with Addison disease only. Thirty-one asymptomatic individuals were identified by positive family history of X-ALD. During follow-up, eight individuals developed childhood cerebral X-ALD (CCALD), one individual developed adrenomyeloneuropathy (AMN), six individuals developed Addison disease only, and five individuals remained asymptomatic. Direct sequencing of ABCD1 confirmed the genetic diagnosis in 29 individuals. Seven patients with CCALD underwent hematopoietic stem cell transplantation (HSCT). Nine patients lost the follow-up. There was no correlation between clinical severity score, Loes score and elevated degree of elevated very long chain fatty acid (VLCFA) levels in CCALD. Our study reports forty-eight new patients with X-ALD and their long-term outcome. Only 35% of the patients presented with neurological features or Addison disease. The remaining individuals were identified due to positive family history. Close monitoring of asymptomatic males resulted in early HSCT to prevent progressive lethal neurodegenerative disease. Identification of patients with X-ALD is important to improve neurodevelopmental outcome of asymptomatic males. Crown Copyright © 2017. Published by Elsevier Ltd. All rights reserved.

  20. X-linked sideroblastic anaemia due to ALAS₂ mutations in the Netherlands: a disease in disguise.

    Science.gov (United States)

    Donker, A E; Raymakers, R A; Nieuwenhuis, H K; Coenen, M J H; Janssen, M C; MacKenzie, M A; Brons, P P T; Swinkels, D W

    2014-05-01

    X-linked sideroblastic anaemia (XLSA; OMIM#300751) is the most common inherited form of sideroblastic anaemia and is associated with several mutations in the erythroid specific 5-aminolevulinate synthase gene (ALAS₂). This gene encodes for aminolevulinic acid synthase 2 (ALAS₂), the catalytic enzyme involved in the first en rate-limiting step of haem biosynthesis.1-3 The disorder is characterised by mostly mild hypochromic microcytic anaemia with bone marrow ring sideroblasts. Even untransfused patients with mild or no anaemia are at risk for severe systemic iron overload due to ineffective erythropoiesis. To date, 61 different ALAS₂ mutations have been reported in 120 families with XLSA. Descriptions of molecularly confirmed case series from the Netherlands, however, are lacking. We reviewed age of presentation, clinical and biochemical features, ALAS₋₂ defects and treatment characteristics of 15 Dutch patients from 11 unrelated families diagnosed with XLSA. In one family a novel pathogenic c.1412G>A (p.Cys471Tyr) mutation was found. All other families shared the previously described c.1355G>A (p.Arg452His) mutation. Haplotype analysis in seven probands with the p.Arg452His mutation strongly suggests that six of them were ancestrally related. Nevertheless, their phenotype was very different. Our patients illustrate the phenotypical heterogeneity in the presentation of XLSA patients, the effectiveness of treatment regimens and the various pitfalls associated with the diagnosis, follow-up and treatment of the disease. A timely diagnosis avoids unnecessary investigations and allows adequate treatment that can prevent systemic iron load with subsequent severe life-threatening complications. Therefore, we suggest considering XLSA in both male and female patients with unexplained iron overload and÷or (mild) microcytic anaemia, also at older age.

  1. Mutations in noncoding regions of GJB1 are a major cause of X-linked CMT

    Science.gov (United States)

    Tomaselli, Pedro J.; Rossor, Alexander M.; Horga, Alejandro; Jaunmuktane, Zane; Carr, Aisling; Saveri, Paola; Piscosquito, Giuseppe; Pareyson, Davide; Laura, Matilde; Blake, Julian C.; Poh, Roy; Polke, James; Houlden, Henry

    2017-01-01

    Objective: To determine the prevalence and clinical and genetic characteristics of patients with X-linked Charcot-Marie-Tooth disease (CMT) due to mutations in noncoding regions of the gap junction β-1 gene (GJB1). Methods: Mutations were identified by bidirectional Sanger sequence analysis of the 595 bases of the upstream promoter region, and 25 bases of the 3′ untranslated region (UTR) sequence in patients in whom mutations in the coding region had been excluded. Clinical and neurophysiologic data were retrospectively collected. Results: Five mutations were detected in 25 individuals from 10 kindreds representing 11.4% of all cases of CMTX1 diagnosed in our neurogenetics laboratory between 1996 and 2016. Four pathogenic mutations, c.-17G>A, c.-17+1G>T, c.-103C>T, and c.-146-90_146-89insT were detected in the 5′UTR. A novel mutation, c.*15C>T, was detected in the 3′ UTR of GJB1 in 2 unrelated families with CMTX1 and is the first pathogenic mutation in the 3′UTR of any myelin-associated CMT gene. Mutations segregated with the phenotype, were at sites predicted to be pathogenic, and were not present in the normal population. Conclusions: Mutations in noncoding DNA are a major cause of CMTX1 and highlight the importance of mutations in noncoding DNA in human disease. Next-generation sequencing platforms for use in inherited neuropathy should therefore include coverage of these regions. PMID:28283593

  2. Striatal dysfunction in X-linked dystonia-parkinsonism is associated with disease progression.

    Science.gov (United States)

    Brüggemann, N; Rosales, R L; Waugh, J L; Blood, A J; Domingo, A; Heldmann, M; Jamora, R D; Münchau, A; Münte, T F; Lee, L V; Buchmann, I; Klein, C

    2017-05-01

    X-linked dystonia-parkinsonism (XDP) is an inherited neurodegenerative adult-onset movement disorder associated with striatal atrophy. As the dopaminergic system has not yet been systemically studied in this basal ganglia model disease, it is unclear whether nigrostriatal dysfunction contributes to parkinsonism in XDP. Pre- and post-synaptic dopaminergic function was assessed in XDP. A total of 10 123 jod-benzamide (IBZM) single-photon emission computed tomography (SPECT) images were obtained for nine patients aged 42.3 ± 9.5 years (SD; range 30-52) and one asymptomatic mutation carrier (38 years), and four ioflupane (FP-CIT) SPECT images were obtained for four patients, aged 41.5 ± 11.6 years (range 30-52 years). Structural magnetic resonance imaging was also performed for all mutation carriers and 10 matched healthy controls. All patients were men who suffered from severe, disabling segmental or generalized dystonia and had varying degrees of parkinsonism. IBZM SPECT images were pathological in 8/9 symptomatic patients with distinct reduced post-synaptic tracer uptake in the caudate nucleus and putamen, and unremarkable in the asymptomatic mutation carrier. Longer disease duration was correlated with lower IBZM binding ratios. All subjects exhibited slightly reduced FP-CIT uptake values compared to controls for each analyzed region (-37% to -41%) which may be linked to basal ganglia volume loss. Visual inspection revealed physiological FP-CIT uptake in 1/4 patients. This nuclear imaging study provides evidence that the functional decline of post-synaptic dopaminergic neurotransmission is related to disease duration and ongoing neurodegeneration. Given the severe striatal cell loss which could be verified with post-synaptic nuclear imaging, both parkinsonism and dystonia in XDP are probably mainly due to striatal dysfunction. © 2017 EAN.

  3. X-linked lethal infantile spinal muscular atrophy: From clinical description to molecular mapping

    Energy Technology Data Exchange (ETDEWEB)

    Baumbach, L.; Schiavi, A. [Univ. of Miami, FL (United States)] [and others

    1994-09-01

    The proximal spinal muscular atrophies (PSMA), one of the most common forms of lower motor neuron disease in children, are characterized by progressive muscle weakness due to loss of anterior horn cells. All three autosomal recessive forms have been mapped to chromosome 5q11.2-11.3, implying an allelic association between these disorders. Recent evidence from our laboratories, as well as others, suggests that a distinct form of lethal neonatal spinal muscular atrophy, associated with early onset contractures, is determined by a gene on the X chromosome. We report our efforts in mapping this disease locus. Our original studies have focused on two unrelated multigenerational families with similar clinical presentations of severe hypotonia, muscle weakness, and a disease course similar to Werdnig Hoffman except for the additional finding of congenital or early onset contractures. Muscle biopsy and/or autopsy were indicative of anterior horn cell loss in affected males. Disease occurrence in each of the families was consistent with an X-linked recessive mode of inheritance. Subsequently, two additional families have been identified, as well as several sporadic male cases. Linkage analysis has been completed in one of these families using highly polymorphic repeats dispersed 10 cM on the X chromosome. Interpretation of results was achieved using an automated data acquisition program. Analysis of over 300 haplotypes generated using PCR-based DNA markers have identified two 16 cM regions on Xp with complete concordance to the disease phenotype. Our currents efforts are focused on the region surrounding the Kallman gene, in attempts to better define a candidate region, as well as analyze possible candidate genes within this region.

  4. X-linked adrenoleukodystrophy: molecular and functional analysis of the ABCD1 gene in Argentinean patients.

    Directory of Open Access Journals (Sweden)

    Cyntia Anabel Amorosi

    Full Text Available X-linked adrenoleukodystrophy (X-ALD is an inherited metabolic disease associated with mutations in the ABCD1 gene that encodes an ATP-binding cassette transporter protein, ALDP. The disease is characterized by increased concentrations of very long-chain fatty acids (VLCFAs in plasma and in adrenal, testicular and nervous tissues, due to a defect in peroxisomal VLCFA β-oxidation. In the present study, we analyzed 10 male patients and 17 female carriers from 10 unrelated pedigrees with X-ALD from Argentina. By sequencing the ABCD1 we detected 9 different mutations, 8 of which were novel. These new mutations were verified by a combination of methods that included both functional (western blot and peroxisomal VLCFA β-oxidation and bioinformatics analysis. The spectrum of novel mutations consists of 3 frameshift (p.Ser284fs*16, p.Glu380Argfs*21 and p.Thr254Argfs*82; a deletion (p.Ser572_Asp575del; a splicing mutation (c.1081+5G>C and 3 missense mutations (p.Ala341Asp, p.His420Pro and p.Tyr547Cys. In one patient 2 changes were found: a known missense (p.His669Arg and an unpublished amino acid substitution (p.Ala19Ser. In vitro studies suggest that p.Ala19Ser is a polymorphism. Moreover, we identified two novel intronic polymorphisms and two amino acid polymorphisms. In conclusion, this study extends the spectrum of mutation in X-ALD and facilitates the identification of heterozygous females.

  5. Mutations, clinical findings and survival estimates in South American patients with X-linked adrenoleukodystrophy.

    Directory of Open Access Journals (Sweden)

    Fernanda dos Santos Pereira

    Full Text Available UNLABELLED: In this study, we analyzed the ABCD1 gene in X-linked adrenoleukodystrophy (X-ALD patients and relatives from 38 unrelated families from South America, as well as phenotypic proportions, survival estimates, and the potential effect of geographical origin in clinical characteristics. METHODS: X- ALD patients from Brazil, Argentina and Uruguay were invited to participate in molecular studies to determine their genetic status, characterize the mutations and improve the genetic counseling of their families. All samples were screened by SSCP analysis of PCR fragments, followed by automated DNA sequencing to establish the specific mutation in each family. Age at onset and at death, male phenotypes, genetic status of women, and the effect of family and of latitude of origin were also studied. RESULTS: We identified thirty-six different mutations (twelve novel. This population had an important allelic heterogeneity, as only p.Arg518Gln was repeatedly found (three families. Four cases carried de novo mutations. Intra-familiar phenotype variability was observed in all families. Out of 87 affected males identified, 65% had the cerebral phenotype (CALD. The mean (95% CI ages at onset and at death of the CALD were 10.9 (9.1-12.7 and 24.7 (19.8-29.6 years. No association was found between phenotypic manifestations and latitude of origin. One index-case was a girl with CALD who carried an ABCD1 mutation, and had completely skewed X inactivation. CONCLUSIONS: This study extends the spectrum of mutations in X-ALD, confirms the high rates of de novo mutations and the absence of common mutations, and suggests a possible high frequency of cerebral forms in our population.

  6. The genetic landscape of X-linked adrenoleukodystrophy: inheritance, mutations, modifier genes, and diagnosis

    Directory of Open Access Journals (Sweden)

    Wiesinger C

    2015-05-01

    Full Text Available Christoph Wiesinger,1 Florian S Eichler,2 Johannes Berger1 1Department of Pathobiology of the Nervous System, Center for Brain Research, Medical University of Vienna, Vienna, Austria; 2Department for Neurology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA Abstract: X-linked adrenoleukodystrophy (X-ALD is caused by mutations in the ABCD1 gene encoding a peroxisomal ABC transporter. In this review, we compare estimates of incidence derived from different populations in order to provide an overview of the worldwide incidence of X-ALD. X-ALD presents with heterogeneous phenotypes ranging from adrenomyeloneuropathy (AMN to inflammatory demyelinating cerebral ALD (CALD. A large number of different mutations has been described, providing a unique opportunity for analysis of functional domains within ABC transporters. Yet the molecular basis for the heterogeneity of clinical symptoms is still largely unresolved, as no correlation between genotype and phenotype exists in X-ALD. Beyond ABCD1, environmental triggers and other genetic factors have been suggested as modifiers of the disease course. Here, we summarize the findings of numerous reports that aimed at identifying modifier genes in X-ALD and discuss potential problems and future approaches to address this issue. Different options for prenatal diagnosis are summarized, and potential pitfalls when applying next-generation sequencing approaches are discussed. Recently, the measurement of very long-chain fatty acids in lysophosphatidylcholine for the identification of peroxisomal disorders was included in newborn screening programs. Keywords: X-ALD, AMN, mutations, incidence, prenatal diagnosis, newborn screening

  7. X-linked adrenoleukodystrophy: molecular and functional analysis of the ABCD1 gene in Argentinean patients.

    Science.gov (United States)

    Amorosi, Cyntia Anabel; Myskóva, Helena; Monti, Mariela Roxana; Argaraña, Carlos Enrique; Morita, Masashi; Kemp, Stephan; Dodelson de Kremer, Raquel; Dvoráková, Lenka; Oller de Ramírez, Ana María

    2012-01-01

    X-linked adrenoleukodystrophy (X-ALD) is an inherited metabolic disease associated with mutations in the ABCD1 gene that encodes an ATP-binding cassette transporter protein, ALDP. The disease is characterized by increased concentrations of very long-chain fatty acids (VLCFAs) in plasma and in adrenal, testicular and nervous tissues, due to a defect in peroxisomal VLCFA β-oxidation. In the present study, we analyzed 10 male patients and 17 female carriers from 10 unrelated pedigrees with X-ALD from Argentina. By sequencing the ABCD1 we detected 9 different mutations, 8 of which were novel. These new mutations were verified by a combination of methods that included both functional (western blot and peroxisomal VLCFA β-oxidation) and bioinformatics analysis. The spectrum of novel mutations consists of 3 frameshift (p.Ser284fs*16, p.Glu380Argfs*21 and p.Thr254Argfs*82); a deletion (p.Ser572_Asp575del); a splicing mutation (c.1081+5G>C) and 3 missense mutations (p.Ala341Asp, p.His420Pro and p.Tyr547Cys). In one patient 2 changes were found: a known missense (p.His669Arg) and an unpublished amino acid substitution (p.Ala19Ser). In vitro studies suggest that p.Ala19Ser is a polymorphism. Moreover, we identified two novel intronic polymorphisms and two amino acid polymorphisms. In conclusion, this study extends the spectrum of mutation in X-ALD and facilitates the identification of heterozygous females.

  8. X-linked adrenoleukodystrophy: ABCD1 de novo mutations and mosaicism.

    Science.gov (United States)

    Wang, Ying; Busin, Rachel; Reeves, Catherine; Bezman, Lena; Raymond, Gerald; Toomer, Cicely J; Watkins, Paul A; Snowden, Ann; Moser, Ann; Naidu, Sakkubai; Bibat, Genila; Hewson, Stacy; Tam, Karen; Clarke, Joe T R; Charnas, Lawrence; Stetten, Gail; Karczeski, Barbara; Cutting, Garry; Steinberg, Steven

    2011-01-01

    X-linked adrenoleukodystrophy (X-ALD) is a progressive peroxisomal disorder affecting adrenal glands, testes and myelin stability that is caused by mutations in the ABCD1 (NM_000033) gene. Males with X-ALD may be diagnosed by the demonstration of elevated very long chain fatty acid (VLCFA) levels in plasma. In contrast, only 80% of female carriers have elevated plasma VLCFA; therefore targeted mutation analysis is the most effective means for carrier detection. Amongst 489 X-ALD families tested at Kennedy Krieger Institute, we identified 20 cases in which the ABCD1 mutation was de novo in the index case, indicating that the mutation arose in the maternal germ line and supporting a new mutation rate of at least 4.1% for this group. In addition, we identified 10 cases in which a de novo mutation arose in the mother or the grandmother of the index case. In two of these cases studies indicated that the mothers were low level gonosomal mosaics. In a third case biochemical, molecular and pedigree analysis indicated the mother was a gonadal mosaic. To the best of our knowledge mosaicism has not been previously reported in X-ALD. In addition, we identified one pedigree in which the maternal grandfather was mosaic for the familial ABCD1 mutation. Less than 1% of our patient population had evidence of gonadal or gonosomal mosaicism, suggesting it is a rare occurrence for this gene and its associated disorders. However, the residual maternal risk for having additional ovum carrying the mutant allele identified in an index case that appears to have a de novo mutation is at least 13%. Copyright © 2011 Elsevier Inc. All rights reserved.

  9. Efficacy of gene therapy for X-linked severe combined immunodeficiency.

    Science.gov (United States)

    Hacein-Bey-Abina, Salima; Hauer, Julia; Lim, Annick; Picard, Capucine; Wang, Gary P; Berry, Charles C; Martinache, Chantal; Rieux-Laucat, Frédéric; Latour, Sylvain; Belohradsky, Bernd H; Leiva, Lily; Sorensen, Ricardo; Debré, Marianne; Casanova, Jean Laurent; Blanche, Stephane; Durandy, Anne; Bushman, Frederic D; Fischer, Alain; Cavazzana-Calvo, Marina

    2010-07-22

    The outcomes of gene therapy to correct congenital immunodeficiencies are unknown. We reviewed long-term outcomes after gene therapy in nine patients with X-linked severe combined immunodeficiency (SCID-X1), which is characterized by the absence of the cytokine receptor common gamma chain. The nine patients, who lacked an HLA-identical donor, underwent ex vivo retrovirus-mediated transfer of gamma chain to autologous CD34+ bone marrow cells between 1999 and 2002. We assessed clinical events and immune function on long-term follow-up. Eight patients were alive after a median follow-up period of 9 years (range, 8 to 11). Gene therapy was initially successful at correcting immune dysfunction in eight of the nine patients. However, acute leukemia developed in four patients, and one died. Transduced T cells were detected for up to 10.7 years after gene therapy. Seven patients, including the three survivors of leukemia, had sustained immune reconstitution; three patients required immunoglobulin-replacement therapy. Sustained thymopoiesis was established by the persistent presence of naive T cells, even after chemotherapy in three patients. The T-cell-receptor repertoire was diverse in all patients. Transduced B cells were not detected. Correction of the immunodeficiency improved the patients' health. After nearly 10 years of follow-up, gene therapy was shown to have corrected the immunodeficiency associated with SCID-X1. Gene therapy may be an option for patients who do not have an HLA-identical donor for hematopoietic stem-cell transplantation and for whom the risks are deemed acceptable. This treatment is associated with a risk of acute leukemia. (Funded by INSERM and others.) 2010 Massachusetts Medical Society

  10. A modified γ-retrovirus vector for X-linked severe combined immunodeficiency.

    Science.gov (United States)

    Hacein-Bey-Abina, Salima; Pai, Sung-Yun; Gaspar, H Bobby; Armant, Myriam; Berry, Charles C; Blanche, Stephane; Bleesing, Jack; Blondeau, Johanna; de Boer, Helen; Buckland, Karen F; Caccavelli, Laure; Cros, Guilhem; De Oliveira, Satiro; Fernández, Karen S; Guo, Dongjing; Harris, Chad E; Hopkins, Gregory; Lehmann, Leslie E; Lim, Annick; London, Wendy B; van der Loo, Johannes C M; Malani, Nirav; Male, Frances; Malik, Punam; Marinovic, M Angélica; McNicol, Anne-Marie; Moshous, Despina; Neven, Benedicte; Oleastro, Matías; Picard, Capucine; Ritz, Jerome; Rivat, Christine; Schambach, Axel; Shaw, Kit L; Sherman, Eric A; Silberstein, Leslie E; Six, Emmanuelle; Touzot, Fabien; Tsytsykova, Alla; Xu-Bayford, Jinhua; Baum, Christopher; Bushman, Frederic D; Fischer, Alain; Kohn, Donald B; Filipovich, Alexandra H; Notarangelo, Luigi D; Cavazzana, Marina; Williams, David A; Thrasher, Adrian J

    2014-10-09

    In previous clinical trials involving children with X-linked severe combined immunodeficiency (SCID-X1), a Moloney murine leukemia virus-based γ-retrovirus vector expressing interleukin-2 receptor γ-chain (γc) complementary DNA successfully restored immunity in most patients but resulted in vector-induced leukemia through enhancer-mediated mutagenesis in 25% of patients. We assessed the efficacy and safety of a self-inactivating retrovirus for the treatment of SCID-X1. We enrolled nine boys with SCID-X1 in parallel trials in Europe and the United States to evaluate treatment with a self-inactivating (SIN) γ-retrovirus vector containing deletions in viral enhancer sequences expressing γc (SIN-γc). All patients received bone marrow-derived CD34+ cells transduced with the SIN-γc vector, without preparative conditioning. After 12.1 to 38.7 months of follow-up, eight of the nine children were still alive. One patient died from an overwhelming adenoviral infection before reconstitution with genetically modified T cells. Of the remaining eight patients, seven had recovery of peripheral-blood T cells that were functional and led to resolution of infections. The patients remained healthy thereafter. The kinetics of CD3+ T-cell recovery was not significantly different from that observed in previous trials. Assessment of insertion sites in peripheral blood from patients in the current trial as compared with those in previous trials revealed significantly less clustering of insertion sites within LMO2, MECOM, and other lymphoid proto-oncogenes in our patients. This modified γ-retrovirus vector was found to retain efficacy in the treatment of SCID-X1. The long-term effect of this therapy on leukemogenesis remains unknown. (Funded by the National Institutes of Health and others; ClinicalTrials.gov numbers, NCT01410019, NCT01175239, and NCT01129544.).

  11. X-Linked Adrenoleukodystrophy: Molecular and Functional Analysis of the ABCD1 Gene in Argentinean Patients

    Science.gov (United States)

    Amorosi, Cyntia Anabel; Myskóva, Helena; Monti, Mariela Roxana; Argaraña, Carlos Enrique; Morita, Masashi; Kemp, Stephan; de Kremer, Raquel Dodelson; Dvoráková, Lenka; de Ramírez, Ana María Oller

    2012-01-01

    X-linked adrenoleukodystrophy (X-ALD) is an inherited metabolic disease associated with mutations in the ABCD1 gene that encodes an ATP-binding cassette transporter protein, ALDP. The disease is characterized by increased concentrations of very long-chain fatty acids (VLCFAs) in plasma and in adrenal, testicular and nervous tissues, due to a defect in peroxisomal VLCFA β-oxidation. In the present study, we analyzed 10 male patients and 17 female carriers from 10 unrelated pedigrees with X-ALD from Argentina. By sequencing the ABCD1 we detected 9 different mutations, 8 of which were novel. These new mutations were verified by a combination of methods that included both functional (western blot and peroxisomal VLCFA β-oxidation) and bioinformatics analysis. The spectrum of novel mutations consists of 3 frameshift (p.Ser284fs*16, p.Glu380Argfs*21 and p.Thr254Argfs*82); a deletion (p.Ser572_Asp575del); a splicing mutation (c.1081+5G>C) and 3 missense mutations (p.Ala341Asp, p.His420Pro and p.Tyr547Cys). In one patient 2 changes were found: a known missense (p.His669Arg) and an unpublished amino acid substitution (p.Ala19Ser). In vitro studies suggest that p.Ala19Ser is a polymorphism. Moreover, we identified two novel intronic polymorphisms and two amino acid polymorphisms. In conclusion, this study extends the spectrum of mutation in X-ALD and facilitates the identification of heterozygous females. PMID:23300730

  12. Mutations in the gene for X-linked adrenoleukodystrophy in patients with different clinical phenotypes

    Energy Technology Data Exchange (ETDEWEB)

    Braun, A.; Ambach, H.; Kammerer, S.; Rolinski, B.; Roscher, A.; Rabl, W. [Univ. of Munich (Germany); Stoeckler, S. [Univ. of Graz (Germany); Gaertner, J. [Univ. of Duesseldorf (Germany); Zierz, S. [Univ. of Bonn (Germany)

    1995-04-01

    Recently, the gene for the most common peroxisomal disorder, X-linked adrenoleukodystrophy (X-ALD), has been described encoding a peroxisomal membrane transporter protein. We analyzed the entire protein-coding sequence of this gene by reverse-transcription PCR, SSCP, and DNA sequencing in five patients with different clinical expressions were cerebral childhood ALD, adrenomyecloneuropathy (AMN), and {open_quotes}Addison disease only{close_quotes} (AD) phenotype. In the three patients exhibiting the classical picture of severe childhood ALD we identified in the 5{prime} portion of the X-ALD gene a 38-bp deletion that causes a frameshift mutation, a 3-bp deletion leading to a deletion of an amino acid in the ATP-binding domain of the ALD protein, and a missense mutation. In the patient with the clinical phenotype of AMN, a nonsense mutation in codon 212, along with a second site mutation at codon 178, was observed. Analysis of the patient with the ADO phenotype revealed a further missense mutation at a highly conserved position in the ALDP/PMP70 comparison. The disruptive nature of two mutations (i.e., the frameshift and the nonsense mutation) in patients with biochemically proved childhood ALD and AMN further strongly supports the hypothesis that alterations in this gene play a crucial role in the pathogenesis of X-ALD. Since the current biochemical techniques for X-ALD carrier detection in affected families lack sufficient reliability, our procedure described for systematic mutation scanning is also capable of improving genetic counseling and prenatal diagnosis. 19 refs., 6 figs., 3 tabs.

  13. Mutational and protein analysis of patients and heterozygous women with X-linked adrenoleukodystrophy

    Energy Technology Data Exchange (ETDEWEB)

    Feigenbaum, V.; Guidoux, S.; Aubourg, P. [Hospital Saint-Vincent de Paul, Paris (France)] [and others

    1996-06-01

    X-linked adrenoleukodystrophy (ALD), a neurodegenerative disorder associated with impaired {beta}-oxidation of very-long-chain fatty acids (VLCFA), is due to mutations in a gene encoding a peroxisomal ATP-binding cassette (ABC) transporter (ALD protein [ALDP]). We analyzed the open reading frame of the ALD gene in 44 French ALD kindred by using SSCP or denaturing gradient-gel electrophoresis and studied the effect of mutations on ALDP by immunocytofluorescence and western blotting of fibroblasts and/or white blood cells. Mutations were detected in 37 of 44 kindreds and were distributed over the whole protein-coding region, with the exception of the C terminus encoded in exon 10. Except for two mutations (delAG1801 and P560L) observed four times each, nearly every ALD family has a different mutation. Twenty-four of 37 mutations were missense mutations leading to amino acid changes located in or close to putative transmembrane segments (TMS 2, 3, 4, and 5), in the EAA-like motif and in the nucleotide fold of the ATP-binding domain of ALDP. Of 38 ALD patients tested, 27 (71%) lacked ALDP immunoreactivity in their fibroblasts and/or white blood cells. More than half of missense mutations studied (11 of 21) resulted in a complete lack of ALDP immunoreactivity, and six missense mutations resulted in decreased ALDP expression. The fibroblasts and/or white blood cells of 15 of 15 heterozygous carrier from ALD kindred with no ALDP showed a mixture of positive- and negative-ALDP immunoreactivity due to X-inactivation. Since 5%-15% of heterozygous women have normal VLCFA levels, the immunodetection of ALDP in white blood cells can be applicable in a majority of ALD kindred, to identify heterozygous women, particularly when the ALD gene mutation has not yet been identified. 35 refs., 2 figs., 2 tabs.

  14. Protective effect of antioxidants on DNA damage in leukocytes from X-linked adrenoleukodystrophy patients.

    Science.gov (United States)

    Marchetti, Desirèe P; Donida, Bruna; da Rosa, Helen T; Manini, Paula R; Moura, Dinara J; Saffi, Jenifer; Deon, Marion; Mescka, Caroline P; Coelho, Daniella M; Jardim, Laura B; Vargas, Carmen R

    2015-06-01

    Toxic metabolites accumulation and oxidative stress have been associated to the pathophysiology of X-linked adrenoleukodystrophy (X-ALD), an inborn error of peroxisome metabolism. Parameters of oxidative damage to proteins and lipids in X-ALD patients were already described in literature; however, DNA injuries were not studied yet. Considering that, the aims were to investigate DNA damage by comet assay in heterozygotes and symptomatic X-ALD patients, to look for associations between DNA damage and lipid peroxidation as measured by urinary 15-F2t-isoprostane; and to evaluate the in vitro effect of N-acetyl-l-cysteine (NAC), trolox (TRO) and rosuvastatin (RSV) on DNA damage in leukocytes from symptomatic patients. Symptomatic patients presented higher DNA damage levels than those found in heterozygotes and controls; heterozygotes and controls showed similar results. In order to investigate the in vitro antioxidant effect on DNA damage, whole blood cells from symptomatic patients were incubated with NAC (1 and 2.5mM), TRO (25 and 75 μM) and RSV (0.5, 2 and 5 μM) before DNA damage analysis. NAC, TRO and RSV, at all tested concentrations, were all capable to reduce DNA damage in symptomatic X-ALD patients until control levels. Finally, DNA damage correlated with urinary isoprostanes and plasmatic levels of TBA-RS and DCFH-DA, allowing to hypothesize that DNA damage might be induced by lipid peroxidation in symptomatic patients. The present work yields experimental evidence that NAC, TRO and RSV reduce the in vitro DNA injury in symptomatic X-ALD patients, what may suggest that the administration of these antioxidants might be considered as an adjuvant therapy for X-ALD. Copyright © 2015 Elsevier Ltd. All rights reserved.

  15. Mutation identification in a canine model of X-linked ectodermal dysplasia.

    Science.gov (United States)

    Casal, Margret L; Scheidt, Jennifer L; Rhodes, James L; Henthorn, Paula S; Werner, Petra

    2005-07-01

    X-linked hypohidrotic ectodermal dysplasia (XHED), an inherited disease recognized in humans, mice, and cattle, is characterized by hypotrichosis, a reduced number or absence of sweat glands, and missing or malformed teeth. In a subset of affected individuals and animals, mutations in the EDA gene (formerly EDI), coding for ectodysplasin, have been found to cause this phenotype. Ectodysplasin is a homotrimeric transmembrane protein with an extracellular TNF-like domain, which has been shown to be involved in the morphogenesis of hair follicles and tooth buds during fetal development. Some human XHED patients also have concurrent immunodeficiency, due to mutations in the NF-kappaB essential modulator protein (IKBKG; formerly NEMO), which is also encoded on the X chromosome. In a breeding colony of dogs with XHED, immune system defects had been suspected because of frequent pulmonary infections and unexpected deaths resulting from pneumonia. To determine if defects in EDA or IKBKG cause XHED in the dogs, linkage analysis and sequencing experiments were performed. A polymorphic marker near the canine EDA gene showed significant linkage to XHED. The canine EDA gene was sequenced and a nucleotide substitution (G to A) in the splice acceptor site of intron 8 was detected in affected dogs. In the presence of the A residue, a cryptic acceptor site within exon 9 is used, leading to a frame shift and use of a premature stop codon that truncates the translation of both isoforms, EDA-A1 and EDA-A2, resulting in the absence of the TNF-like homology domain, the receptor-binding site of ectodysplasin.

  16. Abnormal 8-Hz flicker electroretinograms in carriers of X-linked retinoschisis.

    Science.gov (United States)

    McAnany, J Jason; Park, Jason C; Collison, Frederick T; Fishman, Gerald A; Stone, Edwin M

    2016-08-01

    To evaluate rod-isolated, cone-isolated, and combined rod and cone flicker electroretinograms (ERGs) as a possible means to identify electrophysiological abnormalities in carriers of X-linked retinoschisis (XLRS). Full-field ERGs were recorded from six carriers of XLRS (aged 34-66 years) and eight normally sighted subjects (aged 27-59 years) under rod-isolated (ERGR), cone-isolated (ERGC), and combined rod and cone (ERGR+C) conditions. ERGs were obtained using a four-primary LED-based ganzfeld photostimulator and standard recording techniques. The four primaries were modulated sinusoidally in phase to achieve combined rod and cone activation (ERGR+C) or in different phases to achieve ERGR and ERGC by means of triple silent substitution. After 30 min of dark adaptation, 8- and 15-Hz ERGR, ERGC, and ERGR+C responses were obtained at a mean luminance level of 24 scot. cd/m(2). Standard ISCEV ERGs were also obtained from each subject. The ISCEV and 15-Hz flicker ERGs were generally within the normal range for the carriers. The 8-Hz ERGR, ERGC, and ERGR+C amplitudes were also generally normal. In contrast, the carriers had ERGR, ERGC, and ERGR+C timing abnormalities, with phase advances beyond the range of normal for the ERGR (four carriers), ERGC (four carriers), and ERGR+C (three carriers). Only one carrier had normal 8-Hz responses under all conditions. The 8-Hz ERG timing abnormalities in five of six carriers indicate that retinal function is not necessarily normal in carriers of XLRS. The 8-Hz flicker ERG may be useful for studying retinal function in these individuals.

  17. X-linked agammaglobulinemia diagnosed late in life: case report and review of the literature

    Directory of Open Access Journals (Sweden)

    Krishnaswamy Guha

    2008-06-01

    Full Text Available Abstract Background Common variable immune deficiency (CVID, one of the most common primary immunodeficiency diseases presents in adults, whereas X-linked agammaglobulinemia (XLA, an inherited humoral immunodeficiency, is usually diagnosed early in life after maternal Igs have waned. However, there have been several reports in the world literature in which individuals have either had a delay in onset of symptoms or have been misdiagnosed with CVID and then later found to have mutations in Bruton's tyrosine kinase (BTK yielding a reclassification as adult-onset variants of XLA. The typical finding of absent B cells should suggest XLA rather than CVID and may be a sensitive test to detect this condition, leading to the more specific test (Btk mutational analysis. Further confirmation may be by mutational analyses. Methods The records of 2 patients were reviewed and appropriate clinical data collected. BTK mutational analysis was carried out to investigate the suspicion of adult-presentation of XLA. A review of the world literature on delayed diagnosis of XLA and mild or "leaky" phenotype was performed. Results 2 patients previously diagnosed with CVID associated with virtual absence of CD19+ B cells were reclassified as having a delayed diagnosis and adult-presentation of XLA. Patient 1, a 64 yr old male with recurrent sinobronchial infections had a low level of serum IgG of 360 mg/dl (normal 736–1900, IgA Patient 2, a 46 yr old male with recurrent sinopulmonary infections had low IgG of 260 mg/dl, low IgA Conclusion These two cases represent an unusual adult-presentation of XLA, a humoral immunodeficiency usually diagnosed in childhood and the need to further investigate a suspicion of XLA in adult males with CVID particularly those associated with low to absent CD19+ B cells. A diagnosis of XLA can have significant implications including family counseling, detecting female carriers, and early intervention and treatment of affected male

  18. Mutations in btk in patients with presumed X-linked agammaglobulinemia.

    Science.gov (United States)

    Conley, M E; Mathias, D; Treadaway, J; Minegishi, Y; Rohrer, J

    1998-01-01

    In 1993, two groups showed that X-linked agammaglobulinemia (XLA) was due to mutations in a tyrosine kinase now called Btk. Most laboratories have been able to detect mutations in Btk in 80%-90% of males with presumed XLA. The remaining patients may have mutations in Btk that are difficult to identify, or they may have defects that are phenotypically similar to XLA but genotypically different. We analyzed 101 families in which affected males were diagnosed as having XLA. Mutations in Btk were identified in 38 of 40 families with more than one affected family member and in 56 of 61 families with sporadic disease. Excluding the patients in whom the marked decrease in B cell numbers characteristic of XLA could not be confirmed by immunofluorescence studies, mutations in Btk were identified in 43 of 46 patients with presumed sporadic XLA. Two of the three remaining patients had defects in other genes required for normal B cell development, and the third patient was unlikely to have XLA, on the basis of results of extensive Btk analysis. Our techniques were unable to identify a mutation in Btk in one male with both a family history and laboratory findings suggestive of XLA. DNA samples from 41 of 49 of the mothers of males with sporadic disease and proven mutations in Btk were positive for the mutation found in their son. In the other 8 families, the mutation appeared to arise in the maternal germ line. In 20 families, haplotype analysis showed that the new mutation originated in the maternal grandfather or great-grandfather. These studies indicate that 90%-95% of males with presumed XLA have mutations in Btk. The other patients are likely to have defects in other genes. PMID:9545398

  19. Mutational analysis of Btk, the defective gene in X-linked agammaglobulinemia

    Energy Technology Data Exchange (ETDEWEB)

    Conley, M.E.; Fitch-Hilgenberg, M.E.; Rohrer, J. [St. Jude Children`s Research Hospital, Memphis, TN (United States)

    1994-09-01

    Recent studies have shown that X-linked agammaglobulinemia (XLA), a disorder of B cell development, is due to mutations in an scr-like cytoplasmic tyrosine kinase, Btk. Thus far, mutations in this gene have been identified by sequencing of cDNA. To permit the detection of mutations in genomic DNA, we determined the structure of Btk and identified 19 exons in 37 kb of DNA. PCR primers were designed to amplify each exon with its splice sites. Two overlapping PCR products were employed for exons longer than 230 base pairs. Single strand conformation polymorphism (SSCP) analysis was used to screen genomic DNA from 30 unrelated families presumed to carry a mutation in Btk. It was possible to amplify DNA in every reaction from every patient. None of the DNA samples demonstrated more than one aberrant SSCP pattern. Twenty three mutations were detected in 25 families. Seven point mutations resulting in amino acid substitutions were seen. An additional 7 base pair substitutions gave rise to premature stop codons. Two splice defects were noted. Small insertions or deletions, all resulting in frameshifts and premature stop codons were seen in eight patients. One patient had an A to G transition in the ATG start codon. Two mutations, both at CpG dinucleotides, were seen in more than one family. Haplotype analysis, using CA repeats closely linked to Btk, demonstrated that the mutations in these families arose independently. We conclude from these studies that the mutations in Btk in patients with XLA are highly variable. Large deletions are uncommon, although small 1 to 4 bp insertions or deletions constitute as many as one third of the mutations. Further analysis of patients with amino acid substitutions will permit structure/function correlations.

  20. Immune dysregulation, Polyendocrinopathy, Enteropathy, X-linked (IPEX syndrome: a paradigm of immunodeficiency with autoimmunity

    Directory of Open Access Journals (Sweden)

    Federica eBarzaghi

    2012-07-01

    Full Text Available Immune dysregulation, Polyendocrinopathy, Enteropathy, X-linked (IPEX syndrome is a rare monogenic primary immunodeficiency (PID due to mutations of FOXP3, a key transcription factor for naturally occurring (n regulatory T (Treg cells. The dysfunction of Treg cells is the main pathogenic event leading to the multi-organ autoimmunity that characterizes IPEX syndrome, a paradigm of genetically determined PID with autoimmunity. IPEX has a severe early onset and can become rapidly fatal within the first year of life regardless of the type and site of the mutation. The initial presenting symptoms are severe enteritis and/or type 1 diabetes mellitus, alone or in combination with eczema and elevated serum IgE. Other autoimmune symptoms, such as hypothyroidism, cytopenia, hepatitis, nephropathy, arthritis, and alopecia, can develop in patients who survive the initial acute phase.The current therapeutic options for IPEX patients are limited. Supportive and replacement therapies combined with pharmacological immunosuppression are required to control symptoms at onset. However, these procedures can allow only a reduction of the clinical manifestations without a permanent control of the disease. The only known effective cure for IPEX syndrome is haematopoietic stem cell transplantation, but it is always limited by the availability of a suitable donor and the lack of specific guidelines for bone marrow transplant in the context of this disease.This review aims to summarize the clinical histories and genomic mutations of the IPEX patients described in the literature to date. We will focus on the clinical and immunological features that allow differential diagnosis of IPEX syndrome and distinguish it from other PID with autoimmunity. The efficacy of the current therapies will be reviewed, and possible innovative approaches, based on the latest highlights of the pathogenesis to treat this severe primary autoimmune disease of childhood, will be discussed.

  1. Two novel connexin32 mutations cause early onset X-linked Charcot-Marie-Tooth disease

    Directory of Open Access Journals (Sweden)

    Sand Jette C

    2007-07-01

    Full Text Available Abstract Background X-linked Charcot-Marie Tooth (CMT is caused by mutations in the connexin32 gene that encodes a polypeptide which is arranged in hexameric array and form gap junctions. Methods We describe two novel mutations in the connexin32 gene in two Norwegian families. Results Family 1 had a c.225delG (R75fsX83 which causes a frameshift and premature stop codon at position 247. This probably results in a shorter non-functional protein structure. Affected individuals had an early age at onset usually in the first decade. The symptoms were more severe in men than women. All had severe muscle weakness in the legs. Several abortions were observed in this family. Family 2 had a c.536 G>A (C179Y transition which causes a change of the highly conserved cysteine residue, i.e. disruption of at least one of three disulfide bridges. The mean age at onset was in the first decade. Muscle wasting was severe and correlated with muscle weakness in legs. The men and one woman also had symptom from their hands. The neuropathy is demyelinating and the nerve conduction velocities were in the intermediate range (25–49 m/s. Affected individuals had symmetrical clinical findings, while the neurophysiology revealed minor asymmetrical findings in nerve conduction velocity in 6 of 10 affected individuals. Conclusion The two novel mutations in the connexin32 gene are more severe than the majority of previously described mutations possibly due to the severe structural change of the gap junction they encode.

  2. Diagnosis and Surgical Management of Nonsyndromic Nine Supernumerary Teeth and Leong's Tubercle.

    Science.gov (United States)

    Cruz, Christiane V; Soares, Andrea L; Braga, David N; Costa, Marcelo C

    2016-01-01

    Nonsyndromic multiple supernumerary teeth (ST) and Leong's tubercle are a condition with a very low prevalence and a multidisciplinary approach is required to restore function and aesthetics. So, this case report aimed at presenting a rare case of nonsyndromic nine supernumerary teeth and Leong's tubercle in a pediatric patient, without any evident familial history, showing its diagnosis and surgical management.

  3. Steroid Use in Idiopathic Sudden Sensorineural Hearing Loss: What ...

    African Journals Online (AJOL)

    Idiopathic sudden sensorineural hearing loss is a disease of unknown etiology. Controversy in the literature argues whether the condition should be treated by steroid therapy. In this case study, a Medline literature search was completed to find out if there is any evidence to support its use in this condition.

  4. Clinical and molecular analysis of a four-generation Chinese family with aminoglycoside-induced and nonsyndromic hearing loss associated with the mitochondrial 12S rRNA C1494T mutation

    International Nuclear Information System (INIS)

    Wang Qiuju; Li Qingzhong; Han Dongyi; Zhao Yali; Zhao Lidong; Qian Yaping; Yuan Hu; Li Ronghua; Zhai Suoqiang; Young Wieyen; Guan Minxin

    2006-01-01

    We report here the clinical, genetic, and molecular characterization of a four-generation Chinese family with aminoglycoside-induced and nonsyndromic hearing loss. Five of nine matrilineal relatives had aminoglycoside-induced hearing loss. These matrilineal relatives exhibited variable severity and audiometric configuration of hearing impairment, despite sharing some common features: being bilateral and having sensorineural hearing impairment. Sequence analysis of mitochondrial DNA (mtDNA) in the pedigree identified 16 variants and the homoplasmic 12S rRNA C1494T mutation, which was associated with hearing loss in the other large Chinese family. In fact, the occurrence of the C1494T mutation in these genetically unrelated pedigrees affected by hearing impairment strongly indicated that this mutation is involved in the pathogenesis of aminoglycoside-induced and nonsyndromic hearing loss. However, incomplete penetrance of hearing loss indicated that the C1494T mutation itself is not sufficient to produce a clinical phenotype but requires the involvement of modifier factors for the phenotypic expression. Those mtDNA variants, showing no evolutional conservation, may not have a potential modifying role in the pathogenesis of the C1494T mutation. However, nuclear background seems to contribute to the phenotypic variability of matrilineal relatives in this family. Furthermore, aminoglycosides modulate the expressivity and penetrance of deafness associated with the C1494T mutation in this family

  5. Interaction of a Cyclic, Bivalent Smac Mimetic with the X-Linked Inhibitor of Apoptosis Protein

    Energy Technology Data Exchange (ETDEWEB)

    Nikolovska-Coleska, Zaneta; Meagher, Jennifer L.; Jiang, Sheng; Yang, Chao-Yie; Qiu, Su; Roller, Peter P.; Stuckey, Jeanne A.; Wang, Shaomeng (Michigan); (NIH)

    2009-02-25

    We have designed and synthesized a cyclic, bivalent Smac mimetic (compound 3) and characterized its interaction with the X-linked inhibitor of apoptosis protein (XIAP). Compound 3 binds to XIAP containing both BIR2 and BIR3 domains with a biphasic dose-response curve representing two binding sites with IC{sub 50} values of 0.5 and 406 nM, respectively. Compound 3 binds to XIAPs containing the BIR3-only and BIR2-only domain with K{sub i} values of 4 nM and 4.4 {mu}M, respectively. Gel filtration experiments using wild-type and mutated XIAPs showed that 3 forms a 1:2 stoichiometric complex with XIAP containing the BIR3-only domain. However, it forms a 1:1 stoichiometric complex with XIAP containing both BIR2 and BIR3 domains, and both BIR domains are involved in the binding. Compound 3 efficiently antagonizes inhibition of XIAP in a cell-free functional assay and is >200 times more potent than its corresponding monovalent compound 2. Determination of the crystal structure of 3 in complex with the XIAP BIR3 domain confirms that 3 induces homodimerization of the XIAP BIR3 domain and provides a structural basis for the cooperative binding of one molecule of compound 3 to two XIAP BIR3 molecules. On the basis of this crystal structure, a binding model of XIAP containing both BIR2 and BIR3 domains and 3 was constructed, which sheds light on the ability of 3 to relieve the inhibition of XIAP with not only caspase-9 but also caspase-3/-7. Compound 3 is cell-permeable, effectively activates caspases in whole cells, and potently inhibits cancer cell growth. Compound 3 is a useful biochemical and pharmacological tool for further elucidating the role of XIAP in regulation of apoptosis and represents a promising lead compound for the design of potent, cell-permeable Smac mimetics for cancer treatment.

  6. Streamlined determination of lysophosphatidylcholines in dried blood spots for newborn screening of X-linked adrenoleukodystrophy.

    Science.gov (United States)

    Turgeon, Coleman T; Moser, Ann B; Mørkrid, Lars; Magera, Mark J; Gavrilov, Dimitar K; Oglesbee, Devin; Raymond, Kimiyo; Rinaldo, Piero; Matern, Dietrich; Tortorelli, Silvia

    2015-01-01

    Pre-symptomatic hematopoietic stem cell transplantation is essential to achieve best possible outcomes for patients with the childhood cerebral form of X-linked adrenoleukodystrophy (X-ALD). We describe a high-throughput method for measurement of C20-C26 lysophosphatidylcholines (LPCs) and biochemical diagnosis of X-ALD using the same dried blood spots (DBS) routinely used for newborn screening. LPCs are extracted from 3-mm DBS punch with methanol containing an isotopically labeled LPC as internal standard. This extract is transferred to a 96-well plate, evaporated and then reconstituted in mobile phase for flow injection analysis tandem mass spectrometry (FIA-MS/MS) in selected reaction monitoring mode for measurement of four different LPCs (C20, C22, C24, C26) and the internal standard (d4-C26-LPC). Analysis time is 1.5min per sample. The mean CVs from the intra- and inter-assay experiments for LPCs were 6.3-15.1% for C20-LPC, 4.4-18.6% for C22-LPC and 4.5-14.3% for C24-LPC. Limits of detection were determined for C20-LPC (LOD=0.03μg/mL), C22-LPC (0.03μg/mL), C24-LPC (0.03μg/mL) and C26-LPC (0.01μg/mL). Reference ranges were established from DBS of 130 newborns and 20 adults. Samples of patients with X-ALD (n=16), peroxisomal biogenesis disorders (n=8), and X-ALD carriers (n=12) were analyzed blindly and all were correctly identified. Analysis of LPC species by FIA-MS/MS is a fast, simple and reliable method to screen for X-ALD and other peroxisomal disorders in DBS. To maximize specificity, abnormal results can be verified by a 2nd tier assay using LC-MS/MS. Copyright © 2014 Elsevier Inc. All rights reserved.

  7. Linkage analysis and physical mapping near the gene for x-linked agammaglobulinemia at Xq22

    Energy Technology Data Exchange (ETDEWEB)

    Parolini, O.; Lassiter, G.L.; Henry, M.J.; Conley, M.E. (Univ. of Tennessee College of Medicine, Memphis (United States) St. Jude Children' s Research Hospital, Memphis, TN (United States)); Hejtmancik, J.F. (National Inst. of Health, Bethesda, MD (United States)); Allen, R.C.; Belmont, J.W. (Baylor College of Medicine, Houston, TX (United States)); Barker, D.F. (Univ. of Utah, Salt Lake City (United States))

    1993-02-01

    The gene for x-linked agammaglobulinemia (XLA) has been mapped to Xq22. No recombinations have been reported between the gene and the prob p212 at DXS178; however, this probe is informative in only 30-40% of women and the reported flanking markers, DXS3 and DXS94, and 10-15 cM apart. To identify additional probes that might be useful in genetic counseling, we examined 11 polymorphisms that have been mapped to the Xq21.3-q22 region in 13 families with XLA. In addition, pulsed-field gel electrophoresis and yeast artificial chromosomes (YACs) were used to further characterize the segman of DNA within which the gene for SLA must lie. The results demonstrated that DXS366 and DXS442, which share a 430-kb pulsed-field fragment, could replace DXS3 as proximal flanking markers. Probes at DXS178 and DXS265 identified the same 145-kb pulsed-field fragment, and both loci were contained within a 200-kb YAC identified with the probe p212. A highly polymorphic CA repeat (DCS178CA) was isolated from one end of this YAC and used in linkage analysis. Probes at DXS101 and DXS328 shared several pulsed-field fragments, the smallest of which was 250 kb. No recombinations were seen between XLA and the DXS178-DXS265-DXS178CA complex, DXS101, DXS328, DXS87, or the gene for proteolipid protein (PLP). Key crossovers, when combined with the linkage data from families with Alport syndrome, suggested the following order of loci: cen-DXS3-DXS366-DXS442-(PLP, DXS101, DXS328, DXS178-DXS265-DXS178CA complex, XL)-(DXS87, DXS94)-DXS327-(DXS350, DXS362)-tel. Our studies also limit the segment of DNA within which the XLA gene must lie to the 3- to 4-cM distance between DCS442 and DXS94 and they identify and orient polymorphisms that can be used in genetic counseling not only for XLA but also for Pelizaeus-Merzbacher disease (PLP deficiency), Alport syndrome (COL4A5 deficiency), and Fabry disease ([alpha]-galactosidase A difficiency). 31 refs., 5 figs., 2 tabs.

  8. Clinical features and mutation analysis of X-linked agammaglobulinemia in 20 Chinese patients.

    Science.gov (United States)

    Qin, Xian; Jiang, Li-Ping; Tang, Xue-Mei; Wang, Mo; Liu, En-Mei; Zhao, Xiao-Dong

    2013-08-01

    X-linked agammagobulinemia (XLA) is a primary immunodeficiency caused by Bruton's tyrosine kinase (BTK) gene mutation. XLA patients have an extremely small amount of peripheral B cells and profound deficiency in all immunoglobulin isotypes. We analyzed the clinical, immunologic, and molecular characteristics of children with XLA in an attempt to improve the diagnosis and treatment of XLA in China. Twenty children with XLA-compatible phenotypes from 18 unrelated families were enrolled in this study. The BTK gene was amplified and sequenced, followed by mutation analysis in these children and their female relatives. Eighteen different mutations of the BTK gene were identified in the 20 patients. Eleven mutations had been reported previously including eight missense mutations (c.994C>T, c.1987C>A, c.1885G>T, c.502T>C, c.1085C>T, c.1816C>T, c.214C>T, c.1912G>A) and three nonsense mutations (c.1267T>A, c.1793C>G, c.1618C>T). Seven novel mutations of the BTK gene were also presented and included five missense mutations (c.134T>A, c.1646T>A, c.1829C>G, c.711G>T, c.1235G>A), one splice-site mutation (c.523+1G>A) and one insertion mutation (c.1024-1025in sTTGCTAAAGCAACTGCTAAAGCAAG). Eight out of 18 mutations of the BTK gene were located in the TK domain, 4 in the PH domain, 4 in the SH2 domain and 2 in the TH domain. Genetic study for carrier status was carried out in 18 families with definite BTK gene mutations. Nine carriers with BTK gene mutations were identified. Six families without carriers were detected, and 3 patients were not tested in this study. Our results support that molecular genetic testing represents an important tool for early confirmed diagnosis of congenital agammaglobulinemia and may allow accurate carrier detection and prenatal diagnosis.

  9. Clinical and Genetic Features of Chinese X-linked Charcot-Marie-Tooth Type 1 Disease

    Science.gov (United States)

    Lu, Yuan-Yuan; Lyu, He; Jin, Su-Qin; Zuo, Yue-Huan; Liu, Jing; Wang, Zhao-Xia; Zhang, Wei; Yuan, Yun

    2017-01-01

    Background: X-linked Charcot-Marie-Tooth type 1 (CMT1X) disease is one of the most common forms of inherited neuropathy caused by mutations in the gap junction beta-1 protein (GJB1) gene (also known as connexin 32). This study presented the clinical and genetic features of a series of Chinese patients with GJB1 gene mutations. Methods: A total of 22 patients from unrelated families, who were referred to Department of Neurology, Peking University First Hospital from January 2005 to January 2016, were identified with GJB1 mutations. Their clinical records and laboratory findings were retrospectively collected and reviewed. Mutations in the GJB1 gene were analyzed by targeted next-generation sequencing (NGS). Nucleotide alternations were confirmed with Sanger sequencing. Results: The CMT1X patients predominantly showed distal muscle weakness of lower limbs with mild sensory disturbance. The mean age of onset was 15.6 ± 8.7 years (ranging from 1 year to 42 years). The sudden onset of cerebral symptoms appeared in four patients (18.2%); two were initial symptoms. One case had constant central nervous system (CNS) signs. There were 19 different heterozygous mutations, including 15 known mutations and four novel mutations (c.115G>T, c.380T>A, c.263C>A, and c.818_819insGGGCT). Among the 22 Chinese patients with CMT1X, the frequency of the GJB1 mutation was 4.5% in transmembrane domain 1 (TM1), 4.5% in TM2, 22.7% in TM3, 9.1% in TM4, 4.5% in extracellular 1 (EC1), 27.3% in EC2, 9.1% in intracellular loop, 13.6% in the N-terminal domain, and 4.5% in the C-terminal domain. CMT1X with CNS impairment appeared in five (22.7%) of these patients. Conclusions: This study indicated that CNS impairment was not rare in Chinese CMT1X patients. Mutations in the EC2 domain of the GJB1 gene were hotspot in Chinese CMT1X patients. PMID:28469099

  10. Unusual late presentation of X-linked chronic granulomatous disease in an adult female with a somatic mosaic for a novel mutation in CYBB

    NARCIS (Netherlands)

    Wolach, Baruch; Scharf, Yitshak; Gavrieli, Ronit; de Boer, Martin; Roos, Dirk

    2005-01-01

    Most patients with chronic granulomatous disease (CGD) have mutations in the X-linked CYBB gene that encodes gp91(phox), a component of the phagocyte NADPH oxidase. The resulting X-linked form of CGD is usually manifested in boys. Rarely, X-CGD is encountered in female carriers with extreme

  11. New domains of neural cell-adhesion molecule L1 implicated in X-linked hydrocephalus and MASA syndrome

    Energy Technology Data Exchange (ETDEWEB)

    Jouet, M.; Kenwick, S. [Univ. of Cambridge (United Kingdom); Moncla, A. [Hopital d`Enfants de la Timone, Marseillas (United Kingdom)] [and others

    1995-06-01

    The neural cell-adhesion molecule L1 is involved in intercellular recognition and neuronal migration in the CNS. Recently, we have shown that mutations in the gene encoding L1 are responsible for three related disorders; X-linked hydrocephalus, MASA (mental retardation, aphasia, shuffling gait, and adducted thumbs) syndrome, and spastic paraplegia type I (SPG1). These three disorders represent a clinical spectrum that varies not only between families but sometimes also within families. To date, 14 independent L1 mutations have been reported and shown to be disease causing. Here we report nine novel L1 mutations in X-linked hydrocephalus and MASA-syndrome families, including the first examples of mutations affecting the fibronectin type III domains of the molecule. They are discussed in relation both to phenotypes and to the insights that they provide into L1 function. 39 refs., 5 figs., 3 tabs.

  12. A novel mutation in the ABCD1 gene of a Moroccan patient with X-linked adrenoleukodystrophy: case report.

    Science.gov (United States)

    Karkar, Adnane; Barakat, Abdelhamid; Bakhchane, Amina; Fettah, Houda; Slassi, Ilham; Dorboz, Imen; Boespflug-Tanguy, Odile; Nadifi, Sellama

    2015-11-25

    X-linked adrenoleukodystrophy (X-ALD; OMIM: 300100) is the most common peroxisomal disease caused by mutations in the ATP-binding cassette, sub-family D member 1 gene or ABCD1 (geneID: 215), the coding gene for the adrenoleukodystrophy protein (ALDP), which is an ATP-binding transport protein associated to an active transport of very long chain fatty acids (VLCFAs). Dysfunction of ALDP induces an accumulation of VLCFAs in all tissues leading to a neurodegenerative disorder that involves the nervous system white matter. In our case report, magnetic resonance imaging (MRI) as well as the high levels of VLCFAs prompted the diagnosis the X-ALD. Molecular analysis of ABCD1 gene have shown a pathogenic homozygous nonsense mutation (c.1677C > G; p.(Tyr559*)) in exon 7. Thus, we identified here a novel mutation in the ABCD1 gene in a Moroccan patient causing X-linked adrenoleukodystrophy.

  13. In vitro effect of N-acetyl-L-cysteine on glutathione and sulfhydryl levels in X-linked adrenoleukodystrophy patients

    Directory of Open Access Journals (Sweden)

    Desirèe Padilha Marchetti

    2017-04-01

    Full Text Available Introduction: Recent evidence shows that oxidative stress seems to be related with the pathophysiology of X-linked adrenoleukodystrophy (X-ALD, a neurodegenerative disorder. Methods: In the present study, the in vitro effect of N-acetyl-L-cysteine (NAC on glutathione (GSH and sulfhydryl levels in X-ALD patients was evaluated. Results: A significant reduction of GSH and sulfhydryl content was observed in X-ALD patients compared to the control group. Furthermore, 5 mM of NAC, in vitro, led to an increase in GSH content and sulfhydryl groups in these patients. Conclusion: These data probably indicate that an adjuvant therapy with the antioxidant NAC could improve the oxidative imbalance in X-ALD patients. Keywords: X- linked adrenoleukodystrophy; N-acetyl-L-cysteine; glutathione; sulfhydryl

  14. Psychiatric Diagnoses in Individuals with Non-Syndromic Oral Clefts

    DEFF Research Database (Denmark)

    Pedersen, Dorthe Almind; Wehby, George L; Murray, Jeffrey C

    2016-01-01

    found no increased risk of mood disorders and anxiety-related disorders. CONCLUSION: Individuals with non-syndromic OC had significantly higher risk of psychiatric diagnoses compared with individuals without OC. However, the elevated risk was observed for individuals with CLP and CP.......90-1.17), but CLP was associated with a small increased risk (HR = 1.13, 95% CI: 1.01-1.26), whereas individuals with CP had the largest increased risk (HR = 1.45, 95% CI: 1.30-1.62). The largest differences were found in schizophrenia-like disorders, mental retardation and pervasive developmental disorders, but we...

  15. Screening of Connexin 26 in Nonsyndromic Hearing Loss

    OpenAIRE

    Moreira, Danielle; Silva, Daniela da; Lopez, Priscila; Mantovani, Jair Cortez

    2014-01-01

    Introduction The first locus for nonsyndromic autosomal recessive hearing loss is on chromosome 13q11-22. The 35delGmutation is present in 80% of cases in which GJB2 is involved, which makes the study of this mutation very important. The viability and benefits of screening for mutations in the connexin 26 gene are now beginning to change the diagnostic evaluation and identification of the etiology of hearing loss.Objective To investigate the occurrence of the 35delG mutation in patients with ...

  16. A novel AVPR2 splice site mutation leads to partial X-linked nephrogenic diabetes insipidus in two brothers.

    Science.gov (United States)

    Schernthaner-Reiter, Marie Helene; Adams, David; Trivellin, Giampaolo; Ramnitz, Mary Scott; Raygada, Margarita; Golas, Gretchen; Faucz, Fabio R; Nilsson, Ola; Nella, Aikaterini A; Dileepan, Kavitha; Lodish, Maya; Lee, Paul; Tifft, Cynthia; Markello, Thomas; Gahl, William; Stratakis, Constantine A

    2016-05-01

    X-linked nephrogenic diabetes insipidus (NDI, OMIM#304800) is caused by mutations in the arginine vasopressin (AVP, OMIM*192340) receptor type 2 (AVPR2, OMIM*300538) gene. A 20-month-old boy and his 8-year-old brother presented with polyuria, polydipsia, and failure to thrive. Both boys demonstrated partial DDAVP (1-desamino-8-D AVP or desmopressin) responses; thus, NDI diagnosis was delayed. While routine sequencing of AVPR2 showed a potential splice site variant, it was not until exome sequencing confirmed the AVPR2 splice site variant and did not reveal any more likely candidates that the patients' diagnosis was made and proper treatment was instituted. Both patients were hemizygous for two AVPR2 variants predicted in silico to affect AVPR2 messenger RNA (mRNA) splicing. A minigene assay revealed that the novel AVPR2 c.276A>G mutation creates a novel splice acceptor site leading to 5' truncation of AVPR2 exon 2 in HEK293 human kidney cells. Both patients have been treated with high-dose DDAVP with a remarkable improvement of their symptoms and accelerated linear growth and weight gain. We present here a unique case of partial X-linked NDI due to an AVPR2 splice site mutation; patients with diabetes insipidus of unknown etiology may harbor splice site mutations that are initially underestimated in their pathogenicity on sequence analysis. • X-linked nephrogenic diabetes insipidus is caused by AVPR2 mutations, and disease severity can vary depending on the functional effect of the mutation. What is New: • We demonstrate here that a splice site mutation in AVPR2 leads to partial X-linked NDI in two brothers. • Treatment with high-dose DDAVP led to improvement of polyuria and polydipsia, weight gain, and growth.

  17. Central precocious puberty in a patient with X-linked adrenal hypoplasia congenita and Xp21 contiguous gene deletion syndrome

    Directory of Open Access Journals (Sweden)

    Ji Won Koh

    2013-06-01

    Full Text Available X-linked adrenal hypoplasia congenita is caused by the mutation of DAX-1 gene (dosage-sensitive sex reversal, adrenal hypoplasia critical region, on chromosome X, gene 1, and can occur as part of a contiguous gene deletion syndrome in association with glycerol kinase (GK deficiency, Duchenne muscular dystrophy and X-linked interleukin-1 receptor accessory protein-like 1 (IL1RAPL1 gene deficiency. It is usually associated with hypogonadotropic hypogonadism, although in rare cases, it has been reported to occur in normal puberty or even central precocious puberty. This study addresses a case in which central precocious puberty developed in a boy with X-linked adrenal hypoplasia congenita who had complete deletion of the genes DAX-1, GK and IL1RAPL1 (Xp21 contiguous gene deletion syndrome. Initially he was admitted for the management of adrenal crisis at the age of 2 months, and managed with hydrocortisone and florinef. At 45 months of age, his each testicular volumes of 4 mL and a penile length of 5 cm were noted, with pubic hair of Tanner stage 2. His bone age was advanced and a gonadotropin-releasing hormone (GnRH stimulation test showed a luteinizing hormone peak of 8.26 IU/L, confirming central precocious puberty. He was then treated with a GnRH agonist, as well as steroid replacement therapy. In Korea, this is the first case of central precocious puberty developed in a male patient with X-linked adrenal hypoplasia congenita.

  18. A Splice Defect in the EDA Gene in Dogs with an X-Linked Hypohidrotic Ectodermal Dysplasia (XLHED) Phenotype

    OpenAIRE

    Waluk, Dominik P.; Zur, Gila; Kaufmann, Ronnie; Welle, Monika M.; Jagannathan, Vidhya; Dr?gem?ller, Cord; M?ller, Eliane J.; Leeb, Tosso; Galichet, Arnaud

    2016-01-01

    X-linked hypohidrotic ectodermal dysplasia (XLHED) caused by variants in the EDA gene represents the most common ectodermal dysplasia in humans. We investigated three male mixed-breed dogs with an ectodermal dysplasia phenotype characterized by marked hypotrichosis and multifocal complete alopecia, almost complete absence of sweat and sebaceous glands, and altered dentition with missing and abnormally shaped teeth. Analysis of SNP chip genotypes and whole genome sequence data from the three a...

  19. Significant Correction of Disease after Postnatal Administration of Recombinant Ectodysplasin A in Canine X-Linked Ectodermal Dysplasia

    OpenAIRE

    Casal, Margret L. ; Lewis, John R. ; Mauldin, Elizabeth A. ; Tardivel, Aubry ; Ingold, Karine ; Favre, Manuel ; Paradies, Fabrice ; Demotz, Stéphane ; Gaide, Olivier ; Schneider, Pascal 

    2007-01-01

    Patients with defective ectodysplasin A (EDA) are affected by X-linked hypohidrotic ectodermal dysplasia (XLHED), a condition characterized by sparse hair, inability to sweat, decreased lacrimation, frequent pulmonary infections, and missing and malformed teeth. The canine model of XLHED was used to study the developmental impact of EDA on secondary dentition, since dogs have an entirely brachyodont, diphyodont dentition similar to that in humans, as opposed to mice, which have only permanent...

  20. PROTECTIVE LEVELS OF VARICELLA-ZOSTER ANTIBODY DID NOT EFFECTIVELY PREVENT CHICKENPOX IN AN X-LINKED AGAMMAGLOBULINEMIA PATIENT

    Directory of Open Access Journals (Sweden)

    Fernanda Aimée NOBRE

    2015-10-01

    Full Text Available SUMMARY We describe the case of an eight-year-old boy with X-linked agammaglobulinemia who developed mild varicella despite regular intravenous immunoglobulin (IVIG therapy. He maintained protective antibody levels against varicella and the previous batches of IVIG that he received had adequate varicella-specific IgG levels. The case illustrates that IVIG may not prevent VZV infection.

  1. Refractory Chronic Pleurisy Caused by Helicobacter equorum-Like Bacterium in a Patient with X-Linked Agammaglobulinemia ▿

    Science.gov (United States)

    Funato, Michinori; Kaneko, Hideo; Ohkusu, Kiyofumi; Sasai, Hideo; Kubota, Kazuo; Ohnishi, Hidenori; Kato, Zenichiro; Fukao, Toshiyuki; Kondo, Naomi

    2011-01-01

    We describe a 35-year-old man with X-linked agammaglobulinemia who had refractory chronic pleurisy caused by a Helicobacter equorum-like bacterium. Broad-range bacterial PCR targeting the 16S and 23S rRNA genes and in situ hybridization targeting the 16S rRNA gene of H. equorum confirmed the presence of this pathogen in a human for the first time. PMID:21677071

  2. In vivo confocal microscopy of pre-Descemet corneal dystrophy associated with X-linked ichthyosis: a case report.

    Science.gov (United States)

    Shi, Hui; Qi, Xiao-Feng; Liu, Tao-Tao; Hao, Qian; Li, Xiao-Hong; Liang, Ling-Ling; Wang, Yi-Miao; Cui, Zhi-Hua

    2017-03-16

    Pre-Descemet corneal dystrophy (PDCD) is characterized by the presence of numerous, tiny, polymorphic opacities immediately anterior to Descemet membrane, which is a rare form of corneal stromal dystrophy and hard to be diagnosed. In vivo confocal microscopy (IVCM) is a useful tool to examine the minimal lesions of the cornea at the cellular level. In this article, we report a rare case of PDCD associated with X-linked ichthyosis and evaluate IVCM findings. We present a 34-year-old male Chinese patient with PDCD associated with X-linked ichthyosis. Slit-lamp biomicroscopy showed the presence of tiny and pleomorphic opacities in the posterior stroma immediately anterior to Descemet membrane bilaterally. IVCM revealed regular distributed hyperreflective particles inside the enlarged and activated keratocytes in the posterior stroma. Hyperreflective particles were also observed dispersedly outside the keratocytes in the anterior stroma. Dermatological examination revealed that the skin over the patient's entire body was dry and coarse, with thickening and scaling of the skin in the extensor side of the extremities. PCR results demonstrated that all ten exons and part flanking sequences of STS gene failed to produce any amplicons in the patient. IVCM is useful for analyzing the living corneal structural changes in rare corneal dystrophies. We first reported the IVCM characteristics of PDCD associated with X-linked ichthyosis, which was caused by a deletion of the steroid sulfatase (STS) gene, confirmed by gene analysis.

  3. The stability of hexacosanoyl lysophosphatidylcholine in dried-blood spot quality control materials for X-linked adrenoleukodystrophy newborn screening.

    Science.gov (United States)

    Haynes, Christopher A; De Jesús, Víctor R

    2015-01-01

    Newborn screening for X-linked adrenoleukodystrophy utilizes tandem mass spectrometry to analyze dried-blood spot specimens. Quality control materials (dried-blood spots enriched with hexacosanoyl lysophosphatidylcholine) were prepared and stored at different temperatures for up to 518days to evaluate the stability of this biomarker for X-linked adrenoleukodystrophy. Dried-blood spot storage included desiccant (45, 171, and 518days) or omitted desiccant (53days at >90% relative humidity). Specimens were stored for 171 and 518days at -20°C, 4°C, ambient temperature, and 37°C. Each weekday for 45days, a bag of specimens stored at 4°C was warmed to ambient temperature and one specimen was removed for storage at -80°C. Specimens were analyzed by high-performance liquid-chromatography electrospray ionization tandem mass spectrometry and data was plotted as concentration (micromoles per liter) vs. time. Linear regression provided slope and y-intercept values for each storage condition. Small slope values (0.01 or less) and y-intercept values close to the enrichment indicated less than 11% loss of hexacosanoyl lysophosphatidylcholine under all storage conditions tested. Quality control materials for X-linked adrenoleukodystrophy are stable for at least 1year when stored with desiccant. Published by Elsevier Inc.

  4. Combination of a Haploidentical Stem Cell Transplant With Umbilical Cord Blood for Cerebral X-Linked Adrenoleukodystrophy.

    Science.gov (United States)

    Jiang, Hua; Jiang, Min-Yan; Liu, Sha; Cai, Yan-Na; Liang, Cui-Li; Liu, Li

    2015-08-01

    Childhood cerebral X-linked adrenoleukodystrophy is a rapidly progressive neurodegenerative disorder that affects central nervous system myelin and the adrenal cortex. Hematopoietic stem cell transplantation is the best available curative therapy if performed during the early stages of disease. Only 30% of patients who might benefit from a hematopoietic stem cell transplant will have a full human leukocyte antigen-matched donor, which is considered to be the best choice. We present a 5-year-old boy with cerebral X-linked adrenoleukodystrophy whose brain magnetic resonance imaging severity score was 7 and who needed an immediate transplantation without an available full human leukocyte antigen-matched donor. We combined haploidentical and umbilical cord blood sources for transplantation and saw encouraging results. After transplantation, the patient showed neurological stability for 6 months and the level of very long chain fatty acids had decreased. By 1 year, the patient appeared to gradually develop cognition, motor, and visual disturbances resulting from possible mix chimerism. Transplantation of haploidentical stem cells combined with the infusion of umbilical cord blood is a novel approach for treating cerebral X-linked adrenoleukodystrophy. It is critical to monitor posttransplant chimerism and carry out antirejection therapy timely for a beneficial clinical outcome. Copyright © 2015 Elsevier Inc. All rights reserved.

  5. X-linked gene expression in the Virginia opossum: differences between the paternally derived Gpd and Pgk-A loci

    Energy Technology Data Exchange (ETDEWEB)

    Samollow, P.B.; Ford, A.L.; VandeBerg, J.L.

    1987-01-01

    Expression of X-linked glucose-6-phosphate dehydrogenase (G6PD) and phosphoglycerate kinase-A (PGK-A) in the Virginia opossum (Didelphis virginiana) was studied electrophoretically in animals from natural populations and those produced through controlled laboratory crosses. Blood from most of the wild animals exhibited a common single-banded phenotype for both enzymes. Rare variant animals, regardless of sex, exhibited single-banded phenotypes different in mobility from the common mobility class of the respective enzyme. The laboratory crosses confirmed the allelic basis for the common and rare phenotypes. Transmission of PGK-A phenotypes followed the pattern of determinate (nonrandom) inactivation of the paternally derived Pgk-A allele, and transmission of G6PD also was consistent with this pattern. A survey of tissue-specific expression of G6PD phenotypes of heterozygous females revealed, in almost all tissues, three-banded patterns skewed in favor of the allele that was expressed in blood cells. Three-banded patterns were never observed in males or in putatively homozygous females. These patterns suggest simultaneous, but unequal, expression of the maternally and paternally derived Gpd alleles within individual cells. The absence of such partial expression was noted in a parallel survey of females heterozygous at the Pgd-A locus. Thus, it appears that Gpd and Pgk-A are X-linked in D. virginiana and subject to preferential paternal allele inactivation, but that dosage compensation may not be complete for all paternally derived X-linked genes.

  6. Woman with x-linked recessive dystonia-parkinsonism: clue to the epidemiology of parkinsonism in Filipino women?

    Science.gov (United States)

    Domingo, Aloysius; Lee, Lillian V; Brüggemann, Norbert; Freimann, Karen; Kaiser, Frank J; Jamora, Roland D G; Rosales, Raymond L; Klein, Christine; Westenberger, Ana

    2014-09-01

    Despite recessive inheritance, X-linked dystonia-parkinsonism (Lubag disease) has also been described in women presenting with a late-onset isolated parkinsonian syndrome. Interestingly, unlike in other populations, there is a slight female predominance in the prevalence of parkinsonism in the Philippines. In a Filipino woman with suspected Parkinson disease, we confirmed the presence of all changes specific for X-linked dystonia-parkinsonism in genomic DNA. Subsequently, we analyzed complementary DNA and evaluated the methylation status of the androgen receptor gene. Owing to extremely skewed (98%:2%) X-chromosome inactivation, the patient expressed almost solely the mutated allele in a disease-specific change, rendering her molecularly comparable with a hemizygously affected man. Skewed X-chromosome inactivation is the likely cause of parkinsonism in this heterozygous mutation carrier. Because women carriers of the genetic changes specific for X-linked dystonia-parkinsonism are common in the Philippines, the epigenetic factor of nonrandom X-chromosome inactivation may contribute to the skewing of the sex prevalence of parkinsonism toward women in this country, warranting further investigation.

  7. X-linked adrenoleukodystrophy: clinical and laboratory findings in 15 Brazilian patients

    Directory of Open Access Journals (Sweden)

    Carmen R. Vargas

    2000-06-01

    Full Text Available Adrenoleukodystrophy (X-ALD is an X-linked recessively inherited peroxisomal disorder, phenotypically heterogeneous, characterized by progressive white-matter demyelination of the central nervous system and adrenocortical insufficiency. We investigated 15 male X-ALD patients varying in age from 7 to 39, diagnosed among 108 suspected patients referred for investigation. Plasma levels of very long chain fatty acids (VLCFA were measured at our laboratory using gas chromatography (GC. Eleven cases of childhood X-ALD and four cases of adrenomyeloneuropathy (AMN were diagnosed. Adrenal leukodystrophy insufficiency and limb weakness were the most frequent symptoms, appearing in 12, 8 and 6 of the patients, respectively. Physician awareness of X-ALD seems inadequate to judge by age at diagnosis and lengthy interval between the start of symptoms and diagnosis. This is the first published series of Brazilian patients with X-ALD. We determined signs and symptoms relevant for diagnosis, as early identification seems important for treatment outcome. In addition, diagnosis identifies carriers, who could benefit from genetic counselling and prenatal diagnosis.Adrenoleucodistrofia (X-ALD é uma desordem peroxissomal com padrão de herança ligada ao X, fenotipicamente heterogênea, caracterizada por uma progressiva desmielinização da substância branca do sistema nervoso central e por insuficiência adrenal. Foram investigados por nós 15 pacientes do sexo masculino com sinais clínicos sugestivos de X-ALD, com idade entre 7 e 39 anos, diagnosticados entre 108 pacientes encaminhados para investigação por suspeita clínica. Os níveis plasmáticos dos ácidos graxos de cadeia muito longa (VLCFA foram dosados em nosso laboratório através de cromatografia gasosa (GC. Onze (73% casos da forma infantil de X-ALD (ALD e 4 (27% casos de adrenomieloneuropatia (AMN foram diagnosticados. Insuficiência leucodistrofia adrenal e fraqueza muscular foram os sinais mais

  8. [Two families of X-linked lymphoproliferative disease type 1 characterized by agammaglobulinemia].

    Science.gov (United States)

    Li, W Y; Chen, J S; Zhao, Q; Dai, R X; Wang, Y P; Zhao, H Y; Chen, X M; Xue, X H; Sun, X Y; Tang, X M; Zhang, Y; Ding, Y; Zhao, X D; Zhang, Z Y

    2017-05-04

    Objective: To investigate the clinical and immunological laboratory features, mutations in SH2D1A gene and SAP protein expression in four children of two families with X-linked lymphoproliferative disease type 1(XLP-1). Method: Four patients (Family A including Patient 1 and Patient 2, Family B including Patient 3 and Patient 4) and their maternal relatives were enrolled in this study. The clinical manifestation, EBV infection status and chest CT scan were analyzed. The absolute and relative numbers of lymphocyte subsets, T lymphocyte proliferative response, SAP protein expression were assessed by flow cytometry. Quantification of signal joint TCR rearrangementexcision circle (sjTRECs), CDR3 spectratyping of TCRvβ and gene mutation of SH2D1A were detected by PCR based on genomic DNA or cDNA. Result: Four male patients from two families were diagnosed with XLP-1. The ages of disease onset were more than 1 year, more than 1 year, more than 1 month and 6 months. The ages at diagnosis were nine years and ten months, sixteen years and eight months, fourteen years and ten months, four years and nine months. All patients had recurrent infections and EBV infection. Patients 1, 2, and 3 had agammaglobulinemia and Patient 4 had hypogammaglobulinemia. Chest CT scan showed all patients had atelectasis and pneumonia, and Patient 3 had bronchiectasis. Patient 3 was diagnosised as Burkitt lymphoma. For immunological function, all patients exhibited reduced CD4/CD8 ratios, increased numbers of exhausted T lymphocyte, decreased number of NK cell. The numbers of total B lymphocyte and naïve B lymphocyte were normal, but the number of memory B lymphocyte declined in all cases. Four patients' copy numbers of sjTRECs were low and CDR3 spectratypings of TCRvβ showed mildly skewed. But their T lymphocyte proliferative response was normal. SAP protein expression in four cases were measured by flow cytometry. Two patients from Family A were absent and two patients from Family B showed

  9. An ex vivo gene therapy approach in X-linked retinoschisis.

    Science.gov (United States)

    Bashar, Abu E; Metcalfe, Andrew L; Viringipurampeer, Ishaq A; Yanai, Anat; Gregory-Evans, Cheryl Y; Gregory-Evans, Kevin

    2016-01-01

    X-linked retinoschisis (XLRS) is juvenile-onset macular degeneration caused by haploinsufficiency of the extracellular cell adhesion protein retinoschisin (RS1). RS1 mutations can lead to either a non-functional protein or the absence of protein secretion, and it has been established that extracellular deficiency of RS1 is the underlying cause of the phenotype. Therefore, we hypothesized that an ex vivo gene therapy strategy could be used to deliver sufficient extracellular RS1 to reverse the phenotype seen in XLRS. Here, we used adipose-derived, syngeneic mesenchymal stem cells (MSCs) that were genetically modified to secrete human RS1 and then delivered these cells by intravitreal injection to the retina of the Rs1h knockout mouse model of XLRS. MSCs were electroporated with two transgene expression systems (cytomegalovirus (CMV)-controlled constitutive and doxycycline-induced Tet-On controlled inducible), both driving expression of human RS1 cDNA. The stably transfected cells, using either constitutive mesenchymal stem cell (MSC) or inducible MSC cassettes, were assayed for their RS1 secretion profile. For single injection studies, 100,000 genetically modified MSCs were injected into the vitreous cavity of the Rs1h knockout mouse eye at P21, and data were recorded at 2, 4, and 8 weeks post-injection. The control groups received either unmodified MSCs or vehicle injection. For the multiple injection studies, the mice received intravitreal MSC injections at P21, P60, and P90 with data collection at P120. For the single- and multiple-injection studies, the outcomes were measured with electroretinography, optokinetic tracking responses (OKT), histology, and immunohistochemistry. Two lines of genetically modified MSCs were established and found to secrete RS1 at a rate of 8 ng/million cells/day. Following intravitreal injection, RS1-expressing MSCs were found mainly in the inner retinal layers. Two weeks after a single injection of MSCs, the area of the schisis

  10. Is Celiac Disease an Etiological Factor in Children with Nonsyndromic Intellectual Disability?

    Science.gov (United States)

    Sezer, Taner; Balcı, Oya; Özçay, Figen; Bayraktar, Nilufer; Alehan, Füsun

    2016-03-01

    To determine the prevalence of celiac disease in children and adolescents with nonsyndromic intellectual disability, we investigated serum levels of tissue transglutaminase antibody and total IgA from 232 children with nonsyndromic intellectual disability and in a healthy control group of 239 children. Study participants who were positive for tissue transglutaminase antibody underwent a duodenal biopsy. A total of 3 patients in the nonsyndromic intellectual disability group (5.45%) and 1 in the control group (0.41%) had positive serum tissue transglutaminase antibody (P > .05). Duodenal biopsy confirmed celiac disease in only 1 patient who had nonsyndromic intellectual disability. In this present study, children with nonsyndromic intellectual disability did not exhibit a higher celiac disease prevalence rate compared with healthy controls. Therefore, we suggest that screening test for celiac disease should not be necessary as a part of the management of mild and moderate nonsyndromic intellectual disability. However, cases of severe nonsyndromic intellectual disability could be examined for celiac disease. © The Author(s) 2015.

  11. Radiological quiz. Sudden sensorineural hearing loss due to multiple sclerosis.

    Science.gov (United States)

    Cabbarzade, Cavid; Özgen, Burçe; Sennaroglu, Levent

    2014-01-01

    A case with sudden sensorineural hearing loss (SSNHL) owing to multiple sclerosis (MS) who had clinical and dramatic radiological improvement just after medical therapy was reported in this article. Case report and review of related literature. A 22-year-old female patient with MS related SSNHL was presented in this article. Magnetic resonance imaging (MRI) revealed an MS plaque localized at pons extending from right cochlear nucleus to proximal part of the right cochlear nerve. Most dramatic recovery was present in the 5th day control MRI, where the plaque located on pons disappeared completely. On the 10th day control audiogram hearing recovery was observed and pure tone audiogram levels were almost normal. Sudden sensorineural hearing loss owing to MS is seen more common than expected. It has good prognosis. Magnetic resonance imaging is also thought to have an important role in diagnosis and treatment efficacy of SSNHL owing to MS. Published by Elsevier Urban & Partner Sp. z.o.o.

  12. Non-syndrome multiple supernumerary teeth: A case report.

    Science.gov (United States)

    Gündüz, Kaan; Muğlali, Mehtap

    2007-05-01

    The purpose of this case report is to present a case of a non-syndrome male patient with multiple supplemental supernumerary teeth in three quadrants of his mouth. Supernumerary teeth are described as the teeth formed in excess of the number found in a normal dentition. Prevalence of supernumerary teeth varies between 0.1% and 3.8% in the general Caucasian population. Multiple supernumerary teeth are not a common occurrence, although a single or a few supernumerary tooth/teeth in each case have been widely reported in the literature. An 11-year-old male presented for a routine preventive dental visit. A routine panoramic radiograph showed the presence of multiple supernumerary teeth which were located in the maxillary right canine incisor region, the maxillary left premolar region, and the mandibular right premolar region. The family's medical history was non-contributory, and an extraoral examination did not reveal any abnormality. It is rare to find multiple supernumerary teeth in individuals with no other associated diseases or syndromes. This case report presents a case of a non-syndrome male patient with multiple supplemental supernumerary teeth in three quadrants of his mouth.

  13. Ocular Disorders in Turkish Children with Sensorineural Hearıng Loss: A Cross-Sectional Study and Literature Review.

    Science.gov (United States)

    Ozer, Pinar Altiaylik; Kabatas, Emrah Utku; Ertugrul, Gokce Tasdemir; Kurtul, Bengi Ece; Kaygusuz, Umut; Ozgursoy, Selmin Karatayli

    2016-09-14

    To investigate types and frequencies of ocular disorders in children with sensorineural hearing loss (SNHL), and to emphasize the importance of ophthalmological examination in these children. A retrospective analysis of the examination records of children examined in our instutititon between January 2011 and September 2014 was performed. Ocular disorders of children with SHNL were selectively reviewed. Among 55340 patients, SNHL was present in 110 (0.2%). SNHL was bilateral in 104 patients (94.5%) and unilateral in 6 (5.5%). Ninety-one cases had congenital hearing loss (83%), and 19 (17%) had acquired SNHL. Forty cases (36%) had an ocular disorder, either refractive or non-refractive or both. Seventy cases (64%) had normal ocular examination. No difference was found between congenital or acquired SNHL cases in terms of possessing an ocular disorder (p=0.0962). The most common ocular abnormality was refractive error, mainly hypermetropia (21%). There was no significant difference between the prevalences of ocular abnormalities among cases with different lateralites or severities of SNHL (p=0.051, p=0.874, respectively). Twenty-six cases (23.6%) had SNHL as a component of a genetically defined syndrome. All of them had coexisting refractive or non-refractive ocular abnormalities. Some genetic, non-syndromic abnormalities, including Achondroplasia, Celiac disease, and focal segmental glomerulosclerosis, were diagnosed in four cases, among whom refractive errors and/or strabismus were detected. Due to the common coexistence of ocular problems and SNHL in children, ophthalmological screening is crucial. Families and healthcare providers should be informed about the critical role of ophthalmic assesment in these children for their future quality of life.

  14. P300 in individuals with sensorineural hearing loss

    Directory of Open Access Journals (Sweden)

    Ana Cláudia Mirandola Barbosa Reis

    2015-04-01

    Full Text Available INTRODUCTION: Behavioral and electrophysiological auditory evaluations contribute to the understanding of the auditory system and of the process of intervention.OBJECTIVE: To study P300 in subjects with severe or profound sensorineural hearing loss.METHODS: This was a descriptive cross-sectional prospective study. It included 29 individuals of both genders with severe or profound sensorineural hearing loss without other type of disorders, aged 11 to 42 years; all were assessed by behavioral audiological evaluation and auditory evoked potentials.RESULTS: A recording of the P3 wave was obtained in 17 individuals, with a mean latency of 326.97 ms and mean amplitude of 3.76 V. There were significant differences in latency in relation to age and in amplitude according to degree of hearing loss. There was a statistically significant association of the P300 results with the degrees of hearing loss (p = 0.04, with the predominant auditory communication channels (p < 0.0001, and with time of hearing loss.CONCLUSIONS: P300 can be recorded in individuals with severe and profound congenital sensorineural hearing loss; it may contribute to the understanding of cortical development and is a good predictor of the early intervention outcome.

  15. Pediatric unilateral sensorineural hearing loss: implications and management.

    Science.gov (United States)

    Dornhoffer, James R; Dornhoffer, John L

    2016-12-01

    The purpose of this review is to summarize current studies detailing the impact of unilateral sensorineural hearing loss in children and the most current modalities of treatment used in its management. Current studies corroborate historic views on the impact of unilateral sensorineural hearing loss on patient wellbeing and academic success and stress the use of additional surveillance and studies to diagnose those patients that may pass standard screening practices and suffer from lack of prompt and proper care. With respect to management, notable findings include the continuous development of improved conventional and contralateral routing of signal amplification devices that may act to provide alternatives to percutaneous bone-anchored hearing aid implantation. These include improvements in more conventional hearing aid technology, so as to bridge the performance gap with the classical bone-anchored hearing aid implant, and the development of partially implanted transcutaneous bone conduction hearing devices. Due to dissatisfaction with sound localization, a new and significant development is the burgeoning accumulation of research on cochlear implantation for the treatment of unilateral sensorineural hearing loss in children. With advances in technology in historic modalities of treatment, and the advent of new modalities such as cochlear implantation, the clinician has a wide armamentarium by which to provide treatment to patients based on clinical circumstances and patient desires.

  16. Pediatric Idiopathic Intracranial Hypertension Presenting With Sensorineural Hearing Loss.

    Science.gov (United States)

    Reitsma, Sietze; Stokroos, Robert; Weber, Jacobiene W; van Tongeren, Joost

    2015-12-01

    To present the rare case of a young boy with idiopathic intracranial hypertension presenting with bilateral sensorineural hearing loss developing over several months. This was accompanied by headaches, otalgia, tinnitus, and vertigo. Furthermore, we aim to provide a concise review on this matter, as this report represents the second case in literature of pediatric idiopathic intracranial hypertension presenting with hearing loss. Workup of a 9-year-old boy with bilateral sensorineural hearing loss, including (among others) physical examination, audiometry, diagnostic imaging, and lumbar puncture. Physical examination including fundoscopy as well as imaging showed no abnormalities. At presentation, pure tone audiometry revealed bone conduction thresholds of about 30 dB HL in both ears. Two months later, this declined to about 35 dB HL in both ears. Lumbar puncture revealed an increased intracranial pressure. The boy was thus diagnosed with idiopathic intracranial hypertension. After the lumbar puncture, the otological complaints gradually resolved, and the hearing normalized (bone conduction thresholds of 0-5 dB HL). Although rare, sensorineural hearing loss in the pediatric population together with otalgia, tinnitus, and vertigo can be due to idiopathic intracranial hypertension and as such can be reversible. © The Author(s) 2015.

  17. Sudden sensorineural hearing loss as the first manifestation of chronic myeloid leukaemia: case report.

    Science.gov (United States)

    Diao, M; Tian, F; Sun, J

    2014-11-01

    Sudden sensorineural hearing loss rarely occurs in patients with chronic myeloid leukaemia. We present a case report of a patient who presented with sudden sensorineural hearing loss as the first manifestation of chronic myeloid leukaemia, and review the mechanisms responsible for sudden sensorineural hearing loss in leukaemic patients. A 31-year-old female presented to our clinic with unilateral sudden sensorineural hearing loss and tinnitus. Pure tone audiometry revealed profound sensorineural hearing loss in the left ear at all frequencies. During an investigation into her hearing loss, the patient was found to have chronic myeloid leukaemia. Every case of sudden sensorineural hearing loss must be carefully evaluated, and haematological disorders must be considered in the differential diagnosis of sudden hearing loss.

  18. Bilateral sudden sensorineural hearing loss as a first symptom of infective endocarditis: two case reports.

    Science.gov (United States)

    Chroni, M; Prappa, E; Kokkevi, I

    2018-02-21

    Septic emboli are an unusual cause of sudden sensorineural hearing loss, for which few reports exist in the literature. This paper presents two cases of sudden sensorineural hearing loss, initially considered as idiopathic, but which were caused by septic emboli. Hearing loss in these cases was bilateral, sequential and total. The first patient had mild fever one week prior to their presentation with sudden sensorineural hearing loss; the other patient had no additional symptoms at presentation. These patients were later diagnosed with infective endocarditis, at two and seven months following the sudden sensorineural hearing loss respectively, showing that septic emboli had been the cause of sudden sensorineural hearing loss. Septic emboli should be considered as a possible cause of sudden sensorineural hearing loss in cases of total hearing loss. This form of hearing loss should prompt the otolaryngologist to further investigate for infective endocarditis.

  19. A systematic search for linkage with nonsyndromic recessive deafness in two large Middle Eastern inbred kindreds excludes more than 30% of the genome

    Energy Technology Data Exchange (ETDEWEB)

    Weiss, S.; Korostishevsky, M. [Sackler Faculty of Medicine, Ramat-Aviv (Israel); Frydman, M. [Haim Sheba Medical Center, Tel-Hashomer (Israel)] [and others

    1994-09-01

    It has been estimated that as many as 35 loci may individually cause autosomal recessive non-syndromic deafness. The extreme genetic heterogeneity, limited clinical differentiation and phenotypic assortative mating in many western countries make many families unsuitable for genetic linkage studies. Recently the first of those loci was mapped (to 13q) in two consanguineous families from northern Tunisia. We are studying two large highly consanguineous Middle Eastern kindreds (a total of 26 deaf in 98 sampled individuals). Examination in each family showed no evidence of clinical heterogeneity and indicated an uncomplicated profound bilateral sensorineural deafness. We have been able to exclude the 13q locus as the cause of deafness in each kindred and have also excluded such `candidate` loci as regions as those causing Usher`s syndrome type 1 (11q13)(11p), Usher`s syndrome type II (1q32-q41), Waardenburg syndrome type I (2q37), branchio-oto-renal syndrome (8q12-q13), Monge`s deafness (5q31), and Treacher Collins syndrome (5q31.3-q33.3). To date, no lod scores greater than 1 have been obtained in either kindred using 150 RFLT`s, VNTR`s and highly polymorphic microsatellite markers (CA repeats and tetranucleotides). By Morton`s criterion a minimum of 30% of the autosomal genome can be excluded for each kindred separately.

  20. Mutations in CIB2, a calcium and integrin binding protein, cause Usher syndrome type 1J and nonsyndromic deafness DFNB48

    Science.gov (United States)

    Riazuddin, Saima; Belyantseva, Inna A.; Giese, Arnaud; Lee, Kwanghyuk; Indzhykulian, Artur A.; Nandamuri, Sri Pratima; Yousaf, Rizwan; Sinha, Ghanshyam P.; Lee, Sue; Terrell, David; Hegde, Rashmi S.; Ali, Rana A.; Anwar, Saima; Andrade-Elizondo, Paula B.; Sirmaci, Asli; Parise, Leslie V.; Basit, Sulman; Wali, Abdul; Ayub, Muhammad; Ansar, Muhammad; Ahmad, Wasim; Khan, Shaheen N.; Akram, Javed; Tekin, Mustafa; Riazuddin, Sheikh; Cook, Tiffany; Buschbeck, Elke K.; Frolenkov, Gregory I.; Leal, Suzanne M.; Friedman, Thomas B.; Ahmed, Zubair M.

    2012-01-01

    Sensorineural hearing loss is genetically heterogeneous. Here we report that mutations in CIB2, encoding a Ca2+- and integrin-binding protein, are associated with nonsyndromic deafness (DFNB48) and Usher syndrome type 1J (USH1J). There is one mutation of CIB2 that is a prevalent cause of DFNB48 deafness in Pakistan; other CIB2 mutations contribute to deafness elsewhere in the world. In rodents, CIB2 is localized in the mechanosensory stereocilia of inner ear hair cells and in retinal photoreceptor and pigmented epithelium cells. Consistent with molecular modeling predictions of Ca2+ binding, CIB2 significantly decreased the ATP-induced Ca2+ responses in heterologous cells, while DFNB48 mutations altered CIB2 effects on Ca2+ responses. Furthermore, in zebrafish and Drosophila, CIB2 is essential for the function and proper development of hair cells and retinal photoreceptor cells. We show that CIB2 is a new member of the vertebrate Usher interactome. PMID:23023331

  1. Clinical Application of Screening for GJB2 Mutations before Cochlear Implantation in a Heterogeneous Population with High Rate of Autosomal Recessive Nonsyndromic Hearing Loss

    Directory of Open Access Journals (Sweden)

    Masoud Motasaddi Zarandy

    2011-01-01

    Full Text Available Clinical application of mutation screening and its effect on the outcome of cochlear implantation is widely debated. We investigated the effect of mutations in GJB2 gene on the outcome of cochlear implantation in a population with a high rate of consanguineous marriage and autosomal recessive nonsyndromic hearing loss. Two hundred and one children with profound prelingual sensorineural hearing loss were included. Forty-six patients had 35delG in GJB2. Speech awareness thresholds (SATs and speech recognition thresholds (SRTs improved following implantation, but there was no difference in performance between patients with GJB2-related deafness versus control (all >0.10. Both groups had produced their first comprehensible words within the same period of time following implantation (2.27 months in GJB2-related deaf versus 2.62 months in controls, =0.22. Although our findings demonstrate the need to uncover unidentified genetic causes of hereditary deafness, they do not support the current policy for genetic screening before cochlear implantation, nor prove a prognostic value.

  2. Thiol/disulphide homeostasis as a novel indicator of oxidative stress in sudden sensorineural hearing loss.

    Science.gov (United States)

    Dinc, M E; Ulusoy, S; Is, A; Ayan, N N; Avincsal, M O; Bicer, C; Erel, O

    2016-05-01

    To investigate a novel oxidative stress marker, thiol/disulphide literature homeostasis, in patients with idiopathic sudden sensorineural hearing loss, and to compare the results with healthy controls for the first time. Thirty-two patients with idiopathic sudden sensorineural hearing loss and 30 healthy individuals were included in the study. Serum native thiol, total thiol and disulphide levels were measured, and disulphide/native thiol and disulphide/total thiol ratios were determined in all subjects. Serum native thiol and total thiol levels were significantly lower in patients with sudden sensorineural hearing loss compared with controls (p sudden sensorineural hearing loss in those patients.

  3. X-linked familial exudative vitreoretinopathy caused by an arginine to leucine substitution in exon 3 of the Norrie gene

    Energy Technology Data Exchange (ETDEWEB)

    Johnson, K.; Perry, Y.M.; Ferrell, R.E. [Univ. of Pittsburg, PA (United States)] [and others

    1994-09-01

    Familial exudative vitreoretinopathy (FEVR) is a disorder characterized by abnormal vascularization of the peripheral retina affecting both the retina and the vitreous body. This is a bilateral disorder and leads to a clinical phenotype resembling retinopathy of prematurity, but affected individuals experience a normal gestational period, and they do not have a history of oxygen therapy. Manifestations of the disorder may include retinal folds, retinal traction, sub- or intraretinal exudates, and in severe cases enophthalmos or phthisis ultimately leading to blindness. Autosomal dominant and X-linked patterns of segregation have been reported. We studied a large three-generation family in which FEVR segregated as an X-linked recessive trait. The Norrie gene was examined because of a prior report of mutation in this gene in a small X-linked FEVR family. Exons 1-3 of the Norrie gene were amplified and screened for mutations by single stranded conformational analysis. A variant conformer of exon 3 was observed in an affected male and in combination with the normal conformer in an obligate carrier female. Sequence analysis revealed a G{r_arrow}T transversion destroying an MspI restriction site. The mutation was present in all affected males, and all obligate carrier females were heterozygous for the mutation. The mutation was not present in unaffected males or in 108 randomly selected normal females. The G{r_arrow}T mutation leads to the substitution of a hydrophobic leucine residue for the positively charged arginine normally present at position 121 of the Norrie gene product. This study confirms that mutation in the Norrie gene can lead to the FEVR phenotype and the existence of allelic heterogeneity.

  4. Testing the face shape hypothesis in twins discordant for nonsyndromic orofacial clefting

    DEFF Research Database (Denmark)

    Roosenboom, Jasmien; Indencleef, Karlijne; Hens, Greet

    2017-01-01

    Nonsyndromic orofacial clefts (OFCs) are complex traits characterized by multifactorial inheritance and wide phenotypic variability. Numerous studies have shown subtle differences in the faces of unaffected relatives from cleft families compared to controls, the implication being that such outward...

  5. The Nance-Horan syndrome: a rare X-linked ocular-dental trait with expression in heterozygous females.

    Science.gov (United States)

    Bixler, D; Higgins, M; Hartsfield, J

    1984-07-01

    This report describes two families with the Nance-Horan syndrome, an X-linked trait featuring lenticular cataracts and anomalies of tooth shape and number. Previous reports have described blindness in affected males but posterior sutural cataracts with normal vision as the primary ocular expression in heterozygous females. In one of these two families, the affected female is not only blind in one eye but reportedly had supernumerary central incisors (mesiodens) removed. This constitutes the most severe ocular and dental expression of this gene in heterozygous females yet reported.

  6. [Identification of a novel GPR143 mutation in a Chinese family affected with X-linked ocular albinism].

    Science.gov (United States)

    Zhao, Qi; Guan, Menglong; Wang, Ling; Liao, Yong; Li-Ling, Jesse; Wan, Huajing

    2017-04-10

    To detect mutation of GPR143 gene in a Chinese patient affected with ocular albinism. Peripheral blood samples were collected from the proband and his parents. The coding regions of the GPR143 gene were subjected to PCR amplification and Sanger sequencing. A previously unreported mutation (c.758T>A) was found in exon 6 of the GPR143 gene in the proband and his mother. The same mutation was not found in his father. As predicted, the mutation has resulted in a stop codon, causing premature termination of protein translation. A novel mutation of the GPR143 gene related to X-linked ocular albinism has been identified.

  7. Risk of sudden sensorineural hearing loss in patients with common preexisting sensorineural hearing impairment: a population-based study in Taiwan.

    Directory of Open Access Journals (Sweden)

    Malcolm Koo

    Full Text Available The role of preexisting sensorineural hearing impairment on the risk for sudden sensorineural hearing loss (SSHL is still unclear. In this study, we aimed to assess the risk of SSHL in patients with common preexisting sensorineural hearing impairment using population-based data.A population-based case-control study design was used to analyze claims data between January 2001 and December 2011 obtained from the Taiwan National Health Insurance Research Database. The cases consisted of 514 patients with SSHL and the controls were frequency matched to 2,570 cases by sex, 10-year age group, and year of index date. Common sensorineural hearing impairments were retrospectively assessed in the cases and controls. Associations between sensorineural hearing impairment and risk of SSHL were evaluated using unconditional univariate and multivariate logistic regression analyses.The mean age for the 3,084 study subjects was 53.1 years (standard deviation, S.D. = 15.6. Of the 514 cases, 49 (9.5% had sensorineural hearing impairment while only 44 (1.7% of the 2,570 controls had the same condition. Univariate logistic regression analyses indicated that preexisting sensorineural hearing impairment was significantly associated with SSHL (odds ratio, OR = 6.05, p < 0.001. Other comorbidities including hypertension, diabetes mellitus, and hyperlipidemia also showed significant associations with SSHL. Similar results were obtained when the association between SSHL and sensorineural hearing impairment was adjusted with either all the covariates (adjusted OR = 6.22, p < 0.001 or with only those selected using a backward elimination procedure (adjusted OR = 6.20, p < 0.001.Results from this population-based case-control study revealed that common sensorineural hearing impairment might be a novel risk factor for SSHL.

  8. Genetic Basis of Nonsyndromic and Syndromic Tooth Agenesis

    Science.gov (United States)

    Ye, Xiaoqian; Attaie, Ali B.

    2016-01-01

    Human dentition development is a long and complex process which involves a series of reciprocal and sequential interactions between the embryonic stomodeal epithelium and the underlying neural crest–derived mesenchyme. Despite environment disturbances, tooth development is predominantly genetically controlled. To date, more than 200 genes have been identified in tooth development. These genes implied in various signaling pathways such as the bone morphogenetic protein, fibroblast growth factor, sonic hedgehog homolog, ectodysplasin A, wingless-type MMTV integration site family (Wnt), and transform growth factor pathways. Mutations in any of these strictly balanced signaling cascades may cause arrested odontogenesis and/or other dental defects. This article aims to review current knowledge about the genetic mechanisms responsible for selective nonsyndromic tooth agenesis in humans and to present a detailed summary of syndromes with hypodontia as regular features and their causative genes. PMID:27895972

  9. Nonsyndromic cleft lip and palate, gastric cancer and tooth agenesis.

    Science.gov (United States)

    Cardoso, E-F; Martelli, D-R-B; Machado, R-A; Coletta, R-D; de Souza, J-D; Barbosa, F-T; de Figueiredo, M-F-L; Coelho, L-G-V; Martelli-Júnior, H

    2018-01-01

    To determine the frequency of nonsyndromic cleft lip and/or palate (NSCL/P) in first-degree relatives and to analyze the prevalence of tooth agenesis in patients with gastric cancer. This cross-sectional, observational, case-control study included 798 patients attended at hospital Santa Casa in Montes Claros, Minas Gerais and Alfa Institute of Gastroenterology of the Federal University of the Minas Gerais. Information on basic demographic data and tooth agenesis of both groups and their family history of NSCL/P in first-degree relatives were evaluated. The collected information was stored in a database and analyzed using statistical program SPSS version 21.0 and the values with pcancer and in the frequency of NSCL/P in the first-degree relatives of patients with gastric cancer.

  10. Childhood cerebral X-linked adrenoleukodystrophy more than 5 years after hematopoietic cell transplantation: the first case from Serbia and southeastern Europe.

    Science.gov (United States)

    Potic, Ana; Rovelli, Attilio M; Uziel, Graziella; Kozic, Dusko; Mladenovic, Jelena; Milic-Rasic, Vedrana

    2010-12-01

    We report the clinical course, brain magnetic resonance imaging (MRI), and proton magnetic resonance spectroscopy findings in a boy with childhood cerebral X-linked adrenoleukodystrophy whose neurological disease keeps progressing more than 5 years after conventional hematopoietic cell transplantation with full donor-derived engraftment accomplishment. The described clinical and radiological findings follow all phases of this childhood cerebral X-linked adrenoleukodystrophy: from the clinically asymptomatic pretransplant stage to the present day. This is the first patient not only from Serbia but from the entire area of Southeastern Europe who underwent hematopoietic cell transplantation for childhood cerebral X-linked adrenoleukodystrophy. The presented disease course and the posttransplant outcome in the only case of transplanted adrenoleukodystrophy from Serbia enhances the overwhelming appeal for better X-linked adrenoleukodystrophy screening, earlier disease detection, and contributes to the well-known anticipation of the refined hematopoietic cell transplantation eligibility criteria in future adrenoleukodystrophy treatment.

  11. Missense mutation in exon 7 of the common gamma chain gene causes a moderate form of X-linked combined immunodeficiency.

    OpenAIRE

    Schmalstieg, F C; Leonard, W J; Noguchi, M; Berg, M; Rudloff, H E; Denney, R M; Dave, S K; Brooks, E G; Goldman, A S

    1995-01-01

    Clinical and immunologic features of a recently recognized X-linked combined immunodeficiency disease (XCID) suggested that XCID and X-linked severe combined immunodeficiency (XSCID) might arise from different genetic defects. The recent discovery of mutations in the common gamma chain (gamma c) gene, a constituent of several cytokine receptors, in XSCID provided an opportunity to test directly whether a previously unrecognized mutation in this same gene was responsible for XCID. The status o...

  12. Screening of 20 patients with X-linked mental retardation using chromosome X-specific array-MAPH.

    Science.gov (United States)

    Kousoulidou, Ludmila; Parkel, Sven; Zilina, Olga; Palta, Priit; Puusepp, Helen; Remm, Maido; Turner, Gillian; Boyle, Jackie; van Bokhoven, Hans; de Brouwer, Arjan; Van Esch, Hilde; Froyen, Guy; Ropers, Hans-Hilger; Chelly, Jamel; Moraine, Claude; Gecz, Jozef; Kurg, Ants; Patsalis, Philippos C

    2007-01-01

    The rapid advancement of high-resolution DNA copy number assessment methods revealed the significant contribution of submicroscopic genetic imbalances to abnormal phenotypes, including mental retardation. In order to detect submicroscopic genetic imbalances, we have screened 20 families with X-linked mental retardation (XLMR) using a chromosome X-specific array-MAPH platform with median resolution of 238kb. Among the 20 families, 18 were experimental, as they were not previously screened with any microarray method, and two were blind controls with known aberrations, as they were previously screened by array-CGH. This study presents the first clinical application of chromosome X-specific array-MAPH methodology. The screening of 20 affected males from 20 unrelated XLMR families resulted in the detection of an unknown deletion, spanning a region of 7-23kb. Family studies and population screening demonstrated that the detected deletion is an unknown rare copy number variant. One of the control samples, carrying approximately 6-Mb duplication was correctly identified, moreover it was found to be interrupted by a previously unknown 19kb region of normal copy number. The second control 50kb deletion was not identified, as this particular region was not covered by array-MAPH probes. This study demonstrates that the chromosome X-specific array-MAPH platform is a valuable tool for screening patients with XLMR, or other X-linked disorders, and emerges the need for introducing new high-resolution screening methods for the detection of genetic imbalances.

  13. X-Linked Agammagobulinemia in a Large Series of North African Patients: Frequency, Clinical Features and Novel BTK Mutations.

    Science.gov (United States)

    Aadam, Zahra; Kechout, Nadia; Barakat, Abdelhamid; Chan, Koon-Wing; Ben-Ali, Meriem; Ben-Mustapha, Imen; Zidi, Fethi; Ailal, Fatima; Attal, Nabila; Doudou, Fatouma; Abbadi, Mohamed-Cherif; Kaddache, Chawki; Smati, Leila; Touri, Nabila; Chemli, Jalel; Gargah, Tahar; Brini, Ines; Bakhchane, Amina; Charoute, Hicham; Jeddane, Leila; El Atiqi, Sara; El Hafidi, Naïma; Hida, Mustapha; Saile, Rachid; Alj, Hanane Salih; Boukari, Rachida; Bejaoui, Mohamed; Najib, Jilali; Barbouche, Mohamed-Ridha; Lau, Yu-Lung; Mellouli, Fethi; Bousfiha, Ahmed Aziz

    2016-04-01

    X-linked agammagobulinemia (XLA) is a primary immunodeficiency caused by Bruton's tyrosine kinase (BTK) gene defect. XLA patients have absent or reduced number of peripheral B cells and a profound deficiency in all immunoglobulin isotypes. This multicenter study reports the clinical, immunological and molecular features of Bruton's disease in 40 North African male patients. Fifty male out of 63 (male and female) patients diagnosed with serum agammaglobulinemia and non detectable to less than 2% peripheral B cells were enrolled. The search for BTK gene mutations was performed for all of them by genomic DNA amplification and Sanger sequencing. We identified 33 different mutations in the BTK gene in 40 patients including 12 missense mutations, 6 nonsense mutations, 6 splice-site mutations, 5 frameshift, 2 large deletions, one complex mutation and one in-frame deletion. Seventeen of these mutations are novel. This large series shows a lower frequency of XLA among male patients from North Africa with agammaglobulinemia and absent to low B cells compared with other international studies (63.5% vs. 85%). No strong evidence for genotype-phenotype correlation was observed. This study adds to other reports from highly consanguineous North African populations, showing lower frequency of X-linked forms as compared to AR forms of the same primary immunodeficiency. Furthermore, a large number of novel BTK mutations were identified and could further help identify carriers for genetic counseling.

  14. Cog-Wheel Octameric Structure of RS1, the Discoidin Domain Containing Retinal Protein Associated with X-Linked Retinoschisis.

    Directory of Open Access Journals (Sweden)

    Martin Bush

    Full Text Available RS1, also known as retinoschisin, is a disulphide-linked, discoidin domain containing homo-oligomeric protein that plays a crucial role in maintaining the cellular and synaptic organization of the retina. This is highlighted by the finding that over 130 mutations in RS1 cause X-linked retinoschisis, a retinal degenerative disease characterized by the splitting of the retinal cell layers, disruption of the photoreceptor-bipolar synapses, degeneration of photoreceptors, and severe loss in central vision. In this study, we investigated the arrangement of the RS1 subunits within the oligomer complex using single particle electron microscopy. RS1 was seen as two stacked rings with each ring displaying a symmetrical cog wheel-like structure with eight teeth or projections corresponding to the RS1 subunits. Three dimensional reconstruction and molecular modelling indicated that the discoidin domain, the principal functional unit of RS1, projects outward, and the Rs1 domain and C-terminal segment containing intermolecular disulphide bonds are present in the inner ring to form the core octameric structure. These studies provide a basis for further understanding the role of the novel core RS1 octameric complex in retinal cell biology and X-linked retinoschisis.

  15. A Genome-wide Association Study of Nonsyndromic Cleft Palate Identifies an Etiologic Missense Variant in GRHL3

    DEFF Research Database (Denmark)

    Leslie, Elizabeth J; Liu, Huan; Carlson, Jenna C

    2016-01-01

    Cleft palate (CP) is a common birth defect occurring in 1 in 2,500 live births. Approximately half of infants with CP have a syndromic form, exhibiting other physical and cognitive disabilities. The other half have nonsyndromic CP, and to date, few genes associated with risk for nonsyndromic CP......-type GRHL3, and in zebrafish embryos, perturbed periderm development. We conclude that this mutation is an etiologic variant for nonsyndromic CP and is one of few functional variants identified to date for nonsyndromic orofacial clefting. This finding advances our understanding of the genetic basis...

  16. [Prognostic factors of sudden sensorineural hearing loss in children].

    Science.gov (United States)

    Li, Fengjiao; Xue, Xijun; Wang, Li; Yang, Fengbo; Wang, Hongyang; Guan, Jing; Du, Wan; Xiong, Wenping; Wu, Kaiwen; Wu, Mukun; Yin, Zifang; Lan, Lan; Wang, Dayong; Wang, Qiuju

    2015-11-01

    The aim of this retrospective study was to analyze the recovery rate of sudden sensorineural hearing loss in children, and explore the prognostic factors in order to guide the clinical diagnosis and treatment. A retrospective review was conducted for the prognosis of children with sudden sensorineural hearing loss during the past 5 years (from November 2010 to May 2015) in Chinese PLA General Hospital. This paper have a complete clinical data of 101 patients (113 ears)with sudden hearing loss, ranging from 0 to 18 years old Patients were divided into four groups according to hearing recovery and eight putative prognostic factors were analyzed. Among 101 patients (113 ears), the ratio of male and female was 60:53. Treatment was initiated from 1 to 183 days after disease onset, with an average of (18.5 ± 22.1) d. Bilateral and unilateral hearing loss were 24 ears and 89 ears, respectively. The proportion of mild hearing loss, moderate hearing loss, severe hearing loss and profound hearing loss were 7.1%, 6.2%, 23.9% and 62.8%, respectively. Vertigo and tinnitus occurred in 54.9% and 77.9% of the patients, respectively. After the treatment, the complete recovery rate was 9.7% and the overall recovery rate was 36.3%. The degree of hearing loss, earlier treatment onset, sex and bilateral involvement were significantly associated with hearing recovery (P Sudden sensorineural hearing loss in children was generally identified as severe and profound hearing loss, but after positive and timely treatment, it can be improved or even cured. The mild hearing loss, earlier treatment onset, unilateral hearing loss and female were positive prognostic factors. The concurrence of tinnitus or vertigo, the results of ABR and DPOAE had no significant influence on prognosis.

  17. [Subclinical sensorineural hearing loss in female patients with rheumatoid arthritis].

    Science.gov (United States)

    Treviño-González, José Luis; Villegas-González, Mario Jesús; Muñoz-Maldonado, Gerardo Enrique; Montero-Cantu, Carlos Alberto; Nava-Zavala, Arnulfo Hernán; Garza-Elizondo, Mario Alberto

    2015-01-01

    The rheumatoid arthritis is a clinical entity capable to cause hearing impairment that can be diagnosed promptly with high frequencies audiometry. To detect subclinical sensorineural hearing loss in patients with rheumatoid arthritis. Cross-sectional study on patients with rheumatoid arthritis performing high frequency audiometry 125Hz to 16,000Hz and tympanometry. The results were correlated with markers of disease activity and response to therapy. High frequency audiometry was performed in 117 female patients aged from 19 to 65 years. Sensorineural hearing loss was observed at a sensitivity of pure tones from 125 to 8,000 Hz in 43.59%, a tone threshold of 10,000 to 16,000Hz in 94.02% patients in the right ear and in 95.73% in the left ear. Hearing was normal in 8 (6.84%) patients. Hearing loss was observed in 109 (93.16%), and was asymmetric in 36 (30.77%), symmetric in 73 (62.37%), bilateral in 107 (91.45%), unilateral in 2 (1.71%), and no conduction and/or mixed hearing loss was encountered. Eight (6.83%) patients presented vertigo, 24 (20.51%) tinnitus. Tympanogram type A presented in 88.90% in the right ear and 91.46% in the left ear, with 5.98 to 10.25% type As. Stapedius reflex was present in 75.3 to 85.2%. Speech discrimination in the left ear was significantly different (p = 0.02)in the group older than 50 years. No association was found regarding markers of disease activity, but there was an association with the onset of rheumatoid arthritis disease. Patients with rheumatoid arthritis had a high prevalence of sensorineural hearing loss for high and very high frequencies. Copyright © 2015 Academia Mexicana de Cirugía A.C. Published by Masson Doyma México S.A. All rights reserved.

  18. Sensorineural hearing loss in insulin-dependent diabetic patients

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    Koosha A.

    2007-11-01

    Full Text Available Background: Among patients who have sensorineural hearing loss of unknown etiology, diabetes is one of the diseases to be routinely investigated. The relationship between diabetes mellitus and hearing loss is still controversial. The purpose of this study was to examine the prevalence of sensorineural hearing loss in patients with insulin-dependent diabetes mellitus (IDDM compared to control group.Methods: In a cross-sectional study pure tone audiometry (PTA and speech audiometry was performed in 62 patients with insulin-dependent diabetes mellitus (IDDM, aged under 40 years, and in 62 randomly selected age-matched non-diabetic control subjects. Subjects with otological and other metabolic diseases were excluded from the study. We applied the SPSS.10 statistical analysis software Chi-square and student's test. Results: Statistical analysis showed that the hearing of the diabetic patients were significantly worsen than the control subjects. The hearing level tended to be worsen in the diabetic patients than that in control subjects, but the differences were statistically significant only at frequencies of 250,500, 4000 and 8000 Hz p>0.05(. There wasn't statistical significant difference between sex in two study groups p>0.05(. The mean duration of diabetes was no statistically significant with hearing loss p>0.05(. The frequency of complications such as retinopathy, nephropathy, and neuropathy in the diabetic groups had no correlation with speech threshold (p>0.05(.‏ There were no significant differences between speech reception threshold, speech discrimination score and acoustic reflex in two groups.Conclusions: We conclude that type I diabetes mellitus can cause sensorineural hearing loss.

  19. The relationship between neonatal hyperbilirubinemia and sensorineural hearing loss.

    Science.gov (United States)

    Corujo-Santana, Cándido; Falcón-González, Juan Carlos; Borkoski-Barreiro, Silvia Andrea; Pérez-Plasencia, Daniel; Ramos-Macías, Ángel

    2015-01-01

    Severe jaundice that requires exchange transfusion has become a relatively rare situation today. About 60% of full term neonates and 80% of premature ones will suffer from jaundice within the first week of life. Hyperbilirubinemia at birth is a risk factor associated with hearing loss that is usually further linked to other factors that might have an effect on hearing synergistically. This study aimed to identify the relationship between hyperbilirubinemia at birth as a risk factor for sensorineural hearing loss in children born at Complejo Hospitalario Universitario Insular Materno-Infantil de Gran Canaria, in the 2007-2011 period. This was a retrospective study of 796 newborns that had hyperbilirubinemia at birth, using transient evoked otoacoustic emissions and evoked auditory brainstem response. Hundred eighty-five newborns (23.24%) were referred for evoked auditory brainstem response. Hearing loss was diagnosed for 35 (4.39%): 18 neonates (51.43%) with conductive hearing loss and 17 (48.57%) with sensorineural hearing loss, 3 of which were diagnosed as bilateral profound hearing loss. Half of the children had other risk factors associated, the most frequent being exposure to ototoxic medications. The percentage of children diagnosed with sensorineural hearing loss that suffered hyperbilirubinemia at birth is higher than for the general population. Of those diagnosed, none had levels of indirect bilirubin≥20mg/dl, only 47% had hyperbilirubinemia at birth as a risk factor and 53% had another auditory risk factor associated. Copyright © 2014 Elsevier España, S.L.U. and Sociedad Española de Otorrinolaringología y Patología Cérvico-Facial. All rights reserved.

  20. Cochlear implantation for severe sensorineural hearing loss caused by lightning.

    Science.gov (United States)

    Myung, Nam-Suk; Lee, Il-Woo; Goh, Eui-Kyung; Kong, Soo-Keun

    2012-01-01

    Lightning strike can produce an array of clinical symptoms and injuries. It may damage multiple organs and cause auditory injuries ranging from transient hearing loss and vertigo to complete disruption of the auditory system. Tympanic-membrane rupture is relatively common in patients with lightning injury. The exact pathogenetic mechanisms of auditory lesions in lightning survivors have not been fully elucidated. We report the case of a 45-year-old woman with bilateral profound sensorineural hearing loss caused by a lightning strike, who was successfully rehabilitated after a cochlear implantation. Copyright © 2012 Elsevier Inc. All rights reserved.

  1. [Analyses prognostic factors relevant to sudden sensorineural hearing loss].

    Science.gov (United States)

    Wang, Jun; Xiao, Shuifang; Zeng, Zhengang; Zhen, Zhen; Zhang, Xuexi; Lin, Feng; Dong, Mingmin; Lu, Wei; Qin, Zhaobing; Zuo, Bin; Bai, Xianfeng

    2015-06-01

    To investigate the prognostic factors relevant to sudden sensorineural hearing loss. The internationally accepted standardized clinical research methods, unified design, and unified program were adopted to conduct the prospective clinical multi-center study. The sudden deafness patients between 18 to 65 years old, with the course of this disorder less than two weeks, and without any medical treatments were collected, and then, divided into four types according to the hearing curve: type A, acute sensorineural hearing loss in low tone frequencies; type B, acute sensorineural hearing loss in high tone frequencies; type C, acute sensorineural hearing loss in all frequencies; and type D, total deafness. The factors, in terms of age, gender, type of initial audiogram, time delay before the first visit, and severity of hearing loss, were included in the analyses. A total of 1 024 cases with single side sudden deafness were collected in the study from 33 hospitals in China from August 2007 to October 2011, inclusive of for 492 males (48.05%) and 532 females (51.95%). The average age was (41.2 ± 12.8) years old. There were 553 cases (54.00%) in left ear, and 471 cases (46.00%) in right ear. The curative effects of different types were shown as follows: the type in low tone frequencies had the highest rate of 90.73%, the type in all frequencies was 82.59%; the type of total deafness was 70.29%; and the type in high tone frequencies had the lowest rate of 65.96%. It had significant difference of the effective rate between different types (χ(2) = 231.58, P = 0.000). Age, time delay before first visit, and severity of initial hearing loss were significantly correlated with hearing improvement. Initial audiogram of SSNHL might predict hearing recovery. The young in age and a short time delay before starting treatment are positive prognostic factors for hearing recovery in SSNHL. The initial severity of hearing loss is negative prognostic factor of hearing recovery.

  2. Sudden sensorineural hearing loss after non-otologic surgery.

    Science.gov (United States)

    Page, Joshua Cody; Peters, Bob

    2015-01-01

    Sudden sensorineural hearing loss following non-otologic surgery is a rare event described in the medical literature. Cardiopulmonary bypass surgery is most commonly associated with this type of hearing loss. Our case report and review of the literature describe two cases with postoperative hearing loss - neither of which are cardiac surgeries - making them exceedingly rare in the medical literature. Regardless of the rarity of this unfortunate event, the possibility for permanent hearing loss is a potentially devastating unanticipated complication and one that all surgeons should be aware. Copyright © 2015 Elsevier Inc. All rights reserved.

  3. Identification of evidence for autoimmune pathology of bilateral sudden sensorineural hearing loss using proteomic analysis.

    Science.gov (United States)

    Lee, Jeon Mi; Kim, Jin Young; Bok, Jinwoong; Kim, Kyu-Sung; Choi, Jae Young; Kim, Sung Huhn

    2017-10-01

    Sudden sensorineural hearing loss (S-SNHL) is an inner ear disorder with an abrupt hearing loss occurring sudden sensorineural hearing loss; LC-MS: liquid chromatography-mass spectrometry; MS: mass spectrometry; autoAb: autoantibody; 1-DE: one-dimensional electrophoresis. Copyright © 2017 Elsevier Inc. All rights reserved.

  4. Mapping X-linked ophthalmic diseases. IV. Provisional assignment of the locus for X-linked congenital cataracts and microcornea (the Nance-Horan syndrome) to Xp22.2-p22.3.

    Science.gov (United States)

    Lewis, R A; Nussbaum, R L; Stambolian, D

    1990-01-01

    The Nance-Horan syndrome (NHS) is an infrequent X-linked disorder typified by dense congenital central cataracts, microcornea, anteverted and simplex pinnae, brachymetacarpalia, and numerous dental anomalies. The regional location of the genetic mutation causing NHS is unknown. The authors applied the modern molecular techniques of analysis of restriction fragment length polymorphisms to five multigenerational kindreds in which NHS segregated. Provisional linkage is established to two DNA markers--DXS143 at Xp22.3-p22.2 and DXS43 at Xp22.2. Regional localization of NHS will provide potential antenatal diagnosis in families at risk for the disease and will enhance understanding of the multifaceted genetic defects.

  5. Combined transplantation of neural precursor cells and olfactory ensheathing cells for the treatment of X-linked adrenoleukodystrophy in children

    Directory of Open Access Journals (Sweden)

    Yang H

    2017-04-01

    Full Text Available Hui Yang,1,* Yu Zhang,1,* Zhaoyan Wang,1 Wei Lu,1 Fang Liu,1 Xin Yu,2 Xiaoyan Zheng,1 Yinxiang Yang,1 Zuo Luan,1 Suqing Qu1 1Department of Pediatrics, 2Department of Neurological Surgery, Navy General Hospital, Beijing, People’s Republic of China *These authors contributed equally to this work. Abstract: Hematopoietic stem cell transplantation is only suitable for early-stage adrenoleukodystrophy (ALD. In this study, we observed the therapeutic efficacy of combined transplantation of neural precursor cells (NPCs and olfactory ensheathing cells (OECs on late-stage X-linked ALD in nine children who were admitted in our hospital between June 2009 and January 2014. Related patient information included onset time 3 months to 1 year, magnetic resonance imaging (MRI score 11.02±0.90, and neurologic function score 2–3. All patients received combined transplantation of NPCs and OECs by injection around the lateral angle of the frontotemporal–occipital lesion under MRI guidance. It was found that the visual function, sleep, and communication obstacles were improved significantly without evidence of disease progression in six (66.7% of the nine patients within 1 month after transplantation. In two of the six patients, the lesions became significantly smaller than before, although their MRI scores remained unchanged significantly. In addition, cell therapy did not induce any irreversible adverse event during the study period, indicating that combined transplantation of NPCs and OECs was safe and reliable, and could improve the clinical manifestations of ALD in children within a short time. Although this cell therapy was not able to halt the progression of the disease 1–3 months after transplantation, it could still be used as an early treatment and provide patients with more opportunities for hematopoietic stem cell transplantation, which is the only effective long-term treatment for X-linked ALD at present. The preliminary results from this study

  6. Autosomal dominant inherited non-syndromic sensorineural hearing impairment : phenotype and genotype correlations of DFNA2-DFNA13-DFNA14-DFNA21

    NARCIS (Netherlands)

    Kunst, H.P.M.

    1999-01-01

    Hearing impairment is one of the most prevalent disorders. About 10% of the population aged 55-60 years suffers from significant hearing impairment, this increases to about 50% at the age of 80 years. In this thesis the phenotype of 5 families is described extensively, each family showed about 20-40

  7. Functional Study of Ectodysplasin-A Mutations Causing Non-Syndromic Tooth Agenesis

    Science.gov (United States)

    Liu, Yang; Liu, Haochen; Zhao, Hongshan; Zhang, Guozhong; Snead, Malcolm L.; Han, Dong; Feng, Hailan

    2016-01-01

    Recent studies have demonstrated that ectodysplasin-A (EDA) mutations are associated with non-syndromic tooth agenesis. Indeed, we were the first to report three novel EDA mutations (A259E, R289C and R334H) in sporadic non-syndromic tooth agenesis. We studied the mechanism linking EDA mutations and non-syndromic tooth agenesis in human embryonic kidney 293T cells and mouse ameloblast-derived LS8 cells transfected with mutant isoforms of EDA. The receptor binding capability of the mutant EDA1 protein was impaired in comparison to wild-type EDA1. Although the non-syndromic tooth agenesis-causing EDA1 mutants possessed residual binding capability, the transcriptional activation of the receptor’s downstream target, nuclear factor κB (NF-κB), was compromised. We also analyzed the changes of selected genes in other signaling pathways, such as WNT and BMP, after EDA mutation. We found that non-syndromic tooth agenesis-causing EDA1 mutant proteins upregulate BMP4 (bone morphogenetic protein 4) mRNA expression and downregulate WNT10A and WNT10B (wingless-type MMTV integration site family member 10A and 10B) mRNA expression. Our results indicated that non-syndromic tooth agenesis causing EDA mutations (A259E, R289C and R334H) were loss-of-function, and suggested that EDA may regulate the expression of WNT10A, WNT10B and BMP4 via NF-κB during tooth development. The results from our study may help to understand the molecular mechanism linking specific EDA mutations with non-syndromic tooth agenesis. PMID:27144394

  8. THIAMINE–RESPONSIVE MEGALOBLASTIC ANEMIA, SENSORINEURAL DEAFNESS AND DIABETES MELLITUS

    Directory of Open Access Journals (Sweden)

    M. Kadivar R. Moradian

    2006-11-01

    Full Text Available Abstract- The syndrome of diabetes mellitus, sensorineural deafness and megaloblastic anemia dose not result from thiamine deficiency. The previous reported patients had no sign of beriberi, had normal nutrition, and had no evidence of malabsorption. The features of this syndrome with apparent inheritance of autosomal recessive trait may define this puzzling syndrome as a true thiamine dependency state. The first Iranian patient was described by Vossough et al. in 1995. We found nine new cases with diagnostic criteria of thiamine responsive megaloblastic anemia during eight years of our study. In two patients, presentation of diabetes and anemia was concomitant. All of them were deaf with sensorineural hearing loss which was detected in infancy up to two years of age. The presence of congenital valvular heart disease was eliminated by normal echocardiography, but cardiomyopathy was discovered in two. Nonspecific amino-aciduria was discovered in three but urinary screening tests for hereditary orotic aciduria were negative. Ox-Phos biochemistry of muscle mitochondria which demonstrates severe defect in complexes I, III, IV in diabetes mellitus associated with deafness, were done but was unremarkable in our patients. Urinary methylmalonic acid and methyl malonyl carnitine by GS/MS and TMS was done in our patients and showed abnormal results in six patients. Thiamine gene, SLC 19A2, was detected in four patients.

  9. Sudden onset unilateral sensorineural hearing loss after rabies vaccination.

    Science.gov (United States)

    Okhovat, Saleh; Fox, Richard; Magill, Jennifer; Narula, Antony

    2015-12-15

    A 33-year-old man developed profound sudden onset right-sided hearing loss with tinnitus and vertigo, within 24 h of pretravel rabies vaccination. There was no history of upper respiratory tract infection, systemic illness, ototoxic medication or trauma, and normal otoscopic examination. Pure tone audiograms (PTA) demonstrated right-sided sensorineural hearing loss (thresholds 90-100 dB) and normal left-sided hearing. MRI internal acoustic meatus, viral serology (hepatitis B, C, HIV and cytomegalovirus) and syphilis screen were normal. Positive Epstein-Barr virus IgG, viral capsid IgG and anticochlear antibodies (anti-HSP-70) were noted. Initial treatment involved a course of high-dose oral prednisolone and acyclovir. Repeat PTAs after 12 days of treatment showed a small improvement in hearing thresholds. Salvage intratympanic steroid injections were attempted but failed to improve hearing further. Sudden onset sensorineural hearing loss (SSNHL) is an uncommon but frightening experience for patients. This is the first report of SSNHL following rabies immunisation in an adult. 2015 BMJ Publishing Group Ltd.

  10. Endothelial Dysfunction in Idiopathic Sudden Sensorineural Hearing Loss: A Review

    Science.gov (United States)

    Quaranta, Nicola; De Ceglie, Vincenzo; D’Elia, Alessandra

    2016-01-01

    An endothelial dysfunction has been described in idiopathic sudden sensorineural hearing loss (ISSHL) patients. The purpose of our review was to: i) identify, evaluate and review recent research about cardiovascular risk factors involvement and signs of endothelial dysfunction in ISSHL; ii) implication of these discovering in clinical practice and future research. A Medline literature search was conducted to identify any study on the involvement of endothelial dysfunction in ISSHL, published in the English language in the last decade. The following MEDLINE search terms were used: sudden sensorineural hearing loss (SSHL) and endothelial dysfunction (text words). Additional studies were identified by hand searching the references of original articles and review articles. Studies were not excluded on the basis of the qualitative or quantitative definitions of SSHL, treatment regimens, or outcome measures. Data were extracted from included papers by a reviewer. Information on the patients, investigations, methods, interventions, and outcomes were systematically analyzed. Characteristics and results of all included studies were reviewed systematically. High levels of adhesion molecules, hyperhomocysteinemia and lower folate levels, unbalanced oxidative status, a lower value of flow-mediated dilatation of brachial artery and a reduced percentage of circulating endothelial progenitor cells in patients affected by ISSHL support the hypothesis that this syndrome should be considered as a microcirculation disorder based on endothelial dysfunction and drive clinicians to implement all the traditional strategies used for preventing cardiovascular events, to also reduce the likelihood of ISSHL occurrence. PMID:27588164

  11. Isolated Sensorineural Hearing Loss as a Sequela after Lightning Strike

    Directory of Open Access Journals (Sweden)

    Mahfuz Turan

    2015-01-01

    Full Text Available In most of the surviving patients after a lightning strike, audiovestibular abnormalities have been reported. The most frequently reported type of abnormalities is a tympanic membrane perforation with hearing loss and external ear canal burn. However a sensor neural hearing loss and mixed type hearing loss can also occur, but these occur rarely. A nineteen-year-old female patient had, after a lightning strike, serious burns on the left ear, behind the ear, and on the chest and neck. She also had in her left ear 108 dB hearing loss with irregular central perforation and in her right ear 52 dB sensorineural hearing loss. There was no hearing loss before the strike. A hearing aid was recommended for the right ear and good care and follow-up were recommended for the left ear. A lightning strike can cause serious audiological damage. Therefore, it is necessary to make a careful audiovestibular evaluation of the patients. Although there exist rarely healed cases from sensorineural hearing loss after lightning strike in literature, in our case hearing loss occurred bilaterally and then it healed unilaterally. This condition is quite rare in literature.

  12. Adjunctive hyperbaric oxygen treatment for idiopathic sudden sensorineural hearing loss.

    Science.gov (United States)

    Chin, Chun-Shih; Lee, Tsai-Yun; Wu, Ming-Feng

    2017-01-01

    This study aims to evaluate the hearing gain efficacy from adjunctive hyperbaric oxygen (HBO₂) treatment in patients with idiopathic sudden sensorineural hearing loss (ISSHL). A retrospective analysis of chart reviews was performed on patients with ISSHL between January 2013 through December 2015. All patients were referred to us from our ENT Department for adjunctive hyperbaric oxygen treatment. The results were assessed through pure-tone audiometry (PTA) data change (hearing gain), both before and after HBO₂) treatment. Age, gender, affected ear side, HBO₂) treatment sessions, both before and after HBO₂ treatment PTA were all recorded. Ninety-three (93) patients with ISSHL were included in the study. The average hearing gain in this study was 17.9 dB (p=0.001), where a total of 46 (49.46%) patients showed an improvement (hearing gain≥dB) in response to HBO₂ treatment (p=0.002). Patients with the poorest initial severity of hearing loss who displayed a greater degree of hearing improvement after HBO₂ treatment were male and in the 40- to 59-year-old age group. This study found that adjunctive hyperbaric oxygen treatment was efficacious for patients with idiopathic sudden sensorineural hearing loss. The total average hearing gain was recorded to be 17.9 dB.

  13. Relapsing Remitting Multiple Sclerosis in X-Linked Charcot-Marie-Tooth Disease with Central Nervous System Involvement

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    Georgios Koutsis

    2015-01-01

    Full Text Available We report a patient with relapsing remitting multiple sclerosis (MS and X-linked Charcot-Marie-Tooth disease (CMTX, carrying a GJB1 mutation affecting connexin-32 (c.191G>A, p. Cys64Tyr which was recently reported by our group. This is the third case report of a patient with CMTX developing MS, but it is unique in the fact that other family members carrying the same mutation were found to have asymptomatic central nervous system (CNS involvement (diffuse white matter hyperintensity on brain MRI and extensor plantars. Although this may be a chance association, the increasing number of cases with CMTX and MS, especially with mutations involving the CNS, may imply some causative effect and provide insights into MS pathogenesis.

  14. A novel mutation in the ABCD1 gene of a Korean boy diagnosed with X-linked adrenoleukodystrophy.

    Science.gov (United States)

    Park, Jeong A; Jun, Kyung Ran; Han, Sung-Hee; Kim, Gu-Hwan; Yoo, Han-Wook; Hur, Yun Jung

    2012-04-25

    X-linked adrenoleukodystrophy (ALD; MIM #300100) is a neurodegenerative disorder caused by mutations in the ABCD1 adrenoleukodystrophy protein gene. The ABCD1 gene mutations have been reported by laboratories in China and Japan, but not in Korea. This case report describes a Korean boy diagnosed with X-ALD. Direct sequencing for the ABCD1 gene in this boy and his mother detected Tyr620His missense mutation, caused by cDNA nucleotide change 1858 T>C in exon 8 (c.1858T>C). This missense variant was novel and predicted to be possibly damaging by the PolyPhen and SIFT prediction software. Moreover, this is the first report in Korean. Copyright © 2012 Elsevier B.V. All rights reserved.

  15. X-linked adrenoleukodystrophy (X-ALD: clinical presentation and guidelines for diagnosis, follow-up and management

    Directory of Open Access Journals (Sweden)

    Engelen Marc

    2012-08-01

    Full Text Available Abstract X-linked adrenoleukodystrophy (X-ALD is the most common peroxisomal disorder. The disease is caused by mutations in the ABCD1 gene that encodes the peroxisomal membrane protein ALDP which is involved in the transmembrane transport of very long-chain fatty acids (VLCFA; ≥C22. A defect in ALDP results in elevated levels of VLCFA in plasma and tissues. The clinical spectrum in males with X-ALD ranges from isolated adrenocortical insufficiency and slowly progressive myelopathy to devastating cerebral demyelination. The majority of heterozygous females will develop symptoms by the age of 60 years. In individual patients the disease course remains unpredictable. This review focuses on the diagnosis and management of patients with X-ALD and provides a guideline for clinicians that encounter patients with this highly complex disorder.

  16. Retinal Ganglion Cell Loss in X-linked Adrenoleukodystrophy with anABCD1Mutation (Gly266Arg).

    Science.gov (United States)

    Ohkuma, Yasuhiro; Hayashi, Takaaki; Yoshimine, Syouyou; Tsuneoka, Hiroshi; Terao, Yoko; Akiyama, Masaharu; Ida, Hiroyuki; Ohashi, Toya; Okumura, Akihisa; Ebihara, Nobuyuki; Murakami, Akira; Shimozawa, Nobuyuki

    2014-01-01

    The authors here report a single case of a 10-year-old male patient who presented with severe vision loss associated with progressive demyelination. The patient was diagnosed with X-linked childhood cerebral adrenoleukodystrophy (ALD). Genetic analysis demonstrated a missense mutation (Gly266Arg) in exon 1 of the ABCD1 gene. His corrected visual acuity confirmed the absolute lack of light perception in both eyes. Funduscopy revealed severe pallor of the optic disc in both eyes. Spectral-domain optical coherence tomography showed thinning of the retinal ganglion cell and inner plexiform layers (GCL and IPL). Thinning of the GCL and IPL may be due to transneuronal retrograde degeneration of ganglion cells secondary to optic tract demyelination.

  17. Rituximab for lymphoproliferative disease prior to haematopoietic stem cell transplantation for X-linked severe combined immunodeficiency.

    Science.gov (United States)

    Trahair, Toby N; Wainstein, Brynn; Manton, Nicholas; Bourne, Anthony J; Ziegler, John B; Rice, Michael; Russell, Susan J

    2008-02-01

    Lymphoproliferative disease (LPD) is a complication of congenital and acquired immunodeficiency states. There are a number of treatment options for LPD arising after haematopoietic stem cell or solid organ transplantation including reduction of immunosuppression, targeted therapies, such as the anti-CD20 monoclonal antibody, rituximab, and EBV specific cytotoxic lymphocytes. Treatment of LPD in children with congenital immunodeficiency syndromes remains unsatisfactory and is associated with a high mortality rate. We recently managed an infant found to have polymorphic LPD concurrent with X-linked severe combined immunodeficiency (SCID). Haematopoietic stem cell transplantation (HSCT) had to be deferred because of progressive LPD. Treatment with rituximab resulted in regression of the LPD following which the patient received a 5/6 HLA matched umbilical cord blood (UCB) transplant. The patient remains well 20 months following transplantation. Rituximab treatment may have a useful role in the control of LPD associated with congenital immunodeficiency prior to HSCT. (c) 2007 Wiley-Liss, Inc.

  18. X-linked adrenoleukodystrophy (X-ALD): clinical presentation and guidelines for diagnosis, follow-up and management.

    Science.gov (United States)

    Engelen, Marc; Kemp, Stephan; de Visser, Marianne; van Geel, Björn M; Wanders, Ronald J A; Aubourg, Patrick; Poll-The, Bwee Tien

    2012-08-13

    X-linked adrenoleukodystrophy (X-ALD) is the most common peroxisomal disorder. The disease is caused by mutations in the ABCD1 gene that encodes the peroxisomal membrane protein ALDP which is involved in the transmembrane transport of very long-chain fatty acids (VLCFA; ≥ C22). A defect in ALDP results in elevated levels of VLCFA in plasma and tissues. The clinical spectrum in males with X-ALD ranges from isolated adrenocortical insufficiency and slowly progressive myelopathy to devastating cerebral demyelination. The majority of heterozygous females will develop symptoms by the age of 60 years. In individual patients the disease course remains unpredictable. This review focuses on the diagnosis and management of patients with X-ALD and provides a guideline for clinicians that encounter patients with this highly complex disorder.

  19. Gastric adenocarcinoma in the context of X-linked agammaglobulinemia: case report and review of the literature.

    Science.gov (United States)

    Staines Boone, Aidé Tamara; Torres Martínez, María Guadalupe; López Herrera, Gabriela; de Leija Portilla, Julia O; Espinosa Padilla, Sara Elva; Espinosa Rosales, Francisco J; Lugo Reyes, Saúl Oswaldo

    2014-02-01

    The hallmarks of X-linked Agammaglobulinemia (XLA) are panhypogammaglobulinemia, absent B-cells, and recurrent sinopulmonary and gastrointestinal infections starting at an early age, as well as other infections like cellulitis, meningitis, arthritis and sepsis. A number of non-infectious complications have been reported in these patients, including autoimmune diseases and malignancy, especially lymphomas. Here, we report the case of a 30-year old man who developed gastric adenocarcinoma in the context of XLA. Previous reports of, and hypotheses addressing the development of cancer in patients with XLA, are also summarized. Solid cancer in XLA affects mainly the gastrointestinal tract and seems to be related to chronic infection. A natural evolution can be traced back from gastric adenocarcinoma to megaloblastic anemia due to achlorhydria in the context of chronic infection; periodic endoscopy thus seems justified to detect and treat carcinoma in early stages.

  20. Clinical and molecular analysis of 49 patients with X-linked agammaglobulinemia from a single center in Argentina.

    Science.gov (United States)

    Basile, Natalia; Danielian, Silvia; Oleastro, Matias; Rosenzweig, Sergio; Prieto, Emma; Rossi, Jorge; Roy, Adriana; Zelazko, Marta

    2009-01-01

    Argentina has a large number of patients with definite diagnosis of X-linked agammaglobulinemia reported in the Latin-American registry. Forty-nine of them were seen in our referral pediatric hospital, between 1987 and 2005. A retrospective study of clinical, laboratory, and molecular data showed that respiratory tract infections were the most frequent initial clinical presentation and the most common among all manifestations prior to diagnosis (69%). Up to diagnosis, we found a high frequency of severe infections (sepsis, 14% and meningitis, 16%) and a high proportion of patients with chronic lung disease. During follow-up, the development of chronic lung disease was significantly related with age at diagnosis and inappropriate treatment. Although molecular diagnosis has been available in our center for the past 10 years, there is no doubt that awareness for early recognition of immunodeficiency should be improved through broader and more comprehensive education programs emphasizing characteristics of patients with immunodeficiencies.

  1. A novel BTK gene mutation creates a de-novo splice site in an X-linked agammaglobulinemia patient.

    Science.gov (United States)

    Chear, Chai Teng; Ripen, Adiratna Mat; Mohamed, Sharifah Adlena Syed; Dhaliwal, Jasbir Singh

    2015-04-15

    Bruton's tyrosine kinase (BTK), encoded by the BTK gene, is a cytoplasmic protein critical in B cell development. Mutations in the BTK gene cause X-linked agammaglobulinemia (XLA), a primary immunodeficiency with characteristically low or absent B cells and antibodies. This report describes a five year-old boy who presented with otitis externa, arthritis, reduced immunoglobulins and no B cells. Flow cytometry showed undetectable monocyte BTK expression. Sequencing revealed a novel mutation at exon 13 of the BTK gene which created a de novo splice site with a proximal 5 nucleotide loss resulting in a truncated BTK protein. The patient still suffered from ear infection despite intravenous immunoglobulin replacement therapy. In this study, mosaicism was seen only in the mother's genomic DNA. These results suggest that a combination of flow cytometry and BTK gene analysis is important for XLA diagnosis and carrier screening. Copyright © 2015 Elsevier B.V. All rights reserved.

  2. A novel Bruton's tyrosine kinase gene (BTK) invariant splice site mutation in a Malaysian family with X-linked agammaglobulinemia.

    Science.gov (United States)

    Chear, Chai Teng; Gill, Harvindar Kaur; Ramly, Nazatul Haslina; Dhaliwal, Jasbir Singh; Bujang, Noraini; Ripen, Adiratna Mat; Mohamad, Saharuddin Bin

    2013-12-01

    X-linked agammaglobulinemia (XLA) is a rare genetic disorder caused by mutations in the Bruton's tyrosine kinase (BTK) gene. These mutations cause defects in early B cell development. A patient with no circulating B cells and low serum immunoglobulin isotypes was studied as were his mother and sister. Monocyte BTK protein expression was evaluated by flow cytometry. The mutation was determined using PCR and followed by sequencing. Flow cytometry showed the patient lacked BTK protein expression in his monocytes while the mother and sister had 62% and 40% of the monocytes showing BTK protein expressions respectively. The patient had a novel base substitution in the first nucleotide of intron 9 in the BTK gene, and the mutation was IVS9+1Gagammaglobulinemia and may be used for subsequent genetic counseling, carrier detection and prenatal diagnosis.

  3. Neuropsychological profile of a Filipino gentleman with X-linked dystonia-parkinsonism: a case report of Lubag disease.

    Science.gov (United States)

    Howe, Laura L S; Kellison, Ida L; Fernandez, Hubert H; Okun, Michael S; Bowers, Dawn

    2009-01-01

    X-Linked Dystonia-Parkinsonism (XDP or "Lubag") is a progressive neurodegenerative disorder unique to the Island of Panay in the Philippines. Imaging and autopsy studies have suggested involvement of the caudate and putamen in late stages. Because the clinical presentation of patients with XDP resembles that of patients with Parkinson disease or dystonia, it is reasonable to predict the neuropsychological profile might be similar; however, the neuropsychological profile of a XDP patient has not previously been published. We present the neuropsychological findings of a 67-year-old gentleman with a 10-year history of XDP who presented with parkinsonian and dystonic symptoms. He was evaluated for suitability for deep brain stimulation surgery. Neuropsychological findings demonstrated diffuse impairment involving memory, visuospatial, language, and executive functioning.

  4. Combating oncogene activation associated with retrovirus-mediated gene therapy of X-linked severe combined immunodeficiency

    Directory of Open Access Journals (Sweden)

    B.E. Strauss

    2007-05-01

    Full Text Available A successful gene therapy clinical trial that also encountered serious adverse effects has sparked extensive study and debate about the future directions for retrovirus-mediated interventions. Treatment of X-linked severe combined immunodeficiency with an oncoretrovirus harboring a normal copy of the gc gene was applied in two clinical trials, essentially curing 13 of 16 infants, restoring a normal immune system without the need for additional immune-related therapies. Approximately 3 years after their gene therapy, tragically, 3 of these children, all from the same trial, developed leukemia as a result of this experimental treatment. The current understanding of the mechanism behind this leukemogenesis involves three critical and cooperating factors, i.e., viral integration, oncogene activation, and the function of the therapeutic gene. In this review, we will explore the causes of this unwanted event and some of the possibilities for reducing the risk of its reoccurrence.

  5. Mutations in the gene for the common gamma chain (gammac) in X-linked severe combined immunodeficiency.

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    Fugmann, S D; Müller, S; Friedrich, W; Bartram, C R; Schwarz, K

    1998-12-01

    X-linked severe combined immunodeficiency (XSCID) constitutes a disorder of the immune system caused by mutations in the gene encoding the common gamma chain (gammac), a subunit of the IL-2, IL-4, IL-7, IL-9 and IL-15 receptors, which are necessary for lymphocyte development and function. In this study the IL2RG gene of 31 patients with severe combined immunodeficiency (SCID) was examined by nonradioactive single-strand conformation polymorphism and sequence analysis. Among the 11 patients with XSCID, ten different mutations were identified in the IL2RG gene, including eight novel mutations. Ninety percent of the mothers of the XSCID patients are carriers of the mutated allele. One patient showed low numbers of B-cells, a striking deviation from the classical B-cell-positive and T-cell-negative phenotype.

  6. Correlation between connexin 32 gene mutations and clinical phenotype in X-linked dominant Charcot-Marie-Tooth neuropathy

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    Ionasescu, V.; Ionasescu, R.; Searby, C. [Univ. of Iowa Hospitals and Clinics, Iowa City, IA (United States)

    1996-06-14

    We studied the relationship between the genotype and clinical phenotype in 27 families with dominant X-linked Charcot-Marie-Tooth (CMTX1) neuropathy. Twenty-two families showed mutations in the coding region of the connexin32 (cx32) gene. The mutations include four nonsense mutations, eight missense mutations, two medium size deletions, and one insertion. Most missense mutations showed a mild clinical phenotype (five out of eight), whereas all nonsense mutations, the larger of the two deletions, and the insertion that produced frameshifts showed severe phenotypes. Five CMTX1 families with mild clinical phenotype showed no point mutations of the cx32 gene coding region. Three of these families showed positive genetic linkage with the markers of the Xq13.1 region. The genetic linkage of the remaining two families could not be evaluated because of their small size. 25 refs., 1 fig., 1 tab.

  7. Extracellular matrix mineralization in periodontal tissues: Noncollagenous matrix proteins, enzymes, and relationship to hypophosphatasia and X-linked hypophosphatemia.

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    McKee, Marc D; Hoac, Betty; Addison, William N; Barros, Nilana M T; Millán, José L; Chaussain, Catherine

    2013-10-01

    As broadly demonstrated for the formation of a functional skeleton, proper mineralization of periodontal alveolar bone and teeth - where calcium phosphate crystals are deposited and grow within an extracellular matrix - is essential for dental function. Mineralization defects in tooth dentin and cementum of the periodontium invariably lead to a weak (soft or brittle) dentition in which teeth become loose and prone to infection and are lost prematurely. Mineralization of the extremities of periodontal ligament fibers (Sharpey's fibers) where they insert into tooth cementum and alveolar bone is also essential for the function of the tooth-suspensory apparatus in occlusion and mastication. Molecular determinants of mineralization in these tissues include mineral ion concentrations (phosphate and calcium), pyrophosphate, small integrin-binding ligand N-linked glycoproteins and matrix vesicles. Amongst the enzymes important in regulating these mineralization determinants, two are discussed at length here, with clinical examples given, namely tissue-nonspecific alkaline phosphatase and phosphate-regulating gene with homologies to endopeptidases on the X chromosome. Inactivating mutations in these enzymes in humans and in mouse models lead to the soft bones and teeth characteristic of hypophosphatasia and X-linked hypophosphatemia, respectively, where the levels of local and systemic circulating mineralization determinants are perturbed. In X-linked hypophosphatemia, in addition to renal phosphate wasting causing low circulating phosphate levels, phosphorylated mineralization-regulating small integrin-binding ligand N-linked glycoproteins, such as matrix extracellular phosphoglycoprotein and osteopontin, and the phosphorylated peptides proteolytically released from them, such as the acidic serine- and aspartate-rich-motif peptide, may accumulate locally to impair mineralization in this disease. © 2013 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  8. Characterization of Crohn disease in X-linked inhibitor of apoptosis-deficient male patients and female symptomatic carriers.

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    Aguilar, Claire; Lenoir, Christelle; Lambert, Nathalie; Bègue, Bernadette; Brousse, Nicole; Canioni, Danielle; Berrebi, Dominique; Roy, Maryline; Gérart, Stéphane; Chapel, Helen; Schwerd, Tobias; Siproudhis, Laurent; Schäppi, Michela; Al-Ahmari, Ali; Mori, Masaaki; Yamaide, Akiko; Galicier, Lionel; Neven, Bénédicte; Routes, John; Uhlig, Holm H; Koletzko, Sibylle; Patel, Smita; Kanegane, Hirokazu; Picard, Capucine; Fischer, Alain; Bensussan, Nadine Cerf; Ruemmele, Frank; Hugot, Jean-Pierre; Latour, Sylvain

    2014-11-01

    Crohn disease is an inflammatory bowel disease (IBD) with a complex mode of inheritance. Although nucleotide binding and oligomerization domain containing 2 (NOD2) is the strongest risk factor, the cause of Crohn disease remains unknown in the majority of the cases. X-linked inhibitor of apoptosis (XIAP) deficiency causes X-linked lymphoproliferative syndrome type 2. IBD has been reported in some XIAP-deficient patients. We characterize the IBD affecting a large cohort of patients with mutations in XIAP and examine the possible pathophysiologic mechanisms. We performed a phenotypical and histologic analysis of the IBD affecting 17 patients with hemizygous mutations in XIAP, including 3 patients identified by screening 83 patients with pediatric-onset IBD. The X chromosome inactivation was analyzed in female carriers of heterozygous XIAP mutations, including 2 adults with IBD. The functional consequences of XIAP deficiency were analyzed. Clinical presentation and histology of IBD in patients with XIAP deficiency overlapped with those of patients with Crohn disease. The age at onset was variable (from 3 months to 41 years), and IBD was severe and difficult to treat. In 2 patients hematopoietic stem cell transplantation fully restored intestinal homeostasis. Monocytes of patients had impaired NOD2-mediated IL-8 and monocyte chemoattractant protein 1 (MCP-1) production, as well as IL-10, in response to NOD2 and Toll-like receptor 2/4 costimulation. Nucleotide binding and oligomerization domain containing 1 (NOD1)-mediated IL-6 and IL-8 production was defective in fibroblasts from XIAP-deficient patients. The 2 heterozygous female carriers of XIAP mutations with IBD displayed abnormal expression of the XIAP mutated allele, resulting in impaired activation of the NOD2 pathway. IBD in patients with XIAP deficiency is similar to Crohn disease and is associated with defective NOD2 function in monocytes. Importantly, we report that it is not restricted to male patients

  9. Prognostic value of glomerular collagen IV immunofluorescence studies in male patients with X-linked Alport syndrome.

    Science.gov (United States)

    Massella, Laura; Gangemi, Concetta; Giannakakis, Kostas; Crisafi, Antonella; Faraggiana, Tullio; Fallerini, Chiara; Renieri, Alessandra; Muda, Andrea Onetti; Emma, Francesco

    2013-05-01

    X-linked Alport syndrome (X-AS) is caused by mutations of the COL4A5 gene, which encodes for the collagen IV α5 chain (α5[COLIV]), resulting in structural and functional abnormalities of the glomerular basement membrane (GBM) and leading to CKD. The aim of the present study was to evaluate the prognostic value of residual collagen IV chain expression in the GBM of patients with X-AS. The medical records of 22 patients with X-AS from 21 unrelated families collected between 1987 and 2009 were reviewed (median age at last follow-up, 19.9 years; range, 5.4-35.1 years); GBM expression of α1, α3, and α5(COLIV) chains was assessed by immunofluorescence microscopy. GBM distribution of the α5(COLIV) chain was diffuse in 1 and segmental or absent in 21 of the 22 patients; the expression of the α3(COLIV) chain was diffuse in 5 of 22 patients and segmental or absent in 17 of 22 patients. Patients with diffuse staining for the α3(COLIV) chain presented with proteinuria significantly later (median age, 16.9 versus 6.1 years; P=0.02) and reached an estimated GFR < 90 ml/min per 1.73 m(2) at an older age (median age, 27.0 versus 14.9 years; P=0.01) compared with patients with segmental or absent staining. Two thirds of patients with abnormal α3(COLIV) expression by immunofluorescence studies had null or truncating COL4A5 mutations, as opposed to none of the 4 tested patients with diffuse α3(COLIV) chain glomerular distribution. These results indicate that maintained expression of the α3(COLIV) chain is an early positive prognostic marker in patients with X-linked Alport symdrome.

  10. Atypical femur fracture in an adolescent boy treated with bisphosphonates for X-linked osteoporosis based on PLS3 mutation.

    Science.gov (United States)

    van de Laarschot, Denise M; Zillikens, M Carola

    2016-10-01

    Long-term use of bisphosphonates has raised concerns about the association with Atypical Femur Fractures (AFFs) that have been reported mainly in postmenopausal women. We report a case of an 18-year-old patient with juvenile osteoporosis based on X-linked osteoporosis due to a PLS3 mutation who developed a low trauma femoral fracture after seven years of intravenous and two years of oral bisphosphonate use, fulfilling the revised ASBMR diagnostic criteria of an AFF. The occurrence of AFFs has not been described previously in children or adolescents. The underlying monogenetic bone disease in our case strengthens the possibility of a genetic predisposition at least in some cases of AFF. We cannot exclude that a transverse fracture of the tibia that also occurred after a minor trauma at age 16 might be part of the same spectrum of atypical fractures related to the use of bisphosphonates. In retrospect our patient experienced prodromal pain prior to both the tibia and the femur fracture. Case reports of atypical fractures in children with a monogenetic bone disease such as Osteogenesis Imperfecta (OI) or juvenile osteoporosis are important to consider in the discussion about optimal duration of bisphosphonate therapy in growing children. In conclusion, this case report 1) highlights that AFFs also occur in adolescents treated with bisphosphonates during childhood and pain in weight-bearing bones can point towards this diagnosis 2) supports other reports suggesting that low trauma fractures of other long bones besides the femur may be related to long-term use of bisphosphonates 3) strengthens the concept of an underlying genetic predisposition in some cases of AFF, now for the first time reported in X-linked osteoporosis due to a mutation in PLS3 and 4) should be considered in decisions about the duration of bisphosphonate therapy in children with congenital bone disorders. Copyright © 2016. Published by Elsevier Inc.

  11. Mutations in two large pedigrees highlight the role of ZNF711 in X-linked intellectual disability.

    Science.gov (United States)

    van der Werf, Ilse M; Van Dijck, Anke; Reyniers, Edwin; Helsmoortel, Céline; Kumar, Ajay Anand; Kalscheuer, Vera M; de Brouwer, Arjan Pm; Kleefstra, Tjitske; van Bokhoven, Hans; Mortier, Geert; Janssens, Sandra; Vandeweyer, Geert; Kooy, R Frank

    2017-03-20

    Intellectual disability (ID) affects approximately 1-2% of the general population and is characterized by impaired cognitive abilities. ID is both clinically as well as genetically heterogeneous, up to 2000 genes are estimated to be involved in the emergence of the disease with various clinical presentations. For many genes, only a few patients have been reported and causality of some genes has been questioned upon the discovery of apparent loss-of-function mutations in healthy controls. Description of additional patients strengthens the evidence for the involvement of a gene in the disease and can clarify the clinical phenotype associated with mutations in a particular gene. Here, we present two large four-generation families with a total of 11 males affected with ID caused by mutations in ZNF711, thereby expanding the total number of families with ID and a ZNF711 mutation to four. Patients with mutations in ZNF711 all present with mild to moderate ID and poor speech accompanied by additional features in some patients, including autistic features and mild facial dysmorphisms, suggesting that ZNF711 mutations cause non-syndromic ID. Copyright © 2016 Elsevier B.V. All rights reserved.

  12. Should metabolic diseases be systematically screened in nonsyndromic autism spectrum disorders?

    Directory of Open Access Journals (Sweden)

    Manuel Schiff

    Full Text Available BACKGROUND: In the investigation of autism spectrum disorders (ASD, a genetic cause is found in approximately 10-20%. Among these cases, the prevalence of the rare inherited metabolic disorders (IMD is unknown and poorly evaluated. An IMD responsible for ASD is usually identified by the associated clinical phenotype such as dysmorphic features, ataxia, microcephaly, epilepsy, and severe intellectual disability (ID. In rare cases, however, ASD may be considered as nonsyndromic at the onset of a related IMD. OBJECTIVES: To evaluate the utility of routine metabolic investigations in nonsyndromic ASD. PATIENTS AND METHODS: We retrospectively analyzed the results of a metabolic workup (urinary mucopolysaccharides, urinary purines and pyrimidines, urinary creatine and guanidinoacetate, urinary organic acids, plasma and urinary amino acids routinely performed in 274 nonsyndromic ASD children. RESULTS: The metabolic parameters were in the normal range for all but 2 patients: one with unspecific creatine urinary excretion and the other with persistent 3-methylglutaconic aciduria. CONCLUSIONS: These data provide the largest ever reported cohort of ASD patients for whom a systematic metabolic workup has been performed; they suggest that such a routine metabolic screening does not contribute to the causative diagnosis of nonsyndromic ASD. They also emphasize that the prevalence of screened IMD in nonsyndromic ASD is probably not higher than in the general population (<0.5%. A careful clinical evaluation is probably more reasonable and of better medical practice than a costly systematic workup.

  13. Dose passive smoking induce sensorineural hearing loss in children?

    Science.gov (United States)

    Talaat, Hossam Sanyelbhaa; Metwaly, Mohamed Akram; Khafagy, Ahmed Hafez; Abdelraouf, Hatem Ragaa

    2014-01-01

    Smoking plays major role in development of vascular and respiratory serious diseases. It has been reported that negative smoker children are prone for conductive hearing impairment due to repeated attacks of Eustachian tube dysfunction and middle ear effusion. This study aims to identify negative smoking as potential risk factor for development of sensorineural hearing loss. This study was done between January 2010 and November 2012. 411 children aged 5-11 years (8.2 ± 1.5) participated in this study; they were children attending the Ear, Nose, and Throat clinic of a tertiary care hospital and their siblings. The inclusion criteria were: (i) normal speech and language, (ii) absence of any disease or condition that may cause sensorineural hearing loss, and (iii) normal middle ear function on the day of hearing assessment. They were divided into three groups according to the exposure to second-hand smoke at home; group of "no exposure" whereas no smoker in the family (131 children), group of 'mild exposure" whereas the father was the only smoking parent and smoking was prohibited at home (155 children), and group of "heavy exposure", whereas the mother was smoking, or the father was freely smoking at home and in the presence of his children (125 children). Audiological evaluation in the form of pure tone and speech audiometry and immitancemetry was done for the study group. Audiological evaluation revealed that the prevalence of hearing loss was 3.8%, 4.5% and 12% in the "no exposure", "mild exposure", and "heavy exposure" groups, respectively. Significant difference was only detected between the high exposure group and the other two groups. All children had minimal sensorineural hearing loss, i.e. threshold of frequencies showing hearing loss was 20 or 25 dB HL. The risk ratios (95% confidence interval) for hearing loss in the study subgroups were 1.18 (0.38, 3.64) for mild exposure group (p>0.05), 3.14 (1.18, 8.3) for heavy exposure group (phearing loss, and it is

  14. Epileptiform electroencephalogram abnormality in children with congenital sensorineural hearing loss.

    Science.gov (United States)

    El-Badry, Mohamed Mohamed; Hamdy, Nermin Aly; Sobhy, Sayed; Gamal, Reham

    2014-04-01

    This work was designed to study electroencephalogram findings in children with congenital sensorineural hearing loss and correlate these findings with the SNHL parameters as duration, etiology, severity, and type. Ninety children with bilateral congenital sensorineural hearing loss served as the study group. They were free from any neurological disorders or symptoms that are commonly associated with abnormal electroencephalogram as convulsions or loss of consciousness. Twenty children having normal hearing with no history of otological or neurological disorders served as the control group. All children participating in the study were subjected to full medical and audiological history, otological examination, neurological examination, audiological evaluation and electroencephalogram recording. Mean age of the children in the control group was 3.56 ± 2.1 years and mean age of the children in the study group was 3.8 ± 2.2 years. While none of the control children had abnormal electroencephalogram, 38 (42.2%) of children with congenital SNHL had epileptiform electroencephalogram abnormality. The epileptiform abnormality was generalized in 14 children (36.8%), focal temporal in 17 children (44.7%) and focal other than temporal in 7 children (18.4%). According to the hemispheric side affected, the abnormality was right in 14 children (36.8%), left in 10 children (26.3%) and bilateral in 14 children (36.8%). No statistically significant predominance of specific site or side of the epileptiform abnormality was found. Similarly, no statistical significant prevalent of the epileptiform abnormality was found in relation to the age or sex of children, duration of hearing loss or etiology of hearing loss (i.e., genetic vs. neonatal insults). On the other hand, the epileptiform abnormality was statistically prevalent in children with moderate degree of hearing loss, and in children with auditory neuropathy spectrum disorder. The epileptiform electroencephalogram abnormality is

  15. Early Reading Abilities of Bilingual Children With Nonsyndromic Orofacial Clefts.

    Science.gov (United States)

    Cheong, Michelle Heng Yue; Young, Selena Ee-Li; Young, Dawn Patricia Chuan Yu; Lee, Mary Lay Choo; Rickard Liow, Susan Jane

    2018-02-01

    To investigate the early reading abilities, and related cognitive-linguistic processes, in bilingual children with nonsyndromic cleft lip and/or palate (CL/P), and to identify deficits that might be amenable to intervention. Bilingual participants with CL/P aged 5 to 6 years who were English-dominant ( n=17) or Mandarin-dominant ( n=18) were recruited using consecutive sampling from a national cleft treatment center and matched pairwise to a sample of typically developing (TD) children on language dominance, age, and socioeconomic status. All participants were assessed in English on single-word reading accuracy using the Wide Range Achievement Test (4th Ed), and key cognitive-linguistic factors associated with reading development: phonological awareness, rapid automatized naming (RAN), receptive and expressive vocabulary, and verbal short-term and working memory. CL/P and TD groups were compared within language dominance group (Mandarin or English) for all measures. The Mandarin-dominant CL/P group had significantly poorer reading accuracy and phonological awareness than their TD peers. Additionally, regardless of language dominance, faster RAN correlated significantly with better reading accuracy in both the CL/P groups but not the TD groups. Children with CL/P who are learning English as a second language are at greater risk of reading difficulties. Furthermore, the cognitive-linguistic processes underlying early reading in bilingual children with CL/P differ from those of their TD peers. Routine screening and tailored intervention is advisable.

  16. Altered Contralateral Auditory Cortical Morphology in Unilateral Sudden Sensorineural Hearing Loss.

    Science.gov (United States)

    Fan, Wenliang; Zhang, Wenjuan; Li, Jing; Zhao, Xueyan; Mella, Grace; Lei, Ping; Liu, Yuan; Wang, Haha; Cheng, Huamao; Shi, Hong; Xu, Haibo

    2015-12-01

    To investigate the cerebral gray matter volume alterations in unilateral sudden sensorineural hearing loss patients within the acute period by the voxel-based morphometry method, and to determine if hearing impairment is associated with regional gray matter alterations in unilateral sudden sensorineural hearing loss patients. Prospective case study. Tertiary class A teaching hospital. Thirty-nine patients with left-side unilateral sudden sensorineural hearing loss and 47 patients with right-side unilateral sudden sensorineural hearing loss. Diagnostic. To compare the regional gray matter of unilateral sudden sensorineural hearing loss patients and healthy control participants. Compared with control groups, patients with left side unilateral sudden sensorineural hearing loss had significant gray matter reductions in the right middle temporal gyrus and right superior temporal gyrus, whereas patients with right side unilateral sudden sensorineural hearing loss showed gray matter decreases in the left superior temporal gyrus and left middle temporal gyrus. A significant negative correlation with the duration of the sudden sensorineural hearing loss (R = -0.427, p = 0.012 for left-side unilateral SSNHL and R = -0.412, p = 0.013 for right-side unilateral SSNHL) was also found in these brain areas. There was no region with increased gray matter found in both groups of unilateral sudden sensorineural hearing loss patients. This study confirms that detectable decreased contralateral auditory cortical morphological changes have occurred in unilateral SSNHL patients within the acute period by voxel-based morphometry methods. The gray matter volumes of these brain areas also perform a negative correlation with the duration of the disease, which suggests a gradual brain structural impairment after the progression of the disease.

  17. Sensorineural and conductive hearing loss in infants diagnosed in the program of universal newborn hearing screening.

    Science.gov (United States)

    Wroblewska-Seniuk, Katarzyna; Dabrowski, Piotr; Greczka, Grazyna; Szabatowska, Katarzyna; Glowacka, Agata; Szyfter, Witold; Mazela, Jan

    2018-02-01

    The aim of this study was to analyze infants diagnosed with sensorineural or conductive hearing deficit and to identify risk factors associated with these defects. A retrospective analysis of infants diagnosed with hearing deficit based on the database of the universal newborn hearing screening program and medical records of the patients. 27 935 infants were covered by the universal neonatal hearing screening program. 109 (0.39%) were diagnosed with hearing deficit and referred for treatment and rehabilitation. 56 (51.4%) children were diagnosed with conductive, 38 (34.9%) with sensorineural and 15 (13.8%) with mixed type of hearing deficit. Children with sensorineural hearing deficit more frequently suffered from hyperbilirubinemia (p conductive hearing loss were more frequently diagnosed with isolated craniofacial anomalies (p hearing deficit occurred almost 3 times more often bilaterally than unilaterally (p hearing deficit, the difference was not significant. In children with conductive and mixed type of hearing loss the impairment was mainly mild while among those with sensorineural hearing deficit in almost 45% it was severe and profound (p hearing screening test by means of otoacoustic emissions and the final diagnosis of hearing deficit we found that the highest agreement rate was observed in children with sensorineural hearing loss (p hearing deficit was similar in children with sensorineural, conductive and mixed type of hearing loss, only hyperbilirubinemia seemed to predispose to sensorineural hearing deficit and isolated craniofacial malformations seemed to be associated with conductive hearing loss. Sensorineural hearing deficit usually occurred bilaterally and was severe or profound, while conductive and mixed type of hearing deficit were most often of mild degree. Most children with the final diagnosis of sensorineural hearing deficit had positive result of hearing screening by means of otoacoustic emissions. Copyright © 2017 Elsevier B.V. All

  18. Prenatal Three-Dimensional Ultrasound Detection of Adducted Thumbs in X-Linked Hydrocephaly: Two Case Reports with Molecular Genetic Studies

    Science.gov (United States)

    Corral, Edgardo; Barrios, Andres; Isnard, Monica; Saugier-Veber, Pascale; Fortier, Sophie M.; Durrin, Sarah; Sepulveda, Waldo

    2015-01-01

    X-linked hydrocephaly is a rare sex-linked genetic recessive condition occurring in 1/30,000 deliveries. Adduction of thumbs and mental retardation are additional associated clinical findings. We describe two cases of X-linked hydrocephaly with associated adducted thumbs that were diagnosed prenatally with the combined use of three-dimensional (3D) ultrasound and fetal blood sampling for cytogenetic and molecular analyses. This report suggests that 3D ultrasound can facilitate the identification of adducted thumbs in fetuses affected by X-linked hydrocephaly and supports evaluation of the fetal hands as an integral part of the ultrasound anatomical assessment in male fetuses with hydrocephaly secondary to aqueductal stenosis. PMID:26078893

  19. Acute sensorineural hearing loss and severe otalgia due to scrub typhus

    Directory of Open Access Journals (Sweden)

    Kim Dong-Min

    2009-10-01

    Full Text Available Abstract Background Scrub typhus is an acute febrile illness caused by Orientia tsutsugamushi. Case presentations We encountered a patient with sensorineural hearing loss complicating scrub typhus, and three patients with scrub typhus who complained of otalgia, which was sudden onset, severe, paroxysmal, intermittent yet persistent pain lasting for several seconds, appeared within 1 week after the onset of fever and rash. The acute sensorineural hearing loss and otalgia were resolved after antibiotic administration. Conclusion When patients in endemic areas present with fever and rash and have sensorineural hearing loss or otalgia without otoscopic abnormalities, clinicians should suspect scrub typhus and consider empirical antibiotic therapy.

  20. Molecular Basis of DFNB73: Mutations of BSND Can Cause Nonsyndromic Deafness or Bartter Syndrome

    Science.gov (United States)

    Riazuddin, Saima; Anwar, Saima; Fischer, Martin; Ahmed, Zubair M.; Khan, Shahid Y.; Janssen, Audrey G.H.; Zafar, Ahmad U.; Scholl, Ute; Husnain, Tayyab; Belyantseva, Inna A.; Friedman, Penelope L.; Riazuddin, Sheikh; Friedman, Thomas B.; Fahlke, Christoph

    2009-01-01

    BSND encodes barttin, an accessory subunit of renal and inner ear chloride channels. To date, all mutations of BSND have been shown to cause Bartter syndrome type IV, characterized by significant renal abnormalities and deafness. We identified a BSND mutation (p.I12T) in four kindreds segregating nonsyndromic deafness linked to a 4.04-cM interval on chromosome 1p32.3. The functional consequences of p.I12T differ from BSND mutations that cause renal failure and deafness in Bartter syndrome type IV. p.I12T leaves chloride channel function unaffected and only interferes with chaperone function of barttin in intracellular trafficking. This study provides functional data implicating a hypomorphic allele of BSND as a cause of apparent nonsyndromic deafness. We demonstrate that BSND mutations with different functional consequences are the basis for either syndromic or nonsyndromic deafness. PMID:19646679