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Sample records for autosomal-recessive cone-rod dystrophy

  1. Mutations in PCDH21 cause autosomal recessive cone-rod dystrophy

    DEFF Research Database (Denmark)

    Østergaard, Elsebet; Batbayli, M; Dunø, Morten

    2010-01-01

    Cone-rod dystrophy is a retinal dystrophy with early loss of cone photoreceptors and a parallel or subsequent loss of rod photoreceptors. It may be syndromic, but most forms are non-syndromic with autosomal dominant, autosomal recessive or X-linked recessive inheritance.......Cone-rod dystrophy is a retinal dystrophy with early loss of cone photoreceptors and a parallel or subsequent loss of rod photoreceptors. It may be syndromic, but most forms are non-syndromic with autosomal dominant, autosomal recessive or X-linked recessive inheritance....

  2. Molecular and phenotypic analysis of a family with autosomal recessive cone-rod dystrophy and Stargardt disease.

    NARCIS (Netherlands)

    Yzer, S.; Born, L.I. van den; Zonneveld, M.N.; Lopez, I.; Ayyagari, R.; Teye-Botchway, L.; Mota-Vieira, L.; Cremers, F.P.M.; Koenekoop, R.K.

    2007-01-01

    PURPOSE: To identify the causative gene mutations in three siblings with severe progressive autosomal recessive cone-rod dystrophy (arCRD) and their fifth paternal cousin with Stargardt disease (STGD1) and to specify the phenotypes. METHODS: We evaluated eight sibs of one family, three family

  3. An intronic deletion in the PROM1 gene leads to autosomal recessive cone-rod dystrophy.

    Science.gov (United States)

    Eidinger, Osnat; Leibu, Rina; Newman, Hadas; Rizel, Leah; Perlman, Ido; Ben-Yosef, Tamar

    2015-01-01

    To investigate the genetic basis for autosomal recessive cone-rod dystrophy (CRD) in a consanguineous Israeli Jewish family. Patients underwent a detailed ophthalmic evaluation, including eye examination, visual field testing, optical coherence tomography (OCT), and electrophysiological tests, electroretinography (ERG) and visual evoked potential (VEP). Genome-wide homozygosity mapping using a single nucleotide polymorphism (SNP) array was performed to identify homozygous regions shared among two of the affected individuals. Mutation screening of the underlying gene was performed with direct sequencing. In silico and in vitro analyses were used to predict the effect of the identified mutation on splicing. The affected family members are three siblings who have various degrees of progressive visual deterioration, glare, color vision abnormalities, and night vision difficulties. Visual field tests revealed central scotomas of different extension. Cone and rod ERG responses were reduced, with cones more severely affected. Homozygosity mapping revealed several homozygous intervals shared among two of the affected individuals. One included the PROM1 gene. Sequence analysis of the 26 coding exons of PROM1 in one affected individual revealed no mutations in the coding sequence or in intronic splice sites. However, in intron 21, proximate to the intron-exon junction, we observed a homozygous 10 bp deletion between positions -26 and -17 (c.2281-26_-17del). The deletion was linked to a known SNP, c.2281-6C>G. The deletion cosegregated with the disease in the family, and was not detected in public databases or in 101 ethnically-matched control individuals. In silico analysis predicted that this deletion would lead to altered intron 21 splicing. Bioinformatic analysis predicted that a recognition site for the SRSF2 splicing factor is located within the deleted sequence. The in vitro splicing assay demonstrated that c.2281-26_-17del leads to complete exon 22 skipping. A novel

  4. Phenotypic spectrum of autosomal recessive cone-rod dystrophies caused by mutations in the ABCA4 (ABCR) gene.

    NARCIS (Netherlands)

    Klevering, B.J.; Blankenagel, A.; Maugeri, A.; Cremers, F.P.M.; Hoyng, C.B.; Rohrschneider, K.

    2002-01-01

    PURPOSE: To describe the phenotype of 12 patients with autosomal recessive or isolated cone-rod types of progressive retinal degeneration (CRD) caused by mutations in the ABCA4 gene. METHODS: The charts of patients who had originally received a diagnosis of isolated or autosomal recessive CRD were

  5. Microarray-based mutation analysis of the ABCA4 (ABCR) gene in autosomal recessive cone-rod dystrophy and retinitis pigmentosa.

    NARCIS (Netherlands)

    Klevering, B.J.; Ijzer, S.; Rohrschneider, K.; Zonneveld-Vrieling, M.N.; Allikmets, R.; Born, L.I. van den; Maugeri, A.; Hoyng, C.B.; Cremers, F.P.M.

    2004-01-01

    Mutations in the ABCA4 gene have been associated with autosomal recessive Stargardt disease (STGD1), cone-rod dystrophy (CRD), and retinitis pigmentosa (RP). We employed a recently developed genotyping microarray, the ABCR400-chip, to search for known ABCA4 mutations in patients with isolated or

  6. Mutations in the ABCA4 (ABCR) Gene Are the Major Cause of Autosomal Recessive Cone-Rod Dystrophy

    Science.gov (United States)

    Maugeri, Alessandra; Klevering, B. Jeroen; Rohrschneider, Klaus; Blankenagel, Anita; Brunner, Han G.; Deutman, August F.; Hoyng, Carel B.; Cremers, Frans P. M.

    2000-01-01

    The photoreceptor cell–specific ATP-binding cassette transporter gene (ABCA4; previously denoted “ABCR”) is mutated in most patients with autosomal recessive (AR) Stargardt disease (STGD1) or fundus flavimaculatus (FFM). In addition, a few cases with AR retinitis pigmentosa (RP) and AR cone-rod dystrophy (CRD) have been found to have ABCA4 mutations. To evaluate the importance of the ABCA4 gene as a cause of AR CRD, we selected 5 patients with AR CRD and 15 patients with isolated CRD, all from Germany and The Netherlands . Single-strand conformation–polymorphism analysis and sequencing revealed 19 ABCA4 mutations in 13 (65%) of 20 patients. In six patients, mutations were identified in both ABCA4 alleles; in seven patients, mutations were detected in one allele. One complex ABCA4 allele (L541P;A1038V) was found exclusively in German patients with CRD; one patient carried this complex allele homozygously, and five others were compound heterozygous. These findings suggest that mutations in the ABCA4 gene are the major cause of AR CRD. A primary role of the ABCA4 gene in STGD1/FFM and AR CRD, together with the gene's involvement in an as-yet-unknown proportion of cases with AR RP, strengthens the idea that mutations in the ABCA4 gene could be the most frequent cause of inherited retinal dystrophy in humans. PMID:10958761

  7. Genetics Home Reference: cone-rod dystrophy

    Science.gov (United States)

    ... common cause of autosomal recessive cone-rod dystrophy , accounting for 30 to 60 percent of cases. At ... Patient Support and Advocacy Resources (4 links) American Foundation for the Blind Foundation Fighting Blindness Retina International ...

  8. Cone rod dystrophies

    Directory of Open Access Journals (Sweden)

    Hamel Christian P

    2007-02-01

    Full Text Available Abstract Cone rod dystrophies (CRDs (prevalence 1/40,000 are inherited retinal dystrophies that belong to the group of pigmentary retinopathies. CRDs are characterized by retinal pigment deposits visible on fundus examination, predominantly localized to the macular region. In contrast to typical retinitis pigmentosa (RP, also called the rod cone dystrophies (RCDs resulting from the primary loss in rod photoreceptors and later followed by the secondary loss in cone photoreceptors, CRDs reflect the opposite sequence of events. CRD is characterized by primary cone involvement, or, sometimes, by concomitant loss of both cones and rods that explains the predominant symptoms of CRDs: decreased visual acuity, color vision defects, photoaversion and decreased sensitivity in the central visual field, later followed by progressive loss in peripheral vision and night blindness. The clinical course of CRDs is generally more severe and rapid than that of RCDs, leading to earlier legal blindness and disability. At end stage, however, CRDs do not differ from RCDs. CRDs are most frequently non syndromic, but they may also be part of several syndromes, such as Bardet Biedl syndrome and Spinocerebellar Ataxia Type 7 (SCA7. Non syndromic CRDs are genetically heterogeneous (ten cloned genes and three loci have been identified so far. The four major causative genes involved in the pathogenesis of CRDs are ABCA4 (which causes Stargardt disease and also 30 to 60% of autosomal recessive CRDs, CRX and GUCY2D (which are responsible for many reported cases of autosomal dominant CRDs, and RPGR (which causes about 2/3 of X-linked RP and also an undetermined percentage of X-linked CRDs. It is likely that highly deleterious mutations in genes that otherwise cause RP or macular dystrophy may also lead to CRDs. The diagnosis of CRDs is based on clinical history, fundus examination and electroretinogram. Molecular diagnosis can be made for some genes, genetic counseling is

  9. [From gene to disease: from the ABCA4 gene to Stargardt disease, cone-rod dystrophy and retinitis pigmentosa

    NARCIS (Netherlands)

    Cremers, F.P.M.; Maugeri, A.; Klevering, B.J.; Hoefsloot, L.H.; Hoyng, C.B.

    2002-01-01

    Autosomal recessive Stargardt disease is caused by mutations in the ABCA4 gene. Mutations in ABCA4 are also found in two-thirds of cases with autosomal recessive cone-rod dystrophy, and a small fraction of patients with autosomal recessive retinitis pigmentosa. Patients with autosomal recessive

  10. Further delineation of spondylometaphyseal dysplasia with cone-rod dystrophy

    NARCIS (Netherlands)

    Sousa, Sérgio B.; Russell-Eggitt, Isabelle; Hall, Christine; Hall, Bryan D.; Hennekam, Raoul C. M.

    2008-01-01

    There are several entities that combine a skeletal dysplasia with a retinal dystrophy. Recently, another possibly autosomal recessive entity was added to this group characterized by a specific spondylometaphyseal dysplasia and a cone-rod dystrophy, without other significant impairments. The entity

  11. An ADAM9 mutation in canine cone-rod dystrophy 3 establishes homology with human cone-rod dystrophy 9.

    Science.gov (United States)

    Goldstein, Orly; Mezey, Jason G; Boyko, Adam R; Gao, Chuan; Wang, Wei; Bustamante, Carlos D; Anguish, Lynne J; Jordan, Julie Ann; Pearce-Kelling, Susan E; Aguirre, Gustavo D; Acland, Gregory M

    2010-08-11

    To identify the causative mutation in a canine cone-rod dystrophy (crd3) that segregates as an adult onset disorder in the Glen of Imaal Terrier breed of dog. Glen of Imaal Terriers were ascertained for crd3 phenotype by clinical ophthalmoscopic examination, and in selected cases by electroretinography. Blood samples from affected cases and non-affected controls were collected and used, after DNA extraction, to undertake a genome-wide association study using Affymetrix Version 2 Canine single nucleotide polymorphism chips and 250K Sty Assay protocol. Positional candidate gene analysis was undertaken for genes identified within the peak-association signal region. Retinal morphology of selected crd3-affected dogs was evaluated by light and electron microscopy. A peak association signal exceeding genome-wide significance was identified on canine chromosome 16. Evaluation of genes in this region suggested A Disintegrin And Metalloprotease domain, family member 9 (ADAM9), identified concurrently elsewhere as the cause of human cone-rod dystrophy 9 (CORD9), as a strong positional candidate for canine crd3. Sequence analysis identified a large genomic deletion (over 20 kb) that removed exons 15 and 16 from the ADAM9 transcript, introduced a premature stop, and would remove critical domains from the encoded protein. Light and electron microscopy established that, as in ADAM9 knockout mice, the primary lesion in crd3 appears to be a failure of the apical microvilli of the retinal pigment epithelium to appropriately invest photoreceptor outer segments. By electroretinography, retinal function appears normal in very young crd3-affected dogs, but by 15 months of age, cone dysfunction is present. Subsequently, both rod and cone function degenerate. Identification of this ADAM9 deletion in crd3-affected dogs establishes this canine disease as orthologous to CORD9 in humans, and offers opportunities for further characterization of the disease process, and potential for genetic

  12. Mutations in MFSD8, encoding a lysosomal membrane protein, are associated with nonsyndromic autosomal recessive macular dystrophy

    NARCIS (Netherlands)

    Roosing, S.; Born, L.I. van den; Sangermano, R.; Banfi, S.; Koenekoop, R.K.; Zonneveld-Vrieling, M.N.; Klaver, C.C.; Lith-Verhoeven, J.J. van; Cremers, F.P.M.; Hollander, A.I. den; Hoyng, C.B.

    2015-01-01

    PURPOSE: This study aimed to identify the genetic defects in 2 families with autosomal recessive macular dystrophy with central cone involvement. DESIGN: Case series. PARTICIPANTS: Two families and a cohort of 244 individuals with various inherited maculopathies and cone disorders. METHODS:

  13. The ADAMTS18 gene is responsible for autosomal recessive early onset severe retinal dystrophy

    Directory of Open Access Journals (Sweden)

    Peluso Ivana

    2013-01-01

    Full Text Available Abstract Background Inherited retinal dystrophies, including Retinitis Pigmentosa and Leber Congenital Amaurosis among others, are a group of genetically heterogeneous disorders that lead to variable degrees of visual deficits. They can be caused by mutations in over 100 genes and there is evidence for the presence of as yet unidentified genes in a significant proportion of patients. We aimed at identifying a novel gene for an autosomal recessive form of early onset severe retinal dystrophy in a patient carrying no previously described mutations in known genes. Methods An integrated strategy including homozygosity mapping and whole exome sequencing was used to identify the responsible mutation. Functional tests were performed in the medaka fish (Oryzias latipes model organism to gain further insight into the pathogenic role of the ADAMTS18 gene in eye and central nervous system (CNS dysfunction. Results This study identified, in the analyzed patient, a homozygous missense mutation in the ADAMTS18 gene, which was recently linked to Knobloch syndrome, a rare developmental disorder that affects the eye and the occipital skull. In vivo gene knockdown performed in medaka fish confirmed both that the mutation has a pathogenic role and that the inactivation of this gene has a deleterious effect on photoreceptor cell function. Conclusion This study reveals that mutations in the ADAMTS18 gene can cause a broad phenotypic spectrum of eye disorders and contribute to shed further light on the complexity of retinal diseases.

  14. Missense mutations in the adhalin gene linked to autosomal recessive muscular dystrophy

    Energy Technology Data Exchange (ETDEWEB)

    Roberds, S.L.; Anderson, R.D.; Lim, L.E. [Univ. of Iowa, Iowa City, IA (United States)] [and others

    1994-09-01

    Adhalin, the 50-kDa dystrophin-associated glycoprotein, is deficient in skeletal muscle of patients having severe childhood autosomal recessive muscular dystrophy (SCARMD). In several North African families, SCARMD has been linked to markers in the pericentromeric region of chromosome l3q, but SCARMD has been excluded from linkage to this locus in other families. To determine whether the adhalin gene might be involved in SCARMD, human adhalin cDNA and large portions of the adhalin gene were cloned. Adhalin is a transmembrane glycoprotein with an extracellular domain bearing limited homology to domains of entactin and nerve growth factor receptor, suggesting that adhalin may serve as a receptor for an extracellular matrix protein. The adhalin gene was mapped to chromosome 17q12-q21.33, excluding the gene from involvement in 13q-linked SCARMD. A polymorphic microsatellite was identified within intron 6 of the adhalin gene, and one allelic variant of this marker cosegregated with the disease phenotype in a large French family with a lod score of 3.61 at 0 recombination. Adhalin is undetectable in skeletal muscle from affected members of this family. Missense mutations were identified within the adhalin gene that might cause SCARMD in this family. Thus, genetic defects in at least two components, dystrophin and adhalin, of the dystrophin-glycoprotein complex can independently cause muscular dystrophies.

  15. Cone-rod dystrophy can be a manifestation of Danon disease

    NARCIS (Netherlands)

    A.A.H.J. Thiadens (Alberta); N.W.R. Slingerland (Niki); R.J. Florijn (Ralph); G.H. Visser (Gerhard Henk); F.C.C. Riemslag (Frans); C.C.W. Klaver (Caroline)

    2012-01-01

    textabstractBackground Danon disease is a neuromuscular disorder with variable expression in the eye. We describe a family with Danon disease and cone-rod dystrophy (CRD). Methods Affected males of one family with Danon were invited for an extensive ophthalmologic examination, including color vision

  16. Distribution of skeletal muscle involvement in autosomal recessive distal muscular dystrophy. A clinical and computed tomographic study

    Energy Technology Data Exchange (ETDEWEB)

    Mizusawa, Hidehiro; Nakanishi, Takao; Kobayashi, Fumie

    1987-02-01

    Distribution of skeletal muscle involvement in 5 cases with autosomal recessive distal muscular dystrophy was studied clinically and by computed tomography (CT). Manual muscle test showed muscle involvement with a predilection for flexors in the lower leg and adductors in the thigh. Flexion and extension of the thigh and the lower leg was impaired to similar degree. In progressed cases, neck flexors and trunk muscles were also affected mildly. CT disclosed more clearly the preferential involvement of flexors in the lower leg, and involvement of both hamstrings center dot adductors group and extensors group of the thigh to similar degree. However, m. popliteus was curiously well preserved. In addition, there was a stage showing high density and hypertrophy of m. sartorius, m. gracilis, m. adductor, m. biceps femoris, m. semimenbranosus, m. semitendinosus or m. rectus femoris, which in thought to be compensatory hypertrophy. M. gluteus minimus in the pelvic girdle and m. dorsi proprii in the trunk were also liable to be affected. The CT findings are regarded as characteristic features noted clearly before muscle weakness and atrophy become apparent clinically. CT is very useful for distinguishing distal muscular dystrophy from rimmed vacuolar distal myopathy in which m. quadriceps femoris and flexors of the lower leg are usually well preserved without compensatory hypertrophy on CT.

  17. RNA interference gene therapy in dominant retinitis pigmentosa and cone-rod dystrophy mouse models caused by GCAP1 mutations

    Directory of Open Access Journals (Sweden)

    Li eJiang

    2014-04-01

    Full Text Available RNA interference (RNAi knockdown is an efficacious therapeutic strategy for silencing genes causative for dominant retinal dystrophies. To test this, we used self-complementary (sc AAV2/8 vector to develop an RNAi-based therapy in two dominant retinal degeneration mouse models. The allele-specific model expresses transgenic bovine GCAP1(Y99C establishing a rapid RP-like phenotype, whereas the nonallele-specific model expresses mouse GCAP1(L151F producing a slowly progressing cone/rod dystrophy (CORD. The late onset GCAP1(L151F-CORD mimics the dystrophy observed in human GCAP1-CORD patients. Subretinal injection of scAAV2/8 carrying shRNA expression cassettes specific for bovine or mouse GCAP1 showed strong expression at one week post-injection. In both allele-specific (GCAP1(Y99C-RP and nonallele-specific (GCAP1(L151F-CORD models of dominant retinal dystrophy, RNAi-mediated gene silencing enhanced photoreceptor survival, delayed onset of degeneration and improved visual function. Such results provide a proof of concept toward effective RNAi-based gene therapy mediated by scAAV2/8 for dominant retinal disease based on GCAP1 mutation. Further, nonallele-specific RNAi knockdown of GCAP1 may prove generally applicable toward the rescue of any human GCAP1-based dominant cone-rod dystrophy.

  18. Phenotypic diversity in autosomal-dominant cone-rod dystrophy elucidated by adaptive optics retinal imaging.

    Science.gov (United States)

    Song, Hongxin; Rossi, Ethan A; Stone, Edwin; Latchney, Lisa; Williams, David; Dubra, Alfredo; Chung, Mina

    2018-01-01

    Several genes causing autosomal-dominant cone-rod dystrophy (AD-CRD) have been identified. However, the mechanisms by which genetic mutations lead to cellular loss in human disease remain poorly understood. Here we combine genotyping with high-resolution adaptive optics retinal imaging to elucidate the retinal phenotype at a cellular level in patients with AD-CRD harbouring a defect in the GUCA1A gene. Nine affected members of a four-generation AD-CRD pedigree and three unaffected first-degree relatives underwent clinical examinations including visual acuity, fundus examination, Goldmann perimetry, spectral domain optical coherence tomography and electroretinography. Genome-wide scan followed by bidirectional sequencing was performed on all affected participants. High-resolution imaging using a custom adaptive optics scanning light ophthalmoscope (AOSLO) was performed for selected participants. Clinical evaluations showed a range of disease severity from normal fundus appearance in teenaged patients to pronounced macular atrophy in older patients. Molecular genetic testing showed a mutation in in GUCA1A segregating with disease. AOSLO imaging revealed that of the two teenage patients with mild disease, one had severe disruption of the photoreceptor mosaic while the other had a normal cone mosaic. AOSLO imaging demonstrated variability in the pattern of cone and rod cell loss between two teenage cousins with early AD-CRD, who had similar clinical features and had the identical disease-causing mutation in GUCA1A . This finding suggests that a mutation in GUCA1A does not lead to the same degree of AD-CRD in all patients. Modifying factors may mitigate or augment disease severity, leading to different retinal cellular phenotypes. © Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2018. All rights reserved. No commercial use is permitted unless otherwise expressly granted.

  19. Cloning of the canine ABCA4 gene and evaluation in canine cone-rod dystrophies and progressive retinal atrophies.

    Science.gov (United States)

    Kijas, James W; Zangerl, Barbara; Miller, Brian; Nelson, Jacque; Kirkness, Ewen F; Aguirre, Gustavo D; Acland, Gregory M

    2004-03-29

    To characterize a novel early onset canine retinal disease, and evaluate the ATP-binding cassette transporter gene ABCA4 as a potential candidate gene in this and other canine retinal degenerations. Retinal disease was characterized ophthalmoscopically and electroretinographically in two pit bull terrier dogs and their purpose-bred descendants. All 50 exons of the canine ABCA4 gene were amplified, cloned and sequenced from retinal mRNA of a normal, a carrier and an affected animal, and polymorphisms identified. The latter were used to search for association between ABCA4 and retinal disease both within the study pedigrees and in additional canine breeds segregating retinal degenerations. The disease derived from either founder is distinguished by early, severe, and rapidly progressive loss of cone function accompanied by progressive rod loss that is only relatively slower. Cloning and comparative sequencing of ABCA4 identified six point mutations, none of which were obviously pathogenic. Crossbreeding studies revealed that the diseases in the two founders, although similar, are nonallelic. Pedigree analysis of segregating polymorphisms revealed dissociation between ABCA4 and both retinal phenotypes. The early, severe cone dysfunction in these diseases distinguish them from other forms of canine Progressive Retinal Atrophy. The development of a research population segregating these diseases presents two large animal models for the heterogenous human diseases termed cone-rod dystrophies. Analysis of the canine ABCA4 homolog gene documented its sequence and identified a set of point mutations that were used to exclude this gene as causal to these canine cone-rod dystrophies.

  20. Clinical results from low-level laser therapy in patients with autosomal dominant cone-rod dystrophy

    Science.gov (United States)

    Koev, K.; Avramov, L.; Borissova, E.

    2018-03-01

    The objective of this study is to examine long-term effects of low-level laser therapy (LLLT) in patients with autosomal dominant cone-rod dystrophy (CRDs). A He-Ne Laser with continuous emission at 633 nm (01 mW/cm2) was used on five patients with autosomal dominant pedigree of Romani origin with non-syndromic CRDs. The laser radiation was applied transpupillary to the macula six times for three minutes every other day. The experiment was conducted for a period of three years. The clinical evaluation included best corrected visual acuity determination, funduscopy, Humphrey perimetry, Farnsworth Hue-28 color testing, fluorescein angiography, and full-field electroretinogram (ERG). All affected individuals presented reduced visual acuity (0.01 – 0.4) and photophobia. The funduscopic examination and fluorescein angiography revealed advanced changes including bone spicule-like pigment deposits in the midperiphery and the macular area, along with retinal atrophy, narrowing of the vessels, and waxy optic discs. The visual fields demonstrated central scotoma. The electrophysiologic examination of the patients detected an abnormal cone-rod ERG (20 – 30 μV) with photopic amplitudes more markedly reduced than the scotopic. Flicker responses were missing and Farnsworth Hue-28 test found protanopia. There was a statistically significant increase in the visual acuity (p<0.001, end of study versus baseline) for CRDs patients for the period of three years after the treatment with LLLT. Following the LLLT, the central absolute scotoma in CRDs was reduced, as was the prevalence of metamorphopsia in CRDs. This study shows that LLLT may prove be a novel long-lasting therapeutic option for both forms of CRDs. It is a highly effective treatment resulting in a long-term improvement of the visual acuity.

  1. A novel CRX mutation by whole-exome sequencing in an autosomal dominant cone-rod dystrophy pedigree

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    Qin-Kang Lu

    2015-12-01

    Full Text Available AIM: To identify the disease-causing gene mutation in a Chinese pedigree with autosomal dominant cone-rod dystrophy (adCORD. METHODS: A southern Chinese adCORD pedigree including 9 affected individuals was studied. Whole-exome sequencing (WES, coupling the Agilent whole-exome capture system to the Illumina HiSeq 2000 DNA sequencing platform was used to search the specific gene mutation in 3 affected family members and 1 unaffected member. After a suggested variant was found through the data analysis, the putative mutation was validated by Sanger DNA sequencing of samples from all available family members. RESULTS: The results of both WES and Sanger sequencing revealed a novel nonsense mutation c.C766T (p.Q256X within exon 5 of CRX gene which was pathogenic for adCORD in this family. The mutation could affect photoreceptor-specific gene expression with a dominant-negative effect and resulted in loss of the OTX tail, thus the mutant protein occupies the CRX-binding site in target promoters without establishing an interaction and, consequently, may block transactivation. CONCLUSION: All modes of Mendelian inheritance in CORD have been observed, and genetic heterogeneity is a hallmark of CORD. Therefore, conventional genetic diagnosis of CORD would be time-consuming and labor-intensive. Our study indicated the robustness and cost-effectiveness of WES in the genetic diagnosis of CORD.

  2. Autosomal recessive cerebellar ataxias

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    Palau Francesc

    2006-11-01

    Full Text Available Abstract Autosomal recessive cerebellar ataxias (ARCA are a heterogeneous group of rare neurological disorders involving both central and peripheral nervous system, and in some case other systems and organs, and characterized by degeneration or abnormal development of cerebellum and spinal cord, autosomal recessive inheritance and, in most cases, early onset occurring before the age of 20 years. This group encompasses a large number of rare diseases, the most frequent in Caucasian population being Friedreich ataxia (estimated prevalence 2–4/100,000, ataxia-telangiectasia (1–2.5/100,000 and early onset cerebellar ataxia with retained tendon reflexes (1/100,000. Other forms ARCA are much less common. Based on clinicogenetic criteria, five main types ARCA can be distinguished: congenital ataxias (developmental disorder, ataxias associated with metabolic disorders, ataxias with a DNA repair defect, degenerative ataxias, and ataxia associated with other features. These diseases are due to mutations in specific genes, some of which have been identified, such as frataxin in Friedreich ataxia, α-tocopherol transfer protein in ataxia with vitamin E deficiency (AVED, aprataxin in ataxia with oculomotor apraxia (AOA1, and senataxin in ataxia with oculomotor apraxia (AOA2. Clinical diagnosis is confirmed by ancillary tests such as neuroimaging (magnetic resonance imaging, scanning, electrophysiological examination, and mutation analysis when the causative gene is identified. Correct clinical and genetic diagnosis is important for appropriate genetic counseling and prognosis and, in some instances, pharmacological treatment. Due to autosomal recessive inheritance, previous familial history of affected individuals is unlikely. For most ARCA there is no specific drug treatment except for coenzyme Q10 deficiency and abetalipoproteinemia.

  3. Adhalin, the 50 kD dystrophin associated protein, is not the locus for severe childhood autosomal recessive dystrophy (SCARMD)

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    McNally, E.M.; Selig, S.; Kunkel, L.M. [Children`s Hospital, Boston, MA (United States)

    1994-09-01

    Mutations in the carboxyl-terminus in dystrophin are normally sufficient to produce severely dystrophic muscle. This portion of dystrophin binds a complex of dystrophin-associated glycoproteins (DAGs). The genes encoding these DAGs are candidate genes for causing neuromuscular disease. Immunoreactivity for adhalin, the 50 kD DAG, is absent in muscle biopsies from patients with SCARMD, a form of dystrophy clinically similar Duchenne muscular dystrophy. Prior linkage analysis in SCARMD families revealed that the disease gene segregates with markers on chromosome 13. To determine the molecular role that adhalin may play in SCARMD, human cDNA and genomic sequences were isolated. Primers were designed based on predicted areas of conservation in rabbit adhalin and used in RT-PCR with human skeletal and cardiac muscle. RT-PCR products were confirmed by sequence as human adhalin and then used as probes for screening human cDNA and genomic libraries. Human and rabbit adhalin are 90% identical, and among the cDNAs, a novel splice form of adhalin was seen which may encode part of the 35 kD component of the dystrophin-glycoprotein complex. To our surprise, only human/rodent hybrids containing human chromosome 17 amplified adhalin sequences in a PCR analysis. FISH analysis with three overlapping genomic sequences confirmed the chromosome 17 location and further delineated the map position to 17q21. Therefore, adhalin is excluded as the gene causing SCARMD.

  4. B3GALNT2 mutations associated with non-syndromic autosomal recessive intellectual disability reveal a lack of genotype-phenotype associations in the muscular dystrophy-dystroglycanopathies

    NARCIS (Netherlands)

    Maroofian, R.; Riemersma, M.; Jae, L.T.; Zhianabed, N.; Willemsen, M.H.; Wissink-Lindhout, W.M.; Willemsen, M.A.A.P.; Brouwer, A.P.M. de; Mehrjardi, M.Y.V.; Ashrafi, M.R.; Kusters, B.; Kleefstra, T.; Jamshidi, Y.; Nasseri, M.; Pfundt, R.; Brummelkamp, T.R.; Abbaszadegan, M.R.; Lefeber, D.J.; Bokhoven, H. van

    2017-01-01

    BACKGROUND: The phenotypic severity of congenital muscular dystrophy-dystroglycanopathy (MDDG) syndromes associated with aberrant glycosylation of alpha-dystroglycan ranges from the severe Walker-Warburg syndrome or muscle-eye-brain disease to mild, late-onset, isolated limb-girdle muscular

  5. B3GALNT2 mutations associated with non-syndromic autosomal recessive intellectual disability reveal a lack of genotype-phenotype associations in the muscular dystrophy-dystroglycanopathies.

    Science.gov (United States)

    Maroofian, Reza; Riemersma, Moniek; Jae, Lucas T; Zhianabed, Narges; Willemsen, Marjolein H; Wissink-Lindhout, Willemijn M; Willemsen, Michèl A; de Brouwer, Arjan P M; Mehrjardi, Mohammad Yahya Vahidi; Ashrafi, Mahmoud Reza; Kusters, Benno; Kleefstra, Tjitske; Jamshidi, Yalda; Nasseri, Mojila; Pfundt, Rolph; Brummelkamp, Thijn R; Abbaszadegan, Mohammad Reza; Lefeber, Dirk J; van Bokhoven, Hans

    2017-12-22

    The phenotypic severity of congenital muscular dystrophy-dystroglycanopathy (MDDG) syndromes associated with aberrant glycosylation of α-dystroglycan ranges from the severe Walker-Warburg syndrome or muscle-eye-brain disease to mild, late-onset, isolated limb-girdle muscular dystrophy without neural involvement. However, muscular dystrophy is invariably found across the spectrum of MDDG patients. Using linkage mapping and whole-exome sequencing in two families with an unexplained neurodevelopmental disorder, we have identified homozygous and compound heterozygous mutations in B3GALNT2. The first family comprises two brothers of Dutch non-consanguineous parents presenting with mild ID and behavioral problems. Immunohistochemical analysis of muscle biopsy revealed no significant aberrations, in line with the absence of a muscular phenotype in the affected siblings. The second family includes five affected individuals from an Iranian consanguineous kindred with mild-to-moderate intellectual disability (ID) and epilepsy without any notable neuroimaging, muscle, or eye abnormalities. Complementation assays of the compound heterozygous mutations identified in the two brothers had a comparable effect on the O-glycosylation of α-dystroglycan as previously reported mutations that are associated with severe muscular phenotypes. In conclusion, we show that mutations in B3GALNT2 can give rise to a novel MDDG syndrome presentation, characterized by ID associated variably with seizure, but without any apparent muscular involvement. Importantly, B3GALNT2 activity does not fully correlate with the severity of the phenotype as assessed by the complementation assay.

  6. Genetics Home Reference: autosomal recessive primary microcephaly

    Science.gov (United States)

    ... Disorders ClinicalTrials.gov (1 link) ClinicalTrials.gov Scientific Articles on PubMed (1 link) PubMed OMIM (7 links) MICROCEPHALY 1, PRIMARY, AUTOSOMAL RECESSIVE MICROCEPHALY 2, PRIMARY, AUTOSOMAL ...

  7. A Nonsense Mutation in PDE6H Causes Autosomal-Recessive Incomplete Achromatopsia.

    NARCIS (Netherlands)

    Kohl, S.; Coppieters, F.; Meire, F.; Schaich, S.; Roosing, S.; Brennenstuhl, C.; Bolz, S.; Genderen, M.M. van; Riemslag, F.C.; Lukowski, R.; Hollander, A.I. den; Cremers, F.P.M.; Baere, E. de; Hoyng, C.B.; Wissinger, B.

    2012-01-01

    Achromatopsia (ACHM) is an autosomal-recessive retinal dystrophy characterized by color blindness, photophobia, nystagmus, and severely reduced visual acuity. Its prevalence has been estimated to about 1 in 30,000 individuals. Four genes, GNAT2, PDE6C, CNGA3, and CNGB3, have been implicated in ACHM,

  8. Carrier testing for autosomal-recessive disorders.

    Science.gov (United States)

    Vallance, Hilary; Ford, Jason

    2003-08-01

    The aim of carrier testing is to identify carrier couples at risk of having offspring with a serious genetic (autosomal recessive) disorder. Carrier couples are offered genetic consultation where their reproductive options, including prenatal diagnosis, are explained. The Ashkenazi Jewish population is at increased risk for several recessively inherited disorders (Tay-Sachs disease, Cystic fibrosis, Canavan disease, Gaucher disease, Familial Dysautonomia, Niemann-Pick disease, Fanconi anemia, and Bloom syndrome). Unlike Tay-Sachs disease, there is no simple biochemical or enzymatic test to detect carriers for these other disorders. However, with the rapid identification of disease-causing genes in recent years, DNA-based assays are increasingly available for carrier detection. Approximately 5% of the world's population carries a mutation affecting the globin chains of the hemoglobin molecule. Among the most common of these disorders are the thalassemias. The global birth rate of affected infants is at least 2 per 1000 (in unscreened populations), with the greatest incidence in Southeast Asian, Indian, Mediterranean, and Middle Eastern ethnic groups. Carriers are detected by evaluation of red cell indices and morphology, followed by more sophisticated hematological testing and molecular analyses. The following issues need to be considered in the development of a carrier screening program: (1) test selection based on disease severity and test accuracy; (2) funding for testing and genetic counselling; (3) definition of the target population to be screened; (4) development of a public and professional education program; (5) informed consent for screening; and (6) awareness of community needs.

  9. Autosomal Recessive Polycystic Kidney Disease: Antenatal Diagnosis and Histopathological Correlation

    Directory of Open Access Journals (Sweden)

    Dayananda Kumar Rajanna

    2013-01-01

    Full Text Available Autosomal recessive polycystic kidney disease (ARPKD is one of the most common inheritable disease manifesting in infancy and childhood with a frequency of 1:6,000 to 1:55,000 births. The patient in her second trimester presented with a history of amenorrhea. Ultrasound examination revealed bilateral, enlarged, hyperechogenic kidneys, placentomegaly, and severe oligohydramnios. The pregnancy was terminated. An autopsy was performed on the fetus. Both the kidneys were found to be enlarged and the cut surface showed numerous cysts. The liver sections showed changes due to fibrosis. The final diagnosis of autosomal recessive polycystic kidney disease was made based on these findings. In this article, we correlate the ante-natal ultrasound and histopathological findings in autosomal recessive polycystic kidney disease.

  10. Genetics Home Reference: autosomal recessive hyper-IgE syndrome

    Science.gov (United States)

    ... Diseases Health Topic: Pneumonia Health Topic: Skin Infections Genetic and Rare Diseases Information Center (1 link) Autosomal recessive hyper IgE syndrome Additional NIH Resources (2 links) National Institute of Allergy and Infectious Diseases: DOCK8 Deficiency National Institute of Allergy and ...

  11. Two novel mutations in ILDR1 gene cause autosomal recessive ...

    Indian Academy of Sciences (India)

    Table 1. Autosomal recessive nonsyndromic hearing loss loci and related genes. STR-markers and primers used for screening the loci are listed. Repeated sequence. Locus. Gene STR marker. Position. Forward primer. Reverse primer. Length (bp). DFNB2 MYOTA D11s911 77448582-77448892 CA. D11S937. 77854318- ...

  12. Exome Sequencing and Directed Clinical Phenotyping Diagnose Cholesterol Ester Storage Disease Presenting as Autosomal Recessive Hypercholesterolemia

    NARCIS (Netherlands)

    Stitziel, Nathan O.; Fouchier, Sigrid W.; Sjouke, Barbara; Peloso, Gina M.; Moscoso, Alessa M.; Auer, Paul L.; Goel, Anuj; Gigante, Bruna; Barnes, Timothy A.; Melander, Olle; Orho-Melander, Marju; Duga, Stefano; Sivapalaratnam, Suthesh; Nikpay, Majid; Martinelli, Nicola; Girelli, Domenico; Jackson, Rebecca D.; Kooperberg, Charles; Lange, Leslie A.; Ardissino, Diego; McPherson, Ruth; Farrall, Martin; Watkins, Hugh; Reilly, Muredach P.; Rader, Daniel J.; de Faire, Ulf; Schunkert, Heribert; Erdmann, Jeanette; Samani, Nilesh J.; Charnas, Lawrence; Altshuler, David; Gabriel, Stacey; Kastelein, John J. P.; Defesche, Joep C.; Nederveen, Aart J.; Kathiresan, Sekar; Hovingh, G. Kees

    2013-01-01

    Objective Autosomal recessive hypercholesterolemia is a rare inherited disorder, characterized by extremely high total and low-density lipoprotein cholesterol levels, that has been previously linked to mutations in LDLRAP1. We identified a family with autosomal recessive hypercholesterolemia not

  13. Autosomal recessive progressive myoclonus epilepsy due to impaired ceramide synthesis.

    Science.gov (United States)

    Ferlazzo, Edoardo; Striano, Pasquale; Italiano, Domenico; Calarese, Tiziana; Gasparini, Sara; Vanni, Nicola; Fruscione, Floriana; Genton, Pierre; Zara, Federico

    2016-09-01

    Autosomal recessive progressive myoclonus epilepsy due to impaired ceramide synthesis is an extremely rare condition, so far reported in a single family of Algerian origin presenting an unusual, severe form of progressive myoclonus epilepsy characterized by myoclonus, generalized tonic-clonic seizures and moderate to severe cognitive impairment, with probable autosomal recessive inheritance. Disease onset was between 6 and 16 years of age. Genetic study allowed to identify a homozygous nonsynonymous mutation in CERS1, the gene encoding ceramide synthase 1, a transmembrane protein of the endoplasmic reticulum (ER), catalyzes the biosynthesis of C18-ceramides. The mutation decreased C18-ceramide levels. In addition, downregulation of CerS1 in neuroblastoma cell line showed activation of ER stress response and induction of proapoptotic pathways. This observation demonstrates that impairment of ceramide biosynthesis underlies neurodegeneration in humans.

  14. Autosomal recessive osteopetrosis with a unique imaging finding: multiple encephaloceles

    International Nuclear Information System (INIS)

    Saglam, Dilek; Bilgici, Meltem Ceyhan; Bekci, Tuemay; Albayrak, Canan; Albayrak, Davut

    2017-01-01

    Osteopetrosis is a hereditary form of sclerosing bone dysplasia with various radiological and clinical presentations. The autosomal recessive type, also known as malignant osteopetrosis, is the most severe type, with the early onset of manifestations. A 5-month-old infant was admitted to our hospital with recurrent respiratory tract infections. Chest X-ray and skeletal survey revealed the classic findings of osteopetrosis, including diffuse osteosclerosis and bone within a bone appearance. At follow-up, the patient presented with, thickened calvarium, multiple prominent encephaloceles, and dural calcifications leading to the intracranial clinical manifestations with bilateral hearing and sight loss. Autosomal recessive osteopetrosis is one of the causes of encephaloceles and this finding may become dramatic if untreated. (orig.)

  15. Autosomal recessive osteopetrosis with a unique imaging finding: multiple encephaloceles

    Energy Technology Data Exchange (ETDEWEB)

    Saglam, Dilek; Bilgici, Meltem Ceyhan; Bekci, Tuemay [Ondokuz Mayis University, Department of Radiology, School of Medicine, Kurupelit, Samsun (Turkey); Albayrak, Canan; Albayrak, Davut [Ondokuz Mayis University, Department of Pediatrics, School of Medicine, Kurupelit, Samsun (Turkey)

    2017-05-15

    Osteopetrosis is a hereditary form of sclerosing bone dysplasia with various radiological and clinical presentations. The autosomal recessive type, also known as malignant osteopetrosis, is the most severe type, with the early onset of manifestations. A 5-month-old infant was admitted to our hospital with recurrent respiratory tract infections. Chest X-ray and skeletal survey revealed the classic findings of osteopetrosis, including diffuse osteosclerosis and bone within a bone appearance. At follow-up, the patient presented with, thickened calvarium, multiple prominent encephaloceles, and dural calcifications leading to the intracranial clinical manifestations with bilateral hearing and sight loss. Autosomal recessive osteopetrosis is one of the causes of encephaloceles and this finding may become dramatic if untreated. (orig.)

  16. Mutations of the tyrosinase gene produce autosomal recessive ocular albinism

    Energy Technology Data Exchange (ETDEWEB)

    King, R.A.; Summers, C.G.; Oetting, W.S. [Univ. of Minnesota, Minneapolis, MN (United States)] [and others

    1994-09-01

    Albinism has historically been divided into ocular (OA) and oculocutaneous (OCA) types based on the presence or absence of clinically apparent skin and hair involvement in an individual with the ocular features of albinism. The major genes for OCA include the tyrosinase gene in OCA1 and the P gene in OCA2. X-linked and autosomal recessive OA have been described and the responsible genes have not been identified. We now present six Caucasian individuals who have the phenotype of autosomal recessive OA but who have OCA1 as shown by the presence of mutations of the tyrosinase. They had white or very light hair and white skin at birth, and cutaneous pigment developed in the first decade of life. At ages ranging from 1.5-23 years, hair color was dark blond to light brown. The skin had generalized pigment and well developed tan was present on the exposed arm and face skin of four. Iris pigment was present and iris translucency varied. Molecular analysis of the tyrosinase gene, using PCR amplification and direct di-deoxy sequencing showed the following mutations: E398Z/E398Q, P406S/g346a, R402E/T373K, ?/D383N, and H211N/T373K. The homozygous individual was not from a known consanguineous mating. T373K is the most common tyrosinase gene mutation in our laboratory. Three of these mutations are associated with a total loss of tyrosinase activity (g346a splice-site, T373K, and D383N), while four are associated with residual enzyme activity (H211N, R402E, E398Q, and P406S). These studies show that mutations of the tyrosinase gene can produce the phenotype of autosomal recessive OA in an individual who has normal amounts of cutaneous pigment and the ability to tan after birth. This extends the phenotypic range of OCA1 to normal cutaneous pigment after early childhood, and suggest that mutations of the tyrosinase gene account for a significant number of individuals with autosomal recessive OA.

  17. Autosomal recessive mode of inheritance of a Coffin-Siris like syndrome.

    Science.gov (United States)

    Bonioli, E; Palmieri, A; Bertola, A; Bellini, C

    1995-01-01

    Autosomal recessive mode of inheritance of a Coffin-Siris like syndrome: Coffin-Siris syndrome is a rare mental retardation/multiple congenital anomalies syndrome; so far its pattern of inheritance is under debate. We report a child affected by this syndrome, the pedigree of which is consistent with autosomal recessive inheritance.

  18. Linkage of autosomal recessive lamellar ichthyosis to chromosome 14q

    Energy Technology Data Exchange (ETDEWEB)

    Russell, L.J.; Compton, J.G.; Bale, S.J. [National Institute of Arthritis and Musculoskeletal and Skin Diseases, Bethesda, MD (United States); DiGiovanna, J.J. [National Cancer Institute, Bethesda, MD (United States); Hashem, N. [Ains-Shams Univ. Medical Genetics Center, Cairo (Egypt)

    1994-12-01

    The authors have mapped the locus for lamellar ichthyosis (LI), an autosomal recessive skin disease characterized by abnormal cornification of the epidermis. Analysis using both inbred and outbred families manifesting severe LI showed complete linkage to several markers within a 9.3-cM region on chromosome 14q11. Affected individuals in inbred families were also found to have striking homozygosity for markers in this region. Linkage-based genetic counseling and prenatal diagnosis is now available for informative at-risk families. Several transcribed genes have been mapped to the chromosome 14 region containing the LI gene. The transglutaminase 1 gene (TGM1), which encodes one of the enzymes responsible for cross-linking epidermal proteins during formation of the stratum corneum, maps to this interval. The TGM1 locus was completely linked to LI (Z = 9.11), suggesting that TGM1 is a good candidate for further investigation of this disorder. The genes for four serine proteases also map to this region but are expressed only in hematopoietic or mast cells, making them less likely candidates.

  19. Otologic Manifestations of Autosomal Recessive Congenital Ichthyosis in Children.

    Science.gov (United States)

    Martín-Santiago, A; Rodríguez-Pascual, M; Knöpfel, N; Hernández-Martín, Á

    2015-11-01

    Few studies have investigated ear involvement in nonsyndromic autosomal recessive congenital ichthyosis (ARCI). To assess the type and frequency of otologic manifestations of ARCI in patients under follow-up at the pediatric dermatology department of our hospital. We prospectively studied the presence of ear pain, ear itching, tinnitus, otitis, cerumen impaction, accumulation of epithelial debris, and hearing loss. Daily hygiene measures, topical treatments, medical-surgical interventions, and frequency of visits to an ear, nose, and throat (ENT) specialist were noted in the patients' medical records. Ear examination and hearing tests were performed in all cases. Ten patients were studied: 2 had a self-healing collodion baby phenotype and 8 had ichthyosis. There was mention of otologic manifestations in the records of all 8 patients with ichthyosis (100%); 6 of these patients (75%) had abnormalities in the external auditory canal examination and 2 (25%) had conductive hearing loss. Our findings are limited by the small number of patients studied, all of whom were younger than 19 years. The involvement of both dermatologists and ENT specialists in the management of patients with ichthyosis is crucial to ensure the application of the best therapeutic and preventive measures. More studies are needed to assess the prevalence and impact on quality of life of ear involvement in patients with ichthyosis and to determine the optimal interval between ENT visits for these patients. Copyright © 2015 Elsevier España, S.L.U. and AEDV. All rights reserved.

  20. Spectrum of Autosomal Recessive Congenital Ichthyosis in Scandinavia

    DEFF Research Database (Denmark)

    Hellström Pigg, Maritta; Bygum, Anette; Gånemo, Agneta

    2016-01-01

    Autosomal recessive congenital ichthyosis (ARCI) represents a heterogeneous group of rare disorders of cornification with 3 major subtypes: harlequin ichthyosis (HI), lamellar ichthyosis (LI) and congenital ichthyosiform erythroderma (CIE). A 4th subtype has also been proposed: pleomorphic...... ichthyosis (PI), characterized by marked skin changes at birth and subsequently mild symptoms. In nationwide screenings of suspected cases of ARCI in Denmark and Sweden, we identified 132 patients (age range 0.1-86 years) classified as HI (n = 7), LI (n = 70), CIE (n = 17) and PI (n = 38). At birth......-100%). A scoring (0-4) of ichthyosis/ery-thema past infancy showed widely different mean values in the subgroups: HI (3.2/3.1), LI (2.4/0.6), CIE (1.8/1.6), PI (1.1/0.3). Novel or recurrent mutations were found in 113 patients: TGM1 (n = 56), NIPAL4 (n = 15), ALOX12B (n = 15), ABCA12 (n = 8), ALOXE3 (n = 9), SLC27...

  1. MR cholangiography in children with autosomal recessive polycystic kidney disease

    International Nuclear Information System (INIS)

    Jung, G.; Benz-Bohm, G.; Kugel, H.; Keller, K.M.; Querfeld, U.

    1999-01-01

    Background. Magnetic resonance cholangiography (MRC) is a relatively new, non-invasive imaging technique of the biliary tree that has shown good correlation with endoscopic retrograde cholangiopancreatography. The liver manifestation of autosomal recessive polycystic kidney disease (ARPKD) is congenital hepatic fibrosis (CHF). CHF may be accompanied by Caroli's disease, which is characterised by a non-obstructive dilation of the intrahepatic bile ducts. Objective. A prospective study was conducted to determine the presence and extent of Caroli's disease in children with ARPKD. Materials and methods. Seven children with ARPKD aged from 3.0 to 10.1 years were examined. CHF was confirmed in all biopsied cases (5 of 7). All children had been followed by repeated abdominal US examinations for many years. The MR examination included a morphological imaging study using a T2-weighted turbo spin-echo sequence and a heavily T2-weighted inversion-recovery turbo spin-echo sequence with three-dimensional maximum intensity projection (MIP) reconstructions for MRC. Results. The diagnosis of Caroli's disease could be made in one case by US; in two other children Caroli's disease was suspected, but the differentiation from hepatic cysts was not possible. By MRC, Caroli's disease could be diagnosed in three of seven children. Furthermore, MRC with MIP reconstructions demonstrated the extent of the disease by showing the entire biliary tree from different angles. Conclusions. MRC is a valuable method to establish the diagnosis and demonstrate the extent of Caroli's disease. (orig.)

  2. Autosomal recessive agammaglobulinemia: a novel non-sense mutation in CD79a.

    Science.gov (United States)

    Khalili, Abbas; Plebani, Alessandro; Vitali, Massimiliano; Abolhassani, Hassan; Lougaris, Vassilios; Mirminachi, Babak; Rezaei, Nima; Aghamohammadi, Asghar

    2014-02-01

    This study describes the fifth case worldwide of autosomal recessive agammaglobulinemia due to a novel non-sense mutation in CD79a gene with a severe unusual onset due to an invasive central nervous system infection.

  3. Autosomal Recessive Polycystic Kidney Disease and Epidemiologic Factors

    Directory of Open Access Journals (Sweden)

    Parsa Yousefichaijan

    2017-01-01

    Full Text Available Background Autosomal recessive polycystic kidney disease (ARPKD is a heterogeneous inherited disorder most commonly seen in childhood. The presentation is usually a palpable large mass in the flank or abdomen appearing at infancy or birth, leading to electrolyte abnormalities, pulmonary hypoplasia, oligohydramnious and the Potter’s syndrome. The survival rate of this disease is 70%. Multiple mutations of the polycystic kidney and hepatic disease 1 (PKHD1 are known that can cause ARPKD. On the other hand, mutations in PKHD1 have also been identified in about 30% of children with congenital hepatic fibrosis (the Caroli’s syndrome without any evidence of kidney involvement. Based on this evidence, not everyone with PKHD1 mutations will present with ARPKD. Recent studies have shown that nongenetic factors, including environmental exposures had a significant effect on manifestations of ARPKD. The present study aimed at investigating the possible link between ARPKD and its epidemiologic factors, hypothesizing that these epidemiologic conditions would influence the incidence of ARPKD. Objectives The present study aimed at evaluating a possible link between the ARPKD and its epidemiologic factors. Methods In this case-control study, children with ARPKD referred to Amirkabir hospital in Arak city, Iran, were compared with noninfected children. Examinations, interviews, and questionnaires were performed to collect data and the disease was diagnosed by a physician. Results The results of this study showed no significant relationship between epidemiological factors such as age, place of residence for families, sex, family education/occupation/ income, body mass index, stunted growth, slow growth, good growth, milk intake, water intake, failure to thrive and ARPKD. Conclusions Based on our findings, epidemiological factors did not have a significant effect on the occurrence of ARPKD.

  4. A Novel Homozygous Missense Mutation in HOXC13 Leads to Autosomal Recessive Pure Hair and Nail Ectodermal Dysplasia.

    Science.gov (United States)

    Li, Xiaoxiao; Orseth, Meredith Lee; Smith, J Michael; Brehm, Mary Abigail; Agim, Nnenna Gebechi; Glass, Donald Alexander

    2017-03-01

    Pure hair and nail ectodermal dysplasia (PHNED) is a rare disorder that presents with hypotrichosis and nail dystrophy while sparing other ectodermal structures such as teeth and sweat glands. We describe a homozygous novel missense mutation in the HOXC13 gene that resulted in autosomal recessive PHNED in a Hispanic child. The mutation c.812A>G (p.Gln271Arg) is located within the DNA-binding domain of the HOXC13 gene, cosegregates within the family, and is predicted to be maximally damaging. This is the first reported case of a missense HOXC13 mutation resulting in PHNED and the first reported case of PHNED identified in a North American family. Our findings illustrate the critical role of HOXC13 in human hair and nail development. © 2017 Wiley Periodicals, Inc.

  5. A Dutch family with autosomal recessively inherited lower motor neuron predominant motor neuron disease due to optineurin mutations

    NARCIS (Netherlands)

    Beeldman, Emma; van der Kooi, Anneke J.; de Visser, Marianne; van Maarle, Merel C.; van Ruissen, Fred; Baas, Frank

    2015-01-01

    Approximately 10% of motor neuron disease (MND) patients report a familial predisposition for MND. Autosomal recessively inherited MND is less common and is most often caused by mutations in the superoxide dismutase 1 (SOD1) gene. In 2010, autosomal recessively inherited mutations in the optineurin

  6. An autosomal recessive disorder with retardation of growth, mental deficiency, ptosis, pectus excavatum and camptodactyly

    International Nuclear Information System (INIS)

    Khaldi, F.; Bennaceur, B.; Hammou, A.; Hamza, M.; Gharbi, H.A.

    1988-01-01

    Two strikingly similar brothers issued from consanguineous parents in the second degree present the following patterns of anomalies: Retardation of growth, mental deficiency, ocular abnormalities, pectus excavatum and camptodactyly. The ocular abnormalities include ptosis, microphthalmia and hypertelorism. No endocrine or metabolic aberrations are found. The authors conclude that the disorder has probably an autosomal recessive mode of transmission. (orig.)

  7. Spectrum of mutations in the renin-angiotensin system genes in autosomal recessive renal tubular dysgenesis

    DEFF Research Database (Denmark)

    Gribouval, Olivier; Morinière, Vincent; Pawtowski, Audrey

    2012-01-01

    Autosomal recessive renal tubular dysgenesis (RTD) is a severe disorder of renal tubular development characterized by early onset and persistent fetal anuria leading to oligohydramnios and the Potter sequence, associated with skull ossification defects. Early death occurs in most cases from anuri...

  8. Prenatal diagnosis of autosomal recessive Robinow syndrome using 3D ultrasound

    DEFF Research Database (Denmark)

    Jeppesen, Bolette F.; Buciek, Hanne Hove; Kreiborg, Sven

    2017-01-01

    This article hypothesizes that it is possible to detect and diagnose both the autosomal recessive and dominant forms prenatally using ultrasound. By focusing on the characteristic phenotypical presentation, the examinator is able to diagnose the syndrome prenatally, which is of clinical importance...

  9. Autosomal recessive retinitis pigmentosa with RP1 mutations is associated with myopia

    NARCIS (Netherlands)

    Chassine, T.; Bocquet, B.; Daien, V.; Avila-Fernandez, A.; Ayuso, C.; Collin, R.W.J.; Corton, M.; Hejtmancik, J.F.; Born, L.I. van den; Klevering, B.J.; Riazuddin, S.A.; Sendon, N.; Lacroux, A.; Meunier, I.; Hamel, C.P.

    2015-01-01

    OBJECTIVE: To determine the refractive error in patients with autosomal recessive retinitis pigmentosa (arRP) caused by RP1 mutations and to compare it with that of other genetic subtypes of RP. METHODS: Twenty-six individuals had arRP with RP1 mutations, 25 had autosomal dominant RP (adRP) with RP1

  10. The efficacy of microarray screening for autosomal recessive retinitis pigmentosa in routine clinical practice

    NARCIS (Netherlands)

    Huet, R.A.C. van; Pierrache, L.H.; Meester-Smoor, M.A.; Klaver, C.C.; Born, L.I. van den; Hoyng, C.B.; Wijs, I.J. de; Collin, R.W.J.; Hoefsloot, L.H.; Klevering, B.J.

    2015-01-01

    PURPOSE: To determine the efficacy of multiple versions of a commercially available arrayed primer extension (APEX) microarray chip for autosomal recessive retinitis pigmentosa (arRP). METHODS: We included 250 probands suspected of arRP who were genetically analyzed with the APEX microarray between

  11. Biallelic Mutations in CRB1 Underlie Autosomal Recessive Familial Foveal Retinoschisis

    NARCIS (Netherlands)

    Vincent, A.; Ng, J.; Gerth-Kahlert, C.; Tavares, E.; Maynes, J.T.; Wright, T.; Tiwari, A.; Tumber, A.; Li, S.; Hanson, J.V.; Bahr, A.; MacDonald, H.; Bahr, L.; Westall, C.; Berger, W.; Cremers, F.P.M.; Hollander, A.I. den; Heon, E

    2016-01-01

    PURPOSE: To identify the genetic cause of autosomal recessive familial foveal retinoschisis (FFR). METHODS: A female sibship with FFR was identified (Family-A; 17 and 16 years, respectively); panel based genetic sequencing (132 genes) and comparative genome hybridization (142 genes) were performed.

  12. Mutations in AGBL5, Encoding alpha-Tubulin Deglutamylase, Are Associated With Autosomal Recessive Retinitis Pigmentosa

    NARCIS (Netherlands)

    Astuti, G.D.; Arno, G.; Hull, S.; Pierrache, L.; Venselaar, H.; Carss, K.; Raymond, F.L.; Collin, R.W.J.; Faradz, S.M.; Born, L.I. van den; Webster, A.R.; Cremers, F.P.

    2016-01-01

    Purpose: AGBL5, encoding ATP/GTP binding protein-like 5, was previously proposed as an autosomal recessive retinitis pigmentosa (arRP) candidate gene based on the identification of missense variants in two families. In this study, we performed next-generation sequencing to reveal additional RP cases

  13. CNGB3 mutations account for 50% of all cases with autosomal recessive achromatopsia.

    NARCIS (Netherlands)

    Kohl, S.; Varsanyi, B.; Antunes, G.A.; Baumann, B.; Hoyng, C.B.; Jagle, H.; Rosenberg, T.; Kellner, U.; Lorenz, B.; Salati, R.; Jurklies, B.; Farkas, A.; Andreasson, S.; Weleber, R.G.; Jacobson, S.G.; Rudolph, G.; Castellan, C.; Dollfus, H.; Legius, E.; Anastasi, M.; Bitoun, P.; Lev, D.; Sieving, P.A.; Munier, F.L.; Zrenner, E.; Sharpe, L.T.; Cremers, F.P.M.; Wissinger, B.

    2005-01-01

    Achromatopsia is a congenital, autosomal recessively inherited disorder characterized by a lack of color discrimination, low visual acuity (<0.2), photophobia, and nystagmus. Mutations in the genes for CNGA3, CNGB3, and GNAT2 have been associated with this disorder. Here, we analyzed the spectrum

  14. Autosomal recessive ichthyosis with hypotrichosis syndrome: further delineation of the phenotype

    NARCIS (Netherlands)

    Avrahami, L.; Maas, S.; Pasmanik-Chor, M.; Rainshtein, L.; Magal, N.; Smitt, J. H. S.; van Marle, J.; Shohat, M.; Basel-Vanagaite, L.

    2008-01-01

    Autosomal recessive ichthyosis with hypotrichosis (ARIH) syndrome, which is characterized by congenital ichthyosis, abnormal hair and corneal involvement, has recently been shown in one consanguineous Israeli Arab family to be caused by a mutation in the ST14 gene, which encodes serine protease

  15. Progeria (Hutchison - Gilford syndrome in siblings: In an autosomal recessive pattern of inheritance

    Directory of Open Access Journals (Sweden)

    Raghu Tanjore

    2001-09-01

    Full Text Available Progeria is an autosomal dominant, premature aging syndrome. Six and three year old female siblings had sclcrodermatous changes over the extremities, alopecia, beaked nose, prominent veins and bird-like facies. Radiological features were consistent with features of progeria. The present case highlights rarity of progeria in siblings with a possible autosomal recessive pattern.

  16. Calpain 12 Function Revealed through the Study of an Atypical Case of Autosomal Recessive Congenital Ichthyosis.

    Science.gov (United States)

    Bochner, Ron; Samuelov, Liat; Sarig, Ofer; Li, Qiaoli; Adase, Christopher A; Isakov, Ofer; Malchin, Natalia; Vodo, Dan; Shayevitch, Ronna; Peled, Alon; Yu, Benjamin D; Fainberg, Gilad; Warshauer, Emily; Adir, Noam; Erez, Noam; Gat, Andrea; Gottlieb, Yehonatan; Rogers, Tova; Pavlovsky, Mor; Goldberg, Ilan; Shomron, Noam; Sandilands, Aileen; Campbell, Linda E; MacCallum, Stephanie; McLean, W H Irwin; Ast, Gil; Gallo, Richard L; Uitto, Jouni; Sprecher, Eli

    2017-02-01

    Congenital erythroderma is a rare and often life-threatening condition, which has been shown to result from mutations in several genes encoding important components of the epidermal differentiation program. Using whole exome sequencing, we identified in a child with congenital exfoliative erythroderma, hypotrichosis, severe nail dystrophy and failure to thrive, two heterozygous mutations in ABCA12 (c.2956C>T, p.R986W; c.5778+2T>C, p. G1900Mfs*16), a gene known to be associated with two forms of ichthyosis, autosomal recessive congenital ichthyosis, and harlequin ichthyosis. Because the patient displayed an atypical phenotype, including severe hair and nail manifestations, we scrutinized the exome sequencing data for additional potentially deleterious genetic variations in genes of relevance to the cornification process. Two mutations were identified in CAPN12, encoding a member of the calpain proteases: a paternal missense mutation (c.1511C>A; p.P504Q) and a maternal deletion due to activation of a cryptic splice site in exon 9 of the gene (c.1090_1129del; p.Val364Lysfs*11). The calpain 12 protein was found to be expressed in both the epidermis and hair follicle of normal skin, but its expression was dramatically reduced in the patient's skin. The downregulation of capn12 expression in zebrafish was associated with abnormal epidermal morphogenesis. Small interfering RNA knockdown of CAPN12 in three-dimensional human skin models was associated with acanthosis, disorganized epidermal architecture, and downregulation of several differentiation markers, including filaggrin. Accordingly, filaggrin expression was almost absent in the patient skin. Using ex vivo live imaging, small interfering RNA knockdown of calpain 12 in skin from K14-H2B GFP mice led to significant hair follicle catagen transformation compared with controls. In summary, our results indicate that calpain 12 plays an essential role during epidermal ontogenesis and normal hair follicle cycling and that

  17. ALS5/SPG11/KIAA1840 mutations cause autosomal recessive axonal Charcot-Marie-Tooth disease.

    Science.gov (United States)

    Montecchiani, Celeste; Pedace, Lucia; Lo Giudice, Temistocle; Casella, Antonella; Mearini, Marzia; Gaudiello, Fabrizio; Pedroso, José L; Terracciano, Chiara; Caltagirone, Carlo; Massa, Roberto; St George-Hyslop, Peter H; Barsottini, Orlando G P; Kawarai, Toshitaka; Orlacchio, Antonio

    2016-01-01

    Charcot-Marie-Tooth disease is a group of hereditary peripheral neuropathies that share clinical characteristics of progressive distal muscle weakness and atrophy, foot deformities, distal sensory loss, as well as diminished tendon reflexes. Hundreds of causative DNA changes have been found, but much of the genetic basis of the disease is still unexplained. Mutations in the ALS5/SPG11/KIAA1840 gene are a frequent cause of autosomal recessive hereditary spastic paraplegia with thin corpus callosum and peripheral axonal neuropathy, and account for ∼ 40% of autosomal recessive juvenile amyotrophic lateral sclerosis. The overlap of axonal Charcot-Marie-Tooth disease with both diseases, as well as the common autosomal recessive inheritance pattern of thin corpus callosum and axonal Charcot-Marie-Tooth disease in three related patients, prompted us to analyse the ALS5/SPG11/KIAA1840 gene in affected individuals with autosomal recessive axonal Charcot-Marie-Tooth disease. We investigated 28 unrelated families with autosomal recessive axonal Charcot-Marie-Tooth disease defined by clinical, electrophysiological, as well as pathological evaluation. Besides, we screened for all the known genes related to axonal autosomal recessive Charcot-Marie-Tooth disease (CMT2A2/HMSN2A2/MFN2, CMT2B1/LMNA, CMT2B2/MED25, CMT2B5/NEFL, ARCMT2F/dHMN2B/HSPB1, CMT2K/GDAP1, CMT2P/LRSAM1, CMT2R/TRIM2, CMT2S/IGHMBP2, CMT2T/HSJ1, CMTRID/COX6A1, ARAN-NM/HINT and GAN/GAN), for the genes related to autosomal recessive hereditary spastic paraplegia with thin corpus callosum and axonal peripheral neuropathy (SPG7/PGN, SPG15/ZFYVE26, SPG21/ACP33, SPG35/FA2H, SPG46/GBA2, SPG55/C12orf65 and SPG56/CYP2U1), as well as for the causative gene of peripheral neuropathy with or without agenesis of the corpus callosum (SLC12A6). Mitochondrial disorders related to Charcot-Marie-Tooth disease type 2 were also excluded by sequencing POLG and TYMP genes. An additional locus for autosomal recessive Charcot

  18. ALS5/SPG11/ KIAA1840 mutations cause autosomal recessive axonal Charcot–Marie–Tooth disease

    Science.gov (United States)

    Montecchiani, Celeste; Pedace, Lucia; Lo Giudice, Temistocle; Casella, Antonella; Mearini, Marzia; Gaudiello, Fabrizio; Pedroso, José L.; Terracciano, Chiara; Caltagirone, Carlo; Massa, Roberto; St George-Hyslop, Peter H.; Barsottini, Orlando G. P.; Kawarai, Toshitaka

    2016-01-01

    Abstract Charcot–Marie–Tooth disease is a group of hereditary peripheral neuropathies that share clinical characteristics of progressive distal muscle weakness and atrophy, foot deformities, distal sensory loss, as well as diminished tendon reflexes. Hundreds of causative DNA changes have been found, but much of the genetic basis of the disease is still unexplained. Mutations in the ALS5/SPG11/ KIAA1840 gene are a frequent cause of autosomal recessive hereditary spastic paraplegia with thin corpus callosum and peripheral axonal neuropathy, and account for ∼40% of autosomal recessive juvenile amyotrophic lateral sclerosis. The overlap of axonal Charcot–Marie–Tooth disease with both diseases, as well as the common autosomal recessive inheritance pattern of thin corpus callosum and axonal Charcot–Marie–Tooth disease in three related patients, prompted us to analyse the ALS5/SPG11/ KIAA1840 gene in affected individuals with autosomal recessive axonal Charcot–Marie–Tooth disease. We investigated 28 unrelated families with autosomal recessive axonal Charcot–Marie–Tooth disease defined by clinical, electrophysiological, as well as pathological evaluation. Besides, we screened for all the known genes related to axonal autosomal recessive Charcot–Marie-Tooth disease (CMT2A2/HMSN2A2/ MFN2 , CMT2B1/ LMNA , CMT2B2/ MED25 , CMT2B5/ NEFL , ARCMT2F/dHMN2B/ HSPB1 , CMT2K/ GDAP1 , CMT2P/ LRSAM1 , CMT2R/ TRIM2 , CMT2S/ IGHMBP2 , CMT2T/ HSJ1 , CMTRID/ COX6A1 , ARAN-NM/ HINT and GAN/ GAN ), for the genes related to autosomal recessive hereditary spastic paraplegia with thin corpus callosum and axonal peripheral neuropathy (SPG7/ PGN , SPG15/ ZFYVE26, SPG21/ ACP33 , SPG35/ FA2H , SPG46/ GBA2 , SPG55/ C12orf65 and SPG56/ CYP2U1 ), as well as for the causative gene of peripheral neuropathy with or without agenesis of the corpus callosum ( SLC12A6 ) . Mitochondrial disorders related to Charcot–Marie–Tooth disease type 2 were also excluded by sequencing POLG and

  19. Infantile variant of Bartter syndrome and sensorineural deafness: A new autosomal recessive disorder

    Energy Technology Data Exchange (ETDEWEB)

    Landau, D.; Shalev, H.; Carmi, Rivka; Ohaly, M. [Univ. of the Negev, Ashkelon (Israel)

    1995-12-04

    The infantile variant of Bartter syndrome (IBS) is usually associated with maternal polyhydramnios, premature birth, postnatal polyuria and hypokalemic hypochloremic metabolic alkalosis and a typical appearance. IBS is thought to be an autosomal recessive trait. Several congenital tubular defects are associated with sensorineural deafness (SND). However, an association between the IBS and SND has not been reported so far. Here we describe 5 children of an extended consanguineous Bedouin family with IBS and SND. In 3 of the cases, the typical electrolyte imbalance and facial appearance were detected neonatally. SND was detected as early as age 1 month, suggesting either coincidental homozygotization of 2 recessive genes or a pleiotropic effect of one autosomal recessive gene. This association suggests that evaluation of SND is warranted in every case of IBS. 35 refs., 2 figs., 2 tabs.

  20. A Novel Mutation in the Transglutaminase-1 Gene in an Autosomal Recessive Congenital Ichthyosis Patient

    Directory of Open Access Journals (Sweden)

    D. Vaigundan

    2014-01-01

    Full Text Available Structure-function implication on a novel homozygous Trp250/Gly mutation of transglutaminase-1 (TGM1 observed in a patient of autosomal recessive congenital ichthyosis is invoked from a bioinformatics analysis. Structural consequences of this mutation are hypothesized in comparison to homologous enzyme human factor XIIIA accepted as valid in similar structural analysis and are projected as guidelines for future studies at an experimental level on TGM1 thus mutated.

  1. Improved Structure and Function in Autosomal Recessive Polycystic Rat Kidneys with Renal Tubular Cell Therapy.

    Science.gov (United States)

    Kelly, K J; Zhang, Jizhong; Han, Ling; Kamocka, Malgorzata; Miller, Caroline; Gattone, Vincent H; Dominguez, Jesus H

    2015-01-01

    Autosomal recessive polycystic kidney disease is a truly catastrophic monogenetic disease, causing death and end stage renal disease in neonates and children. Using PCK female rats, an orthologous model of autosomal recessive polycystic kidney disease harboring mutant Pkhd1, we tested the hypothesis that intravenous renal cell transplantation with normal Sprague Dawley male kidney cells would improve the polycystic kidney disease phenotype. Cytotherapy with renal cells expressing wild type Pkhd1 and tubulogenic serum amyloid A1 had powerful and sustained beneficial effects on renal function and structure in the polycystic kidney disease model. Donor cell engraftment and both mutant and wild type Pkhd1 were found in treated but not control PCK kidneys 15 weeks after the final cell infusion. To examine the mechanisms of global protection with a small number of transplanted cells, we tested the hypothesis that exosomes derived from normal Sprague Dawley cells can limit the cystic phenotype of PCK recipient cells. We found that renal exosomes originating from normal Sprague Dawley cells carried and transferred wild type Pkhd1 mRNA to PCK cells in vivo and in vitro and restricted cyst formation by cultured PCK cells. The results indicate that transplantation with renal cells containing wild type Pkhd1 improves renal structure and function in autosomal recessive polycystic kidney disease and may provide an intra-renal supply of normal Pkhd1 mRNA.

  2. Genetic Causes of Putative Autosomal Recessive Intellectual Disability Cases in Hamedan Province

    Directory of Open Access Journals (Sweden)

    Milad Bastami

    2012-04-01

    Full Text Available Objective: The aim of this study was to investigate the genetic causes of autosomal recessive intellectual disabilities (AR-ID in Hamadan province of Iran. Materials & Methods: In this descriptive-analytical cross-sectional study, 25 families with more than one affected with putative autosomal recessive intellectual disability were chosen with collaboration of Welfare Organization of Hamadan province. Families were included a total of 60 patients (39 male and 21 female whose intellectual disability had been confirmed by Raven IQ test. Each family was asked for clinical examination and getting consent form. Blood sample was collected from each family. One proband from each family was tested for CGG repeat expansion in FMR1 gene, chromosomal abnormalities and inborn errors of metabolism. We also performed homozygosity mapping based on STR markers for seven known MCPH loci in families with primary microcephaly and AR-ID. Results: Five families had full mutation of Fragile X syndrome. No chromosomal abnormalities were identified. Metabolic screening revealed one family with Medium Chain Acyl CoA Dehydrogenase deficiency. None of three families with primary microcephaly and AR-ID showed linkage to any of known seven MCPH loci. Conclusion: The main causes of ID in Hamadan province were Fragile X syndrome and Autosomal Recessive Primary Microcephaly with the frequencies of 20% and 12%, respectively.

  3. Confirmation of ADAMTSL4 mutations for autosomal recessive isolated bilateral ectopia lentis.

    Science.gov (United States)

    Greene, V Bennouna; Stoetzel, C; Pelletier, V; Perdomo-Trujillo, Y; Liebermann, L; Marion, V; De Korvin, H; Boileau, C; Dufier, J L; Dollfus, H

    2010-03-01

    Ectopia lentis (EL) is a zonular disease where alteration of the zonular fibers leads progressively to lens dislocation. It is most often associated with systemic diseases such as Marfan syndrome, Weill-Marchesani syndrome or homocystinuria. Isolated non syndromic ectopia lentis (IEL) is reported in families with autosomal inheritance, with dominant forms being more common than recessive. LTBP2 truncating mutations have been described as a cause of autosomal recessive ectopia lentis as a primary or secondary feature in patients showing ocular (eg, glaucoma) or extraocular manifestations (eg, Marfanoid habitus). Recently, ADAMTSL4 has been shown to be responsible for isolated autosomal recessive ectopia lentis in an inbred family. Herein we show a consanguineous family that carries a novel homozygous splice mutation IVS4-1G>A/IVS4-1G>A in ADAMTSL4 responsible for isolated autosomal recessive EL, thus confirming the involvement of this gene in this condition and underlining the major role of ADAMTS proteases in zonular fibers homeostasis.

  4. One-step noninvasive prenatal testing (NIPT) for autosomal recessive homozygous point mutations using digital PCR.

    Science.gov (United States)

    Chang, Mun Young; Ahn, Soyeon; Kim, Min Young; Han, Jin Hee; Park, Hye-Rim; Seo, Han Kyu; Yoon, Jinsun; Lee, Seungmin; Oh, Doo-Yi; Kang, Changsoo; Choi, Byung Yoon

    2018-02-13

    Previously, we introduced a noninvasive prenatal testing (NIPT) protocol for diagnosing compound heterozygous autosomal recessive point mutations via maternal plasma DNA and simulated control genomic DNA sampling based on fetal DNA fraction. In our present study, we have improved our NIPT protocol to make it possible to diagnose homozygous autosomal recessive point mutations without the need to acquire fetal DNA fraction. Moreover, chi-squared test and empirical statistical range based on the proportion of mutant allele reads among the total reads served as the gatekeeping method. If this method yielded inconclusive results, then the Bayesian method was performed; final conclusion was drawn from the results of both methods. This protocol was applied to three families co-segregating congenital sensorineural hearing loss with monogenic homozygous mutations in prevalent deafness genes. This protocol successfully predicted the fetal genotypes from all families without the information about fetal DNA fraction using one-step dPCR reactions at least for these three families. Furthermore, we suspect that confirmatory diagnosis under this protocol is possible, not only by using picodroplet dPCR, but also by using the more readily available chip-based dPCR, making our NIPT protocol more useful in the diagnosis of autosomal recessive point mutations in the future.

  5. Improved Structure and Function in Autosomal Recessive Polycystic Rat Kidneys with Renal Tubular Cell Therapy.

    Directory of Open Access Journals (Sweden)

    K J Kelly

    Full Text Available Autosomal recessive polycystic kidney disease is a truly catastrophic monogenetic disease, causing death and end stage renal disease in neonates and children. Using PCK female rats, an orthologous model of autosomal recessive polycystic kidney disease harboring mutant Pkhd1, we tested the hypothesis that intravenous renal cell transplantation with normal Sprague Dawley male kidney cells would improve the polycystic kidney disease phenotype. Cytotherapy with renal cells expressing wild type Pkhd1 and tubulogenic serum amyloid A1 had powerful and sustained beneficial effects on renal function and structure in the polycystic kidney disease model. Donor cell engraftment and both mutant and wild type Pkhd1 were found in treated but not control PCK kidneys 15 weeks after the final cell infusion. To examine the mechanisms of global protection with a small number of transplanted cells, we tested the hypothesis that exosomes derived from normal Sprague Dawley cells can limit the cystic phenotype of PCK recipient cells. We found that renal exosomes originating from normal Sprague Dawley cells carried and transferred wild type Pkhd1 mRNA to PCK cells in vivo and in vitro and restricted cyst formation by cultured PCK cells. The results indicate that transplantation with renal cells containing wild type Pkhd1 improves renal structure and function in autosomal recessive polycystic kidney disease and may provide an intra-renal supply of normal Pkhd1 mRNA.

  6. Mutations in c10orf11, a melanocyte-differentiation gene, cause autosomal-recessive albinism.

    Science.gov (United States)

    Grønskov, Karen; Dooley, Christopher M; Østergaard, Elsebet; Kelsh, Robert N; Hansen, Lars; Levesque, Mitchell P; Vilhelmsen, Kaj; Møllgård, Kjeld; Stemple, Derek L; Rosenberg, Thomas

    2013-03-07

    Autosomal-recessive albinism is a hypopigmentation disorder with a broad phenotypic range. A substantial fraction of individuals with albinism remain genetically unresolved, and it has been hypothesized that more genes are to be identified. By using homozygosity mapping of an inbred Faroese family, we identified a 3.5 Mb homozygous region (10q22.2-q22.3) on chromosome 10. The region contains five protein-coding genes, and sequencing of one of these, C10orf11, revealed a nonsense mutation that segregated with the disease and showed a recessive inheritance pattern. Investigation of additional albinism-affected individuals from the Faroe Islands revealed that five out of eight unrelated affected persons had the nonsense mutation in C10orf11. Screening of a cohort of autosomal-recessive-albinism-affected individuals residing in Denmark showed a homozygous 1 bp duplication in C10orf11 in an individual originating from Lithuania. Immunohistochemistry showed localization of C10orf11 in melanoblasts and melanocytes in human fetal tissue, but no localization was seen in retinal pigment epithelial cells. Knockdown of the zebrafish (Danio rerio) homolog with the use of morpholinos resulted in substantially decreased pigmentation and a reduction of the apparent number of pigmented melanocytes. The morphant phenotype was rescued by wild-type C10orf11, but not by mutant C10orf11. In conclusion, we have identified a melanocyte-differentiation gene, C10orf11, which when mutated causes autosomal-recessive albinism in humans. Copyright © 2013 The American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.

  7. Autosomal recessive dilated cardiomyopathy due to DOLK mutations results from abnormal dystroglycan O-mannosylation.

    Directory of Open Access Journals (Sweden)

    Dirk J Lefeber

    2011-12-01

    Full Text Available Genetic causes for autosomal recessive forms of dilated cardiomyopathy (DCM are only rarely identified, although they are thought to contribute considerably to sudden cardiac death and heart failure, especially in young children. Here, we describe 11 young patients (5-13 years with a predominant presentation of dilated cardiomyopathy (DCM. Metabolic investigations showed deficient protein N-glycosylation, leading to a diagnosis of Congenital Disorders of Glycosylation (CDG. Homozygosity mapping in the consanguineous families showed a locus with two known genes in the N-glycosylation pathway. In all individuals, pathogenic mutations were identified in DOLK, encoding the dolichol kinase responsible for formation of dolichol-phosphate. Enzyme analysis in patients' fibroblasts confirmed a dolichol kinase deficiency in all families. In comparison with the generally multisystem presentation in CDG, the nonsyndromic DCM in several individuals was remarkable. Investigation of other dolichol-phosphate dependent glycosylation pathways in biopsied heart tissue indicated reduced O-mannosylation of alpha-dystroglycan with concomitant functional loss of its laminin-binding capacity, which has been linked to DCM. We thus identified a combined deficiency of protein N-glycosylation and alpha-dystroglycan O-mannosylation in patients with nonsyndromic DCM due to autosomal recessive DOLK mutations.

  8. A Defect in NIPAL4 Is Associated with Autosomal Recessive Congenital Ichthyosis in American Bulldogs.

    Science.gov (United States)

    Casal, Margret L; Wang, Ping; Mauldin, Elizabeth A; Lin, Gloria; Henthorn, Paula S

    2017-01-01

    Autosomal recessive congenital ichthyosis in the American bulldog is characterized by generalized scaling and erythema with adherent scale on the glabrous skin. We had previously linked this disorder to NIPAL4, which encodes the protein ichthyin. Sequencing of NIPAL4 revealed a homozygous single base deletion (CanFam3.1 canine reference genome sequence NC_06586.3 g.52737379del), the 157th base (cytosine) in exon 6 of NIPAL4 as the most likely causative variant in affected dogs. This frameshift deletion results in a premature stop codon producing a truncated and defective NIPAL4 (ichthyin) protein of 248 amino acids instead of the wild-type length of 404. Obligate carriers were confirmed to be heterozygous for this variant, and 150 clinically non-affected dogs of other breeds were homozygous for the wild-type gene. Among 800 American bulldogs tested, 34% of clinically healthy dogs were discovered to be heterozygous for the defective allele. More importantly, the development of this canine model of autosomal recessive congenital ichthyosis will provide insight into the development of new treatments across species.

  9. A Defect in NIPAL4 Is Associated with Autosomal Recessive Congenital Ichthyosis in American Bulldogs.

    Directory of Open Access Journals (Sweden)

    Margret L Casal

    Full Text Available Autosomal recessive congenital ichthyosis in the American bulldog is characterized by generalized scaling and erythema with adherent scale on the glabrous skin. We had previously linked this disorder to NIPAL4, which encodes the protein ichthyin. Sequencing of NIPAL4 revealed a homozygous single base deletion (CanFam3.1 canine reference genome sequence NC_06586.3 g.52737379del, the 157th base (cytosine in exon 6 of NIPAL4 as the most likely causative variant in affected dogs. This frameshift deletion results in a premature stop codon producing a truncated and defective NIPAL4 (ichthyin protein of 248 amino acids instead of the wild-type length of 404. Obligate carriers were confirmed to be heterozygous for this variant, and 150 clinically non-affected dogs of other breeds were homozygous for the wild-type gene. Among 800 American bulldogs tested, 34% of clinically healthy dogs were discovered to be heterozygous for the defective allele. More importantly, the development of this canine model of autosomal recessive congenital ichthyosis will provide insight into the development of new treatments across species.

  10. Proprotein Convertase Subtilisin Kexin Type 9 Inhibition for Autosomal Recessive Hypercholesterolemia-Brief Report.

    Science.gov (United States)

    Thedrez, Aurélie; Sjouke, Barbara; Passard, Maxime; Prampart-Fauvet, Simon; Guédon, Alexis; Croyal, Mikael; Dallinga-Thie, Geesje; Peter, Jorge; Blom, Dirk; Ciccarese, Milco; Cefalù, Angelo B; Pisciotta, Livia; Santos, Raul D; Averna, Maurizio; Raal, Frederick; Pintus, Paolo; Cossu, Maria; Hovingh, Kees; Lambert, Gilles

    2016-08-01

    Proprotein convertase subtilisin kexin type 9 (PCSK9) inhibitors lower low-density lipoprotein (LDL) cholesterol in the vast majority of patients with autosomal dominant familial hypercholesterolemia. Will PCSK9 inhibition with monoclonal antibodies, in particular alirocumab, be of therapeutic value for patients with autosomal recessive hypercholesterolemia (ARH)? Primary lymphocytes were obtained from 28 genetically characterized ARH patients and 11 controls. ARH lymphocytes treated with mevastatin were incubated with increasing doses of recombinant PCSK9 with or without saturating concentrations of alirocumab. Cell surface LDL receptor expression measured by flow cytometry and confocal microscopy was higher in ARH than in control lymphocytes. PCSK9 significantly reduced LDL receptor expression in ARH lymphocytes albeit to a lower extent than in control lymphocytes (25% versus 76%, respectively), an effect reversed by alirocumab. Fluorescent LDL cellular uptake, also measured by flow cytometry, was reduced in ARH lymphocytes compared with control lymphocytes. PCSK9 significantly lowered LDL cellular uptake in ARH lymphocytes, on average by 18%, compared with a 46% reduction observed in control lymphocytes, an effect also reversed by alirocumab. Overall, the effects of recombinant PCSK9, and hence of alirocumab, on LDL receptor expression and function were significantly less pronounced in ARH than in control cells. PCSK9 inhibition with alirocumab on top of statin treatment has the potential to lower LDL cholesterol in some autosomal recessive hypercholesterolemia patients. © 2016 American Heart Association, Inc.

  11. More Than Ataxia: Hyperkinetic Movement Disorders in Childhood Autosomal Recessive Ataxia Syndromes

    Science.gov (United States)

    Pearson, Toni S.

    2016-01-01

    Background The autosomal recessive ataxias are a heterogeneous group of disorders that are characterized by complex neurological features in addition to progressive ataxia. Hyperkinetic movement disorders occur in a significant proportion of patients, and may sometimes be the presenting motor symptom. Presentations with involuntary movements rather than ataxia are diagnostically challenging, and are likely under-recognized. Methods A PubMed literature search was performed in October 2015 utilizing pairwise combinations of disease-related terms (autosomal recessive ataxia, ataxia–telangiectasia, ataxia with oculomotor apraxia type 1 (AOA1), ataxia with oculomotor apraxia type 2 (AOA2), Friedreich ataxia, ataxia with vitamin E deficiency), and symptom-related terms (movement disorder, dystonia, chorea, choreoathetosis, myoclonus). Results Involuntary movements occur in the majority of patients with ataxia–telangiectasia and AOA1, and less frequently in patients with AOA2, Friedreich ataxia, and ataxia with vitamin E deficiency. Clinical presentations with an isolated hyperkinetic movement disorder in the absence of ataxia include dystonia or dystonia with myoclonus with predominant upper limb and cervical involvement (ataxia–telangiectasia, ataxia with vitamin E deficiency), and generalized chorea (ataxia with oculomotor apraxia type 1, ataxia-telangiectasia). Discussion An awareness of atypical presentations facilitates early and accurate diagnosis in these challenging cases. Recognition of involuntary movements is important not only for diagnosis, but also because of the potential for effective targeted symptomatic treatment. PMID:27536460

  12. Autosomal recessive transmission of MYBPC3 mutation results in malignant phenotype of hypertrophic cardiomyopathy.

    Directory of Open Access Journals (Sweden)

    Yilu Wang

    Full Text Available BACKGROUND: Hypertrophic cardiomyopathy (HCM due to mutations in genes encoding sarcomere proteins is most commonly inherited as an autosomal dominant trait. Since nearly 50% of HCM cases occur in the absence of a family history, a recessive inheritance pattern may be involved. METHODS: A pedigree was identified with suspected autosomal recessive transmission of HCM. Twenty-six HCM-related genes were comprehensively screened for mutations in the proband with targeted second generation sequencing, and the identified mutation was confirmed with bi-directional Sanger sequencing in all family members and 376 healthy controls. RESULTS: A novel missense mutation (c.1469G>T, p.Gly490Val in exon 17 of MYBPC3 was identified. Two siblings with HCM were homozygous for this mutation, whereas other family members were either heterozygous or wild type. Clinical evaluation showed that both homozygotes manifested a typical HCM presentation, but none of others, including 5 adult heterozygous mutation carriers up to 71 years of age, had any clinical evidence of HCM. CONCLUSIONS: Our data identified a MYBPC3 mutation in HCM, which appeared autosomal recessively inherited in this family. The absence of a family history of clinical HCM may be due to not only a de novo mutation, but also recessive mutations that failed to produce a clinical phenotype in heterozygous family members. Therefore, consideration of recessive mutations leading to HCM is essential for risk stratification and genetic counseling.

  13. Identification of C12orf4 as a gene for autosomal recessive intellectual disability.

    Science.gov (United States)

    Philips, A K; Pinelli, M; de Bie, C I; Mustonen, A; Määttä, T; Arts, H H; Wu, K; Roepman, R; Moilanen, J S; Raza, S; Varilo, T; Scala, G; Cocozza, S; Gilissen, C; van Gassen, K L I; Järvelä, I

    2017-01-01

    Intellectual disability (ID) is a major health problem in our society. Genetic causes of ID remain unknown because of its vast heterogeneity. Here we report two Finnish families and one Dutch family with affected individuals presenting with mild to moderate ID, neuropsychiatric symptoms and delayed speech development. By utilizing whole exome sequencing (WES), we identified a founder missense variant c.983T>C (p.Leu328Pro) in seven affected individuals from two Finnish consanguineous families and a deletion c.799_1034-429delinsTTATGA (p.Gln267fs) in one affected individual from a consanguineous Dutch family in the C12orf4 gene on chromosome 12. Both the variants co-segregated in the respective families as an autosomal recessive trait. Screening of the p.Leu328Pro variant showed enrichment in the North Eastern sub-isolate of Finland among anonymous local blood donors with a carrier frequency of 1:53, similar to other disease mutations with a founder effect in that region. To date, only one Arab family with a three affected individuals with a frameshift insertion variant in C12orf4 has been reported. In summary, we expand and establish the clinical and mutational spectrum of C12orf4 variants. Our findings implicate C12orf4 as a causative gene for autosomal recessive ID. © 2016 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  14. Autoimmune polyendocrinopathy candidiasis ectodermal dystrophy.

    Science.gov (United States)

    Kisand, Kai; Peterson, Pärt

    2015-07-01

    Autoimmune polyendocrinopathy candidiasis ectodermal dystrophy (APECED) is an autosomal recessive disease caused by mutations in the autoimmune regulator (AIRE) gene. This review focuses on the clinical and immunological features of APECED, summarizes the current knowledge on the function of AIRE and discusses the importance of autoantibodies in disease diagnosis and prognosis. Additionally, we review the outcome of recent immunomodulatory treatments in APECED patients.

  15. [Autosomal recessive polycystic kidney disease and complex nephronophtisis medullary cystic disease].

    Science.gov (United States)

    2008-12-01

    Reseach during the past decade has led to the discovery that defects in some proteins that localize to primary cilia or the basal body are the main contributors to renal cyst development. Autosomal recessive polycystic disease and nephronophthisis- medullary cystic kidney disease are named ciliopathies. The cilium is a microtubule-based organelle that is found on most mammalian cells. Cilia-mediated hypothesis has evolved into the concept of cystogenesis, cilia bend by fluid initiate a calcium influx that prevents cyst formation. Cilia might sense stimuli in the cell enviroment and control cell polarity and mitosis. A new set of pathogenic mechanisms in renal cystic disease defined new therapeutic targets, control of intracellular calcium, inhibition of cAMP and down regulation cannonical Wnt signaling.

  16. SBF1 mutations associated with autosomal recessive axonal neuropathy with cranial nerve involvement.

    Science.gov (United States)

    Manole, Andreea; Horga, Alejandro; Gamez, Josep; Raguer, Nuria; Salvado, Maria; San Millán, Beatriz; Navarro, Carmen; Pittmann, Alan; Reilly, Mary M; Houlden, Henry

    2017-01-01

    Biallelic mutations in the SBF1 gene have been identified in one family with demyelinating Charcot-Marie-Tooth disease (CMT4B3) and two families with axonal neuropathy and additional neurological and skeletal features. Here we describe novel sequence variants in SBF1 (c.1168C>G and c.2209_2210del) as the potential causative mutations in two siblings with severe axonal neuropathy, hearing loss, facial weakness and bulbar features. Pathogenicity of these variants is supported by co-segregation and in silico analyses and evolutionary conservation. Our findings suggest that SBF1 mutations may cause a syndromic form of autosomal recessive axonal neuropathy (AR-CMT2) in addition to CMT4B3.

  17. Identification of Mutations in SDR9C7 in 6 Families with Autosomal Recessive Congenital Ichthyosis

    DEFF Research Database (Denmark)

    Hotz, A; Fagerberg, C; Vahlquist, A

    2018-01-01

    a large consanguineous family were described as ARCI due to a homozygous mutation in LIPN.(7) However, the first symptoms appeared only from the age of 5 years and the criterion of a congenital form of ichthyosis is not fulfilled. In this study we report the clinical and molecular findings of seven ARCI......Autosomal recessive congenital ichthyosis (ARCI) is a heterogeneous group of disorders of keratinization. To date, ARCI has been associated with following genes: ABCA12, ALOX12B, ALOXE3, CERS3, CYP4F22, NIPAL4, TGM1, PNPLA1 and recently SDR9C7 and SULT2B1.(1-6) Furthermore, seven patients from...... patients who carried five previously unreported mutations in SDR9C7. This article is protected by copyright. All rights reserved....

  18. Birth prevalence and mutation spectrum in danish patients with autosomal recessive albinism

    DEFF Research Database (Denmark)

    Grønskov, Karen; Ek, Jakob; Sand, Annie

    2009-01-01

    PURPOSE: The study was initiated to investigate the mutation spectrum of four OCA genes and to calculate the birth prevalence in patients with autosomal recessive albinism. METHODS: Mutation analysis using dHPLC or direct DNA sequencing of TYR, OCA2, TYRP1, and MATP was performed in 62 patients....... Two mutations in one OCA gene explained oculocutaneous albinism (OCA) in 44% of the patients. Mutations in TYR were found in 26% of patients, while OCA2 and MATP caused OCA in 15% and 3%, respectively. No mutations were found in TYRP1. Of the remaining 56% of patients, 29% were heterozygous...... for a mutation in either TYR or OCA2, and 27% were without mutations in any of the four genes. Exclusive expression of the mutant allele was found in four heterozygous patients. A minimum birth prevalence of 1 in 14,000 was calculated, based on register data on 218 patients. The proportion of OCA to autosomal...

  19. Autosomal recessive chronic granulomatous disease presenting with cutaneous dermatoses and ocular infection.

    Science.gov (United States)

    Low, L C M; Manson, A L; Hardman, C; Carton, J; Seneviratne, S L; Ninis, N

    2013-04-01

    Dermatoses such as eczematous dermatitis and cutaneous infection are recognized presentations of primary immunodeficiency (PID). However, atopic dermatitis affects approximately 10% of infants, and cutaneous infections are not uncommon in children, therefore the challenge for the dermatologist is to distinguish the few patients that have PID from the many that do not. We report on a 6-year-old girl who was ultimately diagnosed with autosomal recessive chronic granulomatous disease (AR-CGD) after presenting to various hospitals with dermatitis, scalp plaques recalcitrant to treatment, and recurrent infections over a 3-year period, and describe some aspects of her diagnosis and management. This report highlights the importance of considering rare disorders such as AR-CGD in the differential diagnosis of recurrent or recalcitrant dermatological infections in children. © The Author(s). CED © 2012 British Association of Dermatologists.

  20. Diagnosis and Management of Hepatobiliary Complications in Autosomal Recessive Polycystic Kidney Disease

    Directory of Open Access Journals (Sweden)

    Andrew Wehrman

    2017-05-01

    Full Text Available Autosomal recessive polycystic kidney disease (ARPKD is a congenital hepatorenal fibrocystic disease. The hepatic manifestations of ARPKD can range from asymptomatic to portal hypertension and massively dilated biliary system that results in liver transplantation. Hepatic complications of ARPKD typically present with signs of portal hypertension (splenomegaly and thrombocytopenia or cholangitis. Liver disease in ARPKD does not always correlate with severity of renal disease. Management of ARPKD-related liver disease is largely treating specific symptoms, such as antibiotics for cholangitis or endoscopic treatment for variceal bleeding. If complications cannot be managed medically, liver transplantation may be indicated. This mini-review will discuss the clinical manifestations and management of children with ARPKD liver disease.

  1. The efficacy of microarray screening for autosomal recessive retinitis pigmentosa in routine clinical practice.

    Science.gov (United States)

    van Huet, Ramon A C; Pierrache, Laurence H M; Meester-Smoor, Magda A; Klaver, Caroline C W; van den Born, L Ingeborgh; Hoyng, Carel B; de Wijs, Ilse J; Collin, Rob W J; Hoefsloot, Lies H; Klevering, B Jeroen

    2015-01-01

    To determine the efficacy of multiple versions of a commercially available arrayed primer extension (APEX) microarray chip for autosomal recessive retinitis pigmentosa (arRP). We included 250 probands suspected of arRP who were genetically analyzed with the APEX microarray between January 2008 and November 2013. The mode of inheritance had to be autosomal recessive according to the pedigree (including isolated cases). If the microarray identified a heterozygous mutation, we performed Sanger sequencing of exons and exon-intron boundaries of that specific gene. The efficacy of this microarray chip with the additional Sanger sequencing approach was determined by the percentage of patients that received a molecular diagnosis. We also collected data from genetic tests other than the APEX analysis for arRP to provide a detailed description of the molecular diagnoses in our study cohort. The APEX microarray chip for arRP identified the molecular diagnosis in 21 (8.5%) of the patients in our cohort. Additional Sanger sequencing yielded a second mutation in 17 patients (6.8%), thereby establishing the molecular diagnosis. In total, 38 patients (15.2%) received a molecular diagnosis after analysis using the microarray and additional Sanger sequencing approach. Further genetic analyses after a negative result of the arRP microarray (n = 107) resulted in a molecular diagnosis of arRP (n = 23), autosomal dominant RP (n = 5), X-linked RP (n = 2), and choroideremia (n = 1). The efficacy of the commercially available APEX microarray chips for arRP appears to be low, most likely caused by the limitations of this technique and the genetic and allelic heterogeneity of RP. Diagnostic yields up to 40% have been reported for next-generation sequencing (NGS) techniques that, as expected, thereby outperform targeted APEX analysis.

  2. Autosomal recessive primary microcephaly (MCPH): clinical manifestations, genetic heterogeneity and mutation continuum

    Science.gov (United States)

    2011-01-01

    Autosomal Recessive Primary Microcephaly (MCPH) is a rare disorder of neurogenic mitosis characterized by reduced head circumference at birth with variable degree of mental retardation. In MCPH patients, brain size reduced to almost one-third of its original volume due to reduced number of generated cerebral cortical neurons during embryonic neurogensis. So far, seven genetic loci (MCPH1-7) for this condition have been mapped with seven corresponding genes (MCPH1, WDR62, CDK5RAP2, CEP152, ASPM, CENPJ, and STIL) identified from different world populations. Contribution of ASPM and WDR62 gene mutations in MCPH World wide is more than 50%. By and large, primary microcephaly patients are phenotypically indistinguishable, however, recent studies in patients with mutations in MCPH1, WDR62 and ASPM genes showed a broader clinical and/or cellular phenotype. It has been proposed that mutations in MCPH genes can cause the disease phenotype by disturbing: 1) orientation of mitotic spindles, 2) chromosome condensation mechanism during embryonic neurogenesis, 3) DNA damage-response signaling, 4) transcriptional regulations and microtubule dynamics, 5) certain unknown centrosomal mechanisms that control the number of neurons generated by neural precursor cells. Recent discoveries of mammalian models for MCPH have open up horizons for researchers to add more knowledge regarding the etiology and pathophysiology of MCPH. High incidence of MCPH in Pakistani population reflects the most probable involvement of consanguinity. Genetic counseling and clinical management through carrier detection/prenatal diagnosis in MCPH families can help reducing the incidence of this autosomal recessive disorder. PMID:21668957

  3. Loss of VPS13C Function in Autosomal-Recessive Parkinsonism Causes Mitochondrial Dysfunction and Increases PINK1/Parkin-Dependent Mitophagy

    NARCIS (Netherlands)

    Lesage, S.; Drouet, V.; Majounie, E.; Deramecourt, V.; Jacoupy, M.; Nicolas, A.; Cormier-Dequaire, F.; Hassoun, S.M.; Pujol, C.; Ciura, S.; Erpapazoglou, Z.; Usenko, T.; Maurage, C.A.; Sahbatou, M.; Liebau, S.; Ding, J.; Bilgic, B.; Emre, M.; Erginel-Unaltuna, N.; Guven, G.; Tison, F.; Tranchant, C.; Vidailhet, M.; Corvol, J.C.; Krack, P.; Leutenegger, A.L.; Nalls, M.A.; Hernandez, D.G.; Heutink, P.; Gibbs, J.R.; Hardy, J.; Wood, N.W.; Gasser, T.; Durr, A.; Deleuze, J.F.; Tazir, M.; Destee, A.; Lohmann, E.; Kabashi, E.; Singleton, A.; Corti, O.; Brice, A.; Scheffer, H.; Bloem, B.R.; et al.,

    2016-01-01

    Autosomal-recessive early-onset parkinsonism is clinically and genetically heterogeneous. The genetic causes of approximately 50% of autosomal-recessive early-onset forms of Parkinson disease (PD) remain to be elucidated. Homozygozity mapping and exome sequencing in 62 isolated individuals with

  4. Autozygosity mapping of a large consanguineous Pakistani family reveals a novel non-syndromic autosomal recessive mental retardation locus on 11p15-tel

    DEFF Research Database (Denmark)

    Rehman, Shoaib ur; Baig, Shahid Mahmood; Eiberg, Hans

    2011-01-01

    Autosomal recessive inherited mental retardation is an extremely heterogeneous disease and accounts for approximately 25% of all non-syndromic mental retardation cases. Autozygosity mapping of a large consanguineous Pakistani family revealed a novel locus for non-syndromic autosomal recessive men...

  5. A Challenging Case of Hepatoblastoma Concomitant with Autosomal Recessive Polycystic Kidney Disease and Caroli Syndrome—Review of the Literature

    Directory of Open Access Journals (Sweden)

    Nevil Kadakia

    2017-06-01

    Full Text Available We report a rare case of an 18-month-old female with autosomal recessive polycystic kidney disease, Caroli syndrome, and pure fetal type hepatoblastoma. The liver tumor was surgically resected with no chemotherapy given. Now 9 years post resection she demonstrates no local or distant recurrence and stable renal function.

  6. Decreased catalytic activity and altered activation properties of PDE6C mutants associated with autosomal recessive achromatopsia

    DEFF Research Database (Denmark)

    Grau, Tanja; Artemyev, Nikolai O; Rosenberg, Thomas

    2011-01-01

    Mutations in the gene encoding the catalytic subunit of the cone photoreceptor phosphodiesterase (PDE6C) have been recently reported in patients with autosomal recessive inherited achromatopsia (ACHM) and early-onset cone photoreceptor dysfunction. Here we present the results of a comprehensive...

  7. Modeling autosomal recessive cutis laxa type 1C in mice reveals distinct functions for Ltbp-4 isoforms

    DEFF Research Database (Denmark)

    Bultmann-Mellin, Insa; Conradi, Anne; Maul, Alexandra C

    2015-01-01

    Recent studies have revealed an important role for LTBP-4 in elastogenesis. Its mutational inactivation in humans causes autosomal recessive cutis laxa type 1C (ARCL1C), which is a severe disorder caused by defects of the elastic fiber network. Although the human gene involved in ARCL1C has been...

  8. Appearance of autosomal recessive polycystic kidney disease in magnetic resonance imaging and RARE-MR-urography

    International Nuclear Information System (INIS)

    Kern, S.; Uhl, M.; Zimmerhackl, L.B.; Hildebrandt, F.; Ermisch-Omran, B.

    2000-01-01

    Purpose. To describe the appearance of autosomal recessive polycystic kidney disease (ARPKD) on MRI and RARE-MR urography.Materials and methods. Seven boys and one girl (aged 3 months to 14 years, median 2.5 years) were evaluated. Images were obtained with 0.23-T and 1.5-T MR systems using T1-weighted (T1-W) spin-echo, T2-weighted (T2-W) turbo-spin-echo and RARE-MR-urography sequences. Signal intensities, morphological appearance of the affected kidneys and, specifically, the picture of the urinary tract on RARE-MR-urography were evaluated.Results. All children showed kidney enlargement, reniform but humpy kidney shape, homogeneously grainy renal parenchyma, normal renal pelvis and normal calyces. Signal intensity was hyperintense in T2-W images in all cases. In six cases (n = 7), T1-W images were hypointense. On RARE-MR urography a hyperintense, linear radial pattern was seen in the cortex and medulla which represents the characteristic microcystic dilatation of collecting ducts in ARPKD. Three boys and the girl presented with a few circumscribed small subcapsular cysts.Conclusions. In order to confirm the diagnosis of ARPKD, RARE-MR urography seems to be a non-invasive imaging tool that shows directly the microcystic dilated water-filled collecting ducts. (orig.)

  9. EYS Mutations Causing Autosomal Recessive Retinitis Pigmentosa: Changes of Retinal Structure and Function with Disease Progression

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    David B. McGuigan

    2017-07-01

    Full Text Available Mutations in the EYS (eyes shut homolog gene are a common cause of autosomal recessive (ar retinitis pigmentosa (RP. Without a mammalian model of human EYS disease, there is limited understanding of details of disease expression and rates of progression of the retinal degeneration. We studied clinically and with chromatic static perimetry, spectral-domain optical coherence tomography (OCT, and en face autofluoresence imaging, a cohort of 15 patients (ages 12–51 at first visit, some of whom had longitudinal data of function and structure. Rod sensitivity was able to be measured by chromatic perimetry in most patients at their earliest visits and some patients retained patchy rod function into the fifth decade of life. As expected from RP, cone sensitivity persisted after rod function was no longer measurable. The photoreceptor nuclear layer of the central retina was abnormal except at the fovea in most patients at first visit. Perifoveal disease measured over a period of years indicated that photoreceptor structural loss was followed by dysmorphology of the inner retina and loss of retinal pigment epithelial integrity. Although there could be variability in severity, preliminary analyses of the rates of vision loss suggested that EYS is a more rapidly progressive disease than other ciliopathies causing arRP, such as USH2A and MAK.

  10. Autosomal recessive mental retardation syndrome with anterior maxillary protrusion and strabismus: MRAMS syndrome.

    Science.gov (United States)

    Basel-Vanagaite, Lina; Rainshtein, Limor; Inbar, Dov; Gothelf, Doron; Hennekam, Raoul; Straussberg, Rachel

    2007-08-01

    We report on a family in whom the combination of mental retardation (MR), anterior maxillary protrusion, and strabismus segregates. The healthy, consanguineous parents (first cousins) of Israeli-Arab descent had 11 children, 7 of whom (5 girls) were affected. They all had severe MR. Six of the seven had anterior maxillary protrusion with vertical maxillary excess, open bite, and prominent crowded teeth. None of the sibs with normal intelligence had jaw or dental anomalies. The child with MR but without a jaw anomaly was somewhat less severely retarded, had seizures and severe psychosis, which may point to his having a separate disorder. Biochemical and neurological studies, including brain MRI and standard cytogenetic studies, yielded normal results; fragile X was excluded, no subtelomeric rearrangements were detectable, and X-inactivation studies in the mother showed random inactivation. We have been unable to find a similar disorder in the literature, and suggest that this is a hitherto unreported autosomal recessive disorder, which we propose to name MRAMS (mental retardation, anterior maxillary protrusion, and strabismus). (c) 2007 Wiley-Liss, Inc.

  11. COL9A2 and COL9A3 mutations in canine autosomal recessive oculoskeletal dysplasia.

    Science.gov (United States)

    Goldstein, Orly; Guyon, Richard; Kukekova, Anna; Kuznetsova, Tatyana N; Pearce-Kelling, Susan E; Johnson, Jennifer; Aguirre, Gustavo D; Acland, Gregory M

    2010-08-01

    Oculoskeletal dysplasia segregates as an autosomal recessive trait in the Labrador retriever and Samoyed canine breeds, in which the causative loci have been termed drd1 and drd2, respectively. Affected dogs exhibit short-limbed dwarfism and severe ocular defects. The disease phenotype resembles human hereditary arthro-ophthalmopathies such as Stickler and Marshall syndromes, although these disorders are usually dominant. Linkage studies mapped drd1 to canine chromosome 24 and drd2 to canine chromosome 15. Positional candidate gene analysis then led to the identification of a 1-base insertional mutation in exon 1 of COL9A3 that cosegregates with drd1 and a 1,267-bp deletion mutation in the 5' end of COL9A2 that cosegregates with drd2. Both mutations affect the COL3 domain of the respective gene. Northern analysis showed that RNA expression of the respective genes was reduced in affected retinas. These models offer potential for studies such as protein-protein interactions between different members of the collagen gene family, regulation and expression of these genes in retina and cartilage, and even opportunities for gene therapy.

  12. RARE-MR-urography - a new diagnostic method in autosomal recessive polycystic kidney disease

    Energy Technology Data Exchange (ETDEWEB)

    Kern, S.; Uhl, M. [University Hospital Freiburg (Germany). Div. of Pediatric Radiology; Zimmerhackl, L.B.; Hildebrandt, F. [University Hospital Freiburg (Germany). Div. of Pediatric Nephrology

    1999-09-01

    Purpose: To describe the appearance of autosomal recessive polycystic kidney disease (ARPKD) by using a new diagnostic method: RARE-MR-urography. Material and Methods: Eight children were evaluated using MR images from 0.23 T and 1.5 T MR units, using T1-weighted spin-echo and T2-weighted turbo spin-echo sequences and RARE-MR-urography. Signal intensities, morphological appearance of the affected kidneys and, specifically, the picture of the urinary tract in RARE-MR-urography, were evaluated. Results: All children showed enlargement, reniform but humpy kidney shape, homogeneous-grainy renal parenchyma, normal renal pelvis and calyces. Although ARPKD is always associated with some degree of congenital hepatic fibrosis, there was no bile duct dilatation or liver fibrosis at the time of examination. Signal intensity was hyperintense in T2-weighted images in all cases. In 5 cases, T1-weighted images were hypointense. In RARE-MR-urography, hyperintense, linear, radial patterns in cortex and medulla were seen, which represent microcystic dilatation of collecting ducts and are therefore characteristic of ARPKD. Four patients presented with a few circumscribed small subcapsular cysts. Conclusion: RARE-MR-urography is a noninvasive method which demonstrates the pathognomonic water-filled cystic structures throughout the kidneys in ARPKD. (orig.)

  13. A novel autosomal recessive GJA1 missense mutation linked to Craniometaphyseal dysplasia.

    Directory of Open Access Journals (Sweden)

    Ying Hu

    Full Text Available Craniometaphyseal dysplasia (CMD is a rare sclerosing skeletal disorder with progressive hyperostosis of craniofacial bones. CMD can be inherited in an autosomal dominant (AD trait or occur after de novo mutations in the pyrophosphate transporter ANKH. Although the autosomal recessive (AR form of CMD had been mapped to 6q21-22 the mutation has been elusive. In this study, we performed whole-exome sequencing for one subject with AR CMD and identified a novel missense mutation (c.716G>A, p.Arg239Gln in the C-terminus of the gap junction protein alpha-1 (GJA1 coding for connexin 43 (Cx43. We confirmed this mutation in 6 individuals from 3 additional families. The homozygous mutation cosegregated only with affected family members. Connexin 43 is a major component of gap junctions in osteoblasts, osteocytes, osteoclasts and chondrocytes. Gap junctions are responsible for the diffusion of low molecular weight molecules between cells. Mutations in Cx43 cause several dominant and recessive disorders involving developmental abnormalities of bone such as dominant and recessive oculodentodigital dysplasia (ODDD; MIM #164200, 257850 and isolated syndactyly type III (MIM #186100, the characteristic digital anomaly in ODDD. However, characteristic ocular and dental features of ODDD as well as syndactyly are absent in patients with the recessive Arg239Gln Cx43 mutation. Bone remodeling mechanisms disrupted by this novel Cx43 mutation remain to be elucidated.

  14. Risk Factors for Neurocognitive Functioning in Children with Autosomal Recessive Polycystic Kidney Disease

    Directory of Open Access Journals (Sweden)

    Stephen R. Hooper

    2017-05-01

    Full Text Available This mini review provides an overview of the issues and challenges inherent in autosomal recessive polycystic kidney disease (ARPKD, with a particular focus on the neurological factors and neurocognitive functioning of this population. ARPKD typically is discovered at the end of pregnancy or during the neonatal developmental period and occurs in approximately 1 in 20,000 live births. During the neonatal period, there is a relatively high risk of death, with many infants dying from respiratory failure. As the child ages, they experience progressive kidney disease and become increasingly vulnerable to liver disease, with many individuals eventually requiring dual organ transplants. This mini review provides a brief description of ARPKD and describes the various factors that place children with ARPKD at risk for neurological and neuropsychological impairment (e.g., a genetic condition leading to chronic kidney disease and eventual transplant; difficult-to-treat hypertension; eventual liver disease; possible dual transplantation of the kidneys and liver; chronic lung disease, including that these factors are present during a critical period of brain development. Further, the mini review discusses the available studies that have addressed the neurocognitive functioning in children with ARPKD. This paper concludes by providing the key clinical and research challenges that face the field of pediatric nephrology with respect to the clinical and scientific study of the neurocognitive functioning of children with ARPKD. Selected directions are offered in both the clinical and research arenas for this multiorgan chronic condition.

  15. CONSANGUINITY AND HOMOZYGOSITY AMONG TUNISIAN PATIENTS WITH AN AUTOSOMAL RECESSIVE DISORDER.

    Science.gov (United States)

    Kelmemi, Wided; Chelly, Imene; Kharrat, Maher; Chaabouni-Bouhamed, Habiba

    2015-11-01

    Consanguineous unions are a deeply rooted social practice among traditional societies. Despite their presumed social advantages, they can result in several health conditions. The aim of this study was: i) to compare consanguinity levels between Tunisian patients affected with autosomal recessive disorders (ARDs) and those with a chromosomal abnormality; and ii) to gain more insight into the mutational status of patients affected with ARDs. Data were collected from 290 files of patients affected by one of five ARDs confirmed by molecular analysis and 248 files of patients with confirmed Down syndrome. Information on the disease, mutation defining the disease, parents' relatedness and geographical origin was gathered. Consanguinity was found among 58% of the ARD patients and among 22% of Down syndrome patients, and a homozygous status was found in 90% of the patients born to related parents and in 70% of patients born to unrelated parents. Also, children from unrelated parents from the same geographical background were found to be more frequently affected by homozygous mutations than those from unrelated parents from different geographical backgrounds. The present study shows how marriage practices affect patterns of genetic variations and how they can lead to homogenization in the genetic pool.

  16. WWOX and severe autosomal recessive epileptic encephalopathy: first case in the prenatal period.

    Science.gov (United States)

    Valduga, Mylène; Philippe, Christophe; Lambert, Laetitia; Bach-Segura, Pascale; Schmitt, Emmanuelle; Masutti, Jean Pierre; François, Bénédicte; Pinaud, Patrick; Vibert, Mireille; Jonveaux, Philippe

    2015-05-01

    WWOX has been recently implicated in autosomal recessive spinocerebellar ataxia type 12 (SCAR12) and severe early-onset epileptic encephalopathy (EOEE). By array comparative genomic hybridization, we identified a 0.6 Mb homozygous deletion in 16q23.1 in a fetus presenting with brain anomalies. His older sister who died at the age of 22 months from an EOEE was also homozygous for the copy number variations in 16q23.1. This deletion includes the first six exons of WWOX and results in a null genotype in homozygous patients. This family gives additional support for the implication of WWOX in severe EOEEs. We report for the first time prenatal ultrasound findings in a fetus with a WWOX-null genotype. Our study expands the range of brain abnormalities in WWOX-related EOEEs. This additional family confirms the genotype-phenotype correlation with WWOX-null alleles associated with the most severe form of WWOX-related epileptic encephalopathy with premature death.

  17. Novel compound heterozygous MYO7A mutations in Moroccan families with autosomal recessive non-syndromic hearing loss.

    Directory of Open Access Journals (Sweden)

    Amina Bakhchane

    Full Text Available The MYO7A gene encodes a protein belonging to the unconventional myosin super family. Mutations within MYO7A can lead to either non syndromic hearing loss or to the Usher syndrome type 1B (USH1B. Here, we report the results of genetic analyses performed on Moroccan families with autosomal recessive non syndromic hearing loss that identified two families with compound heterozygous MYO7A mutations. Five mutations (c.6025delG, c.6229T>A, c.3500T>A, c.5617C>T and c.4487C>A were identified in these families, the latter presenting two differently affected branches. Multiple bioinformatics programs and molecular modelling predicted the pathogenic effect of these mutations. In conclusion, the absence of vestibular and retinal symptom in the affected patients suggests that these families have the isolated non-syndromic hearing loss DFNB2 (nonsyndromic autosomal recessive hearing loss presentation, instead of USH1B.

  18. Autosomal recessive spastic ataxia of Charlevoix-Saguenay (ARSACS: typical clinical and neuroimaging features in a Brazilian family

    Directory of Open Access Journals (Sweden)

    J L Pedroso

    2011-01-01

    Full Text Available Autosomal recessive spastic ataxia of Charlevoix-Saguenay (ARSACS is a neurodegenerative disorder characterized by late-infantile onset spastic ataxia and other neurological features. ARSACS has a high prevalence in northeastern Quebec, Canada. Several ARSACS cases have been reported outside Canada in recent decades. This is the first report of typical clinical and neuroimaging features in a Brazilian family with probable diagnosis of ARSACS.

  19. 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.

  20. Targeted next-generation sequencing of a 12.5 Mb homozygous region reveals ANO10 mutations in patients with autosomal-recessive cerebellar ataxia.

    NARCIS (Netherlands)

    Vermeer, S.; Hoischen, A.; Meijer, R.P.; Gilissen, C.F.H.A.; Neveling, K.; Wieskamp, N.A.W.; Brouwer, A.; Koenig, M.; Anheim, M.; Assoum, M.; Drouot, N.; Todorovic, S.; Milic-Rasic, V.; Lochmuller, H.; Stevanin, G.; Goizet, C.; David, A.; Durr, A.; Brice, A.; Kremer, B.; Warrenburg, B.P.C. van de; Schijvenaars, M.M.V.A.P.; Heister, A.; Kwint, M.P.; Arts, P.J.W.; Wijst, J.A.J. van der; Veltman, J.; Kamsteeg, E.J.; Scheffer, H.; Knoers, N.V.A.M.

    2010-01-01

    Autosomal-recessive cerebellar ataxias comprise a clinically and genetically heterogeneous group of neurodegenerative disorders. In contrast to their dominant counterparts, unraveling the molecular background of these ataxias has proven to be more complicated and the currently known mutations

  1. Targeted Next-Generation Sequencing of a 12.5 Mb Homozygous Region Reveals ANO10 Mutations in Patients with Autosomal-Recessive Cerebellar Ataxia

    NARCIS (Netherlands)

    Vermeer, Sascha; Hoischen, Alexander; Meijer, Rowdy P. P.; Gilissen, Christian; Neveling, Kornelia; Wieskamp, Nienke; de Brouwer, Arjan; Koenig, Michel; Anheim, Mathieu; Assoum, Mirna; Drouot, Nathalie; Todorovic, Slobodanka; Milic-Rasic, Vedrana; Lochmueller, Hanns; Stevanin, Giovanni; Goizet, Cyril; David, Albert; Durr, Alexandra; Brice, Alexis; Kremer, Berry; van de Warrenburg, Bart P. C.; Schijvenaars, Mascha M. V. A. P.; Heister, Angelien; Kwint, Michael; Arts, Peer; van der Wijst, Jenny; Veltman, Joris; Kamsteeg, Erik-Jan; Scheffer, Hans; Knoers, Nine

    2010-01-01

    Autosomal-recessive cerebellar ataxias comprise a clinically and genetically heterogeneous group of neurodegenerative disorders. In contrast to their dominant counterparts, unraveling the molecular background of these ataxias has proven to be more complicated and the currently known mutations

  2. Mutations in SULT2B1 Cause Autosomal-Recessive Congenital Ichthyosis in Humans.

    Science.gov (United States)

    Heinz, Lisa; Kim, Gwang-Jin; Marrakchi, Slaheddine; Christiansen, Julie; Turki, Hamida; Rauschendorf, Marc-Alexander; Lathrop, Mark; Hausser, Ingrid; Zimmer, Andreas D; Fischer, Judith

    2017-06-01

    Ichthyoses are a clinically and genetically heterogeneous group of genodermatoses associated with abnormal scaling of the skin over the whole body. Mutations in nine genes are known to cause non-syndromic forms of autosomal-recessive congenital ichthyosis (ARCI). However, not all genetic causes for ARCI have been discovered to date. Using whole-exome sequencing (WES) and multigene panel screening, we identified 6 ARCI-affected individuals from three unrelated families with mutations in Sulfotransferase family 2B member 1 (SULT2B1), showing their causative association with ARCI. Cytosolic sulfotransferases form a large family of enzymes that are involved in the synthesis and metabolism of several steroids in humans. We identified four distinct mutations including missense, nonsense, and splice site mutations. We demonstrated the loss of SULT2B1 expression at RNA and protein levels in keratinocytes from individuals with ARCI by functional analyses. Furthermore, we succeeded in reconstructing the morphologic skin alterations in a 3D organotypic tissue culture model with SULT2B1-deficient keratinocytes and fibroblasts. By thin layer chromatography (TLC) of extracts from these organotypic cultures, we could show the absence of cholesterol sulfate, the metabolite of SULT2B1, and an increased level of cholesterol, indicating a disturbed cholesterol metabolism of the skin upon loss-of-function mutation in SULT2B1. In conclusion, our study reveals an essential role for SULT2B1 in the proper development of healthy human skin. Mutation in SULT2B1 leads to an ARCI phenotype via increased proliferation of human keratinocytes, thickening of epithelial layers, and altered epidermal cholesterol metabolism. Copyright © 2017 American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.

  3. Autosomal recessive retinitis pigmentosa caused by mutations in the MAK gene.

    Science.gov (United States)

    Stone, Edwin M; Luo, Xunda; Héon, Elise; Lam, Byron L; Weleber, Richard G; Halder, Jennifer A; Affatigato, Louisa M; Goldberg, Jacqueline B; Sumaroka, Alexander; Schwartz, Sharon B; Cideciyan, Artur V; Jacobson, Samuel G

    2011-12-28

    To determine the disease expression in autosomal recessive (ar) retinitis pigmentosa (RP) caused by mutations in the MAK (male germ cell-associated kinase) gene. Patients with RP and MAK gene mutations (n = 24; age, 32-77 years at first visit) were studied by ocular examination, perimetry, and optical coherence tomography (OCT). All but one MAK patient were homozygous for an identical truncating mutation in exon 9 and had Ashkenazi Jewish heritage. The carrier frequency of this mutation among 1207 unrelated Ashkenazi control subjects was 1 in 55, making it the most common cause of heritable retinal disease in this population and MAK-associated RP the sixth most common Mendelian disease overall in this group. Visual acuities could be normal into the eighth decade of life. Kinetic fields showed early loss in the superior-temporal quadrant. With more advanced disease, superior and midperipheral function was lost, but the nasal field remained. Only a central island was present at late stages. Pigmentary retinopathy was less prominent in the superior nasal quadrant. Rod-mediated vision was abnormal but detectable in the residual field; all patients had rod>cone dysfunction. Photoreceptor layer thickness was normal centrally but decreased with eccentricity. At the stages studied, there was no evidence of photoreceptor ciliary elongation. The patterns of disease expression in the MAK form of arRP showed some resemblance to patterns described in autosomal dominant RP, especially the form caused by RP1 mutations. The similarity in phenotypes is of interest, considering that there is experimental evidence of interaction between Mak and RP1 in the photoreceptor cilium.

  4. Biallelic Mutations in CRB1 Underlie Autosomal Recessive Familial Foveal Retinoschisis.

    Science.gov (United States)

    Vincent, Ajoy; Ng, Judith; Gerth-Kahlert, Christina; Tavares, Erika; Maynes, Jason T; Wright, Thomas; Tiwari, Amit; Tumber, Anupreet; Li, Shuning; Hanson, James V M; Bahr, Angela; MacDonald, Heather; Bähr, Luzy; Westall, Carol; Berger, Wolfgang; Cremers, Frans P M; den Hollander, Anneke I; Héon, Elise

    2016-05-01

    To identify the genetic cause of autosomal recessive familial foveal retinoschisis (FFR). A female sibship with FFR was identified (Family-A; 17 and 16 years, respectively); panel based genetic sequencing (132 genes) and comparative genome hybridization (142 genes) were performed. Whole-exome sequencing (WES) was performed on both siblings using the Illumina-HiSeq-2500 platform. A sporadic male (Family-B; 35 years) with FFR underwent WES using Illumina NextSeq500. All three affected subjects underwent detailed ophthalmologic evaluation including fundus photography, autofluorescence imaging, spectral-domain optical coherence tomography (SD-OCT), and full-field electroretinogram (ERG). Panel-based genetic testing identified two presumed disease causing variants in CRB1 (p.Gly123Cys and p.Cys948Tyr) in Family-A sibship; no deletion or duplication was detected. WES analysis in the sibship identified nine genes with two or more shared nonsynonymous rare coding sequence variants; CRB1 remained a strong candidate gene, and CRB1 variants segregated with the disease. WES in Family-B identified two presumed disease causing variants in CRB1 (p.Ile167_Gly169del and p.Arg764Cys) that segregated with the disease phenotype. Distance visual acuity was 20/40 or better in all three affected except for the left eye of the older subject (Family-B), which showed macular atrophy. Fundus evaluation showed spoke-wheel appearance at the macula in five eyes. The SD-OCT showed macular schitic changes in inner and outer nuclear layers in all cases. The ERG responses were normal in all subjects. This is the first report to implicate CRB1 as the underlying cause of FFR. This phenotype forms the mildest end of the spectrum of CRB1-related diseases.

  5. Deletion at the GCNT2 Locus Causes Autosomal Recessive Congenital Cataracts.

    Science.gov (United States)

    Irum, Bushra; Khan, Shahid Y; Ali, Muhammad; Daud, Muhammad; Kabir, Firoz; Rauf, Bushra; Fatima, Fareeha; Iqbal, Hira; Khan, Arif O; Al Obaisi, Saif; Naeem, Muhammad Asif; Nasir, Idrees A; Khan, Shaheen N; Husnain, Tayyab; Riazuddin, Sheikh; Akram, Javed; Eghrari, Allen O; Riazuddin, S Amer

    2016-01-01

    The aim of this study is to identify the molecular basis of autosomal recessive congenital cataracts (arCC) in a large consanguineous pedigree. All participating individuals underwent a detailed ophthalmic examination. Each patient's medical history, particularly of cataracts and other ocular abnormalities, was compiled from available medical records and interviews with family elders. Blood samples were donated by all participating family members and used to extract genomic DNA. Genetic analysis was performed to rule out linkage to known arCC loci and genes. Whole-exome sequencing libraries were prepared and paired-end sequenced. A large deletion was found that segregated with arCC in the family, and chromosome walking was conducted to estimate the proximal and distal boundaries of the deletion mutation. Exclusion and linkage analysis suggested linkage to a region of chromosome 6p24 harboring GCNT2 (glucosaminyl (N-acetyl) transferase 2) with a two-point logarithm of odds score of 5.78. PCR amplifications of the coding exons of GCNT2 failed in individuals with arCC, and whole-exome data analysis revealed a large deletion on chromosome 6p in the region harboring GCNT2. Chromosomal walking using multiple primer pairs delineated the extent of the deletion to approximately 190 kb. Interestingly, a failure to amplify a junctional fragment of the deletion break strongly suggests an insertion in addition to the large deletion. Here, we report a novel insertion/deletion mutation at the GCNT2 locus that is responsible for congenital cataracts in a large consanguineous family.

  6. Growth in children with autosomal recessive polycystic kidney disease in the CKiD cohort study

    Directory of Open Access Journals (Sweden)

    Erum Aftab Hartung

    2016-08-01

    Full Text Available Background: Previous studies have suggested that some children with autosomal recessive polycystic kidney disease (ARPKD have growth impairment out of proportion to their degree of chronic kidney disease (CKD. The objective of this study was to systematically compare growth parameters in children with ARPKD to those with other congenital causes of CKD in the Chronic Kidney Disease in Children (CKiD prospective cohort study. Methods: Height standard deviation scores (z-scores, proportion of children with severe short stature (z-score <-1.88, rates of growth hormone use, and annual change in height z-score were analyzed in children with ARPKD (n=22 compared to two matched control groups: children with aplastic/hypoplastic/dysplastic (A/H/D kidneys (n=44 and obstructive uropathy (OU (n=44. Differences in baseline characteristics were tested by Wilcoxon rank sum test or Fisher’s exact test. Matched differences in annual change in height z-score were tested by Wilcoxon signed rank test.Results: Median height z-score in children with ARPKD was -1.1 [interquartile range -1.5, -0.2]; 14% of the ARPKD group had height z-score <-1.88, and 18% were using growth hormone. There were no significant differences in median height z-score, proportion with height z-score <-1.88, growth hormone use, or annual change in height z-score between the ARPKD and control groups. Conclusions: Children with ARPKD and mild-to-moderate CKD in the CKiD cohort have a high prevalence of growth abnormalities, but these are similar to children with other congenital causes of CKD. This study does not support a disease-specific effect of ARPKD on growth, at least in the subset of children with mild-to-moderate CKD.

  7. Growth in Children with Autosomal Recessive Polycystic Kidney Disease in the CKiD Cohort Study.

    Science.gov (United States)

    Hartung, Erum A; Dell, Katherine M; Matheson, Matthew; Warady, Bradley A; Furth, Susan L

    2016-01-01

    Previous studies have suggested that some children with autosomal recessive polycystic kidney disease (ARPKD) have growth impairment out of proportion to their degree of chronic kidney disease (CKD). The objective of this study was to systematically compare growth parameters in children with ARPKD to those with other congenital causes of CKD in the chronic kidney disease in Children (CKiD) prospective cohort study. Height SD scores (z-scores), proportion of children with severe short stature (z-score growth hormone use, and annual change in height z-score were analyzed in children with ARPKD (n = 22) compared with two matched control groups: children with aplastic/hypoplastic/dysplastic kidneys (n = 44) and obstructive uropathy (OU) (n = 44). Differences in baseline characteristics were tested by Wilcoxon rank-sum test or Fisher's exact test. Matched differences in annual change in height z-score were tested by Wilcoxon signed-rank test. Median height z-score in children with ARPKD was -1.1 [interquartile range -1.5, -0.2]; 14% of the ARPKD group had height z-score growth hormone. There were no significant differences in median height z-score, proportion with height z-score growth hormone use, or annual change in height z-score between the ARPKD and control groups. Children with ARPKD and mild-to-moderate CKD in the CKiD cohort have a high prevalence of growth abnormalities, but these are similar to children with other congenital causes of CKD. This study does not support a disease-specific effect of ARPKD on growth, at least in the subset of children with mild-to-moderate CKD.

  8. A Founder Mutation in VPS11 Causes an Autosomal Recessive Leukoencephalopathy Linked to Autophagic Defects.

    Directory of Open Access Journals (Sweden)

    Jinglan Zhang

    2016-04-01

    Full Text Available Genetic leukoencephalopathies (gLEs are a group of heterogeneous disorders with white matter abnormalities affecting the central nervous system (CNS. The causative mutation in ~50% of gLEs is unknown. Using whole exome sequencing (WES, we identified homozygosity for a missense variant, VPS11: c.2536T>G (p.C846G, as the genetic cause of a leukoencephalopathy syndrome in five individuals from three unrelated Ashkenazi Jewish (AJ families. All five patients exhibited highly concordant disease progression characterized by infantile onset leukoencephalopathy with brain white matter abnormalities, severe motor impairment, cortical blindness, intellectual disability, and seizures. The carrier frequency of the VPS11: c.2536T>G variant is 1:250 in the AJ population (n = 2,026. VPS11 protein is a core component of HOPS (homotypic fusion and protein sorting and CORVET (class C core vacuole/endosome tethering protein complexes involved in membrane trafficking and fusion of the lysosomes and endosomes. The cysteine 846 resides in an evolutionarily conserved cysteine-rich RING-H2 domain in carboxyl terminal regions of VPS11 proteins. Our data shows that the C846G mutation causes aberrant ubiquitination and accelerated turnover of VPS11 protein as well as compromised VPS11-VPS18 complex assembly, suggesting a loss of function in the mutant protein. Reduced VPS11 expression leads to an impaired autophagic activity in human cells. Importantly, zebrafish harboring a vps11 mutation with truncated RING-H2 domain demonstrated a significant reduction in CNS myelination following extensive neuronal death in the hindbrain and midbrain. Thus, our study reveals a defect in VPS11 as the underlying etiology for an autosomal recessive leukoencephalopathy disorder associated with a dysfunctional autophagy-lysosome trafficking pathway.

  9. Biallelic SUN5 Mutations Cause Autosomal-Recessive Acephalic Spermatozoa Syndrome.

    Science.gov (United States)

    Zhu, Fuxi; Wang, Fengsong; Yang, Xiaoyu; Zhang, Jingjing; Wu, Huan; Zhang, Zhou; Zhang, Zhiguo; He, Xiaojin; Zhou, Ping; Wei, Zhaolian; Gecz, Jozef; Cao, Yunxia

    2016-10-06

    Acephalic spermatozoa syndrome is a rare and severe form of teratozoospermia characterized by a predominance of headless spermatozoa in the ejaculate. Family clustering and consanguinity suggest a genetic origin; however, causative mutations have yet to be identified. We performed whole-exome sequencing in two unrelated infertile men and subsequent variant filtering identified one homozygous (c.824C>T [p.Thr275Met]) and one compound heterozygous (c.1006C>T [p.Arg356Cys] and c.485T>A [p.Met162Lys]) SUN5 (also named TSARG4) variants. Sanger sequencing of SUN5 in 15 additional unrelated infertile men revealed four compound heterozygous (c.381delA [p.Val128Serfs ∗ 7] and c.824C>T [p.Thr275Met]; c.381delA [p.Val128Serfs ∗ 7] and c.781G>A [p.Val261Met]; c.216G>A [p.Trp72 ∗ ] and c.1043A>T [p.Asn348Ile]; c.425+1G>A/c.1043A>T [p.Asn348Ile]) and two homozygous (c.851C>G [p.Ser284 ∗ ]; c.350G>A [p.Gly114Arg]) variants in six individuals. These 10 SUN5 variants were found in 8 of 17 unrelated men, explaining the genetic defect in 47.06% of the affected individuals in our cohort. These variants were absent in 100 fertile population-matched control individuals. SUN5 variants lead to absent, significantly reduced, or truncated SUN5, and certain variants altered SUN5 distribution in the head-tail junction of the sperm. In summary, these results demonstrate that biallelic SUN5 mutations cause male infertility due to autosomal-recessive acephalic spermatozoa syndrome. Copyright © 2016 American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.

  10. Loss of VPS13C Function in Autosomal-Recessive Parkinsonism Causes Mitochondrial Dysfunction and Increases PINK1/Parkin-Dependent Mitophagy

    OpenAIRE

    Lesage, S.; Drouet, V.; Majounie, E.; Deramecourt, V.; Jacoupy, M.; Nicolas, A.; Cormier-Dequaire, F.; Hassoun, S.M.; Pujol, C.; Ciura, S.; Erpapazoglou, Z.; Usenko, T.; Maurage, C.A.; Sahbatou, M.; Liebau, S.

    2016-01-01

    Autosomal-recessive early-onset parkinsonism is clinically and genetically heterogeneous. The genetic causes of approximately 50% of autosomal-recessive early-onset forms of Parkinson disease (PD) remain to be elucidated. Homozygozity mapping and exome sequencing in 62 isolated individuals with early-onset parkinsonism and confirmed consanguinity followed by data mining in the exomes of 1,348 PD-affected individuals identified, in three isolated subjects, homozygous or compound heterozygous t...

  11. A Naturally Occurring Canine Model of Autosomal Recessive Congenital Stationary Night Blindness.

    Directory of Open Access Journals (Sweden)

    Mineo Kondo

    Full Text Available Congenital stationary night blindness (CSNB is a non-progressive, clinically and genetically heterogeneous disease of impaired night vision. We report a naturally-occurring, stationary, autosomal recessive phenotype in beagle dogs with normal daylight vision but absent night vision. Affected dogs had normal retinas on clinical examination, but showed no detectable rod responses. They had "negative-type" mixed rod and cone responses in full-field ERGs. Their photopic long-flash ERGs had normal OFF-responses associated with severely reduced ON-responses. The phenotype is similar to the Schubert-Bornschein form of complete CSNB in humans. Homozygosity mapping ruled out most known CSNB candidates as well as CACNA2D4 and GNB3. Three remaining genes were excluded based on sequencing the open reading frame and intron-exon boundaries (RHO, NYX, causal to a different form of CSNB (RHO or X-chromosome (NYX, CACNA1F location. Among the genes expressed in the photoreceptors and their synaptic terminals, and mGluR6 cascade and modulators, reduced expression of GNAT1, CACNA2D4 and NYX was observed by qRT-PCR in both carrier (n = 2 and affected (n = 2 retinas whereas CACNA1F was down-regulated only in the affecteds. Retinal morphology revealed normal cellular layers and structure, and electron microscopy showed normal rod spherules and synaptic ribbons. No difference from normal was observed by immunohistochemistry (IHC for antibodies labeling rods, cones and their presynaptic terminals. None of the retinas showed any sign of stress. Selected proteins of mGluR6 cascade and its modulators were examined by IHC and showed that PKCα weakly labeled the rod bipolar somata in the affected, but intensely labeled axonal terminals that appeared thickened and irregular. Dendritic terminals of ON-bipolar cells showed increased Goα labeling. Both PKCα and Goα labeled the more prominent bipolar dendrites that extended into the OPL in affected but not normal retinas

  12. Genetic spectrum of autosomal recessive non-syndromic hearing loss in Pakistani families.

    Directory of Open Access Journals (Sweden)

    Sobia Shafique

    Full Text Available The frequency of inherited bilateral autosomal recessive non-syndromic hearing loss (ARNSHL in Pakistan is 1.6/1000 individuals. More than 50% of the families carry mutations in GJB2 while mutations in MYO15A account for about 5% of recessive deafness. In the present study a cohort of 30 ARNSHL families was initially screened for mutations in GJB2 and MYO15A. Homozygosity mapping was performed by employing whole genome single nucleotide polymorphism (SNP genotyping in the families that did not carry mutations in GJB2 or MYO15A. Mutation analysis was performed for the known ARNSHL genes present in the homozygous regions to determine the causative mutations. This allowed the identification of a causative mutation in all the 30 families including 9 novel mutations, which were identified in 9 different families (GJB2 (c.598G>A, p.Gly200Arg; MYO15A (c.9948G>A, p.Gln3316Gln; c.3866+1G>A; c.8767C>T, p.Arg2923* and c.8222T>C, p.Phe2741Ser, TMC1 (c.362+18A>G, BSND (c.97G>C, p.Val33Leu, TMPRSS3 (c.726C>G, p.Cys242Trp and MSRB3 (c.20T>G, p.Leu7Arg. Furthermore, 12 recurrent mutations were detected in 21 other families. The 21 identified mutations included 10 (48% missense changes, 4 (19% nonsense mutations, 3 (14% intronic mutations, 2 (9% splice site mutations and 2 (9% frameshift mutations. GJB2 accounted for 53% of the families, while mutations in MYO15A were the second most frequent (13% cause of ARNSHL in these 30 families. The identification of novel as well as recurrent mutations in the present study increases the spectrum of mutations in known deafness genes which could lead to the identification of novel founder mutations and population specific mutated deafness genes causative of ARNSHL. These results provide detailed genetic information that has potential diagnostic implication in the establishment of cost-efficient allele-specific analysis of frequently occurring variants in combination with other reported mutations in Pakistani populations.

  13. A common founder mutation of CERKL underlies autosomal recessive retinal degeneration with early macular involvement among Yemenite Jews.

    Science.gov (United States)

    Auslender, Noa; Sharon, Dror; Abbasi, Anan H; Garzozi, Hanna J; Banin, Eyal; Ben-Yosef, Tamar

    2007-12-01

    To investigate the genetic basis and clinical manifestations of a characteristic form of retinal degeneration in the Yemenite Jewish population. Haplotype analysis for all known genes and loci underlying autosomal recessive nonsyndromic retinal degeneration was performed in a Yemenite Jewish family segregating autosomal recessive severe retinal degeneration. The causative mutation was detected by direct sequencing of the underlying gene, and its prevalence in additional affected and unaffected Yemenite Jews was determined. Patients who were homozygous for this mutation underwent ophthalmic evaluation, including funduscopy, electroretinography, electro-oculography, perimetry, and color vision testing. In the studied Yemenite Jewish family, we found evidence for linkage to the CERKL gene. Direct sequencing revealed a novel homozygous splice-site mutation, c.238+1G>A. An in vitro splicing assay demonstrated that this mutation leads to incorrect splicing. c.238+1G>A was found to cause retinal degeneration in six additional Yemenite Jewish families. The carrier frequency of this mutation in the Yemenite Jewish population is 4.4%. All c.238+1G>A homozygotes manifest widespread progressive impairment of rod and cone function with early macular involvement. c.238+1G>A is the second reported mutation of CERKL and is a prevalent founder mutation that underlies approximately 33% of autosomal recessive retinal degeneration cases in the Yemenite Jewish population. It is associated with a characteristic retinal degeneration phenotype with early macular involvement, concomitant progression of rod and cone impairment, and characteristic fundus findings. The identification of this mutation and phenotype will facilitate molecular diagnosis, carrier screening, and genetic counseling in the Yemenite Jewish population.

  14. A homozygous mutation in a consanguineous family consolidates the role of ALDH1A3 in autosomal recessive microphthalmia

    DEFF Research Database (Denmark)

    Roos, L; Fang, M; Dali, C

    2013-01-01

    to the identification of new genes. Very recently, homozygous variations within ALDH1A3 have been associated with autosomal recessive microphthalmia with or without cysts or coloboma, and with variable subphenotypes of developmental delay/autism spectrum disorder in eight families. In a consanguineous family where...... three of the five siblings were affected with microphthalmia/coloboma, we identified a novel homozygous missense mutation in ALDH1A3 using exome sequencing. Of the three affected siblings, one had intellectual disability and one had intellectual disability and autism, while the last one presented...

  15. Inhibitory action of chlorophyllin of autosome recessive lethals induced by irradiation

    International Nuclear Information System (INIS)

    Salceda, V.M.; Pimentel, P.A.E.; Cruces, M.P.

    2006-01-01

    on the damage caused by the radiation, it was into account the presence of lethal and semi lethals autosomal. One observes this way that even without the use of the radiation the semi lethals frequency is diminished when the chlorophyllin is applied, in this case the decrease was significant and although there was decrease in the case of the irradiated group this it was not significant; in the case of the lethal ones it happened the opposite it was not significant in radiation absence on the contrary elevate the frequency of this type of genes, however, before the radiation and with pre-treatment with chlorophyllin this it reduced the frequency of autosomal recessive lethals significantly. This is important because in the case of bound recessive lethals recessive to the sex this doesn't happen. (Author)

  16. Whole Genome Sequencing Identifies Novel Compound Heterozygous Lysosomal Trafficking Regulator Gene Mutations Associated with Autosomal Recessive Chediak-Higashi Syndrome.

    Science.gov (United States)

    Jin, Yaqiong; Zhang, Li; Wang, Senfen; Chen, Feng; Gu, Yang; Hong, Enyu; Yu, Yongbo; Ni, Xin; Guo, Yongli; Shi, Tieliu; Xu, Zigang

    2017-02-01

    Chediak-Higashi syndrome (CHS) is a rare autosomal recessive disease characterized by varying degrees of oculocutaneous albinism, recurrent infections, and a mild bleeding tendency, with late neurologic dysfunction. This syndrome is molecularly characterized by pathognomonic mutations in the LYST (lysosomal trafficking regulator). Using whole genome sequencing (WGS) we attempted to identify novel mutations of CHS based on a family of CHS with atypical symptoms. The two patients demonstrated a phenotypic constellation including partial oculocutaneous albinism, frequency upper respiratory infection or a marginal intelligence, without bleeding tendency and severe immunodeficiency. WGS revealed two compound LYST mutations including a maternally inherited chr1:235969126G > A (rs80338652) and a novel paternally inherited chr1: 235915327A > AT, associated with autosomal recessive CHS. These two variants fall in the coding regions of LYST, resulting in premature truncation of LYST due to R1104X/N2535KfsX2 induced incomplete translation. Notably, the heterozygous carriers (i.e. parents) were unaffected. Our finding also reveals decreased plasma serotonin levels in patients with CHS compared with unaffected individuals for the first time. The present study contributes to improved understanding of the causes of this disease and provides new ideas for possible treatments.

  17. Discriminative Features in Three Autosomal Recessive Cutis Laxa Syndromes: Cutis Laxa IIA, Cutis Laxa IIB, and Geroderma Osteoplastica

    Directory of Open Access Journals (Sweden)

    Ariana Kariminejad

    2017-03-01

    Full Text Available Cutis laxa is a heterogeneous condition characterized by redundant, sagging, inelastic, and wrinkled skin. The inherited forms of this disease are rare and can have autosomal dominant, autosomal recessive, or X-linked inheritance. Three of the autosomal recessive cutis laxa syndromes, namely cutis laxa IIA (ARCL2A, cutis laxa IIB (ARCL2B, and geroderma osteodysplastica (GO, have very similar clinical features, complicating accurate diagnosis. Individuals with these conditions often present with cutis laxa, progeroid features, and hyperextensible joints. These conditions also share additional features, such as short stature, hypotonia, and congenital hip dislocation, but the severity and frequency of these findings are variable in each of these cutis laxa syndromes. The characteristic features for ARCL2A are abnormal isoelectric focusing and facial features, including downslanting palpebral fissures and a long philtrum. Rather, the clinical phenotype of ARCL2B includes severe wrinkling of the dorsum of the hands and feet, wormian bones, athetoid movements, lipodystrophy, cataract and corneal clouding, a thin triangular face, and a pinched nose. Normal cognition and osteopenia leading to pathological fractures, maxillary hypoplasia, and oblique furrowing from the outer canthus to the lateral border of the supraorbital ridge are discriminative features for GO. Here we present 10 Iranian patients who were initially diagnosed clinically using the respective features of each cutis laxa syndrome. Each patient’s clinical diagnosis was then confirmed with molecular investigation of the responsible gene. Review of the clinical features from the cases reported from the literature also supports our conclusions.

  18. Using next-generation sequencing as a genetic diagnostic tool in rare autosomal recessive neurologic Mendelian disorders.

    Science.gov (United States)

    Chen, Zhao; Wang, Jun-Ling; Tang, Bei-Sha; Sun, Zhan-Fang; Shi, Yu-Ting; Shen, Lu; Lei, Li-Fang; Wei, Xiao-Ming; Xiao, Jing-Jing; Hu, Zheng-Mao; Pan, Qian; Xia, Kun; Zhang, Qing-Yan; Dai, Mei-Zhi; Liu, Yu; Ashizawa, Tetsuo; Jiang, Hong

    2013-10-01

    Next-generation sequencing was used to investigate 9 rare Chinese pedigrees with rare autosomal recessive neurologic Mendelian disorders. Five probands with ataxia-telangectasia and 1 proband with chorea-acanthocytosis were analyzed by targeted gene sequencing. Whole-exome sequencing was used to investigate 3 affected individuals with Joubert syndrome, nemaline myopathy, or spastic ataxia Charlevoix-Saguenay type. A list of known and novel candidate variants was identified for each causative gene. All variants were genetically verified by Sanger sequencing or quantitative polymerase chain reaction with the strategy of disease segregation in related pedigrees and healthy controls. The advantages of using next-generation sequencing to diagnose rare autosomal recessive neurologic Mendelian disorders characterized by genetic and phenotypic heterogeneity are demonstrated. A genetic diagnostic strategy combining the use of targeted gene sequencing and whole-exome sequencing with the aid of next-generation sequencing platforms has shown great promise for improving the diagnosis of neurologic Mendelian disorders. Copyright © 2013 Elsevier Inc. All rights reserved.

  19. Autosomal recessive MFN2-related Charcot-Marie-Tooth disease with diaphragmatic weakness: Case report and literature review.

    Science.gov (United States)

    Tan, Christopher A; Rabideau, Marina; Blevins, Amy; Westbrook, Marjorie Jody; Ekstein, Tali; Nykamp, Keith; Deucher, Anne; Harper, Amy; Demmer, Laurie

    2016-06-01

    Pathogenic variants in the mitofusin 2 gene (MFN2) are the most common cause of autosomal dominant Charcot-Marie-Tooth (CMT2) disease, which is typically characterized by axonal sensorimotor neuropathy. We report on a 7-month-old white female with hypotonia, motor delay, distal weakness, and motor/sensory axonal neuropathy in which next-generation sequencing analysis identified compound heterozygous pathogenic variants (c.2054_2069_1170del and c.392A>G) in MFN2. A review of the literature reveals that sporadic and familial cases of compound heterozygous or homozygous pathogenic MFN2 variants have been infrequently described, which indicates that MFN2 can also be inherited in a recessive manner. This case highlights several clinical findings not typically associated with MFN2 pathogenic variants, including young age of onset and rapidly progressing diaphragmatic paresis that necessitated tracheostomy and mechanical ventilation, and adds to the growing list of features identified in autosomal recessive MFN2-related CMT2. Our patient with MFN2-related CMT2 expands the clinical and mutational spectrum of individuals with autosomal recessive CMT2 and identifies a new clinical feature that warrants further observation. © 2016 Wiley Periodicals, Inc. © 2016 Wiley Periodicals, Inc.

  20. Genetic Linkage Analysis of DFNB2 Locus with Autosomal Recessive Hearing Loss in Families Negative for GJB2 Mutations in Khuzestan Province

    OpenAIRE

    Parisa Tahmasebi; Seyed Reza Kazemi Nezhad; Mohammad Amin Tabatabaiefar; Javad Mohammadi Asl; Nader Saki

    2016-01-01

    Abstract Background: Hearing loss is a common sensory impairment in humans which half of its causes are genetic reasons. Genetic hearing loss can be divided into the two types of syndromic and non-syndromic, which 80% of non-syndromic cases is Autosomal Recessive Non-Syndromic Hearing Loss. The aim of the present research is to determine the contribution of DFNB2 locus (MYO7A gene) in causing an autosomal recessive hearing loss in the one group of the deaf families of Khuzestan province. ...

  1. Transcription-terminating mutation in telethonin causing autosomal recessive muscular dystrophy type 2G in a European patient.

    Science.gov (United States)

    Olivé, Montse; Shatunov, Alexey; Gonzalez, Laura; Carmona, Olga; Moreno, Dolores; Quereda, Lidia Gonzalez; Martinez-Matos, J A; Goldfarb, Lev G; Ferrer, Isidro

    2008-12-01

    A 27-year-old woman of Moldavian origin presented at the age of 15 with progressive proximal limb weakness and painful cramps in her calf muscles. Clinical examination revealed prominent muscle weakness in proximal muscles of the lower extremities and distal anterior compartment of legs, and mild weakness in shoulder girdle muscles. In addition, she had marked calf hypertrophy, muscle atrophy involving the anterior and posterior compartments of the thighs, and the distal anterior compartment of legs, as well as mild scapular winging and hyperlordosis. A muscle biopsy taken from the biceps brachii showed mild dystrophic changes, absent vacuoles, and abundant lobulated fibers. Immunofluorescence and Western blot assays demonstrated complete telethonin deficiency. Molecular analysis revealed a homozygous Trp25X mutation in the telethonin (TCAP) gene resulting in termination of transcription at an early point. Four families from Brazil with telethonin deficiency have previously been reported and classified as LGMD2G, but the actual frequency of this disease is unknown. With this current identification of a case outside the Brazilian population, telethonin mutation-associated LGMD should be considered worldwide.

  2. A Mutation in LIPN, Encoding Epidermal Lipase N, Causes a Late-Onset Form of Autosomal-Recessive Congenital Ichthyosis

    Science.gov (United States)

    Israeli, Shirli; Khamaysi, Ziyad; Fuchs-Telem, Dana; Nousbeck, Janna; Bergman, Reuven; Sarig, Ofer; Sprecher, Eli

    2011-01-01

    Autosomal-recessive congenital ichthyoses represent a large and heterogeneous group of disorders of epidermal cornification. Recent data suggest that most of these disorders might result from defective lipid transport and metabolism. In the present study, we describe a late-onset form of recessive ichthyosis in a large consanguineous pedigree. By using a combination of homozygosity mapping and positional candidate-gene screening, we identified a 2 bp deletion in LIPN that segregated with the disease phenotype throughout the family. LIPN encodes one of six acid lipases known to be involved in triglyceride metabolism in mammals . LIPN was found to be exclusively expressed in the epidermis and to be strongly induced during keratinocyte differentiation. PMID:21439540

  3. Mutations in DZIP1L, which encodes a ciliary transition zone protein, cause autosomal recessive polycystic kidney disease

    Science.gov (United States)

    Lu, Hao; Galeano, Maria C. Rondón; Ott, Elisabeth; Kaeslin, Geraldine; Kausalya, P. Jaya; Kramer, Carina; Ortiz-Brüchle, Nadina; Hilger, Nadescha; Metzis, Vicki; Hiersche, Milan; Tay, Shang Yew; Tunningley, Robert; Vij, Shubha; Courtney, Andrew D.; Whittle, Belinda; Wühl, Elke; Vester, Udo; Hartleben, Björn; Neuber, Steffen; Frank, Valeska; Little, Melissa H.; Epting, Daniel; Papathanasiou, Peter; Perkins, Andrew C.; Wright, Graham D.; Hunziker, Walter; Gee, Heon Yung; Otto, Edgar A.; Zerres, Klaus; Hildebrandt, Friedhelm; Roy, Sudipto; Wicking, Carol; Bergmann, Carsten

    2017-01-01

    Autosomal recessive polycystic kidney disease (ARPKD), usually considered to be a genetically homogeneous disease caused by mutations in PKHD1, has been associated with ciliary dysfunction. Here, we describe mutations in the DAZ interacting protein 1-like (DZIP1L) gene in patients with ARPKD, findings we have further validated by loss-of-function studies in mice and zebrafish. DZIP1L localizes to centrioles and at the distal end of basal bodies, and interacts with septin2, a protein implicated in maintenance of the periciliary diffusion barrier at the ciliary transition zone. Consistent with a defect in the diffusion barrier, we found that the ciliary membrane translocation of the PKD proteins, polycystin-1 and −2, is compromised in DZIP1L mutant cells. Together, these data provide the first conclusive evidence that ARPKD is not a homogeneous disorder, and establishes DZIP1L as a second gene involved in its pathogenesis. PMID:28530676

  4. Mutations in DZIP1L, which encodes a ciliary-transition-zone protein, cause autosomal recessive polycystic kidney disease.

    Science.gov (United States)

    Lu, Hao; Galeano, Maria C Rondón; Ott, Elisabeth; Kaeslin, Geraldine; Kausalya, P Jaya; Kramer, Carina; Ortiz-Brüchle, Nadina; Hilger, Nadescha; Metzis, Vicki; Hiersche, Milan; Tay, Shang Yew; Tunningley, Robert; Vij, Shubha; Courtney, Andrew D; Whittle, Belinda; Wühl, Elke; Vester, Udo; Hartleben, Björn; Neuber, Steffen; Frank, Valeska; Little, Melissa H; Epting, Daniel; Papathanasiou, Peter; Perkins, Andrew C; Wright, Graham D; Hunziker, Walter; Gee, Heon Yung; Otto, Edgar A; Zerres, Klaus; Hildebrandt, Friedhelm; Roy, Sudipto; Wicking, Carol; Bergmann, Carsten

    2017-07-01

    Autosomal recessive polycystic kidney disease (ARPKD), usually considered to be a genetically homogeneous disease caused by mutations in PKHD1, has been associated with ciliary dysfunction. Here, we describe mutations in DZIP1L, which encodes DAZ interacting protein 1-like, in patients with ARPKD. We further validated these findings through loss-of-function studies in mice and zebrafish. DZIP1L localizes to centrioles and to the distal ends of basal bodies, and interacts with septin2, a protein implicated in maintenance of the periciliary diffusion barrier at the ciliary transition zone. In agreement with a defect in the diffusion barrier, we found that the ciliary-membrane translocation of the PKD proteins polycystin-1 and polycystin-2 is compromised in DZIP1L-mutant cells. Together, these data provide what is, to our knowledge, the first conclusive evidence that ARPKD is not a homogeneous disorder and further establish DZIP1L as a second gene involved in ARPKD pathogenesis.

  5. The acrocallosal syndrome in first cousins: widening of the spectrum of clinical features and further support for autosomal recessive inheritance.

    Science.gov (United States)

    Schinzel, A

    1988-01-01

    First cousins, related through their mothers, showed a pattern of craniofacial, brain, and limb anomalies consistent with the acrocallosal syndrome. Both patients had a defect of the corpus callosum, macrocephaly with a protruding forehead and occiput, hypertelorism, non-horizontal palpebral fissures, a small nose, notched ear lobes, and postaxial polydactyly of the hands. The boy, in addition, had hypospadias, cryptorchidism, inguinal hernias, duplication with syndactyly of the phalanges of the big toe, and a bipartite right clavicle. The girl had an arachnoidal cyst, a calvarian defect, and digitalisation of the thumbs. Motor and mental development was retarded in both patients. This observation provides further evidence of probable autosomal recessive inheritance of the acrocallosal syndrome and widens the spectrum of clinical findings and the variability of features in this rare malformation syndrome. Images PMID:3385741

  6. Familial Clustering of Unexplained Transient Respiratory Distress in 12 Newborns from Three Unrelated Families Suggests an Autosomal-Recessive Inheritance

    Directory of Open Access Journals (Sweden)

    Andrea Guala

    2007-01-01

    Full Text Available We report on 12 near-term babies from three families in which an unexplained transient respiratory distress was observed. No known risk factor was present in any family and no sequelae were recorded at follow-up. The most common causes of respiratory distress at birth are Neonatal Respiratory Distress Syndrome (NRD and Transient Tachypnea of the Newborn (TTN, and their cumulative incidence is estimated to be about 2%. Genetic factors have been identified in NRD (surfactant genes or suggested for TTN (genes affecting lung liquid clearance. Survivors from NRD may develop clinically relevant sequelae, while TTN does not cause any problem later in life. Our cases do not immediately fit NRD or TTN, while familial recurrence suggests the existence of a previously unreported subgroup on patients with respiratory distress for which autosomal-recessive inheritance is likely.

  7. An autosomal recessive DNASE1L3-related autoimmune disease with unusual clinical presentation mimicking systemic lupus erythematosus.

    Science.gov (United States)

    Carbonella, A; Mancano, G; Gremese, E; Alkuraya, F S; Patel, N; Gurrieri, F; Ferraccioli, G

    2017-06-01

    We describe the third family in the world, after Arabian and Turkish ones, displaying an autosomal recessive autoimmune disease (AID), mimicking systemic lupus erythematosus (SLE), with unusual manifestations due to a homozygous frame-shift variant in DNASE1L3. SLE is a complex AID characterized by multiple organ involvement. Genetic risk variants identified account for only 15% of SLE heritability. Rare Mendelian forms have been reported, including DNASE1L3-related SLE. Through specific genetic tests we identified a homozygous 2 bp-deletion c.289_290delAC (NM_004944.2) in DNASE1L3, predicting frameshift and premature truncation (p.Thr97Ilefs*2). The same mutation was previously reported in three sisters, born from consanguineous parents and affected with hypocomplementemic urticarial vasculitis syndrome (HUVS). As approximately 50% of individuals affected with HUVS develop SLE, it is still unclear whether it is a SLE sub-phenotype or a separate condition.

  8. Neuromuscular blocking effects of cisatracurium and its antagonism with neostigmine in a canine model of autosomal-recessive centronuclear myopathy.

    Science.gov (United States)

    Martin-Flores, M; Paré, M D; Campoy, L; Gleed, R D

    2015-12-01

    Centronuclear myopathy (CNM) is a rare congenital condition associated with skeletal muscle weakness. Patients with CNM may have decreased acetylcholine receptor expression and a reduced number of releasable quanta. Such perturbations could affect the time-course of neuromuscular blocking agents (NMBAs) and their antagonism with cholinesterase inhibitors. As a result of the rarity of CNM, prospective data regarding NMBA use in this subpopulation is scarce. We evaluated the neuromuscular blocking effects of cisatracurium and its antagonism with neostigmine in a canine model of CNM. Six dogs with congenital autosomal-recessive CNM and six controls received cisatracurium 0.15 mg kg(-1) i.v. under general anaesthesia and intermittent positive pressure ventilation. Neuromuscular function was monitored with acceleromyography.When the second response (T2) to train-of-four (TOF) stimulation returned, neostigmine 0.04 mg kg(-1) (with glycopyrrolate) were administered i.v. The onset time, time to spontaneous return of T2, and the time to reach a TOF ratio ≥0.9 after neostigmine administration were recorded. Onset time was no different between groups. Median (interquartile range) time to return of T2 was 27 (24-31) min for control dogs and 26 (22-31) min for CNM dogs (P=0.93).After neostigmine administration, a TOF ratio ≥0.9 was reached in 12 (10-15) min and 17 (16-19) min in control and CNM, respectively (P=0.005). The spontaneous return of T2 was not different between groups. However, neostigmine-facilitated recovery was significantly slower in dogs with CNM. Canine autosomal-recessive CNM does not preclude the use of cisatracurium or its antagonism with neostigmine. © The Author 2015. Published by Oxford University Press on behalf of the British Journal of Anaesthesia. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

  9. A case report of novel mutation in PRF1 gene, which causes familial autosomal recessive hemophagocytic lymphohistiocytosis.

    Science.gov (United States)

    Bordbar, Mohammad Reza; Modarresi, Farzaneh; Farazi Fard, Mohammad Ali; Dastsooz, Hassan; Shakib Azad, Nader; Faghihi, Mohammad Ali

    2017-05-03

    Hemophagocytic Lymphohistiocytosis (HLH) is a life-threatening immunodeficiency and multi-organ disease that affects people of all ages and ethnic groups. Common symptoms and signs of this disease are high fever, hepatosplenomegaly, and cytopenias. Familial form of HLH disease, which is an autosomal recessive hematological disorder is due to disease-causing mutations in several genes essential for NK and T-cell granule-mediated cytotoxic function. For an effective cytotoxic response from cytotoxic T lymphocyte or NK cell encountering an infected cell or tumor cell, different processes are required, including trafficking, docking, priming, membrane fusion, and entry of cytotoxic granules into the target cell leading to apoptosis. Therefore, genes involved in these steps play important roles in the pathogenesis of HLH disease which include PRF1, UNC13D (MUNC13-4), STX11, and STXBP2 (MUNC18-2). Here, we report a novel missense mutation in an 8-year-old boy suffered from hepatosplenomegaly, hepatitis, epilepsy and pancytopenia. The patient was born to a first-cousin parents with no previous documented disease in his parents. To identify mutated gene in the proband, Whole Exome Sequencing (WES) utilizing next generation sequencing was used on an Illumina HiSeq 2000 platform on DNA sample from the patient. Results showed a novel deleterious homozygous missense mutation in PRF1 gene (NM_001083116: exon3: c. 1120 T > G, p.W374G) in the patient and then using Sanger sequencing it was confirmed in the proband and his parents. Since his parents were heterozygous for the identified mutation, autosomal recessive pattern of inheritance was confirmed in the family. Our study identified a rare new pathogenic missense mutation in PRF1 gene in patient with HLH disease and it is the first report of mutation in PRF1 in Iranian patients with this disease.

  10. Two Cases of Autosomal Recessive Congenital Ichthyosis due to CYP4F22 Mutations: Expanding the Genotype of Self-Healing Collodion Baby

    NARCIS (Netherlands)

    Noguera-Morel, L.; Feito-Rodriguez, M.; Maldonado-Cid, P.; Garcia-Minaur, S.; Kamsteeg, E.J.; Gonzalez-Sarmiento, R.; Lucas-Laguna, R. De; Hernandez-Martin, A.; Torrelo, A.

    2016-01-01

    Collodion babies are born with a tight, shiny cast that sheds in a few weeks. After shedding, most patients will display features of autosomal recessive congenital ichthyosis (ARCI) later in life but in up to 10% of cases, the skin eventually becomes normal or only minimally involved, a phenotype

  11. Fine mapping of the autosomal recessive retinitis pigmentosa locus (RP12) on chromosome 1q; exclusion of the phosducin gene (PDC)

    NARCIS (Netherlands)

    van Soest, S.; te Nijenhuis, S.; van den Born, L. I.; Bleeker-Wagemakers, E. M.; Sharp, E.; Sandkuijl, L. A.; Westerveld, A.; Bergen, A. A.

    1996-01-01

    In a previous study on a large pedigree from a genetically isolated population in the Netherlands, we localized a gene for autosomal recessive retinitis pigmentosa with paraarteriolar preservation of the retinal pigment epithelium (PPRPE) on the long arm of chromosome 1. In this study, we present an

  12. DOCK6 mutations are responsible for a distinct autosomal-recessive variant of Adams-Oliver syndrome associated with brain and eye anomalies.

    Science.gov (United States)

    Sukalo, Maja; Tilsen, Felix; Kayserili, Hülya; Müller, Dietmar; Tüysüz, Beyhan; Ruddy, Deborah M; Wakeling, Emma; Ørstavik, Karen Helene; Snape, Katie M; Trembath, Richard; De Smedt, Maryse; van der Aa, Nathalie; Skalej, Martin; Mundlos, Stefan; Wuyts, Wim; Southgate, Laura; Zenker, Martin

    2015-06-01

    Adams-Oliver syndrome (AOS) is characterized by the association of aplasia cutis congenita with terminal transverse limb defects, often accompanied by additional cardiovascular or neurological features. Both autosomal-dominant and autosomal-recessive disease transmission have been observed, with recent gene discoveries indicating extensive genetic heterogeneity. Mutations of the DOCK6 gene were first described in autosomal-recessive cases of AOS and only five DOCK6-related families have been reported to date. Recently, a second type of autosomal-recessive AOS has been attributed to EOGT mutations in three consanguineous families. Here, we describe the identification of 13 DOCK6 mutations, the majority of which are novel, across 10 unrelated individuals from a large cohort comprising 47 sporadic cases and 31 AOS pedigrees suggestive of autosomal-recessive inheritance. DOCK6 mutations were strongly associated with structural brain abnormalities, ocular anomalies, and intellectual disability, thus suggesting that DOCK6-linked disease represents a variant of AOS with a particularly poor prognosis. © 2015 WILEY PERIODICALS, INC.

  13. Corneal dystrophies

    Directory of Open Access Journals (Sweden)

    Klintworth Gordon K

    2009-02-01

    Full Text Available Abstract The term corneal dystrophy embraces a heterogenous group of bilateral genetically determined non-inflammatory corneal diseases that are restricted to the cornea. The designation is imprecise but remains in vogue because of its clinical value. Clinically, the corneal dystrophies can be divided into three groups based on the sole or predominant anatomical location of the abnormalities. Some affect primarily the corneal epithelium and its basement membrane or Bowman layer and the superficial corneal stroma (anterior corneal dystrophies, the corneal stroma (stromal corneal dystrophies, or Descemet membrane and the corneal endothelium (posterior corneal dystrophies. Most corneal dystrophies have no systemic manifestations and present with variable shaped corneal opacities in a clear or cloudy cornea and they affect visual acuity to different degrees. Corneal dystrophies may have a simple autosomal dominant, autosomal recessive or X-linked recessive Mendelian mode of inheritance. Different corneal dystrophies are caused by mutations in the CHST6, KRT3, KRT12, PIP5K3, SLC4A11, TACSTD2, TGFBI, and UBIAD1 genes. Knowledge about the responsible genetic mutations responsible for these disorders has led to a better understanding of their basic defect and to molecular tests for their precise diagnosis. Genes for other corneal dystrophies have been mapped to specific chromosomal loci, but have not yet been identified. As clinical manifestations widely vary with the different entities, corneal dystrophies should be suspected when corneal transparency is lost or corneal opacities occur spontaneously, particularly in both corneas, and especially in the presence of a positive family history or in the offspring of consanguineous parents. Main differential diagnoses include various causes of monoclonal gammopathy, lecithin-cholesterol-acyltransferase deficiency, Fabry disease, cystinosis, tyrosine transaminase deficiency, systemic lysosomal storage

  14. Comprehensive analysis of the achromatopsia genes CNGA3 and CNGB3 in progressive cone dystrophy.

    NARCIS (Netherlands)

    Thiadens, A.A.H.J.; Roosing, S.; Collin, R.W.J.; Moll-Ramirez, N. van; Lith-Verhoeven, J.J. van; Schooneveld, M.J. van; Hollander, A.I. den; Born, L.I. van den; Hoyng, C.B.; Cremers, F.P.M.; Klaver, C.C.

    2010-01-01

    OBJECTIVE: To investigate whether the major achromatopsia genes (CNGA3 and CNGB3) play a role in the cause of progressive cone dystrophy (CD). DESIGN: Prospective multicenter study. PARTICIPANTS: Probands (N = 60) with autosomal recessive (ar) CD from various ophthalmogenetic clinics in The

  15. Comprehensive analysis of the achromatopsia genes CNGA3 and CNGB3 in progressive cone dystrophy

    NARCIS (Netherlands)

    Thiadens, Alberta A. H. J.; Roosing, Susanne; Collin, Rob W. J.; van Moll-Ramirez, Norka; van Lith-Verhoeven, Janneke J. C.; van Schooneveld, Mary J.; den Hollander, Anneke I.; van den Born, L. Ingeborgh; Hoyng, Carel B.; Cremers, Frans P. M.; Klaver, Caroline C. W.

    2010-01-01

    To investigate whether the major achromatopsia genes (CNGA3 and CNGB3) play a role in the cause of progressive cone dystrophy (CD). Prospective multicenter study. Probands (N = 60) with autosomal recessive (ar) CD from various ophthalmogenetic clinics in The Netherlands. All available ophthalmologic

  16. Autosomal recessive congenital ichthyosis: CERS3 mutations identified by a next generation sequencing panel targeting ichthyosis genes.

    Science.gov (United States)

    Youssefian, Leila; Vahidnezhad, Hassan; Saeidian, Amir Hossein; Sotoudeh, Soheila; Mahmoudi, Hamidreza; Daneshpazhooh, Maryam; Aghazadeh, Nessa; Adams, Rebecca; Ghanadan, Alireza; Zeinali, Sirous; Fortina, Paolo; Uitto, Jouni

    2017-11-01

    There are at least 38 mutant genes known to be associated with the ichthyosis phenotypes, and autosomal recessive congenital ichthyosis (ARCI) is a specific subgroup caused by mutations in 13 different genes. Mutations in some of these genes, such as CERS3 with only two previous reports, are rare. In this study, we identified mutations in candidate genes in consanguineous families with ARCI with a next generation sequencing (NGS) array that incorporates 38 ichthyosis associated genes. We applied this sequencing array to DNA from 140 ichthyosis families with high prevalence of consanguinity. Among these patients we identified six distinct, previously unreported mutations in CERS3 in six Iranian families. These mutations in each family co-segregated with the ichthyosis phenotype. The patients demonstrated collodion membrane at birth, acrogeria, generalized scaling, and hyperlinearity of the palms and soles. The presence of a significant percentage of CERS3 mutations in our cohort depicts a marked difference between the etiology of ichthyoses in genetically poorly characterized regions and well-characterized western populations. Also, it shows that rare alleles are more prevalent in the gene pool of consanguineous populations and emphasizes the importance of these population studies for better understanding of ichthyosis pathogenesis.

  17. Type I Transglutaminase Accumulation in the Endoplasmic Reticulum May Be an Underlying Cause of Autosomal Recessive Congenital Ichthyosis*

    Science.gov (United States)

    Jiang, Haibing; Jans, Ralph; Xu, Wen; Rorke, Ellen A.; Lin, Chen-Yong; Chen, Ya-Wen; Fang, Shengyun; Zhong, Yongwang; Eckert, Richard L.

    2010-01-01

    Type I transglutaminase (TG1) is an enzyme that is responsible for assembly of the keratinocyte cornified envelope. Although TG1 mutation is an underlying cause of autosomal recessive congenital ichthyosis, a debilitating skin disease, the pathogenic mechanism is not completely understood. In the present study we show that TG1 is an endoplasmic reticulum (ER) membrane-associated protein that is trafficked through the ER for ultimate delivery to the plasma membrane. Mutation severely attenuates this processing and a catalytically inactive point mutant, TG1-FLAG(C377A), accumulates in the endoplasmic reticulum and in aggresome-like structures where it is ubiquitinylated. This accumulation results from protein misfolding, as treatment with a chemical chaperone permits it to exit the endoplasmic reticulum and travel to the plasma membrane. ER accumulation is also observed for ichthyosis-associated TG1 mutants. Our findings suggest that misfolding of TG1 mutants leads to ubiquitinylation and accumulation in the ER and aggresomes, and that abnormal intracellular processing of TG1 mutants may be an underlying cause of ichthyosis. PMID:20663883

  18. Update on autosomal recessive congenital ichthyosis: mRNA analysis using hair samples is a powerful tool for genetic diagnosis.

    Science.gov (United States)

    Sugiura, Kazumitsu; Akiyama, Masashi

    2015-07-01

    Research on the molecular genetics and pathomechanisms of autosomal recessive congenital ichthyosis (ARCI) has advanced considerably and several causative genes and molecules underlying the disease have been identified. Three major ARCI phenotypes are harlequin ichthyosis (HI), lamellar ichthyosis (LI), and congenital ichthyosiform erythroderma (CIE). Skin barrier defects are involved in the pathogenesis of ARCI. In this review, the causative genes of ARCI and its phenotypes as well as recent advances in the field are summarized. The known causative molecules underlying ARCI include ABCA12, TGM1, ALOXE3, ALOX12B, NIPAL4, CYP4F22, PNPLA1, CERS3, and LIPN. It is important to examine genetic associations and to elucidate the pathomechanisms of ARCI to establish effective therapies and beneficial genetic counseling. Next-generation sequencing is a promising method that enables the detection of causative disease mutations, even in cases of unexpected concomitant genetic diseases. For genetic diagnosis, obtaining mRNA from hair follicle epithelial cells, which are analogous to keratinocytes in the interfollicular epidermis, is convenient and minimally invasive in patients with ARCI. We confirmed that our mRNA analysis method using hair follicle samples can be applied not only to keratinization disorders, but also to other genetic diseases in the dermatology field. Studies that suggest potential next-generation therapies using ARCI model mice are also reviewed. Copyright © 2015 Japanese Society for Investigative Dermatology. Published by Elsevier Ireland Ltd. All rights reserved.

  19. Genetic forms of nephrogenic diabetes insipidus (NDI): Vasopressin receptor defect (X-linked) and aquaporin defect (autosomal recessive and dominant).

    Science.gov (United States)

    Bichet, Daniel G; Bockenhauer, Detlef

    2016-03-01

    Nephrogenic diabetes insipidus (NDI), which can be inherited or acquired, is characterized by an inability to concentrate urine despite normal or elevated plasma concentrations of the antidiuretic hormone, arginine vasopressin (AVP). Polyuria with hyposthenuria and polydipsia are the cardinal clinical manifestations of the disease. About 90% of patients with congenital NDI are males with X-linked NDI who have mutations in the vasopressin V2 receptor (AVPR2) gene encoding the vasopressin V2 receptor. In less than 10% of the families studied, congenital NDI has an autosomal recessive or autosomal dominant mode of inheritance with mutations in the aquaporin-2 (AQP2) gene. When studied in vitro, most AVPR2 and AQP2 mutations lead to proteins trapped in the endoplasmic reticulum and are unable to reach the plasma membrane. Prior knowledge of AVPR2 or AQP2 mutations in NDI families and perinatal mutation testing is of direct clinical value and can avert the physical and mental retardation associated with repeated episodes of dehydration. Copyright © 2016 Elsevier Ltd. All rights reserved.

  20. Localization of a gene for an autosomal recessive form of juvenile Parkinsonism to chromosome 6q25.2-27

    Energy Technology Data Exchange (ETDEWEB)

    Matsumine, Hiroto; Shimoda-Matsubayashi, Satoe; Nakagawa-Hattori, Yuko [Tokyo Metropolitan Ebara Hospital (Japan)] [and others

    1997-03-01

    An autosomal recessive form of juvenile Parkinsonism (AR-JP) (MIM 600116) is a levodopa-responsive Parkinsonism whose pathological finding is a highly selective degeneration of dopaminergic neurons in the zona compacta of the substantia nigra. By linkage analysis of diallelic polymorphism of the Mn-superoxide dismutase gene (SOD2), we found a family with AR-JP showing perfect segregation of the disease with the SOD2 locus. By extending the linkage analysis to 13 families with AR-JP, we discovered strong evidence for the localization of the AR-JP gene at chromosome 6q25.2-27, including the SOD2 locus, with the maximal cumulative pairwise LOD scores of 7.26 and 7.71 at D6S305 ({theta} = .03) and D6S253 ({theta} = .02), respectively. Observation of obligate recombination events, as well as multipoint linkage analysis, placed the AR-JP gene in a 17-cM interval between D6S437 and D6S264. Delineation of the AR-JP gene will be an important step toward our understanding of the molecular mechanism underlying selective degeneration of the nigral neurons. 38 refs., 4 figs., 1 tab.

  1. Unraveling the genetic landscape of autosomal recessive Charcot-Marie-Tooth neuropathies using a homozygosity mapping approach

    Science.gov (United States)

    Zimoń, Magdalena; Battaloǧlu, Esra; Parman, Yesim; Erdem, Sevim; Baets, Jonathan; De Vriendt, Els; Atkinson, Derek; Almeida-Souza, Leonardo; Deconinck, Tine; Ozes, Burcak; Goossens, Dirk; Cirak, Sebahattin; Van Damme, Philip; Shboul, Mohammad; Voit, Thomas; Van Maldergem, Lionel; Dan, Bernard; El-Khateeb, Mohammed S.; Guergueltcheva, Velina; Lopez-Laso, Eduardo; Goemans, Nathalie; Masri, Amira; Züchner, Stephan; Timmerman, Vincent; Topaloǧlu, Haluk; De Jonghe, Peter

    2016-01-01

    Autosomal recessive forms of Charcot-Marie-Tooth disease (ARCMT) are rare but severe disorders of the peripheral nervous system. Their molecular basis is poorly understood due to the extensive genetic and clinical heterogeneity, posing considerable challenges for patients, physicians, and researchers. We report on the genetic findings from a systematic study of a large collection of 174 independent ARCMT families. Initial sequencing of the three most common ARCMT genes (ganglioside-induced differentiation protein 1—GDAP1, SH3 domain and tetratricopeptide repeats-containing protein 2—SH3TC2, histidine-triad nucleotide binding protein 1—HINT1) identified pathogenic mutations in 41 patients. Subsequently, 87 selected nuclear families underwent single nucleotide polymorphism (SNP) genotyping and homozygosity mapping, followed by targeted screening of known ARCMT genes. This strategy provided molecular diagnosis to 22 % of the families. Altogether, our unbiased genetic approach identified pathogenic mutations in ten ARCMT genes in a total of 41.3 % patients. Apart from a newly described founder mutation in GDAP1, the majority of variants constitute private molecular defects. Since the gene testing was independent of the clinical phenotype of the patients, we identified mutations in patients with unusual or additional clinical features, extending the phenotypic spectrum of the SH3TC2 gene. Our study provides an overview of the ARCMT genetic landscape and proposes guidelines for tackling the genetic heterogeneity of this group of hereditary neuropathies. PMID:25231362

  2. Genetic Linkage Analysis of the DFNB21 Locus in Autosomal Recessive Hearing Loss in Large Families from Khuzestan Province

    Directory of Open Access Journals (Sweden)

    Mahtab Khosrofar

    2017-06-01

    Full Text Available Abstract Background: Hearing loss (HL is the most common congenital defect in humans. One or two in thousand newborn babies have prelingual hearing loss. Autosomal recessive non-syndromic hearing loss (ARNSHL is the most common form of hereditary deafness. Hearing loss is more common in the developing countries which is due to genetic and environmental (cultural -health factors reasons. HL has a wide range of clinical demonstrations including: congenital or late onset, conductive or sensory-neural, syndromic or non-syndromic hearing loss. The goal of this project is to determine the portion of the DFNB21 (TECTA in ARNSHL in families with negative GJB2 gene in Khuzestan province. Materials and Methods: We studied 21 families with ARNSHL with at least 4 patients and negative for GJB2 mutations from Khuzestan province. Genetic linkage analysis was performed using STR markers linked to DFNB21 locus. Results: Following genetic linkage analysis and haplotyping, out of 21 families with ARNSHL, one family showed linkage to the DFNB21 (TECTA locus. Conclusion: The results of this project confirm other studies in Iran and give insight into the most common loci causing ARNSHL in Iran which could be helpful in research and clinic.

  3. Investigating Seven Recently Identified Genes in 100 Iranian Families with Autosomal Recessive Non-syndromic Hearing Loss

    Directory of Open Access Journals (Sweden)

    Reihaneh Alikhani

    2015-09-01

    Full Text Available Objectives: Hearing loss (HL is the most common sensory disorder, and affects 1 in 1000 newborns. About 50% of HL is due to genetics and 70% of them are non-syndromic with a recessive pattern of inheritance. Up to now, more than 50 genes have been detected which are responsible for autosomal recessive non-syndromic hearing loss, (ARNSHL. In  Iran, HL is one of the most common disabilities due to consanguineous marriages. The aim was to investigate the prevalence of three new ARHL genes (GJB4, GJC3, and SLITRK6 reported in neighboring countries among Iranian families with ARNSHL. Methods: One hundred unrelated families with at least two affected siblings in consanguineous marriage, who were negative for GJB2 gene mutations, were selected. By using three STR markers for each gene, homozygosity mapping was performed. Results: Two families showed linkage to GJB4, six families were linked to GJC3 and only one family linked to SLITRK6. The samples of these families who showed linkage were sent for Sanger sequencing to detect the causative mutations. However, after analyzing the sequencing results, no mutation could be detected in either of the families. Molecular analysis for these nine families is underway in order to determine the pathogenic mutations using whole exome sequencing. Discussion: These data demonstrate a very low prevalence of mutation in these three genes (GJB4, GJC3, and SLITRK6 in the Iranian population, since no mutation was detected in our study group of 100 families.

  4. COL9A2 and COL9A3 mutations in canine autosomal recessive Oculo-skeletal Dysplasia

    Science.gov (United States)

    Goldstein, Orly; Guyon, Richard; Kukekova, Anna; Pearce-Kelling, Sue; Johnson, Jennifer; Aguirre, Gustavo D.; Acland, Gregory M.

    2010-01-01

    Oculo-skeletal dysplasia segregates in two canine breeds, the Labrador retriever and samoyed, in which the causative loci have been termed drd1 and drd2, respectively. Affected dogs exhibit short-limbed dwarfism together with severe ocular defects, and this phenotype is inherited as an autosomal recessive trait in both breeds. The clinical and pathological appearance resembles human hereditary arthro-ophthalmopathies such as Stickler syndrome, or Marshall Syndrome, although these human disorders are usually dominant. Linkage studies in drd1-informative pedigrees mapped the locus to canine chromosome 24, and led to the identification of an insertional mutation in exon 1 of the gene COL9A3 that cosegregates with the disease. The drd2 locus was similarly mapped to canine chromosome 15 and shown to cosegregate with a 1,267 bp deletion mutation in the 5′ end of COL9A2. Both mutations affect the COL3 domain of the respective gene. Northern analysis showed reduced RNA expression in affected retina compared to normal. These models offer potential for studies such as protein-protein interactions between different members of the collagen gene family; regulation and expression of these genes in retina and cartilage, and even opportunities for gene therapy. PMID:20686772

  5. Autosomal recessive POLR1D mutation with decrease of TCOF1 mRNA is responsible for Treacher Collins syndrome.

    Science.gov (United States)

    Schaefer, Elise; Collet, Corinne; Genevieve, David; Vincent, Marie; Lohmann, Dietmar R; Sanchez, Elodie; Bolender, Chantal; Eliot, Marie-Madeleine; Nürnberg, Gudrun; Passos-Bueno, Maria-Rita; Wieczorek, Dagmar; van Maldergem, Lionel; Doray, Bérénice

    2014-09-01

    Treacher Collins syndrome is a mandibulofacial dysostosis caused by mutations in genes involved in ribosome biogenesis and synthesis. TCOF1 mutations are observed in ~80% of the patients and are inherited in an autosomal dominant manner. Recently, two other genes have been reported in TCOF1, POLR1C, and POLR1D in two unrelated consanguineous families. The four affected children shared the same homozygous mutation in POLR1D (c.163C>G, p.Leu55Val). This mutation is localized in a region encoding the dimerization domain of the RNA polymerase. It is supposed that this mutation impairs RNA polymerase, resulting in a lower amount of mature dimeric ribosomes. A functional analysis of the transcripts of TCOF1 by real-time quantitative reverse transcription-polymerase chain reaction was performed in the first family, demonstrating a 50% reduction in the index case, compatible with this hypothesis. This is the first report of POLR1D mutation being responsible for an autosomal recessive inherited Treacher Collins syndrome. These results reinforce the concept of genetic heterogeneity of Treacher Collins syndrome and underline the importance of combining clinical expertise and familial molecular analyses for appropriate genetic counseling.

  6. Case report of intrafamilial variability in autosomal recessive centronuclear myopathy associated to a novel BIN1 stop mutation

    Directory of Open Access Journals (Sweden)

    Kurul Semra

    2010-12-01

    Full Text Available Abstract Centronuclear myopathies (CNM describe a group of rare muscle diseases typically presenting an abnormal positioning of nuclei in muscle fibers. To date, three genes are known to be associated to a classical CNM phenotype. The X-linked neonatal form (XLCNM is due to mutations in MTM1 and involves a severe and generalized muscle weakness at birth. The autosomal dominant form results from DNM2 mutations and has been described with early childhood and adult onset (ADCNM. Autosomal recessive centronuclear myopathy (ARCNM is less characterized and has recently been associated to mutations in BIN1, encoding amphiphysin 2. Here we present the first clinical description of intrafamilal variability in two first-degree cousins with a novel BIN1 stop mutation. In addition to skeletal muscle defects, both patients have mild mental retardation and the more severely affected male also displays abnormal ventilation and cardiac arrhythmia, thus expanding the phenotypic spectrum of BIN1-related CNM to non skeletal muscle defects. We provide an up-to-date review of all previous cases with ARCNM and BIN1 mutations.

  7. Autosomal recessive posterior column ataxia with retinitis pigmentosa caused by novel mutations in the FLVCR1 gene.

    Science.gov (United States)

    Shaibani, Aziz; Wong, Lee-Jun; Wei Zhang, Victor; Lewis, Richard Alan; Shinawi, Marwan

    2015-01-01

    Posterior column ataxia with retinitis pigmentosa (PCARP) is an autosomal recessive disorder characterized by severe sensory ataxia, muscle weakness and atrophy, and progressive pigmentary retinopathy. Recently, mutations in the FLVCR1 gene were described in four families with this condition. We investigated the molecular basis and studied the phenotype of PCARP in a new family. The proband is a 33-year-old woman presented with sensory polyneuropathy and retinitis pigmentosa (RP). The constellation of clinical findings with normal metabolic and genetic evaluation, including mitochondrial DNA (mtDNA) analysis and normal levels of phytanic acid and vitamin E, prompted us to seek other causes of our patient's condition. Sequencing of FLVCR1 in the proband and targeted mutation testing in her two affected siblings revealed two novel variants, c.1547G > A (p.R516Q) and c.1593+5_+8delGTAA predicted, respectively, to be highly conserved throughout evolution and affecting the normal splicing, therefore, deleterious. This study supports the pathogenic role of FLVCR1 in PCARP and expands the molecular and clinical spectra of PCARP. We show for the first time that nontransmembrane domain (TMD) mutations in the FLVCR1 can cause PCARP, suggesting different mechanisms for pathogenicity. Our clinical data reveal that impaired sensation can be part of the phenotypic spectrum of PCARP. This study along with previously reported cases suggests that targeted sequencing of the FLVCR1 gene should be considered in patients with severe sensory ataxia, RP, and peripheral sensory neuropathy.

  8. Autosomal recessive agammaglobulinemia due to defect in μ heavy chain caused by a novel mutation in the IGHM gene.

    Science.gov (United States)

    Silva, P; Justicia, A; Regueiro, A; Fariña, S; Couselo, J M; Loidi, L

    2017-09-01

    Agammaglobulinemia is a primary immunodeficiency disorder characterized by profoundly low or absent serum antibodies and low or absent circulating B cells. The most common form is X-linked agammaglobulinemia (XLA) caused by mutations in BTK gene. The remaining cases, clinically similar to XLA, are autosomal recessive agammaglobulinemia (ARA). Nearly 30% of ARA cases present mutations in the μ heavy constant region gene IGHM. Here, we present a 7-month-old patient, born from non-consanguineous parents, who is affected by ARA due to defect in the μ heavy chain. The genetic study showed that the patient is compound heterozygous for an IGHM gene deletion and the novel nonsense mutation X57331.1:g.275C>A (p.Tyr43*) (ClinVar Accession Number: SCV000537868.1). This finding allows for an adequate genetic counseling to the family and also broadens the spectrum of already described point mutations at this locus. The IGHM gene is very complex and it is likely that yet unidentified mutations appear in other patients.

  9. Preimplantation genetic diagnosis for a Chinese family with autosomal recessive Meckel-Gruber syndrome type 3 (MKS3.

    Directory of Open Access Journals (Sweden)

    Yanping Lu

    Full Text Available Meckel-Gruber syndrome type 3 is an autosomal recessive genetic defect caused by mutations in TMEM67 gene. In our previous study, we have identified a homozygous TMEM67 mutation in a Chinese family exhibiting clinical characteristics of MKS3, which provided a ground for further PGD procedure. Here we report the development and the first clinical application of the PGD for this MKS3 family. Molecular analysis protocol for clinical PGD procedure was established using 50 single cells in pre-clinical set-up. After whole genomic amplification by multiple displacement amplification with the DNA from single cells, three techniques were applied simultaneously to increase the accuracy and reliability of genetic diagnosis in single blastomere, including real-time PCR with Taq Man-MGB probe, haplotype analysis with polymorphic STR markers and Sanger sequencing. In the clinical PGD cycle, nine embryos at cleavage-stage were biopsied and subjected to genetic diagnosis. Two embryos diagnosed as free of TMEM67 mutation were transferred and one achieving normal pregnancy. Non-invasive prenatal assessment of trisomy 13, 18 and 21 by multiplex DNA sequencing at 18 weeks' gestation excluded the aneuploidy of the analyzed chromosomes. A healthy boy was delivered by cesarean section at 39 weeks' gestation. DNA sequencing from his cord blood confirmed the result of genetic analysis in the PGD cycle. The protocol developed in this study was proved to be rapid and safe for the detection of monogenic mutations in clinical PGD cycle.

  10. Identification of FASTKD2 compound heterozygous mutations as the underlying cause of autosomal recessive MELAS-like syndrome.

    Science.gov (United States)

    Yoo, Da Hye; Choi, Young-Chul; Nam, Da Eun; Choi, Sun Seong; Kim, Ji Won; Choi, Byung-Ok; Chung, Ki Wha

    2017-07-01

    Mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes (MELAS) is a condition that affects many parts of the body, particularly the brain and muscles. This study examined a Korean MELAS-like syndrome patient with seizure, stroke-like episode, and optic atrophy. Target sequencing of whole mtDNA and 73 nuclear genes identified compound heterozygous mutations p.R205X and p.L255P in the FASTKD2. Each of his unaffected parents has one of the two mutations, and both mutations were not found in 302 controls. FASTKD2 encodes a FAS-activated serine-threonine (FAST) kinase domain 2 which locates in the mitochondrial inner compartment. A FASTKD2 nonsense mutation was once reported as the cause of a recessive infantile mitochondrial encephalomyopathy. The present case showed relatively mild symptoms with a late onset age, compared to a previous patient with FASTKD2 mutation, implicating an inter-allelic clinical heterogeneity. Because this study is the second report of an autosomal recessive mitochondrial encephalomyopathy patient with a FASTKD2 mutation, it will extend the phenotypic spectrum of the FASTKD2 mutation. Copyright © 2017. Published by Elsevier B.V.

  11. An autosomal recessive leucoencephalopathy with ischemic stroke, dysmorphic syndrome and retinitis pigmentosa maps to chromosome 17q24.2-25.3

    OpenAIRE

    Bouhouche Ahmed; Benomar Ali; Errguig Leila; Lachhab Lamiae; Bouslam Naima; Aasfara Jehanne; Sefiani Sanaa; Chabraoui Layachi; El Fahime Elmostafa; El Quessar Abdeljalil; Jiddane Mohamed; Yahyaoui Mohamed

    2012-01-01

    Abstract Background Single-gene disorders related to ischemic stroke seem to be an important cause of stroke in young patients without known risk factors. To identify new genes responsible of such diseases, we studied a consanguineous Moroccan family with three affected individuals displaying hereditary leucoencephalopathy with ischemic stroke, dysmorphic syndrome and retinitis pigmentosa that appears to segregate in autosomal recessive pattern. Methods All family members underwent neurologic...

  12. Loss of VPS13C Function in Autosomal-Recessive Parkinsonism Causes Mitochondrial Dysfunction and Increases PINK1/Parkin-Dependent Mitophagy

    Science.gov (United States)

    Lesage, Suzanne; Drouet, Valérie; Majounie, Elisa; Deramecourt, Vincent; Jacoupy, Maxime; Nicolas, Aude; Cormier-Dequaire, Florence; Hassoun, Sidi Mohamed; Pujol, Claire; Ciura, Sorana; Erpapazoglou, Zoi; Usenko, Tatiana; Maurage, Claude-Alain; Sahbatou, Mourad; Liebau, Stefan; Ding, Jinhui; Bilgic, Basar; Emre, Murat; Erginel-Unaltuna, Nihan; Guven, Gamze; Tison, François; Tranchant, Christine; Vidailhet, Marie; Corvol, Jean-Christophe; Krack, Paul; Leutenegger, Anne-Louise; Nalls, Michael A.; Hernandez, Dena G.; Heutink, Peter; Gibbs, J. Raphael; Hardy, John; Wood, Nicholas W.; Gasser, Thomas; Durr, Alexandra; Deleuze, Jean-François; Tazir, Meriem; Destée, Alain; Lohmann, Ebba; Kabashi, Edor; Singleton, Andrew; Corti, Olga; Brice, Alexis; Lesage, Suzanne; Tison, François; Vidailhet, Marie; Corvol, Jean-Christophe; Agid, Yves; Anheim, Mathieu; Bonnet, Anne-Marie; Borg, Michel; Broussolle, Emmanuel; Damier, Philippe; Destée, Alain; Dürr, Alexandra; Durif, Franck; Krack, Paul; Klebe, Stephan; Lohmann, Ebba; Martinez, Maria; Pollak, Pierre; Rascol, Olivier; Tranchant, Christine; Vérin, Marc; Viallet, François; Brice, Alexis; Lesage, Suzanne; Majounie, Elisa; Tison, François; Vidailhet, Marie; Corvol, Jean Christophe; Nalls, Michael A.; Hernandez, Dena G.; Gibbs, J. Raphael; Dürr, Alexandra; Arepalli, Sampath; Barker, Roger A.; Ben-Shlomo, Yoav; Berg, Daniela; Bettella, Francesco; Bhatia, Kailash; de Bie, Rob M.A.; Biffi, Alessandro; Bloem, Bastiaan R.; Bochdanovits, Zoltan; Bonin, Michael; Lesage, Suzanne; Tison, François; Vidailhet, Marie; Corvol, Jean-Christophe; Agid, Yves; Anheim, Mathieu; Bonnet, Anne-Marie; Borg, Michel; Broussolle, Emmanuel; Damier, Philippe; Destée, Alain; Dürr, Alexandra; Durif, Franck; Krack, Paul; Klebe, Stephan; Lohmann, Ebba; Martinez, Maria; Pollak, Pierre; Rascol, Olivier; Tranchant, Christine; Vérin, Marc; Bras, Jose M.; Brockmann, Kathrin; Brooks, Janet; Burn, David J.; Charlesworth, Gavin; Chen, Honglei; Chinnery, Patrick F.; Chong, Sean; Clarke, Carl E.; Cookson, Mark R.; Counsell, Carl; Damier, Philippe; Dartigues, Jean-François; Deloukas, Panos; Deuschl, Günther; Dexter, David T.; van Dijk, Karin D.; Dillman, Allissa; Dong, Jing; Durif, Frank; Edkins, Sarah; Escott-Price, Valentina; Evans, Jonathan R.; Foltynie, Thomas; Gao, Jianjun; Gardner, Michelle; Goate, Alison; Gray, Emma; Guerreiro, Rita; Harris, Clare; van Hilten, Jacobus J.; Hofman, Albert; Hollenbeck, Albert; Holmans, Peter; Holton, Janice; Hu, Michèle; Huang, Xuemei; Huber, Heiko; Hudson, Gavin; Hunt, Sarah E.; Huttenlocher, Johanna; Illig, Thomas; Jónsson, Pálmi V.; Kilarski, Laura L.; Jansen, Iris E.; Lambert, Jean-Charles; Langford, Cordelia; Lees, Andrew; Lichtner, Peter; Limousin, Patricia; Lopez, Grisel; Lorenz, Delia; Lubbe, Steven; Lungu, Codrin; Martinez, María; Mätzler, Walter; McNeill, Alisdair; Moorby, Catriona; Moore, Matthew; Morrison, Karen E.; Mudanohwo, Ese; O’Sullivan, Sean S.; Owen, Michael J.; Pearson, Justin; Perlmutter, Joel S.; Pétursson, Hjörvar; Plagnol, Vincent; Pollak, Pierre; Post, Bart; Potter, Simon; Ravina, Bernard; Revesz, Tamas; Riess, Olaf; Rivadeneira, Fernando; Rizzu, Patrizia; Ryten, Mina; Saad, Mohamad; Simón-Sánchez, Javier; Sawcer, Stephen; Schapira, Anthony; Scheffer, Hans; Schulte, Claudia; Sharma, Manu; Shaw, Karen; Sheerin, Una-Marie; Shoulson, Ira; Shulman, Joshua; Sidransky, Ellen; Spencer, Chris C.A.; Stefánsson, Hreinn; Stefánsson, Kári; Stockton, Joanna D.; Strange, Amy; Talbot, Kevin; Tanner, Carlie M.; Tashakkori-Ghanbaria, Avazeh; Trabzuni, Daniah; Traynor, Bryan J.; Uitterlinden, André G.; Velseboer, Daan; Walker, Robert; van de Warrenburg, Bart; Wickremaratchi, Mirdhu; Williams-Gray, Caroline H.; Winder-Rhodes, Sophie; Wurster, Isabel; Williams, Nigel; Morris, Huw R.; Heutink, Peter; Hardy, John; Wood, Nicholas W.; Gasser, Thomas; Singleton, Andrew B.; Brice, Alexis

    2016-01-01

    Autosomal-recessive early-onset parkinsonism is clinically and genetically heterogeneous. The genetic causes of approximately 50% of autosomal-recessive early-onset forms of Parkinson disease (PD) remain to be elucidated. Homozygozity mapping and exome sequencing in 62 isolated individuals with early-onset parkinsonism and confirmed consanguinity followed by data mining in the exomes of 1,348 PD-affected individuals identified, in three isolated subjects, homozygous or compound heterozygous truncating mutations in vacuolar protein sorting 13C (VPS13C). VPS13C mutations are associated with a distinct form of early-onset parkinsonism characterized by rapid and severe disease progression and early cognitive decline; the pathological features were striking and reminiscent of diffuse Lewy body disease. In cell models, VPS13C partly localized to the outer membrane of mitochondria. Silencing of VPS13C was associated with lower mitochondrial membrane potential, mitochondrial fragmentation, increased respiration rates, exacerbated PINK1/Parkin-dependent mitophagy, and transcriptional upregulation of PARK2 in response to mitochondrial damage. This work suggests that loss of function of VPS13C is a cause of autosomal-recessive early-onset parkinsonism with a distinctive phenotype of rapid and severe progression. PMID:26942284

  13. Diagnostic exome sequencing for patients with a family history of consanguinity: over 38% of positive results are not autosomal recessive pattern.

    Science.gov (United States)

    Powis, Zöe; Farwell, Kelly D; Alamillo, Christina L; Tang, Sha

    2016-02-01

    Diagnostic exome sequencing (DES) is an effective tool for diagnosis in intractable cases where the underlying cause is thought be genetic. It is commonly assumed that patients with a family history of consanguinity will have increased detection rates for rare autosomal recessive Mendelian disorders through DES. Herein, we analyzed the diagnostic yield and relevant inheritance patterns within the DES cases with a reported consanguineous family history. Of the first 500 unselected cases referred for DES, 40 (8.0%) had a known consanguineous family history. Among the 40 cases, 13 (32.5%) received a definitive molecular diagnosis through DES and such positive rate is similar to that of families with no reported consanguinity (139/460, 30.2%, P=0.63). Although homozygous alterations likely related to consanguinity have been identified in eight positive cases, the other five (38.4%) causative mutations were unrelated to autosomal recessive inheritance. Our retrospective analysis demonstrated that individuals with known consanguinity were not more likely to have a positive DES result and a significant portion of the positive findings were not within an autosomal recessive gene. These results highlight that all applicable inheritance patterns should be considered for patients with a known family history of consanguinity.

  14. Prevalence of GJB2 Mutations in Affected Individuals from United Arab Emirates with Autosomal Recessive Nonsyndromic Hearing Loss.

    Science.gov (United States)

    Tlili, Abdelaziz; Al Mutery, Abdullah; Kamal Eddine Ahmad Mohamed, Walaa; Mahfood, Mona; Hadj Kacem, Hassen

    2017-11-01

    Mutations in the gap junction protein beta 2 (GJB2) gene are responsible for more cases of nonsyndromic recessive hearing loss than any other gene. The purpose of our study was to evaluate the prevalence of GJB2 mutations among affected individuals from United Arab Emirates (UAE). There were 50 individuals diagnosed with hereditary hearing loss and 120 healthy individuals enrolled in the study. The Sanger sequencing method was used to screen the GJB2 coding region in all affected individuals. The c.-1G>A variant was determined by the polymerase chain reaction-restriction fragment length polymorphism method in normal individuals. Nine cases with bi-allelic mutations and three cases with mono-allelic mutations were detected in 12 out of 50 patients (24%). The homozygous mutation c.35delG was identified as the cause of hearing loss in six participants (12%). The mutation c.506G>A was identified in three affected individuals (6%). The allelic frequency (14%) and low percentage of individuals that were homozygous (2%) for the c.35delG mutation suggest that there are other genes responsible for nonsyndromic deafness in the UAE population. The results reported here are a preliminary step in collecting epidemiological data regarding autosomal recessive nonsyndromic hearing loss related to GJB2 gene mutations among the UAE population. The c.35delG mutation of the GJB2 gene is the most frequently seen causative mutation in the UAE and is followed by the p.Cys169Tyr mutation.

  15. Mutations in SDR9C7 gene encoding an enzyme for vitamin A metabolism underlie autosomal recessive congenital ichthyosis.

    Science.gov (United States)

    Shigehara, Yohya; Okuda, Shujiro; Nemer, Georges; Chedraoui, Adele; Hayashi, Ryota; Bitar, Fadi; Nakai, Hiroyuki; Abbas, Ossama; Daou, Laetitia; Abe, Riichiro; Sleiman, Maria Bou; Kibbi, Abdul Ghani; Kurban, Mazen; Shimomura, Yutaka

    2016-10-15

    Autosomal recessive congenital ichthyosis (ARCI) is a heterogeneous group of hereditary skin disorder characterized by an aberrant cornification of the epidermis. ARCI is classified into a total of 11 subtypes (ARCI1-ARCI11) based on their causative genes or loci. Of these, the causative gene for only ARCI7 has not been identified, while it was previously mapped on chromosome 12p11.2-q13.1. In this study, we performed genetic analyses for three Lebanese families with ARCI, and successfully determined the linkage interval to 9.47 Mb region on chromosome 12q13.13-q14.1, which was unexpectedly outside of the ARCI7 locus. Whole-exome sequencing and the subsequent Sanger sequencing led to the identification of missense mutations in short chain dehydrogenase/reductase family 9C, member 7 (SDR9C7) gene on chromosome 12q13.3, i.e. two families shared an identical homozygous mutation c.599T > C (p.Ile200Thr) and one family had another homozygous mutation c.214C > T (p.Arg72Trp). In cultured cells, expression of both the mutant SDR9C7 proteins was markedly reduced as compared to wild-type protein, suggesting that the mutations severely affected a stability of the protein. In normal human skin, the SDR9C7 was abundantly expressed in granular and cornified layers of the epidermis. By contrast, in a patient’s skin, its expression in the cornified layer was significantly decreased. It has previously been reported that SDR9C7 is an enzyme to convert retinal into retinol. Therefore, our study not only adds a new gene responsible for ARCI, but also further suggests a potential role of vitamin A metabolism in terminal differentiation of the epidermis in humans.

  16. 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

  17. Two sisters with clinical diagnosis of Wiskott-Aldrich Syndrome: Is the condition in the family autosomal recessive?

    Energy Technology Data Exchange (ETDEWEB)

    Kondoh, T.; Hayashi, K.; Matsumoto, T. [Nagasaki Univ. School of Medicine (Japan)] [and others

    1995-10-09

    We report two sisters in a family representing manifestations of Wiskott-Aldrich syndrome (WAS), an X-linked immunodeficiency disorder. An elder sister had suffered from recurrent infections, small thrombocytopenic petechiae, purpura, and eczema for 7 years. The younger sister had the same manifestations as the elder sister`s for a 2-year period, and died of intracranial bleeding at age 2 years. All the laboratory data of the two patients were compatible with WAS, although they were females. Sialophorin analysis with the selective radioactive labeling method of this protein revealed that in the elder sister a 115-KD band that should be specific for sialophorin was reduced in quantity, and instead an additional 135-KD fragment was present as a main band. Polymerase chain reaction (PCR) analysis of the sialophorin gene and single-strand conformation polymorphism (SSCP) analysis of the PCR product demonstrated that there were no detectable size-change nor electrophoretic mobility change in the DNA from both patients. The results indicated that their sialophorin gene structure might be normal. Studies on the mother-daughter transmission of X chromosome using a pERT84-MaeIII polymorphic marker mapped at Xp21 and HPRT gene polymorphism at Xq26 suggested that each sister had inherited a different X chromosome from the mother. Two explanations are plausible for the occurrence of the WAS in our patients: the WAS in the patients is attributable to an autosomal gene mutation which may regulate the sialophorin gene expression through the WAS gene, or, alternatively, the condition in this family is an autosomal recessive disorder separated etiologically from the X-linked WAS. 17 refs., 6 figs., 1 tab.

  18. Canine disorder mirrors human disease: exonic deletion in HES7 causes autosomal recessive spondylocostal dysostosis in miniature Schnauzer dogs.

    Directory of Open Access Journals (Sweden)

    Cali E Willet

    Full Text Available Spondylocostal dysostosis is a congenital disorder of the axial skeleton documented in human families from diverse racial backgrounds. The condition is characterised by truncal shortening, extensive hemivertebrae and rib anomalies including malalignment, fusion and reduction in number. Mutations in the Notch signalling pathway genes DLL3, MESP2, LFNG, HES7 and TBX6 have been associated with this defect. In this study, spondylocostal dysostosis in an outbred family of miniature schnauzer dogs is described. Computed tomography demonstrated that the condition mirrors the skeletal defects observed in human cases, but unlike most human cases, the affected dogs were stillborn or died shortly after birth. Through gene mapping and whole genome sequencing, we identified a single-base deletion in the coding region of HES7. The frameshift mutation causes loss of functional domains essential for the oscillatory transcriptional autorepression of HES7 during somitogenesis. A restriction fragment length polymorphism test was applied within the immediate family and supported a highly penetrant autosomal recessive mode of inheritance. The mutation was not observed in wider testing of 117 randomly sampled adult miniature schnauzer and six adult standard schnauzer dogs; providing a significance of association of Praw = 4.759e-36 (genome-wide significant. Despite this apparently low frequency in the Australian population, the allele may be globally distributed based on its presence in two unrelated sires from geographically distant locations. While isolated hemivertebrae have been observed in a small number of other dog breeds, this is the first clinical and genetic diagnosis of spontaneously occurring spondylocostal dysostosis in a non-human mammal and offers an excellent model in which to study this devastating human disorder. The genetic test can be utilized by dog breeders to select away from the disease and avoid unnecessary neonatal losses.

  19. Canine disorder mirrors human disease: exonic deletion in HES7 causes autosomal recessive spondylocostal dysostosis in miniature Schnauzer dogs.

    Science.gov (United States)

    Willet, Cali E; Makara, Mariano; Reppas, George; Tsoukalas, George; Malik, Richard; Haase, Bianca; Wade, Claire M

    2015-01-01

    Spondylocostal dysostosis is a congenital disorder of the axial skeleton documented in human families from diverse racial backgrounds. The condition is characterised by truncal shortening, extensive hemivertebrae and rib anomalies including malalignment, fusion and reduction in number. Mutations in the Notch signalling pathway genes DLL3, MESP2, LFNG, HES7 and TBX6 have been associated with this defect. In this study, spondylocostal dysostosis in an outbred family of miniature schnauzer dogs is described. Computed tomography demonstrated that the condition mirrors the skeletal defects observed in human cases, but unlike most human cases, the affected dogs were stillborn or died shortly after birth. Through gene mapping and whole genome sequencing, we identified a single-base deletion in the coding region of HES7. The frameshift mutation causes loss of functional domains essential for the oscillatory transcriptional autorepression of HES7 during somitogenesis. A restriction fragment length polymorphism test was applied within the immediate family and supported a highly penetrant autosomal recessive mode of inheritance. The mutation was not observed in wider testing of 117 randomly sampled adult miniature schnauzer and six adult standard schnauzer dogs; providing a significance of association of Praw = 4.759e-36 (genome-wide significant). Despite this apparently low frequency in the Australian population, the allele may be globally distributed based on its presence in two unrelated sires from geographically distant locations. While isolated hemivertebrae have been observed in a small number of other dog breeds, this is the first clinical and genetic diagnosis of spontaneously occurring spondylocostal dysostosis in a non-human mammal and offers an excellent model in which to study this devastating human disorder. The genetic test can be utilized by dog breeders to select away from the disease and avoid unnecessary neonatal losses.

  20. Disorders of fatty acid oxidation and autosomal recessive polycystic kidney disease-different clinical entities and comparable perinatal renal abnormalities.

    Science.gov (United States)

    Hackl, Agnes; Mehler, Katrin; Gottschalk, Ingo; Vierzig, Anne; Eydam, Marcus; Hauke, Jan; Beck, Bodo B; Liebau, Max C; Ensenauer, Regina; Weber, Lutz T; Habbig, Sandra

    2017-05-01

    Differential diagnosis of prenatally detected hyperechogenic and enlarged kidneys can be challenging as there is a broad phenotypic overlap between several rare genetic and non-genetic disorders. Metabolic diseases are among the rarest underlying disorders, but they demand particular attention as their prognosis and postnatal management differ from those of other diseases. We report two cases of cystic, hyperechogenic and enlarged kidneys detected on prenatal ultrasound images, resulting in the suspected diagnosis of autosomal recessive polycystic kidney disease (ARPKD). Postnatal clinical course and work-up, however, revealed early, neonatal forms of disorders of fatty acid oxidation (DFAO) in both cases, namely, glutaric acidemia type II, based on identification of the novel, homozygous splice-site mutation c.1117-2A > G in the ETFDH gene, in one case and carnitine palmitoyltransferase II deficiency in the other case. Review of pre- and postnatal sonographic findings resulted in the identification of some important differences that might help to differentiate DFAO from ARPKD. In DFAO, kidneys are enlarged to a milder degree than in ARPKD, and the cysts are located ubiquitously, including also in the cortex and the subcapsular area. Interestingly, recent studies have pointed to a switch in metabolic homeostasis, referred to as the Warburg effect (aerobic glycolysis), as one of the underlying mechanisms of cell proliferation and cyst formation in cystic kidney disease. DFAO are characterized by the inhibition of oxidative phosphorylation, resulting in aerobic glycolysis, and thus they do resemble the Warburg effect. We therefore speculate that this inhibition might be one of the pathomechanisms of renal hyperproliferation and cyst formation in DFAO analogous to the reported findings in ARPKD. Neonatal forms of DFAO can be differentially diagnosed in neonates with cystic or hyperechogenic kidneys and necessitate immediate biochemical work-up to provide early

  1. Identification of a novel mutation in the PRCD gene causing autosomal recessive retinitis pigmentosa in a Turkish family.

    Science.gov (United States)

    Pach, Johanna; Kohl, Susanne; Gekeler, Florian; Zobor, Ditta

    2013-01-01

    Progressive rod-cone degeneration (PRCD) is a canine form of autosomal recessive photoreceptor degeneration and serves as an animal model for human retinitis pigmentosa (RP). To date, only two RP-causing mutations of the PRCD gene have been reported in humans. We found a novel mutation in PRCD (c.52C>T, p.R18X) in three siblings affected by RP and present detailed morphologic and functional parameters. A complete ophthalmological examination was performed including psychophysical tests (best-corrected visual acuity, Lanthony Panel D-15 color vision test, and visual field) and electrophysiology (ganzfeld and multifocal electroretinogram). Additionally, color and infrared fundus photography, autofluorescence, and spectral domain optical coherence tomography recordings were performed. Genomic DNA of the three affected individuals was analyzed with high-throughput sequencing for all RP-related genes in a diagnostic set-up. We identified a novel homozygous mutation in PRCD (c.52C>T, p.R18X) with diagnostic high-throughput panel sequencing. All three patients showed an advanced stage of retinitis pigmentosa with reduced visual acuity (mean: 20/80), small residual visual fields (mean for target III4e: 1134.35 deg²), and non-detectable electrophysiological responses. Myopia, posterior subcapsular cataract, bone spicule-like pigmentation, and attenuated arterioles were typical findings. Interestingly, bull's eye maculopathy due to patchy retinal pigment epithelium atrophy was also present in all patients. The mean central retinal thickness observed in optical coherence tomography was 148 µm. The identification of a third mutation in PRCD confirms its role in the pathogenesis of RP. Clinical findings were in line with the morphological changes observed in previous studies. Bull's eye maculopathy seems to be a hallmark of RP due to mutations in the PRCD gene.

  2. Autosomal Recessive Inheritance

    Science.gov (United States)

    ... to sight-saving treatments and plays a key role in reducing visual impairment and blindness. NEI Home Contact Us A-Z Site Map NEI on Social Media Information in Spanish (Información en español) Website, Social ...

  3. Congenital sensorineural deafness in Australian stumpy-tail cattle dogs is an autosomal recessive trait that maps to CFA10.

    Directory of Open Access Journals (Sweden)

    Susan Sommerlad

    2010-10-01

    speckling. Fine mapping was then performed on 45 of these 50 dogs and a further 48 dogs (n = 93. Sequencing candidate gene Sox10 in 6 hearing ASCD, 2 unilaterally deaf ASCD and 2 bilaterally deaf ASCD did not reveal any disease-associated mutations.Deafness in ASCD is an incompletely penetrant autosomal recessive inherited disease that maps to CFA10.

  4. Skeletal muscle, but not cardiovascular function, is altered in a mouse model of autosomal recessive hypophosphatemic rickets

    Directory of Open Access Journals (Sweden)

    Michael J. Wacker

    2016-05-01

    Full Text Available Autosomal recessive hypophosphatemic rickets (ARHR is a heritable disorder characterized by hypophosphatemia, osteomalacia, and poor bone development. ARHR results from inactivating mutations in the DMP1 gene with the human phenotype being recapitulated in the Dmp1 null mouse model which displays elevated plasma fibroblast growth factor 23. While the bone phenotype has been well characterized, it is not known what effects ARHR may also have on skeletal, cardiac, or vascular smooth muscle function, which is critical to understand to treat patients suffering from this condition. In this study, the extensor digitorum longus (EDL- fast-twitch muscle, soleus (SOL- slow-twitch muscle, heart, and aorta were removed from Dmp1 null mice and ex-vivo functional tests were simultaneously performed in collaboration by three different laboratories. Dmp1 null EDL and SOL muscles produced less force than wildtype muscles after normalization for physiological cross sectional area of the muscles. Both EDL and SOL muscles from Dmp1 null mice also produced less force after the addition of caffeine (which releases calcium from the sarcoplasmic reticulum which may indicate problems in excitation contraction coupling in these mice. While the body weights of the Dmp1 null were smaller than wildtype, the heart weight to body weight ratio was higher. However, there were no differences in pathological hypertrophic gene expression compared to wildtype and maximal force of contraction was not different indicating that there may not be cardiac pathology under the tested conditions. We did observe a decrease in the rate of force development generated by cardiac muscle in the Dmp1 null which may be related to some of the deficits observed in skeletal muscle. There were no differences observed in aortic contractions induced by PGF2a or 5-HT or in endothelium-mediated acetylcholine-induced relaxations or endothelium-independent sodium nitroprusside-induced relaxations. In

  5. Two novel mutations in the EYS gene are possible major causes of autosomal recessive retinitis pigmentosa in the Japanese population.

    Directory of Open Access Journals (Sweden)

    Katsuhiro Hosono

    Full Text Available Retinitis pigmentosa (RP is a highly heterogeneous genetic disease including autosomal recessive (ar, autosomal dominant (ad, and X-linked inheritance. Recently, arRP has been associated with mutations in EYS (Eyes shut homolog, which is a major causative gene for this disease. This study was conducted to determine the spectrum and frequency of EYS mutations in 100 Japanese arRP patients. To determine the prevalence of EYS mutations, all EYS exons were screened for mutations by polymerase chain reaction amplification, and sequence analysis was performed. We detected 67 sequence alterations in EYS, of which 21 were novel. Of these, 7 were very likely pathogenic mutations, 6 were possible pathogenic mutations, and 54 were predicted non-pathogenic sequence alterations. The minimum observed prevalence of distinct EYS mutations in our study was 18% (18/100, comprising 9 patients with 2 very likely pathogenic mutations and the remaining 9 with only one such mutation. Among these mutations, 2 novel truncating mutations, c.4957_4958insA (p.S1653KfsX2 and c.8868C>A (p.Y2956X, were identified in 16 patients and accounted for 57.1% (20/35 alleles of the mutated alleles. Although these 2 truncating mutations were not detected in Japanese patients with adRP or Leber's congenital amaurosis, we detected them in Korean arRP patients. Similar to Japanese arRP results, the c.4957_4958insA mutation was more frequently detected than the c.8868C>A mutation. The 18% estimated prevalence of very likely pathogenic mutations in our study suggests a major involvement of EYS in the pathogenesis of arRP in the Japanese population. Mutation spectrum of EYS in 100 Japanese patients, including 13 distinct very likely and possible pathogenic mutations, was largely different from the previously reported spectrum in patients from non-Asian populations. Screening for c.4957_4958insA and c.8868C>A mutations in the EYS gene may therefore be very effective for the genetic testing

  6. Genetic Linkage Analysis of DFNB2 Locus with Autosomal Recessive Hearing Loss in Families Negative for GJB2 Mutations in Khuzestan Province

    Directory of Open Access Journals (Sweden)

    Parisa Tahmasebi

    2016-09-01

    Full Text Available Abstract Background: Hearing loss is a common sensory impairment in humans which half of its causes are genetic reasons. Genetic hearing loss can be divided into the two types of syndromic and non-syndromic, which 80% of non-syndromic cases is Autosomal Recessive Non-Syndromic Hearing Loss. The aim of the present research is to determine the contribution of DFNB2 locus (MYO7A gene in causing an autosomal recessive hearing loss in the one group of the deaf families of Khuzestan province. Materials and Methods: This study was conducted on 26 families with autosomal recessive hearing loss (with 4 patients and negative for GJB2 mutations in Khuzestan province. 22 families suffered from ARNSHL and 4 families suffered from Usher syndrome. Linkage analysis was performed by using STR (Short Tandem Repeat markers related to DFNB2 locus. Each family’s genotype was determined by PCR-PAGE method. Furthermore, haplotypes drawing and LOD score calculations were performed. Results: From 26 families with hearing loss participating in this research, following genetic linkage analysis and haplotypes drawing, two families (7.7% of the families showed linkage to DFNB2 locus. One family (4.5% suffered from ARNSHL and another family suffered from Usher syndrome. Conclusion: The results of the present research show that the contribution of DFNB2 locus in causing hearing loss in the population of Khuzestan province was similar to other studies conducted in Iran and this locus with other important loci should be considered to check in the hearing loss panel.

  7. Targeted Next-Generation Sequencing of a 12.5 Mb Homozygous Region Reveals ANO10 Mutations in Patients with Autosomal-Recessive Cerebellar Ataxia

    Science.gov (United States)

    Vermeer, Sascha; Hoischen, Alexander; Meijer, Rowdy P.P.; Gilissen, Christian; Neveling, Kornelia; Wieskamp, Nienke; de Brouwer, Arjan; Koenig, Michel; Anheim, Mathieu; Assoum, Mirna; Drouot, Nathalie; Todorovic, Slobodanka; Milic-Rasic, Vedrana; Lochmüller, Hanns; Stevanin, Giovanni; Goizet, Cyril; David, Albert; Durr, Alexandra; Brice, Alexis; Kremer, Berry; van de Warrenburg, Bart P.C.; Schijvenaars, Mascha M.V.A.P.; Heister, Angelien; Kwint, Michael; Arts, Peer; van der Wijst, Jenny; Veltman, Joris; Kamsteeg, Erik-Jan; Scheffer, Hans; Knoers, Nine

    2010-01-01

    Autosomal-recessive cerebellar ataxias comprise a clinically and genetically heterogeneous group of neurodegenerative disorders. In contrast to their dominant counterparts, unraveling the molecular background of these ataxias has proven to be more complicated and the currently known mutations provide incomplete coverage for genotyping of patients. By combining SNP array-based linkage analysis and targeted resequencing of relevant sequences in the linkage interval with the use of next-generation sequencing technology, we identified a mutation in a gene and have shown its association with autosomal-recessive cerebellar ataxia. In a Dutch consanguineous family with three affected siblings a homozygous 12.5 Mb region on chromosome 3 was targeted by array-based sequence capture. Prioritization of all detected sequence variants led to four candidate genes, one of which contained a variant with a high base pair conservation score (phyloP score: 5.26). This variant was a leucine-to-arginine substitution in the DUF 590 domain of a 16K transmembrane protein, a putative calcium-activated chloride channel encoded by anoctamin 10 (ANO10). The analysis of ANO10 by Sanger sequencing revealed three additional mutations: a homozygous mutation (c.1150_1151del [p.Leu384fs]) in a Serbian family and a compound-heterozygous splice-site mutation (c.1476+1G>T) and a frameshift mutation (c.1604del [p.Leu535X]) in a French family. This illustrates the power of using initial homozygosity mapping with next-generation sequencing technology to identify genes involved in autosomal-recessive diseases. Moreover, identifying a putative calcium-dependent chloride channel involved in cerebellar ataxia adds another pathway to the list of pathophysiological mechanisms that may cause cerebellar ataxia. PMID:21092923

  8. Unmasking an autosomal recessive disorder by a deletion in the DiGeorge/Velo-cardio-facial chromosome region (DGCR) in 22q11.2

    Energy Technology Data Exchange (ETDEWEB)

    Budarf, M.L.; Michaud, D.; Emanuel, B. [Children`s Hospital of Philadelphia, PA (United States)] [and others

    1994-09-01

    Unmasking an autosomal recessive disorder by constitutional hemizygosity is well documented for the embryonal tumors RB and WAGR, where the second hit is a somatic event. Few deletion-mediated recessive conditions have been reported in patients with germline mutations. The major platelet receptor for von Willebrand factor, Glycoprotein Ib (GpIb), is a complex of two plasma membrane glycoproteins, Ib{alpha} and Ib{beta}, covalently linked by disulfide bonds. Defects in this receptor have been associated with the rare congenital autosomal recessive bleeding disorder, Bernard-Soulier syndrome (BSS). BSS is characterized by prolonged bleeding times, thrombocytopenia and very large platelets. The GpIb{beta} gene has been cloned and we have mapped it within the DGCR. We have identified a patient with phenotypic features of both BSS and VCFS. The patient was referred for 22q11-deletion FISH studies because of a conventricular VSD and mild dysmorphia. FISH with the N25 DiGeorge cosmid demonstrated a deletion in 22q11.2. Western blot analysis of the patient`s platelet proteins demonstrates a complete absence of GpIb{beta}. We suggest that haploinsufficiency for the DGCR in this patient unmasks a mutation in the remaining GpIb{beta} allele, resulting in manifestations of BSS. This mechanism, haploinsufficiency coupled with a mutation of the {open_quotes}normal{close_quotes} chromosome, might explain some of the phenotypic variability seen amongst patients with 22q11.2 microdeletions. These results further suggest that patients with contiguous gene deletion syndromes are at increased risk for autosomal recessive disorders and that they provide the opportunity to {open_quotes}map{close_quotes}disease loci.

  9. Autosomal recessive hyper IgM syndrome associated with activation-induced cytidine deaminase gene in three Turkish siblings presented with tuberculosis lymphadenitis - Case report.

    Science.gov (United States)

    Patiroglu, Turkan; Akar, H Haluk; van der Burg, Mirjam; Unal, Ekrem

    2015-09-01

    The hyper-immunoglobulin M (HIGM) syndrome is a heterogeneous group of genetic disorders characterized by recurrent infections, decreased serum levels of immunoglobulin G (IgG) and IgA, and normal/increased serum levels of IgM. Herein, we describe three Turkish siblings with HIGM syndrome who had a homozygous missense mutation (c.70C>T, p.Arg24Trp) in the activation-induced cytidine deaminase gene which results in autosomal recessive HIGM syndrome. Two of the siblings, sibling 1 and sibling 3, presented with cervical deep abscess and cervical tuberculosis lymphadenitis, respectively.

  10. Autosomal-recessive posterior microphthalmos is caused by mutations in PRSS56, a gene encoding a trypsin-like serine protease

    DEFF Research Database (Denmark)

    Gal, Andreas; Rau, Isabella; El Matri, Leila

    2011-01-01

    heterogeneity of the trait. Using RT-PCR, PRSS56 transcripts were detected in samples derived from the human adult retina, cornea, sclera, and optic nerve. The expression of the mouse ortholog could be first detected in the eye at E17 and was maintained into adulthood. The predicted PRSS56 protein is a 603......Posterior microphthalmos (MCOP) is a rare isolated developmental anomaly of the eye characterized by extreme hyperopia due to short axial length. The population of the Faroe Islands shows a high prevalence of an autosomal-recessive form (arMCOP) of the disease. Based on published linkage data, we...

  11. Prevalence of generalized retinal dystrophy in Denmark

    DEFF Research Database (Denmark)

    Bertelsen, Mette; Jensen, Hanne; Bregnhøj, Jesper F

    2014-01-01

    of this study was to examine the prevalence and diagnostic spectrum of generalized retinal dystrophy in the Danish population. METHODS: A population-based cross-sectional study with data from the Danish Retinitis Pigmentosa Registry that comprises all patients in Denmark with generalized retinal....... RESULTS: Of the 5,602,628 Danish citizens on January 1, 2013, 1622 patients were registered as having a generalized retinal dystrophy and were alive and living in Denmark, corresponding to a prevalence of 1:3,454. In 28% of cases the eye condition was part of a syndrome, while the remaining 72% had eye...... disease only. Aside from simplex cases (45%), the most common hereditary pattern was autosomal recessive (23%). CONCLUSION: This epidemiological survey demonstrates that the prevalence of generalized retinal dystrophy in the Danish population is 1:3454. Many of the dystrophies are the subjects of clinical...

  12. A novel c.5308_5311delGAGA mutation in Senataxin in a Cypriot family with an autosomal recessive cerebellar ataxia

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    Zamba-Papanicolaou Eleni

    2008-04-01

    Full Text Available Abstract Background Senataxin (chromosome 9q34 was recently identified as the causative gene for an autosomal recessive form of Ataxia (ARCA, termed as Ataxia with Oculomotor Apraxia, type 2 (AOA2 and characterized by generalized incoordination, cerebellar atrophy, peripheral neuropathy, "oculomotor apraxia" and increased alpha-fetoprotein (AFP. Here, we report a novel Senataxin mutation in a Cypriot ARCA family. Methods We studied several Cypriot autosomal recessive cerebellar ataxia (ARCA families for linkage to known ARCA gene loci. We linked one family (909 to the SETX locus on chromosome 9q34 and screened the proband for mutations by direct sequencing. Results Sequence analysis revealed a novel c.5308_5311delGAGA mutation in exon 11 of the SETX gene. The mutation has not been detected in 204 control chromosomes from the Cypriot population, the remaining Cypriot ARCA families and 37 Cypriot sporadic cerebellar ataxia patients. Conclusion We identified a novel SETX homozygous c.5308_5311delGAGA mutation that co-segregates with ARCA with cerebellar atrophy and raised AFP.

  13. Clinical characteristics of rod and cone photoreceptor dystrophies in patients with mutations in the C8orf37 gene

    NARCIS (Netherlands)

    Huet, R.A.C. van; Estrada-Cuzcano, A.; Banin, E.; Rotenstreich, Y.; Hipp, S.; Kohl, S.; Hoyng, C.B.; Hollander, A.I. den; Collin, R.W.J.; Klevering, B.J.

    2013-01-01

    PURPOSE: To provide the clinical features in patients with retinal disease caused by C8orf37 gene mutations. METHODS: Eight patients--four diagnosed with retinitis pigmentosa (RP) and four with cone-rod dystrophy (CRD), carrying causal C8orf37 mutations--were clinically evaluated, including

  14. Autosomal-recessive posterior microphthalmos is caused by mutations in PRSS56, a gene encoding a trypsin-like serine protease

    DEFF Research Database (Denmark)

    Gal, Andreas; Rau, Isabella; El Matri, Leila

    2011-01-01

    heterogeneity of the trait. Using RT-PCR, PRSS56 transcripts were detected in samples derived from the human adult retina, cornea, sclera, and optic nerve. The expression of the mouse ortholog could be first detected in the eye at E17 and was maintained into adulthood. The predicted PRSS56 protein is a 603......Posterior microphthalmos (MCOP) is a rare isolated developmental anomaly of the eye characterized by extreme hyperopia due to short axial length. The population of the Faroe Islands shows a high prevalence of an autosomal-recessive form (arMCOP) of the disease. Based on published linkage data, we...... amino acid long secreted trypsin-like serine peptidase. The c.1066dupC is likely to result in a functional null allele, whereas the two point mutations predict the replacement of evolutionary conserved and functionally important residues. Molecular modeling of the p.Trp309Ser mutant suggests that both...

  15. Novel homozygous mutations in the EVC and EVC2 genes in two consanguineous families segregating autosomal recessive Ellis-van Creveld syndrome.

    Science.gov (United States)

    Aziz, Abdul; Raza, Syed I; Ali, Salman; Ahmad, Wasim

    2016-01-01

    Ellis-van Creveld syndrome (EVC) is a rare developmental disorder characterized by short limbs, short ribs, postaxial polydactyly, dysplastic nails, teeth, oral and cardiac abnormalities. It is caused by biallelic mutations in the EVC or EVC2 gene, separated by 2.6 kb of genomic sequence on chromosome 4p16. In the present study, we have investigated two consanguineous families of Pakistani origin, segregating EVC in autosomal recessive manner. Linkage in the families was established to chromosome 4p16. Subsequently, sequence analysis identified a novel nonsense mutation (p.Trp234*) in exon 8 of the EVC2 gene and 15 bp duplication in exon 14 of the EVC gene in the two families. This further expands the mutations in the EVC or EVC2 genes resulting in the EVC syndrome.

  16. Autosomal-recessive posterior microphthalmos is caused by mutations in PRSS56, a gene encoding a trypsin-like serine protease

    DEFF Research Database (Denmark)

    Gal, Andreas; Rau, Isabella; El Matri, Leila

    2011-01-01

    Posterior microphthalmos (MCOP) is a rare isolated developmental anomaly of the eye characterized by extreme hyperopia due to short axial length. The population of the Faroe Islands shows a high prevalence of an autosomal-recessive form (arMCOP) of the disease. Based on published linkage data, we...... refined the position of the disease locus (MCOP6) in an interval of 250 kb in chromosome 2q37.1 in two large Faroese families. We detected three different mutations in PRSS56. Patients of the Faroese families were either homozygous for c.926G>C (p.Trp309Ser) or compound heterozygous for c.926G>C and c.526...

  17. A Register-Based Study of Diseases With an Autosomal Recessive Origin in Small Children in Denmark According to Maternal Country of Origin

    DEFF Research Database (Denmark)

    Gundlund, Anna; Hansen, Anne Vinkel; Pedersen, Grete Skøtt

    2015-01-01

    BACKGROUND: Compared with children born of Danish mothers, the mortality of children, born and living in Denmark, is significantly increased in those with a mother from Afghanistan, Iraq, Pakistan, Somalia, and Turkey. Consanguinity has been suggested to account for part of this disparity. Since...... information on consanguinity is lacking, this suggestion is difficult to test. With an indirect approach, we addressed this question by comparing the risk of diseases with autosomal recessive inheritance in children born in Denmark of Danish-born women and of women born in these five countries, respectively...... ratios for the diseases in children of foreign-born women compared with children of Danish-born women. RESULTS: Compared with offspring of Danish-born women, the risk of a consanguinity-related disease was significantly increased in children of foreign-born women, although the absolute risk was low...

  18. Additional case of Marden-Walker syndrome: support for the autosomal-recessive inheritance adn refinement of phenotype in a surviving patient.

    Science.gov (United States)

    Orrico, A; Galli, L; Zappella, M; Orsi, A; Hayek, G

    2001-02-01

    In this report, we present a 14-year-old girl, born to consanguineous parents, who presented with severe mental retardation, hypotonia, short stature, and congenital joint contractures. The craniofacial features were scaphocephaly, thin/long and immobile face, marked hypoplasia of the midface, temporal narrowness, blepharophimosis, palpebral ptosis, and strabismus. The combination of such a distinctive craniofacial appearance and psychomotor retardation allows us to recognize a new case of the Marden-Walker syndrome. Our patient represents one of the rare cases in which consanguineous mating supports the autosomal-recessive pattern of inheritance of this condition. Furthermore, through refining the phenotype of a surviving patient, this report may contribute to a better recognition of this disorder in older affected children.

  19. Autosomal recessive spastic tetraplegia caused by AP4M1 and AP4B1 gene mutation: expansion of the facial and neuroimaging features.

    Science.gov (United States)

    Tüysüz, Beyhan; Bilguvar, Kaya; Koçer, Naci; Yalçınkaya, Cengiz; Çağlayan, Okay; Gül, Ece; Sahin, Sezgin; Çomu, Sinan; Günel, Murat

    2014-07-01

    Adaptor protein complex-4 (AP4) is a component of intracellular transportation of proteins, which is thought to have a unique role in neurons. Recently, mutations affecting all four subunits of AP4 (AP4M1, AP4E1, AP4S1, and AP4B1) have been found to cause similar autosomal recessive phenotype consisting of tetraplegic cerebral palsy and intellectual disability. The aim of this study was analyzing AP4 genes in three new families with this phenotype, and discussing their clinical findings with an emphasis on neuroimaging and facial features. Using homozygosity mapping followed by whole-exome sequencing, we identified two novel homozygous mutations in AP4M1 and a homozygous deletion in AP4B1 in three pairs of siblings. Spastic tetraplegia, microcephaly, severe intellectual disability, limited speech, and stereotypic laughter were common findings in our patients. All patients also had similar facial features consisting of coarse and hypotonic face, bitemporal narrowing, bulbous nose with broad nasal ridge, and short philtrum which were not described in patients with AP4M1 and AP4B1 mutations previously. The patients presented here and previously with AP4M1, AP4B1, and AP4E1 mutations shared brain abnormalities including asymmetrical ventriculomegaly, thin splenium of the corpus callosum, and reduced white matter volume. The patients also had hippocampal globoid formation and thin hippocampus. In conclusion, disorders due to mutations in AP4 complex have similar neurological, facial, and cranial imaging findings. Thus, these four genes encoding AP4 subunits should be screened in patients with autosomal recessive spastic tetraplegic cerebral palsy, severe intellectual disability, and stereotypic laughter, especially with the described facial and cranial MRI features. © 2014 Wiley Periodicals, Inc.

  20. Confirmation of linkage and refinement of the RP28 locus for autosomal recessive retinitis pigmentosa on chromosome 2p14-p15 in an Indian family.

    Science.gov (United States)

    Kumar, Arun; Shetty, Jyoti; Kumar, Bharath; Blanton, Susan Halloran

    2004-06-15

    To report the linkage analysis of retinitis pigmentosa (RP) in an Indian family. Individuals were examined for symptoms of retinitis pigmentosa and their blood samples were withdrawn for genetic analysis. The disorder was tested for linkage to known 14 adRP and 22 arRP loci using microsatellite markers. Seventeen individuals including seven affecteds participated in the study. All affected individuals had typical RP. The age of onset of the disease ranged from 8-18 years. The disorder in this family segregated either as an autosomal recessive trait with pseudodominance or an autosomal dominant trait. Linkage to an autosomal recessive locus RP28 on chromosome 2p14-p15 was positive with a maximum two-point lod score of 3.96 at theta=0 for D2S380. All affected individuals were homozygous for alleles at D2S2320, D2S2397, D2S380, and D2S136. Recombination events placed the minimum critical region (MCR) for the RP28 gene in a 1.06 cM region between D2S2225 and D2S296. The present data confirmed linkage of arRP to the RP28 locus in a second Indian family. The RP28 locus was previously mapped to a 16 cM region between D2S1337 and D2S286 in a single Indian family. Haplotype analysis in this family has further narrowed the MCR for the RP28 locus to a 1.06 cM region between D2S2225 and D2S296. Of 15 genes reported in the MCR, 14 genes (KIAA0903, OTX1, MDH1, UGP2, VPS54, PELI1, HSPC159, FLJ20080, TRIP-Br2, SLC1A4, KIAA0582, RAB1A, ACTR2, and SPRED2) are either expressed in the eye or retina. Further study needs to be done to test which of these genes is mutated in patients with RP linked to the RP28 locus.

  1. Identification of a Novel Homozygous Nonsense Mutation Confirms the Implication of GNAT1 in Rod-Cone Dystrophy.

    Directory of Open Access Journals (Sweden)

    Cécile Méjécase

    Full Text Available GNAT1, encoding the transducin subunit Gα, is an important element of the phototransduction cascade. Mutations in this gene have been associated with autosomal dominant and autosomal recessive congenital stationary night blindness. Recently, a homozygous truncating GNAT1 mutation was identified in a patient with late-onset rod-cone dystrophy. After exclusion of mutations in genes underlying progressive inherited retinal disorders, by targeted next generation sequencing, a 32 year-old male sporadic case with severe rod-cone dystrophy and his unaffected parents were investigated by whole exome sequencing. This led to the identification of a homozygous nonsense variant, c.963C>A p.(Cys321* in GNAT1, which was confirmed by Sanger sequencing. The mother was heterozygous for this variant whereas the variant was absent in the father. c.963C>A p.(Cys321* is predicted to produce a shorter protein that lacks critical sites for the phototransduction cascade. Our work confirms that the phenotype and the mode of inheritance associated with GNAT1 variants can vary from autosomal dominant, autosomal recessive congenital stationary night blindness to autosomal recessive rod-cone dystrophy.

  2. Purkinje Cell Degeneration and Motor Coordination Deficits in a New Mouse Model of Autosomal Recessive Spastic Ataxia of Charlevoix-Saguenay

    Directory of Open Access Journals (Sweden)

    Man Ding

    2017-05-01

    Full Text Available Autosomal recessive spastic ataxia of Charlevoix-Saguenay (ARSACS is an early-onset neurodegenerative disorder. In 2007, a novel locus, SAX2, which is located on chromosome 17p13 and contains 3 genes, ankyrin repeat and FYVE domain-containing 1 (ANKFY1, β-arrestin 2 (ARRB2 and kinesin family member 1C (KIF1C, was linked to ARSACS. We generated Ankfy1 heterozygous (Ankfy1/+ mice to establish an animal model and examine the pathophysiological basis of ARSACS. The transgenic mice displayed an abnormal gait with progressive motor and cerebellar nerve dysfunction that was highly reminiscent of ARSACS. These clinical features were accompanied by an early-onset and progressive loss of Purkinje cells, followed by gliosis. Additionally, the loss of Ankfy1 function resulted in an abnormal expression of neurotrophic factors (NTFs in the Ankfy1/+ mouse cerebellum. Moreover, Purkinje cells cultured from neonatal Ankfy1/+ mice exhibited a shorter dendritic length and decreased numbers of dendritic spines. Importantly, cerebellar Purkinje cells from Ankfy1/+ mice and cells transfected with a lentiviral Ankfy1 shRNA underwent apoptosis. We propose that transgenic Ankfy1/+ mice are a useful model for studying the pathogenesis of ARSACS and for exploring the molecular mechanisms involved in this neurodegenerative disease.

  3. Paris-Trousseau thrombocytopenia is phenocopied by the autosomal recessive inheritance of a DNA-binding domain mutation in FLI1.

    Science.gov (United States)

    Stevenson, William S; Rabbolini, David J; Beutler, Lucinda; Chen, Qiang; Gabrielli, Sara; Mackay, Joel P; Brighton, Timothy A; Ward, Christopher M; Morel-Kopp, Marie-Christine

    2015-10-22

    Hemizygous deletion of a variable region on chromosome 11q containing FLI1 causes an inherited platelet-related bleeding disorder in Paris-Trousseau thrombocytopenia and Jacobsen syndrome. These multisystem disorders are also characterized by heart anomalies, changes in facial structure, and intellectual disability. We have identified a consanguineous family with autosomal recessive inheritance of a bleeding disorder that mimics Paris-Trousseau thrombocytopenia but has no other features of the 11q23 deletion syndrome. Affected individuals in this family have moderate thrombocytopenia; absent collagen-induced platelet aggregation; and large, fused α-granules in 1% to 5% of circulating platelets. This phenotype was caused by a FLI1 homozygous c.970C>T-point mutation that predicts an arginine-to-tryptophan substitution in the conserved ETS DNA-binding domain of FLI1. This mutation caused a transcription defect at the promoter of known FLI1 target genes GP6, GP9, and ITGA2B, as measured by luciferase assay in HEK293 cells, and decreased the expression of these target proteins in affected members of the family as measured by Western blotting of platelet lysates. This kindred suggests abnormalities in FLI1 as causative of Paris-Trousseau thrombocytopenia and confirms the important role of FLI1 in normal platelet development. © 2015 by The American Society of Hematology.

  4. Summary of mutations underlying autosomal recessive congenital ichthyoses (ARCI) in Arabs with four novel mutations in ARCI-related genes from the United Arab Emirates.

    Science.gov (United States)

    Bastaki, Fatma; Mohamed, Madiha; Nair, Pratibha; Saif, Fatima; Mustafa, Ethar M; Bizzari, Sami; Al-Ali, Mahmoud T; Hamzeh, Abdul Rezzak

    2017-05-01

    Clinical and molecular heterogeneity is a prominent characteristic of congenital ichthyoses, with the involvement of numerous causative loci. Mutations in these loci feature in autosomal recessive congenital ichthyoses (ARCIs) quite variably, with certain genes/mutations being more frequently uncovered in particular populations. In this study, we used whole exome sequencing as well as direct Sanger sequencing to uncover four novel mutations in ARCI-related genes, which were found in families from the United Arab Emirates. In silico tools such as CADD and SIFT Indel were used to predict the functional consequences of these mutations. The here-presented mutations occurred in three genes (ALOX12B, TGM1, ABCA12), and these are a mixture of missense and indel variants with damaging functional consequences on their encoded proteins. This study presents an overview of the mutations that were found in ARCI-related genes in Arabs and discusses molecular and clinical details pertaining to the above-mentioned Emirati cases and their novel mutations with special emphasis on the resulting protein changes. © 2017 The International Society of Dermatology.

  5. Most mutations that cause spinocerebellar ataxia autosomal recessive type 16 (SCAR16) destabilize the protein quality-control E3 ligase CHIP.

    Science.gov (United States)

    Kanack, Adam J; Newsom, Oliver J; Scaglione, Kenneth Matthew

    2018-02-23

    The accumulation of misfolded proteins promotes protein aggregation and neuronal death in many neurodegenerative diseases. To counteract misfolded protein accumulation, neurons have pathways that recognize and refold or degrade aggregation-prone proteins. One U-box-containing E3 ligase, C terminus of Hsc70-interacting protein (CHIP), plays a key role in this process, targeting misfolded proteins for proteasomal degradation. CHIP plays a protective role in mouse models of neurodegenerative disease, and in humans, mutations in CHIP cause spinocerebellar ataxia autosomal recessive type 16 (SCAR16), a fatal neurodegenerative disease characterized by truncal and limb ataxia that results in gait instability. Here, we systematically analyzed CHIP mutations that cause SCAR16 and found that most SCAR16 mutations destabilize CHIP. This destabilization caused mutation-specific defects in CHIP activity, including increased formation of soluble oligomers, decreased interactions with chaperones, diminished substrate ubiquitination, and reduced steady-state levels in cells. Consistent with decreased CHIP stability promoting its dysfunction in SCAR16, most mutant proteins recovered activity when the assays were performed below the mutants' melting temperature. Together, our results have uncovered the molecular basis of genetic defects in CHIP function that cause SCAR16. Our insights suggest that compounds that improve the thermostability of genetic CHIP variants may be beneficial for treating patients with SCAR16. © 2018 by The American Society for Biochemistry and Molecular Biology, Inc.

  6. 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.

  7. Novel Mutations and Mutation Combinations ofTMPRSS3Cause Various Phenotypes in One Chinese Family with Autosomal Recessive Hearing Impairment.

    Science.gov (United States)

    Gao, Xue; Yuan, Yong-Yi; Wang, Guo-Jian; Xu, Jin-Cao; Su, Yu; Lin, Xi; Dai, Pu

    2017-01-01

    Autosomal recessive hearing impairment with postlingual onset is rare. Exceptions are caused by mutations in the TMPRSS3 gene, which can lead to prelingual (DFNB10) as well as postlingual deafness (DFNB8). TMPRSS3 mutations can be classified as mild or severe, and the phenotype is dependent on the combination of TMPRSS3 mutations. The combination of two severe mutations leads to profound hearing impairment with a prelingual onset, whereas severe mutations in combination with milder TMPRSS3 mutations lead to a milder phenotype with postlingual onset. We characterized a Chinese family (number FH1523) with not only prelingual but also postlingual hearing impairment. Three mutations in TMPRSS3 , one novel mutation c.36delC [p.(Phe13Serfs⁎12)], and two previously reported pathogenic mutations, c.916G>A (p.Ala306Thr) and c.316C>T (p.Arg106Cys), were identified. Compound heterozygous mutations of p.(Phe13Serfs⁎12) and p.Ala306Thr manifest as prelingual, profound hearing impairment in the patient (IV: 1), whereas the combination of p.Arg106Cys and p.Ala306Thr manifests as postlingual, milder hearing impairment in the patient (II: 2, II: 3, II: 5), suggesting that p.Arg106Cys mutation has a milder effect than p.(Phe13Serfs⁎12). We concluded that different combinations of TMPRSS3 mutations led to different hearing impairment phenotypes (DFNB8/DFNB10) in this family.

  8. Quantitative magnetic resonance imaging (MRI) assessments of autosomal recessive polycystic kidney disease (ARPKD) progression and response to therapy in an animal model.

    Science.gov (United States)

    Erokwu, Bernadette O; Anderson, Christian E; Flask, Chris A; Dell, Katherine M

    2018-03-14

    Autosomal Recessive Polycystic Kidney Disease (ARPKD) is associated with significant mortality and morbidity and there are currently no disease-specific treatments available for ARPKD patients. One major limitation in establishing new therapies for ARPKD is a lack of sensitive measures of kidney disease progression. Magnetic Resonance Imaging (MRI) can provide multiple quantitative assessments of disease. We applied quantitative image analysis of high resolution (non-contrast) T2-weighted MRI techniques to study cystic kidney disease progression and response to therapy in the PCK rat model of ARPKD. Serial imaging over a 2 month period demonstrated that renal cystic burden (RCB, %)=[total cyst volume (TCV)/total kidney volume (TKV) × 100], TCV and, to a lesser extent, TKV, detected cystic kidney disease progression as well as the therapeutic effect of octreotide, a clinically-available medication shown previously to slow both kidney and liver disease progression in this model. All 3 MRI measures correlated significantly with histologic measures of renal cystic area, although the correlation of RCB and TCV was stronger than that of TKV. These preclinical MRI results provide a basis for applying these quantitative MRI techniques in clinical studies, to stage and measure progression in human ARPKD kidney disease.Pediatric Research accepted article preview online, 14 March 2018. doi:10.1038/pr.2018.24.

  9. Similar clinical, pathological, and genetic features in Chinese patients with autosomal recessive and dominant Charcot-Marie-Tooth disease type 2K.

    Science.gov (United States)

    Fu, Jun; Dai, Shixu; Lu, Yuanyuan; Wu, Rui; Wang, Zhaoxia; Yuan, Yun; Lv, He

    2017-08-01

    Mutations in the ganglioside-induced differentiation-associated protein 1 gene (GDAP1) cause rare subtypes of Charcot-Marie-Tooth disease (CMT2K and CMT4A). CMT2K is an axonal neuropathy while CMT4A is a demyelinating type. In a series of 169 Chinese CMT patients (79 CMT1, 52 CMT2 and 38 unclassified), four unrelated patients (2.37%) were identified with GDAP1 mutations, including two with autosomal recessive CMT2K (AR-CMT2K) and two dominant CMT2K (AD-CMT2K). All patients had disease onset before 5 years of age, and presented with muscle weakness, atrophy, and mild sensory disturbance in distal limbs. Motor nerve conduction velocities of the median nerve were within normal ranges, and compound muscle action potential ranged from 1.5 to 3.8 mV. Sural nerve biopsy revealed loss of large myelinated fibers with regeneration clusters and a few onion bulbs. Electron microscopy showed mitochondrial aggregation in both axons and Schwann cells, and neurofilament accumulation in giant unmyelinated fibers. The p.H256R mutation was found in all patients with GDAP1 compound heterozygous mutations, suggesting that it might be a common mutation in Chinese patients. This study observed no difference in the disease onset, phenotype severity, electrophysiological findings, or pathological changes between AR-CMT2K and AD-CMT2K patients. Copyright © 2017 Elsevier B.V. All rights reserved.

  10. Siblings With Mutations in TRAPPC11 Presenting With Limb-Girdle Muscular Dystrophy 2S.

    Science.gov (United States)

    Fee, Dominic B; Harmelink, Matthew; Monrad, Priya; Pyzik, Erika

    2017-09-01

    Limb-girdle muscular dystrophy 2S (LGMD2S) is an autosomal recessive condition due to mutations in the TRAPPC11 gene. It is recently described with only 9 prior reported individuals. In addition to the muscular dystrophy, some affected individuals have small head size, global developmental delay, seizures, cataracts, and liver problems. Siblings with an uncharacterized LGMD were assessed; whole-exome screening revealed compound heterozygous mutations in the TRAPPC11 gene. Their presentation helps confirm the emerging phenotype for LGMD2S.

  11. Evidence for linkage disequilibrium in chromosome 13-linked Duchenne-like muscular dystrophy

    Energy Technology Data Exchange (ETDEWEB)

    Othmane, K.B.; Speer, M.C.; Stauffer, J. [Duke Univ. Medical Center, Durham, NC (United States)] [and others

    1995-09-01

    Duchenne-like muscular dystrophy (DLMD) is an autosomal recessive Limb Girdle muscular dystrophy (LGMD2C) characterized by late age of onset, proximal muscle weakness leading to disability, high creatine kinase values, normal intelligence and normal dystrophin in muscle biopsy. We have shown previously that three DLMD families from Tunisia are linked to chromosome 13q12. To further localize the LGMD2C gene, we have investigated seven additional families (119 individuals). Both genotyping and two-point linkage analysis were performed as described elsewhere. 7 refs., 1 fig., 1 tab.

  12. Pituitary autoantibodies in autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED).

    Science.gov (United States)

    O'Dwyer, Damien T; McElduff, Patrick; Peterson, Pärt; Perheentupa, Jaakko; Crock, Patricia A

    2007-01-01

    Autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED) is an autosomal recessive disease due to mutations in the AIRE (AutoImmune REgulator) gene. The role of pituitary autoimmunity in APECED is not known. We determined the prevalence of pituitary autoantibodies in a cohort of 67 Finnish patients with APECED from 217 serum samples collected over 26 years by one investigator. Overall, autoantibodies to the 49 kDa cytosolic autoantigen, human pituitary enolase were detected in 39 of the 67 patients (58%). On their first sample, 25 patients had autoantibodies compared to 5 of 68 controls (chi-square, 1df=17.11, pAPECED patients.

  13. Muscle-Eye-Brain Disease; a Rare Form of Syndromic Congenital Muscular Dystrophy

    Directory of Open Access Journals (Sweden)

    Gosal Gurinder S

    2011-03-01

    Full Text Available Congenital muscular dystrophy (CMD is a heterogeneous group of disorders characterized by muscular hypotonia since birth and the histologic features of muscular dystrophy. Syndromic congenital muscular dystrophies are clinically similar autosomal recessive disorders characterized by congenital muscular dystrophy, lissencephaly, and eye anomalies. We present a case of a rare form of syndromic congenital muscular dystrophy in an eight year old girl, born of first- degree consanguinity. She had: global developmental delay; a seizure disorder; hypotonia; progressive muscle contractures including bilateral symmetrical flexion contractures of hips, knees, equinus contracture and thoracolumbar scoliosis; diminished deep tendon reflexes: bilateral premature cataract; pseudophakia; and nystagmus. The patient was also highly myopic. Based on clinical features, muscle biopsy and MRI of the brain, a diagnosis of muscle- eye- brain disease was made. Identification of these patients may help to prevent this crippling disorder in the future siblings of probands by utilizing genetic counselling and mutation analysis.

  14. Beneficial effect of combined treatment with octreotide and pasireotide in PCK rats, an orthologous model of human autosomal recessive polycystic kidney disease.

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    Masanori Kugita

    Full Text Available Increased intracellular cyclic AMP (cAMP in renal tubular epithelia accelerates the progression of polycystic kidney disease (PKD. Thus, decreasing cAMP levels by an adenylyl cyclase inhibitory G protein activator is considered to be an effective approach in ameliorating PKD. In fact, pasireotide (PAS was effective in reducing disease progression in animal models of PKD. However, hyperglycemia caused by the administration of PAS is an adverse effect in its clinical use. Whereas, co-administration of octreotide (OCT with PAS did not increase serum glucose in normal rats. In the current study, we examined the efficacy of combined treatment with OCT and PAS in PCK rats, an autosomal recessive PKD model. Four-week-old PCK males were treated with the long-acting release type of OCT, PAS, or a combination of both (OCT/PAS for 12 weeks. After termination, serum and renal tissue were used for analyses. Kidney weight, kidney weight per body weight, renal cyst area, renal Ki67 expression, and serum urea nitrogen were significantly decreased either in the PAS or OCT/PAS group, compared with vehicle. Renal tissue cAMP content was significantly decreased by PAS or OCT/PAS treatment, but not OCT, compared with vehicle. As a marker of cellular mTOR signaling activity, renal phospho-S6 kinase expression was significantly decreased by OCT/PAS treatment compared with vehicle, OCT, or PAS. Serum glucose was significantly increased by PAS administration, whereas no difference was shown between vehicle and OCT/PAS, possibly because serum glucagon was decreased either by the treatment of OCT alone or co-application of OCT/PAS. In conclusion, since serum glucose levels are increased by the use of PAS, its combination with OCT may reduce the risk of hyperglycemia associated with PAS monotherapy against PKD progression.

  15. Interactions between FATP4 and ichthyin in epidermal lipid processing may provide clues to the pathogenesis of autosomal recessive congenital ichthyosis.

    Science.gov (United States)

    Li, Hao; Vahlquist, Anders; Törmä, Hans

    2013-03-01

    Autosomal recessive congenital ichthyosis (ARCI) is caused by mutations in ≥10 different genes, of which transglutaminase-1 (TGM1) predominates. A rare form is ichthyosis prematurity syndrome (IPS) caused by mutations in SLC27A4 encoding fatty acid transporter protein 4 (FATP4), believed to be an acyl-CoA synthetase activating long- and very-long-chain FA. Another ARCI is caused by mutations in NIPAL4, coding for ichthyin, which is proposed to be a magnesium transporter or a trans-membrane receptor. A possible interaction between FATP4 and ichthyin has not been studied before. To find common denominators in the pathogenesis of ARCI. FATP4 and ichthyin were analyzed by immunofluorescence and proximity ligation assay (PLA) in healthy and ARCI patient skin and in in vitro models of ARCI epidermis. Both proteins were expressed in the upper stratum granulosum of normal epidermis and PLA confirmed a close interaction between FATP4 and ichthyin. In IPS skin lacking FATP4 we found reduced ichthyin expression and this finding could be reproduced in organotypic epidermis with siRNA silenced SLC27A4. In contrast, increased FATP4 staining was found in patients with ichthyin (NIPAL4) mutations and in organotypic epidermis with silenced NIPAL4. In patients with TGM1 mutations, the expression of both FATP4 and ichthyin was increased, but the PLA signal was low probably indicating a malfunctioning protein interaction. Our study suggests that FATP4, ichthyin and TGM1 interact in lipid processing essential for maintaining the epidermal barrier function. It is also hypothesized that ichthyin serves as Mg(2+)-transporter for FATP4 in this process. Copyright © 2012 Japanese Society for Investigative Dermatology. Published by Elsevier Ireland Ltd. All rights reserved.

  16. Autosomal recessive transmission of a rare KRT74 variant causes hair and nail ectodermal dysplasia: allelism with dominant woolly hair/hypotrichosis.

    Science.gov (United States)

    Raykova, Doroteya; Klar, Joakim; Azhar, Aysha; Khan, Tahir Naeem; Malik, Naveed Altaf; Iqbal, Muhammad; Tariq, Muhammad; Baig, Shahid Mahmood; Dahl, Niklas

    2014-01-01

    Pure hair and nail ectodermal dysplasia (PHNED) comprises a heterogeneous group of rare heritable disorders characterized by brittle hair, hypotrichosis, onychodystrophy and micronychia. Autosomal recessive (AR) PHNED has previously been associated with mutations in either KRT85 or HOXC13 on chromosome 12p11.1-q14.3. We investigated a consanguineous Pakistani family with AR PHNED linked to the keratin gene cluster on 12p11.1 but without detectable mutations in KRT85 and HOXC13. Whole exome sequencing of affected individuals revealed homozygosity for a rare c.821T>C variant (p.Phe274Ser) in the KRT74 gene that segregates AR PHNED in the family. The transition alters the highly conserved Phe274 residue in the coil 1B domain required for long-range dimerization of keratins, suggesting that the mutation compromises the stability of intermediate filaments. Immunohistochemical (IHC) analyses confirmed a strong keratin-74 expression in the nail matrix, the nail bed and the hyponychium of mouse distal digits, as well as in normal human hair follicles. Furthermore, hair follicles and epidermis of an affected family member stained negative for Keratin-74 suggesting a loss of function mechanism mediated by the Phe274Ser substitution. Our observations show for the first time that homozygosity for a KRT74 missense variant may be associated with AR PHNED. Heterozygous KRT74 mutations have previously been associated with autosomal dominant woolly hair/hypotrichosis simplex (ADWH). Thus, our findings expand the phenotypic spectrum associated with KRT74 mutations and imply that a subtype of AR PHNED is allelic with ADWH.

  17. Autosomal recessive transmission of a rare KRT74 variant causes hair and nail ectodermal dysplasia: allelism with dominant woolly hair/hypotrichosis.

    Directory of Open Access Journals (Sweden)

    Doroteya Raykova

    Full Text Available Pure hair and nail ectodermal dysplasia (PHNED comprises a heterogeneous group of rare heritable disorders characterized by brittle hair, hypotrichosis, onychodystrophy and micronychia. Autosomal recessive (AR PHNED has previously been associated with mutations in either KRT85 or HOXC13 on chromosome 12p11.1-q14.3. We investigated a consanguineous Pakistani family with AR PHNED linked to the keratin gene cluster on 12p11.1 but without detectable mutations in KRT85 and HOXC13. Whole exome sequencing of affected individuals revealed homozygosity for a rare c.821T>C variant (p.Phe274Ser in the KRT74 gene that segregates AR PHNED in the family. The transition alters the highly conserved Phe274 residue in the coil 1B domain required for long-range dimerization of keratins, suggesting that the mutation compromises the stability of intermediate filaments. Immunohistochemical (IHC analyses confirmed a strong keratin-74 expression in the nail matrix, the nail bed and the hyponychium of mouse distal digits, as well as in normal human hair follicles. Furthermore, hair follicles and epidermis of an affected family member stained negative for Keratin-74 suggesting a loss of function mechanism mediated by the Phe274Ser substitution. Our observations show for the first time that homozygosity for a KRT74 missense variant may be associated with AR PHNED. Heterozygous KRT74 mutations have previously been associated with autosomal dominant woolly hair/hypotrichosis simplex (ADWH. Thus, our findings expand the phenotypic spectrum associated with KRT74 mutations and imply that a subtype of AR PHNED is allelic with ADWH.

  18. An autosomal recessive leucoencephalopathy with ischemic stroke, dysmorphic syndrome and retinitis pigmentosa maps to chromosome 17q24.2-25.3

    Directory of Open Access Journals (Sweden)

    Bouhouche Ahmed

    2012-03-01

    Full Text Available Abstract Background Single-gene disorders related to ischemic stroke seem to be an important cause of stroke in young patients without known risk factors. To identify new genes responsible of such diseases, we studied a consanguineous Moroccan family with three affected individuals displaying hereditary leucoencephalopathy with ischemic stroke, dysmorphic syndrome and retinitis pigmentosa that appears to segregate in autosomal recessive pattern. Methods All family members underwent neurological and radiological examinations. A genome wide search was conducted in this family using the ABI PRISM linkage mapping set version 2.5 from Applied Biosystems. Six candidate genes within the region linked to the disease were screened for mutations by direct sequencing. Results Evidence of linkage was obtained on chromosome 17q24.2-25.3. Analysis of recombination events and LOD score calculation suggests linkage of the responsible gene in a genetic interval of 11 Mb located between D17S789 and D17S1806 with a maximal multipoint LOD score of 2.90. Sequencing of seven candidate genes in this locus, ATP5H, FDXR, SLC25A19, MCT8, CYGB, KCNJ16 and GRIN2C, identified three missense mutations in the FDXR gene which were also found in a homozygous state in three healthy controls, suggesting that these variants are not disease-causing mutations in the family. Conclusion A novel locus for leucoencephalopathy with ischemic stroke, dysmorphic syndrome and retinitis pigmentosa has been mapped to chromosome 17q24.2-25.3 in a consanguineous Moroccan family.

  19. Autosomal recessive non-syndromic hearing loss is caused by novel compound heterozygous mutations in TMC1 from a Tibetan Chinese family.

    Science.gov (United States)

    Lin, Fangzhu; Li, Dejun; Wang, Ping; Fan, Dongyan; De, Ji; Zhu, Wei

    2014-12-01

    Hearing loss is the most common sensory disorder worldwide. Biallelic mutations in 42 different genes have been identified as associated with autosomal recessive non-syndromic hearing loss (ARNSHL). One of the common genes responsible for ARNSHL is TMC1. TMC1 mutations have been reported to cause non-syndromic hearing loss in a variety of populations. The current study is designed to investigate mutations prevalent among Chinese ethnic groups with ARNSHL. Targeted exome sequencing (TES) was employed to study the genetic causes of two siblings with ARNSHL in a Tibetan Chinese family. Variants identified by TES were further confirmed by Sanger sequencing. We identified two distinct variants in the TMC1 gene in two deaf siblings of one Tibetan Chinese family using TES. Both siblings inherited a paternal allele containing a deletion of c.1396_1398AAC (p.Asn466del) and a maternal allele containing an insertion of c.2210_2211insCT (p.Glu737HisfsX2). The former disrupts a highly conserved residue in the large intracellular loop domain adjacent to the fourth transmembrane domain, and the latter causes a truncation of a portion of the C-terminal domain. These variants were compound heterzygous and segregated with the hearing impairment in this family. The novel compound heterozygous mutant alleles of TMC1 identified in this study were responsible for the ARNSHL in this Tibetan Chinese family. Although compound heterozygous mutations in TMC1 occurring in different TMC1 domains have been previously described in Han Chinese; this result suggests that the TMC1 variants contributing to hereditary deafness in Chinese populations may be more complex than initially assumed and that sequence-based diagnostics will be required for a comprehensive evaluation of ARNSHL. Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.

  20. An Empirical Biomarker-Based Calculator for Cystic Index in a Model of Autosomal Recessive Polycystic Kidney Disease-The Nieto-Narayan Formula.

    Directory of Open Access Journals (Sweden)

    Jake A Nieto

    Full Text Available Autosomal recessive polycystic kidney disease (ARPKD is associated with progressive enlargement of the kidneys fuelled by the formation and expansion of fluid-filled cysts. The disease is congenital and children that do not succumb to it during the neonatal period will, by age 10 years, more often than not, require nephrectomy+renal replacement therapy for management of both pain and renal insufficiency. Since increasing cystic index (CI; percent of kidney occupied by cysts drives both renal expansion and organ dysfunction, management of these patients, including decisions such as elective nephrectomy and prioritization on the transplant waitlist, could clearly benefit from serial determination of CI. So also, clinical trials in ARPKD evaluating the efficacy of novel drug candidates could benefit from serial determination of CI. Although ultrasound is currently the imaging modality of choice for diagnosis of ARPKD, its utilization for assessing disease progression is highly limited. Magnetic resonance imaging or computed tomography, although more reliable for determination of CI, are expensive, time-consuming and somewhat impractical in the pediatric population. Using a well-established mammalian model of ARPKD, we undertook a big data-like analysis of minimally- or non-invasive blood and urine biomarkers of renal injury/dysfunction to derive a family of equations for estimating CI. We then applied a signal averaging protocol to distill these equations to a single empirical formula for calculation of CI. Such a formula will eventually find use in identifying and monitoring patients at high risk for progressing to end-stage renal disease and aid in the conduct of clinical trials.

  1. Congenital muscular dystrophies--problems of classification.

    Science.gov (United States)

    Lenard, H G

    1991-04-01

    The classification of congenital muscular dystrophies (CMD), based on perceived clinical and morphological similarities or differences, is controversial. CMD without cerebral involvement has sometimes been divided into a mild and a severe form. This distinction is, however, arbitrary and not uncontested. Whether Ullrich's disease, formerly called atonic-sclerotic dystrophy, is a disease entity and if so, whether it is a primary muscle disorder, is uncertain. CMD without cerebral involvement is inherited in an autosomal recessive fashion in the great majority of cases. CMDs with cerebral involvement are usually classified into at least three forms: the Fukuyama type of CMD, occurring almost exclusively in Japanese patients; CMD with hypomyelination, sometimes also called the occidental type of cerebromuscular dystrophy; and Walker-Warburg syndrome. Muscle-eye-brain disease, described in a number of Finnish patients, may or may not belong in this last category. In CMD with cerebral involvement inheritance is also autosomal recessive. It is possible that single sporadic cases are phenocopies due to infectious or other exogenous causes. Reports of clinical and morphological findings from an increasing number of patients show a high degree of variability within and, on the other hand, certain similarities between the forms of CMD with cerebral involvement. In addition, neuroradiological changes are also found with increasing frequency in CMD patients without clinical neuropsychological abnormalities. It is not unreasonable to speculate that molecular genetic techniques will reveal in the near future a variable defect in one gene locus or defects in a few gene loci as the cause of the various clinical forms of CMDs.

  2. Aberrant Smad3 phosphoisoforms in cyst-lining epithelial cells in the cpk mouse, a model of autosomal recessive polycystic kidney disease.

    Science.gov (United States)

    Hama, Taketsugu; Nakanishi, Koichi; Sato, Masashi; Mukaiyama, Hironobu; Togawa, Hiroko; Shima, Yuko; Miyajima, Masayasu; Nozu, Kandai; Nagao, Shizuko; Takahashi, Hisahide; Sako, Mayumi; Iijima, Kazumoto; Yoshikawa, Norishige; Suzuki, Hiroyuki

    2017-12-01

    Cystic epithelia acquire mesenchymal-like features in polycystic kidney disease (PKD). In this phenotypic alteration, it is well known that transforming growth factor (TGF)-β/Smad3 signaling is involved; however, there is emerging new data on Smad3 phosphoisoforms: Smad3 phosphorylated at linker regions (pSmad3L), COOH-terminal regions (pSmad3C), and both (pSmad3L/C). pSmad3L/C has a pathological role in colorectal cancer. Mesenchymal phenotype-specific cell responses in the TGF-β/Smad3 pathway are implicated in carcinomas. In this study, we confirmed mesenchymal features and examined Smad3 phosphoisoforms in the cpk mouse, a model of autosomal recessive PKD. Kidney sections were stained with antibodies against mesenchymal markers and domain-specific phospho-Smad3. TGF-β, pSmad3L, pSmad3C, JNK, cyclin-dependent kinase (CDK) 4, and c-Myc were evaluated by Western blotting. Cophosphorylation of pSmad3L/C was assessed by immunoprecipitation. α-Smooth muscle actin, which indicates mesenchymal features, was expressed higher in cpk mice. pSmad3L expression was increased in cpk mice and was predominantly localized in the nuclei of tubular epithelial cells in cysts; however, pSmad3C was equally expressed in both cpk and control mice. Levels of pSmad3L, JNK, CDK4, and c-Myc protein in nuclei were significantly higher in cpk mice than in controls. Immunoprecipitation showed that Smad3 was cophosphorylated (pSmad3L/C) in cpk mice. Smad3 knockout/ cpk double-mutant mice revealed amelioration of cpk abnormalities. These findings suggest that upregulating c-Myc through the JNK/CDK4-dependent pSmad3L pathway may be key to the pathophysiology in cpk mice. In conclusion, a qualitative rather than a quantitative abnormality of the TGF-β/Smad3 pathway is involved in PKD and may be a target for disease-specific intervention. Copyright © 2017 the American Physiological Society.

  3. Does anonymous sperm donation increase the risk for unions between relatives and the incidence of autosomal recessive diseases due to consanguinity?

    Science.gov (United States)

    Serre, Jean-Louis; Leutenegger, Anne-Louise; Bernheim, Alain; Fellous, Marc; Rouen, Alexandre; Siffroi, Jean-Pierre

    2014-03-01

    In France gamete donation and notably sperm donation are anonymous. It has been claimed that anonymous artificial insemination by donor (AID) could highly contribute to an increase in the level of consanguinity and the incidence of autosomal recessive diseases, due to the unions between offspring of anonymous donors, unaware of their biological kinship, with the special case of unions between half-siblings. The actual incidence of consanguinity due to AID was compared with that resulting from the two other main sources of consanguinity and recessive diseases, i.e. voluntary unions between related individuals or inadvertent unions between the offspring of a common unknown male ancestor (false paternity). From these data, we estimated that expected unions in France between half sibs per year are 0.12 between offspring of sperm donors (1.2 every 10 years) and 0.5 between offspring of common male ancestors through false paternity (5 every 10 years). More generally, the inadvertent unions between false paternity offspring are roughly four times more frequent than those resulting from anonymous AID. We estimated that in the future, when AID has been in practice for several generations, out the 820 000 annual births in France, respectively, 6 and 25 births will be consanguineous through an unknown common ancestor related to anonymous AID and to a false paternity, both of which are negligible when compared with the 1256 children born from first-degree cousins. About 672 children per year are born with a recessive genetic disease due to the panmictic risk and additional affected cases due to consanguinity would be 34.54 for first-cousin offspring, 0.33 for offspring of individuals related due to false paternity and 0.079 for offspring of individuals related due to anonymous AID. Anonymous AID would therefore be responsible for 0.46% of consanguineous births and for 0.01% of recessive diseases. Therefore, the effect of anonymous AID on half-sibling unions, consanguinity and

  4. Common recessive limb girdle muscular dystrophies differential diagnosis: why and how?

    Directory of Open Access Journals (Sweden)

    Ana Cotta

    2014-09-01

    Full Text Available Limb girdle muscular dystrophies are heterogeneous autosomal hereditary neuromuscular disorders. They produce dystrophic changes on muscle biopsy and they are associated with mutations in several genes involved in muscular structure and function. Detailed clinical, laboratorial, imaging, diagnostic flowchart, photographs, tables, and illustrated diagrams are presented for the differential diagnosis of common autosomal recessive limb girdle muscular dystrophy subtypes diagnosed nowadays at one reference center in Brazil. Preoperative image studies guide muscle biopsy site selection. Muscle involvement image pattern differs depending on the limb girdle muscular dystrophy subtype. Muscle involvement is conspicuous at the posterior thigh in calpainopathy and fukutin-related proteinopathy; anterior thigh in sarcoglycanopathy; whole thigh in dysferlinopathy, and telethoninopathy. The precise differential diagnosis of limb girdle muscular dystrophies is important for genetic counseling, prognostic orientation, cardiac and respiratory management. Besides that, it may probably, in the future, provide specific genetic therapies for each subtype.

  5. The human intrinsic factor-vitamin B12 receptor, cubilin: molecular characterization and chromosomal mapping of the gene to 10p within the autosomal recessive megaloblastic anemia (MGA1) region

    DEFF Research Database (Denmark)

    Kozyraki, R; Kristiansen, M; Silahtaroglu, A

    1998-01-01

    -5445 on the short arm of chromosome 10. This is within the autosomal recessive megaloblastic anemia (MGA1) 6-cM region harboring the unknown recessive-gene locus of juvenile megaloblastic anemia caused by intestinal malabsorption of cobalamin (Imerslund-Gräsbeck's disease). In conclusion, the present...... molecular and genetic information on human cubilin now provides circumstantial evidence that an impaired synthesis, processing, or ligand binding of cubilin is the molecular background of this hereditary form of megaloblastic anemia. Udgivelsesdato: 1998-May-15...

  6. Do consanguineous parents of a child affected by an autosomal recessive disease have more DNA identical-by-descent than similarly-related parents with healthy offspring? Design of a case-control study

    Directory of Open Access Journals (Sweden)

    Cornel Martina C

    2010-07-01

    Full Text Available Abstract Background The offspring of consanguineous relations have an increased risk of congenital/genetic disorders and early mortality. Consanguineous couples and their offspring account for approximately 10% of the global population. The increased risk for congenital/genetic disorders is most marked for autosomal recessive disorders and depends on the degree of relatedness of the parents. For children of first cousins the increased risk is 2-4%. For individual couples, however, the extra risk can vary from zero to 25% or higher, with only a minority of these couples having an increased risk of at least 25%. It is currently not possible to differentiate between high-and low-risk couples. The quantity of DNA identical-by-descent between couples with the same degree of relatedness shows a remarkable variation. Here we hypothesize that consanguineous partners with children affected by an autosomal recessive disease have more DNA identical-by-descent than similarly-related partners who have only healthy children. The aim of the study is thus to establish whether the amount of DNA identical-by-descent in consanguineous parents of children with an autosomal recessive disease is indeed different from its proportion in consanguineous parents who have healthy children only. Methods/Design This project is designed as a case-control study. Cases are defined as consanguineous couples with one or more children with an autosomal recessive disorder and controls as consanguineous couples with at least three healthy children and no affected child. We aim to include 100 case couples and 100 control couples. Control couples are matched by restricting the search to the same family, clan or ethnic origin as the case couple. Genome-wide SNP arrays will be used to test our hypothesis. Discussion This study contains a new approach to risk assessment in consanguineous couples. There is no previous study on the amount of DNA identical-by-descent in consanguineous

  7. Inhibitory action of chlorophyllin of autosome recessive lethals induced by irradiation; Accion inhibidora de la clorofilina de letales recesivos autosonicos inducidos por irradiacion

    Energy Technology Data Exchange (ETDEWEB)

    Salceda, V.M.; Pimentel, P.A.E.; Cruces, M.P. [ININ, 52045 Ocoyoacac, Estado de Mexico (Mexico)]. e-mail: vmss@nuclear.inin.mx

    2006-07-01

    chlorophyllin on the damage caused by the radiation, it was into accothe presence of lethal and semi lethals autosomal. One observes this way that even without the use of the radiation the semi lethals frequency is diminished when the chlorophyllin is applied, in this case the decrease was significant and although there was decrease in the case of the irradiated group this it was not significant; in the case of the lethal ones it happened the opposite it was not significant in radiation absence on the contrary elevate the frequency of this type of genes, however, before the radiation and with pre-treatment with chlorophyllin this it reduced the frequency of autosomal recessive lethals significantly. This is important because in the case of bound recessive lethals recessive to the sex this doesn't happen. (Author)

  8. Prevalence and Diagnostic Spectrum of Generalized Retinal Dystrophy in Danish Children

    DEFF Research Database (Denmark)

    Bertelsen, Mette; Jensen, Hanne; Larsen, Michael

    2013-01-01

    children residing in Denmark aged 0-17 years. Among registered children, the primary diagnosis of generalized retinal dystrophy was assessed by chart review, including fundus photographs and electroretinograms. Age-specific data for live children in Denmark were retrieved from Statistics Denmark. Results...... with increasing age. In 43% of the children the eye condition was part of a syndrome, while the remaining 57% had eye disease only. The most common hereditary pattern was autosomal recessive (99 children, 66%). Conclusions: This epidemiological survey demonstrates that the prevalence of generalized retinal...

  9. Autoimmune polyendocrinopathy candidiasis ectodermal dystrophy: known and novel aspects of the syndrome.

    Science.gov (United States)

    Kisand, Kai; Peterson, Pärt

    2011-12-01

    Autoimmune polyendocrinopathy candidiasis ectodermal dystrophy (APECED) is a monogenic autosomal recessive disease caused by mutations in the autoimmune regulator (AIRE) gene and, as a syndrome, is characterized by chronic mucocutaneous candidiasis and the presentation of various autoimmune diseases. During the last decade, research on APECED and AIRE has provided immunologists with several invaluable lessons regarding tolerance and autoimmunity. This review describes the clinical and immunological features of APECED and discusses emerging alternative models to explain the pathogenesis of the disease. © 2011 New York Academy of Sciences.

  10. Circadian Dynamics of the Cone-Rod Homeobox (CRX) Transcription Factor in the Rat Pineal Gland and Its Role in Regulation of Arylalkylamine N-Acetyltransferase (AANAT)

    DEFF Research Database (Denmark)

    Rohde, Kristian; Rovsing, Louise; Ho, Anthony K

    2014-01-01

    The cone-rod homeobox (Crx) gene encodes a transcription factor in the retina and pineal gland. Crx deficiency influences the pineal transcriptome, including a reduced expression of arylalkylamine N-acetyltransferase (Aanat), a key enzyme in nocturnal pineal melatonin production. However, previous...... that the rhythmic nature of pineal CRX protein may directly modulate the daily profile of Aanat expression by inducing nighttime expression of this enzyme, thus facilitating nocturnal melatonin synthesis in addition to its role in ensuring a correct tissue distribution of Aanat expression....

  11. Microcefalia primária autossômica recessiva em três famílias pernambucanas: aspectos clínicos e moleculares Autosomal recessive primary microcephaly in three families from Pernambuco: clinical and molecular aspects

    Directory of Open Access Journals (Sweden)

    Gabriela F. Leal

    2005-06-01

    Full Text Available OBJETIVOS: descrever os aspectos clínicos de três famílias pernambucanas com microcefalia primária autossômica recessiva e as análises de ligação em uma delas (família 2. MÉTODOS: três famílias consangüíneas pernambucanas, não relacionadas biologicamente, com microcefalia primária, foram estudadas. Os heredogramas e a história clínica dos afetados foram construídos com base em informações obtidas de seus pais e outros parentes. O exame físico foi realizado em todos os afetados, seus genitores e na quase totalidade dos irmãos normais dos afetados. O DNA genômico dos afetados da família 2 e de seus pais foi usado em reações de PCR (polimerase chain reaction com primers elaborados para amplificar marcadores microssatélites ligados aos locos já conhecidos de microcefalia primária autossômica recessiva. Os marcadores amplificados foram submetidos a eletroforese e seus alelos analisados. RESULTADOS: nas três famílias, os afetados apresentavam perímetro cefálico muito reduzido acompanhado de retardo mental e apenas uma paciente (da família 3 manifestava outras alterações neurológicas, mas sem dismorfias associadas. Estudos moleculares demonstraram que a microcefalia, na família 2, não apresentava ligação com nenhum dos locos associados à microcefalia primária autossômica recessiva já conhecidos. CONCLUSÕES: pelo menos mais um gene associado à microcefalia primária autossômica recessiva existe e aguarda identificação.OBJECTIVES: to describe the clinical findings in three families from Pernambuco with autosomal recessive primary microcephaly, and the linkage analysis in one of them (family 2. METHODS: three consanguineous families from Pernambuco, not related one to another and with primary microcephaly, were studied. The genealogical data and the clinical history of the affected individuals were obtained from their parents and other family members. All the affected subjects, almost all their normal

  12. Large deletions of the KCNV2 gene are common in patients with cone dystrophy with supernormal rod response

    DEFF Research Database (Denmark)

    Wissinger, Bernd; Schaich, Simone; Baumann, Britta

    2011-01-01

    Cone dystrophy with supernormal rod response (CDSRR) is considered to be a very rare autosomal recessive retinal disorder. CDSRR is associated with mutations in KCNV2, a gene that encodes a modulatory subunit (Kv8.2) of a voltage-gated potassium channel. In this study, we found that KCNV2 mutations...... KCNV2 gene and one also includes the adjacent VLDLR gene. Furthermore, we investigated N-terminal amino acid substitution mutations for its effect on interaction with Kv2.1 using yeast two-hybrid technology. We found that these mutations dramatically reduce or abolish this interaction suggesting a lack...

  13. Myopathy in autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy.

    Science.gov (United States)

    Watanabe, Mitsuru; Ochi, Hirofumi; Arahata, Hajime; Matsuo, Tomohito; Nagafuchi, Seiho; Ohyagi, Yasumasa; Kira, Jun-Ichi

    2012-06-01

    Autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED) is a rare autosomal recessive disorder caused by monogenic mutations in the autoimmune regulator (AIRE) gene. No attention has been paid to muscle manifestations in this disorder. We aimed to uncover whether progressive myopathy is a component of this disorder. A case description and literature search for APECED cases presenting with myopathy and analysis of AIRE gene expression in biopsied muscles from 4 healthy volunteers and the patient by reverse transcriptase polymerase chain reaction. A 52-year-old woman with APECED caused by AIRE gene mutations developed progressive myopathy involving proximal limb and paraspinal muscles. Muscle biopsy specimens showed myopathic changes without inflammatory cell infiltrate. We detected AIRE gene expression in all muscle tissues examined. An extensive literature search uncovered 5 cases of APECED with myopathy, all of whom had similar features. Progressive myopathy involvement could be a hitherto unknown manifestation of APECED. Copyright © 2012 Wiley Periodicals, Inc.

  14. The first USH2A mutation analysis of Japanese autosomal recessive retinitis pigmentosa patients: a totally different mutation profile with the lack of frequent mutations found in Caucasian patients.

    Science.gov (United States)

    Zhao, Yang; Hosono, Katsuhiro; Suto, Kimiko; Ishigami, Chie; Arai, Yuuki; Hikoya, Akiko; Hirami, Yasuhiko; Ohtsubo, Masafumi; Ueno, Shinji; Terasaki, Hiroko; Sato, Miho; Nakanishi, Hiroshi; Endo, Shiori; Mizuta, Kunihiro; Mineta, Hiroyuki; Kondo, Mineo; Takahashi, Masayo; Minoshima, Shinsei; Hotta, Yoshihiro

    2014-09-01

    Retinitis pigmentosa (RP) is a highly heterogeneous genetic disease. The USH2A gene, which accounts for approximately 74-90% of Usher syndrome type 2 (USH2) cases, is also one of the major autosomal recessive RP (arRP) causative genes among Caucasian populations. To identify disease-causing USH2A gene mutations in Japanese RP patients, all 73 exons were screened for mutations by direct sequencing. In total, 100 unrelated Japanese RP patients with no systemic manifestations were identified, excluding families with obvious autosomal dominant inheritance. Of these 100 patients, 82 were included in this present study after 18 RP patients with very likely pathogenic EYS (eyes shut homolog) mutations were excluded. The mutation analysis of the USH2A revealed five very likely pathogenic mutations in four patients. A patient had only one very likely pathogenic mutation and the others had two of them. Caucasian frequent mutations p.C759F in arRP and p.E767fs in USH2 were not found. All the four patients exhibited typical clinical features of RP. The observed prevalence of USH2A gene mutations was approximately 4% among Japanese arRP patients, and the profile of the USH2A gene mutations differed largely between Japanese patients and previously reported Caucasian populations.

  15. KCNQ1 mutations associated with Jervell and Lange-Nielsen syndrome and autosomal recessive Romano-Ward syndrome in India-expanding the spectrum of long QT syndrome type 1.

    Science.gov (United States)

    Vyas, Bijal; Puri, Ratna D; Namboodiri, Narayanan; Nair, Mohan; Sharma, Deepak; Movva, Sireesha; Saxena, Renu; Bohora, Shomu; Aggarwal, Neeraj; Vora, Amit; Kumar, Jatinder; Singh, Tarandeep; Verma, Ishwar C

    2016-06-01

    Long QT syndrome type 1 (LQT1) is the most common type of all Long QT syndromes (LQTS) and occurs due to mutations in KCNQ1. Biallelic mutations with deafness is called Jervell and Lange-Nielsen syndrome (JLNS) and without deafness is autosomal recessive Romano-Ward syndrome (AR RWS). In this prospective study, we report biallelic mutations in KCNQ1 in Indian patients with LQT1 syndrome. Forty patients with a clinical diagnosis of LQT1 syndrome were referred for molecular testing. Of these, 18 were excluded from the analysis as they did not fulfill the inclusion criteria of broad T wave ECG pattern of the study. Direct sequencing of KCNQ1 was performed in 22 unrelated probands, parents and at-risk family members. Mutations were identified in 17 patients, of which seven had heterozygous mutations and were excluded in this analysis. Biallelic mutations were identified in 10 patients. Five of 10 patients did not have deafness and were categorized as AR RWS, the rest being JLNS. Eight mutations identified in this study have not been reported in the literature and predicted to be pathogenic by in silico analysis. We hypothesize that the homozygous biallelic mutations identified in 67% of families was due to endogamous marriages in the absence of consanguinity. This study presents biallelic gene mutations in KCNQ1 in Asian Indian patients with AR JLNS and RWS. It adds to the scant worldwide literature of mutation studies in AR RWS. © 2016 Wiley Periodicals, Inc. © 2016 Wiley Periodicals, Inc.

  16. Simultaneous Presence of Macular Corneal Dystrophy and Retinitis Pigmentosa in Three Members of a Family

    Directory of Open Access Journals (Sweden)

    Farhad Nejat

    2018-03-01

    Full Text Available Macular corneal dystrophy (MCD is an autosomal recessive hereditary disease. In most cases, various mutations in carbohydrate sulfotransferase 6 (CHST6 gene are the main cause of MCD. These mutations lead to a defect in keratan sulfate synthesis. Retinitis pigmentosa (RP is another eye disorder with nyctalopia as its common symptom. It has been shown that more than 65 genes have been implicated in different forms of RP. Herein, we report on a 9-member family with 2 girls and 5 boys. Both parents, one of the girls and one of the boys had normal eye vision and another boy had keratoconus. Other children (1 girl and 2 boys suffered from both MCD and RP. Corneal transplantation and medical supplements were used for MCD and RP during the follow-up period, respectively. Based on the family tree, it seems that the inheritance of both diseases is autosomal recessive. Based on our search of databases, there is no report on the simultaneous presence of MCD and RP. To the best of our knowledge, the present article is the first case report on this topic. Molecular genetic investigation is needed to clarify the mechanism of concurrent MCD and RP.

  17. Congenital hereditary endothelial dystrophy with progressive sensorineural deafness (Harboyan syndrome

    Directory of Open Access Journals (Sweden)

    Abramowicz Marc

    2008-10-01

    Full Text Available Abstract Harboyan syndrome is a degenerative corneal disorder defined as congenital hereditary endothelial dystrophy (CHED accompanied by progressive, postlingual sensorineural hearing loss. To date, 24 cases from 11 families of various origin (Asian Indian, South American Indian, Sephardi Jewish, Brazilian Portuguese, Dutch, Gypsy, Moroccan, Dominican have been reported. More than 50% of the reported cases have been associated with parental consanguinity. The ocular manifestations in Harboyan syndrome include diffuse bilateral corneal edema occurring with severe corneal clouding, blurred vision, visual loss and nystagmus. They are apparent at birth or within the neonatal period and are indistinguishable from those characteristic of the autosomal recessive CHED (CHED2. Hearing deficit in Harboyan is slowly progressive and typically found in patients 10–25 years old. There are no reported cases with prelinglual deafness, however, a significant hearing loss in children as young as 4 years old has been detected by audiometry, suggesting that hearing may be affected earlier, even at birth. Harboyan syndrome is caused by mutations in the SLC4A11 gene located at the CHED2 locus on chromosome 20p13-p12, indicating that CHED2 and Harboyan syndrome are allelic disorders. A total of 62 different SLC4A11 mutations have been reported in 98 families (92 CHED2 and 6 Harboyan. All reported cases have been consistent with autosomal recessive transmission. Diagnosis is based on clinical criteria, detailed ophthalmological assessment and audiometry. A molecular confirmation of the clinical diagnosis is feasible. A variety of genetic, metabolic, developmental and acquired diseases presenting with clouding of the cornea should be considered in the differential diagnosis (Peters anomaly, sclerocornea, limbal dermoids, congenital glaucoma. Audiometry must be performed to differentiate Harboyan syndrome from CHED2. Autosomal recessive types of CHED (CHED2 and

  18. Blepharophimosis-mental retardation (BMR) syndromes: A proposed clinical classification of the so-called Ohdo syndrome, and delineation of two new BMR syndromes, one X-linked and one autosomal recessive.

    Science.gov (United States)

    Verloes, Alain; Bremond-Gignac, Dominique; Isidor, Bertrand; David, Albert; Baumann, Clarisse; Leroy, Marie-Anne; Stevens, René; Gillerot, Yves; Héron, Delphine; Héron, Bénédicte; Benzacken, Brigitte; Lacombe, Didier; Brunner, Han; Bitoun, Pierre

    2006-06-15

    We report on 11 patients from 8 families with a blepharophimosis and mental retardation syndrome (BMRS) phenotype. Using current nosology, five sporadic patients have Ohdo syndrome, associated with congenital hypothyroidism in two of them (thus also compatible with a diagnosis of Young-Simpson syndrome). In two affected sibs with milder phenotype, compensated hypothyroidism was demonstrated. In another family, an affected boy was born to the unaffected sister of a previously reported patient. Finally, in the last sibship, two affected boys in addition had severe microcephaly and neurological anomalies. A definitive clinical and etiologic classification of BMRS is lacking, but closer phenotypic analysis should lead to a more useful appraisal of the BMRS phenotype. We suggest discontinuing the systematic use of the term "Ohdo syndrome" when referring to patients with BMRS. We propose a classification of BMRS into five groups: (1) del(3p) syndrome, (possibly overlooked in older reports); (2) BMRS, Ohdo type, limited to the original patients of Ohdo; (3) BMRS SBBYS (Say-Barber/Biesecker/Young-Simpson) type, with distinctive dysmorphic features and inconstant anomalies including heart defect, optic atrophy, deafness, hypoplastic teeth, cleft palate, joint limitations, and hypothyroidism. BMRS type SBBYS is probably an etiologically heterogeneous phenotype, as AD and apparently AR forms exist; (4) BMRS, MKB (Maat-Kievit-Brunner) type, with coarse, triangular face, which is probably sex-linked; (5) BMRS V (Verloes) type, a probable new type with severe microcephaly, hypsarrhythmia, adducted thumbs, cleft palate, and abnormal genitalia, which is likely autosomal recessive. Types MKB and V are newly described here. Copyright 2006 Wiley-Liss, Inc.

  19. Autosomal Recessive Myotonia Congenita, A Muscle ...

    African Journals Online (AJOL)

    Background: The muscle diseases are frequently encountered in medical clinics in Nigeria. In many cases however they are not optimally managed. The ion channel diseases, 'channelopathies', are a group of muscle disorders that share a lot of clinical similarity. Misdiagnosis can occur especially in resource poor settings ...

  20. Genetics Home Reference: autosomal recessive congenital methemoglobinemia

    Science.gov (United States)

    ... cell types. Each hemoglobin molecule contains four iron atoms, which are needed to carry oxygen. In normal ... direct-to-consumer genetic testing? What is precision medicine? What is newborn screening? New Pages Obstructive sleep ...

  1. Genetics Home Reference: autosomal recessive hypotrichosis

    Science.gov (United States)

    ... color than expected and is fragile and easily broken. Affected individuals often cannot grow hair longer than ... leading to woolly, fragile hair that is easily broken. A lack of these proteins in the epidermis ...

  2. Bernard-Soulier syndrome (Hemorrhagiparous thrombocytic dystrophy

    Directory of Open Access Journals (Sweden)

    Lanza François

    2006-11-01

    Full Text Available Abstract Bernard-Soulier syndrome (BSS, also known as Hemorrhagiparous thrombocytic dystrophy, is a hereditary bleeding disorder affecting the megakaryocyte/platelet lineage and characterized by bleeding tendency, giant blood platelets and low platelet counts. This syndrome is extremely rare as only ~100 cases have been reported in the literature. Clinical manifestations usually include purpura, epistaxis, menorrhagia, gingival and gastrointestinal bleeding. The syndrome is transmitted as an autosomal recessive trait. The underlying defect is a deficiency or dysfunction of the glycoprotein GPIb-V-IX complex, a platelet-restricted multisubunit receptor required for normal primary hemostasis. The GPIb-V-IX complex binds von Willebrand factor, allowing platelet adhesion and platelet plug formation at sites of vascular injury. Genes coding for the four subunits of the receptor, GPIBA, GPIBB, GP5 and GP9, map to chromosomes 17p12, 22q11.2, 3q29, and 3q21, respectively. Defects have been identified in GPIBA, GPIBB, and GP9 but not in GP5. Diagnosis is based on a prolonged skin bleeding time, the presence of a small number of very large platelets (macrothrombocytopenia, defective ristocetin-induced platelet agglutination and low or absent expression of the GPIb-V-IX complex. Prothrombin consumption is markedly reduced. The prognosis is usually good with adequate supportive care but severe bleeding episodes can occur with menses, trauma and surgical procedures. Treatment of bleeding or prophylaxis during surgical procedures usually requires platelet transfusion.

  3. Diurnal expression of proteins in the retina of the blind cone-rod homeobox (Crx-/- ) mouse and the 129/Sv mouse: a proteomic study.

    Science.gov (United States)

    Møller, Morten; Rath, Martin Fredensborg; Ludvigsen, Maja; Honoré, Bent; Vorum, Henrik

    2017-11-01

    The vertebrate retina contains a circadian clock participating in adaptations to day and night vision. This peripheral clock is independent of the master clock in the suprachiasmatic nucleus (SCN). The retinal clock is located in several cell types, including the photoreceptors. To investigate the role of the circadian clock of the photoreceptor cells in regulation of retinal protein rhythms, we analysed diurnal protein expression in the photoreceptor-deficient cone-rod homeobox knockout mouse (Crx -/- ) and the 129/Sv mouse. 2D gels were made from retinal homogenates of 129/Sv and Crx -/- mice killed at midday and midnight. Stained gels were analysed by use of PDQuest 2D gel analysis software. After trypsin digestion of differential expressed spots, the proteins were identified by LC-MS/MS using a nano-liquid chromatograph connected to a Q-TOF Premier mass spectrometer. These data were used to search the SWISS-PROT database. Both the retinae of the control and the Crx -/- mice exhibited diurnal proteins rhythms. As expected, proteins involved in phototransduction were not detected in the Crx -/- mouse; in this phenotype, however, proteins from spots showing diurnal rhythms were specifically identified as enzymes involved in glucose metabolism, Krebs cycle, and mitochondrial enzymes. Data are available via ProteomeXchange with identifier PXD005556. We show diurnal protein rhythms in the retina of a mouse lacking the rods and cones. The diurnal protein rhythms in this genotype, lacking the circadian clock of the photoreceptors, might be caused by a circadian clock in other retinal cell types or a direct light input to the retina. © 2017 Acta Ophthalmologica Scandinavica Foundation. Published by John Wiley & Sons Ltd.

  4. Muscular Dystrophy

    Science.gov (United States)

    ... The Search for a Cure Print en español Distrofia muscular About MD Muscular dystrophy (MD) is a genetic ... muscles and cause different degrees of muscle weakness. Duchenne muscular dystrophy is the most common and the most ...

  5. Muscular Dystrophy

    Science.gov (United States)

    ... that cause progressive weakness and loss of muscle mass. In muscular dystrophy, abnormal genes (mutations) interfere with the production of proteins needed to form healthy muscle. There are many different kinds of muscular dystrophy. ...

  6. Limb-girdle muscular dystrophy type 2A in Brazilian children

    Directory of Open Access Journals (Sweden)

    Marco Antônio Veloso de Albuquerque

    2015-12-01

    Full Text Available ABSTRACT Calpainopathy is an autosomal recessive limb girdle muscular dystrophy (LGMD2A caused by mutations in CAPN3 gene. Objective To present clinical and histological findings in six children with a molecular diagnosis of LGMD2A and additionally the MRI findings in two of them. Method We retrospectively assessed medical records of 6 patients with mutation on CAPN3 gene. Results All patients were female (three to 12 years. The mean of age of disease onset was 9 years. All of them showed progressive weakness with predominance in lower limbs. Other findings were scapular winging, joint contractures and calf hypertrophy. One female had a more severe phenotype than her dizygotic twin sister that was confirmed by muscle MRI. Muscle biopsies showed a dystrophic pattern in all patients. Conclusion In this cohort of children with LGMD2A, the clinical aspects were similar to adults with the same disorder.

  7. Late-onset Pompe disease with phenotype of the limb-girdle muscular dystrophy

    Directory of Open Access Journals (Sweden)

    S. A. Kurbatov

    2015-01-01

    Full Text Available Pompe disease, also known as type II glycogenosis, is a rare autosomal recessive disease. Two main types include early-onset Pompe disease – severe, rapidly progressive multisystem deficency, manifestating on the first year of life, and late-onset Pompe disease (LOPD, with the age of onset ranging from the first year till late adulthood. Both types are caused by the deficiency of lysosomal acid-α-glucosidase due to the mutations in GAA gene, leading to an excessive storage of glycogen in body cells. LOPD is a slowly progressive disease with a primary lesion of a skeletal, respiratory and cardiac muscles, affected in different grade, and moderately elevated сreatine kinase. It is often difficult to perform differential diagnosis with a large group of hereditary and non-hereditary myopathies. We present a case report of LOPD with signs of limb-girdle muscular dystrophy.

  8. Autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy: report of three cases from Iran.

    Science.gov (United States)

    Seifi-Alan, Mahnaz; Shamsi, Roshanak; Setoodeh, Aria; Sayarifard, Fatemeh; Aghasi, Parisa; Kompani, Farzad; Ghafouri-Fard, Soudeh; Abbasi, Farzaneh

    2016-08-01

    Autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED), also named as autoimmune polyglandular syndrome (APS) type 1, is a rare autosomal recessive disorder caused by mutations in autoimmune regulator (AIRE) gene. It is distinguished by an immune-mediated damage of endocrine tissues, chronic candidiasis, and ectodermal disorder. APECED has been shown to be frequent in some populations including Iranian Jews. Here we report three cases of APECED from two independent Iranian Muslim families. Addison's disease, hypoparathyroidismand mucocutaneous candidiasis were shared clinical manifestations in all patients. Mutational analyses have demonstrated a novel homozygous splice site mutation (c.1095+2T>A) in intron 9 and a previously identified homozygous nonsense mutation (c.415C>T) in exon 3 of patients respectively. Future studies are needed to evaluate the frequency of these variants in Iranian APECED patients which would facilitate genetic counseling as well as prenatal diagnosis.

  9. A multidisciplinary approach to management of autoimmune polyendocrinopathy candidiasis ectodermal dystrophy (APECED).

    Science.gov (United States)

    Gouda, Mohammed Ramzy; Al-Amin, Azzam; Grabsch, Heike; Donnellan, Clare

    2013-01-30

    We present a case of an 18-year-old Caucasian man with a rare autosomal recessive disorder called autoimmune polyendocrinopathy candidiasis ectodermal dystrophy (APECED). This patient had manifestations of all clinical components of this multisystemic disease which included intestinal failure secondary to autoimmune enteropathy. We present a unique multidisciplinary management for this genetic condition. Although patients with APECED do not always have all the disease components (a total of eight exist), the majority have at least 3-5 components. This excludes the psychosexual implications which are often ignored. This case highlights the importance of (1) management of APECED in a multidisciplinary nature that includes a gastroenterologist, immunologist, endocrinologist, dietitians, etc and the (2) management of intestinal failure component of APECED is best suited in a specialist intestinal failure unit where expertise is available for complex malabsorption disorders.

  10. Mild and severe muscular dystrophy caused by a single {gamma}-sarcoglycan mutation

    Energy Technology Data Exchange (ETDEWEB)

    McNally, E.M.; Boennemann, C.G.; Lidov, H.G.W. [Brigham and Women`s Hospital, Boston, MA (United States)] [and others

    1996-11-01

    Autosomal recessive muscular dystrophy is genetically heterogeneous. One form of this disorder, limb-girdle muscular dystrophy type 2C (LGMD 2C), is prevalent in northern Africa and has been shown to be associated with a single mutation in the gene encoding the dystrophin-associated protein {gamma}-sarcoglycan. The previous mutation analysis of {gamma}-sarcoglycan required the availability of muscle biopsies. To establish a mutation assay for genomic DNA, the intron-exon structure of the {gamma}-sarcoglycan gene was determined, and primers were designed to amplify each of the exons encoding {gamma}-sarcoglycan. We studied a group of Brazilian muscular dystrophy patients for mutations in the {gamma}-sarcoglycan gene. These patients were selected on the basis of autosomal inheritance and/or the presence of normal dystrophin and/or deficiency of {alpha}-sarcoglycan immunostaining. Four of 19 patients surveyed had a single, homozygous mutation in the {gamma}-sarcoglycan gene. The mutation identified in these patients, all of African-Brazilian descent, is identical to that seen in the North African population, suggesting that even patients of remote African descent may carry this mutation. The phenotype in these patients varied considerably. Of four families with an identical mutation, three have a severe Duchenne-like muscular dystrophy. However, one family has much milder symptoms, suggesting that other loci may be present that modify the severity of the clinical course resulting from {gamma}-sarcoglycan gene mutations. 19 refs., 5 figs., 3 tabs.

  11. Late-onset Stargardt-like macular dystrophy maps to chromosome 1p13

    Energy Technology Data Exchange (ETDEWEB)

    Kaplan, J.; Gerber, S.; Rozet, J.M. [Hopital des Enfants Malades, Paris (France)] [and others

    1994-09-01

    Stargardt`s disease (MIM 248200), originally described in 1909, is an autosomal recessive condition of childhood, characterized by a sudden and bilateral loss of central vision. Typically, it has an early onset (7 to 12 years), a rapidly progressive course and a poor final outcome. The central area of the retina (macula) displays pigmentary changes in a ring form with depigmentation and atrophy of the retinal pigmentary epithelium (RPE). Perimacular yellowish spots, termed fundus flavimaculatus, are observed in a high percentage of patients. We have recently reported the genetic mapping of Stargardt`s disease to chromosome 1p13. On the other hand, considering that fundus flavimaculatus (MIM 230100) is another form of fleck fundus disease, with a Stargardt-like retinal aspect but with a late-onset and a more progressive course, we decided to test the hypothesis of allelism between typical Stargardt`s disease and late-onset autosomal recessive fundus flavimaculatus. Significant pairwise lod scores were obtained in each of four multiplex families (11 affected individuals, 12 relatives) with four markers of the 1p13 region (Z = 4.79, 4.64, 3.07, 3.16 at loci D1S435, D1S424, D1S236, and D1S415, respectively at {theta} = 0). Multipoint analysis showed that the best estimate for location of the disease gene is between D1S424 and D1S236 (maximum lod score of 5.20) as also observed in Stargardt`s disease. Our results are consistent with the location of the gene responsible of the late-onset Stargardt-like macular dystrophy in the 1p13 region and raise the hypothesis of either allelic mutational events or contiguous genes in this chromosomal region. The question of possible relationship with some age-related macular dystrophies in now open to debate.

  12. Oral mucous squamous cell carcinoma-an anticipated consequence of autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED).

    Science.gov (United States)

    Böckle, Barbara C; Wilhelm, Manuel; Müller, Hansgeorg; Götsch, Claudia; Sepp, Norbert T

    2010-05-01

    Autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED) is a rare autosomal recessive disease caused by mutations in the AIRE gene. We report the case of a female patient with a 967-979del13 mutation in the AIRE gene. Her medical history included autoimmune hypoparathyroidism, Addison disease, and chronic mucocutaneous candidiasis. At the age of 40, she developed multiple white verrucous plaques on the oral mucosa. Histologically, the lesions appeared as moderately differentiated squamous cell carcinomas. The patient subsequently developed multiple local recurrences and therefore required repeated surgery. Notably, a higher incidence rate of oral and esophageal squamous cell carcinoma has been observed in this syndrome. However, the critical pathogenetic pathways implicated in squamous cell carcinoma development in APECED are far from being well understood. Copyright 2009 American Academy of Dermatology, Inc. Published by Mosby, Inc. All rights reserved.

  13. Aspectos clínicos da doença renal policística autossômica recessiva DRPAR Clinical aspects of autosomal recessive polycystic kidney disease

    Directory of Open Access Journals (Sweden)

    Natasha Favoretto Dias

    2010-09-01

    Full Text Available INTRODUÇÃO: A Doença Renal Policística Autossômica Recessiva (DRPAR é uma causa importante de morbidade e mortalidade pediátricas, com um espectro variável de manifestações clínicas. MÉTODOS: A apresentação e evolução clínica de 25 pacientes (Pts foram analisadas através da revisão de prontuários, aplicando-se os formulários propostos por Guay-Woodford et al. As morbidades associadas à doença foram avaliadas quanto à frequência e à idade de manifestação. RESULTADOS: A idade média de diagnóstico foi de 61,45 meses (0 a 336,5 meses, com distribuição similar entre os sexos (52% dos pts do sexo feminino. Houve histórico familiar da doença em 20% dos casos (5/25, com dois casos de consanguinidade. Na análise inicial, diagnosticou-se hipertensão arterial (HAS em 56% dos Pts (14/25; doença renal crônica estágio > 2 (DRC > 2 em 24% (6/25; infecções do trato urinário (ITU em 40% (10/25 e hipertensão portal (HP em 32% dos casos (8/25. Das ultrassonografias abdominais iniciais, 80% demonstraram rins ecogênicos com cistos grosseiros e 64% detectaram fígado e vias biliares normais. Inibidores da ECA foram utilizados em 36% dos Pts, betabloqueadores em 20%, bloqueadores de canais de cálcio em 28% e diuréticos em 36% dos casos. Na análise final, após um tempo de acompanhamento médio de 152,2 meses (29,8 a 274,9 meses, HAS foi diagnosticada em 76% dos Pts, DRC > 2 em 44%, ITU em 52% e HP em 68%. CONCLUSÃO: As altas morbidade e mortalidade associadas à DRPAR justificam a construção de um banco de dados internacional, visando ao estabelecimento de um tratamento de suporte precoce.INTRODUCTION: Autosomal Recessive Polycystic Kidney Disease (ARPKD is an important pediatric cause of morbidity and mortality, with a variable clinical spectrum. METHODS: The clinical presentation and evolution of 25 patients (Pts were analyzed by clinical record review, according to the forms proposed by Guay-Woodford et al

  14. Genetic basis of limb-girdle muscular dystrophies: the 2014 update.

    Science.gov (United States)

    Nigro, Vincenzo; Savarese, Marco

    2014-05-01

    Limb-girdle muscular dystrophies (LGMD) are a highly heterogeneous group of muscle disorders, which first affect the voluntary muscles of the hip and shoulder areas. The definition is highly descriptive and less ambiguous by exclusion: non-Xlinked, non-FSH, non-myotonic, non-distal, nonsyndromic, and non-congenital. At present, the genetic classification is becoming too complex, since the acronym LGMD has also been used for a number of other myopathic disorders with overlapping phenotypes. Today, the list of genes to be screened is too large for the gene-by-gene approach and it is well suited for targeted next generation sequencing (NGS) panels that should include any gene that has been so far associated with a clinical picture of LGMD. The present review has the aim of recapitulating the genetic basis of LGMD ordering and of proposing a nomenclature for the orphan forms. This is useful given the pace of new discoveries. Thity-one loci have been identified so far, eight autosomal dominant and 23 autosomal recessive. The dominant forms (LGMD1) are: LGMD1A (myotilin), LGMD1B (lamin A/C), LGMD1C (caveolin 3), LGMD1D (DNAJB6), LGMD1E (desmin), LGMD1F (transportin 3), LGMD1G (HNRPDL), LGMD1H (chr. 3). The autosomal recessive forms (LGMD2) are: LGMD2A (calpain 3), LGMD2B (dysferlin), LGMD2C (γ sarcoglycan), LGMD2D (α sarcoglycan), LGMD2E (β sarcoglycan), LGMD2F (δ sarcoglycan), LGMD2G (telethonin), LGMD2H (TRIM32), LGMD2I (FKRP), LGMD2J (titin), LGMD2K (POMT1), LGMD2L (anoctamin 5), LGMD2M (fukutin), LGMD2N (POMT2), LGMD2O (POMTnG1), LGMD2P (dystroglycan), LGMD2Q (plectin), LGMD2R (desmin), LGMD2S (TRAPPC11), LGMD2T (GMPPB), LGMD2U (ISPD), LGMD2V (Glucosidase, alpha ), LGMD2W (PINCH2).

  15. Oral health in Autoimmune Polyendocrinopathy Candidiasis Ectodermal Dystrophy (APECED).

    Science.gov (United States)

    McGovern, E; Fleming, P; Costigan, C; Dominguez, M; Coleman, D C; Nunn, J

    2008-12-01

    APECED (Autoimmune Polyendocrinopathy Candidiasis Ectodermal Dystrophy) is a rare autosomal recessive disease characterised primarily by sequential immune-mediated destruction of endocrine tissues, chronic oral or mucocutaneous candidiasis and ectodermal disorders, including hypoplasia of dental enamel. This was to investigate the oral health and presence of enamel defects in a cohort of patients with APECED. 16 patients with APECED (mean age of 13.9 years) were matched for age and gender with healthy controls. A comprehensive medical, dental and drug history was recorded, followed by a clinical assessment of oral health which was determined by assessing periodontal treatment needs, prevalence of dental caries, erosion, fluorosis and enamel defects. The estimated time of the development of the enamel defects and the contemporaneous medical diagnosis were recorded. Oral health of patients with APECED was poor compared with controls, with a higher prevalence of periodontal disease, caries and erosion. There was a significantly (P APECED was poor compared with controls with a higher prevalence of periodontal disease, caries, erosion and enamel defects. The enamel defects in the study population occurred in a chronological pattern and some were associated with a history of systemic disease during the period of tooth development.

  16. Muscular Dystrophy

    Science.gov (United States)

    ... Inheritance patterns Muscular dystrophy Symptoms & causes Diagnosis & treatment Advertisement Mayo Clinic does not endorse companies or products. ... a Job Site Map About This Site Twitter Facebook Google YouTube Pinterest Mayo Clinic is a not- ...

  17. Muscular dystrophy

    Science.gov (United States)

    ... during pregnancy. Alternative Names Inherited myopathy; MD Images Superficial anterior muscles References Sarnat HB. Muscular dystrophies. In: ... the principles of the Health on the Net Foundation (www.hon.ch). The information provided herein should ...

  18. Case Report: Whole exome sequencing reveals a novel frameshift deletion mutation p.G2254fs in COL7A1 associated with autosomal recessive dystrophic epidermolysis bullosa [version 2; referees: 2 approved, 1 approved with reservations

    Directory of Open Access Journals (Sweden)

    Shamsudheen Karuthedath Vellarikkal

    2016-07-01

    Full Text Available Dystrophic epidermolysis bullosa simplex (DEB is a phenotypically diverse inherited skin fragility disorder. It is majorly manifested by appearance of epidermal bullae upon friction caused either by physical or environmental trauma. The phenotypic manifestations also include appearance of milia, scarring all over the body and nail dystrophy. DEB can be inherited in a recessive or dominant form and the recessive form of DEB (RDEB is more severe. In the present study, we identify a novel p.G2254fs mutation in COL7A1 gene causing a sporadic case of RDEB by whole exome sequencing (WES. Apart from adding a novel frameshift Collagen VII mutation to the repertoire of known mutations reported in the disease, to the best of our knowledge, this is the first report of a genetically characterized case of DEB from India.

  19. Case Report: Whole exome sequencing reveals a novel frameshift deletion mutation p.G2254fs in COL7A1 associated with autosomal recessive dystrophic epidermolysis bullosa [version 1; referees: 2 approved, 1 approved with reservations

    Directory of Open Access Journals (Sweden)

    Shamsudheen Karuthedath Vellarikkal

    2016-05-01

    Full Text Available Dystrophic epidermolysis bullosa simplex (DEB is a phenotypically diverse inherited skin fragility disorder. It is majorly manifested by appearance of epidermal bullae upon friction caused either by physical or environmental trauma. The phenotypic manifestations also include appearance of milia, scarring all over the body and nail dystrophy. DEB can be inherited in a recessive or dominant form and the recessive form of DEB (RDEB is more severe. In the present study, we identify a novel p.G2254fs mutation in COL7A1 gene causing a sporadic case of RDEB by whole exome sequencing (WES. Apart from adding a novel frameshift Collagen VII mutation to the repertoire of known mutations reported in the disease, to the best of our knowledge, this is the first report of a genetically characterized case of DEB from India.

  20. A gene for late-onset fundus flavimaculatus with macular dystrophy maps to chromosome 1p13

    Energy Technology Data Exchange (ETDEWEB)

    Gerber, S.; Rozet, J.M.; Bonneau, D.; Souied, E.; Camuzat, A.; Munnich, A.; Kaplan, J. [Hopital des Enfants Malades, Paris (France); Dufier, J.L. [Hopital Laeennec, Paris (France); Amalric, P. [Consultation d`Ophtalmologie, Albi (France); Weissenbach, J. [Genethon, Evry (France)

    1995-02-01

    Fundus flavimaculatus with macular dystrophy is an autosomal recessive disease responsible for a progressive loss of visual acuity in adulthood, with pigmentary changes of the macula, perimacular flecks, and atrophy of the retinal pigmentary epithelium. Since this condition shares several clinical features with Stargardt disease, which has been mapped to chromosome 1p21-p13, we tested the disease for linkage to chromosome 1p. We report the mapping of the disease locus to chromosome 1p13-p21, in the genetic interval defined by loci D1S435 and D1S415, in four multiplex families (maximum lod score 4.79 at recombination fraction 0 for probe AFM217xb2 at locus D1S435). Thus, despite differences in the age at onset, clinical course, and severity, fundus flavimaculatus with macular dystrophy and Stargardt disease are probably allelic disorders. This result supports the view that allelic mutations produce a continuum of macular dystrophies, with onset in early childhood to late adulthood. 16 refs., 3 figs., 1 tab.

  1. Clinical heterogeneity and diagnostic delay of autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy syndrome.

    Science.gov (United States)

    Mazza, Cinzia; Buzi, Fabio; Ortolani, Federica; Vitali, Alberto; Notarangelo, Lucia D; Weber, Giovanna; Bacchetta, Rosa; Soresina, Annarosa; Lougaris, Vassilios; Greggio, Nella A; Taddio, Andrea; Pasic, Srdjan; de Vroede, Monique; Pac, Malgorzata; Kilic, Sara Sebnem; Ozden, Sanal; Rusconi, Roberto; Martino, Silvana; Capalbo, Donatella; Salerno, Mariacarolina; Pignata, Claudio; Radetti, Giorgio; Maggiore, Giuseppe; Plebani, Alessandro; Notarangelo, Luigi D; Badolato, Raffaele

    2011-04-01

    Autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED) is a rare autosomal recessive organ-specific autoimmune disorder that is characterized by a variable combination of (i) chronic mucocutaneous candidiasis, (ii) polyendocrinopathy and/or hepatitis and (iii) dystrophy of the dental enamel and nails. We analyzed the AIRE (autoimmune regulator) gene in subjects who presented any symptom that has been associated with APECED, including candidiasis and autoimmune endocrinopathy. We observed that 83.3% of patients presented at least two of the three typical manifestations of APECED, while the remaining 16.7% of patients showed other signs of the disease. Analysis of the genetic diagnosis of these subjects revealed that a considerable delay occurs in the majority of patients between the appearance of symptoms and the diagnosis. Overall, the mean diagnostic delay in our patients was 10.2 years. These results suggest that molecular analysis of AIRE should be performed in patients with relapsing mucocutaneous candidiasis for early identification of APECED. Copyright © 2010 Elsevier Inc. All rights reserved.

  2. Deficiency of merosin in dystrophic dy mouse homologue of congenital muscular dystrophy

    Energy Technology Data Exchange (ETDEWEB)

    Sunada, Y.; Campbell, K.P. [Univ. of Iowa, Iowa City, IA (United States); Bernier, S.M. [and others

    1994-09-01

    Merosin (laminin M chain) is the predominant laminin isoform in the basal lamina of striated muscle and peripheral nerve and is a native ligand for {alpha}-dystroglycan, a novel laminin receptor. Merosin is linked to the subsarcolemmal actin cytoskeleton via the dystrophin-glycoprotein complex (DGC), which plays an important role for maintenance of normal muscle function. We have mapped the mouse merosin gene, Lamm, to the region containing the dystrophia muscularis (dy) locus on chromosome 10. This suggested the possibility that a mutation in the merosin gene could be responsible for the dy mouse, an animal model for autosomal recessive muscular dystrophy, and prompted us to test this hypothesis. We analyzed the status of merosin expression in dy mouse by immunofluorescence and immunoblotting. In dy mouse skeletal and cardiac muscle and peripheral nerve, merosin was reduced greater than 90% as compared to control mice. However, the expression of laminin B1/B2 chains and collagen type IV was smaller to that in control mice. These findings strongly suggest that merosin deficiency may be the primary defect in the dy mouse. Furthermore, we have identified two patients afflicted with congenital muscular dystrophy with merosin deficiency, providing the basis for future studies of molecular pathogenesis and gene therapy.

  3. TRIM32 ubiquitin E3 ligase, one enzyme for several pathologies: From muscular dystrophy to tumours.

    Science.gov (United States)

    Lazzari, Elisa; Meroni, Germana

    2016-10-01

    TRIM32 is a member of the TRIpartite Motif family characterised by the presence of an N-terminal three-domain-module that includes a RING domain, which confers E3 ubiquitin ligase activity, one or two B-box domains and a Coiled-Coil region that mediates oligomerisation. Several TRIM32 substrates were identified including muscular proteins and proteins involved in cell cycle regulation and cell motility. As ubiquitination is a versatile post-translational modification that can affect target turnover, sub-cellular localisation or activity, it is likely that diverse substrates may be differentially affected by TRIM32-mediated ubiquitination, reflecting its multi-faceted roles in muscle physiology, cancer and immunity. With particular relevance for muscle physiology, mutations in TRIM32 are associated with autosomal recessive Limb-Girdle Muscular Dystrophy 2H, a muscle-wasting disease with variable clinical spectrum ranging from almost asymptomatic to wheelchair-bound patients. In this review, we will focus on the ability of TRIM32 to mark specific substrates for proteasomal degradation discussing how the TRIM32-proteasome axis may (i) be important for muscle homeostasis and for the pathogenesis of muscular dystrophy; and (ii) define either an oncogenic or tumour suppressive role for TRIM32 in the context of different types of cancer. Copyright © 2016 Elsevier Ltd. All rights reserved.

  4. Muscular Dystrophy

    Science.gov (United States)

    ... protein helps muscle cells keep their shape and strength. Without it, muscles break down and a person ... EDMD). The heart muscle may also be affected. Limb-girdle muscular dystrophy ... causes weakness in the lower legs. People with this type of MD might ...

  5. Autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy from the pediatric perspective.

    Science.gov (United States)

    Capalbo, D; Improda, N; Esposito, A; De Martino, L; Barbieri, F; Betterle, C; Pignata, C; Salerno, M

    2013-11-01

    Autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED) is a rare autosomal recessive disease caused by mutations of the AutoImmune REgulator gene. The clinical spectrum of the disease encompasses several autoimmune endocrine and non-endocrine manifestations, which may lead to acute metabolic alterations and eventually life-threatening events. The clinical diagnosis is defined by the presence of at least two components of the classic triad including chronic mucocoutaneous candidiasis (CMC), chronic hypoparathyroidism (CH), Addison's disease (AD). Other common features of the disease are hypergonadotropic hypogonadism, alopecia, vitiligo, autoimmune hepatitis, Type 1 diabetes, gastrointestinal dysfunction. APECED usually begins in childhood. CMC is the first manifestation to appear, usually before the age of 5 yr, followed by CH and then by AD. The clinical phenotype may evolve over several years and many components of the disease may not appear until the 4th or 5th decade of life. The phenotypical expression of the syndrome shows a wide variability even between siblings with the same genotype. In view of this heterogeneity, an early diagnosis of APECED can be very challenging often leading to a considerable diagnostic delay. Therefore, clinicians should be aware that the presence of even a minor component of APECED in children should prompt a careful investigation for other signs and symptoms of the disease, thus allowing an early diagnosis and prevention of severe and life-threatening events. Aim of this review is to focus on clinical presentation, diagnosis and management of the major components of APECED in children particularly focusing on endocrine features of the disease.

  6. Functions of fukutin, a gene responsible for Fukuyama type congenital muscular dystrophy, in neuromuscular system and other somatic organs.

    Science.gov (United States)

    Yamamoto, Tomoko; Shibata, Noriyuki; Saito, Yoshiaki; Osawa, Makiko; Kobayashi, Makio

    2010-06-01

    Fukuyama type congenital muscular dystrophy (FCMD) is an autosomal recessive disease, exhibiting muscular dystrophy, and central nervous system (CNS) and ocular malformations. It is included in alpha-dystroglycanopathy, a group of muscular dystrophy showing reduced glycosylation of alpha-dystroglycan. alpha-Dystroglycan is one of the components of dystrophin-glycoprotein complex linking extracellular and intracellular proteins. The sugar chains of alpha-dystroglycan are receptors for extracellular matrix proteins such as laminin. Fukutin, a gene responsible for FCMD, is presumably related to the glycosylation of alpha-dystroglycan like other causative genes of alpha-dystroglycanopathy. The CNS lesion of FCMD is characterized by cobblestone lissencephaly, associated with decreased glycosylation of alpha-dystroglycan in the glia limitans where the basement membrane is formed. Astrocytes whose endfeet form the glia limitans seem to be greatly involved in the genesis of the CNS lesion. Fukutin is probably necessary for astrocytic function. Other components of the CNS may also need fukutin, such as migration and synaptic function in neurons. However, roles of fukutin in oligodendroglia, microglia, leptomeninges and capillaries are unknown at present. Fukutin is expressed in various somatic organs as well, and appears to work differently between epithelial cells and astrocytes. In the molecular level, since the dystrophin-glycoprotein complex is linked to cell signaling pathways involving c-src and c-jun, fukutin may be able to affect cell proliferation/survival. Fukutin was localized in the nucleus on cancer cell lines. With the consideration that mutations of fukutin give rise to wide spectrum of the clinical phenotype, more unknown functions of fukutin besides the glycosylation of alpha-dystroglycan can be suggested. Trials for novel treatments including gene therapy are in progress in muscular dystrophies. Toward effective therapies with minimal side effects, precise

  7. Limb-girdle muscular dystrophy in Brazilian children: clinical, histological and molecular characterization

    Directory of Open Access Journals (Sweden)

    Marco A. Veloso Albuquerque

    2014-06-01

    Full Text Available Limb-girdle muscular dystrophies (LGMD are a heterogeneous group of genetic muscular dystrophies, involving 16 autosomal recessive subtypes and eight autosomal dominant subtypes. Autosomal recessive dystrophy is far more common than autosomal dominant dystrophy, particularly in children. The clinical course in this group is characterized by progressive proximal weakness, initially in pelvic and after in shoulder-girdle musculature, varying from very mild to severe degree. Significant overlap of clinical phenotypes, with genetic and clinical heterogeneity, constitutes the rule for this group of diseases. Muscle biopsies are useful for histopathologic and immunolabeling studies, and DNA analysis is the gold standard to establish the specific form of muscular dystrophy. Objectives: The aim of this study was to characterize the clinical, histological and molecular aspects in children with LGMD who attend a big public neuromuscular centre in our country to determine the frequency of different forms. Method: Thirty seven patients were classified as LGMD and included in this analysis. The study period extended from 2009-2012. The female to male ratio was 3:1. The age of onset ranged from two to 13 years, mean 7,5 years. Onset in the first decade was seen in 90%. Results: The initial clinical signs included: frequent falls (22 cases, difficulty in climbing stairs (13 cases, walk on tip toes (2 cases, difficulty in rising from the floor (2 cases and difficulty on walking (1 case. The serum CK levels were high in all cases. Among the 37 patients, 15 (40,5% were classified as sarcoglycanopathies (LGMD2C-F, five (13,5% as dysferlinopathy (LGMD2B, five (13,5% as calpainopathy (LGMD2A. Mutations in LMNA gene (LGMD1B, FKRP gene (LGMDI and caveolin gene (LGMD 1C were identified in two (5,5%, two (5,5% and one patient (2,5%, respectively. In seven of 37 cases (19% it was impossible to determine specific diagnosis. Calf hypertrophy, scapular winging and scoliosis

  8. Clinical spectrum of early onset cerebellar ataxia with retained tendon reflexes: an autosomal recessive ataxia not to be missed Espectro clínico da ataxia cerebelar de início precoce com reflexos mantidos: uma ataxia autossômica recessiva para não ser esquecida

    Directory of Open Access Journals (Sweden)

    José Luiz Pedroso

    2013-06-01

    Full Text Available Autosomal recessive cerebellar ataxias are a heterogeneous group of neurological disorders. In 1981, a neurological entity comprised by early onset progressive cerebellar ataxia, dysarthria, pyramidal weakness of the limbs and retained or increased upper limb reflexes and knee jerks was described. This disorder is known as early onset cerebellar ataxia with retained tendon reflexes. In this article, we aimed to call attention for the diagnosis of early onset cerebellar ataxia with retained tendon reflexes as the second most common cause of autosomal recessive cerebellar ataxias, after Friedreich ataxia, and also to perform a clinical spectrum study of this syndrome. In this data, 12 patients from different families met all clinical features for early onset cerebellar ataxia with retained tendon reflexes. Dysarthria and cerebellar atrophy were the most common features in our sample. It is uncertain, however, whether early onset cerebellar ataxia with retained tendon reflexes is a homogeneous disease or a group of phenotypically similar syndromes represented by different genetic entities. Further molecular studies are required to provide definitive answers to the questions that remain regarding early onset cerebellar ataxia with retained tendon reflexes.As ataxias cerebelares autossômicas recessivas são um grupo heterogêneo de doenças neurológicas. Em 1981, foi descrita uma entidade neurológica incluindo ataxia cerebelar progressiva de início precoce, disartria, liberação piramidal e manutenção ou aumento dos reflexos tendíneos nos membros superiores e inferiores. Essa síndrome é conhecida como ataxia cerebelar de início precoce com reflexos mantidos. Neste artigo, o objetivo foi chamar a atenção para o diagnóstico de ataxia cerebelar de início precoce com reflexos mantidos como a segunda causa mais comum de ataxia cerebelar autossômica recessiva, após a ataxia de Friedreich, e também realizar um estudo do espectro cl

  9. Autoimmune Polyendocrinopathy Candidiasis Ectodermal Dystrophy: Insights into Genotype-Phenotype Correlation

    Directory of Open Access Journals (Sweden)

    Donatella Capalbo

    2012-01-01

    Full Text Available Autoimmune polyendocrinopathy candidiasis ectodermal dystrophy (APECED is a rare autosomal recessive disease, caused by mutations of a single gene named autoimmune regulator gene (AIRE which results in a failure of T cell tolerance within the thymus. Chronic mucocutaneous candidiasis, chronic hypoparathyroidism, and Addison’s disease are the hallmarks of the syndrome. APECED is also characterized by several autoimmune endocrine and nonendocrine manifestations, and the phenotype is often complex. Moreover, even though APECED is a monogenic disease, its clinical picture is generally dominated by a wide heterogeneity both in the severity and in the number of components even among siblings with the same AIRE genotype. The variability of its clinical expression implies that diagnosis can be challenging, and a considerable delay often occurs between the appearance of symptoms and the diagnosis. Since a prompt diagnosis is essential to prevent severe complications, clinicians should be aware of all symptoms and signs of suspicion. The aim of this paper is to give an overview on the clinical presentation and diagnostic criteria of APECED and to focus on current knowledge on genotype-phenotype correlation.

  10. Probable high prevalence of limb-girdle muscular dystrophy type 2D in Taiwan.

    Science.gov (United States)

    Liang, Wen-Chen; Chou, Po-Ching; Hung, Chia-Cheng; Su, Yi-Ning; Kan, Tsu-Min; Chen, Wan-Zi; Hayashi, Yukiko K; Nishino, Ichizo; Jong, Yuh-Jyh

    2016-03-15

    Limb-girdle muscular dystrophy type 2D (LGMD2D), an autosomal-recessive inherited LGMD, is caused by the mutations in SGCA. SGCA encodes alpha-sarcoglycan (SG) that forms a heterotetramer with other SGs in the sarcolemma, and comprises part of the dystrophin-glycoprotein complex. The frequency of LGMD2D is variable among different ethnic backgrounds, and so far only a few patients have been reported in Asia. We identified five patients with a novel homozygous mutation of c.101G>T (p.Arg34Leu) in SGCA from a big aboriginal family ethnically consisting of two tribes in Taiwan. Patient 3 is the maternal uncle of patients 1 and 2. All their parents, heterozygous for c.101G>T, denied consanguineous marriages although they were from the same tribe. The heterozygous parents of patients 4 and 5 were from two different tribes, originally residing in different geographic regions in Taiwan. Haplotype analysis showed that all five patients shared the same mutation-associated haplotype, indicating the probability of a founder effect and consanguinity. The results suggest that the carrier rate of c.101G>T in SGCA may be high in Taiwan, especially in the aboriginal population regardless of the tribes. It is important to investigate the prevalence of LGMD2D in Taiwan for early diagnosis and treatment. Copyright © 2016. Published by Elsevier B.V.

  11. Lupus-like panniculitis in a patient with autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED).

    Science.gov (United States)

    Füchtenbusch, M; Vogel, A; Achenbach, P; Gummer, M; Ziegler, A G; Albert, E; Standl, E; Manns, M P

    2003-08-01

    Autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED) is a rare autosomal recessive disorder, characterised by a loss of self-tolerance to endocrine tissues, chronic candidiasis and ectodermal disorders. APECED is associated with mutations of a single gene, designated autoimmune regulator (AIRE). We describe a 31-year-old APECED patient with non-traumatic, cutaneous ulcers on both forearms with features of a lupus-like panniculitis. On admission to the ICU in September 2001, the patient suffered from a ketoacidotic, hyperglycemic coma and adrenal crisis due to an Enterobacter-cloacae sepsis, originating from multiple, necrotising deep cutaneous ulcers. These ulcers spontaneously developed on both forearms, some of which were just emerging, full blown or healing with scars. Histological examination showed signs of a scarring panniculitis and vasculitis. Immunohistochemistry and direct immunofluorescence with characterisation of immunoglobulin and complement-factor binding pattern revealed features of a lupus-like panniculitis. Sequence analysis of all 14 exons of the AIRE gene revealed a R257 X mutation in exon 6 resulting in a nonsense mutation at codon 257 confirming the diagnosis of APECED. Oral treatment with 60 mg/day corticosteroids for two weeks led to complete resolution of all ulcers. In conclusion, mutations in the AIRE gene may provide the genetic background against which additional factors can initiate an autoimmune process. Here, autoimmune panniculitis appears to be an associated feature of the APECED syndrome. Our findings support the use of immunosuppressive therapy for autoimmune disease components of the APECED syndrome.

  12. Becker muscular dystrophy

    Science.gov (United States)

    ... Names Benign pseudohypertrophic muscular dystrophy; Becker's dystrophy Images Superficial anterior muscles References Amato AA. Disorders of the ... the principles of the Health on the Net Foundation (www.hon.ch). The information provided herein should ...

  13. Duchenne muscular dystrophy

    Science.gov (United States)

    ... this page: //medlineplus.gov/ency/article/000705.htm Duchenne muscular dystrophy To use the sharing features on this page, please enable JavaScript. Duchenne muscular dystrophy is an inherited disorder. It involves muscle weakness , ...

  14. Reflex sympathetic dystrophy.

    Science.gov (United States)

    Miller, Ruth L S

    2003-01-01

    Reflex sympathetic dystrophy, also known as complex regional pain syndrome type I, is a multisymptom syndrome usually affecting one or more extremities. It is inadequately understood and, therefore, often frustrating to treat. This article presents a case study of a 23-year career nurse who developed reflex sympathetic dystrophy of the left knee. It also reviews the rationale for reflex sympathetic dystrophy, treatment, and life-care planning for a patient with reflex sympathetic dystrophy.

  15. Autosomal recessive ichthyosis with limb reduction defect: A simple ...

    African Journals Online (AJOL)

    Ichthyosis is a genetically and phenotypically heterogeneous disease that can be isolated and restricted to the skin manifestations or associated with extracutaneous symptoms. One of which is limb reduction defect known as CHILD syndrome; a rare inborn error of metabolism of cholesterol biosynthesis that is usually ...

  16. Autosomal recessive ichthyosis with limb reduction defect: A simple ...

    African Journals Online (AJOL)

    Rabah M. Shawky

    2015-10-01

    Oct 1, 2015 ... Our patient is a 13 year old girl, the first in birth order of first cousin parents, (Fig. 1). She was born at term by cesarean sec- tion of uncomplicated pregnancy. The patient was born in a yellow, tight and shiny sheath that started to desquamate after two to three weeks and replaced by rounded dark scaly ...

  17. Genetics Home Reference: autosomal recessive cerebellar ataxia type 1

    Science.gov (United States)

    ... Canada, but it has since been found in populations worldwide. Related Information What information about a genetic ... are involved in chemical signaling between nerve cells ( neurons ). SYNE1 gene mutations that cause ARCA1 result in ...

  18. Elsahy-Waters Syndrome: Evidence for Autosomal Recessive Inheritance

    NARCIS (Netherlands)

    Castori, Marco; Cascone, Piero; Valiante, Michele; Laino, Luigi; Iannetti, Giorgio; Hennekam, Raoul C. M.; Grammatico, Paola

    2010-01-01

    Elsahy-Waters or branchioskeletogenital syndrome is a rare MCA/MR syndrome characterized by moderate mental retardation, hypospadias and characteristic craniofacial morphology, which includes brachycephaly, facial asymmetry, exotropia, hypertelorism/telechantus, broad nose, concave nasal ridge,

  19. A new variant of autosomal recessive exfoliative ichthyosis.

    Science.gov (United States)

    Zvulunov, A; Cagnano, E; Kachko, L; Shorer, Z; Elbedour, K; Stevens, H

    2002-01-01

    We report unusual congenital ichthyosiform dermatosis in 5 of 12 children in two related families of unaffected, consanguineous Bedouin parents. It appeared shortly after birth as a fine peeling of nonerythematous skin on palms and soles. Gradually it evolved into prominent, well-demarcated areas of peeling skin in moist and traumatized regions. The cutaneous manifestations share features of ichthyosis bullosa of Siemens (IBS) and peeling skin syndrome (PSS). Histologic examination revealed orthokeratosis, a thickened granular cell layer, and spongiosis without epidermolytic hyperkeratosis. On electron microscopy there was prominent intercellular edema and numerous aggregates of keratin filaments in basal keratinocytes. This combination of clinical, histologic, and ultrastructural features has not been previously reported in the heterogeneous group of congenital ichthyoses. We suggest that it represents a new variant of exfoliative ichthyosis.

  20. Two novel mutations in ILDR1 gene cause autosomal recessive ...

    Indian Academy of Sciences (India)

    of Iran's Ministry of Health and Medical Education, writ- ten consent forms were obtained from participants. Physical examination of the affected individuals suggested a nonsyn- dromic HL pattern; no thyroid, ocular or cardiac symptoms were observed. Pure tone audiometry with air and bone con- duction was completed at ...

  1. Two novel mutations in ILDR1 gene cause autosomal recessive ...

    Indian Academy of Sciences (India)

    Social Welfare and Rehabilitation Sciences, for genetic diag- nosis. According to the guidelines of the Ethic Committee .... (b) Pure tone air and bone conduction audiograms from left (blue) and right (red) ears of an affected individual in each family. (c) Sequence chromatographs of the mutated part of the ILDR1 gene in ...

  2. 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...

  3. Subtotal amelia in a child with autosomal recessive hypohidrotic ...

    African Journals Online (AJOL)

    We report an inbred Tunisian family, in which the proband manifested signs of hypohidrotic ectodermal dysplasia, subtotal amelia, scoliosis and left renal agenesis. Two other family members had the full clinical criteria of hypohidrotic ectodermal dysplasia, characterized by deficient sweat glands, hypodontia, hypoplasia of ...

  4. Genetics Home Reference: autosomal recessive congenital stationary night blindness

    Science.gov (United States)

    ... Blindness (Canada) ClinicalTrials.gov (1 link) ClinicalTrials.gov Scientific Articles on PubMed (1 link) PubMed OMIM (6 links) ... SN, Husnain T, Jiao X, MacDonald IM, Riazuddin S, Sieving PA, Katsanis N, Hejtmancik JF. ... article on PubMed Central Zeitz C, Jacobson SG, Hamel ...

  5. Distrofia neuroaxonal infantil: relato de dois casos Infantile neuroaxonal dystrophy: report of two cases

    Directory of Open Access Journals (Sweden)

    ROSANA HERMINIA SCOLA

    1999-12-01

    Full Text Available Descrevemos dois casos de distrofia neuroaxonal infantil ou doença de Seitelberger, que é doença rara, neurodegenerativa, com herança autossômica recessiva. O primeiro caso, sexo masculino, com 8 anos de idade, apresentava atraso do desenvolvimento psicomotor, ataxia e fraqueza muscular. Ao exame físico foi encontrado nistagmo horizontal e vertical com palidez do disco óptico, hipotonia e arreflexia profunda. O segundo caso, sexo masculino, com 1 ano e 6 meses de idade, apresentava atraso do desenvolvimento psicomotor e convulsões. No exame físico, apresentava atrofia de nervo óptico, hipertonia e hiperreflexia. A biópsia de nervo sural de ambos os pacientes mostrou aumento dos axônios, compatível com distrofia neuroaxonal. As características clínicas pleomórficas, bem como os achados neurofisiológicos variáveis tornam difícil firmar o diagnóstico, o qual é ajudado pela confirmação anatomopatológica dos esferóides neuroaxonais.We describe two cases of infantile neuroaxonal dystrophy, which is a rare, neurodegenerative disease, with autosomal recessive inheritance. The first case was an 8 year old boy, with arrested motor and mental development, ataxia and muscle weakness. On physical examination there was horizontal and vertical nystagmus, optic disc atrophy, hypotonia; deep tendon reflexes were absent. The second case was a 1.6 year old boy with arrested motor and mental development, and seizures. On physical examination there was optic atrophy, hypertonia and hyperreflexia. Both patients had on sural nerve biopsy neuronal enlargement, consistent with neuroaxonal dystrophy. Diagnosis without pathological confirmation with neuroaxonal spheroids is very difficult, because the clinical picture is variable and the neurophysiological findings are non specific.

  6. A Rare Form of Retinal Dystrophy Caused by Hypomorphic Nonsense Mutations in CEP290

    Directory of Open Access Journals (Sweden)

    Susanne Roosing

    2017-08-01

    Full Text Available Purpose: To identify the gene defect and to study the clinical characteristics and natural course of disease in a family originally diagnosed with oligocone trichromacy (OT, a rare congenital cone dysfunction syndrome. Methods: Extensive clinical and ophthalmologic assessment was performed on two siblings with OT and long-term follow up data were analyzed. Subsequently, whole exome sequencing (WES and Sanger sequence analysis of CEP290 was performed in the two siblings. Additionally, the identified CEP290 mutations were analyzed in persons with achromatopsia (ACHM (n = 23 and autosomal recessive or isolated cone dystrophy (CD; n = 145. Results: In the first decade of life, the siblings were diagnosed with OT based on low visual acuity, photophobia, nystagmus, and absent cone response on electroretinography , but with normal color discrimination. Over time, the phenotype of OT evolved to a progressive degenerative disease without any CEP290-associated non-ocular features. In both siblings, two nonsense mutations (c.451C>T; p.(Arg151* and c.4723A>T; p.(Lys1575* in CEP290 were found. Previously, p.(Arg151* was demonstrated to induce nonsense-mediated alternative splicing events leading to intact open reading frames of the resulting mRNA products (p.(Leu148_Glu165del and p.(Leu148_Lys172del. mRNA analysis for p.(Lys1575* confirmed a suspected hypomorphic character, as exon 36 skipping was observed in a small fraction of CEP290 mRNA, resulting in a 36 aa in-frame deletion (p.(Glu1569_Trp1604del. No additional cases carrying these variants were identified in the ACHM and CD cohorts. Conclusions: Compound heterozygous hypomorphic mutations in CEP290 may lead to a rare form of cone-dominated retinal dystrophy, a novel phenotype belonging to the CEP290-associated spectrum of ciliopathies. These findings provide insight into the effect of CEP290 mutations on the clinical phenotype.

  7. Type 1 Diabetes in Autoimmune Polyendocrinopathy-Candidiasis-Ectodermal Dystrophy Syndrome (APECED): A "Rare" Manifestation in a "Rare" Disease.

    Science.gov (United States)

    Fierabracci, Alessandra

    2016-07-12

    Type 1 autoimmune polyglandular syndrome (APS1) is a rare autosomal recessive disease, caused by mutations in the autoimmune regulator gene (AIRE); the encoded Aire protein plays an important role in the establishment of the immunological tolerance acting as a transcriptional regulator of the expression of organ-specific antigens within the thymus in perinatal age. While a high prevalence for this rare syndrome is reported in Finland and Scandinavia (Norway), autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy syndrome (APECED) cohorts of patients are also detected in continental Italy and Sardinia, among Iranian Jews, as well as in other countries. The syndrome is diagnosed when patients present at least two out of the three fundamental disorders including chronic mucocutaneous candidiasis, hypoparathyroidism, and Addison's disease. Among the associated conditions insulin-dependent diabetes mellitus (Type 1 diabetes) has been rarely reported in different series of patients and occurring more frequently in Finnish APECED patients. In this review, we analyze the incidence of Type 1 diabetes as a clinical manifestation of APECED in different populations highlighting the peculiar genetic and immunological features of the disease when occurring in the context of this syndrome.

  8. Clinical phenotypes of autoimmune polyendocrinopathycandidiasis-ectodermal dystrophy seen in the Northern Ireland paediatric population over the last 30 years.

    Science.gov (United States)

    Millar, Sarinda; Carson, Dennis

    2012-09-01

    Autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED), also known as autoimmune polyendocrinopathy syndrome type 1, is a rare autosomal recessive disorder with a variable and evolving phenotypic course. It is caused by mutations in the autoimmune regulator (AIRE) gene. APECED syndrome is diagnosed clinically by the presence of 2 from 3 major criteria; chronic mucocutaneous candidasis, primary hypoparathyroidism and primary adrenocortical insufficiency. Many of the patients develop all three before the age of 20 years. There is also a wide spectrum of other associated conditions including endocrine and non endocrine manifestations. This paper reviews the clinical phenotypes seen in the paediatric population of Northern Ireland during the last 30 years detailed from a retrospective review of clinical notes. Eight patients were identified with APECED and all patients were found to be homozygous for the c.964dell3 mutation. A wide clinical variation is apparent within APECED syndrome. Paediatricians should be vigilant of the diagnosis when they encounter any of the features described and consider the future development of associated diseases. In confirmed APECED syndrome, clinical and laboratory investigation is essential to initiate early treatment in the patient and other affected members of the family.

  9. Autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy syndrome (APECED) due to AIRET16M mutation in a consanguineous Greek girl.

    Science.gov (United States)

    Kollios, Konstantinos; Tsolaki, Anastasia; Antachopoulos, Charalampos; Moix, I; Morris, Michael A; Papadopoulou, Maria; Roilides, Emmanuel

    2011-01-01

    Autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy syndrome (APECED) or autoimmune polyendocrine syndrome type 1 (APS-1) is a rare autosomal recessive disease caused by mutations of the AutoImmune REgulator (AIRE) gene, an important mediator of tolerance to self-antigens. It is characterized by two out of three major components: chronic mucocutaneous candidiasis, hypoparathyroidism and Addison's disease. We present an 11-year-old girl suffering from recurrent episodes of mucocutaneous candidiasis and onychomycosis from 1 to 6 years of age, and transient alopecia at the age of 4 years. Hypoparathyroidism and dental enamel hypoplasia were diagnosed at 8 years. Autoantibodies to thyroid and adrenal glands were not detected and all other endocrine functions have remained normal. Genetic analysis revealed that the patient was homozygous for the mutation T16M in exon 1 of the AIRE gene (p.T16M, c.47C>T). This is the first APECED case reported for carrying this mutation in homozygous form. Parents were third cousins and heterozygous carriers of this mutation.

  10. A novel FKRP-related muscular dystrophy founder mutation in South African Afrikaner patients with a phenotype suggestive of a dystrophinopathy

    Directory of Open Access Journals (Sweden)

    M M Mudau

    2017-01-01

    Full Text Available Background. Fukutin-related protein (FKRP muscular dystrophy is an autosomal recessive disorder caused by mutations in the FKRP gene. The condition is often misdiagnosed as a dystrophinopathy. A previously unreported mutation, c.1100T>C in exon 4 of FKRP, had been identified in homozygous form in two white South African (SA Afrikaner patients clinically diagnosed with a dystrophinopathy. Objectives. To investigate whether the c.1100T>C mutation and the common European FKRP mutation c.826C>A are present in other patients of Afrikaner origin with suspected dystrophinopathy, and whether a founder haplotype exists. Methods. The c.1100T>C mutation was initially tested for using an amplification refractory mutation system technique in 45 white SA Afrikaner patients who had tested negative using multiplex ligation probe amplification screening for exonic deletions/duplications in the dystrophin gene. Sequencing analysis was used to confirm the c.1100T>C mutation and screen for the c.826C>A mutation. Two cohorts (each numbering 100 of Afrikaans and other white controls were screened for the c.1100T>C and c.826C>A mutations, respectively. Results. Of the 45 patients, 8 patients (17.8% were homozygous for c.1100T>C, 2 (4.4% were compound heterozygotes for c.1100T>C and c.826C>A, and 1 (2.2% was heterozygous for c.1100T>C with a second unidentified mutation. The c.1100T>C mutation was found in 1/100 controls, but no heterozygotes for the c.826C>A mutation were identified. Linked marker analysis for c.1100T>C showed a common haplotype, suggesting a probable founder mutation in the SA Afrikaner population. Conclusion. FKRP mutations may be relatively common in Afrikaners, and screening should be considered in patients who have a suggestive phenotype and test negative for a dystrophinopathy. This test will be useful for offering diagnostic, carrier and prenatal testing for affected individuals and their families. As FKRP muscular dystrophy is autosomal

  11. Meaning of Muscular Dystrophy

    Science.gov (United States)

    ... Living With MD Print en español Qué significa distrofia muscular What Is Muscular Dystrophy? Muscular dystrophy (say: MUS- ... blood test if a kid has Becker or Duchenne MD. Or the doctor might take a small piece of the muscle and look at it under a microscope to ...

  12. Exome sequencing of index patients with retinal dystrophies as a tool for molecular diagnosis.

    Directory of Open Access Journals (Sweden)

    Marta Corton

    Full Text Available Retinal dystrophies (RD are a group of hereditary diseases that lead to debilitating visual impairment and are usually transmitted as a Mendelian trait. Pathogenic mutations can occur in any of the 100 or more disease genes identified so far, making molecular diagnosis a rather laborious process. In this work we explored the use of whole exome sequencing (WES as a tool for identification of RD mutations, with the aim of assessing its applicability in a diagnostic context.We ascertained 12 Spanish families with seemingly recessive RD. All of the index patients underwent mutational pre-screening by chip-based sequence hybridization and resulted to be negative for known RD mutations. With the exception of one pedigree, to simulate a standard diagnostic scenario we processed by WES only the DNA from the index patient of each family, followed by in silico data analysis. We successfully identified causative mutations in patients from 10 different families, which were later verified by Sanger sequencing and co-segregation analyses. Specifically, we detected pathogenic DNA variants (∼50% novel mutations in the genes RP1, USH2A, CNGB3, NMNAT1, CHM, and ABCA4, responsible for retinitis pigmentosa, Usher syndrome, achromatopsia, Leber congenital amaurosis, choroideremia, or recessive Stargardt/cone-rod dystrophy cases.Despite the absence of genetic information from other family members that could help excluding nonpathogenic DNA variants, we could detect causative mutations in a variety of genes known to represent a wide spectrum of clinical phenotypes in 83% of the patients analyzed. Considering the constant drop in costs for human exome sequencing and the relative simplicity of the analyses made, this technique could represent a valuable tool for molecular diagnostics or genetic research, even in cases for which no genotypes from family members are available.

  13. A novel heterozygous mutation of the AIRE gene in a patient with autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy syndrome (APECED).

    Science.gov (United States)

    Fierabracci, Alessandra; Bizzarri, Carla; Palma, Alessia; Milillo, Annamaria; Bellacchio, Emanuele; Cappa, Marco

    2012-12-10

    Autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy syndrome (APECED) is an autosomal recessive disease due to mutations of the autoimmune regulator (AIRE) gene. Typical manifestations include candidiasis, Addison's disease, and hypoparathyroidism. Type 1 diabetes, alopecia, vitiligo, ectodermal dystrophy, celiac disease and other intestinal dysfunctions, chronic atrophic gastritis, chronic active hepatitis, autoimmune thyroid disorders, pernicious anemia and premature ovarian failure are other rare associated diseases although other conditions have been associated with APECED. What follows is the clinical, endocrinological and molecular data of a female APECED patient coming from Lithuania. The patient was affected by chronic mucocutaneous candidiasis, hypoparathyroidism and pre-clinical Addison's disease. Using direct sequencing of all the 14 exons of the AIRE gene in the patient's DNA, we identified in exon 6 the known mutation c.769 C>T (p.Arg257X) in compound heterozygosity with the newly discovered mutation c.1214delC (p.Pro405fs) in exon 10. The novel mutation results in a frameshift that is predicted to alter the sequence of the protein starting from amino acid 405 as well as to cause its premature truncation, therefore a non-functional Aire protein. A novel mutation has been described in a patient with APECED with classical clinical components, found in compound heterozygosity with the c.769 C>T variation. Expanded epidemiological investigations based on AIRE gene sequencing are necessary to verify the relevancy of the novel mutation to APECED etiopathogenesis in the Lithuanian population and to prove its diagnostic efficacy in association with clinical and immunological findings. Copyright © 2012 Elsevier B.V. All rights reserved.

  14. Low incidence of limb-girdle muscular dystrophy type 2C revealed by a mutation study in Japanese patients clinically diagnosed with DMD.

    Science.gov (United States)

    Okizuka, Yo; Takeshima, Yasuhiro; Itoh, Kyoko; Zhang, Zhujun; Awano, Hiroyuki; Maruyama, Koichi; Kumagai, Toshiyuki; Yagi, Mariko; Matsuo, Masafumi

    2010-03-30

    Limb-girdle muscular dystrophy type 2C (LGMD2C) is an autosomal recessive muscle dystrophy that resembles Duchenne muscular dystrophy (DMD). Although DMD is known to affect one in every 3500 males regardless of race, a widespread founder mutation causing LGMD2C has been described in North Africa. However, the incidence of LGMD2C in Japanese has been unknown because the genetic background remains uncharacterized in many patients clinically diagnosed with DMD. We enrolled 324 patients referred to the Kobe University Hospital with suspected DMD. Mutations in the dystrophin or the SGCG genes were analyzed using not only genomic DNA but also cDNA. In 322 of the 324 patients, responsible mutations in the dystrophin were successfully revealed, confirming DMD diagnosis. The remaining two patients had normal dystrophin expression but absence of gamma-sarcoglycan in skeletal muscle. Mutation analysis of the SGCG gene revealed homozygous deletion of exon 6 in one patient, while the other had a novel single nucleotide insertion in exon 7 in one allele and deletion of exon 6 in the other allele. These mutations created a stop codon that led to a gamma-sarcoglycan deficiency, and we therefore diagnosed these two patients as having LGMD2C. Thus, the relative incidence of LGMD2C among Japanese DMD-like patients can be calculated as 1 in 161 patients suspected to have DMD (2 of 324 patients = 0.6%). Taking into consideration the DMD incidence for the overall population (1/3,500 males), the incidence of LGMD2C can be estimated as 1 per 560,000 or 1.8 per million. To the best of our knowledge, this is the first study to demonstrate a low incidence of LGMD2C in the Japanese population.

  15. Low incidence of limb-girdle muscular dystrophy type 2C revealed by a mutation study in Japanese patients clinically diagnosed with DMD

    Directory of Open Access Journals (Sweden)

    Maruyama Koichi

    2010-03-01

    Full Text Available Abstract Background Limb-girdle muscular dystrophy type 2C (LGMD2C is an autosomal recessive muscle dystrophy that resembles Duchenne muscular dystrophy (DMD. Although DMD is known to affect one in every 3500 males regardless of race, a widespread founder mutation causing LGMD2C has been described in North Africa. However, the incidence of LGMD2C in Japanese has been unknown because the genetic background remains uncharacterized in many patients clinically diagnosed with DMD. Methods We enrolled 324 patients referred to the Kobe University Hospital with suspected DMD. Mutations in the dystrophin or the SGCG genes were analyzed using not only genomic DNA but also cDNA. Results In 322 of the 324 patients, responsible mutations in the dystrophin were successfully revealed, confirming DMD diagnosis. The remaining two patients had normal dystrophin expression but absence of γ-sarcoglycan in skeletal muscle. Mutation analysis of the SGCG gene revealed homozygous deletion of exon 6 in one patient, while the other had a novel single nucleotide insertion in exon 7 in one allele and deletion of exon 6 in the other allele. These mutations created a stop codon that led to a γ-sarcoglycan deficiency, and we therefore diagnosed these two patients as having LGMD2C. Thus, the relative incidence of LGMD2C among Japanese DMD-like patients can be calculated as 1 in 161 patients suspected to have DMD (2 of 324 patients = 0.6%. Taking into consideration the DMD incidence for the overall population (1/3,500 males, the incidence of LGMD2C can be estimated as 1 per 560,000 or 1.8 per million. Conclusions To the best of our knowledge, this is the first study to demonstrate a low incidence of LGMD2C in the Japanese population.

  16. Distrofias retinianas da infância: análise retrospectiva Retinal dystrophies in childhood: retrospective analysis

    Directory of Open Access Journals (Sweden)

    Heloisa Andrade Maestrini

    2004-12-01

    distrofias retinianas da infância são um grupo heterogêneo de doenças que se manifestam por meio de sintomas inespecíficos. Uma análise cuidadosa dos sintomas, o exame oftalmológico completo e os exames complementares, principalmente ERG, testes de visão de cores e campo visual, podem ser úteis em seu diagnóstico.PURPOSE: To describe the clinical features and the results of diagnostic methods in all patients with diagnosis of one of the following retinal dystrophies: Leber congenital amaurosis (LCA, achromatopsia, cone distrophy or cone-rod distrophy, examined at the Low Vision Department of the Federal University of Minas Gerais, in the period of 1992 to 2003. METHODS: Retrospective analysis of charts of 40 patients. Ten had LCA, 17 had achromatopsia, 6 had cone distrophy and 7 had cone-rod distrophy. RESULTS: Visual acuity was extremely low in patients with LCA, ranging from 20/710 to light perception. The mean value for achromatopsia was 20/200, 20/280 for cone distrophy and 20/260 for cone-rod distrophy. High hyperopia was the most common refractional error in LCA patients. Hyperopia was more frequent in cases of achromatopsia and cone distrophy, while in cone-rod distrophy myopia predominated. Fundoscopy was altered in most cases of LCA, cone distrophy and rod-cone distrophy, and normal in most cases of achromatopsia. Oculodigital sign and enophtalmus were found only in LCA patients while photofobia and color vision defects prevailed in other groups. Nistagmus and strabismus were frequent findings in all groups. There was a high incidence of delayed neuro-psycho-motor development in LCA patients. Two of them had also associated genetic syndromes. Patients presented symptoms very early in life in LCA and achromatopsia, while in cone and cone-rod distrophies symptoms appeared later, but never after the age of 10. Consanguinity and positive familial history were strongly associated in all groups. The ERG was extinct in LCA, showed reduced photopic response in

  17. The fatty liver dystrophy (fld) mutation: Developmentally related alterations in hepatic triglyceride metabolism and protein expression

    Energy Technology Data Exchange (ETDEWEB)

    Reue, K.; Rehnmark, S.; Cohen, R.D.; Leete, T.H.; Doolittle, M.H. [West Los Angeles VA Medical Center, CA (United States). Lipid Research Lab.]|[Univ. of California, Los Angeles, CA (United States). Dept. of Medicine; Giometti, C.S.; Mishler, K. [Argonne National Lab., IL (United States); Slavin, B.G. [Univ. of Southern California, Los Angeles, CA (United States)

    1997-07-01

    Fatty liver dystrophy (fld) is an autosomal recessive mutation in mice characterized by hypertriglyceridemia and development of a fatty liver in the early neonatal period. Also associated with the fld phenotype is a tissue-specific deficiency in the expression of lipoprotein lipase and hepatic lipase, as well as elevations in hepatic apolipoprotein A-IV and apolipoprotein C-II mRNA levels. Although these lipid abnormalities resolve at the age of weaning, adult mutant mice exhibit a peripheral neuropathy associated with abnormal myelin formation. The fatty liver in fld/fld neonates is characterized by the accumulation of large triglyceride droplets within the parenchymal cells, and these droplets persist within isolated hepatocytes maintained in culture for several days. To identify the metabolic defect that leads to lipid accumulation, the authors investigated several aspects of cellular triglyceride metabolism. The mutant mice exhibited normal activity of acid triacylglycerol lipase, an enzyme thought to be responsible for hydrolysis of dietary triglycerides in the liver. Metabolic labeling studies performed with oleic acid revealed that free fatty acids accumulate in the liver of 3 day old fld/fld mice, but not in adults. This accumulation in liver was mirrored by elevated free fatty acid levels in plasma of fld/fld neonates, with levels highest in very young mice and returning to normal by the age of one month. Quantitation of fatty acid oxidation in cells isolated from fld/fld neonates revealed that oxidation rate is reduced 60% in hepatocytes and 40% in fibroblasts; hepatocytes from adult fld/fld mice exhibited an oxidation rate similar to those from wild-type mice.

  18. Validation of the finding of hypertrophy of the clava in infantile neuroaxonal dystrophy/PLA2G6 by biometric analysis.

    Science.gov (United States)

    Al-Maawali, A; Yoon, G; Feigenbaum, A S; Halliday, W C; Clarke, J T R; Branson, H M; Banwell, B L; Chitayat, D; Blaser, Susan I

    2016-10-01

    Infantile neuroaxonal dystrophy (INAD), an autosomal recessive neurodegenerative disorder due to PLA2G6 mutation, is classified both as a PLA2G6-associated neurodegeneration (PLAN) disorder and as one of the neurodegeneration with brain iron accumulation (NBIA) disorders. Age of onset and clinical presentation in INAD is variable. Typically described imaging features of cerebellar atrophy, cerebellar cortex bright FLAIR signal, and globus pallidus iron deposition are variable or late findings. We characterize clinical and neuroimaging phenotypes in nine children with confirmed PLA2G6 mutations and show a useful imaging feature, clava hypertrophy, which may aid in earlier identification of patients. Measurements of the clava confirm actual enlargement, rather than apparent enlargement due to volume loss of the other brain stem structures. A retrospective clinical and MRI review was performed. Brain stem measurements were performed and compared with age-matched controls. We identified nine patients, all with novel PLA2G6 gene mutations. MRI, available in eight, showed clava hypertrophy, regardless of age or the absence of other more typically described neuroimaging findings. Brain autopsy in our cohort confirmed prominent spheroid bodies in the clava nuclei. Clava hypertrophy is an important early imaging feature which may aid in indentification of children who would benefit from specific testing for PLA2G6 mutations.

  19. Type 1 Diabetes in Autoimmune Polyendocrinopathy-Candidiasis-Ectodermal Dystrophy Syndrome (APECED): A “Rare” Manifestation in a “Rare” Disease

    Science.gov (United States)

    Fierabracci, Alessandra

    2016-01-01

    Type 1 autoimmune polyglandular syndrome (APS1) is a rare autosomal recessive disease, caused by mutations in the autoimmune regulator gene (AIRE); the encoded Aire protein plays an important role in the establishment of the immunological tolerance acting as a transcriptional regulator of the expression of organ-specific antigens within the thymus in perinatal age. While a high prevalence for this rare syndrome is reported in Finland and Scandinavia (Norway), autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy syndrome (APECED) cohorts of patients are also detected in continental Italy and Sardinia, among Iranian Jews, as well as in other countries. The syndrome is diagnosed when patients present at least two out of the three fundamental disorders including chronic mucocutaneous candidiasis, hypoparathyroidism, and Addison’s disease. Among the associated conditions insulin-dependent diabetes mellitus (Type 1 diabetes) has been rarely reported in different series of patients and occurring more frequently in Finnish APECED patients. In this review, we analyze the incidence of Type 1 diabetes as a clinical manifestation of APECED in different populations highlighting the peculiar genetic and immunological features of the disease when occurring in the context of this syndrome. PMID:27420045

  20. Decreased susceptibility of Candida albicans to azole antifungals: a complication of long-term treatment in autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED) patients.

    Science.gov (United States)

    Rautemaa, Riina; Richardson, Malcolm; Pfaller, Michael; Koukila-Kähkölä, Pirkko; Perheentupa, Jaakko; Saxén, Harri

    2007-10-01

    Autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED, APS1) is an autosomal recessive disease exceptionally common in Finland. Most patients have chronic oral candidiasis from early childhood and this infection has been shown to be carcinogenic. Hence, patients receive repeated treatment and prophylactic courses of antifungals throughout life. In Finland, 92 patients have been diagnosed with APECED and 66 of them are currently alive. Our aim was to study the effect of long-term azole treatment on the candidal colonization of APECED patients and the influence on antifungal susceptibilities. We evaluated the culture reports from 1994 to 2004 of 56 APECED patients followed in Helsinki University Central Hospital. Candida albicans strains of all 11 patients initially reported resistant (n = 27) and 12 patients reported susceptible (n = 16) to fluconazole were re-analysed for their susceptibility to fluconazole. Antifungal usage was analysed up to 30 years back. A total of 162 fungal cultures had been performed. Of these, 75% had been reported positive for Candida and 63% for C. albicans. Eleven patients (31.4%) had been reported to harbour at least once a C. albicans strain resistant to fluconazole. Re-analysis of the stored C. albicans strains originally reported to be resistant to fluconazole revealed a mean MIC of 19.5 mg/L. Multiple courses (>6) of fluconazole annually and low dose prophylaxis are major risk factors for persistent colonization with C. albicans with decreased susceptibility in APECED patients.

  1. Oral and oesophageal squamous cell carcinoma--a complication or component of autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED, APS-I).

    Science.gov (United States)

    Rautemaa, Riina; Hietanen, Jarkko; Niissalo, Sirkku; Pirinen, Sinikka; Perheentupa, Jaakko

    2007-07-01

    Autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED) is an autosomal recessive disease exceptionally common in Finland. It is associated with a limited T lymphocyte defect, an autoimmune response to various tissues, particularly endocrine glands. Most patients have chronic oral candidosis, which has been suggested to be carcinogenic. In Finland 92 patients have been diagnosed with APECED and 66 of them are alive. Our aim was to study the possible association of APECED with oral and oesophageal carcinoma. We evaluated the medical histories of all 92 patients for morbidity, causes of death, and known risk factors for oral cancer. We invited all current patients for a clinical examination of their oral mucosa. Six of the 92 had developed oral or oesophageal squamous cell carcinoma (SCC) by the mean age of 37 (29-44years) and four of them had died from it. The six represent 10% of the patients older than 25years. Five of the six patients had long-lasting oral candidosis. Four of the six had smoked regularly for 15years or more. One patient had been on immunosuppressive therapy for 6years following kidney transplantation when SCC in her mouth occurred. The partial T cell defect of APECED seems to favour the growth of Candida albicans and predispose to chronic mucositis and SCC. Aggressive control of oral candidosis and close follow-up of oral mucosa is a necessity in patients with APECED.

  2. Type 1 Diabetes in Autoimmune Polyendocrinopathy-Candidiasis-Ectodermal Dystrophy Syndrome (APECED: A “Rare” Manifestation in a “Rare” Disease

    Directory of Open Access Journals (Sweden)

    Alessandra Fierabracci

    2016-07-01

    Full Text Available Type 1 autoimmune polyglandular syndrome (APS1 is a rare autosomal recessive disease, caused by mutations in the autoimmune regulator gene (AIRE; the encoded Aire protein plays an important role in the establishment of the immunological tolerance acting as a transcriptional regulator of the expression of organ-specific antigens within the thymus in perinatal age. While a high prevalence for this rare syndrome is reported in Finland and Scandinavia (Norway, autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy syndrome (APECED cohorts of patients are also detected in continental Italy and Sardinia, among Iranian Jews, as well as in other countries. The syndrome is diagnosed when patients present at least two out of the three fundamental disorders including chronic mucocutaneous candidiasis, hypoparathyroidism, and Addison’s disease. Among the associated conditions insulin-dependent diabetes mellitus (Type 1 diabetes has been rarely reported in different series of patients and occurring more frequently in Finnish APECED patients. In this review, we analyze the incidence of Type 1 diabetes as a clinical manifestation of APECED in different populations highlighting the peculiar genetic and immunological features of the disease when occurring in the context of this syndrome.

  3. Facioscapulohumeral muscular dystrophy

    Science.gov (United States)

    ... children. Alternative Names Landouzy-Dejerine muscular dystrophy Images Superficial anterior muscles References Preston DC, Shapiro BE. Proximal, ... the principles of the Health on the Net Foundation (www.hon.ch). The information provided herein should ...

  4. Rhabdomyolysis featuring muscular dystrophies.

    Science.gov (United States)

    Lahoria, Rajat; Milone, Margherita

    2016-02-15

    Rhabdomyolysis is a potentially life threatening condition of various etiology. The association between rhabdomyolysis and muscular dystrophies is under-recognized in clinical practice. To identify muscular dystrophies presenting with rhabdomyolysis at onset or as predominant feature. We retrospectively reviewed clinical and laboratory data of patients with a genetically confirmed muscular dystrophy in whom rhabdomyolysis was the presenting or main clinical manifestation. Thirteen unrelated patients (males=6; females=7) were identified. Median age at time of rhabdomyolysis was 18 years (range, 2-47) and median duration between the first episode of rhabdomyolysis and molecular diagnosis was 2 years. Fukutin-related protein (FKRP) muscular dystrophy (n=6) was the most common diagnosis, followed by anoctaminopathy-5 (n=3), calpainopathy-3 (n=2) and dystrophinopathy (n=2). Four patients experienced recurrent rhabdomyolysis. Eight patients were asymptomatic and 3 reported myalgia and exercise intolerance prior to the rhabdomyolysis. Exercise (n=6) and fever (n=4) were common triggers; rhabdomyolysis was unprovoked in 3 patients. Twelve patients required hospitalization. Baseline CK levels were elevated in all patients (median 1200 IU/L; range, 600-3600). Muscular dystrophies can present with rhabdomyolysis; FKRP mutations are particularly frequent in causing such complication. A persistently elevated CK level in patients with rhabdomyolysis warrants consideration for underlying muscular dystrophy. Copyright © 2015 Elsevier B.V. All rights reserved.

  5. How Is Muscular Dystrophy Diagnosed?

    Science.gov (United States)

    ... Research Information Find a Study Resources and Publications Osteogenesis Imperfecta (OI) Condition Information NICHD Research Information Find ... Print How is muscular dystrophy diagnosed? The first step in diagnosing muscular dystrophy (MD) is a visit ...

  6. Cardiovascular magnetic resonance of cardiomyopathy in limb girdle muscular dystrophy 2B and 2I

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    Habib Philip

    2011-08-01

    Full Text Available Abstract Background Limb girdle muscular dystrophies (LGMD are inclusive of 7 autosomal dominant and 14 autosomal recessive disorders featuring progressive muscle weakness and atrophy. Studies of cardiac function have not yet been well-defined in deficiencies of dysferlin (LGMD2B and fukutin related protein (LGMD2I. In this study of patients with these two forms of limb girdle muscular dystrophy, cardiovascular magnetic resonance (CMR was used to more specifically define markers of cardiomyopathy including systolic dysfunction, myocardial fibrosis, and diastolic dysfunction. Methods Consecutive patients with genetically-proven LGMD types 2I (n = 7 and 2B (n = 9 and 8 control subjects were enrolled. All subjects underwent cardiac magnetic resonance (CMR on a standard 1.5 Tesla clinical scanner with cine imaging for left ventricular (LV volume and ejection fraction (EF measurement, vector velocity analysis of cine data to calculate myocardial strain, and late post-gadolinium enhancement imaging (LGE to assess for myocardial fibrosis. Results Sixteen LGMD patients (7 LGMD2I, 9 LGMD2B, and 8 control subjects completed CMR. All but one patient had normal LV size and systolic function; one (type 2I had severe dilated cardiomyopathy. Of 15 LGMD patients with normal systolic function, LGE imaging revealed focal myocardial fibrosis in 7 (47%. Peak systolic circumferential strain rates were similar in patients vs. controls: εendo was -23.8 ± 8.5vs. -23.9 ± 4.2%, εepi was -11.5 ± 1.7% vs. -10.1 ± 4.2% (p = NS for all. Five of 7 LGE-positive patients had grade I diastolic dysfunction [2I (n = 2, 2B (n = 3]. that was not present in any LGE-negative patients or controls. Conclusions LGMD2I and LGMD2B generally result in mild structural and functional cardiac abnormalities, though severe dilated cardiomyopathy may occur. Long-term studies are warranted to evaluate the prognostic significance of subclinical fibrosis detected by CMR in these patients.

  7. Merosin-positive congenital muscular dystrophy: neuroimaging findings Distrofia muscular congênita merosina-positiva: achados de neuroimagem

    Directory of Open Access Journals (Sweden)

    André Palma da Cunha Matta

    2007-03-01

    Full Text Available Congenital muscle dystrophy (CMD is a heterogeneous group of autosomal recessive myopathies. It is known that CMD may affect the central nervous system (CNS. Some authors have shown that merosin-negative CMD patients may have encephalic metabolic disturbances. In order to study metabolic changes within the brain, the authors performed a magnetic resonance spectroscopy (MRS study in a 1-year-old girl with merosin-positive CMD (MP-CMD. MRS of brain demonstrated that NAA/Cr ratio was decreased (1.52, while Cho/Cr ratio was increased (1.78. These findings suggest that metabolic changes in CNS can also be found in patients with MP-CMD.A distrofia muscular congênita (DMC é um grupo heterogêneo de miopatias autossômicas recessivas que também podem afetar o sistema nervoso central (SNC. Alguns autores mostraram previamente que pacientes com DMC por deficiência da merosina podem apresentar alterações metabólicas no encéfalo. Com o objetivo de estudar as possíveis alterações metabólicas no SNC, os autores realizaram um estudo por ressonância magnética com espectroscopia em uma paciente de 1 ano com DMC sem deficiência da merosina. A razão NAA/Cr estava reduzida (1,52, enquanto que a razão Cho/Cr estava aumentada (1,78. Estes achados sugerem que alterações metabólicas no SNC também podem ser encontradas em pacientes com DMC merosina-positiva.

  8. Natural disease history of mouse models for limb girdle muscular dystrophy types 2D and 2F

    Science.gov (United States)

    Putker, K.; Tanganyika-de Winter, C. L.; Boertje-van der Meulen, J. W.; van Vliet, L.; Overzier, M.; Plomp, J. J.; Aartsma-Rus, A.; van Putten, M.

    2017-01-01

    Limb-girdle muscular dystrophy types 2D and 2F (LGMD 2D and 2F) are autosomal recessive disorders caused by mutations in the alpha- and delta sarcoglycan genes, respectively, leading to severe muscle weakness and degeneration. The cause of the disease has been well characterized and a number of animal models are available for pre-clinical studies to test potential therapeutic interventions. To facilitate transition from drug discovery to clinical trials, standardized procedures and natural disease history data were collected for these mouse models. Implementing the TREAD-NMD standardized operating procedures, we here subjected LGMD2D (SGCA-null), LGMD2F (SGCD-null) and wild type (C57BL/6J) mice to five functional tests from the age of 4 to 32 weeks. To assess whether the functional test regime interfered with disease pathology, sedentary groups were taken along. Muscle physiology testing of tibialis anterior muscle was performed at the age of 34 weeks. Muscle histopathology and gene expression was analysed in skeletal muscles and heart. Muscle histopathology and gene expression was analysed in skeletal muscles and heart. Mice successfully accomplished the functional tests, which did not interfere with disease pathology. Muscle function of SGCA- and SGCD-null mice was impaired and declined over time. Interestingly, female SGCD-null mice outperformed males in the two and four limb hanging tests, which proved the most suitable non-invasive tests to assess muscle function. Muscle physiology testing of tibialis anterior muscle revealed lower specific force and higher susceptibility to eccentric-induced damage in LGMD mice. Analyzing muscle histopathology and gene expression, we identified the diaphragm as the most affected muscle in LGMD strains. Cardiac fibrosis was found in SGCD-null mice, being more severe in males than in females. Our study offers a comprehensive natural history dataset which will be useful to design standardized tests and future pre

  9. Reflex sympathetic dystrophy in hemiplegia.

    Science.gov (United States)

    Gokkaya, Nilufer Kutay Ordu; Aras, Meltem; Yesiltepe, Elcin; Koseoglu, Fusun

    2006-12-01

    There is a high incidence of reflex sympathetic dystrophy of the upper limbs in patients with hemiplegia, and its painful and functional consequences present a problem to specialists in physical medicine and rehabilitation. This study was designed to assess the role of several factors in the occurrence of reflex sympathetic dystrophy in patients with hemiplegia. Ninety-five consecutive stroke patients (63 male and 32 female, mean age 59+/-12 years) admitted to our hospital were evaluated. Of the study group, 29 patients (30.5%) were found to develop reflex sympathetic dystrophy. There were no significant differences between the hemiplegic patient groups with or without reflex sympathetic dystrophy regarding age, gender, etiology, side of involvement, disease duration and the presence of comorbidities. The recovery stages of hemiplegia, as shown by Brunnstrom functional classification, were significantly different between the two groups; patients in lower recovery stages tended to develop reflex sympathetic dystrophy more frequently (Preflex sympathetic dystrophy. Glenohumeral subluxation was present in 37 patients (38.9%) in our study group and the presence of this complication was related to the occurrence of reflex sympathetic dystrophy. The presence of glenohumeral subluxation was significantly higher in patients with reflex sympathetic dystrophy (21/29, 72.4%) when compared to the patients without reflex sympathetic dystrophy (16/66, 24.2%) (Preflex sympathetic dystrophy. These results suggest that lower recovery stages, reduced tonus and glenohumeral subluxation significantly contribute to the occurrence of reflex sympathetic dystrophy in the hemiplegic patient. We believe that preventive and treatment measures should consider these factors as they seem to have in common a higher risk of traumatizing the paralyzed upper limb and causing reflex sympathetic dystrophy.

  10. Therapeutic advances in muscular dystrophy

    OpenAIRE

    Leung, Doris G; Wagner, Kathryn R

    2013-01-01

    The muscular dystrophies comprise a heterogeneous group of genetic disorders that produce progressive skeletal muscle weakness and wasting. There has been rapid growth and change in our understanding of these disorders in recent years, and advances in basic science are being translated into increasing numbers of clinical trials. This review will discuss therapeutic developments in 3 of the most common forms of muscular dystrophy: Duchenne muscular dystrophy, facioscapulohumeral muscular dystr...

  11. Duchenne muscular dystrophy.

    Science.gov (United States)

    Yiu, Eppie M; Kornberg, Andrew J

    2015-08-01

    Duchenne muscular dystrophy, an X-linked disorder, has an incidence of one in 5000 boys and presents in early childhood with proximal muscle weakness. Untreated boys become wheelchair bound by the age of 12 years and die of cardiorespiratory complications in their late teens to early 20s. The use of corticosteroids, non-invasive respiratory support, and active surveillance and management of associated complications have improved ambulation, function, quality of life and life expectancy. The clinical features, investigations and management of Duchenne muscular dystrophy are reviewed, as well as the latest in some of the novel therapies. © 2015 The Authors. Journal of Paediatrics and Child Health © 2015 Paediatrics and Child Health Division (Royal Australasian College of Physicians).

  12. Epidermolysis bullosa simplex associated with muscular dystrophy: phenotype-genotype correlations and review of the literature.

    Science.gov (United States)

    Shimizu, H; Takizawa, Y; Pulkkinen, L; Murata, S; Kawai, M; Hachisuka, H; Udono, M; Uitto, J; Nishikawa, T

    1999-12-01

    Epidermolysis bullosa simplex associated with muscular dystrophy (EBS-MD; OMIM# 226670) is an autosomal recessive disorder caused by genetic defects in the plectin gene. Because EBS-MD is relatively rare, and gene defects have been elucidated only in a limited number of patients, the precise phenotype-genotype correlations have not yet been fully elucidated. The purpose of this study was to define clinical features of EBS-MD and to clarify its phenotype-genotype correlations. Clinical, ultrastructural, immunohistochemical, and molecular features of 4 unrelated Japanese patients with EBS-MD were recorded. In addition, 6 cases with defined plectin gene mutations reported in the literature were reviewed. In skin of the EBS-MD patients, the blister formation always occurs just above the hemidesmosomes, and expression of plectin is absent or markedly reduced in all cases examined. All 10 patients, including 6 cases in the literature, showed generalized blistering at birth or soon thereafter, and experienced nail deformities. In addition, decayed teeth (5 cases), urethral strictures (3), mild palmoplantar hyperkeratosis (2), infantile respiratory complications (2), alopecia (1), and laryngeal webs (1) were present. All 8 patients who were older than 9 years demonstrated considerable muscle weakness, and the majority of them ended up being wheelchair bound. Among the 10 patients, 7 were products of consanguineous marriage, 9 have premature termination codon (PTC) mutations in both alleles of the plectin gene, and 7 cases were homozygous for the mutation. One patient who is homozygous for a 2719del9 in-frame deletion mutation that resulted in elimination of 3 amino acids, QEA, could still walk at the age of 46 and showed milder clinical severity. EBS-MD reveals clinical features not only characteristic of EBS and MD, but also other manifestations including urethral, dental, and respiratory complications. The majority of patients are products of consanguineous marriage and

  13. Immunohistochemical alterations of dystrophin in congenital muscular dystrophy Alterações imuno-hístoquímicas da distrofina na distrofia muscular congênita

    Directory of Open Access Journals (Sweden)

    Lineu Cesar Werneck

    1995-09-01

    Full Text Available The dystrophin distribution in the plasma muscle membrane using immunohystochemistry was studied in 22 children with congenital muscular dystrophy. The dystrophin was detected by immunofluorescence in muscle biopsy through a polyclonal antibody. All the cases had patchy interruptions of the fluorescence in the plasma membrane. A large patchy interruption of the sarcolemma was found in 17 cases, small interruption in 12, and a combination of large and small patchy discontinuity in 7. Small gaps around the fiber like a rosary were found in 15 cases. The frequency of these abnormalities ranged cases from: all fibers in 5 cases, frequent in 8, occasional in 5, and rare in 4. Five cases had total absence of immunofluorescence. These results suggest that the dystrophin expression is abnormal in this group of children and that this type of abnormalities can not be differentiated from early Becker muscular dystrophy nor childhood autosomal recessive muscular dystrophy through immunohystochemistry alone.Foi estudada a distribuição da distrofina na membrana plasmática das fibras musculares em 22 crianças com distrofia muscular congênita, através de técnicas de imuno-histoquímica. A distrofina foi identificada nas biópsias musculares processadas a fresco, por técnicas de imunofluorescência utilizando anticorpos policlonais. Todos os casos tinham interrupções da imunofluorescência na membrana plasmática. Em 17 elas eram grandes, em 12 eram pequenas e em 7 eram de ambos os tipos. Fibras com interrupções pequenas e constantes, como um rosário, foram vistas em 15 casos. Essas anormalidades estavam presentes em todas as fibras em 5 casos, eram frequentes em 8, ocasionais em 5 e raras em 4. Cinco casos mostraram fibras sem distrofina. Esses dados sugerem que a expressão da distrofina é anormal nesse grupo de crianças. Essas anormalidades podem também ser encontradas em casos precoces de distrofia muscular de Becker e distrofia autoss

  14. NMR structure of the first PHD finger of autoimmune regulator protein (AIRE1). Insights into autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED) disease.

    Science.gov (United States)

    Bottomley, Matthew James; Stier, Gunter; Pennacchini, Danilo; Legube, Gaelle; Simon, Bernd; Akhtar, Asifa; Sattler, Michael; Musco, Giovanna

    2005-03-25

    Mutations in the autoimmune regulator protein AIRE1 cause a monogenic autosomal recessively inherited disease: autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED). AIRE1 is a multidomain protein that harbors two plant homeodomain (PHD)-type zinc fingers. The first PHD finger of AIRE1 is a mutational hot spot, to which several pathological point mutations have been mapped. Using heteronuclear NMR spectroscopy, we determined the solution structure of the first PHD finger of AIRE1 (AIRE1-PHD1), and characterized the peptide backbone mobility of the domain. We performed a conformational analysis of pathological AIRE1-PHD1 mutants that allowed us to rationalize the structural impact of APECED-causing mutations and to identify an interaction site with putative protein ligands of the AIRE1-PHD1 domain. The structure unequivocally exhibits the canonical PHD finger fold, with a highly conserved tryptophan buried inside the structure. The PHD finger is stabilized by two zinc ions coordinated in an interleaved (cross-brace) scheme. This zinc coordination resembles RING finger domains, which can function as E3 ligases in the ubiquitination pathway. Based on this fold similarity, it has been suggested that PHD fingers might also function as E3 ligases, although this hypothesis is controversial. At variance to a previous report, we could not find any evidence that AIRE1-PHD1 has an intrinsic E3 ubiquitin ligase activity, nor detect any direct interaction between AIRE1-PHD1 and its putative cognate E2. Consistently, we show that the AIRE1-PHD1 structure is clearly distinct from the RING finger fold. Our results point to a function of the AIRE1-PHD1 domain in protein-protein interactions, which is impaired in some APECED mutations.

  15. Reflex Sympathetic Dystrophy in Children

    Directory of Open Access Journals (Sweden)

    Adnan Ayvaz

    2013-10-01

    Full Text Available    Reflex sympathetic dystrophy (chronic regional pain syndrome isn’t frequently encountered in practical pediatrics and childhood. Reflex sympathetic dystrophy syndrome (RSD is a disorder characterized by widespread localized pain, often along with swelling, discoloration, trophic changes and autonomic abnormalities such as vasomotor disorders. Its etio-pathogenesis hasn’t been completely determined.The disease can form in an area innerved by a partially damaged nerve and usually follows minor injury or trauma. In this paper, two girl patients with reflex sympathetic dystrophy are discussed along with the laboratory and clinic finding by accompaniment the literature as it is rarely seen in childhood.

  16. Causes and consequences of inherited cone disorders

    NARCIS (Netherlands)

    Roosing, S.; Thiadens, A.A.H.J.; Hoyng, C.B.; Klaver, C.C.; Hollander, A.I. den; Cremers, F.P.M.

    2014-01-01

    Hereditary cone disorders (CDs) are characterized by defects of the cone photoreceptors or retinal pigment epithelium underlying the macula, and include achromatopsia (ACHM), cone dystrophy (COD), cone-rod dystrophy (CRD), color vision impairment, Stargardt disease (STGD) and other maculopathies.

  17. Genetics Home Reference: myotonic dystrophy

    Science.gov (United States)

    ... function of other genes. Similar changes in the structure of the DMPK and CNBP genes cause the two forms of myotonic dystrophy . In each case, a segment of DNA is abnormally repeated many times, forming an unstable ...

  18. Duchenne and Becker Muscular Dystrophies

    Science.gov (United States)

    ... dystrophy, we were devastated. Immediately, our hopes and dreams for Mike — playing sports, gradu- ating high school, ... you strength. Never give up your hopes and dreams. My son has graduated from high school, has ...

  19. Clinical polymorphism of stargardt disease in a large consanguineous tunisian family; implications for nosology.

    Science.gov (United States)

    El Matri, Leila; Ouechtati, Farah; Chebil, Ahmed; Largueche, Leila; Abdelhak, Sonia

    2013-10-01

    To describe the polymorphic expression of Stargardt disease in a large Tunisian family with clinical intra- and interfamilial variation of the condition. Twelve subjects from two related families with autosomal recessive Stargardt disease were enrolled. A detailed clinical examination including visual acuity and visual field measurement, fundus photography, fluorescein angiography, electroretinography (ERG) and color vision testing was performed for all subjects. The youngest child from family A manifested typical Stargardt disease while her two brothers presented with Stargardt disease-fundus flavimaculatus (STGD-FFM) and her two sisters demonstrated a peculiar phenotype overlapping Stargardt disease and cone-rod dystrophy; their phenotypic manifestation corresponded well with ERG groups I, II and III, respectively. This uncommon occurrence of an age-related decline in ERG amplitude and worsening of fundus changes is suggestive of a grading pattern in Stargardt disease. Their two cousins in family B, displayed the STGD-FFM phenotype. Despite clinically similar STGD-FFM patterns in both families, age of onset and progression of the phenotype in family B differed from family A. This is the first report on phenotypic variation of Stargardt disease in a large Tunisian family. Regarding phenotype and severity of visual symptoms, family A demonstrated Stargardt disease at various stages of progression. In addition, STGD-FFM appeared to be an independent clinical entity in family B. These findings imply that further parameters are required to classify Stargardt's disease.

  20. Clinical Polymorphism of Stargardt Disease in a Large Consanguineous Tunisian Family; Implications for Nosology

    Directory of Open Access Journals (Sweden)

    Leila El Matri

    2013-01-01

    Full Text Available Purpose: To describe the polymorphic expression of Stargardt disease in a large Tunisian family with clinical intra- and interfamilial variation of the condition. Methods: Twelve subjects from two related families with autosomal recessive Stargardt disease were enrolled. A detailed clinical examination including visual acuity and visual field measurement, fundus photography, fluorescein angiography, electroretinography (ERG and color vision testing was performed for all subjects. Results: The youngest child from family A manifested typical Stargardt disease while her two brothers presented with Stargardt disease-fundus flavimaculatus (STGD-FFM and her two sisters demonstrated a peculiar phenotype overlapping Stargardt disease and cone-rod dystrophy; their phenotypic manifestation corresponded well with ERG groups I, II and III, respectively. This uncommon occurrence of an age-related decline in ERG amplitude and worsening of fundus changes is suggestive of a grading pattern in Stargardt disease. Their two cousins in family B, displayed the STGD-FFM phenotype. Despite clinically similar STGD-FFM patterns in both families, age of onset and progression of the phenotype in family B differed from family A. Conclusion: This is the first report on phenotypic variation of Stargardt disease in a large Tunisian family. Regarding phenotype and severity of visual symptoms, family A demonstrated Stargardt disease at various stages of progression. In addition, STGDFFM appeared to be an independent clinical entity in family B. These findings imply that further parameters are required to classify Stargardt′s disease.

  1. Duchenne muscular dystrophy carriers

    International Nuclear Information System (INIS)

    Matsumura, K.; Nakano, I.

    1989-01-01

    By means of magnetic resonance imaging (MRI), the proton spin-lattice relaxation times (T1 values) of the skeletal muscles were measured in Duchenne muscular dystrophy (DMD) carriers and normal controls. The bound water fraction (BWF) was calculated from the T1 values obtained, according to the fast proton diffusion model. In the DMD carriers, T1 values of the gluteus maximus and quadriceps femoris muscles were significantly higher, and BWFs of these muscles were significantly lower than in normal control. Degenerative muscular changes accompanied by interstitial edema were presumed responsible for this abnormality. No correlation was observed between the muscle T1 and serum creatine kinase values. The present study showed that MRI could be a useful method for studying the dynamic state of water in both normal and pathological skeletal muscles. Its possible utility for DMD carrier detection was discussed briefly. (orig.)

  2. POMT2 mutations cause alpha-dystroglycan hypoglycosylation and Walker-Warburg syndrome.

    NARCIS (Netherlands)

    Reeuwijk, J. van; Janssen, M.; Elzen, C. van der; Beltran Valero de Bernabe, D.; Sabatelli, P.; Merlini, L.; Boon, M.; Scheffer, H.; Brockington, M.; Muntoni, F.; Huynen, M.A.; Verrips, A.; Walsh, C.A.; Barth, P.G.; Brunner, H.G.; Bokhoven, J.H.L.M. van

    2005-01-01

    BACKGROUND: Walker-Warburg syndrome (WWS) is an autosomal recessive condition characterised by congenital muscular dystrophy, structural brain defects, and eye malformations. Typical brain abnormalities are hydrocephalus, lissencephaly, agenesis of the corpus callosum, fusion of the hemispheres,

  3. POMT2 mutations cause alpha-dystroglycan hypoglycosylation and Walker-Warburg syndrome

    NARCIS (Netherlands)

    van Reeuwijk, J.; Janssen, M.; van den Elzen, C.; Beltran-Valero de Bernabé, D.; Sabatelli, P.; Merlini, L.; Boon, M.; Scheffer, H.; Brockington, M.; Muntoni, F.; Huynen, M. A.; Verrips, A.; Walsh, C. A.; Barth, P. G.; Brunner, H. G.; van Bokhoven, H.

    2005-01-01

    Walker-Warburg syndrome (WWS) is an autosomal recessive condition characterised by congenital muscular dystrophy, structural brain defects, and eye malformations. Typical brain abnormalities are hydrocephalus, lissencephaly, agenesis of the corpus callosum, fusion of the hemispheres, cerebellar

  4. POMT2 mutations cause alpha-dystroglycan hypoglycosylation and Walker-Warburg syndrome

    NARCIS (Netherlands)

    van Reeuwijk, J; Janssen, M; van den Elzen, C; de Bernabe, DBV; Sabatelli, P; Merlini, L; Boon, M; Scheffer, H; Brockington, M; Muntoni, F; Huynen, MA; Verrips, A; Walsh, CA; Barth, PG; Brunner, HG; van Bokhoven, H

    2005-01-01

    Background: Walker-Warburg syndrome (WWS) is an autosomal recessive condition characterised by congenital muscular dystrophy, structural brain defects, and eye malformations. Typical brain abnormalities are hydrocephalus, lissencephaly, agenesis of the corpus callosum, fusion of the hemispheres,

  5. Physiology of respiratory disturbances in muscular dystrophies

    Directory of Open Access Journals (Sweden)

    Antonella Lo Mauro

    2016-12-01

    To understand the mechanisms leading to respiratory disturbances in patients with muscular dystrophy. To understand the impact of respiratory disturbances in patients with muscular dystrophy. To provide a brief description of the main forms of muscular dystrophy with their respiratory implications.

  6. [Reflex sympathetic dystrophy].

    Science.gov (United States)

    Oliveira, Marta; Manuela, Manuela; Cantinho, Guilhermina

    2011-01-01

    Reflex Sympathetic Dystrophy is rare in pediatrics. It is a complex regional pain syndrome, of unknown etiology, usually post-traumatic, characterized by dysfunctions of the musculoskeletal, vascular and skin systems: severe persistent pain of a limb, sensory and vascular alterations, associated disability and psychosocial dysfunction. The diagnosis is based in high clinical suspection. In children and adolescents there are aspects that are different from the adult ones. Excessive tests may result in worsening of the clinical symptoms. Bone scintigraphy can help. Pain treatment is difficult, not specific. Physical therapies and relaxation technics give some relief. Depression must be treated. This syndrome includes fibromyalgia and complex regional pain syndrome type I. We present a clinical report of an adolescent girl, referred for pain, cold temperature, pallor and functional disability of an inferior limb, all signals disclosed by a minor trauma. She had been diagnosed depression the year before. The bone scintigraphy was a decisive test. The treatment with gabapentin, C vitamin, physiotherapy and pshycotherapy has been effective.

  7. CT findings of muscular dystrophy

    International Nuclear Information System (INIS)

    Saitoh, Hiroshi

    1991-01-01

    CT scans of muscles in patients with limb girdle type (LG), myotonic type (MYD) and Duchenne type (DMD) dystrophies were obtained at five different body levels: the neck, L3 vertebral body, pelvic girdle, thigh and lower leg. CT numbers, cross sectional areas (CSA) and %CSA of muscle or fat were evaluated in each muscle. The characteristic CT patterns for each type of muscular dystrophy were obtained. Compared with DMD, the gracilis and soleus were more severely damaged in LG and the biceps femoris remained relatively preserved among the hamstrings. In addition, the multifidus of the neck and sternocleidomastoid also were more severely damaged in MYD. This study suggests that CT scan will be useful in the differential diagnosis of these types of muscular dystrophy as well as in planning appropriate rehabilitation and detecting damaged muscles. (author)

  8. Dysautonomia, fibromyalgia and reflex dystrophy

    Science.gov (United States)

    Eisinger, Jean

    2007-01-01

    Autonomic nervous system dysfunction observed in fibromyalgia, characterized without exception by a sympathetic hyperactivity and hyporeactivity, has been reported. However, several studies demonstrated reduced levels of norepinephrine and neuropeptide Y at rest and after tilt table in some patients, which was improved by beta-stimulating agents. These findings support heterogeneity in fibromyalgia-associated dysautonomia. Fibromyalgia could be a generalized sympathetic dystrophy since both conditions are activated by trauma and partly linked to sympathetic mechanisms. Yet they differ on several points: hormonal and neurochemical abnormalities are observed in fibromyalgia whereas activation by peripheral trauma and hyperosteolysis are observed in reflex sympathetic dystrophy. PMID:17626612

  9. Corneal stromal dystrophies: a clinical pathologic study

    Directory of Open Access Journals (Sweden)

    Elvira Barbosa Abreu

    2012-12-01

    Full Text Available INTRODUCTION: Corneal dystrophy is defined as bilateral and symmetric primary corneal disease, without previous associated ocular inflammation. Corneal dystrophies are classified according to the involved corneal layer in superficial, stromal, and posterior dystrophy. Incidence of each dystrophy varies according to the geographic region studied. PURPOSE: To evaluate the prevalence of stromal corneal dystrophies among corneal buttons specimens obtained by penetrating keratoplasty (PK in an ocular pathology laboratory and to correlate the diagnosis with patient age and gender. METHODS: Corneal button cases of penetrating keratoplasty from January-1996 to May-2009 were retrieved from the archives of The Henry C. Witelson Ophthalmic Pathology Laboratory and Registry, Montreal, Canada. The cases with histopathological diagnosis of stromal corneal dystrophies were stained with special stains (Peroxid acid Schiff, Masson trichrome, Congo red analyzed under polarized light, and alcian blue for classification and correlated with epidemiological information (age at time of PK and gender from patients' file. RESULTS: 1,300 corneal buttons cases with clinical diagnose of corneal dystrophy were retrieved. Stromal corneal dystrophy was found in 40 (3.1% cases. Lattice corneal dystrophy was the most prevalent with 26 cases (65%. Nineteen were female (73.07% and the PK was performed at average age of 59.3 years old. Combined corneal dystrophy was found in 8 (20% cases, 5 (62.5% of them were female and the average age of the penetrating keratoplasty was 54.8 years old. Granular corneal dystrophy was represented by 5 (12.5% cases, and 2 (40% of them were female. Penetrating keratoplasty was performed at average age of 39.5 years old in granular corneal dystrophy cases. Macular corneal dystrophy was present in only 1 (2.5% case, in a 36 years old female. CONCLUSION: Systematic histopathological approach and evaluation, including special stains in all stromal

  10. Macrocephaly, epilepsy, autism, dysmorphic features, and mental retardation in two sisters: a new autosomal recessive syndrome?

    OpenAIRE

    Orstavik, K H; Strømme, P; Ek, J; Torvik, A; Skjeldal, O H

    1997-01-01

    We report two sisters with macrocephaly, epilepsy, and severe mental retardation. The first child was a 14 year old girl born at term after a normal pregnancy, with birth weight 3600 g and occipitofrontal circumference (OFC) 36 cm (75th centile). Her head size increased markedly during the first six months of life, and was later stable at 2-3 cm above the 97.5th centile. Her development was characterised by psychomotor delay, epilepsy, and autistic features. Her face appeared mildly dysmorphi...

  11. Completeness of catalogs of autosomal dominant, autosomal recessive, and X-linked phenotypes.

    Science.gov (United States)

    ten Kate, L P

    1992-06-01

    The completeness of McKusick's catalogs of Mendelian Inheritance in Man (MIM) as to the number of phenotypes included was studied by estimating the degree of concordance with the Dutch Gene Catalog of the Department of Medical Genetics of the University of Groningen, The Netherlands. On a total of 355 Mendelian phenotypes described in persons living in The Netherlands or originating from this country, there were nine disease entities which were not present in MIM. As judged from this comparison MIM attains 97.5% completeness (95% CI: 95.3-98.7%). Similar comparisons with data from other countries are needed before a final conclusion can be reached. Corresponding contributors in different countries or linguistic areas might further improve MIM's completeness.

  12. COMPLETENESS OF CATALOGS OF AUTOSOMAL DOMINANT, AUTOSOMAL RECESSIVE, AND X-LINKED PHENOTYPES

    NARCIS (Netherlands)

    TENKATE, LP

    1992-01-01

    The completeness of McKusick's catalogs of Mendelian Inheritance in Man (MIM) as to the number of phenotypes included was studied by estimating the degree of concordance with the Dutch Gene Catalog of the Department of Medical Genetics of the University of Groningen, The Netherlands. On a total of

  13. Exome sequencing identifies truncating mutations in human SERPINF1 in autosomal-recessive osteogenesis imperfecta

    NARCIS (Netherlands)

    Becker, J.; Semler, O.; Gilissen, C.F.H.A.; Li, Y.; Bolz, H.J.; Giunta, C.; Bergmann, C.; Rohrbach, M.; Koerber, F.; Zimmermann, K.; Vries, P.F. de; Wirth, B.; Schoenau, E.; Wollnik, B.; Veltman, J.A.; Hoischen, A.; Netzer, C.

    2011-01-01

    Osteogenesis imperfecta (OI) is a heterogeneous genetic disorder characterized by bone fragility and susceptibility to fractures after minimal trauma. After mutations in all known OI genes had been excluded by Sanger sequencing, we applied next-generation sequencing to analyze the exome of a single

  14. Exome sequencing identifies truncating mutations in human SERPINF1 in autosomal-recessive osteogenesis imperfecta.

    Science.gov (United States)

    Becker, Jutta; Semler, Oliver; Gilissen, Christian; Li, Yun; Bolz, Hanno Jörn; Giunta, Cecilia; Bergmann, Carsten; Rohrbach, Marianne; Koerber, Friederike; Zimmermann, Katharina; de Vries, Petra; Wirth, Brunhilde; Schoenau, Eckhard; Wollnik, Bernd; Veltman, Joris A; Hoischen, Alexander; Netzer, Christian

    2011-03-11

    Osteogenesis imperfecta (OI) is a heterogeneous genetic disorder characterized by bone fragility and susceptibility to fractures after minimal trauma. After mutations in all known OI genes had been excluded by Sanger sequencing, we applied next-generation sequencing to analyze the exome of a single individual who has a severe form of the disease and whose parents are second cousins. A total of 26,922 variations from the human reference genome sequence were subjected to several filtering steps. In addition, we extracted the genotypes of all dbSNP130-annotated SNPs from the exome sequencing data and used these 299,494 genotypes as markers for the genome-wide identification of homozygous regions. A single homozygous truncating mutation, affecting SERPINF1 on chromosome 17p13.3, that was embedded into a homozygous stretch of 2.99 Mb remained. The mutation was also homozygous in the affected brother of the index patient. Subsequently, we identified homozygosity for two different truncating SERPINF1 mutations in two unrelated patients with OI and parental consanguinity. All four individuals with SERPINF1 mutations have severe OI. Fractures of long bones and severe vertebral compression fractures with resulting deformities were observed as early as the first year of life in these individuals. Collagen analyses with cultured dermal fibroblasts displayed no evidence for impaired collagen folding, posttranslational modification, or secretion. SERPINF1 encodes pigment epithelium-derived factor (PEDF), a secreted glycoprotein of the serpin superfamily. PEDF is a multifunctional protein and one of the strongest inhibitors of angiogenesis currently known in humans. Our data provide genetic evidence for PEDF involvement in human bone homeostasis. Copyright © 2011 The American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.

  15. Exome Sequencing Identifies Truncating Mutations in Human SERPINF1 in Autosomal-Recessive Osteogenesis Imperfecta

    OpenAIRE

    Becker, Jutta; Semler, Oliver; Gilissen, Christian; Li, Yun; Bolz, Hanno Jörn; Giunta, Cecilia; Bergmann, Carsten; Rohrbach, Marianne; Koerber, Friederike; Zimmermann, Katharina; de Vries, Petra; Wirth, Brunhilde; Schoenau, Eckhard; Wollnik, Bernd; Veltman, Joris A.

    2011-01-01

    Osteogenesis imperfecta (OI) is a heterogeneous genetic disorder characterized by bone fragility and susceptibility to fractures after minimal trauma. After mutations in all known OI genes had been excluded by Sanger sequencing, we applied next-generation sequencing to analyze the exome of a single individual who has a severe form of the disease and whose parents are second cousins. A total of 26,922 variations from the human reference genome sequence were subjected to several filtering steps...

  16. Autosomal recessive ichthyosis with limb reduction defect: A simple association and not CHILD syndrome

    Directory of Open Access Journals (Sweden)

    Rabah M. Shawky

    2016-07-01

    Full Text Available Ichthyosis is a genetically and phenotypically heterogeneous disease that can be isolated and restricted to the skin manifestations or associated with extracutaneous symptoms. One of which is limb reduction defect known as CHILD syndrome; a rare inborn error of metabolism of cholesterol biosynthesis that is usually restricted to one side of the body. Here we describe an Egyptian child with generalized lamellar ichthyosis and limb reduction defect. Most probably this is a simple association and not a rare case of CHILD syndrome with bilateral skin involvement.

  17. Genetics Home Reference: cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy

    Science.gov (United States)

    ... the first signs of the disorder. About half of affected individuals have a stroke or similar episode before age 40. As the disease progresses, most people with CARASIL also develop mood and personality changes, a decline in thinking ability (dementia), memory ...

  18. Autosomal recessive truncating MAB21L1 mutation associated with a syndromic scrotal agenesis.

    Science.gov (United States)

    Bruel, A-L; Masurel-Paulet, A; Rivière, J-B; Duffourd, Y; Lehalle, D; Bensignor, C; Huet, F; Borgnon, J; Roucher, F; Kuentz, P; Deleuze, J-F; Thauvin-Robinet, C; Faivre, L; Thevenon, J

    2017-02-01

    We report on a boy with a rare malformative association of scrotum agenesis, ophthalmological anomalies, cerebellar malformation, facial dysmorphism and global development delay. The reported patient was carrying a homozygous frameshift in MAB21L1 detected by whole-exome sequencing, considered as the most likely disease-causing variant. Mab21l1 knockout mice present a strikingly similar malformative association of ophthalmological malformations of the anterior chamber and preputial glands hypoplasia. We hypothesize that MAB21L1 haploinsufficiency cause a previously undescribed syndrome with scrotal agenesis, ophthalmological anomalies, facial dysmorphism and gross psychomotor delay as remarkable hallmarks. Four cases from the literature were reported with features suggestive of a similar and recognizable clinical entity. We hypothesize that MAB21L1 should be the culprit gene in these patients. © 2016 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  19. Vici Syndrome: A Rare Autosomal Recessive Syndrome with Brain Anomalies, Cardiomyopathy, and Severe Intellectual Disability

    Directory of Open Access Journals (Sweden)

    R. Curtis Rogers

    2011-01-01

    Full Text Available Purpose. The objective of this study was to present and describe two additional patients diagnosed with Vici syndrome. Methods. Clinical, laboratory, and imaging findings of the two siblings are discussed in detail. The two patients' descriptions are compared with the other eleven patients reported in the literature. We also presented detailed autopsy results on the male sibling, which demonstrated cytoplasmic vacuoles of the cardiomyocytes and confirmed the clinical findings. Results. The patients reported here include the 13th and 14th patients reported with Vici syndrome. The summary of findings present in these patients includes postnatal growth retardation, developmental delay, bilateral cataracts, agenesis of the corpus callosum, cerebellar anomalies, gyral abnormalities, seizures, hypotonia, and cardiomyopathy. Conclusion. Vici syndrome should be suspected in any child with agenesis of the corpus callosum and one of the following findings: cardiomyopathy, cataracts, immune deficiency, or cutaneous hypopigmentation.

  20. Polymicrogyria and myoclonic epilepsy in autosomal recessive cutis laxa type 2A.

    Science.gov (United States)

    Cohen, Rony; Halevy, Ayelet; Aharoni, Sharon; Kraus, Dror; Konen, Osnat; Basel-Vanagaite, Lina; Goldberg-Stern, Hadassa; Straussberg, Rachel

    2016-10-01

    Cutis laxa syndromes are rare inherited disorders of skin and connective tissue metabolism associated with variable systemic involvement. The main clinical manifestation is loose, wrinkled, redundant, inelastic skin, hypotonia, typical facies including short nose and down-slanting palpebral fissures, and varying degrees of developmental delay. The aim of this report is to describe two siblings diagnosed with a moderate form of ATP6V0A2-related cutis laxa with polymicrogyria (cobblestone-like brain dysgenesis). One of the patients has myoclonic epilepsy which may have contributed to his more severe clinical presentation. The literature on cutis laxa syndromes is reviewed.

  1. A Novel Mutation in the EDAR Gene Causes Severe Autosomal Recessive Hypohidrotic Ectodermal Dysplasia

    DEFF Research Database (Denmark)

    Henningsen, Emil; Svendsen, Mathias Tiedemann; Lildballe, D. L.

    2014-01-01

    nasal discharge. The girl was the second born child of first-cousin immigrants from Northern Iraq. A novel homozygous mutation (c.84delC) in the EDAR gene was identified. This mutation most likely causes a frameshift in the protein product (p.S29fs*74). This results in abolition of all ectodysplasin......-mediated NF-kB signalling. This complete loss-of-function mutation likely accounts for the severe clinical abnormalities in ectodermal structures in the described patient. (C) 2014 Wiley Periodicals, Inc....

  2. Autosomal recessive mental retardation syndrome with anterior maxillary protrusion and strabismus: MRAMS syndrome

    NARCIS (Netherlands)

    Basel-Vanagaite, Lina; Rainshtein, Limor; Inbar, Dov; Gothelf, Doron; Hennekam, Raoul; Straussberg, Rachel

    2007-01-01

    We report on a family in whom the combination of mental retardation (MR), anterior maxillary protrusion, and strabismus segregates. The healthy, consanguineous parents (first cousins) of Israeli-Arab descent had 11 children, 7 of whom (5 girls) were affected. They all had severe MR. Six of the seven

  3. ITGB6 loss-of-function mutations cause autosomal recessive amelogenesis imperfecta.

    Science.gov (United States)

    Wang, Shih-Kai; Choi, Murim; Richardson, Amelia S; Reid, Bryan M; Lin, Brent P; Wang, Susan J; Kim, Jung-Wook; Simmer, James P; Hu, Jan C-C

    2014-04-15

    Integrins are cell-surface adhesion receptors that bind to extracellular matrices (ECM) and mediate cell-ECM interactions. Some integrins are known to play critical roles in dental enamel formation. We recruited two Hispanic families with generalized hypoplastic amelogenesis imperfecta (AI). Analysis of whole-exome sequences identified three integrin beta 6 (ITGB6) mutations responsible for their enamel malformations. The female proband of Family 1 was a compound heterozygote with an ITGB6 transition mutation in Exon 4 (g.4545G > A c.427G > A p.Ala143Thr) and an ITGB6 transversion mutation in Exon 6 (g.27415T > A c.825T > A p.His275Gln). The male proband of Family 2 was homozygous for an ITGB6 transition mutation in Exon 11 (g.73664C > T c.1846C > T p.Arg616*) and hemizygous for a transition mutation in Exon 6 of Nance-Horan Syndrome (NHS Xp22.13; g.355444T > C c.1697T > C p.Met566Thr). These are the first disease-causing ITGB6 mutations to be reported. Immunohistochemistry of mouse mandibular incisors localized ITGB6 to the distal membrane of differentiating ameloblasts and pre-ameloblasts, and then ITGB6 appeared to be internalized by secretory stage ameloblasts. ITGB6 expression was strongest in the maturation stage and its localization was associated with ameloblast modulation. Our findings demonstrate that early and late amelogenesis depend upon cell-matrix interactions. Our approach (from knockout mouse phenotype to human disease) demonstrates the power of mouse reverse genetics in mutational analysis of human genetic disorders and attests to the need for a careful dental phenotyping in large-scale knockout mouse projects.

  4. Libyan Boy with Autosomal Recessive Trait (P 22-phox Defect) of ...

    African Journals Online (AJOL)

    We advise that pediatricians and general practitioners who treat chronic cases of lung diseases (with or without chronic diarrhea) should consider primary immunodeficiency disorders in the hope that early diagnosis and treatment may prevent chronic complications especially of the respiratory tract. Furthermore, we state ...

  5. The role of mutant protein level in autosomal recessive catecholamine dependent polymorphic ventricular tachycardia (CPVT2)

    OpenAIRE

    Katz, Guy; Shainberg, Asher; Hochhauser, Edith; Kurtzwald-Josefson, Efrat; Issac, Ahuva; El-Ani, Dalia; Aravot, Dan; Afek, Arnon; Seidman, Jonathan G.; Seidman, Christine E.; Eldar, Michael; Arad, Michael

    2013-01-01

    Humans and genetically engineered mice with recessively inherited CPVT develop arrhythmia which may arise due to malfunction or degradation of calsequestrin (CASQ2). We investigated the relation between protein level and arrhythmia severity in CASQ2D307H/D307H (D307H), compared to CASQ2Δ/Δ (KO) and wild type (WT) mice. CASQ2 expression and Ca2+ transients were recorded in cardiomyocytes from neonatal or adult mice. Arrhythmia was studied in vivo using heart rhythm telemetry at rest, exercise ...

  6. Autosomal recessive mutations in THOC6 cause intellectual disability: syndrome delineation requiring forward and reverse phenotyping.

    Science.gov (United States)

    Amos, J S; Huang, L; Thevenon, J; Kariminedjad, A; Beaulieu, C L; Masurel-Paulet, A; Najmabadi, H; Fattahi, Z; Beheshtian, M; Tonekaboni, S H; Tang, S; Helbig, K L; Alcaraz, W; Rivière, J-B; Faivre, L; Innes, A M; Lebel, R R; Boycott, K M

    2017-01-01

    THOC6 is a part of the THO complex, which is involved in coordinating mRNA processing with export. The THO complex interacts with additional components to form the larger TREX complex (transcription export complex). Previously, a homozygous missense mutation in THOC6 in the Hutterite population was reported in association with syndromic intellectual disability. Using exome sequencing, we identified three unrelated patients with bi-allelic mutations in THOC6 associated with intellectual disability and additional clinical features. Two of the patients were compound heterozygous for a stop and a missense mutation, and the third was homozygous for a missense mutation; the missense mutations were predicted to be pathogenic by in silico analysis and modeling. Clinical features of the three newly identified patients and those previously reported are reviewed; intellectual disability is moderate to severe, and malformations are variable including renal and heart defects, cleft palate, microcephaly, and corpus callosum dysgenesis. Facial features are variable and include tall forehead, short upslanting palpebral fissures +/- deep set eyes, and a long nose with overhanging columella. These subtle facial features render the diagnosis difficult to make in isolation with certainty. Our results expand the mutational and clinical spectrum of this rare disease, confirm that THOC6 is an intellectual disability causing gene, while providing insight into the importance of the THO complex in neurodevelopment. © 2016 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  7. Genetics Home Reference: autosomal recessive spastic ataxia of Charlevoix-Saguenay

    Science.gov (United States)

    ... 12 months and 18 months, as toddlers are learning to walk. The signs and symptoms worsen over ... links) Health Topic: Degenerative Nerve Diseases Health Topic: Movement Disorders Health Topic: Neurologic Diseases Genetic and Rare Diseases ...

  8. Mutations in c10orf11, a melanocyte-differentiation gene, cause autosomal-recessive albinism

    DEFF Research Database (Denmark)

    Grønskov, Karen; Dooley, Christopher M; Østergaard, Elsebet

    2013-01-01

    in an individual originating from Lithuania. Immunohistochemistry showed localization of C10orf11 in melanoblasts and melanocytes in human fetal tissue, but no localization was seen in retinal pigment epithelial cells. Knockdown of the zebrafish (Danio rerio) homolog with the use of morpholinos resulted...... in substantially decreased pigmentation and a reduction of the apparent number of pigmented melanocytes. The morphant phenotype was rescued by wild-type C10orf11, but not by mutant C10orf11. In conclusion, we have identified a melanocyte-differentiation gene, C10orf11, which when mutated causes autosomal...

  9. Hematologically important mutations: The autosomal recessive forms of chronic granulomatous disease (second update)

    NARCIS (Netherlands)

    Roos, Dirk; Kuhns, Douglas B.; Maddalena, Anne; Bustamante, Jacinta; Kannengiesser, Caroline; de Boer, Martin; van Leeuwen, Karin; Köker, M. Yavuz; Wolach, Baruch; Roesler, Joachim; Malech, Harry L.; Holland, Steven M.; Gallin, John I.; Stasia, Marie-José

    2010-01-01

    Chronic granulomatous Disease (CGD) is an immunodeficiency disorder affecting about 1 in 250,000 individuals. The disease is caused by mutations in the genes encoding the components of the leukocyte NADPH oxidase. This enzyme produces superoxide, which is essential in the process of intracellular

  10. Autosomal recessive polycystic kidney disease and congenital hepatic fibrosis (ARPKD/CHF)

    Energy Technology Data Exchange (ETDEWEB)

    Turkbey, Baris; Choyke, Peter L. [National Institutes of Health, Molecular Imaging Program, National Cancer Institute, Bethesda, MD (United States); Ocak, Iclal [National Institutes of Health, Molecular Imaging Program, National Cancer Institute, Bethesda, MD (United States); University of Pittsburgh Medical Center, Department of Radiology, Pittsburgh, PA (United States); Daryanani, Kailash [National Institutes of Health, Clinical Center, Department of Radiology, Bethesda, MD (United States); Font-Montgomery, Esperanza; Lukose, Linda; Bryant, Joy; Tuchman, Maya; Gahl, William A. [National Institutes of Health, National Human Genome Research Institute, Medical Genetics Branch, Bethesda, MD (United States); Mohan, Parvathi [George Washington University, Department of Pediatric Gastroenterology, Washington, DC (United States); Heller, Theo [National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, MD (United States); Gunay-Aygun, Meral [National Institutes of Health, National Human Genome Research Institute, Medical Genetics Branch, Bethesda, MD (United States); National Institutes of Health, Intramural Program, Office of Rare Diseases, Office of the Directors, Bethesda, MD (United States)

    2009-02-15

    ARPKD/CHF is an inherited disease characterized by non-obstructive fusiform dilatation of the renal collecting ducts leading to enlarged spongiform kidneys and ductal plate malformation of the liver resulting in congenital hepatic fibrosis. ARPKD/CHF has a broad spectrum of clinical presentations involving the kidney and liver. Imaging plays an important role in the diagnosis and follow-up of ARPKD/CHF. Combined use of conventional and high-resolution US with MR cholangiography in ARPKD/CHF patients allows detailed definition of the extent of kidney and hepatobiliary manifestations without requiring ionizing radiation and contrast agents. (orig.)

  11. Combined Occurrence of Autosomal Dominant Aniridia and Autosomal Recessive Albinism in Several Members of a Family.

    Science.gov (United States)

    Yahalom, Claudia; Sharon, Dror; Dalia, Eli; Simhon, Shiran Ben; Shemesh, Efrat; Blumenfeld, Anat

    2015-06-01

    To characterize clinical and genetic aspects of a family with a unique combination of two hereditary blinding eye diseases. Comprehensive eye examination of proband and family members. Molecular analyses of the TYR and PAX6 genes. A young couple, both legally blind, requested genetic counselling regarding their ocular condition. The female was previously diagnosed with oculocutaneous albinism (OCA1A) and her spouse was diagnosed with Peters anomaly. A comprehensive clinical examination revealed that the female had OCA1A combined with signs of another ocular disease, showing some similarity to aniridia. A complete ocular examination of her family members revealed that her brother also suffered from the same combined phenotype, her father had typical OCA1A signs, and her mother and sister had aniridia-like phenotype, without clinical diagnosis until the time of presentation. Molecular analysis identified two compound heterozygous TYR mutations known to cause OCAIA and cosegregate with oculocutaneous albinism. In addition, we identified a novel heterozygous PAX6 mutation confirming the atypical aniridia phenotype. We report here a unique and rare clinical phenotype that is explained by the segregation of two severe inherited eye diseases. The clinical and genetic analysis in this family allowed them to receive accurate genetic counseling.

  12. Molecular diagnostic in two families affected with Autosomic Recessive Pigmentary Retinitis

    International Nuclear Information System (INIS)

    Leal Esquivel, A.

    1996-01-01

    This study included two Costa Rican families with members affected by Recessive Pigmentary Autosomic Retinitis (RPAR). The first family (C1) from the province of San Jose, has 10 alive affected members, and 14 obligatory carriers. They present an Early Appearance Degeneration, RPAR tipe1 (cane-cone). The author used polymorphic markers (STRPs) to discard some related regions, with the RP in the literature. He also used the Linkage program, for the analysis of ligaments. The second family (P1), proceeding from Acosta (situated in the province of Alajuela), has 13 alive affected members and 23 obligatory carriers and they present numerous consanguineous unions. This case is a RPAR with Early Appearance (Night Blindness, fat ERG), but with a shower degeneration. The author concludes that, with studies such as this one, there will be a capacity to offer RP molecular diagnostic, and also advance in its knowledge and treatment. (S. Grainger)

  13. Autosomal recessive intestinal lymphangiectasia and lymphedema, with facial anomalies and mental retardation

    NARCIS (Netherlands)

    Hennekam, R. C.; Geerdink, R. A.; Hamel, B. C.; Hennekam, F. A.; Kraus, P.; Rammeloo, J. A.; Tillemans, A. A.

    1989-01-01

    We report on two male and two female relatives with intestinal lymphangiectasia; severe lymphedema of limbs, genitalia, and face; facial anomalies; seizures; mild growth retardation; and moderate mental retardation. Main facial anomalies are a flat face, flat nasal bridge, hypertelorism, small

  14. Mutations in SNX14 cause a distinctive autosomal-recessive cerebellar ataxia and intellectual disability syndrome

    NARCIS (Netherlands)

    Thomas, Anna C.; Williams, Hywel; Setó-Salvia, Núria; Bacchelli, Chiara; Jenkins, Dagan; O'Sullivan, Mary; Mengrelis, Konstantinos; Ishida, Miho; Ocaka, Louise; Chanudet, Estelle; James, Chela; Lescai, Francesco; Anderson, Glenn; Morrogh, Deborah; Ryten, Mina; Duncan, Andrew J.; Pai, Yun Jin; Saraiva, Jorge M.; Ramos, Fabiana; Farren, Bernadette; Saunders, Dawn; Vernay, Bertrand; Gissen, Paul; Straatmaan-Iwanowska, Anna; Baas, Frank; Wood, Nicholas W.; Hersheson, Joshua; Houlden, Henry; Hurst, Jane; Scott, Richard; Bitner-Glindzicz, Maria; Moore, Gudrun E.; Sousa, Sérgio B.; Stanier, Philip

    2014-01-01

    Intellectual disability and cerebellar atrophy occur together in a large number of genetic conditions and are frequently associated with microcephaly and/or epilepsy. Here we report the identification of causal mutations in Sorting Nexin 14 (SNX14) found in seven affected individuals from three

  15. PTRHD1 (C2orf79) mutations lead to autosomal-recessive intellectual disability and parkinsonism.

    Science.gov (United States)

    Khodadadi, Hamidreza; Azcona, Luis J; Aghamollaii, Vajiheh; Omrani, Mir Davood; Garshasbi, Masoud; Taghavi, Shaghayegh; Tafakhori, Abbas; Shahidi, Gholam Ali; Jamshidi, Javad; Darvish, Hossein; Paisán-Ruiz, Coro

    2017-02-01

    Atypical parkinsonism is a neurodegenerative disease that includes diverse neurological and psychiatric manifestations. We aimed to identify the disease-cauisng mutations in a consanguineous family featuring intellectual disability and parkinsonism. Full phenotypic characterization, followed by genome-wide single-nucleotide polymorphism genotyping and whole-genome sequencing, was carried out in all available family members. The chromosome, 2p23.3, was identified as the disease-associated locus, and a homozygous PTRHD1 mutation (c.157C>T) was then established as the disease-causing mutation. The pathogenicity of this PTRHD1 mutation was supported by its segregation with the disease status, its location in a functional domain of the encoding protein, as well as its absence in public databases and ethnicity-matched control chromosomes. Given the role of 2p23 locus in patients with intellectual disability and the previously reported PTRHD1 mutation (c.155G>A) in patients with parkinsonism and cognitive dysfunction, we concluded that the PTRHD1 mutation identified in this study is likely to be responsible for the phenotypic features of the family under consideration. © 2016 International Parkinson and Movement Disorder Society. © 2016 International Parkinson and Movement Disorder Society.

  16. CLPB Variants Associated with Autosomal-Recessive Mitochondrial Disorder with Cataract, Neutropenia, Epilepsy, and Methylglutaconic Aciduria

    DEFF Research Database (Denmark)

    Saunders, Carol; Smith, Laurie; Wibrand, Flemming

    2015-01-01

    3-methylglutaconic aciduria (3-MGA-uria) is a nonspecific finding associated with mitochondrial dysfunction, including defects of oxidative phosphorylation. 3-MGA-uria is classified into five groups, of which one, type IV, is genetically heterogeneous. Here we report five children with a form...... of type IV 3-MGA-uria characterized by cataracts, severe psychomotor regression during febrile episodes, epilepsy, neutropenia with frequent infections, and death in early childhood. Four of the individuals were of Greenlandic descent, and one was North American, of Northern European and Asian descent...

  17. Autosomal recessive long QT syndrome, type 1 in eight families from Saudi Arabia

    NARCIS (Netherlands)

    Bdier, Amnah Y.; Al-Ghamdi, Saleh; Verma, Prashant K.; Dagriri, Khalid; Alshehri, Bandar; Jiman, Omamah A.; Ahmed, Sherif E.; Wilde, Arthur A. M.; Bhuiyan, Zahurul A.; Al-Aama, Jumana Y.

    2017-01-01

    One of the most common primary cardiac arrhythmia syndromes is autosomal dominant long QT syndrome, type 1 (LQT1), chiefly caused by mono-allelic mutations in the KCNQ1 gene. Bi-allelic mutations in the KCNQ1 gene are causal to Jervell and Lange-Nielsen syndrome (JLNS), characterized by severe and

  18. Craniofacial anomalies, humero-radial synostosis, rhizomelic limb shortness: previously unrecognized autosomal recessive syndrome.

    Science.gov (United States)

    Al-Hassnan, Zuhair N; Teebi, Ahmad S

    2007-03-15

    Humero-radial synostosis (HRS) is a rare skeletal anomaly that might be seen in some craniosynostosis syndromes, notably Antley-Bixler syndrome, and in other disorders in association with skeletal anomalies. Here we report on two daughters of first cousin Saudi parents with syndromic HRS. Both patients had distinctive craniofacial features including cranium bifidum occultum, hypertelorism, epicanthus inversus, capillary hemangiomata, and malformed ears. Musculoskeletal examination revealed rhizomelic shortness with normal hands and feet. Skeletal survey showed bilateral HRS with no evidence of craniosynostosis. The craniofacial manifestations in these two patients do not match any of the syndromes known to be associated with HRS. We consider that the constellation is unique and apparently represents a previously unrecognized syndrome. (c) 2007 Wiley-Liss, Inc.

  19. A homozygous missense mutation in the IRBP gene (RBP3) associated with autosomal recessive retinitis pigmentosa.

    NARCIS (Netherlands)

    Hollander, A.I. den; McGee, T.L.; Ziviello, C.; Banfi, S.; Dryja, T.P.; Gonzalez-Fernandez, F.; Ghosh, D.; Berson, E.L.

    2009-01-01

    PURPOSE: Interphotoreceptor retinoid-binding protein (IRBP) has been considered essential for normal rod and cone function, as it mediates the transport of retinoids between the photoreceptors and the retinal pigment epithelium. This study was performed to determine whether mutations in the IRBP

  20. GNB5 Mutations Cause an Autosomal-Recessive Multisystem Syndrome with Sinus Bradycardia and Cognitive Disability.

    Science.gov (United States)

    Lodder, Elisabeth M; De Nittis, Pasquelena; Koopman, Charlotte D; Wiszniewski, Wojciech; Moura de Souza, Carolina Fischinger; Lahrouchi, Najim; Guex, Nicolas; Napolioni, Valerio; Tessadori, Federico; Beekman, Leander; Nannenberg, Eline A; Boualla, Lamiae; Blom, Nico A; de Graaff, Wim; Kamermans, Maarten; Cocciadiferro, Dario; Malerba, Natascia; Mandriani, Barbara; Akdemir, Zeynep Hande Coban; Fish, Richard J; Eldomery, Mohammad K; Ratbi, Ilham; Wilde, Arthur A M; de Boer, Teun; Simonds, William F; Neerman-Arbez, Marguerite; Sutton, V Reid; Kok, Fernando; Lupski, James R; Reymond, Alexandre; Bezzina, Connie R; Bakkers, Jeroen; Merla, Giuseppe

    2016-09-01

    GNB5 encodes the G protein β subunit 5 and is involved in inhibitory G protein signaling. Here, we report mutations in GNB5 that are associated with heart-rate disturbance, eye disease, intellectual disability, gastric problems, hypotonia, and seizures in nine individuals from six families. We observed an association between the nature of the variants and clinical severity; individuals with loss-of-function alleles had more severe symptoms, including substantial developmental delay, speech defects, severe hypotonia, pathological gastro-esophageal reflux, retinal disease, and sinus-node dysfunction, whereas related heterozygotes harboring missense variants presented with a clinically milder phenotype. Zebrafish gnb5 knockouts recapitulated the phenotypic spectrum of affected individuals, including cardiac, neurological, and ophthalmological abnormalities, supporting a direct role of GNB5 in the control of heart rate, hypotonia, and vision. Copyright © 2016 American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.

  1. A novel missense mutation of AIRE gene in a patient with autoimmune polyendocrinopathy, candidiasis and ectodermal dystrophy (APECED), accompanied with progressive muscular atrophy: case report and review of the literature in Japan.

    Science.gov (United States)

    Sato, Kanji; Nakajima, Kishiko; Imamura, Hidehito; Deguchi, Takahisa; Horinouchi, Shuuji; Yamazaki, Kazuko; Yamada, Emiko; Kanaji, Yoshio; Takano, Kazue

    2002-12-01

    Autoimmune polyendocrinopathy, candidiasis, and ectodermal dystrophy (APECED) also known as autoimmune polyglandular syndrome type I, is a rare autosomal recessive disorder that results in several autoimmune diseases due to mutations in the AIRE (autoimmune regulator) gene. A 39-year-old female patient developed chronic mucocutaneous candidiasis at 3 yrs, idiopathic hypoparathyroidism at 11 yrs, chronic hepatitis at 23 yrs, Addison's disease and diabetes mellitus type I at 27 yrs. In addition, the patient developed progressive muscular atrophy of unknown etiology at the beginning of the third decade, and is bedridden at the present time. Her grandparents, parents, brother and daughter did not develop any features of APECED, but her father died of hepatoma. Direct sequencing of the AIRE gene revealed a novel missense mutation at exon 1 (R15C), which was identified to be of maternal origin. The other mutation was not found despite repeated sequencing of the whole coding regions. The R15C mutation was not detected in patients with idiopathic hypoparathyroidism (N= 10), idiopathic Addison's disease (N = 3), and normal subjects (N = 55). Although we could not analyze the father's gene, these results suggest that the patient is probably a compound heterozygote of the AIRE gene, in which the other abnormal allele could not be identified by the present analytical method. These data are compatible with the recent review that only one defective allele was detectable in some patients with clinically evident APECED. We found only six Japanese patients compatible with diagnosis of APECED, indicating that this autoimmune disease is extremely rare in our country.

  2. Retinitis pigmentosa

    Directory of Open Access Journals (Sweden)

    Hamel Christian

    2006-10-01

    Full Text Available Abstract Retinitis pigmentosa (RP is an inherited retinal dystrophy caused by the loss of photoreceptors and characterized by retinal pigment deposits visible on fundus examination. Prevalence of non syndromic RP is approximately 1/4,000. The most common form of RP is a rod-cone dystrophy, in which the first symptom is night blindness, followed by the progressive loss in the peripheral visual field in daylight, and eventually leading to blindness after several decades. Some extreme cases may have a rapid evolution over two decades or a slow progression that never leads to blindness. In some cases, the clinical presentation is a cone-rod dystrophy, in which the decrease in visual acuity predominates over the visual field loss. RP is usually non syndromic but there are also many syndromic forms, the most frequent being Usher syndrome. To date, 45 causative genes/loci have been identified in non syndromic RP (for the autosomal dominant, autosomal recessive, X-linked, and digenic forms. Clinical diagnosis is based on the presence of night blindness and peripheral visual field defects, lesions in the fundus, hypovolted electroretinogram traces, and progressive worsening of these signs. Molecular diagnosis can be made for some genes, but is not usually performed due to the tremendous genetic heterogeneity of the disease. Genetic counseling is always advised. Currently, there is no therapy that stops the evolution of the disease or restores the vision, so the visual prognosis is poor. The therapeutic approach is restricted to slowing down the degenerative process by sunlight protection and vitaminotherapy, treating the complications (cataract and macular edema, and helping patients to cope with the social and psychological impact of blindness. However, new therapeutic strategies are emerging from intensive research (gene therapy, neuroprotection, retinal prosthesis.

  3. Translational Research for Muscular Dystrophy

    Science.gov (United States)

    2015-07-01

    digitorum longus GSM: grip strength measurement LV: left ventricle mRNA: messenger RNA TA: tibialis anterior TGF-β: transforming growth factor...kinase CNF: central nucleated fibers CTSB: cathepsin B DMD: Duchenne muscular dystrophy Dmd: dystrophin gene EBD: evan blue dye EDL: extensor

  4. Genetics of corneal endothelial dystrophies

    Indian Academy of Sciences (India)

    2009-12-31

    Dec 31, 2009 ... Kallam Anji Reddy Molecular Genetics Laboratory, Prof Brien Holden Eye Research Centre,. L. V. Prasad Eye Institute, ... Keywords. genetics; corneal dystrophy; corneal endothelium; gene mapping; mutations. Journal of Genetics .... PPCD and autosomal dominant keratoconus (including ker- atoconus in ...

  5. Glucocorticoids for Duchenne Muscular Dystrophy

    Directory of Open Access Journals (Sweden)

    J Gordon Millichap

    2013-07-01

    Full Text Available Investigators at the Dubowitz Neuromuscular Centre, Great Ormond Street Hospital, and other centers in the UK, conducted a prospective longitudinal study across 17 neuromuscular centers in the UK of 360 boys aged 3-15 years with Duchenne muscular dystrophy who were treated with daily or intermittent (10 days on/10 days off prednisolone for a mean duration of 4 years.

  6. Prednisone Therapy for Duchenne Dystrophy

    Directory of Open Access Journals (Sweden)

    J Gordon Millichap

    2005-02-01

    Full Text Available The effects of prednisone on muscle function and the extent of steroid-related adverse effects were studied in 17 ambulant children with Duchenne muscular dystrophy (DMD at University Hospital, Groningen; Rehabilitation Centre, Utrecht; and Leiden University Medical Centre, the Netherlands.

  7. Faecal incontinence in myotonic dystrophy

    OpenAIRE

    Abercrombie, J; Rogers, J; Swash, M

    1998-01-01

    Two siblings with myotonic dystrophy presented for treatment of faecal incontinence. The pathophysiology of this functional disorder is described with the results of anorectal manometry, EMG, and biopsy of smooth and striated muscle of the anorectal sphincters. Both medical and surgical management of the incontinence was unsatisfactory in the long term. Involvement of gastrointestinal musculature is a characteristic feature the disease.



  8. AMPUTATION AND REFLEX SYMPATHETIC DYSTROPHY

    NARCIS (Netherlands)

    GEERTZEN, JHB; EISMA, WH

    Reflex sympathetic dystrophy is a chronic pain syndrome characterized by chronic burning pain, restricted range of motion, oedema and vasolability. Patients are difficult to treat and the prognosis is very often poor. This report emphasizes that an amputation in case of a reflex sympathetic

  9. Genetics Home Reference: Duchenne and Becker muscular dystrophy

    Science.gov (United States)

    ... Home Health Conditions Duchenne and Becker muscular dystrophy Duchenne and Becker muscular dystrophy Printable PDF Open All ... by progressive muscle weakness and wasting (atrophy). The Duchenne and Becker types of muscular dystrophy are two ...

  10. Duchenne muscular dystrophy: Case report and review

    OpenAIRE

    Rupam Sinha; Soumyabrata Sarkar; Tanya Khaitan; Soumyajit Dutta

    2017-01-01

    Muscular dystrophies are a clinically and heterogeneous group of disorders that all share clinical characteristics of progressive muscular weakness. Duchenne muscular dystrophy (DMD) is the most common X-linked disorder muscular dystrophy in children, presenting in early childhood and characterized by proximal muscle weakness and calf hypertrophy in affected boys. There is usually delay in motor development and eventually wheelchair confinement followed by premature death from cardiac or resp...

  11. Terapia gênica em distrofias hereditárias de retina Gene therapy for inherited retinal dystrophies

    Directory of Open Access Journals (Sweden)

    Monique Côco

    2009-08-01

    Full Text Available As distrofias hereditárias de retina abrangem um amplo número de doenças caracterizadas por lenta e progressiva degeneração da retina. São o resultado de mutações em genes expressos em fotorreceptores e no epitélio pigmentado da retina. A herança pode ser autossômica dominante, autossômica recessiva, ligada ao X recessiva, digênica ou herança mitocondrial. Atualmente não há tratamento para essas doenças e os pacientes convivem com a perda progressiva da visão. O aconselhamento genético e o suporte para reabilitação têm indicação nestes casos. Pesquisas envolvendo a base molecular e genética dessas doenças está continuamente em expansão e ampliam as perspectivas para novas formas de tratamento. Dessa forma, a terapia gênica, que consiste na inserção de material genético exógeno em células de um indivíduo com finalidade terapêutica, tem sido a principal forma de tratamento para as distrofias hereditárias de retina. O olho é um órgão peculiar para a terapia gênica, pois é anatomicamente dividido em compartimentos, imunologicamente privilegiado e com meios transparentes. A maioria das doenças oculares tem defeitos em genes conhecidos. Além disso, há modelo animal bem caracterizado para algumas condições. Propostas para pesquisa clínica em terapia gênica nas degenerações retinianas hereditárias com defeito no gene RPE65, recentemente tiveram aprovação ética e os resultados preliminares obtidos trouxeram grandes expectativas na melhora da qualidade de vida dos pacientes.The inherited retinal dystrophies comprise a large number of disorders characterized by a slow and progressive retinal degeneration. They are the result of mutations in genes that express in either the photoreceptor cells or the retinal pigment epithelium. The mode of inheritance can be autosomal dominant, autosomal recessive, X linked recessive, digenic or mitochondrial DNA inherited. At the moment, there is no treatment for these

  12. Physiology of respiratory disturbances in muscular dystrophies.

    Science.gov (United States)

    Lo Mauro, Antonella; Aliverti, Andrea

    2016-12-01

    Muscular dystrophy is a group of inherited myopathies characterised by progressive skeletal muscle wasting, including of the respiratory muscles. Respiratory failure, i.e . when the respiratory system fails in its gas exchange functions, is a common feature in muscular dystrophy, being the main cause of death, and it is a consequence of lung failure, pump failure or a combination of the two. The former is due to recurrent aspiration, the latter to progressive weakness of respiratory muscles and an increase in the load against which they must contract. In fact, both the resistive and elastic components of the work of breathing increase due to airway obstruction and chest wall and lung stiffening, respectively. The respiratory disturbances in muscular dystrophy are restrictive pulmonary function, hypoventilation, altered thoracoabdominal pattern, hypercapnia, dyspnoea, impaired regulation of breathing, inefficient cough and sleep disordered breathing. They can be present at different rates according to the type of muscular dystrophy and its progression, leading to different onset of each symptom, prognosis and degree of respiratory involvement. A common feature of muscular dystrophy is respiratory failure, i.e. the inability of the respiratory system to provide proper oxygenation and carbon dioxide elimination.In the lung, respiratory failure is caused by recurrent aspiration, and leads to hypoxaemia and hypercarbia.Ventilatory failure in muscular dystrophy is caused by increased respiratory load and respiratory muscles weakness.Respiratory load increases in muscular dystrophy because scoliosis makes chest wall compliance decrease, atelectasis and fibrosis make lung compliance decrease, and airway obstruction makes airway resistance increase.The consequences of respiratory pump failure are restrictive pulmonary function, hypoventilation, altered thoracoabdominal pattern, hypercapnia, dyspnoea, impaired regulation of breathing, inefficient cough and sleep disordered

  13. [Current studies in myotonic dystrophy].

    Science.gov (United States)

    Zhao, Yimeng; Ishiura, Shoichi

    2014-03-01

    Myotonic dystrophy (DM) is a genetic, progressive, multisystemic disease with muscular disorder as its primary symptom. There are two types of DM (DM1 and DM2) caused by mutations in different genes, and in Japan, DM occurs with an incidence of approximately 1 in 20,000. The pathogenic mechanism underlying the disease is RNA toxicity caused by transcripts of aberrantly elongated CTG or CCTG repeats located in the 3' untranslated region or in the intron. The current treatments for DM is limited to symptomatic care. In this review, we will discuss several new therapeutic strategies based on recent studies of RNA toxicity.

  14. [Reflex sympathetic dystrophy of childhood: one case].

    Science.gov (United States)

    Jouary, T; Boralevi, F; Pillet, P; Taieb, A; Léauté-Labrèze, C

    2002-10-01

    Reflex sympathetic dystrophy (Complex Regional Pain Syndrome type 1) is little known by dermatologists. We report a pediatric case of reflex sympathetic dystrophy with predominant cutaneous involvement. A 10 year-old girl presented a warm, painful and relapsing right hand edema for seven months (three outbreaks). The hand was cyanotic, pigmented and painful. Routine blood tests were normal. Radiography and radionuclide bone scan were consistent with stage 1 reflex sympathetic dystrophy. Physiotherapy led to dramatic improvement. Reflex sympathetic dystrophy is known since the XVIIIth century. In the last decade, progress in radiology and bone scan have provided elements for understanding the physiopathology of the disease. Microvascular abnormalities under the control of sympathetic nervous system are characteristic of different stages of reflex sympathetic dystrophy. Recently, neurovascular system experiments showed that sympathetic reflex tonus changes may be controlled by the central nervous system. Dermatologic changes of reflex sympathetic dystrophy are well known: edema and erythema in first stage, cyanosis in second stage, sclerosis and atrophia in third stage, but pediatric cases are rarely reported. Reflex sympathetic dystrophy is a complex disease, however its physiopathology is now understood. The clinical presentation can be atypical and the dermatologist may be the first to be consulted.

  15. Duchenne muscular dystrophy: current cell therapies.

    Science.gov (United States)

    Sienkiewicz, Dorota; Kulak, Wojciech; Okurowska-Zawada, Bożena; Paszko-Patej, Grażyna; Kawnik, Katarzyna

    2015-07-01

    Duchenne muscular dystrophy is a genetically determined X-linked disease and the most common, progressive pediatric muscle disorder. For decades, research has been conducted to find an effective therapy. This review presents current therapeutic methods for Duchenne muscular dystrophy, based on scientific articles in English published mainly in the period 2000 to 2014. We used the PubMed database to identify and review the most important studies. An analysis of contemporary studies of stem cell therapy and the use of granulocyte colony-stimulating factor (G-CSF) in muscular dystrophy was performed.

  16. Muscular dystrophy: from pathogenesis to strategy.

    Science.gov (United States)

    Hsu, Yaw-Don

    2004-06-01

    Muscular dystrophies are a genetically heterogeneous group of degenerative muscle disorders. It characterized by progressive muscle wasting and weakness of variable distribution and severity. There are several subgroups including Duchenne/Becker, fascioscapulohumeral, limb-girdle, oculopharngeal, and congenital muscular dystrophy. Diagnosis is dependent to the characteristic clinical features in distribution of predominant muscle weakness, disease course and age onset as well as variable serum concentration creatine kinase, muscle histology, and genetic inheritance. Nearly 30 genes and encoded proteins are known to give rise to various forms of muscular dystrophy. Development of new prospects therapy for the muscular dystrophies is a big challenge. The target of strategies is aimed at inducing of a functional protein and improving the function of muscle weakness. These strategies include gene, cell and pharmacological therapies. However, efficiency of systemic delivery vectors to targets, immune reaction to vector and gene products, and toxicity to vector that must be solved before an effective treatment is available.

  17. The myotonic dystrophies: diagnosis and management.

    Science.gov (United States)

    Turner, Chris; Hilton-Jones, David

    2010-04-01

    There are currently two clinically and molecularly defined forms of myotonic dystrophy: (1) myotonic dystrophy type 1 (DM1), also known as 'Steinert's disease'; and (2) myotonic dystrophy type 2 (DM2), also known as proximal myotonic myopathy. DM1 and DM2 are progressive multisystem genetic disorders with several clinical and genetic features in common. DM1 is the most common form of adult onset muscular dystrophy whereas DM2 tends to have a milder phenotype with later onset of symptoms and is rarer than DM1. This review will focus on the clinical features, diagnosis and management of DM1 and DM2 and will briefly discuss the recent advances in the understanding of the molecular pathogenesis of these diseases with particular reference to new treatments using gene therapy.

  18. Limb-Girdle Muscular Dystrophy (LGMD)

    Science.gov (United States)

    ... Program Funding Opportunities Contact our Research Team For Families Clinical Trials Finder Tool Get Involved How to ... with LGMD normally encode proteins that play vital roles in muscle function, ... genders are affected equally. When limb-girdle muscular dystrophy ...

  19. Non-Coding RNAs in Muscle Dystrophies

    Directory of Open Access Journals (Sweden)

    Alessandra Ferlini

    2013-09-01

    Full Text Available ncRNAs are the most recently identified class of regulatory RNAs with vital functions in gene expression regulation and cell development. Among the variety of roles they play, their involvement in human diseases has opened new avenues of research towards the discovery and development of novel therapeutic approaches. Important data come from the field of hereditary muscle dystrophies, like Duchenne muscle dystrophy and Myotonic dystrophies, rare diseases affecting 1 in 7000–15,000 newborns and is characterized by severe to mild muscle weakness associated with cardiac involvement. Novel therapeutic approaches are now ongoing for these diseases, also based on splicing modulation. In this review we provide an overview about ncRNAs and their behavior in muscular dystrophy and explore their links with diagnosis, prognosis and treatments, highlighting the role of regulatory RNAs in these pathologies.

  20. [ Sudeck's bone atrophy (reflex sympathetic dystrophy)].

    Science.gov (United States)

    Hayashi, Yasufumi

    2008-07-01

    Reflex sympathetic dystrophy is a disease clinically characterized severe pain, allodynia (severe pain caused by a touch) and over-reaction of pain sensation after a minor injury. In 1994, reflex sympathetic dystrophy was given a name of complex regional pain syndrome type 1 by a international congress, because local blockade of the sympathetic nerve has not been found to be invariably effective. Treatment system for reflex sympathetic dystrophy is composed of medicament therapy including oral administration and/or injection of drug, physical therapy such as thermotherapy and gently passive movement, surgical treatment and psychotherapy. Treatment with injection of pamidronate for 23 patients with reflex sympathetic dystrophy revealed to reduced the grade of pain to two third compared to pre-treatment period, and local intravenous block with local anesthetic drug and steroid hormone disappeared the almost symptoms in cases of early phase.

  1. Genetics Home Reference: Bietti crystalline dystrophy

    Science.gov (United States)

    ... East Asian descent, especially those of Chinese and Japanese background. Researchers suggest that Bietti crystalline dystrophy may ... of Medicine Lister Hill National Center for Biomedical Communications 8600 Rockville Pike, Bethesda, MD 20894, USA HONCode ...

  2. Physiology of respiratory disturbances in muscular dystrophies

    OpenAIRE

    Lo Mauro, Antonella; Aliverti, Andrea

    2016-01-01

    Muscular dystrophy is a group of inherited myopathies characterised by progressive skeletal muscle wasting, including of the respiratory muscles. Respiratory failure, i.e. when the respiratory system fails in its gas exchange functions, is a common feature in muscular dystrophy, being the main cause of death, and it is a consequence of lung failure, pump failure or a combination of the two. The former is due to recurrent aspiration, the latter to progressive weakness of respiratory muscles an...

  3. Duchenne muscular dystrophy: the management of scoliosis

    Science.gov (United States)

    Gardner, Adrian C.; Roper, Helen P.; Chikermane, Ashish A.; Tatman, Andrew J.

    2016-01-01

    This study summaries the current management of scoliosis in patients with Duchenne Muscular Dystrophy. A literature review of Medline was performed and the collected articles critically appraised. This literature is discussed to give an overview of the current management of scoliosis within Duchenne Muscular Dystrophy. Importantly, improvements in respiratory care, the use of steroids and improving surgical techniques have allowed patients to maintain quality of life and improved life expectancy in this patient group. PMID:27757431

  4. Sleep disturbances in myotonic dystrophy type 2

    OpenAIRE

    Shepard, Paul; Lam, Erek M.; St. Louis, Erik K.; Dominik, Jacob

    2012-01-01

    Sleep disorders in myotonic dystrophy type 1 (DM1) are common and include sleep disordered breathing (SDB), hypersomnia, and fatigue. Little is known regarding the occurrence of sleep disturbance in myotonic dystrophy type 2 (DM2). We hypothesized that DM2 patients may frequently harbor sleep disorders. We reviewed medical records of all genetically confirmed cases of DM2 seen at our sleep center between 1997 and 2010 for demographic, laboratory, overnight oximetry, and polysomnography (PSG) ...

  5. Duchenne muscular dystrophy: current cell therapies

    OpenAIRE

    Sienkiewicz, Dorota; Kulak, Wojciech; Okurowska-Zawada, Bożena; Paszko-Patej, Grażyna; Kawnik, Katarzyna

    2015-01-01

    Duchenne muscular dystrophy is a genetically determined X-linked disease and the most common, progressive pediatric muscle disorder. For decades, research has been conducted to find an effective therapy. This review presents current therapeutic methods for Duchenne muscular dystrophy, based on scientific articles in English published mainly in the period 2000 to 2014. We used the PubMed database to identify and review the most important studies. An analysis of contemporary studies of stem cel...

  6. Duchenne muscular dystrophy: the management of scoliosis.

    Science.gov (United States)

    Archer, James E; Gardner, Adrian C; Roper, Helen P; Chikermane, Ashish A; Tatman, Andrew J

    2016-09-01

    This study summaries the current management of scoliosis in patients with Duchenne Muscular Dystrophy. A literature review of Medline was performed and the collected articles critically appraised. This literature is discussed to give an overview of the current management of scoliosis within Duchenne Muscular Dystrophy. Importantly, improvements in respiratory care, the use of steroids and improving surgical techniques have allowed patients to maintain quality of life and improved life expectancy in this patient group.

  7. The heart in Becker muscular dystrophy, facioscapulohumeral dystrophy, and Bethlem myopathy

    NARCIS (Netherlands)

    de Visser, M.; de Voogt, W. G.; la Rivière, G. V.

    1992-01-01

    We report a study, assessing involvement of the heart in 33 familial cases of Becker muscular dystrophy (BMD), 31 familiar cases of facioscapulohumeral (FSH) dystrophy, and 27 familial cases of Bethlem myopathy. In the patients with BMD, correlations of myocardial involvement with age and extent of

  8. Genetics Home Reference: autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy

    Science.gov (United States)

    ... Facebook Twitter Home Health Conditions APECED Autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy Printable PDF Open All Close All ... view the expand/collapse boxes. Description Autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy ( APECED ) is an inherited condition that ...

  9. [Professional outcome of reflex sympathetic dystrophy].

    Science.gov (United States)

    Dauty, M; Renaud, P; Deniaud, C; Tortellier, L; Dubois, C

    2001-03-01

    In spite of physical medicine and rehabilitation care, post-traumatic reflex sympathetic dystrophy can be at the origin of articular deficiency, which decrease the capacity to return to work. The aim of this study is to know the professional future of patients who present post-traumatic reflex sympathetic dystrophy. Eighteen months prospective study, carried out from patients in age to work, hospitalized in physical medicine and rehabilitation unit for ostéo-articular traumatism complicated by reflex sympathetic dystrophy. Description of the population and comorbidity factors preventing professional resumption. Determination of the duration of medical certificate and the modalities of professional resumption. From 16 patients in age to work, only 12 were able to resume a full time profession with an average period of 10.5 months +/- 5. The importance of the, the distale articular location of reflex sympathetic dystrophy (wrist - hand, ankle - foot), the association with a comorbidity such as chronic alcoholism represent pejorative factors of working resumption. Organizations of workstation are often necessary in six cases over eight, if the job is not sedentary. In the most complicated cases, inaptitudes in the work are pronounced with demand of professional reclassifying. Post-traumatic reflex sympathetic dystrophy represents a real challenge for the rehabilitation team, to minimize deficiencies and to help the patient to become again a worker.

  10. Morbidity in reflex sympathetic dystrophy

    Science.gov (United States)

    Murray, C.; Cohen, A.; Perkins, T.; Davidson, J.; Sills, J.

    2000-01-01

    Reflex sympathetic dystrophy (RSD), an unusual diagnosis in general paediatrics, is well recognised by paediatric rheumatologists. This study reports the presentation and the clinical course of 46 patients (35 female, age range 8-15.2) with RSD. The patients saw professionals from an average of 2.3 specialties (range 1-5). Twenty five (54%) had a history of trauma. Median time to diagnosis was 12 weeks (range 1-130). Many children had multiple investigations and treatments. Once diagnosis was made, treatment followed with physiotherapy and analgesics. Median time to recovery was seven weeks (range 1-140), with 27.5% relapsing. Nine children required assessment by the child and adolescent psychiatry team. This disease, though rare, has significant morbidity and it is therefore important to raise clinicians' awareness of RSD in childhood. Children with the condition may then be recognised and referred for appropriate management earlier, and spared unnecessary investigations and treatments which may exacerbate the condition.

 PMID:10685927

  11. Duchenne muscular dystrophy: Case report and review.

    Science.gov (United States)

    Sinha, Rupam; Sarkar, Soumyabrata; Khaitan, Tanya; Dutta, Soumyajit

    2017-01-01

    Muscular dystrophies are a clinically and heterogeneous group of disorders that all share clinical characteristics of progressive muscular weakness. Duchenne muscular dystrophy (DMD) is the most common X-linked disorder muscular dystrophy in children, presenting in early childhood and characterized by proximal muscle weakness and calf hypertrophy in affected boys. There is usually delay in motor development and eventually wheelchair confinement followed by premature death from cardiac or respiratory complications. Treatment modalities such as corticosteroid therapy and use of intermittent positive pressure ventilation have provided improvements in function, ambulation, quality of life, and life expectancy, although novel therapies still aim to provide a cure for this devastating disorder. Here, we present a case of DMD in a 12-year-old male with remarkable clinical and oral manifestations.

  12. Reflex sympathetic dystrophy: reflections from a clinician.

    Science.gov (United States)

    Small, Eric

    2007-05-01

    Reflex sympathetic dystrophy is defined as chronic musculoskeletal pain and autonomic dysfunction. It is a difficult diagnosis to make, and the adolescent often sees many specialists before arriving at the correct diagnosis. In this article I review reflex sympathetic dystrophy and reflect on the differential diagnosis, pertinent medical history, personal characteristics of patients with reflex sympathetic dystrophy, physical examination, and laboratory evaluation. Principles of management are considered, including physical therapy, pharmacology, psychological therapy, and alternative therapies. Accurate diagnosis and management are critical for not prolonging the adolescent's and the family's suffering. It is important to provide aggressive physical therapy, stress management, relaxation training, and close follow-up. It is also critical to avoid immobilization, surgery, or invasive procedures and unnecessary tests.

  13. Duchenne muscular dystrophy: Case report and review

    Directory of Open Access Journals (Sweden)

    Rupam Sinha

    2017-01-01

    Full Text Available Muscular dystrophies are a clinically and heterogeneous group of disorders that all share clinical characteristics of progressive muscular weakness. Duchenne muscular dystrophy (DMD is the most common X-linked disorder muscular dystrophy in children, presenting in early childhood and characterized by proximal muscle weakness and calf hypertrophy in affected boys. There is usually delay in motor development and eventually wheelchair confinement followed by premature death from cardiac or respiratory complications. Treatment modalities such as corticosteroid therapy and use of intermittent positive pressure ventilation have provided improvements in function, ambulation, quality of life, and life expectancy, although novel therapies still aim to provide a cure for this devastating disorder. Here, we present a case of DMD in a 12-year-old male with remarkable clinical and oral manifestations.

  14. Mitochondrial disorders in progressive muscular dystrophies

    Directory of Open Access Journals (Sweden)

    D. A. Kharlamov

    2014-01-01

    Full Text Available The literature review gives data on the role of mitochondrial disorders in the pathogenesis of different progressive muscular dystrophies. It describes changes in Duchenne, limb-girdle, facial scapulohumeral (Landuzi—Degerina muscular dystrophies. The review is based on both clinical and experimental animal studies. Along with the implication of mitochondria in the pathogenesis of the diseases, it describes muscular dystrophy treatment options compensating for energy disorders and overcoming oxidative stress and mitochondrial dysfunction. Mitochondrial studies in different muscle diseases hand physicians treatment modalities that fail to lead to recovery, but compensate for disorders caused by mutations in the genetic apparatus. 

  15. Circulating Biomarkers for Duchenne Muscular Dystrophy.

    Science.gov (United States)

    Aartsma-Rus, Annemieke; Spitali, Pietro

    2015-07-22

    Duchenne muscular dystrophy is the most common form of muscular dystrophy. Genetic and biochemical research over the years has characterized the cause, pathophysiology and development of the disease providing several potential therapeutic targets and/or biomarkers. High throughput - omic technologies have provided a comprehensive understanding of the changes occurring in dystrophic muscles. Murine and canine animal models have been a valuable source to profile muscles and body fluids, thus providing candidate biomarkers that can be evaluated in patients. This review will illustrate known circulating biomarkers that could track disease progression and response to therapy in patients affected by Duchenne muscular dystrophy. We present an overview of the transcriptomic, proteomic, metabolomics and lipidomic biomarkers described in literature. We show how studies in muscle tissue have led to the identification of serum and urine biomarkers and we highlight the importance of evaluating biomarkers as possible surrogate endpoints to facilitate regulatory processes for new medicinal products.

  16. Munchausen's syndrome simulating reflex sympathetic dystrophy.

    Science.gov (United States)

    Rodriguez-Moreno, J; Ruiz-Martin, J M; Mateo-Soria, L; Rozadilla, A; Roig-Escofet, D

    1990-01-01

    A 15 year old girl who had pain, oedema of her left hand, and fever of four months' duration is described. Marked demineralisation of her hand was shown by radiography, and increased articular uptake by technetium-99m bone scan. All these changes were indistinguishable from reflex sympathetic dystrophy. After two admissions to hospital and multiple explorations we discovered that she had induced her symptoms herself and a diagnosis of Munchausen's syndrome was made. As far as we know this presentation has not been previously reported and might help to explain the physiopathology of some signs of reflex sympathetic dystrophy. Images PMID:2270960

  17. Nanotherapy for Duchenne muscular dystrophy.

    Science.gov (United States)

    Nance, Michael E; Hakim, Chady H; Yang, N Nora; Duan, Dongsheng

    2018-03-01

    Duchenne muscular dystrophy (DMD) is a lethal X-linked childhood muscle wasting disease caused by mutations in the dystrophin gene. Nanobiotechnology-based therapies (such as synthetic nanoparticles and naturally existing viral and nonviral nanoparticles) hold great promise to replace and repair the mutated dystrophin gene and significantly change the disease course. While a majority of DMD nanotherapies are still in early preclinical development, several [such as adeno-associated virus (AAV)-mediated systemic micro-dystrophin gene therapy] are advancing for phase I clinical trials. Recent regulatory approval of Ataluren (a nonsense mutation read-through chemical) in Europe and Exondys51 (an exon-skipping antisense oligonucleotide drug) in the United States shall offer critical insight in how to move DMD nanotherapy to human patients. Progress in novel, optimized nano-delivery systems may further improve emerging molecular therapeutic modalities for DMD. Despite these progresses, DMD nanotherapy faces a number of unique challenges. Specifically, the dystrophin gene is one of the largest genes in the genome while nanoparticles have an inherent size limitation per definition. Furthermore, muscle is the largest tissue in the body and accounts for 40% of the body mass. How to achieve efficient bodywide muscle targeting in human patients with nanomedication remains a significant translational hurdle. New creative approaches in the design of the miniature micro-dystrophin gene, engineering of muscle-specific synthetic AAV capsids, and novel nanoparticle-mediated exon-skipping are likely to result in major breakthroughs in DMD therapy. WIREs Nanomed Nanobiotechnol 2018, 10:e1472. doi: 10.1002/wnan.1472 This article is categorized under: Biology-Inspired Nanomaterials > Protein and Virus-Based Structures Therapeutic Approaches and Drug Discovery > Emerging Technologies. © 2017 Wiley Periodicals, Inc.

  18. Respiratory muscle training in Duchenne muscular dystrophy.

    OpenAIRE

    Rodillo, E; Noble-Jamieson, C M; Aber, V; Heckmatt, J Z; Muntoni, F; Dubowitz, V

    1989-01-01

    Twenty two boys with Duchenne muscular dystrophy were entered into a randomised double blind crossover trial to compare respiratory muscle training with a Triflow II inspirometer and 'placebo' training with a mini peak flow meter. Supine posture was associated with significantly impaired lung function, but respiratory muscle training showed no benefit.

  19. Aberrant Myokine Signaling in Congenital Myotonic Dystrophy

    Directory of Open Access Journals (Sweden)

    Masayuki Nakamori

    2017-10-01

    Full Text Available Summary: Myotonic dystrophy types 1 (DM1 and 2 (DM2 are dominantly inherited neuromuscular disorders caused by a toxic gain of function of expanded CUG and CCUG repeats, respectively. Although both disorders are clinically similar, congenital myotonic dystrophy (CDM, a severe DM form, is found only in DM1. CDM is also characterized by muscle fiber immaturity not observed in adult DM, suggesting specific pathological mechanisms. Here, we revealed upregulation of the interleukin-6 (IL-6 myokine signaling pathway in CDM muscles. We also found a correlation between muscle immaturity and not only IL-6 expression but also expanded CTG repeat length and CpG methylation status upstream of the repeats. Aberrant CpG methylation was associated with transcriptional dysregulation at the repeat locus, increasing the toxic RNA burden that upregulates IL-6. Because the IL-6 pathway is involved in myocyte maturation and muscle atrophy, our results indicate that enhanced RNA toxicity contributes to severe CDM phenotypes through aberrant IL-6 signaling. : Congenital myotonic dystrophy (CDM manifests characteristic genetic (very large CTG repeat expansions, epigenetic (CpG hypermethylation upstream of the repeat, and phenotypic (muscle immaturity features not seen in adult DM. Nakamori et al. find phenotype-genotype and epigenotype correlation in CDM muscle and reveal involvement of the IL-6 myokine signaling pathway in the disease process. Keywords: CTCF, ER stress, IL-6, muscular dystrophy, NF-κB, trinucleotide, cytokine, splicing

  20. Brain Function in Duchenne Muscular Dystrophy

    Directory of Open Access Journals (Sweden)

    J. Gordon Millichap

    2002-02-01

    Full Text Available The role of dystrophin disorders in the CNS function of boys with Duchenne muscular dystrophy (DMD and the dystrophin-deficient mdx mouse, an animal model of DMD, is reviewed at the University of New South Wales, University of Sydney, Australia.

  1. A Drosophila model for Duchenne muscular dystrophy

    NARCIS (Netherlands)

    Plas, Mariska Cathelijne van der

    2008-01-01

    Duchenne Muscular Dystrophy (DMD) is a severe X-linked disease characterized by progressive muscle wasting and sometimes mild mental retardation. The disease is caused by mutations in the dystrophin gene. DMD is correlated with the absence of Dp427, which is located along the sarcolemma in skeletal

  2. Duchenne muscular dystrophy - a molecular service

    African Journals Online (AJOL)

    In 1987 a carrier detection and prenatal diagnostic service for. Duchenne muscular dystrophy using molecular technology was instituted at the Department of Human Genetics, Uni- versity of Cape Town, to serve affe.cted families in southern. Africa. DNA samples from 100 affected male subjects and. 350 of their relatives ...

  3. Merosin/laminin-2 and muscular dystrophy

    DEFF Research Database (Denmark)

    Wewer, U M; Engvall, E

    1996-01-01

    and skin. Merosin is the collective name for laminins that share a common subunit, the laminin alpha 2 chain. Merosin-deficient congenital muscular dystrophy (CMD) is caused by mutations in the laminin alpha 2 chain gene. The skin disease Herlitz junctional epidermolysis bullosa is caused by mutations...

  4. Respiratory function in facioscapulohumeral muscular dystrophy 1.

    Science.gov (United States)

    Wohlgemuth, M; Horlings, C G C; van der Kooi, E L; Gilhuis, H J; Hendriks, J C M; van der Maarel, S M; van Engelen, B G M; Heijdra, Y F; Padberg, G W

    2017-06-01

    To test the hypothesis that wheelchair dependency and (kypho-)scoliosis are risk factors for developing respiratory insufficiency in facioscapulohumeral muscular dystrophy, we examined 81 patients with facioscapulohumeral muscular dystrophy 1 of varying degrees of severity ranging from ambulatory patients to wheelchair-bound patients. We examined the patients neurologically and by conducting pulmonary function tests: Forced Vital Capacity, Forced Expiratory Volume in 1 second, and static maximal inspiratory and expiratory mouth pressures. We did not find pulmonary function test abnormalities in ambulant facioscapulohumeral muscular dystrophy patients. Even though none of the patients complained of respiratory dysfunction, mild to severe respiratory insufficiency was found in more than one third of the wheelchair-dependent patients. Maximal inspiratory pressures and maximal expiratory pressures were decreased in most patients, with a trend that maximal expiratory pressures were more affected than maximal inspiratory pressures. Wheelchair-dependent patients with (kypho-)scoliosis showed the most restricted lung function. Wheelchair-dependent patients with (kypho-)scoliosis are at risk for developing respiratory function impairment. We advise examining this group of facioscapulohumeral muscular dystrophy patients periodically, even in the absence of symptoms of respiratory insufficiency, given its frequency and impact on daily life and the therapeutic consequences. Copyright © 2017 Elsevier B.V. All rights reserved.

  5. Visuospatial Attention Disturbance in Duchenne Muscular Dystrophy

    Science.gov (United States)

    De Moura, Maria Clara Drummond Soares; do Valle, Luiz Eduardo Ribeiro; Resende, Maria Bernadete Dutra; Pinto, Katia Osternack

    2010-01-01

    Aim: The cognitive deficits present in the Duchenne muscular dystrophy (DMD) are not yet well characterized. Attention, considered to be the brain mechanism responsible for the selection of sensory stimuli, could be disturbed in DMD, contributing, at least partially, to the observed global cognitive deficit. The aim of this study was to…

  6. Antisense Oligonucleotide Therapy for Inherited Retinal Dystrophies

    NARCIS (Netherlands)

    Gerard, X.; Garanto Iglesias, A.; Rozet, J.M.; Collin, R.W.J.

    2016-01-01

    Inherited retinal dystrophies (IRDs) are an extremely heterogeneous group of genetic diseases for which currently no effective treatment strategies exist. Over the last decade, significant progress has been made utilizing gene augmentation therapy for a few genetic subtypes of IRD, although several

  7. Prevalence of congenital muscular dystrophy in Italy

    Science.gov (United States)

    Graziano, Alessandra; Bianco, Flaviana; D'Amico, Adele; Moroni, Isabella; Messina, Sonia; Bruno, Claudio; Pegoraro, Elena; Mora, Marina; Astrea, Guja; Magri, Francesca; Comi, Giacomo P.; Berardinelli, Angela; Moggio, Maurizio; Morandi, Lucia; Pini, Antonella; Petillo, Roberta; Tasca, Giorgio; Monforte, Mauro; Minetti, Carlo; Mongini, Tiziana; Ricci, Enzo; Gorni, Ksenija; Battini, Roberta; Villanova, Marcello; Politano, Luisa; Gualandi, Francesca; Ferlini, Alessandra; Muntoni, Francesco; Santorelli, Filippo Maria; Bertini, Enrico; Pane, Marika

    2015-01-01

    Objective: We provide a nationwide population study of patients with congenital muscular dystrophy in Italy. Methods: Cases were ascertained from the databases in all the tertiary referral centers for pediatric neuromuscular disorders and from all the genetic diagnostic centers in which diagnostic tests for these forms are performed. Results: The study includes 336 patients with a point prevalence of 0.563 per 100,000. Mutations were identified in 220 of the 336 (65.5%). The cohort was subdivided into diagnostic categories based on the most recent classifications on congenital muscular dystrophies. The most common forms were those with α-dystroglycan glycosylation deficiency (40.18%) followed by those with laminin α2 deficiency (24.11%) and collagen VI deficiency (20.24%). The forms of congenital muscular dystrophy related to mutations in SEPN1 and LMNA were less frequent (6.25% and 5.95%, respectively). Conclusions: Our study provides for the first time comprehensive epidemiologic information and point prevalence figures for each of the major diagnostic categories on a large cohort of congenital muscular dystrophies. The study also reflects the diagnostic progress in this field with an accurate classification of the cases according to the most recent gene discoveries. PMID:25653289

  8. Infrastructure for Clinical Trials in Duchenne Dystrophy

    Science.gov (United States)

    2010-09-13

    following are key research accomplishments for the Year 1 funding period: Manuscripts in process • DM Escolar, C Tesi -Rocha, E Henricson, J Florence, J...in steroid treated Duchenne Muscular Dystrophy. In revision for journal submission. • A. Zimmerman, C. Tesi -Rocha, P.R. Clemens, A. Connolly, S.T

  9. A novel AP4M1 mutation in autosomal recessive cerebral palsy syndrome and clinical expansion of AP-4 deficiency

    OpenAIRE

    Jameel, Muhammad; Klar, Joakim; Tariq, Muhammad; Moawia, Abubakar; Altaf Malik, Naveed; Seema Waseem, Syeda; Abdullah, Uzma; Naeem Khan, Tahir; Raininko, Raili; Baig, Shahid Mahmood; Dahl, Niklas

    2014-01-01

    BACKGROUND: Cerebral palsy (CP) is a heterogeneous neurodevelopmental disorder associated with intellectual disability in one-third of cases. Recent findings support Mendelian inheritance in subgroups of patients with the disease. The purpose of this study was to identify a novel genetic cause of paraplegic CP with intellectual disability in a consanguineous Pakistani family. METHODS: We performed whole-exome sequencing (WES) in two brothers with CP and intellectual disability. Analysis of AP...

  10. High Resolution Ultrasonography for Assessment of Renal Cysts in the PCK Rat Model of Autosomal Recessive Polycystic Kidney Disease

    Directory of Open Access Journals (Sweden)

    Sarika Kapoor

    2016-03-01

    Full Text Available Background/Aims: The PCK rat model of polycystic kidney disease is characterized by the progressive development of renal medullary cysts. Here, we evaluated the suitability of high resolution ultrasonography (HRU to assess the kidney and cyst volume in PCK rats, testing three different ultrasound image analysis methods, and correlating them with kidneys weights and histological examinations. Methods: After inducing anesthesia, PCK rats (n=18 were subjected to HRU to visualize the kidneys, to perform numeric and volumetric measurements of the kidney and any cysts observed, and to generate 3-dimensional images of the cysts within the kidney parenchyma. Results: HRU provided superior information in comparison to microscopic analysis of stained kidney sections. HRU-based kidney volumes correlated strongly with kidney weights (R2=0.809; PConclusion: HRU represents a useful diagnostic tool for kidney and cyst volume measurements in PCK rats. Sequential HRU examinations may be useful to study the effect of drugs on cyst growth without the need to euthanize experimental animals.

  11. Novel missense loss-of-function mutations of WNT1 in an autosomal recessive Osteogenesis imperfecta patient.

    Science.gov (United States)

    Won, Joon Yeon; Jang, Woo Young; Lee, Hye-Ran; Park, Seon Young; Kim, Woo-Young; Park, Jong Hoon; Kim, Yonghwan; Cho, Tae-Joon

    2017-08-01

    Osteogenesis imperfecta (OI) is a heritable skeletal disorder characterized by bone fragility and low bone mass. Recently, loss-of-function mutations of WNT1 have been reported to be causative in OI or osteoporosis. We report an OI patient with novel compound heterozygous WNT1 missense mutations, p.Glu123Asp and p.Cys153Gly. Both mutations are found in the exon 3, and the p.Glu123Asp is the most proximal N-terminus missense mutation among the reported WNT1 missense mutations in OI patients. In vitro functional analysis reveals that while expression of wildtype WNT1 stimulates canonical WNT1-mediated β-catenin signaling, that of individual WNT1 mutant fails to do so, indicative of the pathogenic nature of the WNT1 variants. Although the pathogenic mechanism of WNT1 defects in OI has yet to be uncovered, these findings further contribute to the implications and importance of functional relevance of WNT1 in skeletal disorders. Copyright © 2017. Published by Elsevier Masson SAS.

  12. A mutation in the FOXE3 gene causes congenital primary aphakia in an autosomal recessive consanguineous Pakistani family

    DEFF Research Database (Denmark)

    Anjum, Iram; Eiberg, Hans; Baig, Shahid Mahmood

    2010-01-01

    was shown by diagnostic restriction enzyme digest, and marker analysis of another aphakia family from Madagascar carrying the same mutation excluded the presence of a founder mutation. Clinical re-examination of the family was not possible due to the escalating security concerns and internal displacement...

  13. Altered TGFβ signaling and cardiovascular manifestations in patients with autosomal recessive cutis laxa type I caused by fibulin-4 deficiency

    Science.gov (United States)

    Renard, Marjolijn; Holm, Tammy; Veith, Regan; Callewaert, Bert L; Adès, Lesley C; Baspinar, Osman; Pickart, Angela; Dasouki, Majed; Hoyer, Juliane; Rauch, Anita; Trapane, Pamela; Earing, Michael G; Coucke, Paul J; Sakai, Lynn Y; Dietz, Harry C; De Paepe, Anne M; Loeys, Bart L

    2010-01-01

    Fibulin-4 is a member of the fibulin family, a group of extracellular matrix proteins prominently expressed in medial layers of large veins and arteries. Involvement of the FBLN4 gene in cardiovascular pathology was shown in a murine model and in three patients affected with cutis laxa in association with systemic involvement. To elucidate the contribution of FBLN4 in human disease, we investigated two cohorts of patients. Direct sequencing of 17 patients with cutis laxa revealed no FBLN4 mutations. In a second group of 22 patients presenting with arterial tortuosity, stenosis and aneurysms, FBLN4 mutations were identified in three patients, two homozygous missense mutations (p.Glu126Lys and p.Ala397Thr) and compound heterozygosity for missense mutation p.Glu126Val and frameshift mutation c.577delC. Immunoblotting analysis showed a decreased amount of fibulin-4 protein in the fibroblast culture media of two patients, a finding sustained by diminished fibulin-4 in the extracellular matrix of the aortic wall on immunohistochemistry. pSmad2 and CTGF immunostaining of aortic and lung tissue revealed an increase in transforming growth factor (TGF)β signaling. This was confirmed by pSmad2 immunoblotting of fibroblast cultures. In conclusion, patients with recessive FBLN4 mutations are predominantly characterized by aortic aneurysms, arterial tortuosity and stenosis. This confirms the important role of fibulin-4 in vascular elastic fiber assembly. Furthermore, we provide the first evidence for the involvement of altered TGFβ signaling in the pathogenesis of FBLN4 mutations in humans. PMID:20389311

  14. The emergence of hepatic fibrosis and portal hypertension in infants and children with autosomal recessive polycystic kidney disease

    International Nuclear Information System (INIS)

    Premkumar, A.; Berdon, W.E.; Abramson, S.J.; Newhouse, J.H.; Levy, J.

    1988-01-01

    Long-term imaging and clinical findings are reported in six children whose polycystic kidney disease was detected in infancy or early childhood. Over time (2 years to 20 years) all patients developed portal hypertension from hepatic fibrosis, a problem primarily noted in recessive pattern polycystic kidney disease. Mild renal failure (two patients) was accompanied by serious systemic hypertension in the same patients. In one family, one of the babies also showed dilated right hepatic ducts. Imaging studies included urography and CT although recently ultrasonography was the method of choice. The relative renal and hepatic manifestations in these patients so changed with time that it would seem fallacious to attempt to use rigid classifications based on findings at initial diagnosis. (orig.)

  15. Biallelic Mutations in GNB3 Cause a Unique Form of Autosomal-Recessive Congenital Stationary Night Blindness.

    Science.gov (United States)

    Vincent, Ajoy; Audo, Isabelle; Tavares, Erika; Maynes, Jason T; Tumber, Anupreet; Wright, Thomas; Li, Shuning; Michiels, Christelle; Condroyer, Christel; MacDonald, Heather; Verdet, Robert; Sahel, José-Alain; Hamel, Christian P; Zeitz, Christina; Héon, Elise

    2016-05-05

    Congenital stationary night blindness (CSNB) is a heterogeneous group of non-progressive inherited retinal disorders with characteristic electroretinogram (ERG) abnormalities. Riggs and Schubert-Bornschein are subtypes of CSNB and demonstrate distinct ERG features. Riggs CSNB demonstrates selective rod photoreceptor dysfunction and occurs due to mutations in genes encoding proteins involved in rod phototransduction cascade; night blindness is the only symptom and eye examination is otherwise normal. Schubert-Bornschein CSNB is a consequence of impaired signal transmission between the photoreceptors and bipolar cells. Schubert-Bornschein CSNB is subdivided into complete CSNB with an ON bipolar signaling defect and incomplete CSNB with both ON and OFF pathway involvement. Both subtypes are associated with variable degrees of night blindness or photophobia, reduced visual acuity, high myopia, and nystagmus. Whole-exome sequencing of a family screened negative for mutations in genes associated with CSNB identified biallelic mutations in the guanine nucleotide-binding protein subunit beta-3 gene (GNB3). Two siblings were compound heterozygous for a deletion (c.170_172delAGA [p.Lys57del]) and a nonsense mutation (c.1017G>A [p.Trp339(∗)]). The maternal aunt was homozygous for the nonsense mutation (c.1017G>A [p.Trp339(∗)]). Mutational analysis of GNB3 in a cohort of 58 subjects with CSNB identified a sporadic case individual with a homozygous GNB3 mutation (c.200C>T [p.Ser67Phe]). GNB3 encodes the β subunit of G protein heterotrimer (Gαβγ) and is known to modulate ON bipolar cell signaling and cone transducin function in mice. Affected human subjects showed an unusual CSNB phenotype with variable degrees of ON bipolar dysfunction and reduced cone sensitivity. This unique retinal disorder with dual anomaly in visual processing expands our knowledge about retinal signaling. Copyright © 2016 The American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.

  16. A novel mutation in the sterol 27-hydroxylase gene of a woman with autosomal recessive cerebrotendinous xanthomatosis

    Directory of Open Access Journals (Sweden)

    Garuti Rita

    2010-10-01

    Full Text Available Article abstract Mutations of the gene encoding the mitochondrial enzyme sterol 27-hydroxylase (CYP27A1 gene cause defects in the cholesterol pathway to bile acids that lead to the storage of cholestanol and cholesterol in tendons, lenses and the central nervous system. This disorder is the cause of a clinical syndrome known as cerebrotendinous xanthomatosis (CTX. Since 1991 several mutations of the CYP27A1 gene have been reported. We diagnosed the clinical features of CTX in a caucasian woman. Serum levels of cholestanol and 7α-hydroxycholesterol were elevated and the concentration of 27-hydroxycholesterol was reduced. Bile alcohols in the urine and faeces were increased. The analysis of the CYP27A1 gene showed that the patient was a compound heterozygote carrying two mutations both located in exon 8. One mutation is a novel four nucleotide deletion (c.1330-1333delTTCC that results in a frameshift and the occurrence of a premature stop codon leading to the formation of a truncated protein of 448 amino acids. The other mutation, previously reported, is a C - > T transition (c. c.1381C > T that converts the glutamine codon at position 461 into a termination codon (p.Q461X. These truncated proteins are expected to have no biological function being devoid of the cysteine residue at position 476 of the normal enzyme that is crucial for heme binding and enzyme activity.

  17. Canine Disorder Mirrors Human Disease: Exonic Deletion in HES7 Causes Autosomal Recessive Spondylocostal Dysostosis in Miniature Schnauzer Dogs

    OpenAIRE

    Willet, Cali E.; Makara, Mariano; Reppas, George; Tsoukalas, George; Malik, Richard; Haase, Bianca; Wade, Claire M.

    2015-01-01

    Spondylocostal dysostosis is a congenital disorder of the axial skeleton documented in human families from diverse racial backgrounds. The condition is characterised by truncal shortening, extensive hemivertebrae and rib anomalies including malalignment, fusion and reduction in number. Mutations in the Notch signalling pathway genes DLL3, MESP2, LFNG, HES7 and TBX6 have been associated with this defect. In this study, spondylocostal dysostosis in an outbred family of miniature schnauzer dogs ...

  18. Lethal autosomal recessive epidermolytic ichthyosis due to a novel donor splice-site mutation in KRT10.

    Science.gov (United States)

    Covaciu, C; Castori, M; De Luca, N; Ghirri, P; Nannipieri, A; Ragone, G; Zambruno, G; Castiglia, D

    2010-06-01

    Epidermolytic ichthyosis (EI; MIM 113800), previously named bullous congenital ichthyosiform erythroderma or epidermolytic hyperkeratosis, is a rare and clinically variable defect of cornification characterized by generalized erythema, erosions, scaling and easily breaking blisters that become less frequent later in life while hyperkeratosis increases. EI is caused by dominant mutations in either KRT1 or KRT10, encoding keratin 1 (K1) and keratin 10 (K10), respectively. Usually, mutations are missense substitutions into the highly conserved α-helical rod domains of the proteins. However, three inbred pedigrees in which EI is transmitted as a recessive trait due to KRT10 null mutations have been described. © 2010 The Authors. Journal Compilation © 2010 British Association of Dermatologists.

  19. Relative frequency of GJB2 gene mutations in autosomal recessive non-syndromic hearing loss (ARNSHL patients in Lorestan population

    Directory of Open Access Journals (Sweden)

    mitra Sapahvand

    2007-01-01

    Conclusion: Unexpectedly, in this research just 17 percent of cases are covered. In this study 510 insCGAA mutation was seen. This is a new mutation which is not reported in other studied populations in the world. Hence, this research shows that – at least in our studied population- the effect of other genes that could cause non-syndromic hearing loss is possible and should be studied

  20. Loss of ZMPSTE24 (FACE-1) causes autosomal recessive restrictive dermopathy and accumulation of Lamin A precursors

    NARCIS (Netherlands)

    Navarro, Claire L.; Cadiñanos, Juan; de Sandre-Giovannoli, Annachiara; Bernard, Rafaëlle; Courrier, Sébastien; Boccaccio, Irène; Boyer, Amandine; Kleijer, Wim J.; Wagner, Anja; Giuliano, Fabienne; Beemer, Frits A.; Freije, Jose M.; Cau, Pierre; Hennekam, Raoul C. M.; López-Otín, Carlos; Badens, Catherine; Lévy, Nicolas

    2005-01-01

    Restrictive dermopathy (RD) is characterized by intrauterine growth retardation, tight and rigid skin with prominent superficial vessels, bone mineralization defects, dysplastic clavicles, arthrogryposis and early neonatal death. In two patients affected with RD, we recently reported two different

  1. Hypomorphic mutations in PGAP2, encoding a GPI-anchor-remodeling protein, cause autosomal-recessive intellectual disability

    DEFF Research Database (Denmark)

    Hansen, Lars; Tawamie, Hasan; Murakami, Yoshiko

    2013-01-01

    families. Rescue experiments with the altered proteins in PGAP2-deficient Chinese hamster ovary cell lines showed less expression of cell-surface GPI-anchored proteins DAF and CD59 than of the wild-type protein, substantiating the pathogenicity of the identified alterations. Furthermore, we observed a full...

  2. Clinical and neuroimaging features of autosomal recessive spastic paraplegia 35 (SPG35): case reports, new mutations, and brief literature review.

    Science.gov (United States)

    Mari, Francesco; Berti, Beatrice; Romano, Alessandro; Baldacci, Jacopo; Rizzi, Riccardo; Grazia Alessandrì, M; Tessa, Alessandra; Procopio, Elena; Rubegni, Anna; Lourenḉo, Charles Marques; Simonati, Alessandro; Guerrini, Renzo; Santorelli, Filippo Maria

    2018-02-08

    Spastic paraplegia 35 (SPG35) is a recessive condition characterized by childhood onset, progressive course, complicated by dystonia, dysarthria, cognitive impairment, and epilepsy. Mutations in the FA2H gene have been described in several families, leading to the proposal of a single entity, named fatty acid hydrolase-associated neurodegeneration (FAHN). Several reports have described a polymorphic radiological picture with white matter lesions of various degrees and a distinct form of neurodegeneration with brain iron accumulation. While we reviewed the pertinent literature, we also report three new patients with SPG35, highlighting the possible absence of white matter lesions even after a long neuroimaging follow-up. Three-dimensional modeling of the mutated proteins was helpful to elucidate the role of the site of mutations and the correlation with the residual enzyme activity as determined in cultured skin fibroblasts.

  3. PLEKHG5 deficiency leads to an intermediate form of autosomal-recessive Charcot–Marie–Tooth disease

    Science.gov (United States)

    Azzedine, Hamid; Zavadakova, Petra; Planté-Bordeneuve, Violaine; Vaz Pato, Maria; Pinto, Nuno; Bartesaghi, Luca; Zenker, Jennifer; Poirot, Olivier; Bernard-Marissal, Nathalie; Arnaud Gouttenoire, Estelle; Cartoni, Romain; Title, Alexandra; Venturini, Giulia; Médard, Jean-Jacques; Makowski, Edward; Schöls, Ludger; Claeys, Kristl G.; Stendel, Claudia; Roos, Andreas; Weis, Joachim; Dubourg, Odile; Leal Loureiro, José; Stevanin, Giovanni; Said, Gérard; Amato, Anthony; Baraban, Jay; LeGuern, Eric; Senderek, Jan; Rivolta, Carlo; Chrast, Roman

    2013-01-01

    Charcot–Marie–Tooth disease (CMT) comprises a clinically and genetically heterogeneous group of peripheral neuropathies characterized by progressive distal muscle weakness and atrophy, foot deformities and distal sensory loss. Following the analysis of two consanguineous families affected by a medium to late-onset recessive form of intermediate CMT, we identified overlapping regions of homozygosity on chromosome 1p36 with a combined maximum LOD score of 5.4. Molecular investigation of the genes from this region allowed identification of two homozygous mutations in PLEKHG5 that produce premature stop codons and are predicted to result in functional null alleles. Analysis of Plekhg5 in the mouse revealed that this gene is expressed in neurons and glial cells of the peripheral nervous system, and that knockout mice display reduced nerve conduction velocities that are comparable with those of affected individuals from both families. Interestingly, a homozygous PLEKHG5 missense mutation was previously reported in a recessive form of severe childhood onset lower motor neuron disease (LMND) leading to loss of the ability to walk and need for respiratory assistance. Together, these observations indicate that different mutations in PLEKHG5 lead to clinically diverse outcomes (intermediate CMT or LMND) affecting the function of neurons and glial cells. PMID:23777631

  4. Inherited Retinal Degenerative Disease Registry

    Science.gov (United States)

    2017-09-13

    Eye Diseases Hereditary; Retinal Disease; Achromatopsia; Bardet-Biedl Syndrome; Bassen-Kornzweig Syndrome; Batten Disease; Best Disease; Choroidal Dystrophy; Choroideremia; Cone Dystrophy; Cone-Rod Dystrophy; Congenital Stationary Night Blindness; Enhanced S-Cone Syndrome; Fundus Albipunctatus; Goldmann-Favre Syndrome; Gyrate Atrophy; Juvenile Macular Degeneration; Kearns-Sayre Syndrome; Leber Congenital Amaurosis; Refsum Syndrome; Retinitis Pigmentosa; Retinitis Punctata Albescens; Retinoschisis; Rod-Cone Dystrophy; Rod Dystrophy; Rod Monochromacy; Stargardt Disease; Usher Syndrome

  5. Cognitive and Neurobehavioral Profile in Boys With Duchenne Muscular Dystrophy.

    Science.gov (United States)

    Banihani, Rudaina; Smile, Sharon; Yoon, Grace; Dupuis, Annie; Mosleh, Maureen; Snider, Andrea; McAdam, Laura

    2015-10-01

    Duchenne muscular dystrophy is a progressive neuromuscular condition that has a high rate of cognitive and learning disabilities as well as neurobehavioral disorders, some of which have been associated with disruption of dystrophin isoforms. Retrospective cohort of 59 boys investigated the cognitive and neurobehavioral profile of boys with Duchenne muscular dystrophy. Full-scale IQ of Duchenne muscular dystrophy. © The Author(s) 2015.

  6. Molecular mechanisms of muscle atrophy in myotonic dystrophies

    OpenAIRE

    Timchenko, Lubov

    2013-01-01

    Myotonic dystrophy type 1 (DM1) and myotonic dystrophy type 2 (DM2) are multisystemic diseases that primarily affect skeletal muscle, causing myotonia, muscle atrophy, and muscle weakness. DM1 and DM2 pathologies are caused by expansion of CTG and CCTG repeats in non-coding regions of the genes encoding myotonic dystrophy protein kinase (DMPK) and Zinc finger protein 9 (ZNF9) respectively. These expansions cause DM pathologies through accumulation of mutant RNAs that alter RNA metabolism in p...

  7. CT finding and cerebrospinal fluid proteins in muscular dystrophy patients

    International Nuclear Information System (INIS)

    Hirase, Tsutomu; Ide, Masami; Araki, Shukuro; Okamoto, Hiroshi; Kawasaki, Shoichiro; Imamura, Shigehiro.

    1983-01-01

    We analyzed the microcomponents of protein fractions in the cerebrospinal fluid of patients with various types of muscular dystrophy. The degenerative pattern is characterized by an increase in the prealbumin and a decrease in the γ-globulin fraction is shown in the Duchenne and congenital muscular dystrophy. The increase in CSF IgG, γ-globulin fraction is shown in the myotonic dystrophy. In addition to the abnormality of IQ, EEG, and brain CT, abnormal CSF proteins obviously suggest the presence of CNS involvement in muscular dystrophy. (author)

  8. Pain characterization in Duchenne muscular dystrophy

    Directory of Open Access Journals (Sweden)

    Talita Dias da Silva

    Full Text Available ABSTRACT Duchenne muscular dystrophy (DMD is an X-linked recessive disorder, characterized by progressive muscle weakness. Historically, pain has not been considered to be a major symptom in DMD. Objective To investigate the relationship between DMD and pain. Methods We conducted a systematic review in Medline/PubMed and BVS (virtual library in health databases. We searched for articles that showed the terms “Muscular Dystrophy, Duchenne” and “Pain” in all fields. All studies included boys diagnosed with DMD and the occurrence/amount of pain on this population. Results Initially, there were 175 studies. 167 articles were excluded for not meeting the inclusion criteria. The remaining eight eligible studies, involving pain assessment in DMD, were analyzed. Conclusion Pain is a frequent problem in this population and this symptom is potentially tractable. Studies conclude that pain can directly influence the quality of life of this population.

  9. [Human myopathy and animal muscular dystrophy].

    Science.gov (United States)

    Schapira, G; Dreyfus, J C; Schapira, F

    1977-08-01

    Two hereditary muscular dystrophies similar to human progressive muscular dystrophy (P.M.D. Duchenne type) have been isolated in animals, one in mouse, the other in chicken. The decrease in the activity of glycogenolytic enzymes is similar to that observed in denervated muscle. Isozymic fetal types for several muscular enzymes have been observed as well in chicken as in man, but this fetal type may also be found in neurogenic atrophy. The release in circulation of muscle enzymes seems more specific. But the origin of the genetic lesion is still unknown. We describe here the three different theories about this problem: i.e. neurogenic, vascular, or myogenic. This last theory implies a trouble of membrane permeability.

  10. Dismantling Limb-Girdle Muscular Dystrophy

    OpenAIRE

    Narayanaswami, Pushpa

    2015-01-01

    Muscular dystrophy encompasses a diverse group of genetically determined muscle disorders. The first clinical description of the disorder is attributed to Giovanni Semmola, who, in 1829, described 2 boys affected by a disorder with prominent muscular hypertrophy.1 Between 1850 and 1868, Aran, Meryon, and Duchenne described a progressive atrophy of voluntary muscles, ultimately termed pseudohypertrophic muscular paralysis of children by Duchenne.1,2 Other descriptions followed: familial atroph...

  11. Rehabilitation therapy of Duchenne muscular dystrophy

    OpenAIRE

    ZHANG Cheng; YANG Juan

    2012-01-01

    It is very important that the rehabilitation therapy of Duchenne muscular dystrophy (DMD) can improve the quality of life and delay the disease progression. There are the guidelines for DMD rehabilitation therapy in some countries, but it is not emphasized by clinical doctors in our country. According to our experiences to DMD rehabilitation therapy, we reviewed the progress of DMD rehabilitation therapy. It includes the clinical stages and characteristics of DMD, the general principle and th...

  12. Corneal elastosis within lattice dystrophy lesions.

    Science.gov (United States)

    Pe'er, J; Fine, B S; Dixon, A; Rothberg, D S

    1988-01-01

    Corneal buttons of two patients with lattice corneal dystrophy were studied by light and electron microscopy. They showed elastotic degeneration within the amyloid deposits. The amyloid deposits displayed characteristic staining; the elastotic material (elastin) within the deposits stained positive with Verhoeff-van Gieson and Movat pentachrome stains and showed autofluorescence. The characteristic ultrastructural findings of amyloid and elastotic material were also demonstrated. The possibility of the associations of these two materials in the cornea is discussed. Images PMID:3258531

  13. Urological manifestations of Duchenne muscular dystrophy.

    Science.gov (United States)

    Askeland, Eric J; Arlen, Angela M; Erickson, Bradley A; Mathews, Katherine D; Cooper, Christopher S

    2013-10-01

    Duchenne muscular dystrophy is a dystrophinopathy affecting males that is associated with multiple organ system complications. To our knowledge urological complications of Duchenne muscular dystrophy have been described only anecdotally to date. We reviewed the medical charts of 135 patients with Duchenne or Duchenne-Becker muscular dystrophy for demographics and disease progression, urological diagnoses, intervention and followup. Of 135 patients 67 (50%) had at least 1 documented urological diagnosis and 38 (28%) had multiple manifestations. Lower urinary tract symptoms were the most common urological diagnosis (32% of patients). Survival analysis revealed a median age at onset of lower urinary tract symptoms of 23 years (95% CI 17.7-23.9). Intervention was required in 12 patients (9%), most commonly due to nephrolithiasis. Urological morbidity increased with Duchenne muscular dystrophy progression when stratified by clinical progression. Lower urinary tract symptoms were more common in nonambulatory patients (40.7% vs 19%, p = 0.007), those with a diagnosis of scoliosis (44% vs 19.7%, p = 0.003) and/or scoliosis spine surgery (60% vs 22%, p <0.001), and those on invasive respiratory support (53% vs 29%, p = 0.046). Likewise, nephrolithiasis was more common in nonambulatory patients (10% vs 0%, p = 0.017), those with scoliosis (12% vs 0%, p = 0.004) and/or scoliosis spine surgery (20% vs 1%, p <0.001), and those on invasive respiratory support (29% vs 3%, p <0.001). Only 28% of patients with a urological manifestation were referred to urology. As these patients transition into adolescence and adulthood, the increased prevalence of urological manifestations warrants increased awareness and referral to urologists. Copyright © 2013 American Urological Association Education and Research, Inc. Published by Elsevier Inc. All rights reserved.

  14. Nutrition Considerations in Duchenne Muscular Dystrophy.

    Science.gov (United States)

    Davis, Jillian; Samuels, Emily; Mullins, Lucille

    2015-08-01

    Duchenne muscular dystrophy (DMD) is a serious degenerative muscular disease affecting males. Diagnosis usually occurs in childhood and is confirmed through genetic testing and/or muscle biopsy. Accompanying the disease are several nutrition-related concerns: growth, body composition, energy and protein requirements, constipation, swallowing difficulties, bone health, and complementary medicine. This review article addresses the nutrition aspects of DMD. © 2015 American Society for Parenteral and Enteral Nutrition.

  15. CONGENITAL MYOTONIC DYSTROPHY – CASE REPORT

    Directory of Open Access Journals (Sweden)

    David Neubauer

    2001-07-01

    Full Text Available Background. Myotonic dystrophy is inherited as an autosomal dominant trait. It is characterized by myotonia, myopathy of voluntary and involuntary muscles, frontal baldness in men, cardiac conduction abnormalities, catharacts, intellectual deterioration and endocrinopathy. Men with this disorder have often gonadal atrophy and infertility. On the other hand women are generally fertile. During pregnancy their myopathy worsens, often causing severe obstetrical complications. Their children may develop congenital form of the disease with signs of myopathy in utero and have great difficulties in maintaining life functions after birth, together with other characteristical signs of this form: bilateral facial weakness, severe hypotonia, feeding difficulties, talipes equinovarus and mental retardation. The authors present a female newborn with such congenital form of myotonic dystrophy.Conclusions. The authors have emphasized the importance of medical history, regular updating of all the cases of neuromuscular diseases in the region and clinical characteristics for the recognition of congenital form of myotonic dystrophy because of possible prenatal diagnostics and better antenatal and postantal care.

  16. Management of myocardial damage in muscular dystrophy

    International Nuclear Information System (INIS)

    Tamura, Takuhisa

    2011-01-01

    Heart failure (HF) is a fatal complication in many muscular dystrophy cases and has become the most common cause of death in Duchenne muscular dystrophy (DMD) since 2001. HF deaths in DMD occur in young patients and increase, along with respiratory failure, in older patients. Managing HF, therefore, is the most important component of DMD treatment. Management of HF is necessary in DMD patients of all ages because myocardial damage progresses regardless of age and disability. Electrocardiography, echocardiography, myocardial single-photon emission computed tomography (SPECT), and natriuretic peptides are used for the diagnosis of myocardial damage and chronic HF. Tissue Doppler echocardiography is in particularly useful for early detection of minute myocardial damage and dysfunction in DMD. The first-line drugs for chronic HF are angiotensin-converting enzyme inhibitors, and the prognosis of DMD patients has been improved using these drugs and beta-blockers. Diuretics are added in the presence of pulmonary congestion. Digoxin is most effective at a blood level of 0.5-0.8 ng/mL because of its pharmacokinetics in DMD. Surgical treatment may be necessary in cases of intractable HF. Cardiac resynchronization therapy (biventricular pacing), a treatment with an artificial pacemaker, is indicated for cases that meet specific criteria, including HF with ventricular dyssynchrony. Applications of partial left ventriculectomy (Batista procedure) and left ventricular assist devices in muscular dystrophy are likely in the near future. (author)

  17. Gene therapy for Duchenne muscular dystrophy.

    Science.gov (United States)

    Verhaart, Ingrid E C; Aartsma-Rus, Annemieke

    2012-10-01

    Duchenne muscular dystrophy is a severe neuromuscular disorder for which there is currently no cure. Years of research have come to fruition during the past 18 months with publications on clinical trials for several gene therapy approaches for Duchenne muscular dystrophy. This review covers the present status of these approaches. The exon skipping approach is most advanced in the process of clinical application. Encouraging results have been obtained in two systemic clinical trials and further optimization has increased delivery to the heart in animal models. Limitations of the approach are the mutation-specificity and the anticipated requirement for lifelong treatment. Gene therapy by means of gene transfer holds the promise of more long-lasting effects. Results of a first, early-stage gene therapy trial, using viral vectors to deliver a minidystrophin gene, were reported. Animal studies suggest that it may be possible to overcome the main challenges currently facing gene therapy (immunogenicity of the vector and systemic body-wide delivery). Significant steps have been made in the development of gene therapy approaches for Duchenne muscular dystrophy. These approaches aim to slow down disease progression, requiring robust outcome measures to assess efficacy.

  18. Surgery for scoliosis in Duchenne muscular dystrophy.

    Science.gov (United States)

    Cheuk, Daniel K L; Wong, Virginia; Wraige, Elizabeth; Baxter, Peter; Cole, Ashley

    2013-02-28

    Scoliosis in people with Duchenne muscular dystrophy is usually progressive and treated with surgery. However, it is unclear whether the existing evidence is sufficiently scientifically rigorous to support a recommendation for spinal surgery for most people with Duchenne muscular dystrophy and scoliosis. This is an updated review and an updated search was undertaken in which no new studies were found. To determine the effectiveness and safety of spinal surgery in people with Duchenne muscular dystrophy with scoliosis. We intended to test whether spinal surgery is effective in increasing survival, improving respiratory function, improving quality of life and overall functioning; and whether spinal surgery is associated with severe adverse effects. We searched the specialized registers of the Cochrane Neuromuscular Disease Group (31 July 2012), MEDLINE (January 1966 to July 2012), EMBASE (January 1947 to July 2012), CENTRAL (2012, Issue 7 in the Cochrane Library), CINAHL Plus(January 1937 to July 2012), Proquest Dissertation and Thesis Database (January 1980 to July 2012), and the National Institute of Health Clinical Trials Database (July 2012). No language restrictions were imposed. We planned to include controlled clinical trials using random or quasi-random allocation of treatment evaluating all forms of spinal surgery for scoliosis in people with Duchenne muscular dystrophy in the review. The control interventions would have been no treatment, non-operative treatment, or a different form of spinal surgery. Two authors independently examined the search results and evaluated the study characteristics against inclusion criteria to decide which ones would be included in the review. On searching, 47 studies were relevant but none met the inclusion criteria for the review, because they were not clinical trials but prospective or retrospective reviews of case series. Since there were no randomized controlled clinical trials available to evaluate the effectiveness of

  19. Resistance training in patients with limb-girdle and becker muscular dystrophies

    DEFF Research Database (Denmark)

    Sveen, Marie-Louise; Andersen, Søren P; Ingelsrud, Lina H

    2013-01-01

    In this study we investigated the effect of strength training in patients with limb-girdle muscular dystrophy (LGMD) and Becker muscular dystrophy (BMD).......In this study we investigated the effect of strength training in patients with limb-girdle muscular dystrophy (LGMD) and Becker muscular dystrophy (BMD)....

  20. Central areolar choroidal dystrophy with associated dominant drusen

    Directory of Open Access Journals (Sweden)

    Julie Rodman

    2013-04-01

    Conclusion: Central areolar choroidal dystrophy normally presents without drusen. However, in patients manifesting a specific mutation, central areolar choridal dystrophy may present in conjunction with drusen. It appears that the Arg142Trp mutation is one of the factors predisposing to drusen formation.

  1. Dysphagia is present but mild in myotonic dystrophy type 2

    NARCIS (Netherlands)

    R. Ensink; Bert de Swart; J. van Vliet; A. Tieleman; Baziel van Engelen; S. Knuijt

    2009-01-01

    The phenotype of myotonic dystrophy type 2 (DM2) shows similarities as well as differences to that of myotonic dystrophy type 1 (DM1). Dysphagia, a predominant feature in DM1, has not yet been examined in DM2. In a recent nationwide questionnaire survey of gastrointestinal symptoms in DM2, 12 out of

  2. Epithelioid sarcoma presenting as the reflex sympathetic dystrophy syndrome.

    Science.gov (United States)

    Summers, C. L.; Shahi, M.

    1987-01-01

    A case of reflex sympathetic dystrophy caused by an epithelioid sarcoma is presented. This is the first report of a local peripheral tumour associated with the reflex sympathetic dystrophy syndrome. Images Figure 1 Figure 2 Figure 3 Figure 4 Figure 5 PMID:3671265

  3. Genetic modifiers of Duchenne and facioscapulohumeral muscular dystrophies.

    Science.gov (United States)

    Hightower, Rylie M; Alexander, Matthew S

    2018-01-01

    Muscular dystrophy is defined as the progressive wasting of skeletal muscles that is caused by inherited or spontaneous genetic mutations. Next-generation sequencing has greatly improved the accuracy and speed of diagnosis for different types of muscular dystrophy. Advancements in depth of coverage, convenience, and overall reduced cost have led to the identification of genetic modifiers that are responsible for phenotypic variability in affected patients. These genetic modifiers have been postulated to explain key differences in disease phenotypes, including age of loss of ambulation, steroid responsiveness, and the presence or absence of cardiac defects in patients with the same form of muscular dystrophy. This review highlights recent findings on genetic modifiers of Duchenne and facioscapulohumeral muscular dystrophies based on animal and clinical studies. These genetic modifiers hold great promise to be developed into novel therapeutic targets for the treatment of muscular dystrophies. Muscle Nerve 57: 6-15, 2018. © 2017 Wiley Periodicals, Inc.

  4. Psychiatric disorders appear equally in patients with myotonic dystrophy, facioscapulohumeral dystrophy, and hereditary motor and sensory neuropathy type I.

    NARCIS (Netherlands)

    Kalkman, J.S.; Schillings, M.L.; Zwarts, M.J.; Engelen, B.G.M. van; Bleijenberg, G.

    2007-01-01

    OBJECTIVES: To study the presence of psychiatric comorbidity assessed by the use of a structured clinical interview and self-reported questionnaires in a large sample of patients with adult-onset myotonic dystrophy (DM), facioscapulohumeral muscular dystrophy (FSHD), and hereditary motor and sensory

  5. Signs and symptoms of Duchenne muscular dystrophy and Becker muscular dystrophy among carriers in the Netherlands : a cohort study

    NARCIS (Netherlands)

    Hoogerwaard, EM; Bakker, E; Ippel, PF; Oosterwijk, JC; Majoor-Krakauer, DF; Leschot, NJ; Van Essen, AJ; Brunner, HG; van der Wouw, PA; Wilde, AAM; de Visser, Marianne

    1999-01-01

    Background Carriers of Duchenne muscular dystrophy (DMD) and Becker muscular dystrophy (BMD) may show muscle weakness or dilated cardiomyopathy. Studies focusing on skeletal-muscle involvement were done before DNA analysis was possible. We undertook a cross-sectional study in a population of

  6. Reflex sympathetic dystrophy following pacemaker insertion.

    Science.gov (United States)

    Londhey, Vikram A; Singh, Nishant; Kini, Seema

    2011-09-01

    A 55 year old male presented with pain and swelling over dorsum of right hand and small joints, and loss of sweating over right hand since two months. He was a known case of mitral valve prolapse (MVP) with mitral regurgitation and complete heart block for which pacemaker was implanted 1 year back. Bilateral wrist X-ray was suggestive of pronounced demineralization (osteopenia) in the right hand. He was thus diagnosed to have reflex sympathetic dystrophy syndrome (RSDS) considered to be induced by pacemaker insertion. After treatment with amitryptiline and indomethacin his symptoms dramatically improved.

  7. Rehabilitation therapy of Duchenne muscular dystrophy

    Directory of Open Access Journals (Sweden)

    ZHANG Cheng

    2012-06-01

    Full Text Available It is very important that the rehabilitation therapy of Duchenne muscular dystrophy (DMD can improve the quality of life and delay the disease progression. There are the guidelines for DMD rehabilitation therapy in some countries, but it is not emphasized by clinical doctors in our country. According to our experiences to DMD rehabilitation therapy, we reviewed the progress of DMD rehabilitation therapy. It includes the clinical stages and characteristics of DMD, the general principle and the common therapy methods of DMD rehabilitation. We hope this review may increase recognizing to DMD rehabilitation therapy for the clinical doctors and DMD family members.

  8. Anoctamin 5 muscular dystrophy in Denmark

    DEFF Research Database (Denmark)

    Witting, Nanna; Duno, Morten; Petri, Helle

    2013-01-01

    Since the initial description in 2010 of anoctamin 5 deficiency as a cause of muscular dystrophy, a handful of papers have described this disease in cases of mixed populations. We report the first large regional study and present data on new aspects of prevalence, muscular and cardiac phenotypic...... mutations caused 11 % of our total cohort of LGMD2 cases making it the second most common LGMD2 etiology in Denmark. Eight patients complained of dysphagia and 3 dated symptoms of onset in childhood. Cardiac examinations revealed increased frequency of premature ventricular contractions. Four novel putative...

  9. Genetics and emerging treatments for Duchenne and Becker muscular dystrophy.

    Science.gov (United States)

    Wein, Nicolas; Alfano, Lindsay; Flanigan, Kevin M

    2015-06-01

    Mutations in the DMD gene result in Duchenne or Becker muscular dystrophy due to absent or altered expression of the dystrophin protein. The more severe Duchenne muscular dystrophy typically presents around ages 2 to 5 with gait disturbance, and historically has led to the loss of ambulation by age 12. It is important for the practicing pediatrician, however, to be aware of other presenting signs, such as delayed motor or cognitive milestones, or elevated serum transaminases. Becker muscular dystrophy is milder, often presenting after age 5, with ambulation frequently preserved past 20 years and sometimes into late decades. Copyright © 2015 Elsevier Inc. All rights reserved.

  10. Upper girdle imaging in facioscapulohumeral muscular dystrophy.

    Directory of Open Access Journals (Sweden)

    Giorgio Tasca

    Full Text Available In Facioscapulohumeral muscular dystrophy (FSHD, the upper girdle is early involved and often difficult to assess only relying on physical examination. Our aim was to evaluate the pattern and degree of involvement of upper girdle muscles in FSHD compared with other muscle diseases with scapular girdle impairment.We propose an MRI protocol evaluating neck and upper girdle muscles. One hundred-eight consecutive symptomatic FSHD patients and 45 patients affected by muscular dystrophies and myopathies with prominent upper girdle involvement underwent this protocol. Acquired scans were retrospectively analyzed.The trapezius (100% of the patients and serratus anterior (85% of the patients were the most and earliest affected muscles in FSHD, followed by the latissimus dorsi and pectoralis major, whilst spinati and subscapularis (involved in less than 4% of the patients were consistently spared even in late disease stages. Asymmetry and hyperintensities on short-tau inversion recovery (STIR sequences were common features, and STIR hyperintensities could also be found in muscles not showing signs of fatty replacement. The overall involvement appears to be disease-specific in FSHD as it significantly differed from that encountered in the other myopathies.The detailed knowledge of single muscle involvement provides useful information for correctly evaluating patients' motor function and to set a baseline for natural history studies. Upper girdle imaging can also be used as an additional tool helpful in supporting the diagnosis of FSHD in unclear situations, and may contribute with hints on the currently largely unknown molecular pathogenesis of this disease.

  11. Optical coherence tomography in progressive cone dystrophy.

    Science.gov (United States)

    Zahlava, Jiri; Lestak, Jan; Karel, Ivan

    2014-12-01

    The aim of the study was to analyse different clinical pictures in patients with progressive cone dystrophy (PCD), to compare these with the results of optical coherence tomography (OCT) and to evaluate the benefits of this method for diagnosis. The group consisted of 16 patients (32 eyes) with PCD. All patients were examined for visual acuity, colour sense and visual field. We performed biomicroscopic examination, photo-documentation, fluorescein angiography, electrophysiological tests and OCT. Using biomicroscopy and fluorescein angiography, we found changes in the retinal pigment epithelium ranging from barely detectable changes up to the typical bull's eye appearance. In all the eyes, OCT established statistically significant reduction in the thickness and structural changes in the neuroretina of the macula. Atrophy was evident especially in the outer nuclear layer, in the photoreceptor inner segment/outer segment junction and in the retinal pigment epithelium. Visual acuity was mainly dependent on the degree to which the continuity of the photoreceptor inner segment/outer segment junction layer was maintained. Eyes with better preserved neuroretinal structure in the fovea centralis had generally less reduced thickness of the retina and a better visual acuity. OCT specifies the quantitative and qualitative changes in the macula and may contribute significantly to the diagnosis of the progressive cone dystrophy, particularly in the early stages of the disease which is difficult to diagnose.

  12. Muscle MRI findings in facioscapulohumeral muscular dystrophy

    Energy Technology Data Exchange (ETDEWEB)

    Gerevini, Simonetta; Caliendo, Giandomenico; Falini, Andrea [IRCCS San Raffaele Scientific Institute, Neuroradiology Unit, Head and Neck Department, Milan (Italy); Scarlato, Marina; Previtali, Stefano Carlo [IRCCS San Raffaele Scientific Institute, Department of Neurology, INSPE and Division of Neuroscience, Milan (Italy); Maggi, Lorenzo; Pasanisi, Barbara; Morandi, Lucia [Fondazione IRCCS Istituto Neurologico ' ' Carlo Besta' ' , Neuromuscular Diseases and Neuroimmunology Unit, Milan (Italy); Cava, Mariangela [IRCCS San Raffaele Scientific Institute, Department of Radiology and Center for Experimental Imaging, Milan (Italy)

    2016-03-15

    Facioscapulohumeral muscular dystrophy (FSHD) is characterized by extremely variable degrees of facial, scapular and lower limb muscle involvement. Clinical and genetic determination can be difficult, as molecular analysis is not always definitive, and other similar muscle disorders may have overlapping clinical manifestations. Whole-body muscle MRI examination for fat infiltration, atrophy and oedema was performed to identify specific patterns of muscle involvement in FSHD patients (30 subjects), and compared to a group of control patients (23) affected by other myopathies (NFSHD). In FSHD patients, we detected a specific pattern of muscle fatty replacement and atrophy, particularly in upper girdle muscles. The most frequently affected muscles, including paucisymptomatic and severely affected FSHD patients, were trapezius, teres major and serratus anterior. Moreover, asymmetric muscle involvement was significantly higher in FSHD as compared to NFSHD patients. In conclusion, muscle MRI is very sensitive for identifying a specific pattern of involvement in FSHD patients and in detecting selective muscle involvement of non-clinically testable muscles. Muscle MRI constitutes a reliable tool for differentiating FSHD from other muscular dystrophies to direct diagnostic molecular analysis, as well as to investigate FSHD natural history and follow-up of the disease. (orig.)

  13. Congenital muscular dystrophy with inflammation: Diagnostic considerations

    Directory of Open Access Journals (Sweden)

    Kaumudi Konkay

    2016-01-01

    Full Text Available Background and Purpose: Muscle biopsy features of congenital muscular dystrophies (CMD vary from usual dystrophic picture to normal or nonspecific myopathic picture or prominent fibrosis or striking inflammatory infiltrate, which may lead to diagnostic errors. A series of patients of CMD with significant inflammatory infiltrates on muscle biopsy were correlated with laminin α 2 deficiency on immunohistochemistry (IHC. Material and Methods: Cryostat sections of muscle biopsies from the patients diagnosed as CMD on clinical and muscle biopsy features from 1996 to 2014 were reviewed with hematoxylin and eosin(H&E, enzyme and immunohistochemistry (IHC with laminin α 2. Muscle biopsies with inflammatory infiltrate were correlated with laminin α 2 deficiency. Results: There were 65 patients of CMD, with inflammation on muscle biopsy in 16. IHC with laminin α 2 was available in nine patients, of which six showed complete absence along sarcolemma (five presented with floppy infant syndrome and one with delayed motor milestones and three showed discontinuous, and less intense staining. Conclusions: CMD show variable degrees of inflammation on muscle biopsy. A diagnosis of laminin α 2 deficient CMD should be considered in patients of muscular dystrophy with inflammation, in children with hypotonia/delayed motor milestones.

  14. Sleep disturbances in myotonic dystrophy type 2.

    Science.gov (United States)

    Shepard, Paul; Lam, Erek M; St Louis, Erik K; Dominik, Jacob

    2012-01-01

    Sleep disorders in myotonic dystrophy type 1 (DM1) are common and include sleep-disordered breathing, hypersomnia, and fatigue. Little is known regarding the occurrence of sleep disturbance in myotonic dystrophy type 2 (DM2). We hypothesized that DM2 patients may frequently harbor sleep disorders. We reviewed medical records of all genetically confirmed cases of DM2 seen at our sleep center between 1997 and 2010 for demographic, laboratory, overnight oximetry, and polysomnography (PSG) data. Eight patients (5 women, 3 men) with DM2 were identified. Excessive daytime sleepiness was seen in 6 patients (75%), insomnia in 5 (62.5%), and excessive fatigue in 4 (50%). Obstructive sleep apnea was diagnosed in 3 of 5 patients (60%) studied with PSG. Respiratory muscle weakness was present in all 6 patients (100%) who received pulmonary function testing. Four of 8 (50%) met criteria for diagnosis of restless legs syndrome. The clinical spectrum of DM2 may include a wide range of sleep disturbances. Although respiratory muscle weakness was frequent, sustained sleep-related hypoxia suggestive of hypoventilation was not seen in our patients. Further prospective studies are needed to examine the frequency and scope of sleep disturbances in DM2. Copyright © 2012 S. Karger AG, Basel.

  15. Emerging drugs for Duchenne muscular dystrophy.

    Science.gov (United States)

    Malik, Vinod; Rodino-Klapac, Louise R; Mendell, Jerry R

    2012-06-01

    Duchenne muscular dystrophy (DMD) is the most common, severe childhood form of muscular dystrophy. Treatment is limited to glucocorticoids that have the benefit of prolonging ambulation by approximately 2 years and preventing scoliosis. Finding a more satisfactory treatment should focus on maintaining long-term efficacy with a minimal side effect profile. Authors discuss different therapeutic strategies that have been used in pre-clinical and clinical settings. Multiple treatment approaches have emerged. Most attractive are molecular-based therapies that can express the missing dystrophin protein (exon skipping or mutation suppression) or a surrogate gene product (utrophin). Other approaches include increasing the strength of muscles (myostatin inhibitors), reducing muscle fibrosis and decreasing oxidative stress. Additional targets include inhibiting NF-κB to reduce inflammation or promoting skeletal muscle blood flow and muscle contractility using phosphodiesterase inhibitors or nitric oxide (NO) donors. The potential for each of these treatment strategies to enter clinical trials is a central theme of discussion. The review emphasizes that the goal of treatment should be to find a product at least as good as glucocorticoids with a lower side effect profile or with a significant glucocorticoid sparing effect.

  16. The superhealing MRL background improves muscular dystrophy

    Directory of Open Access Journals (Sweden)

    Heydemann Ahlke

    2012-12-01

    Full Text Available Abstract Background Mice from the MRL or “superhealing” strain have enhanced repair after acute injury to the skin, cornea, and heart. We now tested an admixture of the MRL genome and found that it altered the course of muscle pathology and cardiac function in a chronic disease model of skeletal and cardiac muscle. Mice lacking γ-sarcoglycan (Sgcg, a dystrophin-associated protein, develop muscular dystrophy and cardiomyopathy similar to their human counterparts with limb girdle muscular dystrophy. With disruption of the dystrophin complex, the muscle plasma membrane becomes leaky and muscles develop increased fibrosis. Methods MRL/MpJ mice were bred with Sgcg mice, and cardiac function was measured. Muscles were assessed for fibrosis and membrane leak using measurements of hydroxyproline and Evans blue dye. Quantitative trait locus mapping was conducted using single nucleotide polymorphisms distinct between the two parental strains. Results Introduction of the MRL genome reduced fibrosis but did not alter membrane leak in skeletal muscle of the Sgcg model. The MRL genome was also associated with improved cardiac function with reversal of depressed fractional shortening and the left ventricular ejection fraction. We conducted a genome-wide analysis of genetic modifiers and found that a region on chromosome 2 was associated with cardiac, diaphragm muscle and abdominal muscle fibrosis. Conclusions These data are consistent with a model where the MRL genome acts in a dominant manner to suppress fibrosis in this chronic disease setting of heart and muscle disease.

  17. Expanded clinical spectrum of enhanced S-cone syndrome

    NARCIS (Netherlands)

    Yzer, Suzanne; Barbazetto, Irene; Allikmets, Rando; van Schooneveld, Mary J.; Bergen, Arthur; Tsang, Stephen H.; Jacobson, Samuel G.; Yannuzzi, Lawrence A.

    2013-01-01

    New funduscopic findings in patients with enhanced S-cone syndrome (ESCS) may help clinicians in diagnosing this rare autosomal recessive retinal dystrophy. To expand the clinical spectrum of ESCS due to mutations in the NR2E3 gene. Retrospective, noncomparative case series of 31 patients examined

  18. Bardet-biedel syndrome: a case report and a review of literature ...

    African Journals Online (AJOL)

    Background: Bardet- Biedl syndrome (BBS) is a group of autosomal recessive conditions with overlapping phenotype of rod-cone dystrophy, central obesity, mental retardation, and hypogonadism. There are very few reports of BBS from Sub-Saharan Africa. Objective: To report a case of BBS and review existing literature on ...

  19. Homozygosity Mapping Reveals PDE6C Mutations in Patients with Early-Onset Cone Photoreceptor Disorders

    NARCIS (Netherlands)

    A.A.H.J. Thiadens (Alberta); A.I. Hollander (Anneke); S. Roosing (Susanne); S.B. Nabuurs (Sander); R.C. Zekveld-Vroon (Renate); R.W.J. Collin (Rob); E. de Baere (Elfride); R.K. Koenekoop (Robert); M.J. Schooneveld (Mary); T.M. Strom (Tim); J.J.C. van Lith-Verhoeven (Janneke); A.J. Lotery (Andrew); N. van Moll-Ramirez (Norka); B.P. Leroy (Bart); L.I. van den Born (Ingeborgh); C. Hoyng (Carel); F.P.M. Cremers (Frans); C.C.W. Klaver (Caroline)

    2009-01-01

    textabstractCone photoreceptor disorders form a clinical spectrum of diseases that include progressive cone dystrophy (CD) and complete and incomplete achromatopsia (ACHM). The underlying disease mechanisms of autosomal recessive (ar)CD are largely unknown. Our aim was to identify causative genes

  20. Homozygosity mapping reveals PDE6C mutations in patients with early-onset cone photoreceptor disorders

    NARCIS (Netherlands)

    Thiadens, Alberta A. H. J.; den Hollander, Anneke I.; Roosing, Susanne; Nabuurs, Sander B.; Zekveld-Vroon, Renate C.; Collin, Rob W. J.; de Baere, Elfride; Koenekoop, Robert K.; van Schooneveld, Mary J.; Strom, Tim M.; van Lith-Verhoeven, Janneke J. C.; Lotery, Andrew J.; van Moll-Ramirez, Norka; Leroy, Bart P.; van den Born, L. Ingeborgh; Hoyng, Carel B.; Cremers, Frans P. M.; Klaver, Caroline C. W.

    2009-01-01

    Cone photoreceptor disorders form a clinical spectrum of diseases that include progressive cone dystrophy (CD) and complete and incomplete achromatopsia (ACHM). The underlying disease mechanisms of autosomal recessive (ar)CD are largely unknown. Our aim was to identify causative genes for these

  1. Novel CNGA3 and CNGB3 mutations in two Pakistani families with achromatopsia.

    NARCIS (Netherlands)

    Azam, M.; Collin, R.W.J.; Shah, S.T.; Shah, A.A.; Khan, M.I.; Hussain, A.; Sadeque, A.; Strom, T.M.; Thiadens, A.A.H.J.; Roosing, S.; Hollander, A.I. den; Cremers, F.P.M.; Qamar, R.

    2010-01-01

    PURPOSE: To identify the genetic defect in two Pakistani families with autosomal recessive achromatopsia. METHODS: Two families (RP26 and RP44) were originally diagnosed with retinal dystrophy based upon their medical history. To localize the causative genes in these families, homozygosity mapping

  2. Changing facial phenotype in Cohen syndrome : towards clues for an earlier diagnosis

    NARCIS (Netherlands)

    El Chehadeh-Djebbar, Salima; Blair, Edward; Holder-Espinasse, Muriel; Moncla, Anne; Frances, Anne-Marie; Rio, Marlene; Debray, Francois-Guillaume; Rump, Patrick; Masurel-Paulet, Alice; Gigot, Nadege; Callier, Patrick; Duplomb, Laurence; Aral, Bernard; Huet, Frederic; Thauvin-Robinet, Christel; Faivre, Laurence

    Cohen syndrome (CS) is a rare autosomal recessive condition caused by mutations and/or large rearrangements in the VPS13B gene. CS clinical features, including developmental delay, the typical facial gestalt, chorioretinal dystrophy (CRD) and neutropenia, are well described. CS diagnosis is

  3. Cardiac involvement in patients with limb-girdle muscular dystrophy type 2 and Becker muscular dystrophy

    DEFF Research Database (Denmark)

    Sveen, Marie-Louise; Thune, Jens Jakob; Køber, Lars

    2008-01-01

    OBJECTIVE: To investigate the extent of cardiac involvement in patients with 1 of the 12 groups of recessively inherited limb-girdle muscular dystrophy type 2 (LGMD2A-L) and Becker muscular dystrophy (BMD). DESIGN: Prospective screening. SETTING: Neuromuscular Clinic and Department of Cardiology......-I and in 14 of 30 patients (47%) with BMD. Only a few patients with LGMD2A and unclassified LGMD2 had mild cardiac involvement, whereas 29% and 67% of patients with LGMD2I and LGMD2E, respectively, had cardiac involvement. Cardiac involvement was not correlated with age, muscle strength, or the level...... of dystrophic changes on muscle biopsy. CONCLUSIONS: This study demonstrates a high prevalence of cardiac involvement in patients with LGMD2I, LGMD2E, and BMD. Patients with LGMD2A, LGMD2D, and unclassified LGMD2 have a much lower and milder prevalence of cardiac involvement....

  4. Relevant aspects of golden retriever muscular dystrophy for the study of Duchenne muscular dystrophy in humans

    Directory of Open Access Journals (Sweden)

    Julieta Rodini Engrácia de Moraes

    2017-09-01

    Full Text Available ABSTRACT: Golden Retriever muscular dystrophy (GRMD is the most representative model for studying Duchenne muscular dystrophy (DMD in humans, owing its phenotypic expression. DMD is a recessive disorder linked to the X chromosome in which the loss of dystrophin induces progressive weakness and degeneration of the skeletal and cardiac muscles, which lead to replacement by connective and adipose tissues. Onset of clinical signs occurs between 2 and 5 years of age, and many patients die from heart or respiratory failure. The main studies concerning dystrophic Golden Retrievers (DGR sought to elucidate the pathophysiology of the disease and its clinical implications to develop therapies and alternative treatments to improve the quality of life and increase longevity of DMD patients. This review presents an overview of relevant contributions of the DGR model for elucidating DMD in humans.

  5. Strength training and albuterol in facioscapulohumeral muscular dystrophy.

    NARCIS (Netherlands)

    Kooi, E.L. van der; Vogels, O.J.M.; Asseldonk, R.J. van; Lindeman, E.J.M.; Hendriks, J.C.M.; Wohlgemuth, M.; Maarel, S.M. van der; Padberg, G.W.A.M.

    2004-01-01

    BACKGROUND: In animals and healthy volunteers beta2-adrenergic agonists increase muscle strength and mass, in particular when combined with strength training. In patients with facioscapulohumeral muscular dystrophy (FSHD) albuterol may exert anabolic effects. The authors evaluated the effect of

  6. How Physicians Support Mothers of Children with Duchenne Muscular Dystrophy.

    Science.gov (United States)

    Fujino, Haruo; Saito, Toshio; Matsumura, Tsuyoshi; Shibata, Saki; Iwata, Yuko; Fujimura, Harutoshi; Shinno, Susumu; Imura, Osamu

    2015-09-01

    Communicating about Duchenne muscular dystrophy and its prognosis can be difficult for affected children and their family. We focused on how physicians provide support to the mothers of children with Duchenne muscular dystrophy who have difficulty communicating about the condition with their child. The eligible participants were certified child neurologists of the Japanese Society of Child Neurology. Participants responded to questionnaires consisting of free descriptions of a vignette of a child with Duchenne muscular dystrophy and a mother. We analyzed 263 responses of the participants. We found 4 themes on advising mothers, involving encouraging communication, family autonomy, supporting family, and considering the child's concerns. These results provide a better understanding of the communication between physicians and family members who need help sharing information with a child with Duchenne muscular dystrophy. These findings will assist clinical practitioners in supporting families and the affected children throughout the course of their illness. © The Author(s) 2015.

  7. Strong association between myotonic dystrophy type 2 and autoimmune diseases.

    NARCIS (Netherlands)

    Tieleman, A.A.; Broeder, A. den; Logt, A. van de; Engelen, B.G.M. van

    2009-01-01

    BACKGROUND: Myotonic dystrophy type 2 (DM2) is a dominantly inherited multisystem disorder, characterised by progressive proximal weakness, myotonia, cataracts and cardiac conduction abnormalities. Our clinical impression of an association between DM2 and autoimmune diseases or autoantibody

  8. Immunoglobulins in granular corneal dystrophy Groenouw type I

    DEFF Research Database (Denmark)

    Møller, H U; Bojsen-Møller, M; Schrøder, H D

    1993-01-01

    Three patients with granular corneal dystrophy Groenouw type I underwent corneal grafting, and cryostat sections of the corneal buttons were examined immunohistochemically for immunoglobulins. Positive results were obtained for IgG, Kappa-, and Lambda chains with immunofluorescence technique...

  9. Strength training and albuterol in facioscapulohumeral muscular dystrophy

    NARCIS (Netherlands)

    van der Kooi, EL; Vogels, OJM; van Asseldonk, RJGP; Lindeman, E; Hendriks, JCM; Wohlgemuth, M; van der Maarel, SM; Padberg, GW

    2004-01-01

    Background: In animals and healthy volunteers beta2-adrenergic agonists increase muscle strength and mass, in particular when combined with strength training. In patients with facioscapulohumeral muscular dystrophy (FSHD) albuterol may exert anabolic effects. The authors evaluated the effect of

  10. Genetics Home Reference: lattice corneal dystrophy type I

    Science.gov (United States)

    ... dystrophy type I change single protein building blocks ( amino acids ) in the TGFBI protein. Mutated TGFBI proteins abnormally clump together and form amyloid deposits. However, it is unclear how the ...

  11. Dystrophin analysis in carriers of Duchenne and Becker muscular dystrophy

    NARCIS (Netherlands)

    Hoogerwaard, Edo M.; Ginjaar, Ieke B.; Bakker, Egbert; de Visser, Marianne

    2005-01-01

    Associations between clinical phenotype (muscle weakness, dilated cardiomyopathy) and dystrophin abnormalities in muscle tissue among definite carriers of Duchenne (DMD) and Becker muscular dystrophy (BMD) were investigated. No associations between dystrophin abnormalities and clinical variables in

  12. Pseudodystrophy. A conversion disorder mimicking reflex sympathetic dystrophy.

    Science.gov (United States)

    Driessens, M; Blockx, P; Geuens, G; Dijs, H; Verheyen, G; Stassijns, G

    2002-10-01

    The authors suggest some criteria by which pseudodystrophy and reflex sympathetic dystrophy, although sharing some similar clinical features, can be distinguished as two different conditions, each requiring its own approach and management. The most important distinction is found on bone scintigraphy. In reflex sympathetic dystrophy the bone scan shows a typical increased tracer uptake (at least during stages I and II); in pseudodystrophy there is a normal or decreased tracer uptake in the affected region. Moreover the vascularization is increased in reflex sympathetic dystrophy stage I, whereas in pseudodystrophy hypovascularization is found from the beginning. The clinical features, as well as the results of technical investigations, psychological evaluation and treatment of 4 patients with pseudodystrophy are presented. The importance of distinguishing this condition from reflex sympathetic dystrophy is stressed.

  13. Identification of three distinguishable phenotypes in golden retriever muscular dystrophy

    OpenAIRE

    AMBROSIO, C. E.; FADEL, L.; GAIAD, T. P.; MARTINS, D. S.; ARAUJO, K. P. C.; ZUCCONI, E.; BROLIO, M. P.; GIGLIO, R. F.; MORINI, A. C.; JAZEDJE, T.; FROES, T. R.; FEITOSA, M. L. T.; VALADARES, M. C.; BELTRAO-BRAGA, P. C. B.; MEIRELLES, F. V.

    2009-01-01

    Duchenne muscular dystrophy (DMD) is a human disease characterized by progressive and irreversible skeletal muscle degeneration caused by mutations in genes coding for important muscle proteins. Unfortunately, there is no efficient treatment for this disease; it causes progressive loss of motor and muscular ability until death. The canine model (golden retriever muscular dystrophy) is similar to DMD, showing similar clinical signs. Fifteen dogs were followed from birth and closely observed fo...

  14. CINRG: Infrastructure for Clinical Trials in Duchenne Dystrophy

    Science.gov (United States)

    2012-09-01

    function in patients with muscular dystrophy. We evaluated its utility as an earlier marker of cardiac dysfunction with the goal of using it as...SPP1) gene (-66 T>G -rs28357094) on longitudinal functional measures. Saliva samples for DNA genotyping were available for 280 DMD participants...muscle testing; TGF- transforming growth factor-; TNF- tumor necrosis factor-. Duchenne muscular dystrophy (DMD) is the most common type of

  15. The role of fibrosis in Duchenne muscular dystrophy

    OpenAIRE

    KLINGLER, WERNER; JURKAT-ROTT, KARIN; LEHMANN-HORN, FRANK; SCHLEIP, ROBERT

    2012-01-01

    Muscular dystrophies such as Duchenne muscular dystrophy (DMD) are usually approached as dysfunctions of the affected skeletal myofibres and their force transmission. Comparatively little attention has been given to the increase in connective tissue (fibrosis) which accompanies these muscular changes. Interestingly, an increase in endomysial tissue is apparent long before any muscular degeneration can be observed. Fibrosis is the result of a reactive or reparative process involving mechanical...

  16. Prevalence and correlates of apathy in myotonic dystrophy type 1

    OpenAIRE

    Gallais, Benjamin; Montreuil, Mich?le; Gargiulo, Marcela; Eymard, Bruno; Gagnon, Cynthia; Laberge, Luc

    2015-01-01

    Background Apathy in DM1 has long been acknowledged in clinical practice. However, a major drawback is that the concept has been only sparsely explored in previous specific studies. This study aimed to determine the prevalence of apathy in myotonic dystrophy (DM1), to compare it with facioscapulohumeral dystrophy (FSHD) patients and normal healthy controls, and explore its relationship to psychopathological features and cognitive function. Methods Levels of apathy in 38 DM1 patients with adul...

  17. Pulmonary Endpoints in Duchenne Muscular Dystrophy. A Workshop Summary.

    Science.gov (United States)

    Finder, Jonathan; Mayer, Oscar Henry; Sheehan, Daniel; Sawnani, Hemant; Abresch, R Ted; Benditt, Joshua; Birnkrant, David J; Duong, Tina; Henricson, Erik; Kinnett, Kathi; McDonald, Craig M; Connolly, Anne M

    2017-08-15

    Development of novel therapeutics for treatment of Duchenne muscular dystrophy (DMD) has led to clinical trials that include pulmonary endpoints that allow assessment of respiratory muscle status, especially in nonambulatory subjects. Parent Project Muscular Dystrophy (PPMD) convened a workshop in Bethesda, Maryland, on April 14 and 15, 2016, to summarize published respiratory data in DMD and give guidance to clinical researchers assessing the effect of interventions on pulmonary outcomes in DMD.

  18. Bilateral coexistence of keratoconus and macular corneal dystrophy

    Directory of Open Access Journals (Sweden)

    Ghazi Al-Hamdan

    2009-01-01

    The authors hereby report a 21-year-old female who presented with the typical signs and topographic evidence of keratoconus in association with macular corneal dystrophy. Histopathologic evaluation from the excised corneal button after corneal transplant confirmed the diagnosis. To our knowledge, there is only one previous report in the literature linking the association of keratoconus and macular corneal dystrophy in the same eye bilaterally.

  19. Doppler sonographic assessment of posttraumatic reflex sympathetic dystrophy.

    Science.gov (United States)

    Pekindil, Gökhan; Pekindil, Yesim; Sarikaya, Ali

    2003-04-01

    To reveal the arterial Doppler sonographic findings in cases of posttraumatic reflex sympathetic dystrophy Eleven patients had hand reflex sympathetic dystrophy, and 9 had foot reflex sympathetic dystrophy. The duration of symptoms ranged from 1 to 28 weeks, and the history of fracture ranged from 6 to 48 weeks. Bilateral brachial or popliteal arteries proximal to injuries were evaluated by Doppler sonography with a 7.5-MHz linear transducer. All patients also had triphasic bone scintigraphy and extremity thermography Two patients had monophasic waveforms and 4 had low-pulsatility triphasic waveforms on the affected limbs when compared with the asymptomatic limbs. All opposite asymptomatic limbs had normal triphasic waveforms in these 6 cases. Spectral analysis revealed a loss or decrease of a normal reversed flow component with a reduced pulsatility index on the affected limb. Fourteen other patients had symmetric triphasic waveforms. We observed that the patients who had stage 1 reflex sympathetic dystrophy and warm limbs with durations of symptoms of more than 2 weeks had positive Doppler sonographic findings, whereas all patients with stage 2 reflex sympathetic dystrophy and all with normal skin temperature, regardless of stage, had normal waveforms. Doppler sonography revealed loss of normal triphasic arterial waveforms in some of the cases of stage 1 disease, whereas many cases of stage 1 disease and all cases of stage 2 disease had normal findings. Therefore, we think that Doppler sonography cannot be used for the diagnosis of reflex sympathetic dystrophy but may help in assessing hemodynamic stages of the disease.

  20. Outside in: The matrix as a modifier of muscular dystrophy.

    Science.gov (United States)

    Quattrocelli, Mattia; Spencer, Melissa J; McNally, Elizabeth M

    2017-03-01

    Muscular dystrophies are genetic conditions leading to muscle degeneration and often, impaired regeneration. Duchenne Muscular Dystrophy is a prototypical form of muscular dystrophy, and like other forms of genetically inherited muscle diseases, pathological progression is variable. Variability in muscular dystrophy can arise from differences in the manner in which the primary mutation impacts the affected protein's function; however, clinical heterogeneity also derives from secondary mutations in other genes that can enhance or reduce pathogenic features of disease. These genes, called genetic modifiers, regulate the pathophysiological context of dystrophic degeneration and regeneration. Understanding the mechanistic links between genetic modifiers and dystrophic progression sheds light on pathologic remodeling, and provides novel avenues to therapeutically intervene to reduce muscle degeneration. Based on targeted genetic approaches and unbiased genomewide screens, several modifiers have been identified for muscular dystrophy, including extracellular agonists of signaling cascades. This review will focus on identification and possible mechanisms of recently identified modifiers for muscular dystrophy, including osteopontin, latent TGFβ binding protein 4 (LTBP4) and Jagged1. Moreover, we will review the investigational approaches that aim to target modifier pathways and thereby counteract dystrophic muscle wasting. Copyright © 2016 Elsevier B.V. All rights reserved.

  1. Current treatment of adult Duchenne muscular dystrophy.

    Science.gov (United States)

    Wagner, Kathryn R; Lechtzin, Noah; Judge, Daniel P

    2007-02-01

    Patients with Duchenne muscular dystrophy (DMD) are living longer into adulthood due to a variety of improvements in health care practices. This growing patient population presents new therapeutic challenges. In this article, we review the literature on current treatment of adult DMD as well as our own experience as a multidisciplinary team actively caring for 23 men ages 19-38 years of age. Approximately one quarter of our adult DMD patients have remained on moderate dose corticosteroids. Daily stretching exercises are recommended, particularly of the distal upper extremities. Cardiomyopathy is anticipated, detected, and treated early with afterload reduction. Oxygen saturation monitoring, noninvasive positive pressure ventilation and cough assist devices are routinely used. Other medical issues such as osteoporosis, gastrointestinal and urinary symptoms are addressed. Current and future therapies directed at prolonging the lifespan of those with DMD will result in further increases in this adult population with special needs and concerns. These needs are best addressed in a multidisciplinary clinic.

  2. Natural history of Duchenne muscular dystrophy

    Directory of Open Access Journals (Sweden)

    Qing KE

    2015-05-01

    Full Text Available Duchenne muscular dystrophy (DMD is X-linked recessive hereditary disease. DMD gene mutations result in dystrophin deficiency, which causes not only muscle movement disorders but also scoliosis, cognitive dysfunction, urinary tract diseases, respiratory diseases and heart diseases. Most patients die in early adult for respiratory and circulatory failure. Early multidisciplinary therapies will significantly delay disease progression and improve patients' quality of life. However, DMD diagnosis and treatment exist significantly time delay now. In this study, we review the natural history of DMD, including motor, cognitive, respiratory and heart function, for improving DMD early recognition, diagnosis and treatment, so as to benefit DMD patients. DOI: 10.3969/j.issn.1672-6731.2015.05.004

  3. Intramuscular degeneration process in Duchenne muscular dystrophy

    International Nuclear Information System (INIS)

    Hasegawa, Takeshi; Matsumra, Kiichiro; Hashimoto, Takahiro; Ikehira, Hiroo; Fukuda, Hiroshi; Tateno, Yukio.

    1992-01-01

    Intramuscular degeneration process of Duchenne dystrophy skeletal muscles was investigated by longitudinal skeletal muscle imaging with high-field-strength NMR-CT of 1.5 Tesla. Thigh muscles in 10 cases ranging in age from 4 to 19 years were examined by T 1 -weighted longitudinal images (TR=215∼505 ms, TE=19∼20 ms). The following results were obtained. Skeletal muscle degeneration was depicted as high signal intensity area reflecting its high fat contents. These high signal intensity areas had a longitudinally streaky appearance in parallel direction with myofibers. These findings were more prominent toward myotendon junction than muscle bellies. Skeletal muscle degeneration progressed rapidly between 7 to 10 years of age, and reached a plateau after that. (author)

  4. Fibroblast cultures in duchenne muscular dystrophy

    International Nuclear Information System (INIS)

    Ionasescu, V.; Lara-Braud, C.; Zellweger, H.; Ionasescu, R.; Burmeister, L.

    1977-01-01

    Primary skin fibroblast cultures were grown from forearm pinch skin biopsies obtained from 24 patients with Duchenne muscular dystrophy (DMD) and ten normal controls matched for sex and age. The first subcultures were grown for 7 days and incubated with L-( 3 H)-proline for 24 hours. Intracellular collagen incoption was significantly decreased (2.2 X) and extracellular collagen incorporation significantly increased (1.8 X) in fibroblast cultures from patients with DMD by both collagenase assay and polyacrylamide gel electrophoresis. The synthesis of noncollagen proteins showed low values from the DMD fibroblast cultures. The alterations in synthesis and secretion of collagen and noncollagen proteins were characteristic only for the log phase of DMD fibroblasts. (author)

  5. Reflex sympathetic dystrophy syndrome in a child.

    Science.gov (United States)

    Badri, Talel; Ben Jennet, Salima; Fenniche, Samy; Benmously, Rym; Mokhtar, Inçaf; Hammami, Hatem

    2011-06-01

    Reflex sympathetic dystrophy syndrome (RSDS) is a painful condition that usually follows regional trauma. We report the case of a 13-year-old girl that was seen for a painful swelling of the right hand associated with palmar hyperhidrosis, which occurred after a trauma to the hand. Bone scan images showed early tissue abnormality, which was more significant on the right hand and wrist, as well as moderate bone uptake on the right side. Nonsteroidal anti-inflammatory drugs and alternating hot and cold baths led to a marked improvement. RSDS occurs following trauma or subsequent to various diseases or drug intake. This syndrome is related to impaired tissue microvasculature under the influence of abnormal sympathetic reflex hyperactivity. Bone scan is the diagnostic procedure of choice in RSDS, but it may be normal. Physiotherapy should be preferred in pediatric cases.

  6. Sleep Disordered Breathing in Duchenne Muscular Dystrophy.

    Science.gov (United States)

    LoMauro, Antonella; D'Angelo, Maria Grazia; Aliverti, Andrea

    2017-05-01

    This review aims to explain the inevitable imbalance between respiratory load, drive, and muscular force that occurs in the natural aging of Duchenne muscular dystrophy and that predisposes these patients to sleep disordered breathing (SDB). In DMD, SDB is characterized by oxygen desaturation, apneas, hypercapnia, and hypoventilation during sleep and ultimately develops into respiratory failure during wakefulness. It can be present in all age groups. Young patients risk obstructive apneas because of weight gain, secondary to progressive physical inactivity and prolonged corticosteroid therapy; older patients hypoventilate and desaturate because of respiratory muscle weakness, in particular the diaphragm. These conditions are further exacerbated during REM sleep, the phase of maximal muscle hypotonia during which the diaphragm has to provide most of the ventilation. Evidence is given to the daytime predictors of early symptoms of SDB, important indicators for the proper time to initiate mechanical ventilation.

  7. Neuroaxonal dystrophy in Australian Merino lambs.

    Science.gov (United States)

    Kessell, A E; Finnie, J W; Blumbergs, P C; Manavis, J; Jerrett, I V

    2012-07-01

    Neuroaxonal dystrophy (NAD) is a morphological abnormality in man and animals that is characterized by the occurrence of numerous axonal swellings (spheroids) in the nervous system. NAD has been described in Suffolk lambs in the USA, Merino lambs in Australia and several breeds of sheep in New Zealand. This paper describes the clinicopathological changes of only the second occurrence of NAD reported in Merino lambs. There were some features (myelin loss, gliosis and visual impairment) in these Australian cases that have not been reported previously in ovine NAD. Application of immunohistochemical markers of axonal transport suggested that disruption of this transport mechanism contributed to spheroid development. Crown Copyright © 2011. Published by Elsevier Ltd. All rights reserved.

  8. Creatine kinase response to high-intensity aerobic exercise in adult-onset muscular dystrophy

    DEFF Research Database (Denmark)

    Andersen, Søren P; Sveen, Marie-Louise; Hansen, Regitze S

    2013-01-01

    We investigated the effect of high-intensity exercise on plasma creatine kinase (CK) in patients with muscular dystrophies.......We investigated the effect of high-intensity exercise on plasma creatine kinase (CK) in patients with muscular dystrophies....

  9. Experimental Treatment for Duchenne Muscular Dystrophy Gets Boost from Existing Medication

    Science.gov (United States)

    ... on Research Spotlight on Research Experimental Treatment for Duchenne Muscular Dystrophy Gets Boost from Existing Medication By Colleen Labbe, ... the effects of a promising experimental treatment for Duchenne muscular dystrophy (DMD), according to research partially funded by the ...

  10. Does Body Mass Index Predict Premature Cardiomyopathy Onset for Duchenne Muscular Dystrophy?

    Science.gov (United States)

    McKane, Meghann; Soslow, Jonathan H; Xu, Meng; Saville, Benjamin R; Slaughter, James C; Burnette, W Bryan; Markham, Larry W

    2017-04-01

    Duchenne muscular dystrophy leads to cardiomyopathy. The objective of this study was to estimate the association of body mass index with cardiomyopathy onset. Cardiomyopathy was defined as left ventricular ejection fraction Duchenne muscular dystrophy subjects and age of cardiomyopathy onset.

  11. Outcome of Long-Term Corticosteroid Treatment in Duchenne Muscular Dystrophy

    Directory of Open Access Journals (Sweden)

    J Gordon Millichap

    2007-06-01

    Full Text Available The clinical orthopedic effects of chronic daily corticosteroid treatment were evaluated by chart review in boys with genetically confirmed Duchenne muscular dystrophy (DMD followed at the Ohio State University Muscular Dystrophy Clinic between 2000 and 2003.

  12. Outcome of Long-Term Corticosteroid Treatment in Duchenne Muscular Dystrophy

    OpenAIRE

    J Gordon Millichap

    2007-01-01

    The clinical orthopedic effects of chronic daily corticosteroid treatment were evaluated by chart review in boys with genetically confirmed Duchenne muscular dystrophy (DMD) followed at the Ohio State University Muscular Dystrophy Clinic between 2000 and 2003.

  13. Interpretation of "Diagnosis and management of Duchenne muscular dystrophy: a guide for families (2011 version)"

    OpenAIRE

    Xi-hua LI

    2015-01-01

    The guideline "Diagnosis and management of Duchenne muscular dystrophy" was supported by a 3-year-long project guided by US Centers for Disease Control and Prevention (CDC), in collaboration with patient advocacy groups [Muscular Dystrophy Association (MDA), Parent Project Muscular Dystrophy (PPMD) and United Parent Projects Muscular Dystrophy (UPPMD)] and Translational Research in Europe: Assessment and Treatment of Neuromuscular Disease (TREAT-NMD) network. The main document was published i...

  14. Congenital muscular dystrophy. Part I: a review of phenotypical and diagnostic aspects Distrofia muscular congênita. Parte I: revisão dos aspectos fenotípicos e diagnósticos

    Directory of Open Access Journals (Sweden)

    Umbertina Conti Reed

    2009-03-01

    Full Text Available The congenital muscular dystrophies (CMDs are a group of genetically and clinically heterogeneous hereditary myopathies with preferentially autosomal recessive inheritance, that are characterized by congenital hypotonia, delayed motor development and early onset of progressive muscle weakness associated with dystrophic pattern on muscle biopsy. The clinical course is broadly variable and can comprise the involvement of the brain and eyes. From 1994, a great development in the knowledge of the molecular basis has occurred and the classification of CMDs has to be continuously up dated. We initially present the main clinical and diagnostic data concerning the CMDs related to changes in the complex dystrophin-associated glycoproteins-extracellular matrix: CMD with merosin deficiency (CMD1A, collagen VI related CMDs (Ullrich CMD and Bethlem myopathy, CMDs with abnormal glycosylation of alpha-dystroglycan (Fukuyama CMD, Muscle-eye-brain disease, Walker-Warburg syndrome, CMD1C, CMD1D, and the much rarer CMD with integrin deficiency. Finally, we present other forms of CMDs not related with the dystrophin/glycoproteins/extracellular matrix complex (rigid spine syndrome, CMD1B, CMD with lamin A/C deficiency, and some apparently specific clinical forms not yet associated with a known molecular mechanism. The second part of this review concerning the pathogenesis and therapeutic perspectives of the different subtypes of CMD will be described in a next number.As distrofias musculares congênitas (DMCs são miopatias hereditárias geralmente, porém não exclusivamente, de herança autossômica recessiva, que apresentam grande heterogeneidade genética e clínica. São caracterizadas por hipotonia muscular congênita, atraso do desenvolvimento motor e fraqueza muscular de início precoce associada a padrão distrófico na biópsia muscular. O quadro clínico, de gravidade variável, pode também incluir anormalidades oculares e do sistema nervoso central. A

  15. Congenital muscular dystrophy. Part II: a review of pathogenesis and therapeutic perspectives Distrofia muscular congênita. Parte II: revisão da patogênese e perspectivas terapêuticas

    Directory of Open Access Journals (Sweden)

    Umbertina Conti Reed

    2009-06-01

    Full Text Available The congenital muscular dystrophies (CMDs are a group of genetically and clinically heterogeneous hereditary myopathies with preferentially autosomal recessive inheritance, that are characterized by congenital hypotonia, delayed motor development and early onset of progressive muscle weakness associated with dystrophic pattern on muscle biopsy. The clinical course is broadly variable and can comprise the involvement of the brain and eyes. From 1994, a great development in the knowledge of the molecular basis has occurred and the classification of CMDs has to be continuously up dated. In the last number of this journal, we presented the main clinical and diagnostic data concerning the different subtypes of CMD. In this second part of the review, we analyse the main reports from the literature concerning the pathogenesis and the therapeutic perspectives of the most common subtypes of CMD: MDC1A with merosin deficiency, collagen VI related CMDs (Ullrich and Bethlem, CMDs with abnormal glycosylation of alpha-dystroglycan (Fukuyama CMD, Muscle-eye-brain disease, Walker Warburg syndrome, MDC1C, MDC1D, and rigid spine syndrome, another much rare subtype of CMDs not related with the dystrophin/glycoproteins/extracellular matrix complex.As distrofias musculares congênitas (DMCs são miopatias hereditárias geralmente, porém não exclusivamente, de herança autossômica recessiva, que apresentam grande heterogeneidade genética e clínica. São caracterizadas por hipotonia muscular congênita, atraso do desenvolvimento motor e fraqueza muscular de início precoce associada a padrão distrófico na biópsia muscular. O quadro clínico, de gravidade variável, pode também incluir anormalidades oculares e do sistema nervoso central. A partir de 1994, os conhecimentos sobre genética e biologia molecular das DMCs progrediram rapidamente, sendo a classificação continuamente atualizada. Os aspectos clínicos e diagnósticos dos principais subtipos de DMC

  16. Defective muscle basement membrane and lack of M-laminin in the dystrophic dy/dy mouse

    DEFF Research Database (Denmark)

    Xu, H; Christmas, P; Wu, X R

    1994-01-01

    -linked Duchenne and Becker muscular dystrophies. We have examined M-laminin expression in mice with autosomal recessive muscular dystrophy caused by the mutation dy. The heavy chain of M-laminin was undetectable in skeletal muscle, heart muscle, and peripheral nerve by immunofluorescence and immunoblotting......M-laminin is a major member of the laminin family of basement membrane proteins. It is prominently expressed in striated muscle and peripheral nerve. M-laminin is deficient in patients with the autosomal recessive Fukuyama congenital muscular dystrophy but is normal in patients with the sex...... tissue from dy/dy mice, suggesting that M-laminin heavy-chain mRNA may be produced at very low levels or is unstable. Information about the chromosomal localization of the M heavy-chain in human and mouse suggests that a mutation in the M-chain gene causes the muscular dystrophy in dy/dy mice. The dy...

  17. The Link Between Stress Disorders and Autonomic Dysfunction in Muscular Dystrophy

    OpenAIRE

    Rasna eSabharwal

    2014-01-01

    Muscular dystrophy is a progressive disease of muscle weakness, muscle atrophy and cardiac dysfunction. Patients afflicted with muscular dystrophy exhibit autonomic dysfunction along with cognitive impairment, severe depression, sadness, and anxiety. Although the psychological aspects of cardiovascular disorders and stress disorders are well known, the physiological mechanism underlying this relationship is not well understood, particularly in muscular dystrophy. Therefore, the goal of this p...

  18. FHL1 reduces dystrophy in transgenic mice overexpressing FSHD muscular dystrophy region gene 1 (FRG1.

    Directory of Open Access Journals (Sweden)

    Sandra J Feeney

    Full Text Available Facioscapulohumeral muscular dystrophy (FSHD is an autosomal-dominant disease with no effective treatment. The genetic cause of FSHD is complex and the primary pathogenic insult underlying the muscle disease is unknown. Several disease candidate genes have been proposed including DUX4 and FRG1. Expression analysis studies of FSHD report the deregulation of genes which mediate myoblast differentiation and fusion. Transgenic mice overexpressing FRG1 recapitulate the FSHD muscular dystrophy phenotype. Our current study selectively examines how increased expression of FRG1 may contribute to myoblast differentiation defects. We generated stable C2C12 cell lines overexpressing FRG1, which exhibited a myoblast fusion defect upon differentiation. To determine if myoblast fusion defects contribute to the FRG1 mouse dystrophic phenotype, this strain was crossed with skeletal muscle specific FHL1-transgenic mice. We previously reported that FHL1 promotes myoblast fusion in vitro and FHL1-transgenic mice develop skeletal muscle hypertrophy. In the current study, FRG1 mice overexpressing FHL1 showed an improvement in the dystrophic phenotype, including a reduced spinal kyphosis, increased muscle mass and myofiber size, and decreased muscle fibrosis. FHL1 expression in FRG1 mice, did not alter satellite cell number or activation, but enhanced myoblast fusion. Primary myoblasts isolated from FRG1 mice showed a myoblast fusion defect that was rescued by FHL1 expression. Therefore, increased FRG1 expression may contribute to a muscular dystrophy phenotype resembling FSHD by impairing myoblast fusion, a defect that can be rescued by enhanced myoblast fusion via expression of FHL1.

  19. Neurocognitive Profiles in Duchenne Muscular Dystrophy and Gene Mutation Site

    Science.gov (United States)

    D’Angelo, Maria Grazia; Lorusso, Maria Luisa; Civati, Federica; Comi, Giacomo Pietro; Magri, Francesca; Del Bo, Roberto; Guglieri, Michela; Molteni, Massimo; Turconi, Anna Carla; Bresolin, Nereo

    2011-01-01

    The presence of nonprogressive cognitive impairment is recognized as a common feature in a substantial proportion of patients with Duchenne muscular dystrophy. To investigate the possible role of mutations along the dystrophin gene affecting different brain dystrophin isoforms and specific cognitive profiles, 42 school-age children affected with Duchenne muscular dystrophy, subdivided according to sites of mutations along the dystrophin gene, underwent a battery of tests tapping a wide range of intellectual, linguistic, and neuropsychologic functions. Full-scale intelligence quotient was approximately 1 S.D. below the population average in the whole group of dystrophic children. Patients with Duchenne muscular dystrophy and mutations located in the distal portion of the dystrophin gene (involving the 140-kDa brain protein isoform, called Dp140) were generally more severely affected and expressed different patterns of strengths and impairments, compared with patients with Duchenne muscular dystrophy and mutations located in the proximal portion of the dystrophin gene (not involving Dp140). Patients with Duchenne muscular dystrophy and distal mutations demonstrated specific impairments in visuospatial functions and visual memory (which seemed intact in proximally mutated patients) and greater impairment in syntactic processing. PMID:22000308

  20. Morphologic imaging in muscular dystrophies and inflammatory myopathies

    Energy Technology Data Exchange (ETDEWEB)

    Degardin, Adrian; Lacour, Arnaud; Vermersch, Patrick [CHU de Lille, Clinique neurologique, Lille (France); Morillon, David; Cotten, Anne [CHRU de Lille, Service de Radiologie Osteoarticulaire, Hopital Roger Salengro, Lille (France); Stojkovic, Tanya [G-H Pitie-Salpetriere, Institut de Myologie, Paris (France)

    2010-12-15

    To determine if magnetic resonance imaging (MR imaging) is useful in the diagnostic workup of muscular dystrophies and idiopathic inflammatory myopathies for describing the topography of muscle involvement. MR imaging was performed in 31 patients: 8 with dystrophic myotony types 1 (n = 4) or 2 (n = 4); 11 with limb-girdle muscular dystrophy, including dysferlinopathy, calpainopathy, sarcoglycanopathy, and dystrophy associated with fukutin-related protein mutation; 3 with Becker muscular dystrophy; and 9 with idiopathic inflammatory myopathies, including polymyositis, dermatomyositis, and sporadic inclusion body myositis. Analysis of T1 images enabled us to describe the most affected muscles and the muscles usually spared for each muscular disease. In particular, examination of pelvis, thigh, and leg muscles demonstrated significant differences between the muscular diseases. On STIR images, hyperintensities were present in 62% of our patients with muscular dystrophies. A specific pattern of muscular involvement was established for each muscular disease. Hyperintensities observed on STIR images precede fatty degeneration and are not specific for inflammatory myopathies. (orig.)

  1. Prevalence of cardiomyopathy in duchenne and becker's muscular dystrophy

    International Nuclear Information System (INIS)

    Sultan, A.; Fayaz, M.

    2008-01-01

    Cardiac assessment was not done routinely in Duchenne (DMD) and Becker muscular dystrophy (BMD) patients in Northern region of England while evidence was gathering on progressive cardiomyopathy in these patients. We wanted to find out the prevalence, progression and clinical features of cardiac involvement in Duchenne and Becker muscular dystrophy. Methods: It is a retrospective review of clinical, electrocardiographic and echocardiographic assessments. The notes of 52 Duchenne and Becker muscular dystrophy patients were reviewed out of which 32 had DMD, 6 had Intermediate muscular dystrophy (IMD) and 14 had BMD. Prevalence of preclinical and clinically evident cardiac involvement was 88.4% in DMD and BMD patients. Sixty nine% of patients had clinically evident cardiac involvement but only four patients had cardiac symptoms in the form of palpitations, out of which two were due to respiratory dysfunction and others was due to cardiac failure. Clinical examination of the rest of all of the patients was unremarkable. Electrocardiogram was abnormal in 88.4% of patients. Conduction defects were found in 19.4% of patients. Echocardiogram was abnormal in 80.7% of patients but all were poor echo subjects including those who had normal echocardiogram. Though most patients were asymptomatic, a high percentage had evidence of preclinical and clinically evident cardiac involvement. So in all patients with Xp21 linked muscular dystrophy a routine baseline cardiac assessment should be done at the age of 10 years and reviewed after intervals of one to two years. (author)

  2. [MRI symptomology in reflex sympathetic dystrophy of the foot].

    Science.gov (United States)

    Darbois, H; Boyer, B; Dubayle, P; Lechevalier, D; David, H; Aït-Ameur, A

    1999-08-01

    To describe the MRI findings of reflex sympathetic dystrophy of the foot and ankle. Retrospective study of 50 patients with reflex sympathetic dystrophy of the foot (5 with the cold form, and 45 with the warm form) diagnosed based on clinical and scintigraphic findings. All patients underwent MR imaging. The MRI findings were correlated with the clinical and scintigraphic findings. Patients with the cold form of reflex sympathetic dystrophy had no abnormality of signal at MR imaging. All patients with the warm from of reflex sympathetic dystrophy showed periarticular marrow edema at MR, typically involving more than one bone (mean of 4). Other findings were inconstant: soft tissue edema, joint effusion, and rarely, subchondral band of low T1W signal intensity of unclear etiology. MR imaging, including fat-suppressed T2W or STIR images and noncontrast T1W images, is helpful in patients with the warm or acute form of reflex sympathetic dystrophy of the foot. In patients with the cold form, MR imaging is helpful to exclude another underlying etiology for the symptoms and identify patients with the warm form of the process.

  3. Molecular analysis of facioscapulohumeral muscular dystrophy (FSHD)

    Energy Technology Data Exchange (ETDEWEB)

    Upadhyaya, M.; Maynard, J.; Osborn, M. [Institute of Medical Genetics, Cardiff (United Kingdom)] [and others

    1994-09-01

    Facioscapulohumeral muscular dystrophy (FSHD) is an autosomal dominant disorder characterized by progressive muscle weakness. The disease locus maps to 4q35 and is associated with a de novo DNA rearrangement, detected by a probe p13E-11 (D4F104S1) which maps proximal to the disease locus. An informative distal flanking marker for this condition is still required. Using p13E-11, we have analyzed 35 FSHD families in which the disease is apparently associated with a new mutation. Twenty three of these cases were found to have a smaller rearranged DNA fragment which was not present in either of the parents. Pulsed-field gel analysis of 5 of these families also revealed evidence of DNA deletion. During the course of this study, we identified one case with a DNA rearrangement which was also present in the unaffected mother, but at very low intensity. This finding has been confirmed by pulsed-field gel analysis, and indicates that the mother is probably a gonosomal mosaic. In order to saturate the FSHD region with new DNA markers, a laser microdissection and microcloning technique was used to construct a genomic library from the distal end of chromosome 4. Of the 72 microclones analyzed, 42 mapped into the relevant 4q35 region. 4 sequences were conserved and may be considered potential candidate genes for FSHD. The microclones mapping to 4q35 are under study to identify additional polymorphic markers for the FSHD region.

  4. Nutritional Challenges in Duchenne Muscular Dystrophy.

    Science.gov (United States)

    Salera, Simona; Menni, Francesca; Moggio, Maurizio; Guez, Sophie; Sciacco, Monica; Esposito, Susanna

    2017-06-10

    Neuromuscular diseases (NMDs) represent a heterogeneous group of acquired or inherited conditions. Nutritional complications are frequent in NMDs, but they are sometimes underestimated. With the prolongation of survival in patients with NMDs, there are several nutritional aspects that are important to consider, including the deleterious effects of overnutrition on glucose metabolism, mobility, and respiratory and cardiologic functions; the impact of hyponutrition on muscle and ventilatory function; constipation and other gastrointestinal complications; chewing/swallowing difficulties with an increased risk of aspiration that predisposes to infectious diseases and respiratory complications; as well as osteoporosis with an associated increased risk of fractures. The aim of this review is to provide a comprehensive analysis of the nutritional aspects and complications that can start in children with Duchenne muscular dystrophy (DMD) and increase with ageing. These aspects should be considered in the transition from paediatric clinics to adult services. It is shown that appropriate nutritional care can help to improve the quality of life of DMD patients, and a multidisciplinary team is needed to support nutrition challenges in DMD patients. However, studies on the prevalence of overnutrition and undernutrition, gastrointestinal complications, infectious diseases, dysphagia, and reduced bone mass in the different types of NMDs are needed, and appropriate percentiles of weight, height, body mass index, and body composition appear to be extremely important to improve the management of patients with NMD.

  5. Nutritional Challenges in Duchenne Muscular Dystrophy

    Directory of Open Access Journals (Sweden)

    Simona Salera

    2017-06-01

    Full Text Available Neuromuscular diseases (NMDs represent a heterogeneous group of acquired or inherited conditions. Nutritional complications are frequent in NMDs, but they are sometimes underestimated. With the prolongation of survival in patients with NMDs, there are several nutritional aspects that are important to consider, including the deleterious effects of overnutrition on glucose metabolism, mobility, and respiratory and cardiologic functions; the impact of hyponutrition on muscle and ventilatory function; constipation and other gastrointestinal complications; chewing/swallowing difficulties with an increased risk of aspiration that predisposes to infectious diseases and respiratory complications; as well as osteoporosis with an associated increased risk of fractures. The aim of this review is to provide a comprehensive analysis of the nutritional aspects and complications that can start in children with Duchenne muscular dystrophy (DMD and increase with ageing. These aspects should be considered in the transition from paediatric clinics to adult services. It is shown that appropriate nutritional care can help to improve the quality of life of DMD patients, and a multidisciplinary team is needed to support nutrition challenges in DMD patients. However, studies on the prevalence of overnutrition and undernutrition, gastrointestinal complications, infectious diseases, dysphagia, and reduced bone mass in the different types of NMDs are needed, and appropriate percentiles of weight, height, body mass index, and body composition appear to be extremely important to improve the management of patients with NMD.

  6. Optimizing Bone Health in Duchenne Muscular Dystrophy

    Directory of Open Access Journals (Sweden)

    Jason L. Buckner

    2015-01-01

    Full Text Available Duchenne muscular dystrophy (DMD is an X-linked recessive disorder characterized by progressive muscle weakness, with eventual loss of ambulation and premature death. The approved therapy with corticosteroids improves muscle strength, prolongs ambulation, and maintains pulmonary function. However, the osteoporotic impact of chronic corticosteroid use further impairs the underlying reduced bone mass seen in DMD, leading to increased fragility fractures of long bones and vertebrae. These serious sequelae adversely affect quality of life and can impact survival. The current clinical issues relating to bone health and bone health screening methods in DMD are presented in this review. Diagnostic studies, including biochemical markers of bone turnover and bone mineral density by dual energy X-ray absorptiometry (DXA, as well as spinal imaging using densitometric lateral spinal imaging, and treatment to optimize bone health in patients with DMD are discussed. Treatment with bisphosphonates offers a method to increase bone mass in these children; oral and intravenous bisphosphonates have been used successfully although treatment is typically reserved for children with fractures and/or bone pain with low bone mass by DXA.

  7. Sympathetic skin responses in reflex sympathetic dystrophy.

    Science.gov (United States)

    Bolel, K; Hizmetli, S; Akyüz, A

    2006-07-01

    This study was performed to determine the utility of sympathetic skin response (SSR) in evaluating the sympathetic function and to follow up the effects of sympathetic blockade in reflex sympathetic dystrophy (RSD). Thirty patients having RSD with upper extremity involvement were randomly divided into two groups. Besides medical therapy and exercise, physical therapy agents were applied to both the groups. In addition to this treatment protocol, stellar ganglion blockade was done by diadynamic current in Group II. The normal sides of the patients were used for the control group. SSRs were measured in all the patients before and after the therapy. The amplitude was found to be increased and the latency was found to be decreased in the affected side in both the groups before the therapy. After the therapy, the amplitude was decreased and latency was increased in both the groups. But, the differences in amplitude (P = 0.001) and latency (P = 0.002) before and after the therapy were significantly higher in Group II. (Before the treatment, SSRs were significantly different between the normal and the affected sides in both the groups. The observed change in SSRs after the treatment was higher in Group II.) It was concluded that, SSR can be a useful and noninvasive method in diagnosing the sympathetic dysfunction in RSD and can be used for evaluating the response to sympathetic blockade and other treatment modalities.

  8. Reflex sympathetic dystrophy syndrome and neuromediators.

    Science.gov (United States)

    Pham, Thao; Lafforgue, Pierre

    2003-02-01

    Concepts related to the pathophysiology of reflex sympathetic dystrophy syndrome (RSDS) are changing. Although sympathetic influences are still viewed as the most likely mechanism underlying the development and/or perpetuation of RSDS, these influences are no longer ascribed to an increase in sympathetic tone. Rather, the most likely mechanism may be increased sensitivity to catecholamines due to sympathetic denervation with an increase in the number and/or sensitivity of peripheral axonal adrenoceptors. Several other pathophysiological mechanisms have been suggested, including neurogenic inflammation with the release of neuropeptides by primary nociceptive afferents and sympathetic efferents. These neuromediators, particularly substance P, calcitonin gene-related peptide, and neuropeptide Y (NPY), may play a pivotal role in the genesis of pain in RSDS. They induce an inflammatory response (cutaneous erythema and edema) and lower the pain threshold. Neurogenic inflammation at the site of the lesion with neuromediator accumulation or depletion probably contributes to the pathophysiology of RSDS. However, no single neuromediator has been proved responsible, and other hypotheses continue to arouse interest.

  9. Falls and stumbles in myotonic dystrophy.

    Science.gov (United States)

    Wiles, C M; Busse, M E; Sampson, C M; Rogers, M T; Fenton-May, J; van Deursen, R

    2006-03-01

    To investigate falls and risk factors in patients with myotonic dystrophy type 1 (DM1) compared with healthy volunteers. 13 sequential patients with DM1 from different kindreds were compared with 12 healthy volunteers. All subjects were evaluated using the Rivermead Mobility Index, Performance Oriented Mobility Assessment, and modified Activities Specific Balance Confidence scale. Measures of lower limb muscle strength, gait speed, and 7-day ambulatory activity monitoring were recorded. Subjects returned a weekly card detailing stumbles and falls. 11 of 13 patients (mean age 46.5 years, seven female) had 127 stumbles and 34 falls over the 13 weeks, compared with 10 of 12 healthy subjects (34.4 years, seven female) who had 26 stumbles and three falls. Patients were less active than healthy subjects but had more falls and stumbles per 5000 right steps taken (mean (SD) events, 0.21 (0.29) v 0.02 (0.02), p = 0.007). Patients who fell (n = 6) had on average a lower Rivermead Mobility score, slower self selected gait speed, and higher depression scores than those who did not. DM1 patients stumble or fall about 10 times more often than healthy volunteers. Routine inquiry about falls and stumbles is justified. A study of multidisciplinary intervention to reduce the risk of falls seems warranted.

  10. Perspectives of stem cell therapy in Duchenne muscular dystrophy.

    Science.gov (United States)

    Meregalli, Mirella; Farini, Andrea; Belicchi, Marzia; Parolini, Daniele; Cassinelli, Letizia; Razini, Paola; Sitzia, Clementina; Torrente, Yvan

    2013-09-01

    Muscular dystrophies are heritable and heterogeneous neuromuscular disorders characterized by the primary wasting of skeletal muscle, usually caused by mutations in the proteins forming the link between the cytoskeleton and the basal lamina. As a result of mutations in the dystrophin gene, Duchenne muscular dystrophy patients suffer from progressive muscle atrophy and an exhaustion of muscular regenerative capacity. No efficient therapies are available. The evidence that adult stem cells were capable of participating in the regeneration of more than their resident organ led to the development of potential stem cell treatments for degenerative disorder. In the present review, we describe the different types of myogenic stem cells and their possible use for the progression of cell therapy in Duchenne muscular dystrophy. © 2012 The Authors Journal compilation © 2012 FEBS.

  11. Muscle regeneration and inflammation in patients with facioscapulohumeral muscular dystrophy

    DEFF Research Database (Denmark)

    Hauerslev, S; Ørngreen, M C; Hertz, J M

    2013-01-01

    The aim of this study was to investigate whether inflammation and regeneration are prominent in mildly affected muscles of patients with facioscapulohumeral muscular dystrophy type 1A (FSHD1A). Inflammation in muscle has been suggested by MRI studies in patients with FSHD1A.......The aim of this study was to investigate whether inflammation and regeneration are prominent in mildly affected muscles of patients with facioscapulohumeral muscular dystrophy type 1A (FSHD1A). Inflammation in muscle has been suggested by MRI studies in patients with FSHD1A....

  12. [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.

  13. The paradox of muscle hypertrophy in muscular dystrophy.

    Science.gov (United States)

    Kornegay, Joe N; Childers, Martin K; Bogan, Daniel J; Bogan, Janet R; Nghiem, Peter; Wang, Jiahui; Fan, Zheng; Howard, James F; Schatzberg, Scott J; Dow, Jennifer L; Grange, Robert W; Styner, Martin A; Hoffman, Eric P; Wagner, Kathryn R

    2012-02-01

    Mutations in the dystrophin gene cause Duchenne and Becker muscular dystrophy in humans and syndromes in mice, dogs, and cats. Affected humans and dogs have progressive disease that leads primarily to muscle atrophy. Mdx mice progress through an initial phase of muscle hypertrophy followed by atrophy. Cats have persistent muscle hypertrophy. Hypertrophy in humans has been attributed to deposition of fat and connective tissue (pseudohypertrophy). Increased muscle mass (true hypertrophy) has been documented in animal models. Muscle hypertrophy can exaggerate postural instability and joint contractures. Deleterious consequences of muscle hypertrophy should be considered when developing treatments for muscular dystrophy. Copyright © 2012 Elsevier Inc. All rights reserved.

  14. [Myotonic dystrophy as a contraindication for electroconvulsive therapy?].

    Science.gov (United States)

    Wynhoven, L M L; Scherders, M J W T; van Suijlekom, J A

    2009-01-01

    A 57-year-old woman with medication-resistant major depression was referred to our clinic for electroconvulsive therapy. After an extensive evaluation of our patient's condition we concluded that in this case the comorbid myotonic dystrophy was a contraindication for the performance of electroconvulsive therapy. However, in the current Dutch Psychiatric Association guidelines this illness is not mentioned as a possible contraindication for electroconvulsive therapy. This raises the question of whether myotonic dystrophy should now be incorporated in these guidelines and makes us wonder to what extent our conclusion could have consequences for the treatment of other neuromuscular illnesses.

  15. [Reflex sympathetic dystrophy: description of a case with skin lesions].

    Science.gov (United States)

    Vergara, Aránzazu; Isarría, María J; Prado Sánchez-Caminero, María; Guerra, Aurora

    2005-10-01

    Reflex sympathetic dystrophy or algodystrophy is a poorly defined syndrome in which the patient develops pain disproportionate to the cause. It is included among the complex regional pain syndromes. The symptoms are triggered by some type of trauma, at times trivial, and consist of burning pain, edema, changes in skin color, alterations in vascularization, temperature changes, hyperhidrosis and skin disorders, which primarily consist of atrophic changes. Other less frequent cutaneous manifestations have been described in patients with this syndrome. These include papules, blisters, inflammatory lesions and reticulated hyperpigmentation. We discuss the case of a patient with reflex sympathetic dystrophy who presented with superficial ulcers on the affected limb, which mimicked dermatitis artefacta.

  16. Computed tomography in Duchenne type muscular dystrophy

    International Nuclear Information System (INIS)

    Kawai, Mitsuru; Kunimoto, Masanari; Motoyoshi, Yasufumi; Kuwata, Takashi; Nakano, Imaharu

    1985-01-01

    The computed tomography (CT) scan was performed on 91 Duchenne type muscular dystrophy (DMD) patients on the following four levels; (1) at the level of L3 vertebra, (2) 2-3cm above the symphysis pubica, (3) midposition of the thigh, (4) largest-diameter section of the lower leg. The CT of muscles common to most of the DMD patients were as follows: 1. Muscle atrophy: Muscle atrophy was shown as a reduction in the cross-sectional area of the muscles. Very mild muscle atrophy could be detected either by the clearly identified muscle border or by scattered low-density areas of so-called ''moth-eaten'' appearance within muscles. 2. Fat infiltration: The decrease in radio-density of muscles was interpreted as infiltration of fatty tissue. This type of density change was further classified into diffuse, streaked, cobblestone and salt-and-pepper patterns according to the spacial distribution of low-density areas. 3. Selectivity pattern: As the chronological sequence of DMD muscle degeneration is usually different among individual muscles, it may be seen, in some stages, that some of the synergistic muscles are still only slightly involved, while the others are quite severely atrophied with evident fat infiltration. In certain stages of the disease, most of the patients show relative preservation of particular muscles although they assumed a rounded shape. The most resistent muscle was musculus gracilis, followed by the musculus sartorius, musculus semitendinosus (and/or musculus semimembranosus) in that order. According to the severity of the CT changes, 86 of the 91 patients were classed into five stages from A1 to A5. Morphological stages (A1-A5) were well correlated to the functional disability stages by Ueda with a correlation factor of r=0.88. (J.P.N.)

  17. Bisphosphonate therapy of reflex sympathetic dystrophy syndrome

    Science.gov (United States)

    Adami, S; Fossaluzza, V; Gatti, D; Fracassi, E; Braga, V

    1997-01-01

    OBJECTIVE—The reflex sympathetic dystrophy syndrome (RSDS) is a painful limb disorder, for which a consistently effective treatment has not yet been identified. The disease is associated with increased bone resorption and patchy osteoporosis, which might benefit from treatment with bisphosphonates, powerful inhibitors of bone resorption.
METHODS—Twenty patients with RSDS of foot and hand, were randomly assigned to blind administration of either alendronate intravenously (Istituto Gentili, Pisa, Italy) 7.5 mg dissolved in 250 ml saline solution or placebo saline infusions daily for three days. Two weeks later all patients had an identical treatment course with open labelled alendronate (7.5 mg/day for three days), independent from the results of the first blind treatment.
RESULTS—In the patients treated with blind alendronate the diminution in spontaneous pain, tenderness, and swelling (circumference of the affected limb) and the improvement in motion were significantly different from baseline (p<0.001), from those observed within the first two weeks in the control group (p<0.01), and from week 2 to week 4 (p<0.01). In the patients given blind placebo infusions no relevant symptomatic changes were observed after the first two weeks of follow up, but they responded to the open alendronate therapy given afterwards. In 12 patients with RSDS of the hand the ultradistal bone mineral content (BMC) of the affected arm was considerably lower than that of the controlateral arm (mean (SD)) (426(82) mg/cm versus 688(49)). Six weeks after the beginning of the trial BMC rose by 77(12) mg/cm (p<0.001) in the affected arm, but it did not change in the controlateral.
CONCLUSIONS—These results indicate that bisphosphonates should be considered for the treatment of RSDS, producing consistent and rapid remission of the disease.

 PMID:9135227

  18. Ritodrine-induced rhabdomyolysis, infantile myotonic dystrophy, and maternal myotonic dystrophy unveiled.

    Science.gov (United States)

    Ogoyama, Manabu; Takahashi, Hironori; Kobayashi, Yukako; Usui, Rie; Matsubara, Shigeki

    2017-02-01

    A primiparous pregnant woman in remission of myositis suffered very acute-onset ritodrine-induced rhabdomyolysis. At 29 gestational weeks, ritodrine was administered for threatened preterm labor. Just 3 h later, she complained of severe limb muscle pain, with serum creatinine phosphokinase elevated to 32 019 U/L and myoglobinuria. The muscle pain disappeared immediately after ceasing administration of ritodrine. At 31 weeks, premature rupture of the membranes occurred, necessitating cesarean section, yielding a baby with weak tonus, and the presence of infantile muscle diseases was suspected. Genetic analysis of the infant confirmed myotonic dystrophy (dystrophia myotonica, DM), which prompted us to perform maternal genetic analysis, confirming maternal DM. Ritodrine can induce rhabdomyolysis even in the prodromal phase with a mild phenotype of DM. A literature review suggested that ritodrine-induced rhabdomyolysis may be likely to occur more acutely after ritodrine administration in DM compared with non-DM mothers. © 2016 Japan Society of Obstetrics and Gynecology.

  19. Duchenne muscular dystrophy: High-resolution melting curve ...

    African Journals Online (AJOL)

    Duchenne muscular dystrophy: High-resolution melting curve analysis as an affordable diagnostic mutation scanning tool in a South African cohort. ... Genetic screening for D/BMD in South Africa currently includes multiple ligase-dependent probe amplification (MLPA) for exonic deletions and duplications and linkage ...

  20. Genetics Home Reference: lattice corneal dystrophy type II

    Science.gov (United States)

    ... network of protein filaments that gives structure to cells (the cytoskeleton). Mutations that cause lattice corneal dystrophy type II change a single protein building block (amino acid) in the gelsolin protein. ... from the cell. These protein fragments clump together and form amyloid ...