Sample records for adrenoleukodystrophy

  1. Brain endothelial dysfunction in cerebral adrenoleukodystrophy. (United States)

    Musolino, Patricia L; Gong, Yi; Snyder, Juliet M T; Jimenez, Sandra; Lok, Josephine; Lo, Eng H; Moser, Ann B; Grabowski, Eric F; Frosch, Matthew P; Eichler, Florian S


    See Aubourg (doi:10.1093/awv271) for a scientific commentary on this article.X-linked adrenoleukodystrophy is caused by mutations in the ABCD1 gene leading to accumulation of very long chain fatty acids. Its most severe neurological manifestation is cerebral adrenoleukodystrophy. Here we demonstrate that progressive inflammatory demyelination in cerebral adrenoleukodystrophy coincides with blood-brain barrier dysfunction, increased MMP9 expression, and changes in endothelial tight junction proteins as well as adhesion molecules. ABCD1, but not its closest homologue ABCD2, is highly expressed in human brain microvascular endothelial cells, far exceeding its expression in the systemic vasculature. Silencing of ABCD1 in human brain microvascular endothelial cells causes accumulation of very long chain fatty acids, but much later than the immediate upregulation of adhesion molecules and decrease in tight junction proteins. This results in greater adhesion and transmigration of monocytes across the endothelium. PCR-array screening of human brain microvascular endothelial cells after ABCD1 silencing revealed downregulation of both mRNA and protein levels of the transcription factor c-MYC (encoded by MYC). Interestingly, MYC silencing mimicked the effects of ABCD1 silencing on CLDN5 and ICAM1 without decreasing the levels of ABCD1 protein itself. Together, these data demonstrate that ABCD1 deficiency induces significant alterations in brain endothelium via c-MYC and may thereby contribute to the increased trafficking of leucocytes across the blood-brain barrier as seen in cerebral adrenouleukodystrophy.

  2. Intra familial phenotypical variations in adrenoleukodystrophy

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    Gosalakkal Jayaprakash


    Full Text Available Adrenoleukodystrophy (ALD is an X-linked recessively inherited peroxisomal disorder, characterized by progressive white-matter demyelination of the central nervous system and adrenocortical insufficiency. It has a wide phenotypical variability ranging from symptomatic childhood cerebral form to the asymptomatic with biochemical defects only; sometimes within the same family. We report a family of three siblings diagnosed with ALD confirmed with the mutations in ABCD1 gene having phenotypical variability ranging from pure adrenal insufficiency to progressive neurodegeneration in the same family. The mother was identified as the carrier and maternal uncle was diagnosed with Adrenomyeloneuropathy. We discuss the variable presentation in our family and the possible causes of phenotypical variability.

  3. Bezafibrate for X-linked adrenoleukodystrophy.

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    Marc Engelen

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

  4. Adrenoleukodystrophy: case report and aspects relevant to the otorhinolaryngologist

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    Rapoport, Priscila B


    Full Text Available Introduction: Adrenoleukodystrophy is a genetic disease with heritage standard bound to X, which consists of an alteration of the metabolism and causes an accumulation of fatty acids of a very large chain (AGCML associated to demyelinization of axons and adrenal insufficiency. It may initially manifest with alterations of behavior, hearing, vision, speech, writing, gait, and in the more advanced cases, it results in generalized hypertension, loss of cognitive and motor functions and dysphagia. The diagnosis is confirmed by dosing the AGCML's plasmatic levels, findings of the Magnetic Resonance and karyotype. Case Report: We report the case of A.V.F., 5 years old, sent to the otorhinolaryngology service for school and communication difficulties of auditory evaluation. The audiometry confirmed a bilateral moderate hearing loss. Some months after he evolved with progressive loss of vision, worsening of writing and aggressiveness, and was then forwarded to the neuropediatrician with the hypothesis of neurodegenerative disease. Magnetic Resonance was carried out and showed extensive parieto-occipital lesions. His diagnosis was confirmed through karyotype performed by a geneticist with an immediate beginning of the treatment. Approximately 1 year after the beginning of the symptoms, he presented with severe oropharyngeal dysphagia and silent bronchoaspiration diagnosed by the video-deglutogram exam. Final Comments: Today with gastrotomy. So far, there is no therapy defined for adrenoleukodystrophy. The otorhinolaryngologist must know this disease because, as well as in the case described above, he/she is one of the first professionals.

  5. Diffusion-weighted Magnetic Resonance Imaging in the Early Diagnosis of Neonatal Adrenoleukodystrophy

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    R Nuri Sener


    Full Text Available A newborn baby girl developed seizures right after birth. On the fourth day, the baby was examined using diffusion sequence magnetic resonance imaging (MRI and diagnosed to have neonatal adrenoleukodystrophy. Laboratory findings confirmed the diagnosis. This is the first case of neonatal adrenoleukodystrophy (NALD where diffusion MRI sequence helped in the diagnosis. We find association of NALD with seizures at birth is an extremely rare occurrence, and so far, only one case has been mentioned in the literature.

  6. Infantile Refsum disease: an inherited peroxisomal disorder. Comparison with Zellweger syndrome and neonatal adrenoleukodystrophy. (United States)

    Poll-The, B T; Saudubray, J M; Ogier, H A; Odièvre, M; Scotto, J M; Monnens, L; Govaerts, L C; Roels, F; Cornelis, A; Schutgens, R B


    Three patients affected by infantile Refsum disease are described with mental retardation, minor facial dysmorphia, chorioretinopathy, sensorineural hearing deficit, hepatomegaly, failure to thrive and hypocholesterolaemia. Initially, only an accumulation of phytanic acid was thought to be present. More recent findings showed a biochemical profile very similar to that found in classical Zellweger syndrome or neonatal adrenoleukodystrophy. Morphologically typical peroxisomes were absent in the liver. All three disorders are associated with multiple peroxisomal dysfunction. Because of these similarities pertinent clinical data of our three patients are compared with those of reported patients diagnosed as having infantile Refsum disease, neonatal adrenoleukodystrophy or Zellweger syndrome who survived for several years. Attention is drawn to the difference in severity of clinical features, ranging from infantile Refsum's disease to neonatal adrenoleukodystrophy and, finally, to Zellweger syndrome.

  7. [Anesthetic Management of an Adrenoleukodystrophy Patient for Intrathecal Baclofen Therapy]. (United States)

    Hashimoto, Yuichi; Takahashi, Kei; Yamamoto, Yuko; Ogata, Tokiko; Arai, Takero; Okuda, Yasuhisa


    A 34-year-old man with adrenoleukodystrophy (ALD) was scheduled for pump system insertion of intrathecal baclofen therapy under general anesthesia. ALD, a rare genetic disorder, is associated with a total body increase in long chain fatty acids caused by defective degradation, and includes various nervous system abnormalities, muscular weakness, in addition to adrenal insufficiency. He had contracture of the both legs, and muscular weakness of the left hand, and Mallampati class III, but no respiratory disability. In the operating room, we administered hydrocortisone 100 mg for steroid coverage, and low-dose midazolam, and fentanyl. As spontaneous breathing remained, we could easily see epiglottis and arytenoid cartilage by McGRATH. Therefore we selected rapid-induction of anesthesia with thiamylal, and rocuronium 40 mg, under cricoid pressure. We avoided propofol. Anesthsia was maintained with sevoflurane and remifentanil, monitoring BIS and train of four. No more rocuronium was administered, and anesthesia was uneventful. Intrathecal baclofen therapy is given to patients who have severe contracture. When we selected general anesthesia, we should be aware of the possibility of muscular weakness, and cannot intubate cannot ventilate scenario. PMID:27188115

  8. Lipoid pneumonia as a complication of Lorenzo's oil therapy in a patient with adrenoleukodystrophy. (United States)

    Majori, Maria; Scarascia, Alessandro; Anghinolfi, Miriam; Pisi, Roberta; Gnetti, Letizia; Casalini, Angelo Gianni


    Lipoid pneumonia (LP) is a rare exogenous condition caused by inhalation or aspiration of lipid material into the lungs. It is often associated with the therapeutic use of different types of oil, and the diagnosis is based on the demonstration of lipid-laden macrophages in bronchoalveolar lavage fluid. We reported the case of a 39-year-old male with X-linked adrenoleukodystrophy who developed LP secondary to the use of Lorenzo's oil. To our knowledge, the association between the use of Lorenzo's oil and LP has never been reported in literature. PMID:24992138

  9. Anaesthesia for a child with adrenoleukodystrophy: A case report and review of the literature

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    Sien Hui Tan


    Full Text Available We present a 9-year-old boy with X-linked cerebral adrenoleukodystrophy (X-linked ALD and previous umbilical cord transplant who required general anaesthesia. An anaesthetic plan for each individual should be tailored to ensure the best possible anaesthetic care for these patients. The anaesthetic considerations include mental retardation, seizure disorder, hypotonia, liver function abnormalities, gastro-oesophageal reflux, impaired adrenocortical function and immunosuppression. Pre-operative sedation should be avoided because of hypotonia of the pharyngeal muscles. Anti-convulsants are continued, and potentially epileptogenic anaesthetic agents are avoided. The patient was intubated using a modified rapid sequence induction with a head up position of 30 degrees. Four other cases have been reported in literature. Nevertheless, there is still no established anaesthetic management for these patients, and total intravenous anaesthesia can be considered as a safe and alternative method of anaesthesia. To the best of our knowledge, this is the first reported use of total intravenous anaesthesia with propofol and remifentanil in a case of cerebral adrenoleukodystrophy, and with a favourable outcome.

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

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    Charles Marques Lourenço


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

  11. A novel cell model to study the function of the adrenoleukodystrophy-related protein

    International Nuclear Information System (INIS)

    X-linked adrenoleukodystrophy (X-ALD) is a neurodegenerative disorder due to mutations in the ABCD1 (ALD) gene. ALDRP, the closest homolog of ALDP, has been shown to have partial functional redundancy with ALDP and, when overexpressed, can compensate for the loss-of-function of ALDP. In order to characterize the function of ALDRP and to understand the phenomenon of gene redundancy, we have developed a novel system that allows the controlled expression of the ALDRP-EGFP fusion protein (normal or non-functional mutated ALDRP) using the Tet-On system in H4IIEC3 rat hepatoma cells. The generated stable cell lines express negligible levels of endogenous ALDRP and doxycycline dosage-dependent levels of normal or mutated ALDRP. Importantly, the ALDRP-EGFP protein is targeted correctly to peroxisome and is functional. The obtained cell lines will be an indispensable tool in our further studies aimed at the resolution of the function of ALDRP to characterize its potential substrates in a natural context

  12. Identification of new mutations in Israeli patients with X-linked adrenoleukodystrophy. (United States)

    Neumann, S; Topper, A; Mandel, H; Shapira, I; Golan, O; Gazit, E; Loewenthal, R


    X-linked adrenoleukodystrophy (ALD) is a peroxisomal disorder characterized by impaired peroxisomal betaoxidation of very-long-chain fatty acids (VLCFAs). This is probably due to reduced activation of the VLCFAs and results in demyelination of the nervous system and adrenocortical insufficiency. The ALD gene is localized on Xq28, has 10 exons and encodes a protein of 745 amino acids with significant homology to the membrane peroxisomal protein PMP70. Characterizing the disease causing mutations is of importance in prenatal diagnosis because 12-20% of women who are obligatory carriers show false-negative results when tested for VLCFA in plasma. We have analyzed DNA from blood samples of 7 Jewish (5 Sephardi and 2 Ashkenazi) and 3 Arab Israeli families suffering from ALD. Five missense-type mutations were identified: R104H, Y174C, L229P, R401Q, and G512C. A single mutation, R464X, was nonsense, and two, Y171 frameshift and E471 frameshift, were frameshift. Interestingly, a single mutation was identified in three families of Moroccan Jewish descent, probably due to a founder effect. PMID:11336405

  13. X-linked adrenoleukodystrophy: clinical and laboratory findings in 15 Brazilian patients

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    Carmen R. Vargas


    Full Text Available Adrenoleukodystrophy (X-ALD is an X-linked recessively inherited peroxisomal disorder, phenotypically heterogeneous, characterized by progressive white-matter demyelination of the central nervous system and adrenocortical insufficiency. We investigated 15 male X-ALD patients varying in age from 7 to 39, diagnosed among 108 suspected patients referred for investigation. Plasma levels of very long chain fatty acids (VLCFA were measured at our laboratory using gas chromatography (GC. Eleven cases of childhood X-ALD and four cases of adrenomyeloneuropathy (AMN were diagnosed. Adrenal leukodystrophy insufficiency and limb weakness were the most frequent symptoms, appearing in 12, 8 and 6 of the patients, respectively. Physician awareness of X-ALD seems inadequate to judge by age at diagnosis and lengthy interval between the start of symptoms and diagnosis. This is the first published series of Brazilian patients with X-ALD. We determined signs and symptoms relevant for diagnosis, as early identification seems important for treatment outcome. In addition, diagnosis identifies carriers, who could benefit from genetic counselling and prenatal diagnosis.Adrenoleucodistrofia (X-ALD é uma desordem peroxissomal com padrão de herança ligada ao X, fenotipicamente heterogênea, caracterizada por uma progressiva desmielinização da substância branca do sistema nervoso central e por insuficiência adrenal. Foram investigados por nós 15 pacientes do sexo masculino com sinais clínicos sugestivos de X-ALD, com idade entre 7 e 39 anos, diagnosticados entre 108 pacientes encaminhados para investigação por suspeita clínica. Os níveis plasmáticos dos ácidos graxos de cadeia muito longa (VLCFA foram dosados em nosso laboratório através de cromatografia gasosa (GC. Onze (73% casos da forma infantil de X-ALD (ALD e 4 (27% casos de adrenomieloneuropatia (AMN foram diagnosticados. Insuficiência leucodistrofia adrenal e fraqueza muscular foram os sinais mais


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    R. B. Gagianone


    Full Text Available Introduction The X-linked adrenoleukodystrophy (X-ALD is characterized by mutations in very long chain fatty acids (VLCFA peroxisome transporter, leading to VLCFA accumulation in myelin sheath. In the 70’s and 80’s it was hypothesized that X-ALD is caused by enzymatic deficits in FA-coenzyme A connection, VLCFA degradation or FA elongation. The latter enabled Lorenzo’s oil (LO treatment, which became famous by the homonym movie. The apparent initial therapy effectiveness lead to LO administration in many patients, although with biochemical knowledge progress its relevance has been questioned.Objectives Our aim was to discuss X-ALD researches in “Lipids Metabolism” classes during 2014 Biochemistry courses to Biology and Biomedicine undergraduate students at Fluminense Federal University to illustrate how scientific knowledge is constructed.Materials and MethodsIn order to contrast the recent scientific advances with the information spread to society through “Lorenzo’s Oil”, the movie in edited version was presented to students followed by a questionnaire with Likert scale to evaluate the perception of scientific knowledge exposed by the movie. Afterwards, a Guided Study containing a brief history and discursive questions based upon a paper (Wiesingner, J. Biol. Chem. 288:19269, 2013 was applied in class.Results and DiscussionFrom 58 students who filled in the questionnaire,72,4% considered the movie shows that X-ALD biochemical knowledge has been achieved. This notion was confirmed since 84,5% agreed LO is an effective alternative treatment if X-ALD is early detected. The same percentage agreed that based on the movie the biochemical deficiency relies on an enzyme involved in VLCFA degradation. Although the movie transmits the idea that the cure has been found, 67,2% believed X-ALD biochemical mechanisms are not fully comprehended. ConclusionsThe Guided Study/movie application was very effective because allowed the

  15. CYP4F2 affects phenotypic outcome in adrenoleukodystrophy by modulating the clearance of very long-chain fatty acids. (United States)

    van Engen, Catherine E; Ofman, Rob; Dijkstra, Inge M E; van Goethem, Tessa Jacobs; Verheij, Eveline; Varin, Jennifer; Vidaud, Michel; Wanders, Ronald J A; Aubourg, Patrick; Kemp, Stephan; Barbier, Mathieu


    X-linked adrenoleukodystrophy (ALD) is a severe neurodegenerative disorder caused by the accumulation of very long-chain fatty acids (VLCFA) due to mutations in the ABCD1 gene. The phenotypic spectrum ranges from a fatal cerebral demyelinating disease in childhood (cerebral ALD) to a progressive myelopathy without cerebral involvement in adulthood (adrenomyeloneuropathy). Because ABCD1 mutations have no predictive value with respect to clinical outcome a role for modifier genes was postulated. We report that the CYP4F2 polymorphism rs2108622 increases the risk of developing cerebral ALD in Caucasian patients. The rs2108622 polymorphism (c.1297G>A) results in an amino acid substitution valine for methionine at position 433 (p.V433M). Using cellular models of VLCFA accumulation, we show that p.V433M decreases the conversion of VLCFA into very long-chain dicarboxylic acids by ω-oxidation, a potential escape route for the deficient peroxisomal β-oxidation of VLCFA in ALD. Although p.V433M does not affect the catalytic activity of CYP4F2 it reduces CYP4F2 protein levels markedly. These findings open perspectives for therapeutic interventions in a disease with currently limited treatment options. PMID:27425035

  16. Neurodegeneration in a Drosophila model of adrenoleukodystrophy: the roles of the Bubblegum and Double bubble acyl-CoA synthetases

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    Anna Sivachenko


    Full Text Available Debilitating neurodegenerative conditions with metabolic origins affect millions of individuals worldwide. Still, for most of these neurometabolic disorders there are neither cures nor disease-modifying therapies, and novel animal models are needed for elucidation of disease pathology and identification of potential therapeutic agents. To date, metabolic neurodegenerative disease has been modeled in animals with only limited success, in part because existing models constitute analyses of single mutants and have thus overlooked potential redundancy within metabolic gene pathways associated with disease. Here, we present the first analysis of a very-long-chain acyl-CoA synthetase (ACS double mutant. We show that the Drosophila bubblegum (bgm and double bubble (dbb genes have overlapping functions, and that the consequences of double knockout of both bubblegum and double bubble in the fly brain are profound, affecting behavior and brain morphology, and providing the best paradigm to date for an animal model of adrenoleukodystrophy (ALD, a fatal childhood neurodegenerative disease associated with the accumulation of very-long-chain fatty acids. Using this more fully penetrant model of disease to interrogate brain morphology at the level of electron microscopy, we show that dysregulation of fatty acid metabolism via disruption of ACS function in vivo is causal of neurodegenerative pathologies that are evident in both neuronal cells and their supporting cell populations, and leads ultimately to lytic cell death in affected areas of the brain. Finally, in an extension of our model system to the study of human disease, we describe our identification of an individual with leukodystrophy who harbors a rare mutation in SLC27a6 (encoding a very-long-chain ACS, a human homolog of bgm and dbb.

  17. Disruption of a PEX1-PEX6 interaction is the most common cause of the neurologic disorders Zellweger syndrome, neonatal adrenoleukodystrophy, and infantile Refsum disease. (United States)

    Geisbrecht, B V; Collins, C S; Reuber, B E; Gould, S J


    Peroxisomal matrix protein import requires the action of two AAA ATPases, PEX1 and PEX6. Mutations in either the PEX1 or PEX6 gene are the most common cause of the lethal neurologic disorders Zellweger syndrome, neonatal adrenoleukodystrophy, and infantile Refsum disease and account for disease in 80% of all such patients. We report here that overexpression of PEX6 can suppress the phenotypes of certain PEX1-deficient cells, that overexpression of PEX1 can suppress the phenotypes of certain PEX6-deficient cells, and that these instances of suppression are allele-specific and require partial activity of the mutated gene. In addition to genetic evidence for interaction between PEX1 and PEX6, we find that the PEX1 and PEX6 proteins interact in the yeast two-hybrid assay and physically associate with one another in vitro. We previously identified a missense mutation in PEX1, G843D, which attenuates PEX1 function and is the most common cause of these diseases, present in one-third of all such patients. The G843D mutation attenuates the interaction between PEX1 and PEX6 in both the two-hybrid system and in vitro and appears to be suppressed by overexpression of PEX6. We conclude that PEX1 and PEX6 form a complex of central importance to peroxisome biogenesis and that mutations affecting this complex constitute the most common cause of the Zellweger syndrome spectrum of diseases.

  18. Function of the PEX19-binding site of human adrenoleukodystrophy protein as targeting motif in man and yeast. PMP targeting is evolutionarily conserved. (United States)

    Halbach, André; Lorenzen, Stephan; Landgraf, Christiane; Volkmer-Engert, Rudolf; Erdmann, Ralf; Rottensteiner, Hanspeter


    We predicted in human peroxisomal membrane proteins (PMPs) the binding sites for PEX19, a key player in the topogenesis of PMPs, by virtue of an algorithm developed for yeast PMPs. The best scoring PEX19-binding site was found in the adrenoleukodystrophy protein (ALDP). The identified site was indeed bound by human PEX19 and was also recognized by the orthologous yeast PEX19 protein. Likewise, both human and yeast PEX19 bound with comparable affinities to the PEX19-binding site of the yeast PMP Pex13p. Interestingly, the identified PEX19-binding site of ALDP coincided with its previously determined targeting motif. We corroborated the requirement of the ALDP PEX19-binding site for peroxisomal targeting in human fibroblasts and showed that the minimal ALDP fragment targets correctly also in yeast, again in a PEX19-binding site-dependent manner. Furthermore, the human PEX19-binding site of ALDP proved interchangeable with that of yeast Pex13p in an in vivo targeting assay. Finally, we showed in vitro that most of the predicted binding sequences of human PMPs represent true binding sites for human PEX19, indicating that human PMPs harbor common PEX19-binding sites that do resemble those of yeast. Our data clearly revealed a role for PEX19-binding sites as PMP-targeting motifs across species, thereby demonstrating the evolutionary conservation of PMP signal sequences from yeast to man.

  19. Cerebral X-linked adrenoleukodystrophy: follow-up with magnetic resonance imaging Adrenoleucodistrofia ligada ao X: acompanhamento por ressonância magnética

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    Emerson L. Gasparetto


    Full Text Available OBJECTIVE: To report a case of childhood cerebral X-linked adrenoleukodystrophy (X-ADL, emphasizing the magnetic resonance imaging (MRI findings at initial evaluation and at the follow-up. CASE REPORT: Five year-old boy, who was asymptomatic, presented with diagnosis of X-ADL for MRI evaluation. The initial brain MRI showed a focal area of enhancement at the splenium of the corpus calosum. One year later, the follow-up MRI showed a progression of the corpus calosus lesion, as well as other lesions in the parietal and occipital lobes. CONCLUSION: The brain MRI follow-up of patients with X-ADL is important to show the progression of the lesions.OBJETIVO: Relatar um caso de adrenoleucodistrofia ligada ao X (X-ADL, enfatizando os achados de ressonância magnética (RM na avaliação inicial e no seguimento. DESCRIÇÃO DO CASO: Paciente masculino de cinco anos de idade, assintomático, com diagnóstico de X-ADL, apresentou-se para estudo de RM. O exame inicial mostrou uma área focal de realce no esplênio do corpo caloso. Após um ano, a RM de seguimento evidenciou aumento da lesão do corpo caloso, assim como novas lesões nos lobos occipitais e parietais. CONCLUSÃO: O seguimento por RM de pacientes com X-ADL é importante para a demonstração da progressão das lesões.

  20. Brain Lipotoxicity of Phytanic Acid and Very Long-chain Fatty Acids. Harmful Cellular/Mitochondrial Activities in Refsum Disease and X-Linked Adrenoleukodystrophy. (United States)

    Schönfeld, Peter; Reiser, Georg


    It is increasingly understood that in the aging brain, especially in the case of patients suffering from neurodegenerative diseases, some fatty acids at pathologically high concentrations exert detrimental activities. To study such activities, we here analyze genetic diseases, which are due to compromised metabolism of specific fatty acids, either the branched-chain phytanic acid or very long-chain fatty acids (VLCFAs). Micromolar concentrations of phytanic acid or of VLCFAs disturb the integrity of neural cells by impairing Ca(2+) homeostasis, enhancing oxidative stress or de-energizing mitochondria. Finally, these combined harmful activities accelerate cell death. Mitochondria are more severely targeted by phytanic acid than by VLCFAs. The insertion of VLCFAs into the inner membrane distorts the arrangement of membrane constituents and their functional interactions. Phytanic acid exerts specific protonophoric activity, induces reactive oxygen species (ROS) generation, and reduces ATP generation. A clear inhibition of the Na(+), K(+)-ATPase activity by phytanic acid has also been reported. In addition to the instantaneous effects, a chronic exposure of brain cells to low micromolar concentrations of phytanic acid may produce neuronal damage in Refsum disease by altering epigenetic transcriptional regulation. Myelin-producing oligodendrocytes respond with particular sensitivity to VLCFAs. Deleterious activity of VLCFAs on energy-dependent mitochondrial functions declines with increasing the hydrocarbon chain length (C22:0 > C24:0 > C26:0). In contrast, the reverse sequence holds true for cell death induction by VLCFAs (C22:0 < C24:0 < C26:0). In adrenoleukodystrophy, the uptake of VLCFAs by peroxisomes is impaired by defects of the ABCD1 transporter. Studying mitochondria from ABCD1-deficient and wild-type mice proves that the energy-dependent functions are not altered in the disease model. Thus, a defective ABCD1 apparently exerts no obvious adaptive pressure on

  1. The genotype and phenotype studies of 40 Chinese patients with X-linked adrenoleukodystrophy(X-ALD)%40例X连锁肾上腺脑白质营养不良患者的基因型与表型

    Institute of Scientific and Technical Information of China (English)

    平莉莉; 包新华; 王爱花; 潘虹; 吴晔; 熊晖; 张月华; 秦炯; 吴希如


    Obiective:To elucidate the phenotype and the genotype-phenotype correlations in Chinese patients with X-linked adrenoleukodystrophy(X-ALD).Methods:Clinical features of 40 Chinese patients with X-ALD were studied and mutation spectrums were investigated by polymerase chain reaction (PCR) and sequencing. Results:Among these patients, four were siblings from two unrelated families, the others were unrelated. There were 31 cases with childhood cerebral (CCALD), 8 cases with adolescent cerebral (ACALD) and 1 case with adrenomyeloneuropathy (AMN). Visual impairment, which presented in 12 cases (30%), was the most common initial symptom. Nine (69%) of 13 cases who had hydrocortisone and ACTH measured showed adrenal insufficiency. By follow-up date, 19 cases (47.5%) were dead. The interval from onset to death varied from 1 to 6 years and the average were 3.3 years. The mean age at death was 10.5 years. Eleven cases (27.5%) were in vegetable state. The mean interval from onset to apparently vegetable state was 2.8 years (range from 1 to 6 years). Four cases had progressive neurological disability. Four cases were lost follow-up. One case with CCALD and one case with ACALD progressed slowly. The courses of the disease of these two patients were 5 years and 15 years respectively. Thirty five mutations were identified in 40 cases. Most were located within exon 1-3 (40%, 16/40) and exon 6-8 (42%, 17/40). There is a distinct clustering of missense mutations in exon 6 (17%, 7/40). Five types of mutations were associated with CCALD, three with ACALD and a missense mutation was identified in the patients with AMN. The two patients with long disease courses had a missence mutation c.1559 T>A and a nonsense mutation c.1785 G>A respectively. The siblings with similar manifestations and onset age were observed in two families, whose mutations were c.887 A>G and c.1028 G>T. Conclusion:The phenotypes, disease severity and rate of neurodegeneration could not be predicted by the nature of

  2. Clinical manifest x-linked recessive adrenoleukodystrophy in a female

    DEFF Research Database (Denmark)

    Jack, Gyda Hlin Skuladottir; Malm-Willadsen, Karolina; Frederiksen, Anja;


    primarily affects males; however, females may develop milder symptoms that may be difficult to recognize. The present report describes a 35-year-old female who experienced a feeling of heaviness in the upper and lower limbs, pain in both knees, and difficulty climbing stairs, running, and jumping. Clinical...... examination revealed decreased sensitivity in the feet, particularly to touch. Deep tendon reflexes in the lower limbs were brisk, and Babinski's sign was present bilaterally. Multiple sclerosis (MS) was excluded, and all clinical and biochemical tests were normal. After two years of progressing symptoms, the...... could be attributed to ALD. The present case underlines the importance of reevaluating family history in women presenting with vague neurological symptoms....

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


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


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

  4. Study of Pulmonary Complications in Pediatric Patients With Storage Disorders Undergoing Allogeneic Hematopoietic Stem Cell Transplantation (United States)


    I Cell Disease; Fucosidosis; Globoid Cell Leukodystrophy; Adrenoleukodystrophy; Mannosidosis; Niemann-Pick Disease; Pulmonary Complications; Mucopolysaccharidosis I; Mucopolysaccharidosis VI; Metachromatic Leukodystrophy; Gaucher's Disease; Wolman Disease

  5. Stem Cell Transplant for Inborn Errors of Metabolism (United States)


    Adrenoleukodystrophy; Metachromatic Leukodystrophy; Globoid Cell Leukodystrophy; Gaucher's Disease; Fucosidosis; Wolman Disease; Niemann-Pick Disease; Batten Disease; GM1 Gangliosidosis; Tay Sachs Disease; Sandhoff Disease

  6. UCB Transplant of Inherited Metabolic Diseases With Administration of Intrathecal UCB Derived Oligodendrocyte-Like Cells (United States)


    Adrenoleukodystrophy; Batten Disease; Mucopolysaccharidosis II; Leukodystrophy, Globoid Cell; Leukodystrophy, Metachromatic; Neimann Pick Disease; Pelizaeus-Merzbacher Disease; Sandhoff Disease; Tay-Sachs Disease; Brain Diseases, Metabolic, Inborn

  7. Allogeneic Bone Marrow Transplant for Inherited Metabolic Disorders (United States)


    Mucopolysaccharidosis; Hurler Syndrome; Hunter Syndrome; Maroteaux-Lamy Syndrome; Sly Syndrome; Alpha Mannosidosis; Fucosidosis; Aspartylglucosaminuria; Adrenoleukodystrophy (ALD); Krabbe Disease; Metachromatic Leukodystrophy (MLD); Sphingolipidoses; Peroxisomal Disorders

  8. Peroxisomal very long-chain fatty acid [beta]-oxidation in human skin fibroblasts: activity in Zellweger syndrome and other peroxisomal disorders

    NARCIS (Netherlands)

    Wanders, R.J.A.; Roermund, C.W.T. van; Wijland, M.J.A. van; Heikoop, J.; Schutgens, R.B.H.; Schram, A.W.; Tager, J.M.; Bosch, H. van den; Poll-Thé, B.T.; Saudubray, J.M.; Moser, H.W.; Moser, A.B.


    Since very long-chain fatty acids with a chain length of 24 carbons or more are known to accumulate in tissues and body fluids from patients with the cerebro-hepato-renal (Zellweger) syndrome, infantile Refsum disease, neonatal adrenoleukodystrophy and X-linked adrenoleukodystrophy, we studied very

  9. Human Placental-Derived Stem Cell Transplantation (United States)


    Mucopolysaccharidosis I; Mucopolysaccharidosis VI; Adrenoleukodystrophy; Niemann-Pick Disease; Metachromatic Leukodystrophy; Wolman Disease; Krabbe's Disease; Gaucher's Disease; Fucosidosis; Batten Disease; Severe Aplastic Anemia; Diamond-Blackfan Anemia; Amegakaryocytic Thrombocytopenia; Myelodysplastic Syndrome; Acute Myelogenous Leukemia; Acute Lymphocytic Leukemia

  10. Neurodegeneration in D-bifunctional protein deficiency: diagnostic clues and natural history using serial magnetic resonance imaging

    Energy Technology Data Exchange (ETDEWEB)

    Khan, Aneal [University of Calgary, Department of Medical Genetics and Pediatrics, Alberta Children' s Hospital, Calgary, AB (Canada); Wei, Xing-Chang [University of Calgary, Department of Radiology, Alberta Children' s Hospital, Calgary, AB (Canada); Snyder, Floyd F. [Alberta Children' s Hospital, Biochemical Genetics Laboratory, Calgary, AB (Canada); Mah, Jean K. [University of Calgary, Division of Neurology, Department of Pediatrics, Calgary, AB (Canada); Waterham, Hans; Wanders, Ronald J.A. [University of Amsterdam, Academic Medical Center, Lab Genetic Metabolic Diseases, Amsterdam (Netherlands)


    We report serial neurodegenerative changes on neuroimaging in a rare peroxisomal disease called D-bifunctional protein deficiency. The pattern of posterior to anterior demyelination with white matter disease resembles X-linked adrenoleukodystrophy. We feel this case is important to (1) highlight that D-bifunctional protein deficiency should be considered in cases where the neuroimaging resembles X-linked adrenoleukodystrophy, (2) to show different stages of progression to help identify this disease using neuroimaging in children, and (3) to show that neuroimaging suggesting a leukodystrophy can warrant peroxisomal beta-oxidation studies in skin fibroblasts even when plasma very long chain fatty acids are normal. (orig.)

  11. Retraction of an intrathecal baclofen infusion catheter following suprapubic cystotomy: a case report.

    NARCIS (Netherlands)

    Martens, F.M.J.; Somford, D.M.; Kuppevelt, D.H. van; Burg, M.J. van den; Heesakkers, J.P.F.A.


    INTRODUCTION: Intrathecal baclofen, administered via a Baclofen pump, is used for patients with spasticity. We report here a case of intrathecal catheter retraction following surgery. CASE REPORT: A male patient with adrenoleukodystrophy and a baclofen pump implant was admitted to the urology depart

  12. Phase I/II Pilot Study of Mixed Chimerism to Treat Inherited Metabolic Disorders (United States)


    Hurler Syndrome (MPS I); Hurler-Scheie Syndrome With Early Neurologic Involvement and/or Sensitization to Enzyme Replacement Therapy (ERT); Hunter Syndrome (MPS II); Sanfilippo Syndrome (MPS III); Krabbe Disease (Globoid Leukodystrophy); Metachromatic Leukodystrophy (MLD); Adrenoleukodystrophy (ALD and AMN); Sandhoff Disease; Tay Sachs Disease; Pelizaeus Merzbacher (PMD); Niemann-Pick Disease; Alpha-mannosidosis

  13. MT2013-31: Allo HCT for Metabolic Disorders and Severe Osteopetrosis (United States)


    Mucopolysaccharidosis I; Mucopolysaccharidosis II; Mucopolysaccharidosis VI; Mucopolysaccharidosis VII; Hurler Syndrome; Hunter Syndrome; Maroteaux Lamy Syndrome; Sly Syndrome; Glycoprotein Metabolic Disorders; Alpha Mannosidosis; Fucosidosis; Aspartylglucosaminuria; Adrenoleukodystrophy; Peroxisomal Disorders; Osteopetrosis; Sphingolipidosis; Gangliosidosis; Globoid Cell Leukodystrophy; Metachromatic Leukodystrophy; Niemann Pick B; Niemann Pick C Subtype 2; I-cell Disease

  14. Determination of long-chain fatty acids in serum by gas chromatography coupled to mass spectrometry

    International Nuclear Information System (INIS)

    The quantification of long-chain fatty acids is fundamental for the diagnosis of several peroxisome disorders, particularly those in which the β-oxidation peroxisome of fatty acids is affected. In this work the implementation of an analytical method for the determination of these markers in serum by gas chromatography coupled to mass spectrometry is described. Besides, samples from patients with a diagnostic impression of adrenoleukodystrophy linked to the X chromosome were analyzed. The necessary experimental conditions were achieved for the separation and quantification of C22:0, C24:0 and C26:0 fatty acids in serum, which are biochemical markers of various peroxisome diseases. The application of this method allowed confirming the diagnosis of three patients with a diagnostic impression of adrenoleukodystrophy linked to the X chromosome. The application of the method in daily practice will allow the Cuban medical system to count on a new laboratory parameter for the diagnosis of peroxisome disorders

  15. Child Neurology: Zellweger syndrome


    Lee, Paul R.; Raymond, Gerald V.


    Zellweger syndrome (ZS) is a severe manifestation of disease within the spectrum of peroxisome biogenesis disorders that includes neonatal adrenoleukodystrophy, infantile Refsum disease, and rhizomelic chondroplasia punctata. Patients with ZS present in the neonatal period with a characteristic phenotype of distinctive facial stigmata, pronounced hypotonia, poor feeding, hepatic dysfunction, and often seizures and boney abnormalities. In patients with ZS, a mutation in one of the PEX genes co...

  16. Mutations in the Arabidopsis Peroxisomal ABC Transporter COMATOSE Allow Differentiation between Multiple Functions In Planta: Insights from an Allelic Series


    Dietrich, Daniela; Schmuths, Heike; Lousa, Carine De Marcos; Baldwin, Jocelyn M.; Baldwin, Stephen A.; Baker, Alison; Theodoulou, Frederica L; Holdsworth, Michael J


    COMATOSE (CTS), the Arabidopsis homologue of human Adrenoleukodystrophy protein (ALDP), is required for import of substrates for peroxisomal β-oxidation. A new allelic series and a homology model based on the bacterial ABC transporter, Sav1866, provide novel insights into structure-function relations of ABC subfamily D proteins. In contrast to ALDP, where the majority of mutations result in protein absence from the peroxisomal membrane, all CTS mutants produced stable protein. Mutation of con...

  17. Recent Trends of Polymer Mediated Liposomal Gene Delivery System

    Directory of Open Access Journals (Sweden)

    Shyamal Kumar Kundu


    Full Text Available Advancement in the gene delivery system have resulted in clinical successes in gene therapy for patients with several genetic diseases, such as immunodeficiency diseases, X-linked adrenoleukodystrophy (X-ALD blindness, thalassemia, and many more. Among various delivery systems, liposomal mediated gene delivery route is offering great promises for gene therapy. This review is an attempt to depict a portrait about the polymer based liposomal gene delivery systems and their future applications. Herein, we have discussed in detail the characteristics of liposome, importance of polymer for liposome formulation, gene delivery, and future direction of liposome based gene delivery as a whole.

  18. Computed tomography of neurodegenerative disease in childhood. Serial CT findings and their diagnostic values

    Energy Technology Data Exchange (ETDEWEB)

    Kataoka, Kenkichi; Nakagawa, Yoshihiro; Hojo, Hiroatsu


    Serial computed tomographic scans were performed on seven children with neurodegenerative disorders. In two cases of white-matter diseases (Krabbe's disease and metachromatic leukodystrophy), diffuse, low-density lesions of white matter were visible in the early stage of the diseases. In one case of adrenoleukodystrophy, regional low-density lesions of the white matter around the posterior horns and peculiar high-density strip lesions were visible in the early stage. In two cases of storage-type gray-matter diseases (Tay-Sachs' and infantile Gaucher's disease), there were no abnormalities in the early stage, but diffuse cortical atrophies in the late stage. In one case of Leigh's disease, there were small, low-density lesions of the basal ganglia and multiple low-density lesions of the gray matter in the early stage. In one case of subacute sclerosing panencephalitis, there were no abnormalities in the early stage, but small, low-density lesions of the basal ganglia and diffuse cerebral atrophies in the late stage. Diagnostic values were recognized dominantly in two cases of adrenoleukodystrophy and Leigh's disease. In the other cases, however, serial CT scans were useful in the diagnostic process. (author).

  19. Metabolic disorders with typical alterations in MRI; Stoffwechselstoerungen mit typischen Veraenderungen im MRT

    Energy Technology Data Exchange (ETDEWEB)

    Warmuth-Metz, M. [Klinikum der Universitaet Wuerzburg, Abteilung fuer Neuroradiologie, Wuerzburg (Germany)


    The classification of metabolic disorders according to the etiology is not practical for neuroradiological purposes because the underlying defect does not uniformly transform into morphological characteristics. Therefore typical MR and clinical features of some easily identifiable metabolic disorders are presented. Canavan disease, Pelizaeus-Merzbacher disease, Alexander disease, X-chromosomal adrenoleukodystrophy and adrenomyeloneuropathy, mitochondrial disorders, such as MELAS (mitochondrial encephalopathy, lactic acidosis, and stroke-like episodes) and Leigh syndrome as well as L-2-hydroxyglutaric aciduria are presented. (orig.) [German] Die Einteilung von Stoffwechselstoerungen nach ihrer Aetiologie ist fuer den diagnostischen Neuroradiologen nicht sinnvoll, da sich aus der zugrunde liegenden Stoerung keine Rueckschluesse auf die zu erwartende MR-Morphologie ziehen lassen. Deshalb sollen anhand typischer bildmorphologischer Veraenderungen in Zusammenschau mit den jeweiligen klinischen Charakteristika einige leicht einzuordnende Stoffwechselstoerungen dargestellt werden. Es handelt sich um den Morbus Canavan, Morbus Pelizaeus-Merzbacher, Morbus Alexander, die X-chromosomal vererbte Adrenoleukodystrophie und Adrenomyeloneuropathie, die mitochondrialen Stoerungen MELAS (mitochondriale Enzephalomyopathie, Laktazidose und Stroke-like-Episoden) und Leigh-Syndrom sowie die L-2-Hydroxyglutarazidurie. (orig.)

  20. [Peroxisomal neurologic diseases and Refsum disease: very long chain fatty acids and phytanic acid as diagnostic markers]. (United States)

    Molzer, B; Stöckler, S; Bernheimer, H


    Peroxisomal disorders are genetic metabolic diseases with generalized, multiple, or single functional disturbances of the peroxisome. According to the extent of the functional disturbances 3 groups of diseases can be differentiated: disorders with generalized loss of peroxisomal functions (Zellweger syndrome, ZS; neonatal adrenoleukodystrophy, NALD; infantile Refsum's disease), disorders with multiple enzymatic defects (e.g. rhizomelic chondrodysplasia punctata), and disorders with a single enzymatic defect in the peroxisome, the most important being adrenoleukodystrophy/adrenomyeloneuropathy (ALD/AMN). Adult Refsum's disease, a genetic neurological disorder with phytanic acid accumulation, is due to a mitochondrial enzyme deficiency, but is often considered together with peroxisomal diseases because of phytanic acid (PHYT) accumulation in most peroxisomal diseases. The main clinical and pathological criteria of the major disorders and the biochemical parameters of their differentiation are presented. Elevated levels of very long chain fatty acids (VLCFA) and/or PHYT are the primary diagnostic markers for all peroxisomal disorders and adult Refsum's disease, respectively. Our investigations disclosed 30 ALD/AMN hemizygotes, 16 ALD/AMN heterozygotes, 8 cases of ZS/NALD and 7 patients with adult Refsum's disease. In addition, 15 cases of peroxisomal disorders were confirmed by biochemical investigations in autopsy material. With regard to peroxisomal disorders, therapeutic concepts exist only for ALD/AMN: corticosteroid substitution for adrenal insufficiency, dietary treatment, and bone marrow transplantation (BMT). Adult Refsum's disease can be treated successfully by dietary therapy. In case of dietary treatment and BMT, assay of VLCFA and/or PHYT is important for the biochemical evaluation of these therapies.

  1. PXA1, a putative S. cerevisiae homolog of the human adrenoleukyodystrophy gene

    Energy Technology Data Exchange (ETDEWEB)

    Shani, N.; Watkins, P.A.; Valle, D. [Johns Hopkins Univ. School of Medicine, Baltimore, MD (United States)


    The adrenoleukodystrophy protein (ALDP) and the 70 kD peroxisomal membrane protein (PMP70) are ATP-binding cassette transporters in the peroxisome membrane. The former is defective in X-linked adrenoleukodystrophy (ALD), a neurodegenerative disorder with defective peroxisome oxidation of very long chain fatty acids; the latter is implicated in Zellweger syndrome, a defect in peroxisome biogenesis. The functions and interactions of ALDP and PMP70 in the peroxisomal membrane are not known. To develop a system in which these questions could be addressed, we sought to clone their yeast homologs. Using RT/PCR with degenerate primers and oleic acid (C18:1) induced yeast RNA as template, we amplified a cDNA segment corresponding to a conserved region of ALDP and PMP70. By sequencing amplified products, we found one with homology to both proteins and used it to clone the corresponding full length yeast gene (PXA1). PXA1 encodes a 758 amino acid protein with 28% and 21% overall identity to ALDP and PMP70, respectively which increases to 47% and 39% in a C terminal region of 178 amino acids. The PXA1 protein precipitates with peroxisomes as shown by immunoblot analysis of cell fractionation gradients. Disruption of PXA1 by homologous recombination results in impaired growth on oleic acid and reduced ability to oxidize oleate. The growth phenotype can be corrected by expression of the wild type PXA1 in the mutant strain. Peroxisomes in the PXA1 mutant yeast strain are intact as judged by catalase distribution and electron microscopy. Given the amino acid similarity, fatty acid oxidation defect and lack of an effect on peroxisomal integrity, we hypothesize that PXA1 may be the yeast ortholog of ALDP. Complementation studies to examine this hypothesis are in progress.

  2. [Peroxisomal diseases--a survey]. (United States)

    Theron, J J; van Papendorp, D H


    Peroxisomes are ubiquitous cytoplasmic structures in mammalian tissues. The metabolic functions of these organelles include synthesis of plasmalogens and other ether lipids, beta-oxidation, especially of very long-chain fatty acids (VLCFAs, > C22) and their derivatives, inactivation of hydrogen peroxide by peroxisomal catalase and involvement in several other metabolic pathways, e.g. gluconeogenesis, catabolism of purines and polyamines and detoxification of ethanol. Peroxisomal diseases which may arise from genetic faults in the biogenesis of the organelle or aberrant targeting of one or more proteins to the peroxisome, are divided into three groups based on the extent of loss of peroxisomal functions. Prototype of the first group is the cerebro-hepato-renal syndrome of Zellweger (ZS) which shows generalised loss of peroxisomal functions and absence of demonstrable mature peroxisomes in the liver. Other syndromes which are briefly discussed include neonatal adrenoleukodystrophy (NALD) and infantile Refsum syndrome (IRS) which may be regarded as milder variants of ZS, and diseases caused by loss of a limited number of peroxisomal functions (rhizomelic chondrodysplasia punctate). However, the group of peroxisomal diseases with the highest incidence are those syndromes where only a single peroxisomal function is impaired. The most common peroxisomal disease, X-linked adrenoleukodystrophy (XALD) belongs to this group. XALD develops as a result of an isolated defect of peroxisomal acyl-CoA synthetase with resultant accumulation of VLCFAs, especially C26:0. Primary hyperoxaluria type 1 is caused by deficient activity of peroxisomal alanine: glyoxylate aminotransferase due to aberrant targeting of this enzyme to mitochondria and not peroxisomes, a unique example of a genetic enzyme trafficking defect. The primary diagnosis of these syndromes is usually based on clinical findings and measurement of accumulated or depleted metabolites in the body e.g. VLCFAs, bile acid

  3. Lentiviral Vectors for Cancer Immunotherapy and Clinical Applications

    Energy Technology Data Exchange (ETDEWEB)

    Liechtenstein, Therese, E-mail: [University College London, 5 University Street, London, WC1E 6JF (United Kingdom); Perez-Janices, Noemi; Escors, David [University College London, 5 University Street, London, WC1E 6JF (United Kingdom); Navarrabiomed Fundacion Miguel Servet, 3 Irunlarrea St., Hospital Complex of Navarra, 31008 Pamplona, Navarra (Spain)


    The success of immunotherapy against infectious diseases has shown us the powerful potential that such a treatment offers, and substantial work has been done to apply this strategy in the fight against cancer. Cancer is however a fiercer opponent than pathogen-caused diseases due to natural tolerance towards tumour associated antigens and tumour-induced immunosuppression. Recent gene therapy clinical trials with viral vectors have shown clinical efficacy in the correction of genetic diseases, HIV and cancer. The first successful gene therapy clinical trials were carried out with onco(γ-)retroviral vectors but oncogenesis by insertional mutagenesis appeared as a serious complication. Lentiviral vectors have emerged as a potentially safer strategy, and recently the first clinical trial of patients with advanced leukemia using lentiviral vectors has proven successful. Additionally, therapeutic lentivectors have shown clinical efficacy for the treatment of HIV, X-linked adrenoleukodystrophy, and β-thalassaemia. This review aims at describing lentivectors and how they can be utilized to boost anti-tumour immune responses by manipulating the effector immune cells.

  4. Genetic and phenotypic heterogeneity in disorders of peroxisome biogenesis--a complementation study involving cell lines from 19 patients. (United States)

    Roscher, A A; Hoefler, S; Hoefler, G; Paschke, E; Paltauf, F; Moser, A; Moser, H


    Disorders of peroxisomal biogenesis include the Zellweger syndrome, neonatal adrenoleukodystrophy, infantile Refsum syndrome, and hyperpipecolic acidemia. These names were assigned before the recognition of the peroxisomal defect and the distinction between phenotypes is uncertain. Recent studies have identified at least four complementation groups, and indicate the presence of at least that number of distinct genotypes. The purpose of the present study was to examine the relationship between genotype and phenotype. We studied cultured skin fibroblasts from 19 patients in whom deficiency of peroxisomes had been established. Complementation analysis was performed with the criterion of complementation being the restoration of the capacity to synthesize plasmalogens when fibroblasts from two patients were fused. Six complementation groups were identified, and consisted of one 13 member group, one two member group, and four groups comprising single cases. The phenotype of each group was examined with respect to age of survival, clinical manifestations, and biochemical alterations. The 13 member group included patients with all of the four currently designated phenotypic entities, while the most common phenotype (Zellweger syndrome) was distributed among five of the six groups. We conclude that the currently used clinical categories do not represent distinct genotypes. Apparently different genes code for a similar phenotype and one defective gene may lead to variant phenotypes. Definitive classification and understanding of these disorders await definition of the specific biochemical defect in each of the genotypes.

  5. Molecular Characterization of Peroxisome Biogenesis Disorders with Zellweger Syndrome Spectrum

    Directory of Open Access Journals (Sweden)

    I Nassiri


    Full Text Available Peroxisome biogenesis disorders, Zellweger syndrome spectrum (PBD, ZSS are constituted of three different phenotypically disorders: Zellweger syndrome (ZS, the most severe; neonatal adrenoleukodystrophy (NALD; and infantile refsum disease (IRD, the least severe, that have been originally described based on their biochemical and molecular bases of these disorders which had been fully determined. Individuals with PBD, ZSS usually come to clinical attention in the newborn period or later in childhood. The diagnosis of PBD, ZSS can be definitively determined by biochemical assays. Measurement of plasma very-long-chain fatty acid (VLCFA levels is the most commonly used and most informative initial screen. Mutations in thirteen different PEX genes - those that encode peroxins, the proteins required for normal peroxisome assembly - have been identified in PBD, ZSS. Mutations in PEX1, the most common cause of PBD, ZSS, are observed in about 68% of affected individuals. Sequence analysis is available clinically for the following seven genes: PEX1, PXMP3 (PEX2, PRXR1 (PEX5, PEX6, PEX10, PEX12, and PEX26.

  6. Subcellular location and species specificity of pipecolate degradation

    Energy Technology Data Exchange (ETDEWEB)

    Mihalik, S.J.; Rhead, W.J.


    Defects in pipecolic acid (PA) catabolism are characteristic of several inherited metabolic diseases including hyperpipecolic acidemia, Zellweger's Syndrome, neonatal-onset adrenoleukodystrophy, and infantile Refsum's disease. In the latter three diseases, peroxisomes are abnormal. The authors have studied the subcelluar distribution of the PA degradation to determine a mammalian model for the normal pathway. Crude light and heavy mitochondrial fractions (including lysosomes and peroxisomes) from kidney cortex or liver were separated on Percoll gradients. Individual fractions were then incubated at 37/sup 0/C with 3H-2,3,4,5,6 L-PA. Using ion exchange chromatography, the production of 3H ..cap alpha..-aminoadipic acid (AAA) and 3H-H2O were quantitated. AAA production paralleled the activity of the mitochondrial marker enzyme, glutamate dehydrogenase, in the rabbit, guinea pig, dog, pig, and sheep. 3H-AAA production ranged from 382 to 13,900 pmol/mg prot/h. Guinea pig kidney cortex exhibited highest specific activity. The mitochondrial enzyme was absent from human liver (n=3) and liver and kidney cortex from rat, mouse, and monkey. In these tissues, the activity followed the pattern of the peroxisomal core enzyme, urate oxidase.

  7. Resistance to erucic acid as a selectable marker for peroxisomal activity: isolation of revertants of an infantile Refsum disease cell line. (United States)

    Bachir Bioukar, E; Straehli, F; Ng, K H; Rolland, M O; Hashimoto, T; Carreau, J P; Deschatrette, J


    A system based on the ability of cells to oxidize very long-chain fatty acids (VLCFA) was developed to select in vitro normal human fibroblasts from fibroblasts of patients suffering from peroxisomal disorders with multienzymatic deficiencies: Zellweger syndrome, neonatal adrenoleukodystrophy, infantile Refsum disease (IRD). Cells treated with various concentrations of erucic acid (C22:1 n-9) revealed an enhanced toxicity of this fatty acid for the fibroblasts of patients compared with normal cells. This differential toxicity is correlated with variable accumulations of C22:1 n-9 and the absence of beta-oxidation products in the mutants. Revertants from clonal IRD cell lines were isolated in the selective medium at frequencies ranging from 3 x 10(-7) to 4 x 10(-6) depending on the line. After six weeks of growth in the absence of selective pressure, the variants exhibited a resistance level to C22:1 n-9 identical to that of normal cells. Furthermore, beta-oxidation of VLCFA is re-established in these selected cells as well as dihydroxyacetone phosphate acyltransferase activity. Immunoblot experiments also demonstrated a restored pattern of acyl-CoA oxidase molecular forms. Last, immunofluorescence studies revealed the presence of cytoplasmic structures that were absent in the original IRD cells. Thus, both the deficiencies in metabolic pathways and paucity of the organelle are at least partially corrected in the selected clones.

  8. Lentiviral Vectors for Cancer Immunotherapy and Clinical Applications

    International Nuclear Information System (INIS)

    The success of immunotherapy against infectious diseases has shown us the powerful potential that such a treatment offers, and substantial work has been done to apply this strategy in the fight against cancer. Cancer is however a fiercer opponent than pathogen-caused diseases due to natural tolerance towards tumour associated antigens and tumour-induced immunosuppression. Recent gene therapy clinical trials with viral vectors have shown clinical efficacy in the correction of genetic diseases, HIV and cancer. The first successful gene therapy clinical trials were carried out with onco(γ-)retroviral vectors but oncogenesis by insertional mutagenesis appeared as a serious complication. Lentiviral vectors have emerged as a potentially safer strategy, and recently the first clinical trial of patients with advanced leukemia using lentiviral vectors has proven successful. Additionally, therapeutic lentivectors have shown clinical efficacy for the treatment of HIV, X-linked adrenoleukodystrophy, and β-thalassaemia. This review aims at describing lentivectors and how they can be utilized to boost anti-tumour immune responses by manipulating the effector immune cells

  9. Enzymatic characterization of ELOVL1, a key enzyme in very long-chain fatty acid synthesis. (United States)

    Schackmann, Martin J A; Ofman, Rob; Dijkstra, Inge M E; Wanders, Ronald J A; Kemp, Stephan


    X-linked adrenoleukodystrophy (X-ALD) is a neurometabolic disease that is caused by mutations in the ABCD1 gene. ABCD1 protein deficiency impairs peroxisomal very long-chain fatty acid (VLCFA) degradation resulting in increased cytosolic VLCFA-CoA levels, which are further elongated by the VLCFA-specific elongase, ELOVL1. In adulthood, X-ALD most commonly manifests as a gradually progressive myelopathy (adrenomyeloneuropathy; AMN) without any curative or disease modifying treatments. We recently showed that bezafibrate reduces VLCFA accumulation in X-ALD fibroblasts by inhibiting ELOVL1. Although, in a clinical trial, bezafibrate was unable to lower VLCFA levels in plasma or lymphocytes in X-ALD patients, inhibition of ELOVL1 remains an attractive therapeutic option. In this study, we investigated the kinetic characteristics of ELOVL1 using X-ALD fibroblasts and microsomal fractions from ELOVL1 over-expressing HEK293 cell lines and analyzed the inhibition kinetics of a series of fibrates. Our data show that the CoA esters of bezafibrate and gemfibrozil reduce chain elongation by specifically inhibiting ELOVL1. These fibrates can therefore serve as lead compounds for the development of more potent and more specific inhibitors for ELOVL1. PMID:25499606

  10. State of the art. Four easy pieces: interconnections between tissue injury, intermediary metabolism, autoimmunity, and chronic degeneration. (United States)

    Steinman, Lawrence


    Four questions are posed: (1) Can tissue damage itself provoke autoimmunity? (2) Can genetic mutations of key structures produce tissue pathology and thus provoke autoimmunity? (3) Can acute immune damage produce tissue degeneration without further hallmarks of an immune response? (4) Can intermediary metabolism modulate immune damage to tissues? Four answers are given: (1) Tissue injury itself may lead to autoimmunity. Both innate and adaptive immunity may arise as a response to tissue injury, and the immune attack can further damage tissue. (2) Genetic mutations can lead to an immune response indistinguishable from autoimmunity, exemplified from Duchenne's Muscular Dystrophy and X-linked adrenoleukodystrophy. (3) Chronic immune damage may lead to tissue degeneration, with or without further hallmarks of an immune response. Variations on this theme, including inverse scenarios, are also possible: Inborn errors of metabolism may lead to tissue damage that may provoke an adaptive and or innate immune response. The immune response might further damage tissue. (4) Finally, perturbations of intermediary metabolism may modulate the immune response, controlling the extent of immune-mediated damage. Examples are taken from perturbations in the cholesterol pathway that influence the characteristics of the immune response, and with tryptophan metabolites that modulate autoimmunity and graft rejection. Inflammatory, degenerative, and autoimmune neurological disease will be discussed in terms of their implications for pathogenic mechanisms underlying chronic obstructive pulmonary disease.

  11. Human ATP-binding cassette (ABC transporter family

    Directory of Open Access Journals (Sweden)

    Vasiliou Vasilis


    Full Text Available Abstract There exist four fundamentally different classes of membrane-bound transport proteins: ion channels; transporters; aquaporins; and ATP-powered pumps. ATP-binding cassette (ABC transporters are an example of ATP-dependent pumps. ABC transporters are ubiquitous membrane-bound proteins, present in all prokaryotes, as well as plants, fungi, yeast and animals. These pumps can move substrates in (influx or out (efflux of cells. In mammals, ABC transporters are expressed predominantly in the liver, intestine, blood-brain barrier, blood-testis barrier, placenta and kidney. ABC proteins transport a number of endogenous substrates, including inorganic anions, metal ions, peptides, amino acids, sugars and a large number of hydrophobic compounds and metabolites across the plasma membrane, and also across intracellular membranes. The human genome contains 49 ABC genes, arranged in eight subfamilies and named via divergent evolution. That ABC genes are important is underscored by the fact that mutations in at least I I of these genes are already known to cause severe inherited diseases (eg cystic fibrosis and X-linked adrenoleukodystrophy [X-ALD]. ABC transporters also participate in the movement of most drugs and their metabolites across cell surface and cellular organelle membranes; thus, defects in these genes can be important in terms of cancer therapy, pharmacokinetics and innumerable pharmacogenetic disorders.

  12. Lentiviral Vectors for Cancer Immunotherapy and Clinical Applications

    Directory of Open Access Journals (Sweden)

    David Escors


    Full Text Available The success of immunotherapy against infectious diseases has shown us the powerful potential that such a treatment offers, and substantial work has been done to apply this strategy in the fight against cancer. Cancer is however a fiercer opponent than pathogen-caused diseases due to natural tolerance towards tumour associated antigens and tumour-induced immunosuppression. Recent gene therapy clinical trials with viral vectors have shown clinical efficacy in the correction of genetic diseases, HIV and cancer. The first successful gene therapy clinical trials were carried out with onco(g-retroviral vectors but oncogenesis by insertional mutagenesis appeared as a serious complication. Lentiviral vectors have emerged as a potentially safer strategy, and recently the first clinical trial of patients with advanced leukemia using lentiviral vectors has proven successful. Additionally, therapeutic lentivectors have shown clinical efficacy for the treatment of HIV, X-linked adrenoleukodystrophy, and b-thalassaemia. This review aims at describing lentivectors and how they can be utilized to boost anti-tumour immune responses by manipulating the effector immune cells.

  13. Disorders of adrenal development. (United States)

    Ferraz-de-Souza, Bruno; Achermann, John C


    Human adrenal development is a complex and relatively poorly understood process. However, significant insight into some of the mechanisms regulating adrenal development and function is being obtained through the analysis of individuals and families with adrenal hypoplasia. Adrenal hypoplasia can occur: (1) secondary to defects in pituitary adrenocorticotropin (ACTH) synthesis, processing and release (secondary adrenal hypoplasia; e.g. HESX1, LHX4, SOX3, TPIT, pituitary POMC, PC1); (2) as part of several ACTH resistance syndromes (e.g. MC2R/ACTHR, MRAP, Alacrima, Achalasia, Addison disease), or as (3) a primary defect in the development of the adrenal gland itself (primary adrenal hypoplasia; e.g. DAX1/NR0B1 - dosage-sensitive sex reversal, adrenal hypoplasia congenita critical region on the X chromosome 1). Indeed, the X-linked form of primary adrenal hypoplasia due to deletions or mutations in the orphan nuclear receptor DAX1 occurs in around half of male infants presenting with a salt-losing adrenal crisis, where no obvious steroidogenic defect (e.g. 21-hydroxylase deficiency), metabolic abnormality (e.g. neonatal adrenoleukodystrophy) or physical cause (e.g. adrenal haemorrhage) is found. Establishing the underlying basis of adrenal failure can have important implications for investigating associated features, the likely long-term approach to treatment, and for counselling families about the risk of other children being affected.

  14. Remission of primary low-grade gastric lymphomas of the mucosa-associated lymphoid tissue type in immunocompromised pediatric patients

    Institute of Scientific and Technical Information of China (English)

    Yasuharu Ohno; Taichirou Kosaka; Izumi Muraoka; Takashi Kanematsu; Akira Tsuru; Eiichi Kinoshita; Hiroyuki Moriuchi


    We report the remission of primary gastric lymphoma of the mucosa-associated lymphoid tissue (MALT) type in two immunocompromised pediatric patients. Patient 1,a 14-year-old boy in an immunocompromised state of unknown cause, complained of repeated abdominal pain.Examinations revealed gastric MALT with local invasionand lymph node involvement. Serum anti-Helicobacter pylori (H pylori) antibody was positive. H pylori eradication was abandoned due to its adverse effects. The MALT lesion spontaneously regressed over the next 24 months without any treatment for lymphoma. Patient 2, a 6-year-old boy, underwent cord blood transplantation for the treatment of adrenoleukodystrophy. He was administered immunosuppressants for graft-versus-host disease after transplantation. Nausea and hematochezia appeared and further examinations revealed gastric MALT with H pylori gastritis. Treatment consisting of medication for the H pylori infection alone eradicated the Hpylori and completely resolved the patient's MALT lesion,as well. Patients 1 and 2 were followed up over periods of 10 years and 3 years, respectively, without any signs of relapse. In conclusion, gastric lymphoma of the MALT type can be cured by conservative treatment even in immunocompromised pediatric patients.

  15. Endocrine manifestations related to inherited metabolic diseases in adults

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    Vantyghem Marie-Christine


    Full Text Available Abstract Most inborn errors of metabolism (IEM are recessive, genetically transmitted diseases and are classified into 3 main groups according to their mechanisms: cellular intoxication, energy deficiency, and defects of complex molecules. They can be associated with endocrine manifestations, which may be complications from a previously diagnosed IEM of childhood onset. More rarely, endocrinopathies can signal an IEM in adulthood, which should be suspected when an endocrine disorder is associated with multisystemic involvement (neurological, muscular, hepatic features, etc.. IEM can affect all glands, but diabetes mellitus, thyroid dysfunction and hypogonadism are the most frequent disorders. A single IEM can present with multiple endocrine dysfunctions, especially those involving energy deficiency (respiratory chain defects, and metal (hemochromatosis and storage disorders (cystinosis. Non-autoimmune diabetes mellitus, thyroid dysfunction and/or goiter and sometimes hypoparathyroidism should steer the diagnosis towards a respiratory chain defect. Hypogonadotropic hypogonadism is frequent in haemochromatosis (often associated with diabetes, whereas primary hypogonadism is reported in Alström disease and cystinosis (both associated with diabetes, the latter also with thyroid dysfunction and galactosemia. Hypogonadism is also frequent in X-linked adrenoleukodystrophy (with adrenal failure, congenital disorders of glycosylation, and Fabry and glycogen storage diseases (along with thyroid dysfunction in the first 3 and diabetes in the last. This is a new and growing field and is not yet very well recognized in adulthood despite its consequences on growth, bone metabolism and fertility. For this reason, physicians managing adult patients should be aware of these diagnoses.

  16. Biosafety challenges for use of lentiviral vectors in gene therapy. (United States)

    Rothe, Michael; Modlich, Ute; Schambach, Axel


    Lentiviral vectors are promising tools for the genetic modification of cells in biomedical research and gene therapy. Their use in recent clinical trials for the treatment of adrenoleukodystrophy, β-thalassemia, Wiskott-Aldrich- Syndrome and metachromatic leukodystrophy underlined their efficacy for therapies especially in case of hereditary diseases. In comparison to gammaretroviral LTR-driven vectors, which were employed in the first clinical trials, lentiviral vectors present with some favorable features like the ability to transduce also non-dividing cells and a potentially safer insertion profile. However, genetic modification with viral vectors in general and stable integration of the therapeutic gene into the host cell genome bear concerns with respect to different levels of personal or environmental safety. Among them, insertional mutagenesis by enhancer mediated dysregulation of neighboring genes or aberrant splicing is still the biggest concern. However, also risks like immunogenicity of vector particles, the phenotoxicity of the transgene and potential vertical or horizontal transmission by replication competent retroviruses need to be taken into account. This review will give an overview on biosafety aspects that are relevant to the use of lentiviral vectors for genetic modification and gene therapy. Furthermore, assay systems aiming at evaluating biosafety in preclinical settings and recent promising clinical trials including efforts of monitoring of patients after gene therapy will be discussed.

  17. Brain microsomal fatty acid elongation is increased in abcd1-deficient mouse during active myelination phase. (United States)

    Morita, Masashi; Kawamichi, Misato; Shimura, Yusuke; Kawaguchi, Kosuke; Watanabe, Shiro; Imanaka, Tsuneo


    The dysfunction of ABCD1, a peroxisomal ABC protein, leads to the perturbation of very long chain fatty acid (VLCFA) metabolism and is the cause of X-linked adrenoleukodystrophy. Abcd1-deficient mice exhibit an accumulation of saturated VLCFAs, such as C26:0, in all tissues, especially the brain. The present study sought to measure microsomal fatty acid elongation activity in the brain of wild-type (WT) and abcd1-deficient mice during the course of development. The fatty acid elongation activity in the microsomal fraction was measured by the incorporation of [2-(14)C]malonyl-CoA into fatty acids in the presence of C16:0-CoA or C20:0-CoA. Cytosolic fatty acid synthesis activity was completely inhibited by the addition of N-ethylmaleimide (NEM). The microsomal fatty acid elongation activity in the brain was significantly high at 3 weeks after birth and decreased substantially at 3 months after birth. Furthermore, we detected two different types of microsomal fatty acid elongation activity by using C16:0-CoA or C20:0-CoA as the substrate and found the activity toward C20:0-CoA in abcd1-deficient mice was higher than the WT 3-week-old animals. These results suggest that during the active myelination phase the microsomal fatty acid elongation activity is stimulated in abcd1-deficient mice, which in turn perturbs the lipid composition in myelin. PMID:26108493

  18. Activation of Sterol Regulatory Element Binding Factors by Fenofibrate and Gemfibrozil Stimulate Myelination in Zebrafish

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    Yuhei Nishimura


    Full Text Available Oligodendrocytes are major myelin-producing cells and play essential roles in the function of a healthy nervous system. However, they are also one of the most vulnerable neural cell types in the central nervous system (CNS, and myelin abnormalities in the CNS are found in a wide variety of neurological disorders, including multiple sclerosis, adrenoleukodystrophy, and schizophrenia. There is an urgent need to identify small molecular weight compounds that can stimulate myelination. In this study, we performed comparative transcriptome analysis to identify pharmacodynamic effects common to miconazole and clobetasol, which have been shown to stimulate myelination by mouse oligodendrocyte progenitor cells (OPCs. Of the genes differentially expressed in both miconazole- and clobetasol-treated mouse OPCs compared with untreated cells, we identified differentially expressed genes (DEGs common to both drug treatments. Gene ontology analysis revealed that these DEGs are significantly associated with the sterol biosynthetic pathway, and further bioinformatics analysis suggested that sterol regulatory element binding factors (SREBFs might be key upstream regulators of the DEGs. In silico screening of a public database for chemicals associated with SREBF activation identified fenofibrate, a peroxisome proliferator-activated receptor α (PPARα agonist, as a drug that increases the expression of known SREBF targets, raising the possibility that fenofibrate may also stimulate myelination. To test this, we performed in vivo imaging of zebrafish expressing a fluorescent reporter protein under the control of the myelin basic protein (mbp promoter. Treatment of zebrafish with fenofibrate significantly increased expression of the fluorescent reporter compared with untreated zebrafish. This increase was attenuated by co-treatment with fatostatin, a specific inhibitor of SREBFs, confirming that the fenofibrate effect was mediated via SREBFs. Furthermore, incubation

  19. Histone deacetylase inhibitor upregulates peroxisomal fatty acid oxidation and inhibits apoptotic cell death in abcd1-deficient glial cells.

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    Jaspreet Singh

    Full Text Available In X-ALD, mutation/deletion of ALD gene (ABCD1 and the resultant very long chain fatty acid (VLCFA derangement has dramatically opposing effects in astrocytes and oligodendrocytes. While loss of Abcd1 in astrocytes produces a robust inflammatory response, the oligodendrocytes undergo cell death leading to demyelination in X-linked adrenoleukodystrophy (X-ALD. The mechanisms of these distinct pathways in the two cell types are not well understood. Here, we investigated the effects of Abcd1-knockdown and the subsequent alteration in VLCFA metabolism in human U87 astrocytes and rat B12 oligodendrocytes. Loss of Abcd1 inhibited peroxisomal β-oxidation activity and increased expression of VLCFA synthesizing enzymes, elongase of very long chain fatty acids (ELOVLs (1 and 3 in both cell types. However, higher induction of ELOVL's in Abcd1-deficient B12 oligodendrocytes than astrocytes suggests that ELOVL pathway may play a prominent role in oligodendrocytes in X-ALD. While astrocytes are able to maintain the cellular homeostasis of anti-apoptotic proteins, Abcd1-deletion in B12 oligodendrocytes downregulated the anti-apototic (Bcl-2 and Bcl-xL and cell survival (phospho-Erk1/2 proteins, and upregulated the pro-apoptotic proteins (Bad, Bim, Bax and Bid leading to cell loss. These observations provide insights into different cellular signaling mechanisms in response to Abcd1-deletion in two different cell types of CNS. The apoptotic responses were accompanied by activation of caspase-3 and caspase-9 suggesting the involvement of mitochondrial-caspase-9-dependent mechanism in Abcd1-deficient oligodendrocytes. Treatment with histone deacetylase (HDAC inhibitor suberoylanilide hydroxamic acid (SAHA corrected the VLCFA derangement both in vitro and in vivo, and inhibited the oligodendrocytes loss. These observations provide a proof-of principle that HDAC inhibitor SAHA may have a therapeutic potential for X-ALD.

  20. Diffusion Magnetic Resonance Imaging Patterns in Metabolic and Toxic Brain Disorders

    International Nuclear Information System (INIS)

    Purpose: To evaluate metabolic and toxic brain disorders that manifest with restricted, elevated, or both restricted and elevated diffusion patterns on diffusion magnetic resonance imaging (MRI). Material and Methods: Echo-planar diffusion MRI examinations were obtained in 34 pediatric patients with metabolic and toxic brain disorders proved by appropriate laboratory studies. The MRI unit operated at 1.5T with a gradient strength of 30 mT/meter, and a rise time of 600 s. b=1000 s/mm2 images and apparent diffusion coefficient (ADC) maps with ADC values were studied. Results: Three patterns were observed: 1. A restricted diffusion pattern (high signal on b=1000 s/mm2 images and low ADC values); 2. an elevated diffusion pattern (normal signal on b=1000 s/mm2 images and high ADC values); and 3. a mixed pattern (coexistent restricted and increased diffusion patterns in the same patient). Disorders manifesting with a restricted diffusion pattern included metachromatic leukodystrophy (n=2), phenylketonuria (n=3), maple syrup urine disease (intermediate form) (n=1), infantile neuroaxonal dystrophy (n=1), Leigh (n=2), Wilson (n=3), and Canavan disease (n=1). Disorders with an elevated diffusion pattern included phenylketonuria (n=1), adrenoleukodystrophy (n=1), merosin-deficient congenital muscular dystrophy (n=2), mucopolysaccharidosis (n=2), Lowe syndrome (n=1), Leigh (n=2), Alexander (n=1), Pelizaeus-Merzbacher (n=1), and Wilson (n=3) disease. Disorders with a mixed pattern included L-2 hydroxyglutaric aciduria (n=2), non-ketotic hyperglycinemia (n=1), infantile neuroaxonal dystrophy (n=2), maple syrup urine disease (n=1), and Leigh (n=1) disease. Conclusion: The findings suggested that the three different diffusion patterns reflect the histopathological changes associated with the disorders and different stages of a particular disorder. It is likely that the restricted diffusion pattern corresponds to abnormalities related to myelin, and the elevated diffusion pattern

  1. Health benefits of docosahexaenoic acid (DHA) (United States)

    Horrocks, L A; Yeo, Y K


    Docosahexaenoic acid (DHA) is essential for the growth and functional development of the brain in infants. DHA is also required for maintenance of normal brain function in adults. The inclusion of plentiful DHA in the diet improves learning ability, whereas deficiencies of DHA are associated with deficits in learning. DHA is taken up by the brain in preference to other fatty acids. The turnover of DHA in the brain is very fast, more so than is generally realized. The visual acuity of healthy, full-term, formula-fed infants is increased when their formula includes DHA. During the last 50 years, many infants have been fed formula diets lacking DHA and other omega-3 fatty acids. DHA deficiencies are associated with foetal alcohol syndrome, attention deficit hyperactivity disorder, cystic fibrosis, phenylketonuria, unipolar depression, aggressive hostility, and adrenoleukodystrophy. Decreases in DHA in the brain are associated with cognitive decline during aging and with onset of sporadic Alzheimer disease. The leading cause of death in western nations is cardiovascular disease. Epidemiological studies have shown a strong correlation between fish consumption and reduction in sudden death from myocardial infarction. The reduction is approximately 50% with 200 mg day(-1)of DHA from fish. DHA is the active component in fish. Not only does fish oil reduce triglycerides in the blood and decrease thrombosis, but it also prevents cardiac arrhythmias. The association of DHA deficiency with depression is the reason for the robust positive correlation between depression and myocardial infarction. Patients with cardiovascular disease or Type II diabetes are often advised to adopt a low-fat diet with a high proportion of carbohydrate. A study with women shows that this type of diet increases plasma triglycerides and the severity of Type II diabetes and coronary heart disease. DHA is present in fatty fish (salmon, tuna, mackerel) and mother's milk. DHA is present at low levels in

  2. Diffusion Magnetic Resonance Imaging Patterns in Metabolic and Toxic Brain Disorders

    Energy Technology Data Exchange (ETDEWEB)

    Sener, R.N. [Ege Univ. Hospital, Bornova, Izmir (Turkey). Dept. of Radiology


    Purpose: To evaluate metabolic and toxic brain disorders that manifest with restricted, elevated, or both restricted and elevated diffusion patterns on diffusion magnetic resonance imaging (MRI). Material and Methods: Echo-planar diffusion MRI examinations were obtained in 34 pediatric patients with metabolic and toxic brain disorders proved by appropriate laboratory studies. The MRI unit operated at 1.5T with a gradient strength of 30 mT/meter, and a rise time of 600 s. b=1000 s/mm{sup 2} images and apparent diffusion coefficient (ADC) maps with ADC values were studied. Results: Three patterns were observed: 1. A restricted diffusion pattern (high signal on b=1000 s/mm{sup 2} images and low ADC values); 2. an elevated diffusion pattern (normal signal on b=1000 s/mm2 images and high ADC values); and 3. a mixed pattern (coexistent restricted and increased diffusion patterns in the same patient). Disorders manifesting with a restricted diffusion pattern included metachromatic leukodystrophy (n=2), phenylketonuria (n=3), maple syrup urine disease (intermediate form) (n=1), infantile neuroaxonal dystrophy (n=1), Leigh (n=2), Wilson (n=3), and Canavan disease (n=1). Disorders with an elevated diffusion pattern included phenylketonuria (n=1), adrenoleukodystrophy (n=1), merosin-deficient congenital muscular dystrophy (n=2), mucopolysaccharidosis (n=2), Lowe syndrome (n=1), Leigh (n=2), Alexander (n=1), Pelizaeus-Merzbacher (n=1), and Wilson (n=3) disease. Disorders with a mixed pattern included L-2 hydroxyglutaric aciduria (n=2), non-ketotic hyperglycinemia (n=1), infantile neuroaxonal dystrophy (n=2), maple syrup urine disease (n=1), and Leigh (n=1) disease. Conclusion: The findings suggested that the three different diffusion patterns reflect the histopathological changes associated with the disorders and different stages of a particular disorder. It is likely that the restricted diffusion pattern corresponds to abnormalities related to myelin, and the elevated

  3. Involvement of the carboxyl-terminal region of the yeast peroxisomal half ABC transporter Pxa2p in its interaction with Pxa1p and in transporter function.

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    Cheng-Yi Chuang

    Full Text Available BACKGROUND: The peroxisome is a single membrane-bound organelle in eukaryotic cells involved in lipid metabolism, including β-oxidation of fatty acids. The human genetic disorder X-linked adrenoleukodystrophy (X-ALD is caused by mutations in the ABCD1 gene (encoding ALDP, a peroxisomal half ATP-binding cassette [ABC] transporter. This disease is characterized by defective peroxisomal β-oxidation and a large accumulation of very long-chain fatty acids in brain white matter, adrenal cortex, and testis. ALDP forms a homodimer proposed to be the functional transporter, whereas the peroxisomal transporter in yeast is a heterodimer comprising two half ABC transporters, Pxa1p and Pxa2p, both orthologs of human ALDP. While the carboxyl-terminal domain of ALDP is engaged in dimerization, it remains unknown whether the same region is involved in the interaction between Pxa1p and Pxa2p. METHODS/PRINCIPAL FINDINGS: Using a yeast two-hybrid assay, we found that the carboxyl-terminal region (CT of Pxa2p, but not of Pxa1p, is required for their interaction. Further analysis indicated that the central part of the CT (designated CT2 of Pxa2p was indispensable for its interaction with the carboxyl terminally truncated Pxa1_NBD. An interaction between the CT of Pxa2p and Pxa1_NBD was not detected, but could be identified in the presence of Pxa2_NBD-CT1. A single mutation of two conserved residues (aligned with X-ALD-associated mutations at the same positions in ALDP in the CT2 of the Pxa2_NBD-CT protein impaired its interaction with Pxa1_NBD or Pxa1_NBD-CT, resulting in a mutant protein that exhibited a proteinase K digestion profile different from that of the wild-type protein. Functional analysis of these mutant proteins on oleate plates indicated that they were defective in transporter function. CONCLUSIONS/SIGNIFICANCE: The CT of Pxa2p is involved in its interaction with Pxa1p and in transporter function. This concept may be applied to human ALDP studies

  4. Quantitative MRI of the spinal cord and brain in adrenomyeloneuropathy: in vivo assessment of structural changes. (United States)

    Castellano, Antonella; Papinutto, Nico; Cadioli, Marcello; Brugnara, Gianluca; Iadanza, Antonella; Scigliuolo, Graziana; Pareyson, Davide; Uziel, Graziella; Köhler, Wolfgang; Aubourg, Patrick; Falini, Andrea; Henry, Roland G; Politi, Letterio S; Salsano, Ettore


    Adrenomyeloneuropathy is the late-onset form of X-linked adrenoleukodystrophy, and is considered the most frequent metabolic hereditary spastic paraplegia. In adrenomyeloneuropathy the spinal cord is the main site of pathology. Differently from quantitative magnetic resonance imaging of the brain, little is known about the feasibility and utility of advanced neuroimaging in quantifying the spinal cord abnormalities in hereditary diseases. Moreover, little is known about the subtle pathological changes that can characterize the brain of adrenomyeloneuropathy subjects in the early stages of the disease. We performed a cross-sectional study on 13 patients with adrenomyeloneuropathy and 12 age-matched healthy control subjects who underwent quantitative magnetic resonance imaging to assess the structural changes of the upper spinal cord and brain. Total cord areas from C2-3 to T2-3 level were measured, and diffusion tensor imaging metrics, i.e. fractional anisotropy, mean, axial and radial diffusivity values were calculated in both grey and white matter of spinal cord. In the brain, grey matter regions were parcellated with Freesurfer and average volume and thickness, and mean diffusivity and fractional anisotropy from co-registered diffusion maps were calculated in each region. Brain white matter diffusion tensor imaging metrics were assessed using whole-brain tract-based spatial statistics, and tractography-based analysis on corticospinal tracts. Correlations among clinical, structural and diffusion tensor imaging measures were calculated. In patients total cord area was reduced by 26.3% to 40.2% at all tested levels (P statistics showed a marked reduction of fractional anisotropy, increase of radial diffusivity (P < 0.001) and no axial diffusivity changes in several white matter tracts, including corticospinal tracts and optic radiations, indicating predominant demyelination. Tractography-based analysis confirmed the results within corticospinal tracts. No