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1.
Mol Genet Metab ; 142(2): 108489, 2024 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-38718669

RESUMEN

BACKGROUND: Canavan disease is a devastating neurometabolic disorder caused by accumulation of N acetylaspartate in brain and body fluids due to genetic defects in the aspartoacylase gene (ASPA). New gene therapies are on the horizon but will require early presymptomatic diagnosis to be fully effective. METHODS: We therefore developed a fast and highly sensitive liquid chromatography mass spectrometry (LC-MS/MS)-based method for quantification of N-acetylaspartate in dried blood spots and established reference ranges for neonates and older controls. With this test, we investigated 45 samples of 25 Canavan patients including 8 with a neonatal sample. RESULTS: Measuring N-acetylaspartate concentration in dried blood with this novel test, all Canavan patients (with variable severity) were well separated from the control group (median; range: 5.7; 1.6-13.6 µmol/L [n = 45] vs 0.44; 0.24-0.99 µmol/L [n = 59] (p < 0.05)). There was also no overlap when comparing neonatal samples of Canavan patients (7.3; 5.1-9.9 µmol/L [n = 8]) and neonatal controls (0.93; 0.4-1.8 µmol/L [n = 784]) (p < 0.05). CONCLUSIONS: We have developed a new LC-MS/MS-based screening test for early postnatal diagnosis of Canavan disease that should be further evaluated in a population-based study once a promising treatment becomes available. The method meets the general requirements of newborn screening and should be appropriate for multiplexing with other screening approaches that combine chromatographic and mass spectrometry techniques.


Asunto(s)
Ácido Aspártico , Enfermedad de Canavan , Pruebas con Sangre Seca , Tamizaje Neonatal , Espectrometría de Masas en Tándem , Humanos , Enfermedad de Canavan/diagnóstico , Enfermedad de Canavan/sangre , Enfermedad de Canavan/genética , Recién Nacido , Tamizaje Neonatal/métodos , Pruebas con Sangre Seca/métodos , Espectrometría de Masas en Tándem/métodos , Ácido Aspártico/análogos & derivados , Ácido Aspártico/sangre , Cromatografía Liquida , Femenino , Masculino , Lactante , Preescolar , Cromatografía Líquida con Espectrometría de Masas , Amidohidrolasas
2.
Nat Commun ; 15(1): 4026, 2024 May 13.
Artículo en Inglés | MEDLINE | ID: mdl-38740822

RESUMEN

Unstable proteins are prone to form non-native interactions with other proteins and thereby may become toxic. To mitigate this, destabilized proteins are targeted by the protein quality control network. Here we present systematic studies of the cytosolic aspartoacylase, ASPA, where variants are linked to Canavan disease, a lethal neurological disorder. We determine the abundance of 6152 of the 6260 ( ~ 98%) possible single amino acid substitutions and nonsense ASPA variants in human cells. Most low abundance variants are degraded through the ubiquitin-proteasome pathway and become toxic upon prolonged expression. The data correlates with predicted changes in thermodynamic stability, evolutionary conservation, and separate disease-linked variants from benign variants. Mapping of degradation signals (degrons) shows that these are often buried and the C-terminal region functions as a degron. The data can be used to interpret Canavan disease variants and provide insight into the relationship between protein stability, degradation and cell fitness.


Asunto(s)
Amidohidrolasas , Enfermedad de Canavan , Proteolisis , Humanos , Amidohidrolasas/genética , Amidohidrolasas/metabolismo , Enfermedad de Canavan/genética , Enfermedad de Canavan/metabolismo , Células HEK293 , Sustitución de Aminoácidos , Mutación , Complejo de la Endopetidasa Proteasomal/metabolismo , Complejo de la Endopetidasa Proteasomal/genética , Estabilidad Proteica , Ubiquitina/metabolismo , Termodinámica
3.
Zhonghua Yi Xue Yi Chuan Xue Za Zhi ; 41(2): 225-229, 2024 Feb 10.
Artículo en Chino | MEDLINE | ID: mdl-38311564

RESUMEN

OBJECTIVE: To analyze the clinical phenotype and genetic characteristics for a child with Canavan disease. METHODS: A child who was admitted to the Children's Hospital Affiliated to Shandong University on April 9, 2021 for inability to uphold his head for 2 months and increased muscle tone for one week was subjected to whole exome sequencing, and candidate variants were verified by Sanger sequencing. RESULTS: Genetic testing revealed that the child has harbored compound heterozygous variants of the ASPA gene, including a paternally derived c.556_559dupGTTC (p. L187Rfs*5) and a maternally derived c.919delA (p. S307Vfs*24). Based on the guidelines from the American College of Medical Genetics and Genomics, both variants were predicted to be pathogenic (PVS1+PM2_Supporting+PM3). CONCLUSION: The c.556_559dupGTTC (p.L187Rfs*5) and c.919delA (p.S307Vfs*24) compound heterozygous variants of the ASPA gene probably underlay the pathogenesis of Canavan disease in this child.


Asunto(s)
Enfermedad de Canavan , Niño , Humanos , Enfermedad de Canavan/genética , Pruebas Genéticas , Genómica , Mutación , Fenotipo
4.
Stem Cell Res ; 76: 103325, 2024 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-38309148

RESUMEN

Canavan disease (CD, OMIM# 271900) is an autosomal recessive neurodegenerative disorder caused by homozygous or compound heterozygous mutations in ASPA gene, which result in catalytic deficiency of the aspartoacylase enzyme and the accumulation of N-acetylaspartic acid (NAA). Clinical presentation varies according to the age of disease onset. Here, we generated a human induced pluripotent stem cell line (hiPSCs) SDQLCHi064-A from a 5-month old boy with CD carrying two novel frame shift mutations c.556_559dupGTTC (p.L187Rfs*5) and c.919delA (p.S307Vfs*24) of the ASPA gene, in order for us to better understanding the disease.


Asunto(s)
Enfermedad de Canavan , Células Madre Pluripotentes Inducidas , Masculino , Humanos , Lactante , Enfermedad de Canavan/genética , Enfermedad de Canavan/metabolismo , Células Madre Pluripotentes Inducidas/metabolismo , Mutación/genética , Homocigoto , Amidohidrolasas/genética , Amidohidrolasas/metabolismo
5.
Ann Clin Transl Neurol ; 11(4): 1059-1062, 2024 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-38282243

RESUMEN

Canavan disease is a leukodystrophy caused by ASPA mutations that diminish oligodendroglial aspartoacylase activity, and is characterized by markedly elevated brain concentrations of the aspartoacylase substrate N-acetyl-l-aspartate (NAA) and by astroglial and intramyelinic vacuolation. Astroglia express NaDC3 (encoded by SLC13A3), a sodium-coupled transporter for NAA and other dicarboxylates. Astroglial conditional Slc13a3 deletion in aspartoacylase-deficient Canavan disease model mice ("CD mice") reversed brain NAA elevation and improved motor function. These results demonstrate that astroglial NaDC3 contributes to brain NAA elevation in CD mice, and suggest that suppressing astroglial NaDC3 activity would ameliorate human Canavan disease.


Asunto(s)
Enfermedad de Canavan , Enfermedades Neurodegenerativas , Animales , Ratones , Ácido Aspártico , Astrocitos , Encéfalo , Enfermedad de Canavan/genética , Enfermedad de Canavan/terapia , Oligodendroglía
6.
J Inherit Metab Dis ; 47(2): 230-243, 2024 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-38011891

RESUMEN

Canavan disease (CD) is a leukodystrophy caused by mutations in the N-acetylaspartate (NAA) hydrolase aspartoacylase (ASPA). Inability to degrade NAA and its accumulation in the brain results in spongiform myelin degeneration. NAA is mainly synthesized by neurons, where it is also a precursor of the neuropeptide N-acetylaspartylglutamate (NAAG). Hydrolysis of this peptide by glutamate carboxypeptidases is an additional source of extracellular NAA besides the instant neuronal release of NAA. This study examines to what extent NAA released from NAAG contributes to NAA accumulation and pathogenesis in the brain of Aspanur7/nur7 mutant mice, an established model of CD. Towards this aim, Aspanur7/nur7 mice with additional deficiencies in NAAG synthetase genes Rimklb and/or Rimkla were generated. Loss of myelin in Aspanur7/nur7 mice was not significantly affected by Rimkla and Rimklb deficiency and there was also no obvious change in the extent of brain vacuolation. Astrogliosis was slightly reduced in the forebrain of Rimkla and Rimklb double deficient Aspanur7/nur7 mice. However, only minor improvements at the behavioral level were found. The brain NAA accumulation in CD mice was, however, not significantly reduced in the absence of NAAG synthesis. In summary, there was only a weak tendency towards reduced pathogenic symptoms in Aspanur7/nur7 mice deficient in NAAG synthesis. Therefore, we conclude that NAAG metabolism has little influence on NAA accumulation in Aspanur7/nur7 mice and development of pathological symptoms in CD.


Asunto(s)
Enfermedad de Canavan , Ratones , Animales , Enfermedad de Canavan/genética , Enfermedad de Canavan/metabolismo , Enfermedad de Canavan/patología , Encéfalo/patología , Vaina de Mielina/metabolismo , Vaina de Mielina/patología , Neuronas/metabolismo , Amidohidrolasas/genética , Amidohidrolasas/metabolismo , Modelos Animales de Enfermedad , Ácido Aspártico/metabolismo , Ligasas/metabolismo
7.
Glia ; 71(12): 2832-2849, 2023 12.
Artículo en Inglés | MEDLINE | ID: mdl-37610133

RESUMEN

Canavan disease (CD) is a recessively inherited pediatric leukodystrophy resulting from inactivating mutations to the oligodendroglial enzyme aspartoacylase (ASPA). ASPA is responsible for hydrolyzing the amino acid derivative N-acetyl-L-aspartate (NAA), and without it, brain NAA concentrations increase by 50% or more. Infants and children with CD present with progressive cognitive and motor delays, cytotoxic edema, astroglial vacuolation, and prominent spongiform brain degeneration. ASPA-deficient CD mice (Aspanur7/nur7 ) present similarly with elevated NAA, widespread astroglial dysfunction, ataxia, and Purkinje cell (PC) dendritic atrophy. Bergmann glia (BG), radial astrocytes essential for cerebellar development, are intimately intertwined with PCs, where they regulate synapse stability, functionality, and plasticity. BG damage is common to many neurodegenerative conditions and frequently associated with PC dysfunction and ataxia. Here, we report that, in CD mice, BG exhibit significant morphological alterations, decreased structural associations with PCs, loss of synaptic support proteins, and altered calcium dynamics. We also find that BG dysfunction predates cerebellar vacuolation and PC damage in CD mice. Previously, we developed an antisense oligonucleotide (ASO) therapy targeting Nat8l (N-acetyltransferase-8-like, "Nat8l ASO") that inhibits the production of NAA and reverses ataxia and PC atrophy in CD mice. Here, we show that Nat8l ASO administration in adult CD mice also leads to BG repair. Furthermore, blocking astroglial uptake of NAA is neuroprotective in astroglia-neuron cocultures exposed to elevated NAA. Our findings suggest that restoration of BG structural and functional integrity could be a mechanism for PC regeneration and improved motor function.


Asunto(s)
Enfermedad de Canavan , Enfermedades Neurodegenerativas , Humanos , Niño , Lactante , Ratones , Animales , Enfermedad de Canavan/genética , Enfermedad de Canavan/metabolismo , Enfermedad de Canavan/patología , Calcio , Ataxia/patología , Oligodendroglía/metabolismo , Enfermedades Neurodegenerativas/patología , Ácido Aspártico , Atrofia/complicaciones , Atrofia/patología
8.
Adv Sci (Weinh) ; 10(23): e2206910, 2023 08.
Artículo en Inglés | MEDLINE | ID: mdl-37271923

RESUMEN

Demyelinating disorders are among the most common and debilitating diseases in neurology. Canavan disease (CD) is a lethal demyelinating disease caused by mutation of the aspartoacylase (ASPA) gene, which leads to the accumulation of its substrate N-acetyl-l-aspartate (NAA), and consequently demyelination and vacuolation in the brain. In this study, hypoimmunogenic human induced pluripotent stem cell (iPSC)-derived oligodendrocyte progenitor cells (OPC) are developed from a healthy donor as an "off-the-shelf" cell therapy. Hypoimmunogenic iPSCs are generated through CRISPR/Cas9 editing of the human leukocyte antigen (HLA) molecules in healthy donor-derived iPSCs and differentiated into OPCs. The OPCs are engrafted into the brains of CD (nur7) mice and exhibit widespread distribution in the brain. The engrafted OPCs mature into oligodendrocytes that express the endogenous wildtype ASPA gene. Consequently, the transplanted mice exhibit elevated human ASPA expression and enzymatic activity and reduced NAA level in the brain. The transplanted OPCs are able to rescue major pathological features of CD, including defective myelination, extensive vacuolation, and motor function deficits. Moreover, the hypoimmunogenic OPCs exhibit low immunogenicity both in vitro and in vivo. The hypoimmunogenic OPCs can be used as "off-the-shelf" universal donor cells to treat various CD patients and many other demyelinating disorders, especially autoimmune demyelinating diseases, such as multiple sclerosis.


Asunto(s)
Enfermedad de Canavan , Células Madre Pluripotentes Inducidas , Esclerosis Múltiple , Células Precursoras de Oligodendrocitos , Humanos , Ratones , Animales , Vaina de Mielina/metabolismo , Vaina de Mielina/patología , Células Madre Pluripotentes Inducidas/patología , Células Precursoras de Oligodendrocitos/patología , Oligodendroglía/metabolismo , Enfermedad de Canavan/genética , Enfermedad de Canavan/metabolismo , Enfermedad de Canavan/patología
9.
Prog Neurobiol ; 226: 102460, 2023 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-37149081

RESUMEN

Myelinating oligodendrocytes are essential for neuronal communication and homeostasis of the central nervous system (CNS). One of the most abundant molecules in the mammalian CNS is N-acetylaspartate (NAA), which is catabolized into L-aspartate and acetate by the enzyme aspartoacylase (ASPA) in oligodendrocytes. The resulting acetate moiety is thought to contribute to myelin lipid synthesis. In addition, affected NAA metabolism has been implicated in several neurological disorders, including leukodystrophies and demyelinating diseases such as multiple sclerosis. Genetic disruption of ASPA function causes Canavan disease, which is hallmarked by increased NAA levels, myelin and neuronal loss, large vacuole formation in the CNS, and early death in childhood. Although NAA's direct role in the CNS is inconclusive, in peripheral adipose tissue, NAA-derived acetate has been found to modify histones, a mechanism known to be involved in epigenetic regulation of cell differentiation. We hypothesize that a lack of cellular differentiation in the brain contributes to the disruption of myelination and neurodegeneration in diseases with altered NAA metabolism, such as Canavan disease. Our study demonstrates that loss of functional Aspa in mice disrupts myelination and shifts the transcriptional expression of neuronal and oligodendrocyte markers towards less differentiated stages in a spatiotemporal manner. Upon re-expression of ASPA, these oligodendrocyte and neuronal lineage markers are either improved or normalized, suggesting that NAA breakdown by Aspa plays an essential role in the maturation of neurons and oligodendrocytes. Also, this effect of ASPA re-expression is blunted in old mice, potentially due to limited ability of neuronal, rather than oligodendrocyte, recovery.


Asunto(s)
Enfermedad de Canavan , Ratones , Animales , Enfermedad de Canavan/genética , Enfermedad de Canavan/metabolismo , Linaje de la Célula , Epigénesis Genética , Sistema Nervioso Central/metabolismo , Oligodendroglía , Vaina de Mielina/metabolismo , Mamíferos
10.
J Ultrasound ; 26(4): 757-764, 2023 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-35187608

RESUMEN

Canavan disease (CD; MIM 271,900) or spongy degeneration of the central nervous system (CNS) is a lethal, rare autosomal recessive leukodystrophy, first described in 1931 (Canavan in Arch Neurol Psychiatry 25: 299-308, 1931). The clinical presentation includes severe neurologic impairment and macrocephaly with onset of symptoms at the age of 3-5 months. Biochemical and genetic fundamentals of the disease are elucidated. Imaging diagnosis is principally based on MRI with important role of MR spectroscopy. We report the cerebral sonographic findings in a severely affected infant with CD: Diffuse hyperechogenicity and small multicystic changes of white matter as well as an inverted pattern of echogenicity between cortical gray and subcortical white matter. These findings are compared to to the few cases found in literature and to normal ultrasound examples. Finally, ultrasound and MRI imaging findings are correlated.


Asunto(s)
Enfermedades Óseas , Enfermedad de Canavan , Humanos , Lactante , Enfermedad de Canavan/diagnóstico por imagen , Enfermedad de Canavan/genética , Ultrasonografía , Imagen por Resonancia Magnética
12.
Eur J Hum Genet ; 31(1): 73-80, 2023 01.
Artículo en Inglés | MEDLINE | ID: mdl-36202930

RESUMEN

Mild/juvenile Canavan disease (M/JCD) is less frequently reported in the literature and little is known about its pathogenetic mechanisms. We report a comprehensive investigation into the pathogenetic mechanism of a novel NM_000049.4(ASPA):c.526G>A variant in two families. The families belong to Telugu Devanga Chettiar community (TDC) from southern India. TDC has a complex history of migration from their historical origin centuries ago with high endogamy. TDC probably has the highest clustering M/JCD recorded historically (around 24 cases). The pathogenic variant was shown to cause non-classical splicing defect resulting in two different transcripts. The splicing aberration, a loss of function mechanism coupled with a milder missense effect can explain the milder phenotype compared to the infantile-onset CD. The high clustering of an extremely rare form of neurodegenerative disorder with reduced fitness, led us to speculate the possibility of a founder event. Genotyping array of TDC and multiple distinct populations of Indian origin for several population genetic parameters was performed. It yielded robust signatures of a founder event in TDC, such as a high fixation index, increased runs of homozygosity and identity-by-descent in the absence of consanguinity; a large haplotype with high linkage disequilibrium among markers comprising the pathogenic variant; a robust population structure; mutation dating, estimating the age of the potential founder of TDC at around 375 years; possibly a high carrier rate in TDC. This study has not only focused its attention on natural history and pathogenetics but also paves way for carrier screening programs in TDC and future therapeutic studies.


Asunto(s)
Enfermedad de Canavan , Humanos , Enfermedad de Canavan/genética , Genética de Población , Mutación , Haplotipos , Genómica , Análisis por Conglomerados , Efecto Fundador
13.
Zhonghua Yi Xue Yi Chuan Xue Za Zhi ; 39(8): 859-863, 2022 Aug 10.
Artículo en Chino | MEDLINE | ID: mdl-35929936

RESUMEN

OBJECTIVE: To explore the genetic basis for a Chinese patient suspected for Canavan disease. METHODS: Whole exome sequencing (WES) was carried out for the proband, and candidate variants were verified by Sanger sequencing of the proband, her parents and brother. Prenatal diagnosis was provided to her mother by chorionic villi sampling (CVS) upon her subsequent pregnancy. RESULTS: The proband, a 4-month-old female infant, had manifested drowsiness, hypotonia and apathy. Urine metabolism screening showed elevated N-acetylaspartic acid. Cranial magnetic resonance imaging revealed abnormal myelination and multiple abnormal signals in large brain areas. WES revealed that the proband has harbored compound heterozygous variants of the ASPA gene, namely c.187A>G (p.Arg63Gly) in exon 1 and c.634+1G>A (P.?) in exon 4. Sanger sequencing confirmed that the c.187A>G (p.Arg63Gly) and c.634+1G>A (p.?) variants were respectively inherited from her mother and father. Her phenotypically normal brother has carried a heterozygous c.634+1G>A (p.?) variant. Prenatal diagnosis by CVS indicated that the fetus was a heterozygous carrier of the c.187A>G variant. CONCLUSION: WES can facilitate the diagnosis of Canavan disease, particularly for those lacking specific phenotypes of the disease. The compound heterozygous variants of the ASPA gene probably underlay the Canavan disease in this patient, and the result has enabled prenatal diagnosis for this family.


Asunto(s)
Enfermedad de Canavan , Enfermedad de Canavan/diagnóstico , Enfermedad de Canavan/genética , China , Femenino , Humanos , Masculino , Mutación , Linaje , Embarazo , Diagnóstico Prenatal
14.
Orphanet J Rare Dis ; 16(1): 227, 2021 05 19.
Artículo en Inglés | MEDLINE | ID: mdl-34011350

RESUMEN

BACKGROUND: Canavan disease (CD, MIM # 271900) is a rare and devastating leukodystrophy of early childhood. To identify clinical features that could serve as endpoints for treatment trials, the clinical course of CD was studied retrospectively and prospectively in 23 CD patients. Results were compared with data of CD patients reported in three prior large series. Kaplan Meier survival analysis including log rank test was performed for pooled data of 82 CD patients (study cohort and literature patients). RESULTS: Onset of symptoms was between 0 and 6 months. Psychomotor development of patients was limited to abilities that are usually gained within the first year of life. Macrocephaly became apparent between 4 and 18 months of age. Seizure frequency was highest towards the end of the first decade. Ethnic background was more diverse than in studies previously reported. A CD severity score with assessment of 11 symptoms and abilities was developed. CONCLUSIONS: Early hallmarks of CD are severe psychomotor disability and macrocephaly that develop within the first 18 months of life. While rare in the first year of life, seizures increase in frequency over time in most patients. CD occurs more frequently outside Ashkenazi Jewish communities than previously reported. Concordance of phenotypes between siblings but not patients with identical ASPA mutations suggest the influence of yet unknown modifiers. A CD severity score may allow for assessment of CD disease severity both retrospectively and prospectively.


Asunto(s)
Enfermedad de Canavan , Amidohidrolasas/genética , Enfermedad de Canavan/genética , Humanos , Lactante , Mutación , Fenotipo , Estudios Retrospectivos
15.
PLoS Genet ; 17(4): e1009539, 2021 04.
Artículo en Inglés | MEDLINE | ID: mdl-33914734

RESUMEN

Canavan disease is a severe progressive neurodegenerative disorder that is characterized by swelling and spongy degeneration of brain white matter. The disease is genetically linked to polymorphisms in the aspartoacylase (ASPA) gene, including the substitution C152W. ASPA C152W is associated with greatly reduced protein levels in cells, yet biophysical experiments suggest a wild-type like thermal stability. Here, we use ASPA C152W as a model to investigate the degradation pathway of a disease-causing protein variant. When we expressed ASPA C152W in Saccharomyces cerevisiae, we found a decreased steady state compared to wild-type ASPA as a result of increased proteasomal degradation. However, molecular dynamics simulations of ASPA C152W did not substantially deviate from wild-type ASPA, indicating that the native state is structurally preserved. Instead, we suggest that the C152W substitution interferes with the de novo folding pathway resulting in increased proteasomal degradation before reaching its stable conformation. Systematic mapping of the protein quality control components acting on misfolded and aggregation-prone species of C152W, revealed that the degradation is highly dependent on the molecular chaperone Hsp70, its co-chaperone Hsp110 as well as several quality control E3 ubiquitin-protein ligases, including Ubr1. In addition, the disaggregase Hsp104 facilitated refolding of aggregated ASPA C152W, while Cdc48 mediated degradation of insoluble ASPA protein. In human cells, ASPA C152W displayed increased proteasomal turnover that was similarly dependent on Hsp70 and Hsp110. Our findings underscore the use of yeast to determine the protein quality control components involved in the degradation of human pathogenic variants in order to identify potential therapeutic targets.


Asunto(s)
Amidohidrolasas/genética , Enfermedad de Canavan/genética , Proteínas del Choque Térmico HSP110/genética , Proteínas HSP70 de Choque Térmico/genética , Sustitución de Aminoácidos/genética , Enfermedad de Canavan/patología , Proteínas de Choque Térmico/genética , Humanos , Chaperonas Moleculares/genética , Mutación/genética , Saccharomyces cerevisiae/genética , Proteínas de Saccharomyces cerevisiae/genética , Ubiquitina-Proteína Ligasas/genética
16.
Sci Rep ; 11(1): 3231, 2021 02 05.
Artículo en Inglés | MEDLINE | ID: mdl-33547378

RESUMEN

This study evaluates the genetic spectrum of leukodystrophies and leukoencephalopathies in Iran. 152 children, aged from 1 day to 15 years, were genetically tested for leukodystrophies and leukoencephalopathies based on clinical and neuroradiological findings from 2016 to 2019. Patients with a suggestive specific leukodystrophy, e. g. metachromatic leukodystrophy, Canavan disease, Tay-Sachs disease were tested for mutations in single genes (108; 71%) while patients with less suggestive findings were evaluated by NGS. 108 of 152(71%) had MRI patterns and clinical findings suggestive of a known leukodystrophy. In total, 114(75%) affected individuals had (likely) pathogenic variants which included 38 novel variants. 35 different types of leukodystrophies and genetic leukoencephalopathies were identified. The more common identified disorders included metachromatic leukodystrophy (19 of 152; 13%), Canavan disease (12; 8%), Tay-Sachs disease (11; 7%), megalencephalic leukodystrophy with subcortical cysts (7; 5%), X-linked adrenoleukodystrophy (8; 5%), Pelizaeus-Merzbacher-like disease type 1 (8; 5%), Sandhoff disease (6; 4%), Krabbe disease (5; 3%), and vanishing white matter disease (4; 3%). Whole exome sequencing (WES) revealed 90% leukodystrophies and genetic leukoencephalopathies. The total diagnosis rate was 75%. This unique study presents a national genetic data of leukodystrophies; it may provide clues to the genetic pool of neighboring countries. Patients with clinical and neuroradiological evidence of a genetic leukoencephalopathy should undergo a genetic analysis to reach a definitive diagnosis. This will allow a diagnosis at earlier stages of the disease, reduce the burden of uncertainty and costs, and will provide the basis for genetic counseling and family planning.


Asunto(s)
Enfermedades Desmielinizantes del Sistema Nervioso Central Hereditarias/genética , Leucodistrofia Metacromática/genética , Leucoencefalopatías/genética , Adolescente , Enfermedad de Canavan/epidemiología , Enfermedad de Canavan/genética , Niño , Preescolar , Femenino , Pruebas Genéticas , Enfermedades Desmielinizantes del Sistema Nervioso Central Hereditarias/epidemiología , Humanos , Lactante , Recién Nacido , Irán/epidemiología , Leucodistrofia de Células Globoides/epidemiología , Leucodistrofia de Células Globoides/genética , Leucodistrofia Metacromática/epidemiología , Leucoencefalopatías/epidemiología , Masculino , Mutación
17.
BMC Med Genet ; 21(1): 216, 2020 11 02.
Artículo en Inglés | MEDLINE | ID: mdl-33138774

RESUMEN

BACKGROUND: To determine the carrier frequency and pathogenic variants of common genetic disorders in the north Indian population by using next generation sequencing (NGS). METHODS: After pre-test counselling, 200 unrelated individuals (including 88 couples) were screened for pathogenic variants in 88 genes by NGS technology. The variants were classified as per American College of Medical Genetics criteria. Pathogenic and likely pathogenic variants were subjected to thorough literature-based curation in addition to the regular filters. Variants of unknown significance were not reported. Individuals were counselled explaining the implications of the results, and cascade screening was advised when necessary. RESULTS: Of the 200 participants, 52 (26%) were found to be carrier of one or more disorders. Twelve individuals were identified to be carriers for congenital deafness, giving a carrier frequency of one in 17 for one of the four genes tested (SLC26A4, GJB2, TMPRSS3 and TMC1 in decreasing order). Nine individuals were observed to be carriers for cystic fibrosis, with a frequency of one in 22. Three individuals were detected to be carriers for Pompe disease (frequency one in 67). None of the 88 couples screened were found to be carriers for the same disorder. The pathogenic variants observed in many disorders (such as deafness, cystic fibrosis, Pompe disease, Canavan disease, primary hyperoxaluria, junctional epidermolysis bullosa, galactosemia, medium chain acyl CoA deficiency etc.) were different from those commonly observed in the West. CONCLUSION: A higher carrier frequency for genetic deafness, cystic fibrosis and Pompe disease was unexpected, and contrary to the generally held view about their prevalence in Asian Indians. In spite of the small sample size, this study would suggest that population-based carrier screening panels for India would differ from those in the West, and need to be selected with due care. Testing should comprise the study of all the coding exons with its boundaries in the genes through NGS, as all the variants are not well characterized. Only study of entire coding regions in the genes will detect carriers with adequate efficiency, in order to reduce the burden of genetic disorders in India and other resource poor countries.


Asunto(s)
Acil-CoA Deshidrogenasa/deficiencia , Enfermedad de Canavan/genética , Fibrosis Quística/genética , Epidermólisis Ampollosa de la Unión/genética , Galactosemias/genética , Enfermedad del Almacenamiento de Glucógeno Tipo II/genética , Pérdida Auditiva Sensorineural/genética , Hiperoxaluria Primaria/genética , Errores Innatos del Metabolismo Lipídico/genética , Acil-CoA Deshidrogenasa/genética , Adulto , Enfermedad de Canavan/epidemiología , Conexina 26 , Conexinas/genética , Fibrosis Quística/epidemiología , Epidermólisis Ampollosa de la Unión/epidemiología , Femenino , Galactosemias/epidemiología , Expresión Génica , Tamización de Portadores Genéticos/estadística & datos numéricos , Asesoramiento Genético , Enfermedad del Almacenamiento de Glucógeno Tipo II/epidemiología , Pérdida Auditiva Sensorineural/epidemiología , Heterocigoto , Secuenciación de Nucleótidos de Alto Rendimiento , Humanos , Hiperoxaluria Primaria/epidemiología , India/epidemiología , Errores Innatos del Metabolismo Lipídico/epidemiología , Masculino , Proteínas de la Membrana/genética , Persona de Mediana Edad , Mutación , Proteínas de Neoplasias/genética , Serina Endopeptidasas/genética , Transportadores de Sulfato/genética
18.
Brain Dev ; 42(2): 222-225, 2020 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-31839386

RESUMEN

BACKGROUND: Canavan disease is a genetic neurodegenerative leukodystrophy that results in the spongy degeneration of the white matter. Its key clinical features in the infantile form are developmental delay, visual problems and macrocephaly. Congenital and juvenile forms have also been described. PATIENT DESCRIPTION: We report on a 13-year-old boy who is a high school student in a public school. He was diagnosed with juvenile Canavan disease, presenting with intentional tremor as the only clinical finding. RESULTS: Magnetic resonance imaging revealed mainly the involvement of the caudate nucleus and pons extending to the mesencephalon and also the putamen and the thalamus, with no apparent signal increase in the cerebral white matter. A homozygous p.Gly274Arg (c.820A>G) missense mutation was identified. CONCLUSION: Juvenile Canavan disease with mainly pons involvement has not been published before. Pons, caudate nucleus and basal ganglia involvement without any white matter being involved could be expected in juvenile Canavan disease as a rare form of the disease.


Asunto(s)
Enfermedad de Canavan/genética , Enfermedad de Canavan/patología , Puente/patología , Adolescente , Amidohidrolasas/genética , Ganglios Basales/patología , Encéfalo/patología , Enfermedad de Canavan/diagnóstico , Discapacidades del Desarrollo/patología , Humanos , Imagen por Resonancia Magnética , Masculino , Megalencefalia , Puente/metabolismo , Sustancia Blanca/patología
20.
Mol Ther ; 26(3): 793-800, 2018 03 07.
Artículo en Inglés | MEDLINE | ID: mdl-29456021

RESUMEN

Canavan disease, a leukodystrophy caused by loss-of-function ASPA mutations, is characterized by brain dysmyelination, vacuolation, and astrogliosis ("spongiform leukodystrophy"). ASPA encodes aspartoacylase, an oligodendroglial enzyme that cleaves the abundant brain amino acid N-acetyl-L-aspartate (NAA) to L-aspartate and acetate. Aspartoacylase deficiency results in a 50% or greater elevation in brain NAA concentration ([NAAB]). Prior studies showed that homozygous constitutive knockout of Nat8l, the gene encoding the neuronal NAA synthesizing enzyme N-acetyltransferase 8-like, prevents aspartoacylase-deficient mice from developing spongiform leukodystrophy. We now report that brain Nat8l knockdown elicited by intracerebroventricular/intracisternal administration of an adeno-associated viral vector carrying a short hairpin Nat8l inhibitory RNA to neonatal aspartoacylase-deficient AspaNur7/Nur7 mice lowers [NAAB] and suppresses development of spongiform leukodystrophy.


Asunto(s)
Acetiltransferasas/genética , Amidohidrolasas/deficiencia , Enfermedad de Canavan/genética , Enfermedad de Canavan/metabolismo , Animales , Encéfalo/metabolismo , Encéfalo/patología , Enfermedad de Canavan/patología , Enfermedad de Canavan/fisiopatología , Dependovirus/genética , Modelos Animales de Enfermedad , Expresión Génica , Técnicas de Silenciamiento del Gen , Vectores Genéticos/administración & dosificación , Vectores Genéticos/genética , Ratones , Ratones Noqueados , Actividad Motora , Neuronas/metabolismo , ARN Mensajero/genética , Transducción Genética
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