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1.
Epilepsia ; 2024 Jul 02.
Artigo em Inglês | MEDLINE | ID: mdl-38953796

RESUMO

OBJECTIVE: DYNC1H1 variants are involved on a disease spectrum from neuromuscular disorders to neurodevelopmental disorders. DYNC1H1-related epilepsy has been reported in small cohorts. We dissect the electroclinical features of 34 patients harboring de novo DYNC1H1 pathogenic variants, identify subphenotypes on the DYNC1H1-related epilepsy spectrum, and compare the genotype-phenotype correlations observed in our cohort with the literature. METHODS: Patients harboring de novo DYNC1H1 pathogenic variants were recruited through international collaborations. Clinical data were retrospectively collected. Latent class analysis was performed to identify subphenotypes. Multivariable binary logistic regression analysis was applied to investigate the association with DYNC1H1 protein domains. RESULTS: DYNC1H1-related epilepsy presented with infantile epileptic spasms syndrome (IESS) in 17 subjects (50%), and in 25% of these individuals the epileptic phenotype evolved into Lennox-Gastaut syndrome (LGS). In 12 patients (35%), focal onset epilepsy was defined. In two patients, the epileptic phenotype consisted of generalized myoclonic epilepsy, with a progressive phenotype in one individual harboring a frameshift variant. In approximately 60% of our cohort, seizures were drug-resistant. Malformations of cortical development were noticed in 79% of our patients, mostly on the lissencephaly-pachygyria spectrum, particularly with posterior predominance in a half of them. Midline and infratentorial abnormalities were additionally reported in 45% and 27% of subjects. We have identified three main classes of subphenotypes on the DYNC1H1-related epilepsy spectrum. SIGNIFICANCE: We propose a classification in which pathogenic de novo DYNC1H1 variants feature drug-resistant IESS in half of cases with potential evolution to LGS (Class 1), developmental and epileptic encephalopathy other than IESS and LGS (Class 2), or less severe focal or genetic generalized epilepsy including a progressive phenotype (Class 3). We observed an association between stalk domain variants and Class 1 phenotypes. The variants p.Arg309His and p.Arg1962His were common and associated with Class 1 subphenotype in our cohort. These findings may aid genetic counseling of patients with DYNC1H1-related epilepsy.

2.
J Med Genet ; 60(10): 1026-1034, 2023 10.
Artigo em Inglês | MEDLINE | ID: mdl-37197783

RESUMO

BACKGROUND: RNA polymerase III-related or 4H leukodystrophy (POLR3-HLD) is an autosomal recessive hypomyelinating leukodystrophy characterized by neurological dysfunction, hypodontia and hypogonadotropic hypogonadism. The disease is caused by biallelic pathogenic variants in POLR3A, POLR3B, POLR1C or POLR3K. Craniofacial abnormalities reminiscent of Treacher Collins syndrome have been originally described in patients with POLR3-HLD caused by biallelic pathogenic variants in POLR1C. To date, no published studies have appraised in detail the craniofacial features of patients with POLR3-HLD. In this work, the specific craniofacial characteristics of patients with POLR3-HLD associated with biallelic pathogenic variants in POLR3A, POLR3B and POLR1C are described. METHODS: The craniofacial features of 31 patients with POLR3-HLD were evaluated, and potential genotype-phenotype associations were evaluated. RESULTS: Various craniofacial abnormalities were recognized in this patient cohort, with each individual presenting at least one craniofacial abnormality. The most frequently identified features included a flat midface (61.3%), a smooth philtrum (58.0%) and a pointed chin (51.6%). In patients with POLR3B biallelic variants, a thin upper lip was frequent. Craniofacial anomalies involving the forehead were most commonly associated with biallelic variants in POLR3A and POLR3B while a higher proportion of patients with POLR1C biallelic variants demonstrated bitemporal narrowing. CONCLUSION: Through this study, we demonstrated that craniofacial abnormalities are common in patients with POLR3-HLD. This report describes in detail the dysmorphic features of POLR3-HLD associated with biallelic variants in POLR3A, POLR3B and POLR1C.


Assuntos
Doenças Desmielinizantes , Doenças Neurodegenerativas , Humanos , RNA Polimerase III/genética , Padrões de Herança , RNA Polimerases Dirigidas por DNA/genética
3.
Am J Hum Genet ; 102(5): 985-994, 2018 05 03.
Artigo em Inglês | MEDLINE | ID: mdl-29656860

RESUMO

N-alpha-acetylation is a common co-translational protein modification that is essential for normal cell function in humans. We previously identified the genetic basis of an X-linked infantile lethal Mendelian disorder involving a c.109T>C (p.Ser37Pro) missense variant in NAA10, which encodes the catalytic subunit of the N-terminal acetyltransferase A (NatA) complex. The auxiliary subunit of the NatA complex, NAA15, is the dimeric binding partner for NAA10. Through a genotype-first approach with whole-exome or genome sequencing (WES/WGS) and targeted sequencing analysis, we identified and phenotypically characterized 38 individuals from 33 unrelated families with 25 different de novo or inherited, dominantly acting likely gene disrupting (LGD) variants in NAA15. Clinical features of affected individuals with LGD variants in NAA15 include variable levels of intellectual disability, delayed speech and motor milestones, and autism spectrum disorder. Additionally, mild craniofacial dysmorphology, congenital cardiac anomalies, and seizures are present in some subjects. RNA analysis in cell lines from two individuals showed degradation of the transcripts with LGD variants, probably as a result of nonsense-mediated decay. Functional assays in yeast confirmed a deleterious effect for two of the LGD variants in NAA15. Further supporting a mechanism of haploinsufficiency, individuals with copy-number variant (CNV) deletions involving NAA15 and surrounding genes can present with mild intellectual disability, mild dysmorphic features, motor delays, and decreased growth. We propose that defects in NatA-mediated N-terminal acetylation (NTA) lead to variable levels of neurodevelopmental disorders in humans, supporting the importance of the NatA complex in normal human development.


Assuntos
Anormalidades Múltiplas/genética , Transtorno do Espectro Autista/genética , Predisposição Genética para Doença , Variação Genética , Deficiência Intelectual/genética , Acetiltransferase N-Terminal A/genética , Acetiltransferase N-Terminal E/genética , Adolescente , Adulto , Linhagem Celular , Criança , Éxons/genética , Feminino , Regulação da Expressão Gênica , Humanos , Masculino , Pessoa de Meia-Idade , Mutação/genética , Acetiltransferase N-Terminal A/metabolismo , Acetiltransferase N-Terminal E/metabolismo , Linhagem , Fenótipo , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Saccharomyces cerevisiae/metabolismo
4.
Hum Mutat ; 41(1): 150-168, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31448840

RESUMO

Xq22 deletions that encompass PLP1 (Xq22-PLP1-DEL) are notable for variable expressivity of neurological disease traits in females ranging from a mild late-onset form of spastic paraplegia type 2 (MIM# 312920), sometimes associated with skewed X-inactivation, to an early-onset neurological disease trait (EONDT) of severe developmental delay, intellectual disability, and behavioral abnormalities. Size and gene content of Xq22-PLP1-DEL vary and were proposed as potential molecular etiologies underlying variable expressivity in carrier females where two smallest regions of overlap (SROs) were suggested to influence disease. We ascertained a cohort of eight unrelated patients harboring Xq22-PLP1-DEL and performed high-density array comparative genomic hybridization and breakpoint-junction sequencing. Molecular characterization of Xq22-PLP1-DEL from 17 cases (eight herein and nine published) revealed an overrepresentation of breakpoints that reside within repeats (11/17, ~65%) and the clustering of ~47% of proximal breakpoints in a genomic instability hotspot with characteristic non-B DNA density. These findings implicate a potential role for genomic architecture in stimulating the formation of Xq22-PLP1-DEL. The correlation of Xq22-PLP1-DEL gene content with neurological disease trait in female cases enabled refinement of the associated SROs to a single genomic interval containing six genes. Our data support the hypothesis that genes contiguous to PLP1 contribute to EONDT.


Assuntos
Deleção Cromossômica , Cromossomos Humanos X , Estudos de Associação Genética , Predisposição Genética para Doença , Doenças do Sistema Nervoso/diagnóstico , Doenças do Sistema Nervoso/genética , Característica Quantitativa Herdável , Criança , Pré-Escolar , Pontos de Quebra do Cromossomo , Mapeamento Cromossômico , Hibridização Genômica Comparativa , Feminino , Estudos de Associação Genética/métodos , Humanos , Masculino , Linhagem , Fenótipo , Sequências Repetitivas de Ácido Nucleico , Fatores Sexuais , Síndrome , Inativação do Cromossomo X
5.
Am J Hum Genet ; 101(1): 65-74, 2017 Jul 06.
Artigo em Inglês | MEDLINE | ID: mdl-28669405

RESUMO

KCNQ5 is a highly conserved gene encoding an important channel for neuronal function; it is widely expressed in the brain and generates M-type current. Exome sequencing identified de novo heterozygous missense mutations in four probands with intellectual disability, abnormal neurological findings, and treatment-resistant epilepsy (in two of four). Comprehensive analysis of this potassium channel for the four variants expressed in frog oocytes revealed shifts in the voltage dependence of activation, including altered activation and deactivation kinetics. Specifically, both loss-of-function and gain-of-function KCNQ5 mutations, associated with increased excitability and decreased repolarization reserve, lead to pathophysiology.


Assuntos
Epilepsia/genética , Predisposição Genética para Doença , Deficiência Intelectual/genética , Canais de Potássio KCNQ/genética , Mutação/genética , Eletroencefalografia , Humanos , Ativação do Canal Iônico , Canais de Potássio KCNQ/química , Proteínas Mutantes/química , Proteínas Mutantes/genética , Fenótipo , Alinhamento de Sequência
6.
Genet Med ; 22(5): 878-888, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-31949314

RESUMO

PURPOSE: Determination of genotypic/phenotypic features of GATAD2B-associated neurodevelopmental disorder (GAND). METHODS: Fifty GAND subjects were evaluated to determine consistent genotypic/phenotypic features. Immunoprecipitation assays utilizing in vitro transcription-translation products were used to evaluate GATAD2B missense variants' ability to interact with binding partners within the nucleosome remodeling and deacetylase (NuRD) complex. RESULTS: Subjects had clinical findings that included macrocephaly, hypotonia, intellectual disability, neonatal feeding issues, polyhydramnios, apraxia of speech, epilepsy, and bicuspid aortic valves. Forty-one novelGATAD2B variants were identified with multiple variant types (nonsense, truncating frameshift, splice-site variants, deletions, and missense). Seven subjects were identified with missense variants that localized within two conserved region domains (CR1 or CR2) of the GATAD2B protein. Immunoprecipitation assays revealed several of these missense variants disrupted GATAD2B interactions with its NuRD complex binding partners. CONCLUSIONS: A consistent GAND phenotype was caused by a range of genetic variants in GATAD2B that include loss-of-function and missense subtypes. Missense variants were present in conserved region domains that disrupted assembly of NuRD complex proteins. GAND's clinical phenotype had substantial clinical overlap with other disorders associated with the NuRD complex that involve CHD3 and CHD4, with clinical features of hypotonia, intellectual disability, cardiac defects, childhood apraxia of speech, and macrocephaly.


Assuntos
Deficiência Intelectual , Megalencefalia , Transtornos do Neurodesenvolvimento , Criança , Feminino , Fatores de Transcrição GATA/genética , Humanos , Deficiência Intelectual/genética , Transtornos do Neurodesenvolvimento/genética , Nucleossomos , Fenótipo , Gravidez , Proteínas Repressoras
8.
Hum Mutat ; 40(8): 1013-1029, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31021519

RESUMO

SATB2-associated syndrome (SAS) is an autosomal dominant neurodevelopmental disorder caused by alterations in the SATB2 gene. Here we present a review of published pathogenic variants in the SATB2 gene to date and report 38 novel alterations found in 57 additional previously unreported individuals. Overall, we present a compilation of 120 unique variants identified in 155 unrelated families ranging from single nucleotide coding variants to genomic rearrangements distributed throughout the entire coding region of SATB2. Single nucleotide variants predicted to result in the occurrence of a premature stop codon were the most commonly seen (51/120 = 42.5%) followed by missense variants (31/120 = 25.8%). We review the rather limited functional characterization of pathogenic variants and discuss current understanding of the consequences of the different molecular alterations. We present an expansive phenotypic review along with novel genotype-phenotype correlations. Lastly, we discuss current knowledge of animal models and present future prospects. This review should help provide better guidance for the care of individuals diagnosed with SAS.


Assuntos
Proteínas de Ligação à Região de Interação com a Matriz/genética , Mutação , Transtornos do Neurodesenvolvimento/genética , Fatores de Transcrição/genética , Adolescente , Animais , Criança , Pré-Escolar , Códon de Terminação , Modelos Animais de Doenças , Feminino , Rearranjo Gênico , Estudos de Associação Genética , Humanos , Masculino , Mutação de Sentido Incorreto , Polimorfismo de Nucleotídeo Único
9.
Ann Neurol ; 84(2): 274-288, 2018 08.
Artigo em Inglês | MEDLINE | ID: mdl-30014503

RESUMO

OBJECTIVE: To comprehensively describe the natural history of vanishing white matter (VWM), aiming at improving counseling of patients/families and providing natural history data for future therapeutic trials. METHODS: We performed a longitudinal multicenter study among 296 genetically confirmed VWM patients. Clinical information was obtained via disease-specific clinical questionnaire, Health Utilities Index and Guy's Neurological Disability Scale assessments, and chart review. RESULTS: First disease signs occurred at a median age of 3 years (mode = 2 years, range = before birth to 54 years); 60% of patients were symptomatic before the age of 4 years. The nature of the first signs varied for different ages of onset. Overall, motor problems were the most common presenting sign, especially in children. Adolescent and adult onset patients were more likely to exhibit cognitive problems early after disease onset. One hundred two patients were deceased. Multivariate Cox regression analysis revealed a positive relation between age at onset and both preservation of ambulation and survival. Absence of stress-provoked episodes and absence of seizures predicted more favorable outcome. In patients with onset before 4 years, earlier onset was associated with more severe disability and higher mortality. For onset from 4 years on, disease course was generally milder, with a wide variation in severity. There were no significant differences for sex or for the 5 eIF2B gene groups. The results confirm the presence of a genotype-phenotype correlation. INTERPRETATION: The VWM disease spectrum consists of a continuum with extremely wide variability. Age at onset is a strong predictor for disease course. Ann Neurol 2018;84:274-288.


Assuntos
Leucoencefalopatias/diagnóstico por imagem , Leucoencefalopatias/genética , Substância Branca/diagnóstico por imagem , Adolescente , Adulto , Idade de Início , Criança , Pré-Escolar , Feminino , Seguimentos , Humanos , Lactente , Recém-Nascido , Leucoencefalopatias/epidemiologia , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade , Adulto Jovem
10.
Am J Med Genet A ; 179(8): 1556-1564, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31099476

RESUMO

Biallelic pathogenic variants in AARS2, a gene encoding the mitochondrial alanyl-tRNA synthetase, result in a spectrum of findings ranging from infantile cardiomyopathy to adult-onset progressive leukoencephalopathy. In this article, we present three unrelated individuals with novel compound heterozygous pathogenic AARS2 variants underlying diverse clinical presentations. Patient 1 is a 51-year-old man with adult-onset progressive cognitive, psychiatric, and motor decline and leukodystrophy. Patient 2 is a 34-year-old man with childhood-onset progressive tremor followed by the development of polyneuropathy, ataxia, and mild cognitive and psychiatric decline without leukodystrophy on imaging. Patient 3 is a 57-year-old woman with childhood-onset tremor and nystagmus which preceded dystonia, chorea, ataxia, depression, and cognitive decline marked by cerebellar atrophy and white matter disease. These cases expand the clinical heterogeneity of AARS2-related disorders, given that the first and third case represent some of the oldest known survivors of this disease, the second is adult-onset AARS2-related neurological decline without leukodystrophy, and the third is biallelic AARS2-related disorder involving a partial gene deletion.


Assuntos
Alanina-tRNA Ligase/genética , Estudos de Associação Genética , Predisposição Genética para Doença , Variação Genética , Fenótipo , Adulto , Alelos , Encéfalo/diagnóstico por imagem , Encéfalo/patologia , Análise Mutacional de DNA , Feminino , Estudos de Associação Genética/métodos , Testes Genéticos , Genótipo , Humanos , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Mutação , Doenças do Sistema Nervoso/diagnóstico , Doenças do Sistema Nervoso/genética , Exame Neurológico
11.
Neurogenetics ; 19(1): 41-47, 2018 01.
Artigo em Inglês | MEDLINE | ID: mdl-29322350

RESUMO

Rett syndrome (RTT) is caused by mutations in methyl-CpG-binding protein 2 (MECP2), but defects in a handful of other genes (e.g., CDKL5, FOXG1, MEF2C) can lead to presentations that resemble, but do not completely mirror, classical RTT. In this study, we attempted to identify other monogenic disorders that share features with RTT. We performed a retrospective chart review on n = 319 patients who had undergone clinical whole exome sequencing (WES) for further etiological evaluation of neurodevelopmental diagnoses that remained unexplained despite extensive prior workup. From this group, we characterized those who (1) possessed features that were compatible with RTT based on clinical judgment, (2) subsequently underwent MECP2 sequencing and/or MECP2 deletion/duplication analysis with negative results, and (3) ultimately arrived at a diagnosis other than RTT with WES. n = 7 patients had clinical features overlapping RTT with negative MECP2 analysis but positive WES providing a diagnosis. These seven patients collectively possessed pathogenic variants in six different genes: two in KCNB1 and one each in FOXG1, IQSEC2, MEIS2, TCF4, and WDR45. n = 2 (both with KCNB1 variants) fulfilled criteria for atypical RTT. RTT-associated features included the following: loss of hand or language skills (n = 3; IQSEC2, KCNB1 x 2); disrupted sleep (n = 4; KNCB1, MEIS2, TCF4, WDR45); stereotyped hand movements (n = 5; FOXG1, KNCB1 x 2, MEIS2, TCF4); bruxism (n = 3; KCNB1 x 2; TCF4); and hypotonia (n = 7). Clinically based diagnoses can be misleading, evident by the increasing number of genetic conditions associated with features of RTT with negative MECP2 mutations.


Assuntos
Síndrome de Rett/diagnóstico , Síndrome de Rett/genética , Proteínas de Transporte/genética , Feminino , Fatores de Transcrição Forkhead/genética , Deleção de Genes , Duplicação Gênica , Fatores de Troca do Nucleotídeo Guanina/genética , Proteínas de Homeodomínio/genética , Humanos , Masculino , Proteína 2 de Ligação a Metil-CpG/genética , Técnicas de Diagnóstico Molecular , Proteínas do Tecido Nervoso/genética , Fenótipo , Estudos Retrospectivos , Canais de Potássio Shab/genética , Fator de Transcrição 4/genética , Fatores de Transcrição/genética , Sequenciamento do Exoma
12.
Am J Med Genet A ; 173(6): 1495-1501, 2017 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-28394409

RESUMO

Rett syndrome (RTT) is caused by MECP2 mutations, resulting in various neurological symptoms. Prolonged corrected QT interval (QTc) is also reported and is a speculated cause of sudden death in RTT. The purpose of this study was to correlate QTc in RTT patients with age, clinical severity, and genotype. 100 RTT patients (98 females, 2 males) with MECP2 mutations underwent baseline neurological evaluation (KKI-RTT Severity Scale) and QTc measurement (standard 12 lead electrocardiogram) as part of our prospective natural history study. Mean QTc of the cohort was 422.6 msec, which did not exceed the normal values for age. 7/100 patients (7%) had QTc prolongation (>450 msec). There was a trend for increasing QTc with age and clinical severity (P = 0.09). No patients with R106C, R106W, R133C, R168*, R270*, R294*, R306C, R306H, and R306P mutations demonstrated QTc prolongation. There was a relatively high proportion of QTc prolongation in patients with R255* mutations (2/8, 25%) and large deletions (1/4, 25%). The overall presence of QTc prolongation did not correlate with mutation category (P = 0.52). Our findings demonstrate that in RTT, the prevalence of QTc prolongation is lower than previously reported. Hence, all RTT patients warrant baseline ECG; if QTc is prolonged, then cardiac followup is warranted. If initial QTc is normal, then annual ECGs, particularly in younger patients, may not be necessary. However, larger sample sizes are needed to solidify the association between QTc and age and clinical severity. The biological and clinical significance of mild QTc prolongation above the normative data remains undetermined.


Assuntos
Morte Súbita Cardíaca , Eletrocardiografia , Proteína 2 de Ligação a Metil-CpG/genética , Síndrome de Rett/genética , Adolescente , Fatores Etários , Criança , Pré-Escolar , Feminino , Genótipo , Sistema de Condução Cardíaco/fisiopatologia , Humanos , Lactente , Masculino , Mutação , Síndrome de Rett/epidemiologia , Síndrome de Rett/fisiopatologia
13.
Am J Med Genet A ; 170(9): 2265-73, 2016 09.
Artigo em Inglês | MEDLINE | ID: mdl-27282546

RESUMO

Mutations in BRAT1, encoding BRCA1-associated ATM activator 1, are associated with a severe phenotype known as rigidity and multifocal seizure syndrome, lethal neonatal (RMFSL; OMIM # 614498), characterized by intractable seizures, hypertonia, autonomic instability, and early death. We expand the phenotypic spectrum of BRAT1 related disorders by reporting on four individuals with various BRAT1 mutations resulting in clinical severity that is either mild or moderate compared to the severe phenotype seen in RMFSL. Representing mild severity are three individuals (Patients 1-3), who are girls (including two sisters, Patients 1-2) between 4 and 10 years old, with subtle dysmorphisms, intellectual disability, ataxia or dyspraxia, and cerebellar atrophy on brain MRI; additionally, Patient 3 has well-controlled epilepsy and microcephaly. Representing moderate severity is a 15-month-old boy (Patient 4) with severe global developmental delay, refractory epilepsy, microcephaly, spasticity, hyperkinetic movements, dysautonomia, and chronic lung disease. In contrast to RMFSL, his seizure onset occurred later at 4 months of age, and he is still alive. All four of the individuals have compound heterozygous BRAT1 mutations discovered via whole exome sequencing: c.638dupA (p.Val214Glyfs*189); c.803+1G>C (splice site mutation) in Patients 1-2; c.638dupA (p.Val214Glyfs*189); c.419T>C (p.Leu140Pro) in Patient 3; and c.171delG (p.Glu57Aspfs*7); c.419T>C (p.Leu140Pro) in Patient 4. Only the c.638dupA (p.Val214Glyfs*189) mutation has been previously reported in association with RMFSL. These patients illustrate that, compared with RMFSL, BRAT1 mutations can result in both moderately severe presentations evident by later-onset epilepsy and survival past infancy, as well as milder presentations that include intellectual disability, ataxia/dyspraxia, and cerebellar atrophy. © 2016 Wiley Periodicals, Inc.


Assuntos
Estudos de Associação Genética , Mutação , Proteínas Nucleares/genética , Fenótipo , Encéfalo/patologia , Cerebelo/anormalidades , Criança , Pré-Escolar , Hibridização Genômica Comparativa , Análise Mutacional de DNA , Epilepsia/diagnóstico , Epilepsia/genética , Exoma , Fácies , Feminino , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Lactente , Deficiência Intelectual/diagnóstico , Deficiência Intelectual/genética , Imageamento por Ressonância Magnética , Masculino , Linhagem , Índice de Gravidade de Doença
14.
Neuropediatrics ; 47(6): 349-354, 2016 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-27564080

RESUMO

Leukodystrophies were defined in the 1980s as progressive genetic disorders primarily affecting myelin of the central nervous system. At that time, a limited number of such disorders and no associated gene defects were known. The majority of the leukodystrophy patients remained without a specific diagnosis. In the following two decades, magnetic resonance imaging pattern recognition revolutionized the field, allowing the definition of numerous novel leukodystrophies. Their genetic defects were usually identified through genetic linkage studies. This process required substantial numbers of cases and many rare disorders remained unclarified. As recently as 2010, 50% of the leukodystrophy patients remained unclassified. Since 2011, whole-exome sequencing has resulted in an exponential increase in numbers of known, distinct, genetically determined, ultrarare leukodystrophies. We performed a retrospective study concerning three historical cohorts of unclassified leukodystrophy patients and found that currently at least 80% of the patients can be molecularly classified. Based on the original definition of the leukodystrophies, numerous defects in proteins important in myelin structure, maintenance, and function were expected. By contrast, a high percentage of the newly identified gene defects affect the housekeeping process of mRNA translation, shedding new light on white matter pathobiology and requiring adaptation of the leukodystrophy definition.


Assuntos
Doenças Desmielinizantes Hereditárias do Sistema Nervoso Central , Doenças Desmielinizantes Hereditárias do Sistema Nervoso Central/diagnóstico , Doenças Desmielinizantes Hereditárias do Sistema Nervoso Central/genética , Doenças Desmielinizantes Hereditárias do Sistema Nervoso Central/história , História do Século XIX , História do Século XX , História do Século XXI , Humanos , RNA Polimerase III/genética , Receptores de Fator Estimulador das Colônias de Granulócitos e Macrófagos/genética
15.
Ann Neurol ; 76(4): 473-83, 2014 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-25131622

RESUMO

OBJECTIVE: Whole exome sequencing (WES) represents a significant breakthrough in clinical genetics as a powerful tool for etiological discovery in neurodevelopmental disorders. To better characterize the genetic landscape of neurodevelopmental disorders, we analyzed patients in our pediatric neurogenetics clinic who underwent WES. METHODS: We performed a retrospective cohort study on 78 patients with various neurodevelopmental disabilities and unrevealing workup prior to WES. We characterized their molecular diagnoses, clinical features, and whether their previous treatment plan changed due to WES results. RESULTS: The overall presumptive diagnostic rate for our cohort was 41% (n = 32 of 78 patients). Nineteen patients had a single autosomal dominant (AD) disorder, 11 had a single autosomal recessive (AR) disorder, 1 had an X-linked dominant disorder, and 1 had both an AD and an AR disorder. The 32 patients with pathogenic or likely pathogenic variants exhibited various neurobehavioral and neuroimaging abnormalities, including intellectual disability/developmental delay (n = 28), cerebral palsy-like encephalopathy (n = 11), autism spectrum disorder (n = 5), delayed/hypomyelination (n = 7), and cerebellar abnormalities (n = 9). The results of WES affected management for all patients with a presumptive diagnosis, triggering reproductive planning (n = 27), disease monitoring initiation (n = 4), investigation of systemic involvement of the disorder(s) (n = 6), alteration of presumed disease inheritance pattern (n = 7), changing of prognosis (n = 10), medication discontinuation (n = 5) or initiation (n = 2), and clinical trial education (n = 3). INTERPRETATION: The high diagnostic yield of WES supports its use in pediatric neurology practices. It may also lead to earlier diagnosis, impacting medical management, prognostication, and family planning. WES therefore serves as a critical tool for the child neurologist.


Assuntos
Deficiências do Desenvolvimento/diagnóstico , Deficiências do Desenvolvimento/genética , Exoma/genética , Doenças do Sistema Nervoso/diagnóstico , Doenças do Sistema Nervoso/genética , Análise de Sequência de DNA/métodos , Adolescente , Adulto , Criança , Pré-Escolar , Estudos de Coortes , Feminino , Predisposição Genética para Doença/genética , Humanos , Lactente , Masculino , Pediatria , Adulto Jovem
16.
Ann Neurol ; 76(4): 529-540, 2014 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-25164438

RESUMO

OBJECTIVE: Numerous studies have demonstrated increased load of de novo copy number variants or single nucleotide variants in individuals with neurodevelopmental disorders, including epileptic encephalopathies, intellectual disability, and autism. METHODS: We searched for de novo mutations in a family quartet with a sporadic case of epileptic encephalopathy with no known etiology to determine the underlying cause using high-coverage whole exome sequencing (WES) and lower-coverage whole genome sequencing. Mutations in additional patients were identified by WES. The effect of mutations on protein function was assessed in a heterologous expression system. RESULTS: We identified a de novo missense mutation in KCNB1 that encodes the KV 2.1 voltage-gated potassium channel. Functional studies demonstrated a deleterious effect of the mutation on KV 2.1 function leading to a loss of ion selectivity and gain of a depolarizing inward cation conductance. Subsequently, we identified 2 additional patients with epileptic encephalopathy and de novo KCNB1 missense mutations that cause a similar pattern of KV 2.1 dysfunction. INTERPRETATION: Our genetic and functional evidence demonstrate that KCNB1 mutation can result in early onset epileptic encephalopathy. This expands the locus heterogeneity associated with epileptic encephalopathies and suggests that clinical WES may be useful for diagnosis of epileptic encephalopathies of unknown etiology.


Assuntos
Deficiências do Desenvolvimento/genética , Epilepsia/genética , Predisposição Genética para Doença/genética , Mutação de Sentido Incorreto/genética , Canais de Potássio Shab/genética , Animais , Biotinilação , Células CHO , Criança , Pré-Escolar , Cricetulus , Feminino , Humanos , Masculino , Potenciais da Membrana/genética , Técnicas de Patch-Clamp , Fenótipo , Transfecção
17.
Am J Med Genet A ; 167A(5): 1147-51, 2015 May.
Artigo em Inglês | MEDLINE | ID: mdl-25851414

RESUMO

Recently, mutations in FARS2, which encodes for mitochondrial phenylalanyl-tRNA synthetase, have been implicated in autosomal recessive combined oxidative phosphorylation deficiency 14. Associated clinical features in three previously reported patients with confirmed FARS2 mutations include infantile onset epilepsy, and a fatal Alpers-like encephalopathy. Herein, we report on two siblings with global developmental delay, dysarthria and tremor and compound heterozygous FARS2 abnormalities. They have a heterozygous missense mutation, c.1255C>T which predicts p.Arg419Cys in exon 7 of FARS2, inherited from their father and uncovered on exome sequencing, and an interstitial deletion of chromosome 6p25.1 inherited from their mother and uncovered on SNP array. This interstitial deletion includes all of exon 6 and parts of introns 5 and 6 of FARS2. Biochemical studies were also consistent with a mitochondrial disorder. While these siblings had considerable developmental difficulties, they are making consistent developmental progress and appear to be considerably less severely affected than the other patients reported in the literature with FARS2 associated mitochondrial disease. Thus, this study expands the phenotypic spectrum of FARS2 related disease and emphasizes intragenic deletion in the list of causative mutations.


Assuntos
Lobo Frontal/fisiopatologia , Mitocôndrias/genética , Doenças Mitocondriais/genética , Fenilalanina-tRNA Ligase/genética , Adolescente , Criança , Pré-Escolar , Exoma/genética , Éxons/genética , Feminino , Lobo Frontal/diagnóstico por imagem , Humanos , Imageamento por Ressonância Magnética , Masculino , Mitocôndrias/enzimologia , Mitocôndrias/patologia , Doenças Mitocondriais/diagnóstico por imagem , Doenças Mitocondriais/fisiopatologia , Mutação de Sentido Incorreto , Linhagem , Radiografia , Irmãos , Substância Branca/diagnóstico por imagem , Substância Branca/fisiopatologia
18.
Brain ; 137(Pt 7): 1921-30, 2014 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-24785942

RESUMO

Hypomyelination with atrophy of the basal ganglia and cerebellum is a rare leukoencephalopathy that was identified using magnetic resonance imaging in 2002. In 2013, whole exome sequencing of 11 patients with the disease revealed that they all had the same de novo mutation in TUBB4A, which encodes tubulin ß-4A. We investigated the mutation spectrum in a cohort of 42 patients and the relationship between genotype and phenotype. Patients were selected on the basis of clinical and magnetic resonance imaging abnormalities that are indicative of hypomyelination with atrophy of the basal ganglia and cerebellum. Genetic testing and a clinical inventory were performed, and sequential magnetic resonance images were evaluated using a standard protocol. The heterozygous TUBB4A mutation observed in the first 11 patients was the most common (25 patients). Additionally, 13 other heterozygous mutations were identified, located in different structural domains of tubulin ß-4A. We confirmed that the mutations were de novo in all but three patients. In two of these three cases we lacked parental DNA and in one the mutation was also found in the mother, most likely due to mosaicism. Patients showed a phenotypic continuum ranging from neonatal to childhood disease onset, normal to delayed early development and slow to more rapid neurological deterioration. Neurological symptomatology consisted of extrapyramidal movement abnormalities, spasticity, ataxia, cognitive deficit and sometimes epilepsy. Three patients died and the oldest living patient was 29 years of age. The patients' magnetic resonance images showed an absent or disappearing putamen, variable cerebellar atrophy and highly variable cerebral atrophy. Apart from hypomyelination, myelin loss was evident in several cases. Three severely affected patients had similar, somewhat atypical magnetic resonance image abnormalities. The study results were strongly suggestive of a genotype-phenotype correlation. The 25 patients with the common c.745G>A mutation generally had a less rapidly progressive disease course than the 17 cases with other TUBB4A mutations. Overall, this work demonstrates that the distinctive magnetic resonance imaging pattern for hypomyelination with atrophy of the basal ganglia and cerebellum defines a homogeneous clinical phenotype of variable severity. Patients almost invariably have prominent extrapyramidal movement abnormalities, which are rarely seen in patients with hypomyelination of different origin. A dominant TUBB4A mutation is also associated with dystonia type 4, in which magnetic resonance images of the brain seem normal. It is highly likely that there is a disease continuum associated with TUBB4A mutations, of which hypomyelination with atrophy of the basal ganglia and cerebellum and dystonia type 4 are the extremes. This would indicate that extrapyramidal movement abnormalities constitute the core feature of the disease spectrum related to dominant TUBB4A mutations and that all other features are variable.


Assuntos
Gânglios da Base/patologia , Cerebelo/patologia , Leucoencefalopatias/patologia , Mutação/genética , Tubulina (Proteína)/genética , Adolescente , Fatores Etários , Atrofia/patologia , Criança , Pré-Escolar , Feminino , Estudos de Associação Genética , Humanos , Lactente , Leucoencefalopatias/genética , Imageamento por Ressonância Magnética , Masculino , Adulto Jovem
19.
Am J Med Genet A ; 164A(7): 1802-7, 2014 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-24706558

RESUMO

Hypomyelination with atrophy of the basal ganglia and cerebellum (H-ABC) has recently been associated with a single heterozygous p.D249N mutation in TUBB4A. We describe two novel mutations in this gene. A p.C239F mutation was found in one of the originally described H-ABC patients, for whom we provide follow-up 11 years after the original publication. The second novel mutation, p.R262H, was found in a patient with a typical clinical presentation for H-ABC, but with a novel neuroimaging phenotype, given the absence of atrophy of the putamen and caudate nucleus despite 7 years of follow-up. The recent recognition of TUBB4A mutations as the underlying etiology of H-ABC will likely lead to the identification of subtler clinical and neuroimaging presentations of this disorder, like in our third patient. Thus mutations in this gene should be suspected in any patient with hypomyelination, regardless of the long-term presence of neostriatal atrophy.


Assuntos
Gânglios da Base/patologia , Cerebelo/patologia , Transtornos Heredodegenerativos do Sistema Nervoso/diagnóstico , Transtornos Heredodegenerativos do Sistema Nervoso/genética , Mutação , Fenótipo , Tubulina (Proteína)/genética , Atrofia , Criança , Feminino , Seguimentos , Heterozigoto , Humanos , Lactente , Imageamento por Ressonância Magnética , Masculino , Neuroimagem , Análise de Sequência de DNA
20.
Semin Neurol ; 34(3): 249-57, 2014 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-25192503

RESUMO

Recently, Mendelian disorders of the DNA methylation machinery have been described which demonstrate the complex roles of epigenetics in neurodevelopment and disease. For example, defects of DNMT1, the maintenance methyltransferase, lead to adult-onset progressive neurologic disorders, whereas defects of the de novo methyltransferases DNMT3A and DNMT3B lead to nonprogressive neurodevelopmental conditions. Furthermore, patients with DNMT3A deficiency demonstrate overgrowth, a feature common to disorders of histone machinery and imprinting disorders, highlighting the interconnectedness of the many epigenetic layers. Disorders of the DNA methylation machinery include both the aforementioned "writers" and also the "readers" of the methyl mark, such as MeCP2, the cause of Rett syndrome. Any dosage disruption, either haploinsufficiency or overexpression of DNA methylation machinery leads to widespread gene expression changes in trans, disrupting expression of a subset of target genes that contribute to individual disease phenotypes. In contrast, classical imprinting disorders such as Angelman syndrome have been thought generally to cause epigenetic dysregulation in cis. However, the recent description of multilocus methylation disorders challenges this generalization. Here, in addition to summarizing recent developments in identifying the pathogenesis of these diseases, we highlight clinical considerations and some unexpected therapeutic opportunities, such as topoisomerase inhibitors for classical imprinting disorders.


Assuntos
Metilação de DNA , Epigênese Genética , Predisposição Genética para Doença/genética , Inteligência/genética , Doenças do Sistema Nervoso/genética , Animais , DNA (Citosina-5-)-Metiltransferases/genética , DNA (Citosina-5-)-Metiltransferases/metabolismo , Humanos , DNA Metiltransferase 3B
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