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1.
J Med Genet ; 60(6): 578-586, 2023 06.
Artigo em Inglês | MEDLINE | ID: mdl-36319078

RESUMO

PURPOSE: In this study, we describe the phenotype and genotype of the largest cohort of patients with Joubert syndrome (JS) carrying pathogenic variants on one of the most frequent causative genes, CC2D2A. METHODS: We selected 53 patients with pathogenic variants on CC2D2A, compiled and analysed their clinical, neuroimaging and genetic information and compared it to previous literature. RESULTS: Developmental delay (motor and language) was nearly constant but patients had normal intellectual efficiency in 74% of cases (20/27 patients) and 68% followed mainstream schooling despite learning difficulties. Epilepsy was found in only 13% of cases. Only three patients had kidney cysts, only three had genuine retinal dystrophy and no subject had liver fibrosis or polydactyly. Brain MRIs showed typical signs of JS with rare additional features. Genotype-phenotype correlation findings demonstrate a homozygous truncating variant p.Arg950* linked to a more severe phenotype. CONCLUSION: This study contradicts previous literature stating an association between CC2D2A-related JS and ventriculomegaly. Our study implies that CC2D2A-related JS is linked to positive neurodevelopmental outcome and low rate of other organ defects except for homozygous pathogenic variant p.Arg950*. This information will help modulate patient follow-up and provide families with accurate genetic counselling.


Assuntos
Anormalidades Múltiplas , Anormalidades do Olho , Doenças Renais Císticas , Humanos , Cerebelo/diagnóstico por imagem , Cerebelo/patologia , Doenças Renais Císticas/diagnóstico , Doenças Renais Císticas/genética , Anormalidades Múltiplas/genética , Anormalidades Múltiplas/patologia , Anormalidades do Olho/diagnóstico , Anormalidades do Olho/genética , Anormalidades do Olho/patologia , Retina/diagnóstico por imagem , Retina/patologia , Proteínas do Citoesqueleto
2.
J Med Genet ; 59(7): 669-677, 2022 07.
Artigo em Inglês | MEDLINE | ID: mdl-34321324

RESUMO

BACKGROUND: Variants in HECW2 have recently been reported to cause a neurodevelopmental disorder with hypotonia, seizures and impaired language; however, only six variants have been reported and the clinical characteristics have only broadly been defined. METHODS: Molecular and clinical data were collected from clinical and research cohorts. Massive parallel sequencing was performed and identified individuals with a HECW2-related neurodevelopmental disorder. RESULTS: We identified 13 novel missense variants in HECW2 in 22 unpublished cases, of which 18 were confirmed to have a de novo variant. In addition, we reviewed the genotypes and phenotypes of previously reported and new cases with HECW2 variants (n=35 cases). All variants identified are missense, and the majority of likely pathogenic and pathogenic variants are located in or near the C-terminal HECT domain (88.2%). We identified several clustered variants and four recurrent variants (p.(Arg1191Gln);p.(Asn1199Lys);p.(Phe1327Ser);p.(Arg1330Trp)). Two variants, (p.(Arg1191Gln);p.(Arg1330Trp)), accounted for 22.9% and 20% of cases, respectively. Clinical characterisation suggests complete penetrance for hypotonia with or without spasticity (100%), developmental delay/intellectual disability (100%) and developmental language disorder (100%). Other common features are behavioural problems (88.9%), vision problems (83.9%), motor coordination/movement (75%) and gastrointestinal issues (70%). Seizures were present in 61.3% of individuals. Genotype-phenotype analysis shows that HECT domain variants are more frequently associated with cortical visual impairment and gastrointestinal issues. Seizures were only observed in individuals with variants in or near the HECT domain. CONCLUSION: We provide a comprehensive review and expansion of the genotypic and phenotypic spectrum of HECW2 disorders, aiding future molecular and clinical diagnosis and management.


Assuntos
Deficiência Intelectual , Transtornos do Neurodesenvolvimento , Ubiquitina-Proteína Ligases , Genótipo , Humanos , Deficiência Intelectual/genética , Hipotonia Muscular/genética , Hipotonia Muscular/patologia , Transtornos do Neurodesenvolvimento/genética , Fenótipo , Convulsões/genética , Ubiquitina-Proteína Ligases/genética
3.
Ann Neurol ; 87(4): 609-617, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-31995250

RESUMO

OBJECTIVE: GM2 gangliosidoses are lysosomal diseases due to biallelic mutations in the HEXA (Tay-Sachs disease [TS]) or HEXB (Sandhoff disease [SD]) genes, with subsequent low hexosaminidase(s) activity. Most patients have childhood onset, but some experience the first symptoms during adolescence/adulthood. This study aims to clarify the natural history of adult patients with GM2 gangliosidosis. METHODS: We retrospectively described 12 patients from a French cohort and 45 patients from the literature. RESULTS: We observed 4 typical presentations: (1) lower motoneuron disorder responsible for proximal lower limb weakness that subsequently expanded to the upper limbs, (2) cerebellar ataxia, (3) psychosis and/or severe mood disorder (only in the TS patients), and (4) a complex phenotype mixing the above 3 manifestations. The psoas was the first and most affected muscle in the lower limbs, whereas the triceps and interosseous were predominantly involved in the upper limbs. A longitudinal study of compound motor action potentials showed a progressive decrease in all nerves, with different kinetics. Sensory potentials were sometimes abnormally low, mainly in the SD patients. The main brain magnetic resonance imaging feature was cerebellar atrophy, even in patients without cerebellar symptoms. The prognosis was mainly related to gait disorder, as we showed that beyond 20 years of disease evolution, half of the patients were wheelchair users. INTERPRETATION: Improved knowledge of GM2 gangliosidosis in adults will help clinicians achieve correct diagnoses and better inform patients on the evolution and prognosis. It may also contribute to defining proper outcome measures when testing emerging therapies. ANN NEUROL 2020;87:609-617.


Assuntos
Doença de Sandhoff/fisiopatologia , Doença de Tay-Sachs/fisiopatologia , Potenciais de Ação , Adolescente , Adulto , Idade de Início , Idoso , Atrofia , Encéfalo/diagnóstico por imagem , Encéfalo/patologia , Cerebelo/diagnóstico por imagem , Cerebelo/patologia , Criança , Disfunção Cognitiva/fisiopatologia , Disfunção Cognitiva/psicologia , Estudos de Coortes , Transtornos de Deglutição/fisiopatologia , Progressão da Doença , Disartria/fisiopatologia , Distonia/fisiopatologia , Eletrodiagnóstico , Eletromiografia , Feminino , Marcha Atáxica/fisiopatologia , Gangliosidoses GM2/diagnóstico por imagem , Gangliosidoses GM2/fisiopatologia , Gangliosidoses GM2/psicologia , Humanos , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Doença dos Neurônios Motores/fisiopatologia , Espasticidade Muscular/fisiopatologia , Debilidade Muscular/fisiopatologia , Condução Nervosa , Doença de Sandhoff/diagnóstico por imagem , Doença de Sandhoff/psicologia , Doença de Tay-Sachs/diagnóstico por imagem , Doença de Tay-Sachs/psicologia , Adulto Jovem
4.
Eur J Hum Genet ; 26(7): 996-1006, 2018 07.
Artigo em Inglês | MEDLINE | ID: mdl-29695756

RESUMO

High-throughput sequencing (HTS) of human genome coding regions allows the simultaneous screen of a large number of genes, significantly improving the diagnosis of non-syndromic intellectual disabilities (ID). HTS studies permit the redefinition of the phenotypical spectrum of known disease-causing genes, escaping the clinical inclusion bias of gene-by-gene Sanger sequencing. We studied a cohort of 903 patients with ID not reminiscent of a well-known syndrome, using an ID-targeted HTS of several hundred genes and found de novo heterozygous variants in TCF4 (transcription factor 4) in eight novel patients. Piecing together the patients from this study and those from previous large-scale unbiased HTS studies, we estimated the rate of individuals with ID carrying a disease-causing TCF4 mutation to 0.7%. So far, TCF4 molecular abnormalities were known to cause a syndromic form of ID, Pitt-Hopkins syndrome (PTHS), which combines severe ID, developmental delay, absence of speech, behavioral and ventilation disorders, and a distinctive facial gestalt. Therefore, we reevaluated ten patients carrying a pathogenic or likely pathogenic variant in TCF4 (eight patients included in this study and two from our previous ID-HTS study) for PTHS criteria defined by Whalen and Marangi. A posteriori, five patients had a score highly evocative of PTHS, three were possibly consistent with this diagnosis, and two had a score below the defined PTHS threshold. In conclusion, these results highlight TCF4 as a frequent cause of moderate to profound ID and broaden the clinical spectrum associated to TCF4 mutations to nonspecific ID.


Assuntos
Sequenciamento de Nucleotídeos em Larga Escala , Hiperventilação/genética , Deficiência Intelectual/genética , Fator de Transcrição 4/genética , Adolescente , Adulto , Criança , Pré-Escolar , Fácies , Feminino , Humanos , Hiperventilação/diagnóstico , Hiperventilação/patologia , Deficiência Intelectual/diagnóstico , Deficiência Intelectual/patologia , Masculino , Mutação , Fenótipo , Adulto Jovem
5.
J Med Genet ; 54(12): 843-851, 2017 12.
Artigo em Inglês | MEDLINE | ID: mdl-28954837

RESUMO

BACKGROUND: Phosphomannomutase 2-congenital disorder of glycosylation (PMM2-CDG) is a multisystem inborn error of metabolism. OBJECTIVES: To better characterise the natural history of PMM2-CDG. METHODS: Medical charts of 96 patients with PMM2-CDG (86 families, 41 males, 55 females) were retrospectively reviewed. Data on clinical, laboratory and molecular parameters at diagnosis were analysed. Follow-up data at last examination were reported for 25 patients. RESULTS: The patients were born between 1963 and 2011. Diagnosis of PMM2-CDG was made at a mean (SD) age of 6.8 (8.5) years. The presenting signs were mostly neurological (hypotonia, intellectual disability, cerebellar syndrome) and observed in almost all the patients. A total of 38 patients (14 males, 24 females) exhibited, in addition to neurological signs, visceral features including at least one of these: feeding difficulty requiring a nutritional support (n=23), cardiac features (n=20; pericarditis: 14, cardiac malformation: 9, cardiomyopathy: 2), hepato-gastrointestinal features (n=12; chronic diarrhoea: 7, protein-losing enteropathy: 1, ascites: 3, liver failure: 1, portal hypertension: 1), kidney features (n=4; nephrotic syndrome: 2, tubulopathy: 2) and hydrops fetalis (n=1). Twelve patients died at a mean age of 3.8 years (especially from pericarditis and other cardiac issues). Laboratory abnormalities mostly included elevated transaminases and abnormal coagulation parameters. High thyreostimulin levels, hypocholesterolemia, hypoalbuminemia and elevated transaminases were associated with the visceral phenotype. Besides the common Arg141His PMM2 variant harboured by half of the patients, 45 different variants were observed. CONCLUSIONS: PMM2-CDG clinical phenotype is heterogeneous in terms of clinical course, with no clear division between neurological and visceral presentations.


Assuntos
Defeitos Congênitos da Glicosilação/diagnóstico , Defeitos Congênitos da Glicosilação/genética , Estudos de Associação Genética , Fosfotransferases (Fosfomutases)/genética , Adolescente , Alelos , Substituição de Aminoácidos , Criança , Pré-Escolar , Defeitos Congênitos da Glicosilação/mortalidade , Feminino , Seguimentos , Humanos , Lactente , Masculino , Mutação , Fenótipo , Fosfotransferases (Fosfomutases)/metabolismo
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