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1.
J Med Genet ; 57(11): 777-785, 2020 11.
Artigo em Inglês | MEDLINE | ID: mdl-32170003

RESUMO

PURPOSE: To analyse the clinical spectrum, genetic features, specific D4Z4 hypomethylation status and genotype-phenotype correlations for somatic mosaicism in facioscapulohumeral dystrophy (FSHD). METHODS: This was a prospective, hospital-based, case-control, observational study of 35 participants with FSHD with somatic mosaicism recruited over 10 years, with 17 penetrant patients and 18 non-penetrant mutation carriers. This study also included a univariate comparison of 17 paired mosaic and non-mosaic patients with FSHD. RESULTS: Mosaic participants with FSHD varied in age of diagnosis (median 45; range 15-65 years), muscle strength (FSHD clinical score median 0; range 0-10 points), clinical severity (age-corrected clinical severity score (ACSS) median 0; range 0-467 points), D4Z4 repeats (median 3; range 2-5 units), mosaic proportion (median 55%; range 27%-72%) and D4Z4 methylation extent (median 49.82%; range 27.17%-64.51%). The genotypic severity scale and D4Z4 methylation extent were significantly associated with ACSS (p1=0.003; p2=0.002). Among the matched pairs, the 17 mosaic patients had shorter D4Z4 repeats, lower FSHD clinical scores and lower ACSS than non-mosaic patients. Additionally, 34 of 35 (97%) participants carried two mosaic arrays, while a single patient had three mosaic arrays (3%). Two cases also carried four-type non-mosaic arrays on chromosome 10 (translocation configuration). CONCLUSIONS: Broadly, this large mosaic FSHD cohort exhibited significant clinical heterogeneity and relatively slight disease severity. Both genotypic severity scale and D4Z4 hypomethylation status served as modifiers of clinical phenotypes. Consistent with previous reports, mitotic interchromosomal/intrachromosomal gene conversion without crossover was here identified as a major genetic mechanism underlying mosaic FSHD.


Assuntos
Metilação de DNA/genética , Estudos de Associação Genética , Mosaicismo , Distrofia Muscular Facioescapuloumeral/genética , Adolescente , Adulto , Idoso , Cromossomos Humanos Par 4/genética , Feminino , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Distrofia Muscular Facioescapuloumeral/patologia , Linhagem , Fenótipo , Adulto Jovem
2.
Hum Mutat ; 40(12): 2334-2343, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31373411

RESUMO

Intermediate Charcot-Marie-Tooth (CMT) disease is a heterogeneous group of inherited neuropathies characterized by progressive muscle weakness and atrophy of the distal extremities, distal sensory loss. There were still a large proportion of causative genes for intermediate CMT failed to be identified. Here, using whole-exome sequencing technique, we identified two novel missense mutations in ATP1A1 gene, c.620C>T (p.S207F) and c.2629G>A (p.G877S), in two Chinese CMT families. Further functional analysis revealed that these mutations led to the loss function of the ATP1A1 protein. The two mutations did not affect the levels of messenger RNA but possessed a damaging effect on ATP1A1 protein expression and they downregulated the protein levels of ATP1A1 by promoting its proteasome degradation. Taken together, we confirmed ATP1A1 as a novel causative gene for intermediate CMT.


Assuntos
Doença de Charcot-Marie-Tooth/genética , Sequenciamento do Exoma/métodos , Mutação de Sentido Incorreto , ATPase Trocadora de Sódio-Potássio/genética , ATPase Trocadora de Sódio-Potássio/metabolismo , Adulto , Idade de Início , Idoso , Linhagem Celular , Doença de Charcot-Marie-Tooth/metabolismo , China , Regulação para Baixo , Feminino , Células HeLa , Humanos , Masculino , Pessoa de Meia-Idade , Linhagem , Complexo de Endopeptidases do Proteassoma/metabolismo , Proteólise , ATPase Trocadora de Sódio-Potássio/química , Adulto Jovem
5.
Neurol Genet ; 10(3): e200162, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38841628

RESUMO

Background and Objectives: Spinocerebellar ataxia type 3 (SCA3) is a hereditary ataxia that occurs worldwide. Clinical patterns were observed, including the one characterized by marked spastic paraplegia. This study investigated the clinical features, disease progression, and multiparametric imaging aspects of patients with SCA3. Methods: We retrospectively analyzed 249 patients with SCA3 recruited from the Organization for Southeast China for cerebellar ataxia research between October 2014 and December 2020. Of the 249 patients, 145 were selected and assigned to 2 groups based on neurologic examination: SCA3 patients with spastic paraplegia (SCA3-SP) and SCA3 patients with nonspastic paraplegia (SCA3-NSP). Participants underwent 3.0-T brain MRI examinations, and voxel-wise and volume-of-interest-based approaches were used for the resulting images. A tract-based spatial statistical approach was used to investigate the white matter (WM) alterations using diffusion tensor imaging, neurite orientation dispersion, and density imaging metrics. Multiple linear regression analyses were performed to compare the clinical and imaging parameters between the 2 groups. The longitudinal data were evaluated using a linear mixed-effects model. Results: Forty-three patients with SCA3-SP (mean age, 37.58years ± 11.72 [SD]; 18 women) and 102 patients with SCA3-NSP (mean age, 47.42years ± 12.50 [SD]; 39 women) were analyzed. Patients with SCA3-SP were younger and had a lower onset age but a larger cytosine-adenine-guanine repeat number, as well as higher clinical severity scores (all corrected p < 0.05). The estimated progression rates of the Scale for the Assessment and Rating of Ataxia (SARA) and International Cooperative Ataxia Rating Scale scores were higher in the SCA3-SP subgroup than in the SCA3-NSP subgroup (SARA, 2.136 vs 1.218 points; ICARS, 5.576 vs 3.480 points; both p < 0.001). In addition, patients with SCA3-SP showed gray matter volume loss in the precentral gyrus with a decreased neurite density index in the WM of the corticospinal tract and cerebellar peduncles compared with patients with SCA3-NSP. Discussion: SCA3-SP differs from SCA3-NSP in clinical features, multiparametric brain imaging findings, and longitudinal follow-up progression.

6.
J Neurol ; 271(2): 918-928, 2024 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-37848650

RESUMO

BACKGROUND: Many neuroscience and neurology studies have forced a reconsideration of the traditional motor-related scope of cerebellar function, which has now expanded to include various cognitive functions. Spinocerebellar ataxia type 3 (SCA3; the most common hereditary ataxia) is neuropathologically characterized by cerebellar atrophy and frequently presents with cognitive impairment. OBJECTIVE: To characterize cognitive impairment in SCA3 and investigate the cerebellum-cognition associations. METHODS: This prospective, cross-sectional cohort study recruited 126 SCA3 patients and 41 healthy control individuals (HCs). Participants underwent a brain 3D T1-weighted images as well as neuropsychological tests. Voxel-based morphometry (VBM) and region of interest (ROI) approaches were performed on the 3D T1-weighted images. CERES was used to automatically segment cerebellums. Patients were grouped into cognitively impaired (CI) and cognitively preserved (CP), and clinical and MRI parameters were compared. Multivariable regression models were fitted to examine associations between cerebellar microstructural alterations and cognitive domain impairments. RESULTS: Compared to HCs, SCA3 patients showed cognitive domain impairments in information processing speed, verbal memory, executive function, and visuospatial perception. Between CI and CP subgroups, the CI subgroup was older and had lower education, as well as higher severity scores. VBM and ROI analyses revealed volume loss in cerebellar bilateral lobule VI, right lobule Crus I, and right lobule IV of the CI subgroup, and all these cerebellar lobules were associated with the above cognitive domain impairments. CONCLUSIONS: Our findings demonstrate the multiple cognitive domain impairments in SCA3 patients and indicate the responsible cerebellar lobules for the impaired cognitive domain(s).


Assuntos
Disfunção Cognitiva , Doença de Machado-Joseph , Humanos , Cerebelo/diagnóstico por imagem , Disfunção Cognitiva/diagnóstico por imagem , Disfunção Cognitiva/etiologia , Estudos Transversais , Doença de Machado-Joseph/complicações , Doença de Machado-Joseph/diagnóstico por imagem , Imageamento por Ressonância Magnética/métodos , Estudos Prospectivos
7.
Orphanet J Rare Dis ; 18(1): 356, 2023 Nov 16.
Artigo em Inglês | MEDLINE | ID: mdl-37974208

RESUMO

BACKGROUND: Limb-girdle muscular dystrophies (LGMDs) are a group of heterogeneous inherited diseases predominantly characterized by limb-girdle muscle weakness and dystrophic changes on histological analysis. The frequency of LGMD subtypes varies among regions in China and ethnic populations worldwide. Here, we analyzed the prevalence of LGMD subtypes, their corresponding clinical manifestations, and molecular data in a cohort of LGMD patients in Southeast China. METHODS: A total of 81 consecutive patients with clinically suspected LGMDs from 62 unrelated families across Southeast China were recruited for targeted next-generation sequencing and whole-exome sequencing from July 2017 to February 2020. RESULTS: Among 50 patients (41 families) with LGMDs, the most common subtypes were LGMD-R2/LGMD2B (36.6%) and LGMD-R1/LGMD2A (29.3%). Dystroglycanopathies (including LGMD-R9/LGMD2I, LGMD-R11/LGMD2K, LGMD-R14/LGMD2N and LGMD-R20/LGMD2U) were the most common childhood-onset subtypes and were found in 12.2% of the families. A total of 14.6% of the families had the LGMD-R7/LGMD2G subtype, and the mutation c.26_33dupAGGTGTCG in TCAP was the most frequent (83.3%). The only patient with the rare subtype LGMD-R18/LGMD2S had TRAPPC11 mutations; had a later onset than those previously reported, and presented with proximal‒distal muscle weakness, walking aid dependency, fatty liver disease and diabetes at 33 years of age. A total of 22.0% of the patients had cardiac abnormalities, and one patient with LMNA-related muscular dystrophy/LGMD1B experienced sudden cardiac death at 37 years of age. A total of 15.4% of the patients had restrictive respiratory insufficiency. Muscle imaging in patients with LGMD-R1/LGMD2A and LGMD-R2/LGMD2B showed subtle differences, including more severe fatty infiltration of the posterior thigh muscles in those with LGMD-R1/LGMD2A and edema in the lower leg muscles in those with LGMD-R2/LGMD2B. CONCLUSION: We determined the prevalence of different LGMD subtypes in Southeast China, described the detailed clinical manifestations and distinct muscle MRI patterns of these LGMD subtypes and reported the frequent mutations and the cardiorespiratory involvement frequency in our cohort, all of which might facilitate the differential diagnosis of LGMDs, allowing more timely treatment and guiding future clinical trials.


Assuntos
População do Leste Asiático , Distrofia Muscular do Cíngulo dos Membros , Humanos , Criança , Distrofia Muscular do Cíngulo dos Membros/diagnóstico , Músculo Esquelético/patologia , Debilidade Muscular/patologia
8.
Neurology ; 101(3): e225-e237, 2023 07 18.
Artigo em Inglês | MEDLINE | ID: mdl-37225433

RESUMO

BACKGROUND AND OBJECTIVES: The objective of this study was to examine whether the regional methylation levels at the most distal D4Z4 repeat units (RU) in the 4qA-permissive haplotype were associated with disease severity and progression in facioscapulohumeral muscular dystrophy type 1 (FSHD1). METHODS: This 21-year, retrospective, observational cohort study was conducted at the Fujian Neuromedical Center (FNMC) in China. Methylation levels of the most distal D4Z4 RU, including 10 CpGs, were assessed in all participants by bisulfite sequencing. Patients with FSHD1 were stratified into 4 groups based on methylation percentage quartiles, including LM1 (low methylation), LM2 (low to intermediate methylation), LM3 (intermediate to high methylation), and highest methylation (HM) levels. Patients received evaluations of motor function focusing on lower extremity (LE) progression at baseline and in follow-ups. FSHD clinical score (CS), age-corrected clinical severity scale (ACSS), and modified Rankin scale were used to assess motor function. RESULTS: The methylation levels of the 10 CpGs were significantly lower in all 823 patients with genetically confirmed FSHD1 than in 341 healthy controls (HCs). CpG6 methylation levels could distinguish the following: (1) patients with FSHD1 from HCs; (2) symptomatic from asymptomatic/unaffected patients; (3) patients with LE involvement from those without LE involvement, with AUCs (95% CI) of 0.9684 (0.9584-0.9785), 0.7417 (0.6903-0.7931), and 0.6386 (0.5816-0.6956), respectively. Lower CpG6 methylation levels were correlated with higher CS (r = -0.392), higher ACSS (r = -0.432), and earlier onset age of first-ever muscle weakness (r = 0.297). For the LM1, LM2, LM3, and HM groups, the respective proportions of LE involvement were 52.9%, 44.2%, 36.9%, and 23.4%; and onset ages of LE involvement were 20, 26.5, 25, and 26.5 years. Cox regression analysis-adjusted for sex, age at examination, D4Z4 RU, and 4qA/B haplotype-showed that the LM1, LM2, and LM3 groups (i.e., groups with lower methylation levels) had a higher risk of independent ambulation loss, with HRs (95% CI) of 3.523 (1.565-7.930), 3.356 (1.458-7.727), and 2.956 (1.245-7.020), respectively. DISCUSSION: 4q35 distal D4Z4 hypomethylation is correlated with disease severity and progression to lower extremity involvement.


Assuntos
Distrofia Muscular Facioescapuloumeral , Humanos , Distrofia Muscular Facioescapuloumeral/genética , Distrofia Muscular Facioescapuloumeral/diagnóstico , Estudos Retrospectivos , Metilação de DNA/genética , Gravidade do Paciente
9.
Stem Cell Res ; 60: 102678, 2022 04.
Artigo em Inglês | MEDLINE | ID: mdl-35093715

RESUMO

Facioscapulohumeral muscular dystrophy (FSHD) is one of the most common muscular dystrophy. FSHD type 1 (FSHD1) is caused by multicopy contraction of D4Z4 repeats on chromosome 4q35. Human induced pluripotent stem cell (hiPSC) lines serve as important research models for various types of diseases in vitro. Here, we reprogrammed human peripheral blood mononuclear cells (PMBCs) into hiPSCs with episomal plasmid from two FSHD1 patients. These hiPSC lines maintained normal karyotype and exhibited typical morphology. Both of them could express pluripotency markers and differentiate into three layers. The hiPSC lines could be used for screening potential therapeutic targets and mechanism research.


Assuntos
Células-Tronco Pluripotentes Induzidas , Distrofia Muscular Facioescapuloumeral , Adulto , Humanos , Células-Tronco Pluripotentes Induzidas/metabolismo , Leucócitos Mononucleares/metabolismo , Distrofia Muscular Facioescapuloumeral/genética , Distrofia Muscular Facioescapuloumeral/metabolismo
10.
Lancet Reg Health West Pac ; 18: 100323, 2022 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-35024656

RESUMO

BACKGROUND: Facioscapulohumeral muscular dystrophy type 1 (FSHD1) is a rare disease, which is often underdiagnosed due to its heterogeneous presentations and complex molecular genetic basis, leading to a lack of population-based epidemiology data, especially of prevalence and disease progression. METHODS: Fujian Neuromedical Centre (FNMC) is a diagnosis centre for clinical-genetic FSHD in China, and the only one employing pulsed-field gel electrophoresis (PFGE)-based Southern blotting for all FSHD1 genetic tests. Three sources distributed across all six spatial zones in China, were used to obtain information regarding FSHD1 events, namely, FNMC, Genetic and Myopathy Group (branches of the Neurology Society of the Chinese Medical Association), and "FSHD-China" (an organization supported by FSHD patients). During 2001-2020, all genetically-confirmed FSHD1 from China were registered in FNMC. Follow-up was conducted in the 20-year period to obtain data on disease progression, which was mainly described in terms of independent ambulation loss. FINDINGS: Of the 1,744 FSHD1 genetic tests (total test number 1,802) included in the analysis, 997 (57.2%) patients from 620 families were diagnosed with FSHD1. The estimated prevalence of genetically-confirmed FSHD1 in China is 0.75 per million (95% confidence interval [CI], 0.70-0.79) during 2001-2020, with 0.78 (95% CI, 0.72-0.85) in males and 0.71 (95% CI, 0.65-0.78) in females. The estimated prevalence increased from 0.22 (95% CI, 0.19-0.26) per million in 2001-2015 to 0.53 (95% CI, 0.49-0.57) per million in 2016-2020 (p < 0.001). The prevalence in Fujian province was 7.10 per million, 4.66 per million, and 2.44 per million, during 2001-2020, 2001-2015, and 2016-2020, respectively. Among the 861 symptomatic plus asymptomatic patients of the total 997 patients, the median onset age at first-ever muscle weakness was 16 years of age (range 1-81); the median number of contracted D4Z4 repeats was 5 units (range 1-9); the median 4qA-allele-specific methylation level was 41% (range 14%-69%). Of the 977 symptomatic patients followed-up during 2001-2020, 117 patients (12.0%) lost independent ambulation. The expected duration from onset of first-ever muscle weakness to onset of independent ambulation loss was 40 years. The group with loss of independent ambulation had a smaller number of contracted D4Z4 repeats (p < 0.001) and had an earlier onset age of first-ever muscle weakness (p < 0.001) compared to the group without loss of independent ambulation. INTERPRETATION: Our research captures the largest genetically-confirmed FSHD1 population worldwide, to calculate its prevalence of 0.75 per million in China from 2001 to 2020. Approximately 12.0% of symptomatic plus asymptomatic patients of FSHD1 will lose independent ambulation in 40 years from onset of first-ever muscle weakness. FUNDING: This work has been supported by the grants (U2005201, 81870902, N.W.) and (81974193, 81671237, Z.Q.W.) from the National Natural Science Foundation of China; Joint Funds for the Innovation of Science and Technology of Fujian Province (2018Y9082) (N.W.), and the Key Clinical Specialty Discipline Construction Program of Fujian (N.W.).

11.
Neuromuscul Disord ; 30(2): 137-143, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-32005491

RESUMO

Limb girdle muscular dystrophy LGMD R7 telethonin-related is a rare autosomal recessive muscle disorder characterized by proximal muscle weakness of pelvic and shoulder girdles. Mutation in TCAP is responsible for LGMD R7, and the disease has a wide geographic distribution in diverse populations, but genotype-phenotype relationships remain unclear. We collected 5 LGMD R7 patients from three unrelated Chinese families. The average onset age was 16 ± 1.41; the initial symptoms included progressive proximal muscle weakness in limbs, difficulty in fast running, and asymmetric muscle atrophy in calves. Muscle MR imaging showed varying severity of fatty infiltration in the pelvic girdle, thigh, and calf muscles, and the severity of muscle infiltration was related to the length of the disease course. Muscle histopathology revealed aberrantly sized muscle fibers, internal nuclei, split fibers, rimmed vacuoles, monocyte invasion, and necrotic fibers. Sequencing identified one novel and one previously reported TCAP mutation. Our study extends the known distribution of this rare muscular dystrophy and presents the first detailed clinical and genetic characterizations of LGMD R7 cases from the Chinese population. Our work expands the mutation spectrum known for LGMD R7 and emphasizes the need for clinicians to consider TCAP mutations when evaluating patients with symptoms of limb girdle muscular dystrophy.


Assuntos
Conectina/genética , Músculo Esquelético/patologia , Distrofia Muscular do Cíngulo dos Membros , Adulto , Idade de Início , China , Feminino , Humanos , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Músculo Esquelético/diagnóstico por imagem , Distrofia Muscular do Cíngulo dos Membros/genética , Distrofia Muscular do Cíngulo dos Membros/patologia , Distrofia Muscular do Cíngulo dos Membros/fisiopatologia , Linhagem
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