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1.
Clin Genet ; 96(3): 207-215, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31066047

RESUMO

Congenital muscular dystrophies (CMDs) are clinically and genetically heterogeneous conditions. We launched a nationwide study to determine the frequency of CMD in the Chinese population and assess the status of diagnosis and disease management for CMD in China. Cases were chosen from databases in 34 tertiary academic hospitals from 29 first-level administrative divisions (provinces, municipalities, autonomous regions, and special administrative regions), and medical records were reviewed to confirm the diagnoses. The study included 409 patients, of those patients who consented to genetic testing (n = 340), mutations were identified in 286 of them. The most common forms identified were LAMA2-related CMD (36.4%), followed by COL6-related CMD (23.2%) and α-dystroglycanopathy (21.0%). The forms of CMD related to mutations in LMNA and SEPN1 were less frequent (12.5% and 2.4%, respectively). We also recorded a significant difference in the diagnostic capabilities and disease management of CMD, with this being relatively backward in research centers from less developed regions. We provide, for the first time, comprehensive epidemiologic information of CMD in a large cohort of Chinese people. To our knowledge, this is the largest sample size of its kind so far highlighting the prevalence of CMD in China.

2.
Sci Rep ; 8(1): 14989, 2018 Oct 09.
Artigo em Inglês | MEDLINE | ID: mdl-30301903

RESUMO

Although recessive mutations in LAMA2 are already known to cause laminin α2-related muscular dystrophy, a rare neuromuscular disorder, large deletions or duplications within this gene are not well-characterized. In this study, we applied next-generation sequencing-based copy number variation profiling in 114 individuals clinically diagnosed with laminin α2-related muscular dystrophy, including 96 who harboured LAMA2 mutations and 34 who harboured intragenic rearrangements. In total, we detected 18 distinct LAMA2 copy number variations that have been reported only among Chinese, 10 of which are novel. The frequency of CNVs in the cohort was 19.3%. Deletion of exon 4 was detected in 10 alleles of eight patients, accounting for 27% of all copy number variations. These patients are Han Chinese and were found to have the same haplotype and sequence at the breakpoint junction, suggesting that exon 4 deletion is a founder mutation in Chinese Han and a mutation hotspot. Moreover, the data highlight our approach, a modified next-generation sequencing assay, as a robust and sensitive tool to detect LAMA2 variants; the assay identifies 85.7% of breakpoint junctions directly alongside sequence information. The method can be applied to clinical samples to determine causal variants underlying various Mendelian disorders.

3.
Sci Rep ; 8(1): 6254, 2018 Apr 19.
Artigo em Inglês | MEDLINE | ID: mdl-29674629

RESUMO

Clinically, some patients having genetic (idiopathic) epilepsy with photosensitive seizures were difficult to be diagnosed. We aimed to discuss whether the genetic (idiopathic) epilepsy with photosensitive seizures is a focal entity, a generalized entity or a continuum. Twenty-two patients with idiopathic epilepsies and photoconvulsive response (PCR) were retrospectively recruited. In the medical records, the seizure types included "generalized tonic-clonic seizures (GTCS)" in 15, "partial secondarily GTCS (PGTCS)" in 3, partial seizures (PS) in 3, myoclonic seizures in 2, eyelid myoclonus in one, and only febrile seizures in one. Seizure types of PCR included GTCS (1/22), PGTCS (6/22), PS (9/22), electrical seizures (ES) (3/22) and GTCS/PGTCS (3/22). Combined the medical history with PCR results, they were diagnosed as: idiopathic (photosensitive) occipital lobe epilepsy (I(P)OE) in 12, genetic (idiopathic) generalized epilepsy (GGE) in one, GGE/I(P)OE in 5, pure photosensitive seizure in one, and epilepsy with undetermined generalized or focal seizure in 3. So, the dichotomy between generalized and focal seizures might have been out of date regarding to pathophysiological advances in epileptology. To some extent, it would be better to recognize the idiopathic epilepsy with photosensitive seizures as a continuum between focal and generalized seizures.

4.
Brain Dev ; 40(4): 299-310, 2018 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-29307466

RESUMO

OBJECTIVE: To investigate high-frequency oscillations (HFOs) in epileptic encephalopathy with continuous spike-and-wave during sleep (CSWS) with different etiologies. METHODS: Twenty-one CSWS patients treated with methylprednisolone were divided into structural group and genetic/unknown group. Comparisons were made between the two etiological groups: selected clinical variables including gender, age parameters, seizure frequencies and antiepileptic drugs; distribution of HFOs in pre-methylprednisolone electroencephalography (EEG) and percentage changes of HFOs and spikes after methylprednisolone treatment. RESULTS: There were 7 patients (33%) in structural group and 14 patients (68%) in genetic/unknown group. No significant difference was found between the two groups regarding selected clinical variables. HFOs were found in 12 patients in pre-methylprednisolone EEG. The distribution of HFOs was focal and accordant with lesions in 5 of structural group, and it was also focal but in different brain regions in 7 of genetic/unknown group. The percentage reduction of total HFOs and spikes was 81% (158/195) and 19% (1956/10,037) in structural group, while 98% (315/323) and 55% (6658/12,258) in genetic/unknown group after methylprednisolone treatment. CONCLUSION: The etiologies had no distinct correlation with some clinical characteristics in CSWS. HFOs recorded on scalp EEG might not only be used as makers of seizure-onset zone (SOZ), but also have association with functional disruption of brain networks. Both HFOs and spikes reduced more in genetic/unknown patients than that in structural patients after methylprednisolone treatment and HFOs were more sensitive to treatment than spikes.


Assuntos
Encéfalo/fisiopatologia , Eletroencefalografia , Epilepsia/etiologia , Epilepsia/fisiopatologia , Sono/fisiologia , Adolescente , Anticonvulsivantes/uso terapêutico , Encéfalo/efeitos dos fármacos , Criança , Pré-Escolar , Epilepsia/tratamento farmacológico , Feminino , Humanos , Masculino , Metilprednisolona/uso terapêutico , Couro Cabeludo , Sono/efeitos dos fármacos , Resultado do Tratamento
5.
Sci Rep ; 7(1): 7056, 2017 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-28765568

RESUMO

The protein O-mannose beta-1,2-N-acetylglucosaminyltransferase 1 (POMGNT1) gene is one of 18 genes involved in the pathogenesis of α-dystroglycanopathies(α-DGPs) such as muscle-eye-brain disease (MEB). Our study aimed to retrospectively analyze and characterize the clinical and genetic features of three MEB patients with POMGNT1 mutations. One female and two male patients from three unrelated families were diagnosed with MEB, manifesting hypotonia at birth, mental retardation, structural brain defects, and ocular malformations. The novel missense mutations c.296 T > C and c.794 G > C were revealed in patient 2 and patient 3 respectively by next-generation sequencing (NGS). Further NGS data analysis revealed that all three patients had the same novel copy number variations (CNV) g.6668-8257del, which was homozygous in patient 1 and heterozygous in patients 2 and 3. By long-range polymerase chain reaction (PCR) and Sanger sequencing, it was shown that the two breakpoints of the CNV localized to two AluY elements and displayed 42-bp of microhomology. The CNV was confirmed as a founder mutation by haplotype analysis. Our study indicated that NGS is a clinically useful method of detecting α-DGPs genes -related CNV, and the CNV is likely to be caused by Alu-Alu recombination or from a single ancestor bearing the deletion chromosome.

6.
Clin Neurophysiol ; 128(1): 220-226, 2017 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-27940146

RESUMO

OBJECTIVE: To study the atonic elements combined or uncombined with epileptic spasms in infantile spasms. METHODS: The demographic data, clinical characteristics, electroencephalogram (EEG), and polyelectromyography (PEMG) features were analyzed in 12 infantile spasm patients with atonic elements. RESULTS: A total of 29 EEGs were recorded. Hypsarrhythmia or hypsarrhythmia variants were identified during interictal EEG. Insular or clustered epileptic spasms occurred in all. Three subtypes of atonic elements combined or uncombined with epileptic spasms (spasm-atonic, pure atonic, and atonic-spasm seizures) were observed electroclinically, which could present insularly or in cluster or altered with epileptic spasms in the same cluster. The ictal EEG showed generalized high-amplitude slow waves presenting alone or combined with other patterns. The corresponding PEMG showed an obvious electrical silence alone or preceding or following a crescendo-decrescendo pattern generated from myoelectric burst. CONCLUSIONS: Atonic elements combined or uncombined with epileptic spasms was a newly noticed phenomenon in infantile spasms, which was artificially divided into three subtypes here. It might be a variant of epileptic spasms or a unique seizure type. SIGNIFICANCE: Atonic elements combined or uncombined with epileptic spasms was a previously ignored phenomenon in infantile spasms, which should be seriously considered in clinical practice.


Assuntos
Eletroencefalografia/métodos , Eletromiografia/métodos , Epilepsia Tipo Ausência/diagnóstico , Epilepsia Tipo Ausência/fisiopatologia , Espasmos Infantis/diagnóstico , Espasmos Infantis/fisiopatologia , Epilepsia Tipo Ausência/epidemiologia , Feminino , Seguimentos , Humanos , Lactente , Recém-Nascido , Masculino , Estudos Retrospectivos , Espasmos Infantis/epidemiologia
7.
J Hum Genet ; 61(12): 1013-1020, 2016 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-27439679

RESUMO

Mutations in the fukutin-related protein (FKRP) gene have been associated with dystroglycanopathies, which are common in Europe but rare in Asia. Our study aimed to retrospectively analyze and characterize the clinical, myopathological and genetic features of 12 Chinese patients with FKRP mutations. Three patients were diagnosed with congenital muscular dystrophy type 1C (MDC1C) and nine patients were diagnosed with limb girdle muscular dystrophy type 2I (LGMD2I). Three muscle biopsy specimens had dystrophic changes and reduced glycosylated α-dystroglycan staining, and two showed reduced expression of laminin α2. Two known and 13 novel mutations were identified in our single center cohort. Interestingly, the c.545A>G mutation was found in eight of the nine LGMD2I patients as a founder mutation and this founder mutation in Chinese patients differs from the one seen in European patients. Moreover, patients homozygous for the c.545A>G mutation were clinically asymptomatic, a less severe phenotype than in compound heterozygous patients with the c.545A>G mutation. The 13 novel mutations of FKRP significantly expanded the mutation spectrum of MDC1C and LGMD2I, and the different founder mutations indicate the ethnic difference in FKRP mutations.


Assuntos
Efeito Fundador , Estudos de Associação Genética , Mutação , Fenótipo , Proteínas/genética , Adolescente , Biópsia , Encéfalo/patologia , Criança , Pré-Escolar , Feminino , Genótipo , Haplótipos , Humanos , Lactente , Imagem por Ressonância Magnética , Masculino , Músculo Esquelético/patologia , Distrofias Musculares/diagnóstico , Distrofias Musculares/genética , Distrofia Muscular do Cíngulo dos Membros/diagnóstico , Distrofia Muscular do Cíngulo dos Membros/genética
8.
J Hum Genet ; 61(8): 753-9, 2016 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-27193224

RESUMO

Protein O-mannosyltransferase 1 (POMT1) is a glycosyltransferase involved in α-dystroglycan glycosylation. POMT1 mutations cause a wide spectrum of clinical conditions from Walker-Warburg syndrome (WWS), which involves muscle, eye and brain abnormalities, to mild forms of limb-girdle muscular dystrophy with mental retardation. We aimed to elucidate the impact of different POMT1 mutations on the clinical phenotype. We report five Chinese patients with POMT1 mutations: one had a typical clinical manifestation of WWS, and the other four were diagnosed with congenital muscular dystrophy with mental retardation of varying severity. We analyzed the influence of the POMT1 mutations on POMT activity by assaying the patients' muscles and cultured skin fibroblasts. We demonstrated different levels of decreased POMT activity that correlated highly with decreased α-dystroglycan glycosylation. Our results suggest that POMT activity is inversely proportional to clinical severity, and demonstrate that skin fibroblasts can be used for differential diagnosis of patients with α-dystroglycanopathies. We have provided clinical, histological, enzymatic and genetic evidence of POMT1 involvement in five unrelated Chinese patients.


Assuntos
Estudos de Associação Genética , Genótipo , Manosiltransferases/genética , Manosiltransferases/metabolismo , Mutação , Fenótipo , Adolescente , Criança , Pré-Escolar , Análise Mutacional de DNA , Ecocardiografia , Ativação Enzimática , Feminino , Humanos , Lactente , Imagem por Ressonância Magnética , Masculino , Músculo Esquelético/metabolismo , Músculo Esquelético/patologia , Distrofias Musculares/diagnóstico , Distrofias Musculares/enzimologia , Distrofias Musculares/genética , Gravidez , Diagnóstico Pré-Natal
9.
Brain Dev ; 38(2): 242-9, 2016 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-26304763

RESUMO

PURPOSE: LAMA2-related muscular dystrophy (LAMA2 MD) is an autosomal recessive inherited disease caused by LAMA2 gene mutation. The spectrum of the phenotype is expanding in recent years partially due to the definitive diagnosis of molecular genetics. We investigated the phenotype and genotype in a LAMA2 MD family manifesting as limb-girdle muscular dystrophy (LGMD). METHODS: The clinical information of the proband and his family was collected. Muscle biopsy and immunohistochemical staining for the muscle specimen were performed. The genomic DNA of the family was extracted from the peripheral blood, and genetic testing was analyzed using the next generation sequencing and multiplex ligation dependent probe amplification (MLPA). The point mutation was verified by Sanger sequencing while exonic deletion was verified by array comparative genomic hybridization. RESULTS: The patient had mild motor retardation when he was young, and no obvious weakness was reported. Muscle biopsy showed mild atrophy in histochemical staining. Immunohistochemical staining using antibody against merosin showed nearly normal expression surrounding the muscle fiber. The proband's sister had similar symptoms. By analyzing the gene test we found that compound heterozygous LAMA2 mutation inherited from the parents respectively. One coming from the father was a gross deletion expanding from exon 36 to exon 65. The other from the mother was a missense mutation c.1358G>C (p.Cys453Ser). Sanger sequencing verified the point mutation. Array comparative genomic hybridization confirmed a long stretch of deletion about 27.6-34.7 kb. The sister had the same mutations as the proband. We diagnosed the first late onset LAMA2 MD Chinese patients on molecular level and genetic counseling is available. CONCLUSION: We investigated the phenotype and genotype in a family manifesting as limb-girdle muscular dystrophy (LGMD). This LAMA2 MD family manifesting as LGMD was identified in molecular genetic level and their phenotypes was described.


Assuntos
Laminina/genética , Distrofia Muscular do Cíngulo dos Membros/genética , Adulto , Grupo com Ancestrais do Continente Asiático/genética , Sequência de Bases , Criança , Pré-Escolar , Hibridização Genômica Comparativa , Éxons , Feminino , Estudos de Associação Genética , Testes Genéticos , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Masculino , Pessoa de Meia-Idade , Dados de Sequência Molecular , Linhagem , Mutação Puntual , Deleção de Sequência
10.
Zhonghua Er Ke Za Zhi ; 53(6): 436-41, 2015 Jun.
Artigo em Chinês | MEDLINE | ID: mdl-26310554

RESUMO

OBJECTIVE: To summarize clinical features and diagnosis of Chinese infantile patients with glycogen storage disease type II (GSD II). METHOD: Six infant patients with GSD II diagnosed from January 2012 to June 2014 in the Department of Pediatrics, Peking University First Hospital were enrolled into this study. Clinical information of the 6 patients, including clinical manifestation, blood biochemistry, chest X-ray, echocardiogram, electrocardiogram, acid alpha-glucosidase (GAA) activity and GAA gene mutation analysis by direct sequencing of polymerase chain reaction (PCR) product were reviewed. RESULT: Of the 6 patients, five were female and one was male, five of whom were classic infantile type while the other one was atypical. The age of onset ranged from birth to 3-month-old. All patients had varying degrees of generalized muscle weakness, hypotonia and development retardation or retrogression. Other common findings were feeding difficulties in two patients, tongue weakness in two patients, respiratory distress in four patients, macroglossia in one patient, and hepatomegaly in two patients. Left ventricular hypertrophy and cardiomegaly were obvious in all the six patients. All six patients were found to have a enlarged heart in physical examination, and three patients who underwent a chest X-ray examination had an enlarged heart shadow. Four patients who had an echocardiography were found to have myocardial hypertrophy. The electrocardiogram in three patients showed short PR intervals and high voltage. The creatine kinase (CK) levels were three to seven times elevated. The mildest elevated CK was 441 IU/L, and the highest CK level was 1 238 U/L. Assay of GAA enzyme activity in whole blood showed significantly reduced activity (1.3 nmol/ (spot·d) to 2 nmol/(spot·d)) in the patients tested. Gene sequencing in 4 patients showed 8 pathogenic mutations, including 6 missense mutations, one nonsense mutation and one frameshift mutation. The missense mutations were c.998C > A (p.Thr333Lys), c.1280T > C (p.Met427Thr), c.1760T > C (p.Leu587Pro), c.1924G > T (p.Val642Phe), c.2012T > A (p.Met671Lys) and c.2105G > A (p.Arg702His). The nonsense mutation was c2662G > T (p.Glu888X), and the frameshift mutation was c2812_2813delTG (p.Cys938fs). The 5 classic infantile patients died at the age of 7 to 22 months. The atypical infantile patient was 2 years and five months old according to our latest follow up. CONCLUSION: Infantile GSD II had similar motor manifestations and cardiac involvements, blood biochemical test, imaging findings, enzyme assays, though there were slight differences. The probability of GSD II should be taken into consideration if an infant has both muscular disease and cardiac involvement.


Assuntos
Doença de Depósito de Glicogênio Tipo II/diagnóstico , Doença de Depósito de Glicogênio Tipo II/patologia , Grupo com Ancestrais do Continente Asiático , Feminino , Humanos , Lactente , Recém-Nascido , Macroglossia/congênito , Masculino , Debilidade Muscular , Mutação , Mutação de Sentido Incorreto , Reação em Cadeia da Polimerase , alfa-Glucosidases/genética , alfa-Glucosidases/metabolismo
11.
PLoS One ; 10(6): e0129699, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-26098624

RESUMO

This study aimed to analyze the correlation between the phenotype and genotype of Chinese patients with early-onset lamin A (LMNA)-related muscular dystrophy (MD). The clinical and myopathological data of 21 Chinese pediatric patients with early-onset LMNA-related MD were collected and analyzed. LMNA gene mutation analysis was performed by direct sequencing of genomic DNA. Sublocalization of wild-type and mutant proteins were observed by immunofluorescence using cultured fibroblasts and human embryonic kidney 293 (HEK 293) cell. Seven patients were diagnosed with Emery-Dreifuss muscular dystrophy (EDMD) and 14 were diagnosed with LMNA-associated congenital muscular dystrophy (L-CMD). Four biopsy specimens from the L-CMD cases exhibited inflammatory changes. Abnormal nuclear morphology was observed with both transmission electron microscopy and lamin A/C staining. We identified 10 novel and nine known LMNA gene mutations in the 21 patients. Some mutations (c.91G>A, c.94_96delAAG, c.116A>G, c.745C>T, c.746G>A, and c.1580G>C) were well correlated with EDMD or L-CMD. LMNA-related MD has a common symptom triad of muscle weakness, joint contractures, and cardiac involvement, but the severity of symptoms and disease progression differ greatly. Inflammatory change in biopsied muscle is a characteristic of early-stage L-CMD. Phenotype-genotype analysis determines that some mutations are well correlated with LMNA-related MD.


Assuntos
Genótipo , Lamina Tipo A/genética , Distrofia Muscular de Emery-Dreifuss/genética , Fenótipo , Criança , Pré-Escolar , Feminino , Fibroblastos/metabolismo , Humanos , Lactente , Masculino , Distrofia Muscular de Emery-Dreifuss/diagnóstico , Mutação de Sentido Incorreto
12.
Brain Dev ; 37(9): 880-6, 2015 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-25814170

RESUMO

PURPOSE: Fukuyama congenital muscular dystrophy (FCMD) is a congenital muscular dystrophy rarely reported outside Japan. Here, we report three patients with Fukuyama congenital muscular dystrophy (FCMD) in China who shared a similar clinical phenotype and 3-kb insertion in the FKTN 3' untranslated region. METHODS: Immunofluorescence staining was undertaken on muscle biopsies from three patients using alpha dystroglycan antibody (IIH6). Genomic DNA from patients and parents was extracted from peripheral blood leukocytes. Polymerase chain reaction and DNA sequencing were employed to analyze the exons and surrounding intron sequences of the fukutin (FKTN) gene to detect mutations. Haplotype analysis was also performed on each patient and their parents. RESULTS: All patients had delayed mental and motor development, febrile convulsions, muscle weakness, and moderate to significant raised levels of serum creatine kinase (7000-11,160 U/L, 25-60×normal). Brain MRI scans showed micropolygyria and extensive dysplasia in the white matter and brainstem. Electromyography revealed myopathic changes. Muscle immunofluorescence studies demonstrated reduced IIH6 staining. Genetic testing showed compound heterozygous mutations of FKTN. Cases 1 and 2 had a c.139C>T (p.Arg47(∗)) heterozygous mutation. Case 3 had a c.346C>T (p.Gln116(∗)) heterozygous mutation. CONCLUSION: All patients had a heterozygous 3-kb insertion in the FKTN 3' untranslated region. Haplotype analyses suggested that these patients had the same haplotype as Japanese patients.


Assuntos
Efeito Fundador , Proteínas de Membrana/genética , Mutação , Síndrome de Walker-Warburg/genética , Regiões 3' não Traduzidas , Grupo com Ancestrais do Continente Asiático , Encéfalo/patologia , Criança , Pré-Escolar , Feminino , Humanos , Lactente , Masculino , Músculo Esquelético/patologia , Síndrome de Walker-Warburg/patologia
13.
Zhonghua Er Ke Za Zhi ; 53(10): 741-6, 2015 Oct.
Artigo em Chinês | MEDLINE | ID: mdl-26758109

RESUMO

OBJECTIVE: To elucidate the usefulness of next generation sequencing for diagnosis of inherited myopathy, and to analyze the relevance between clinical phenotype and genotype in inherited myopathy. METHOD: Related genes were selected for SureSelect target enrichment system kit (Panel Version 1 and Panel Version 2). A total of 134 patients who were diagnosed as inherited myopathy clinically underwent next generation sequencing in Department of Pediatrics, Peking University First Hospital from January 2013 to June 2014. Clinical information and gene detection result of the patients were collected and analyzed. RESULT: Seventy-seven of 134 patients (89 males and 45 females, visiting ages from 6-month-old to 26-year-old, average visiting age was 6 years and 1 month) underwent next generation sequencing by Panel Version 1 in 2013, and 57 patients underwent next generation sequencing by Panel Version 2 in 2014. The gene detection revealed that 74 patients had pathogenic gene mutations, and the positive rate of genetic diagnosis was 55.22%. One patient was diagnosed as metabolic myopathy. Five patients were diagnosed as congenital myopathy; 68 were diagnosed as muscular dystrophy, including 22 with congenital muscular dystrophy 1A (MDC1A), 11 with Ullrich congenital muscular dystrophy (UCMD), 6 with Bethlem myopathy (BM), 12 with Duchenne muscular dystrophy (DMD) caused by point mutations in DMD gene, 5 with LMNA-related congenital muscular dystrophy (L-CMD), 1 with Emery-Dreifuss muscular dystrophy (EDMD), 7 with alpha-dystroglycanopathy (α-DG) patients, and 4 with limb-girdle muscular dystrophy (LGMD) patients. CONCLUSION: Next generation sequencing plays an important role in diagnosis of inherited myopathy. Clinical and biological information analysis was essential for screening pathogenic gene of inherited myopathy.


Assuntos
Análise Mutacional de DNA , Doenças Genéticas Inatas/diagnóstico , Sequenciamento de Nucleotídeos em Larga Escala , Doenças Musculares/diagnóstico , Adolescente , Criança , Pré-Escolar , Contratura , Feminino , Doenças Genéticas Inatas/genética , Testes Genéticos , Genótipo , Humanos , Lactente , Masculino , Técnicas de Diagnóstico Molecular , Doenças Musculares/genética , Distrofias Musculares/congênito , Distrofia Muscular do Cíngulo dos Membros , Distrofia Muscular de Duchenne , Distrofia Muscular de Emery-Dreifuss , Mutação , Fenótipo , Esclerose , Síndrome de Walker-Warburg , Adulto Jovem
14.
World J Pediatr ; 10(2): 126-32, 2014 May.
Artigo em Inglês | MEDLINE | ID: mdl-24801232

RESUMO

BACKGROUND: We determined the clinical and molecular genetic characteristics of 8 Chinese patients with Ullrich congenital muscular dystrophy (UCMD). METHODS: Clinical data of probands were collected and muscle biopsies of patients were analyzed. Exons of COL6A1, COL6A2 and COL6A3 were analyzed by direct sequencing. Mutations in COL6A1, COL6A2 and COL6A3 were identified in 8 patients. RESULTS: Among these mutations, 5 were novel [three in the triple helical domain (THD) and 2 in the second C-terminal (C2) domain]. We also identified five known missense or in-frame deletion mutations in THD and C domains. Immunohistochemical studies on muscle biopsies from patients showed reduced level of collagen VI at the muscle basement membrane and mis-localization of the protein in interstitial and perivascular regions. CONCLUSIONS: The novel mutations we identified underscore the importance of THD and C2 domains in the assembly and function of collagen VI, thereby providing useful information for the genetic counseling of UCMD patients.


Assuntos
Colágeno Tipo VI/genética , Distrofias Musculares/genética , Mutação , Esclerose/genética , Adolescente , Alelos , Substituição de Aminoácidos , Biópsia , Criança , Pré-Escolar , China , Códon , Feminino , Mutação da Fase de Leitura , Humanos , Imuno-Histoquímica , Masculino , Distrofias Musculares/diagnóstico , Mutação de Sentido Incorreto , Polimorfismo de Nucleotídeo Único , Esclerose/diagnóstico , Deleção de Sequência
15.
Zhonghua Yi Xue Za Zhi ; 92(40): 2820-4, 2012 Oct 30.
Artigo em Chinês | MEDLINE | ID: mdl-23290209

RESUMO

OBJECTIVE: To explore the clinical features and gene mutation of a Chinese family with Bethlem myopathy in three generations. METHODS: The clinical data of proband and his family members was collected. Genomic DNA from the patient and his family members was extracted routinely from peripheral blood leukocytes. Polymerase chain reaction and DNA direct sequencing were employed to analyze COL6A1, A2 and A3 genes to determine the mutation. And the relationship between genotype and phenotype was analyzed. Furthermore, the patient's skin fibroblast was cultured and immunofluorescent staining was performed with anti-collagen VI antibody. And the expression pattern of type VI collagen in extracellular matrix between the control and the patient's fibroblast was compared. RESULTS: In this family, 9 patients conformed to the clinical diagnosis of Bethlem myopathy. The features included motor development delay after late infantile period, generalized muscle weakness, walking unstability, distal hyper laxity, proximal joint contractures, skin changes (including hypertrophic scars) and normal intellectual development. Serum creatine kinase (CK) level became mildly elevated and electromyography showed myogenic injury. Disease progressed slowly but the lifespan was not affected. Mutation in exon 2 of COL6A1 gene with c.111-129 deletion was detected in 7 patients in this family. Immunofluorescent staining of type VI collagen in cultured skin fibroblast showed reduced expression of collagen VI in extracellular matrix in the patient compared with the control. CONCLUSIONS: Our study has defined the clinical features of Bethlem myopathy. According to molecular genetic analysis, 7 patients in this family have in-frame deletion mutations of COL6A1 and they conform to autosomal dominant inheritance. And genetic counseling and prenatal diagnosis are available. This is the first Chinese report of Bethlem myopathy family.


Assuntos
Contratura/genética , Distrofias Musculares/congênito , Deleção de Sequência , Adolescente , Grupo com Ancestrais do Continente Asiático/genética , Colágeno Tipo VI/genética , Análise Mutacional de DNA , Genoma Humano , Humanos , Masculino , Distrofias Musculares/genética , Linhagem
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