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1.
Brain ; 139(Pt 3): 674-91, 2016 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-26700687

RESUMO

Congenital myopathies are a clinically and genetically heterogeneous group of muscle disorders characterized by congenital or early-onset hypotonia and muscle weakness, and specific pathological features on muscle biopsy. The phenotype ranges from foetal akinesia resulting in in utero or neonatal mortality, to milder disorders that are not life-limiting. Over the past decade, more than 20 new congenital myopathy genes have been identified. Most encode proteins involved in muscle contraction; however, mutations in ion channel-encoding genes are increasingly being recognized as a cause of this group of disorders. SCN4A encodes the α-subunit of the skeletal muscle voltage-gated sodium channel (Nav1.4). This channel is essential for the generation and propagation of the muscle action potential crucial to muscle contraction. Dominant SCN4A gain-of-function mutations are a well-established cause of myotonia and periodic paralysis. Using whole exome sequencing, we identified homozygous or compound heterozygous SCN4A mutations in a cohort of 11 individuals from six unrelated kindreds with congenital myopathy. Affected members developed in utero- or neonatal-onset muscle weakness of variable severity. In seven cases, severe muscle weakness resulted in death during the third trimester or shortly after birth. The remaining four cases had marked congenital or neonatal-onset hypotonia and weakness associated with mild-to-moderate facial and neck weakness, significant neonatal-onset respiratory and swallowing difficulties and childhood-onset spinal deformities. All four surviving cohort members experienced clinical improvement in the first decade of life. Muscle biopsies showed myopathic features including fibre size variability, presence of fibrofatty tissue of varying severity, without specific structural abnormalities. Electrophysiology suggested a myopathic process, without myotonia. In vitro functional assessment in HEK293 cells of the impact of the identified SCN4A mutations showed loss-of-function of the mutant Nav1.4 channels. All, apart from one, of the mutations either caused fully non-functional channels, or resulted in a reduced channel activity. Each of the affected cases carried at least one full loss-of-function mutation. In five out of six families, a second loss-of-function mutation was present on the trans allele. These functional results provide convincing evidence for the pathogenicity of the identified mutations and suggest that different degrees of loss-of-function in mutant Nav1.4 channels are associated with attenuation of the skeletal muscle action potential amplitude to a level insufficient to support normal muscle function. The results demonstrate that recessive loss-of-function SCN4A mutations should be considered in patients with a congenital myopathy.


Assuntos
Hipocinesia/diagnóstico , Hipocinesia/genética , Mutação/genética , Miopatias Congênitas Estruturais/diagnóstico , Miopatias Congênitas Estruturais/genética , Canal de Sódio Disparado por Voltagem NAV1.4/genética , Adolescente , Adulto , Animais , Criança , Pré-Escolar , Feminino , Células HEK293 , Humanos , Recém-Nascido , Masculino , Linhagem , Índice de Gravidade de Doença , Xenopus laevis
2.
Am J Hum Genet ; 86(3): 434-9, 2010 Mar 12.
Artigo em Inglês | MEDLINE | ID: mdl-20170896

RESUMO

Autosomal-dominant brachydactyly type E (BDE) is a congenital limb malformation characterized by small hands and feet predominantly as a result of shortened metacarpals and metatarsals. In a large pedigree with BDE, short stature, and learning disabilities, we detected a microdeletion of approximately 900 kb encompassing PTHLH, the gene coding for parathyroid hormone related protein (PTHRP). PTHRP is known to regulate the balance between chondrocyte proliferation and the onset of hypertrophic differentiation during endochondral bone development. Inactivation of Pthrp in mice results in short-limbed dwarfism because of premature differentiation of chondrocyte. On the basis of our initial finding, we tested further individuals with BDE and short stature for mutations in PTHLH. We identified two missense (L44P and L60P), a nonstop (X178WextX( *)54), and a nonsense (K120X) mutation. The missense mutation L60P was tested in chicken micromass culture with the replication-competent avian sarcoma leukosis virus retroviral expression system and was shown to result in a loss of function. Thus, loss-of-function mutations in PTHLH cause BDE with short stature.


Assuntos
Deformidades Congênitas dos Membros/genética , Mutação , Proteína Relacionada ao Hormônio Paratireóideo/genética , Animais , Células Cultivadas , Embrião de Galinha , Códon sem Sentido , Modelos Animais de Doenças , Feminino , Deformidades Congênitas do Pé/genética , Deformidades Congênitas do Pé/patologia , Genes Dominantes , Transtornos do Crescimento/genética , Transtornos do Crescimento/patologia , Deformidades Congênitas da Mão/genética , Deformidades Congênitas da Mão/patologia , Humanos , Deformidades Congênitas dos Membros/patologia , Masculino , Camundongos , Camundongos Knockout , Mutação de Sentido Incorreto , Proteína Relacionada ao Hormônio Paratireóideo/deficiência , Linhagem , Fenótipo , Mutação Puntual , Proteínas Recombinantes/genética , Proteínas Recombinantes/metabolismo , Deleção de Sequência
3.
Muscle Nerve ; 47(1): 89-95, 2013 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-23042586

RESUMO

INTRODUCTION: Fatigue and excessive daytime sleepiness are frequent complaints in myotonic dystrophy type 1 (DM1) that often overlap. We aimed to construct a combined fatigue and daytime sleepiness rating scale for DM1 using the Rasch measurement model. METHODS: Questionnaires, including the Epworth sleepiness scale, fatigue severity scale, and daytime sleepiness scale, were completed by 354 patients. Data were subjected to Rasch analyses and tested for required measurement issues such as appropriate response categories, absence of item bias, local independence, and unidimensionality. RESULTS: The initial 22 items did not meet Rasch model expectations. After rescoring and removing misfitting items, the final 12-item scale showed good model fit and unidimensionality. High internal consistency (person separation index = 0.80) and validity were demonstrated. CONCLUSIONS: The Rasch-built Fatigue and Daytime Sleepiness Scale, developed specifically for DM1 patients, provides interval measures on a single continuum. Its use is suggested for future clinical trials and therapeutic follow-up.


Assuntos
Fadiga/diagnóstico , Distrofia Miotônica/fisiopatologia , Sono/fisiologia , Avaliação de Sintomas/métodos , Adolescente , Adulto , Idoso , Fadiga/complicações , Fadiga/fisiopatologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Distrofia Miotônica/complicações , Índice de Gravidade de Doença , Inquéritos e Questionários
4.
Am J Med Genet A ; 149A(10): 2226-30, 2009 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-19725130

RESUMO

Genotypic and phenotypic data are presented on three adult siblings with mild to moderate mental retardation and mild dysmorphic features. All three siblings showed a chromosome 20 gain at the q-telomere and loss at the p-telomere in routine subtelomeric MLPA screening. Analysis of GTG-banded chromosomes did not detect any abnormalities, but subtelomeric fluorescent in situ hybridization (FISH) confirmed cryptic partial monosomy of chromosome region 20p13 --> 20pter and cryptic partial trisomy of chromosome region 20q13.33 --> 20qter. Furthermore, FISH analysis in the mother showed a cryptic inv(20)(p13q13.33). This explained the cytogenetic mechanism underlying the chromosomal imbalance in the three children, that is, the meiotic formation of a recombinant chromosome 20 due to crossing-over in the inverted segment. All three children thus carried a rec(20)dup(20q)inv(20)(p13q13.33)mat chromosome. SNP array analysis enabled rapid and detailed imbalance sizing and showed a 1.06 Mb loss in 20p13 and a 2.51 Mb gain in 20q13.33, comprising 21 and 78 genes, respectively. The maternal inversion is the largest described thus far for chromosome 20, comprising 94.4% of its length. Such large inversions result in a particularly high risk for live-born unbalanced offspring because the partial monosomy and trisomy segments are small. Moreover, the inversion size is directly related to the percentage of unbalanced gametes due to high crossing-over change within the inverted segment. The fact that all three children carry an identical chromosomal rearrangement has consequences for genetic counseling for carriers of large pericentric inversions, as the recurrence risk is very high.


Assuntos
Deleção Cromossômica , Inversão Cromossômica , Cromossomos Humanos Par 20 , Irmãos , Trissomia , Anormalidades Múltiplas/genética , Adulto , Quebra Cromossômica , Inversão Cromossômica/genética , Mapeamento Cromossômico/métodos , Feminino , Humanos , Padrões de Herança/genética , Masculino , Análise em Microsséries/métodos , Mães , Técnicas de Amplificação de Ácido Nucleico , Polimorfismo de Nucleotídeo Único , Trissomia/diagnóstico , Trissomia/genética , Adulto Jovem
5.
Eur J Hum Genet ; 23(4): 543-6, 2015 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-24986827

RESUMO

We identified an identical and recurrent 9.4-Mbp deletion at chromosome bands 2p11.2-2p12, which occurred de novo in two unrelated patients. It is flanked at the distal and proximal breakpoints by two homologous segmental duplications consisting of low copy repeat (LCR) blocks in direct orientation, which have >99% sequence identity. Despite the fact that the deletion was almost 10 Mbp in size, the patients showed a relatively mild clinical phenotype, that is, mild-to-moderate intellectual disability, a happy disposition, speech delay and delayed motor development. Their phenotype matches with that of previously described patients. The 2p11.2-2p12 deletion includes the REEP1 gene that is associated with spastic paraplegia and phenotypic features related to this are apparent in most 2p11.2-2p12 deletion patients, but not in all. Other hemizygous genes that may contribute to the clinical phenotype include LRRTM1 and CTNNA2. We propose a recurrent but rare 2p11.2-2p12 deletion syndrome based on (1) the identical, non-random localisation of the de novo deletion breakpoints in two unrelated patients and a patient from literature, (2) the patients' phenotypic similarity and their phenotypic overlap with other 2p deletions and (3) the presence of highly identical LCR blocks flanking both breakpoints, consistent with a non-allelic homologous recombination (NAHR)-mediated rearrangement.


Assuntos
Cromossomos Humanos Par 2/genética , Proteínas de Membrana Transportadoras/genética , Duplicações Segmentares Genômicas , Deleção de Sequência , Adolescente , Alelos , Pré-Escolar , Variações do Número de Cópias de DNA , Deficiências do Desenvolvimento/genética , Feminino , Estudo de Associação Genômica Ampla , Recombinação Homóloga , Humanos , Deficiência Intelectual/genética , Masculino , Proteínas de Membrana/genética , Proteínas do Tecido Nervoso/genética , Análise de Sequência com Séries de Oligonucleotídeos , Fenótipo , alfa Catenina/genética
6.
Eur J Hum Genet ; 23(9): 1151-7, 2015 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-25537362

RESUMO

Fetal akinesia deformation sequence (FADS) refers to a clinically and genetically heterogeneous group of disorders with congenital malformations related to impaired fetal movement. FADS can result from mutations in CHRNG, CHRNA1, CHRND, DOK7 and RAPSN; however, these genes only account for a minority of cases. Here we identify MUSK as a novel cause of lethal FADS. Fourteen affected fetuses from a Dutch genetic isolate were traced back to common ancestors 11 generations ago. Homozygosity mapping in two fetuses revealed MUSK as a candidate gene. All tested cases carried an identical homozygous variant c.1724T>C; p.(Ile575Thr) in the intracellular domain of MUSK. The carrier frequency in the genetic isolate was 8%, exclusively found in heterozygous carriers. Consistent with the established role of MUSK as a tyrosine kinase that orchestrates neuromuscular synaptogenesis, the fetal myopathy was accompanied by impaired acetylcholine receptor clustering and reduced tyrosine kinase activity at motor nerve endings. A functional assay in myocytes derived from human fetuses confirmed that the variant blocks MUSK-dependent motor endplate formation. Taken together, the results strongly support a causal role of this founder mutation in MUSK, further expanding the gene set associated with FADS and offering new opportunities for prenatal genetic testing.


Assuntos
Artrogripose/genética , Efeito Fundador , Placa Motora/genética , Mutação , Receptores Proteína Tirosina Quinases/genética , Receptores Colinérgicos/genética , Alelos , Sequência de Aminoácidos , Artrogripose/diagnóstico , Artrogripose/patologia , Sequência de Bases , Feminino , Feto , Expressão Gênica , Frequência do Gene , Genes Letais , Testes Genéticos , Homozigoto , Humanos , Masculino , Dados de Sequência Molecular , Placa Motora/patologia , Células Musculares/metabolismo , Células Musculares/patologia , Países Baixos , Linhagem , Diagnóstico Pré-Natal , Cultura Primária de Células , Receptores Colinérgicos/química
7.
Ned Tijdschr Geneeskd ; 156(7): A4224, 2012.
Artigo em Holandês | MEDLINE | ID: mdl-22333400

RESUMO

Small fibre neuropathy is a neuropathy of the small non-myelinated C-fibres and myelinated Aδ-fibres. Clinically, an isolated small fibre neuropathy is distinguished by sensory and autonomic symptoms, with practically no abnormalities on neurological examination other than possible distorted pain and temperature sensation. Specific diagnostic tests for small fibre neuropathy are skin biopsy, including a count of the intra-epidermal small nerve fibres that cross the basal membrane, and quantitative sensory and autonomic testing. Diabetes mellitus is the most frequent underlying cause of small fibre neuropathy. Other causes can be classified into the following categories: toxic (e.g. alcohol), metabolic, immune-mediated, infectious and hereditary. Recently, in a substantial proportion (29%) of a group of patients with idiopathic small fibre neuropathy, a SCN9A gene mutation was demonstrated, which leads to hyperexcitability of the dorsal root ganglion neurons. Treatment of small fibre neuropathy consists of symptomatic pain relief and, if possible, treatment of the underlying cause of the condition.


Assuntos
Fibras Nervosas/patologia , Dor/etiologia , Doenças do Sistema Nervoso Periférico/diagnóstico , Transtornos de Sensação/diagnóstico , Técnicas de Diagnóstico Neurológico , Humanos , Mutação , Condução Nervosa , Dor/prevenção & controle , Doenças do Sistema Nervoso Periférico/genética , Doenças do Sistema Nervoso Periférico/terapia , Transtornos de Sensação/genética , Transtornos de Sensação/terapia , Limiar Sensorial , Sensação Térmica
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