RESUMO
Labyrinthine aplasia, microtia, and microdontia (LAMM) is an autosomal recessive condition causing profound congenital deafness, complete absence of inner ear structures (usually Michel's aplasia), microtia (usually type 1) and microdontia. To date, several families have been described with this condition and a number of mutations has been reported. We report on eight further cases of LAMM syndrome including three novel mutations, c. 173T>C p.L58P; c. 284G>A p.(Arg95Gln) and c.325_327delinsA p.(Glu109Thrfs*18). Congenital deafness was the primary presenting feature in all affected individuals and consanguinity in all but two families. We compare the features in our patients to those previously reported in LAMM, and describe a milder, asymmetrical phenotype associated with FGF3 mutations.
Assuntos
Microtia Congênita/genética , Microtia Congênita/patologia , Orelha Interna/anormalidades , Fator 3 de Crescimento de Fibroblastos/genética , Perda Auditiva Neurossensorial/genética , Perda Auditiva Neurossensorial/patologia , Anormalidades Dentárias/genética , Anormalidades Dentárias/patologia , Adulto , Pré-Escolar , Consanguinidade , Análise Mutacional de DNA , Surdez/congênito , Orelha Interna/patologia , Feminino , Humanos , Lactente , Recém-Nascido , Masculino , Mutação , FenótipoAssuntos
Anormalidades Craniofaciais/diagnóstico , Anormalidades Craniofaciais/genética , Nanismo/diagnóstico , Nanismo/genética , Homozigoto , Instabilidade Articular/diagnóstico , Instabilidade Articular/genética , Mutação , Nucleotidases/genética , Ossificação Heterotópica/diagnóstico , Ossificação Heterotópica/genética , Polidactilia/diagnóstico , Polidactilia/genética , Fácies , Testes Genéticos , Humanos , Fenótipo , RadiografiaRESUMO
Many clinical features of autosomal centronuclear myopathies (CNM) and X-linked myotubular myopathy (XLMTM) are common to congenital myasthenic syndromes (CMS). We describe three children whose clinical and electrophysiological findings originally suggested CMS, in whom CNM was diagnosed pathologically, though not yet genetically characterised. A fourth case, with XLMTM, also showed electrophysiological features of a neuromuscular transmission defect. Three (including the XLMTM case) showed improved strength with acetylcholinesterase inhibitor treatment. We also studied neuromuscular junction structure and function in the MTM1 knockdown zebrafish model of XLMTM, demonstrating abnormal neuromuscular junction organization; anticholinesterase therapy resulted in marked clinical response. These observations suggest that a neuromuscular transmission defect may accompany CNM and contribute to muscle weakness. Muscle biopsy should be considered in infants suspected to have CMS, especially if treatment response is incomplete, or no CMS gene mutation is identified. Treatment with acetylcholinesterase inhibitors may benefit some CNM patients. This warrants further confirmation.
Assuntos
Inibidores da Colinesterase/uso terapêutico , Miopatias Congênitas Estruturais/tratamento farmacológico , Miopatias Congênitas Estruturais/fisiopatologia , Junção Neuromuscular/fisiopatologia , Transmissão Sináptica/fisiologia , Adolescente , Animais , Biópsia , Criança , Inibidores da Colinesterase/farmacologia , Modelos Animais de Doenças , Eletromiografia , Feminino , Técnicas de Inativação de Genes , Humanos , Lactente , Masculino , Músculo Esquelético/patologia , Miopatias Congênitas Estruturais/genética , Junção Neuromuscular/efeitos dos fármacos , Proteínas Tirosina Fosfatases não Receptoras/genética , Brometo de Piridostigmina/farmacologia , Brometo de Piridostigmina/uso terapêutico , Transmissão Sináptica/efeitos dos fármacos , Resultado do Tratamento , Peixe-Zebra , Proteínas de Peixe-Zebra/genéticaRESUMO
Dynamin 2 (DNM2)-related dominant centronuclear myopathy is usually a mild disorder, but more severe variants have been associated with mutations affecting the pleckstrin homology (PH) domain of the protein, mainly implicated in different forms of Charcot-Marie-Tooth Disease (CMT). Whilst DNM2-related CMT may feature non-neurological findings including cataracts, this has not been reported in DNM2-related centronuclear myopathy. We report a girl presenting from birth with hypotonia, respiratory and feeding difficulties. Motor development was delayed and at 9years she lost the ability to walk. She had ptosis, external ophthalmoplegia and bilateral cataracts. Muscle biopsy showed increase in central nuclei with type 1 hypotrophy and fibrosis. DNM2 screening revealed a novel heterozygous substitution (c.1862T>C; p.Leu621Pro) affecting the PH domain of the protein. Her further course was progressive and at 14years she died from respiratory failure. Our findings expand the phenotypical spectrum associated with DNM2 mutations and provide a new clinical indicator for involvement of this gene in patients with centronuclear myopathy.
Assuntos
Catarata/genética , Dinamina II/genética , Miopatias Congênitas Estruturais/genética , Adolescente , Substituição de Aminoácidos , Criança , Progressão da Doença , Evolução Fatal , Feminino , Humanos , Lactente , Recém-Nascido , Músculo Esquelético/patologia , Miopatias Congênitas Estruturais/patologia , Fenótipo , Análise de Sequência de DNARESUMO
Harlequin ichthyosis (HI) is the most severe form of autosomal-recessive, congenital ichthyosis. Affected infants have markedly impaired barrier function and are more susceptible to infection. Abnormalities in the localization of epidermal lipids as well as abnormal lamellar granule formation are features of HI skin. Previously, we and others have shown that mutations in the ABCA12 gene encoding an adenosine triphosphate-binding cassette (ABC) transporter underlie the skin disease HI. In this study, we have sequenced the ABCA12 gene in an additional 14 patients and show that all contain mutations, with the majority being either nonsense substitution or frameshift mutations. Eleven HI patients had bi-allelic ABCA12 mutations, whereas in the remaining three HI patients in this study, ABCA12 mutations were detected on only one allele by sequencing. In addition, the one patient from the previous study where no sequence mutations were detected was screened for heterozygous deletions. A combination of oligonucleotide arrays, multiplex PCR analysis and single-nucleotide polymorphism genotyping revealed a heterozygous intragenic deletion in exon 8. These mutation data establish ABCA12 as the major HI gene.