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Congenital myasthenic syndromes (CMS) are a heterogeneous group of genetic disorders that give rise to a defect in neuromuscular transmission. We described here three patients with a characteristic phenotype of recessive CMS and presenting mutation in the gene encoding rapsyn (RAPSN). Familial analysis showed that one allelic mutation failed to be detected by direct sequencing. An allelic quantification on patient's DNA identified three novel multi-exon deletions of RAPSN. These three genomic rearrangements in RAPSN represent 15% of our CMS patients with RAPSN mutations and we emphasize that single-nucleotide polymorphism markers and a gene dosage method should be performed in addition to DNA direct sequencing analysis particularly when there is a genetic counselling issue.
Asunto(s)
Exones/genética , Proteínas Musculares/genética , Síndromes Miasténicos Congénitos/genética , Análisis de Secuencia de ADN , Eliminación de Secuencia/genética , Adolescente , Adulto , Niño , Femenino , Humanos , Lactante , Recién Nacido , Adulto JovenRESUMEN
Life-threatening cardiac and respiratory complications are common in LMNA-related myopathies and early diagnosis is important for optimal patient care. Lamin A/C related congenital muscular dystrophy (L-CMD) is often caused by de novo mutation in LMNA, affecting a single child in a family. Germinal mosaicism is a rarer variant that can lead to two children inheriting the same new heterozygous mutation from a clinically unaffected parent. Both patterns mimic autosomal recessive (AR) inheritance and the possibility of de novo L-CMD may be forgotten since most causes of congenital muscular dystrophy follow AR inheritance. To illustrate the challenge of diagnosing L-CMD, we present a consanguineous family in which two children have early onset LMNA-related myopathy likely due to paternal germinal mosaicism. This emphasises that germinal mosaicism (and de novo mutations) for LMNA can arise in any family and direct gene sequencing is required to confirm or exclude the diagnosis.
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Lamina Tipo A/genética , Mosaicismo , Músculo Esquelético/metabolismo , Enfermedades Musculares/diagnóstico , Enfermedades Musculares/genética , Mutación/genética , Adolescente , Argelia , Niño , Trastornos de los Cromosomas/genética , Análisis Mutacional de ADN , Diagnóstico Diferencial , Femenino , Genes Recesivos/genética , Pruebas Genéticas , Genotipo , Humanos , Patrón de Herencia/genética , Músculo Esquelético/patología , Músculo Esquelético/fisiopatología , Enfermedades Musculares/congénito , Distrofias Musculares/diagnóstico , Distrofias Musculares/genética , Linaje , Fenotipo , Análisis de Secuencia de ADN/normasRESUMEN
OBJECTIVE: To describe a new entity of congenital muscular dystrophies caused by de novo LMNA mutations. METHODS: Fifteen patients presenting with a myopathy of onset in the first year of life were subjected to neurological and genetic evaluation. Histopathological and immunohistochemical analyses were performed for all patients. RESULTS: The 15 patients presented with muscle weakness in the first year of life, and all had de novo heterozygous LMNA mutations. Three of them had severe early-onset disease, no motor development, and the rest experienced development of a "dropped head" syndrome phenotype. Despite variable severity, there was a consistent clinical pattern. Patients typically presented with selective axial weakness and wasting of the cervicoaxial muscles. Limb involvement was predominantly proximal in upper extremities and distal in lower extremities. Talipes feet and a rigid spine with thoracic lordosis developed early. Proximal contractures appeared later, most often in lower limbs, sparing the elbows. Ten children required ventilatory support, three continuously through tracheotomy. Cardiac arrhythmias were observed in four of the oldest patients but were symptomatic only in one. Creatine kinase levels were mild to moderately increased. Muscle biopsies showed dystrophic changes in nine children and nonspecific myopathic changes in the remaining. Markedly atrophic fibers were common, most often type 1, and a few patients showed positive inflammatory markers. INTERPRETATION: The LMNA mutations identified appear to correlate with a relatively severe phenotype. Our results further broaden the spectrum of laminopathies and define a new disease entity that we suggest is best classified as a congenital muscular dystrophy (LMNA-related congenital muscular dystrophy, or L-CMD).
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Lamina Tipo A/genética , Distrofia Muscular de Cinturas/genética , Distrofia Muscular de Cinturas/patología , Mutación/genética , Adulto , Niño , Preescolar , Femenino , Marcadores Genéticos/genética , Humanos , MasculinoRESUMEN
Laminopathies are now recognized as a group of disorders due to mutations of the LMNA gene, which encodes A-type lamins. Primarily, mutations in LMNA have been associated to the autosomal forms of Emery-Dreifuss muscular dystrophy, a rare slowly progressive humero-peroneal muscular dystrophy accompanied by early contractures and dilated cardiomyopathy with conduction defects. LMNA mutations have been reported to be responsible for up to 10 distinct phenotypes that affect specifically either the skeletal and/or cardiac muscle, the adipose tissue, the peripheral nervous tissue, the bone tissue or more recently premature ageing. So far more than 180 different LMNA mutations have been identified in 903 individuals. The first studies of phenotype/genotype relationships revealed no dear relation between the phenotype and the type and/or the localization of the mutation, except perhaps for the globular tail domain of lamins A/C. Studies of the consequences of LMNA mutations in the skin cultured fibroblasts from the patients reveal abnormal nuclei in variable proportions, with dysmorphic nuclei exhibiting abnormal patterns of expression of B-type lamins and emerin. Finally, the development of KO and KI LMNA mice, will certainly give further insight into the pathophysiological mechanisms associated with LMNA mutations. For example, Lmna(H222P/H222P) mice harbour phenotypes reminiscent of Emery-Dreifuss muscular dystrophy.
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Laminas/genética , Distrofia Muscular de Emery-Dreifuss/genética , Mutación/genética , Animales , HumanosRESUMEN
Oculopharyngeal muscular dystrophy (OPMD) is mainly characterized by ptosis and dysphagia. The genetic cause is a short expansion of a (GCN)10 repeat encoding for polyalanine in the poly(A) binding protein nuclear 1 (PABPN1) gene to (GCN)12-17 repeats. The (GCN)11/Ala11 allele has so far been described to be either a polymorphism or a recessive allele with no effect on the phenotype in the heterozygous state. Here we report the clinical and histopathological phenotype of a patient carrying a single (GCN)11/Ala11 heterozygous allele and presenting an atypical form of OPMD with dysphagia and late and mild oculomotor symptoms. Intranuclear inclusions were observed in his muscle biopsy. This suggests a dominant mode of expression of the (GCN)11/Ala11 allele associated with a partial penetrance of OPMD.
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BACKGROUND: Mutations of the LMNA gene, encoding the nuclear envelope proteins lamins A and C, have been associated with 7 distinct pathologic conditions. OBJECTIVE: To report 5 cases with the same missense mutation in exon 6 of the LMNA gene, resulting in an E358K substitution in the central rod domain. DESIGN: Case report. SETTING: Three muscle centers in England. PATIENTS: Five patients with missense mutations of the LMNA gene. RESULTS: All 5 individuals had muscle involvement, but the onset, severity, distribution of muscle weakness, and presence of associated features were highly variable. Three patients had humeroperoneal distribution of weakness and typical features of Emery-Dreifuss muscular dystrophy. Two other patients showed additional novel features. One had congenital onset and predominant axial weakness, with poor neck control and inability to sit independently at the age of 21 months. Another patient presented in childhood with an unusual pattern of muscle weakness, short stature, and midface hypoplasia with striking fat accumulation around the face and neck, in contrast to wasting of adipose tissue and muscle in the limbs. She developed both respiratory failure and cardiac arrhythmias in her late 20s. CONCLUSION: Our cases expand the clinical spectrum associated with mutations in the LMNA gene and further illustrate the overlapping phenotypes of the laminopathies.
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Lamina Tipo A/genética , Distrofias Musculares/genética , Distrofias Musculares/fisiopatología , Fenotipo , Adulto , Niño , Femenino , Humanos , Lactante , Masculino , Músculo Esquelético/patología , Mutación Missense , Reacción en Cadena de la PolimerasaRESUMEN
Emery Dreifuss muscular dystrophy is a genetically heterogeneous disorder characterized by the clinical triad of early onset contractures, progressive muscular wasting and weakness with humeroperoneal distribution and cardiac conduction defects. Mutations in the Lamin A/C (LMNA) gene are responsible for the autosomal dominant and the autosomal recessive forms. Familiar and sporadic patients carrying mutations in the LMNA gene show high variability in the clinical symptomatology and age of onset. In this report, we describe four families harboring missense mutations in the LMNA gene and we show that the effect of mutations ranges from silent to fully penetrant. We suggest that incomplete penetrance of dominant mutations in the LMNA gene is a common feature and we emphasize the significance of mutational analysis in relatives of sporadic cases of laminopathies, as asymptomatic carriers face high risk of sudden cardiac death.
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Lamina Tipo A/genética , Distrofia Muscular de Emery-Dreifuss/genética , Mutación , Penetrancia , Adolescente , Adulto , Creatina Quinasa/metabolismo , Análisis Mutacional de ADN/métodos , Exones , Femenino , Genes Dominantes , Predisposición Genética a la Enfermedad , Genotipo , Heterocigoto , Humanos , Masculino , LinajeRESUMEN
The four-and-half LIM domain protein 1 (FHL1) is highly expressed in skeletal and cardiac muscle. Mutations of the FHL1 gene have been associated with diverse chronic myopathies including reducing body myopathy, rigid spine syndrome (RSS), and Emery-Dreifuss muscular dystrophy. We investigated a family with a mutation (p.C150R) in the second LIM domain of FHL1. In this family, a brother and a sister were affected by RSS, and their mother had mild lower limbs weakness. The 34-year-old female had an early and progressive rigidity of the cervical spine and severe respiratory insufficiency. Muscle mass evaluated by DXA was markedly reduced, while fat mass was increased to 40%. CT scan showed an almost complete substitution of muscle by fibro-adipose tissue. Muscle biopsy showed accumulation of FHL1 throughout the cytoplasm and around myonuclei into multiprotein aggregates with aggresome/autophagy features as indicated by ubiquitin, p62, and LC3 labeling. DNA deposits, not associated with nuclear lamina components and histones, were also detected in the aggregates, suggesting nuclear degradation. Ultrastructural analysis showed the presence of dysmorphic nuclei, accumulation of tubulofilamentous and granular material, and perinuclear accumulation of autophagic vacuoles. These data point to involvement of the aggresome-autophagy pathway in the pathophysiological mechanism underlying the muscle pathology of FHL1 C150R mutation.
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Desmin myopathy is a heterogeneous neuromuscular disorder characterized by skeletal myopathy and cardiomyopathy, inherited mostly in an autosomal dominant pattern. We report a five generation Uruguayan family with severe cardiomyopathy and skeletal myopathy. Its most striking features are: atrial dilation, arrhythmia, conduction block and sudden death due to conduction impairment. Affected skeletal muscle shows alteration of mitochondria with paracrystallin inclusions and granulofilamentous material scattered in the muscle fibres. This family carries an unusual deletion p.E114del within the 1A rod domain of desmin. Transfected cells expressing the mutated desmin show punctuated and speckled cytoplasmic aggregates. The mutation causes a local conformational change in heptads a/d residues and charge positions. These findings lead to the hypothesis that coiled-coil interactions may be impaired, resulting in severe alterations in the desmin network. This is the first time that a mutation affecting this domain in the desmin molecule is described in a desminopathy.