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1.
Brain ; 142(9): 2605-2616, 2019 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-31332438

RESUMO

Distal hereditary motor neuropathies are a rare subgroup of inherited peripheral neuropathies hallmarked by a length-dependent axonal degeneration of lower motor neurons without significant involvement of sensory neurons. We identified patients with heterozygous nonsense mutations in the αII-spectrin gene, SPTAN1, in three separate dominant hereditary motor neuropathy families via next-generation sequencing. Variable penetrance was noted for these mutations in two of three families, and phenotype severity differs greatly between patients. The mutant mRNA containing nonsense mutations is broken down by nonsense-mediated decay and leads to reduced protein levels in patient cells. Previously, dominant-negative αII-spectrin gene mutations were described as causal in a spectrum of epilepsy phenotypes.

4.
Neurology ; 92(6): e587-e593, 2019 Feb 05.
Artigo em Inglês | MEDLINE | ID: mdl-30635494

RESUMO

OBJECTIVE: To determine the molecular etiology of disease in 4 individuals from 2 unrelated families who presented with proximal muscle weakness and features suggestive of mitochondrial disease. METHODS: Clinical information and neuroimaging were reviewed. Genome sequencing was performed on affected individuals and biological parents. RESULTS: All affected individuals presented with muscle weakness and difficulty walking. In one family, both children had neonatal respiratory distress while the other family had 2 children with episodic deteriorations. In each family, muscle biopsy demonstrated ragged red fibers. MRI was suggestive of a mitochondrial leukoencephalopathy, with extensive deep cerebral white matter T2 hyperintense signal and selective involvement of the middle blade of the corpus callosum. Through genome sequencing, homozygous GFPT1 missense variants were identified in the affected individuals of each family. The variants detected (p.Arg14Leu and p.Thr151Lys) are absent from population databases and predicted to be damaging by in silico prediction tools. Following the genetic diagnosis, nerve conduction studies were performed and demonstrated a decremental response to repetitive nerve stimulation, confirming the diagnosis of myasthenia. Treatment with pyridostigmine was started in one family with favorable response. CONCLUSIONS: GFPT1 encodes a widely expressed protein that controls the flux of glucose into the hexosamine-biosynthesis pathway that produces precursors for glycosylation of proteins. GFPT1 variants and defects in other enzymes of this pathway have previously been associated with congenital myasthenia. These findings identify leukoencephalopathy as a previously unrecognized phenotype in GFPT1-related disease and suggest that mitochondrial dysfunction could contribute to this disorder.

6.
7.
Hum Mutat ; 39(12): 1980-1994, 2018 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-30168660

RESUMO

SH3 and cysteine-rich domain-containing protein 3 (STAC3) is an essential component of the skeletal muscle excitation-contraction coupling (ECC) machinery, though its role and function are not yet completely understood. Here, we report 18 patients carrying a homozygous p.(Trp284Ser) STAC3 variant in addition to a patient compound heterozygous for the p.(Trp284Ser) and a novel splice site change (c.997-1G > T). Clinical severity ranged from prenatal onset with severe features at birth, to a milder and slowly progressive congenital myopathy phenotype. A malignant hyperthermia (MH)-like reaction had occurred in several patients. The functional analysis demonstrated impaired ECC. In particular, KCl-induced membrane depolarization resulted in significantly reduced sarcoplasmic reticulum Ca2+ release. Co-immunoprecipitation of STAC3 with CaV 1.1 in patients and control muscle samples showed that the protein interaction between STAC3 and CaV 1.1 was not significantly affected by the STAC3 variants. This study demonstrates that STAC3 gene analysis should be included in the diagnostic work up of patients of any ethnicity presenting with congenital myopathy, in particular if a history of MH-like episodes is reported. While the precise pathomechanism remains to be elucidated, our functional characterization of STAC3 variants revealed that defective ECC is not a result of CaV 1.1 sarcolemma mislocalization or impaired STAC3-CaV 1.1 interaction.

9.
J Neurol Sci ; 359(1-2): 256-9, 2015 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-26671124

RESUMO

BACKGROUND: Dysferlinopathy is caused by a very wide range of autosomal recessively inherited mutations of the Dysferlin gene. It causes a spectrum of muscle diseases including limb-girdle muscular dystrophy (LGMD) 2B and Miyoshi myopathy (MM). We describe the clinical course and mutational analyses of 15 Iranian patients with dysferlinopathy from 9 different families. METHODS: Genomic DNA was extracted from peripheral blood and 55 exons and flanking intronic boundaries of the dysferlin gene (DYSF; NM_003494.2) were screened for mutations and analyzed. RESULTS: From 15 studied patients in 9 families, 5 patients were male. Seven families had consanguineous marriage. Median age of onset was 16.8; and the median age of diagnosis was 26.6. The onset was clearly distal in 7 patients, and proximal in 6 patients. Three patients had partial biceps atrophy and 13 showed prominent calf muscle wasting. Foot plantar flexors, deep finger flexors and hip adductors were predominantly involved. Genetic testing showed homozygous mutation of dysferlin gene in 9 probands, 5 of which were not previously reported. CONCLUSION: This work, in fact, may help shed some light on the pattern of this morbidity in Iran, an effort that may have not been attempted so far.


Assuntos
Proteínas de Membrana/genética , Proteínas Musculares/genética , Distrofia Muscular do Cíngulo dos Membros/genética , Distrofia Muscular do Cíngulo dos Membros/fisiopatologia , Mutação/genética , Adolescente , Adulto , Análise Mutacional de DNA , Disferlina , Saúde da Família , Feminino , Humanos , Irã (Geográfico) , Imagem por Ressonância Magnética , Masculino , Músculo Esquelético/patologia , Distrofia Muscular do Cíngulo dos Membros/patologia , Adulto Jovem
10.
Med Sci (Paris) ; 31 Spec No 3: 20-7, 2015 Nov.
Artigo em Francês | MEDLINE | ID: mdl-26546927

RESUMO

GNE myopathy is a rare neuromuscular disease whose description is fairly recent. It predominantly affects the adult population and is an inherited autosomal recessive disorder. Although universal and ubiquitous, GNE myopathy prevails in the Jewish community of Persian origin, living in Iran, Israel or in the United States. This condition has also been reported in great number in populations of far-East Asia (Japan and neighboring countries) and, closer to France, in Bulgaria. GNE myopathy causes muscle weakness in the extremities (distal myopathy), affecting initially and predominantly foot flexor muscles. The generic term of GNE myopathy is now fully accepted and encompasses two previously described entities: the quadriceps sparing myopathy, (also referred to as the autosomal recessive form of inclusion body myopathy (hIBM) and the Nonaka type distal myopathy (or distal myopathy with rimmed vacuoles DMRV). This myopathy is due to mutations in the GNE gene encoding a bifunctional enzyme, the UDP-N-acetylglucosamine-2-epimerase/N-acetylmannosamine kinase. This enzyme plays a role at two levels in the metabolic pathway leading to the synthesis of sialic acid. Sialic acid, also known as N-acetylneuraminic acid (Neu5Ac or NANA), is a monosaccharide essential to other protein or lipid molecules requiring sugar residues on their surface in order to function efficiently. GNE myopathy is characterized by histological lesions (rimmed vacuoles) within muscle fibers. They are fairly typical in a suggestive context, but non-specific and inconsistent from one muscle to another. The diagnosis of GNE myopathy is essentially based on clinical clues, including muscle imaging, and is confirmed by genetic studies. If promising therapeutic trials are being developed to compensate for this recently unveiled metabolic defect, the treatment of this myopathy remains purely supportive to date.


Assuntos
Miopatias Distais , Complexos Multienzimáticos/deficiência , Adulto , Idade de Início , Animais , Grupo com Ancestrais do Continente Asiático/genética , Bulgária/epidemiologia , Ensaios Clínicos como Assunto , Preparações de Ação Retardada , Diagnóstico Diferencial , Modelos Animais de Doenças , Miopatias Distais/diagnóstico , Miopatias Distais/etnologia , Miopatias Distais/genética , Miopatias Distais/fisiopatologia , Método Duplo-Cego , Genes Recessivos , Terapia Genética , Humanos , Israel/epidemiologia , Japão/epidemiologia , Judeus/genética , Lipossomos , Modelos Moleculares , Complexos Multienzimáticos/química , Complexos Multienzimáticos/genética , Músculo Esquelético/ultraestrutura , Ácido N-Acetilneuramínico/administração & dosagem , Ácido N-Acetilneuramínico/metabolismo , Ácido N-Acetilneuramínico/uso terapêutico , Especificidade de Órgãos , Conformação Proteica , Sistema de Registros , Estados Unidos/epidemiologia , Vacúolos/ultraestrutura
12.
Brain ; 137(Pt 1): 44-56, 2014 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-24253200

RESUMO

Childhood onset motor neuron diseases or neuronopathies are a clinically heterogeneous group of disorders. A particularly severe subgroup first described in 1894, and subsequently called Brown-Vialetto-Van Laere syndrome, is characterized by progressive pontobulbar palsy, sensorineural hearing loss and respiratory insufficiency. There has been no treatment for this progressive neurodegenerative disorder, which leads to respiratory failure and usually death during childhood. We recently reported the identification of SLC52A2, encoding riboflavin transporter RFVT2, as a new causative gene for Brown-Vialetto-Van Laere syndrome. We used both exome and Sanger sequencing to identify SLC52A2 mutations in patients presenting with cranial neuropathies and sensorimotor neuropathy with or without respiratory insufficiency. We undertook clinical, neurophysiological and biochemical characterization of patients with mutations in SLC52A2, functionally analysed the most prevalent mutations and initiated a regimen of high-dose oral riboflavin. We identified 18 patients from 13 families with compound heterozygous or homozygous mutations in SLC52A2. Affected individuals share a core phenotype of rapidly progressive axonal sensorimotor neuropathy (manifesting with sensory ataxia, severe weakness of the upper limbs and axial muscles with distinctly preserved strength of the lower limbs), hearing loss, optic atrophy and respiratory insufficiency. We demonstrate that SLC52A2 mutations cause reduced riboflavin uptake and reduced riboflavin transporter protein expression, and we report the response to high-dose oral riboflavin therapy in patients with SLC52A2 mutations, including significant and sustained clinical and biochemical improvements in two patients and preliminary clinical response data in 13 patients with associated biochemical improvements in 10 patients. The clinical and biochemical responses of this SLC52A2-specific cohort suggest that riboflavin supplementation can ameliorate the progression of this neurodegenerative condition, particularly when initiated soon after the onset of symptoms.


Assuntos
Paralisia Bulbar Progressiva/genética , Perda Auditiva Neurossensorial/genética , Mutação/genética , Receptores Acoplados a Proteínas-G/genética , Adolescente , Encéfalo/patologia , Paralisia Bulbar Progressiva/tratamento farmacológico , Carnitina/análogos & derivados , Carnitina/sangue , Criança , Pré-Escolar , Exoma/genética , Feminino , Genótipo , Perda Auditiva Neurossensorial/tratamento farmacológico , Humanos , Processamento de Imagem Assistida por Computador , Imagem por Ressonância Magnética , Masculino , Análise em Microsséries , Doença dos Neurônios Motores/fisiopatologia , Exame Neurológico , Linhagem , RNA/biossíntese , RNA/genética , Riboflavina/uso terapêutico , Análise de Sequência de DNA , Nervo Sural/patologia , Vitaminas/uso terapêutico , Adulto Jovem
13.
Neurol India ; 61(6): 622-6, 2013 Nov-Dec.
Artigo em Inglês | MEDLINE | ID: mdl-24441330

RESUMO

In this report, we describe a new mutation located in the coiled 1B domain of desmin and associated with a predominant cardiac involvement and a high degree of cardiac sudden death in a large Indian pedigree with 12 affected members. The index cases was 38-year-old man who presented with progressive difficulty in gripping footwear of 5 years duration with the onset in the left lower limb followed by right lower limb in 6 months. 3 years from onset, he developed lower limb proximal and truncal muscle weakness. There was mild atrophy of the shoulder girdle muscles with grade 3 weakness, moderate wasting of thigh and anterior leg muscles with proximal muscle weakness and foot drop. At 40 years, he had a pacemaker implanted. The 9 exons and intronic boundaries of the desmin gene were sequenced and a heterozygous nucleotide change c. 734A > G in exon 3 was identified.


Assuntos
Cardiomiopatias/genética , Desmina/genética , Distrofias Musculares/genética , Mutação , Adulto , Grupo com Ancestrais do Continente Asiático/genética , Sequência de Bases , Cardiomiopatias/patologia , Cardiomiopatias/fisiopatologia , Feminino , Humanos , Índia , Masculino , Pessoa de Meia-Idade , Dados de Sequência Molecular , Distrofias Musculares/patologia , Distrofias Musculares/fisiopatologia , Linhagem
14.
Brain ; 135(Pt 9): 2875-82, 2012 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-22740598

RESUMO

Brown-Vialetto-Van Laere syndrome was first described in 1894 as a rare neurodegenerative disorder characterized by progressive sensorineural deafness in combination with childhood amyotrophic lateral sclerosis. Mutations in the gene, SLC52A3 (formerly C20orf54), one of three known riboflavin transporter genes, have recently been shown to underlie a number of severe cases of Brown-Vialetto-Van Laere syndrome; however, cases and families with this disease exist that do not appear to be caused by SLC52A3 mutations. We used a combination of linkage and exome sequencing to identify the disease causing mutation in an extended Lebanese Brown-Vialetto-Van Laere kindred, whose affected members were negative for SLC52A3 mutations. We identified a novel mutation in a second member of the riboflavin transporter gene family (gene symbol: SLC52A2) as the cause of disease in this family. The same mutation was identified in one additional subject, from 44 screened. Within this group of 44 patients, we also identified two additional cases with SLC52A3 mutations, but none with mutations in the remaining member of this gene family, SLC52A1. We believe this strongly supports the notion that defective riboflavin transport plays an important role in Brown-Vialetto-Van Laere syndrome. Initial work has indicated that patients with SLC52A3 defects respond to riboflavin treatment clinically and biochemically. Clearly, this makes an excellent candidate therapy for the SLC52A2 mutation-positive patients identified here. Initial riboflavin treatment of one of these patients shows promising results.


Assuntos
Paralisia Bulbar Progressiva/genética , Exoma , Perda Auditiva Neurossensorial/genética , Doença dos Neurônios Motores/genética , Mutação , Receptores Acoplados a Proteínas-G/genética , Alelos , Criança , Pré-Escolar , Feminino , Frequência do Gene , Genótipo , Humanos , Masculino , Linhagem , Polimorfismo de Nucleotídeo Único
15.
Ann Neurol ; 71(5): 719-23, 2012 May.
Artigo em Inglês | MEDLINE | ID: mdl-22522483

RESUMO

The transcription factor EGR2 is expressed in Schwann cells, where it controls peripheral nerve myelination. Mutations of EGR2 have been found in patients with congenital hypomyelinating neuropathy or Charcot-Marie-Tooth disease type 1D. In a patient with congenital amyelinating neuropathy, we observed pathological abnormalities recapitulating the peripheral nervous system phenotype of homozygous Egr2-null mice. This patient, born from consanguineous parents, showed no EGR2 immunoreactivity in Schwann cells and harbored a homozygous 10.7-kilobase-long deletion encompassing a myelin-specific enhancer of EGR2. This regulatory mutation is the first genetic abnormality associated with congenital amyelinating neuropathy in humans.


Assuntos
Doença de Charcot-Marie-Tooth/genética , Doença de Charcot-Marie-Tooth/patologia , Proteína 2 de Resposta de Crescimento Precoce/genética , Elementos Facilitadores Genéticos/genética , Bainha de Mielina/patologia , Sequência de Bases , Feminino , Homozigoto , Humanos , Lactente , Recém-Nascido , Dados de Sequência Molecular , Linhagem , Reação em Cadeia da Polimerase , Deleção de Sequência
16.
Eur J Hum Genet ; 19(4): 452-7, 2011 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-21248746

RESUMO

Mutation of the LARGE gene is the rarest of the six known genetic causes of α-dystroglycanopathy. We report further a family with MDC1D due to a complex genomic rearrangement that was not apparent on standard sequencing of LARGE. Two sisters in a consanguineous family had moderate mental retardation and cerebellar malformations, together with dystrophic changes and markedly reduced α-dystroglycan glycosylation staining on muscle biopsy. There was homozygous linkage to the LARGE locus but sequencing of LARGE coding regions was normal. Analysis of LARGE cDNA showed an abnormal sequence inserted between exons 10 and 11, in most of the transcripts, predicted to introduce a premature stop codon. The abnormal sequence mapped to a spliced EST (DA935254) of unknown function, normally located at 100 kb centromeric of LARGE on chromosome 22q12.3. Quantitative PCR analysis of the EST and adjacent regions showed twice the normal copy number in patients' genomic DNA samples, consistent with a large intra-chromosomal duplication inserted into intron 10 of LARGE in a homozygous state. This insertion was associated with deletion of a central region of intron 10, but the exact break points of the deletion/duplication were not found, suggesting that an even more complex rearrangement may have occurred. The exact function of LARGE, a golgi protein, remains uncertain. POMT and POMGnT enzyme activities were normal in patients' lymphoblast cells, suggesting that defects in LARGE do not affect the initiation of O-mannosyl glycans.


Assuntos
Distroglicanas/deficiência , Íntrons/genética , Distrofias Musculares/genética , N-Acetilglucosaminiltransferases/genética , Sequência de Bases , Criança , Pré-Escolar , Duplicação Cromossômica/genética , Códon sem Sentido , Éxons , Feminino , Humanos , Mutação INDEL , Deficiência Intelectual/genética , Manosiltransferases/metabolismo , N-Acetilglucosaminiltransferases/metabolismo , Processamento de RNA/genética
17.
Indian J Pediatr ; 77(4): 431-3, 2010 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-20358311

RESUMO

Congenital myopathies are a group of genetic disorders characterized by generalised muscle hypotonia and weakness of varying severity. They are distinct entities and do not include muscular dystrophies, metabolic myopathies and mitochondrial disorders. Myotubular myopathy is a rare sub type within this group of disorders. Clinical differentiation of the various types is difficult and requires muscle biopsy with histopathological and immunohistochemical studies for specific diagnosis. Gene studies are a prerequisite for genetic counseling adn prenatal diagnosis. Here presented three cases of X-linked myotubular myopathy in three Indian families where the diagnosis was established by mutation analysis in the MTM1 gene in all, and supported his histopathology in two. All three families had history of previous male neonatal deaths with similar complaints. Molecular analysis revealed hemizygous mutations in the MTM1 gene including c.1261-10A>G in case, 1, c.70C>T (R24X) in case 2, and a previously unreported mutation, c.924_926delCTT(p. F308del), in case 3. Genetic counseling was performed regarding the X-linked inheritance, their 50% risk of recurrence in boys in subsequent pregnancies, and a feasibility of prenatal diagnosis. This is the first report of cases of X-linked myotubular myopathy from India.


Assuntos
Doenças Genéticas Ligadas ao Cromossomo X/genética , Mutação , Miopatias Congênitas Estruturais/diagnóstico , Miopatias Congênitas Estruturais/genética , Proteínas Tirosina Fosfatases não Receptoras/genética , Humanos , Recém-Nascido , Masculino , Músculo Esquelético/patologia , Miopatias Congênitas Estruturais/patologia
18.
Neurol India ; 56(3): 289-97, 2008 Jul-Sep.
Artigo em Inglês | MEDLINE | ID: mdl-18974555

RESUMO

Dysferlinopathies encompass a large variety of neuromuscular diseases characterized by the absence of dysferlin in skeletal muscle and an autosomal recessive mode of inheritance. So far, three main phenotypes have been reported: Miyoshi myopathy (MM), limb girdle muscular dystrophy type 2B (LGMD 2B), and distal myopathy with anterior tibial onset (DMAT). A growing number of clinical variants have recently been described with a much wider range of symptoms and onset. Although rare, dysferlinopathies can account for up to 30% of progressive recessive muscular dystrophies in certain geographical areas, notably in the Middle East and the Indian subcontinent. Dysferlin is a large protein involved in membrane repair and vesicle trafficking and interacts probably with important immunological pathways. New insights in its pathophysiology may result in innovative therapies in the near future.


Assuntos
Proteínas de Membrana/genética , Proteínas Musculares/genética , Doenças Neuromusculares/genética , Animais , Disferlina , Genótipo , Humanos , Músculo Esquelético/metabolismo , Músculo Esquelético/patologia , Doenças Neuromusculares/diagnóstico , Doenças Neuromusculares/epidemiologia , Doenças Neuromusculares/patologia , Doenças Neuromusculares/terapia , Fenótipo
19.
Ann Neurol ; 59(6): 905-11, 2006 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-16607617

RESUMO

OBJECTIVE: Eosinophilic myositis (EM) constitutes a rare pathological entity characterized by eosinophilic infiltration of skeletal muscles, usually associated with parasite infections, systemic disorders, or the intake of drugs or L-tryptophan. The exclusion of such causes defines the spectrum of idiopathic EM. Based on a protein analysis performed in one affected patient, we identified the gene encoding calpain-3, CAPN3, as a candidate for a subset of idiopathic EM. METHODS: We screened CAPN3 for mutations using DHPLC and direct sequencing in six unrelated patients, recruited for EM diagnosed after histological examination of muscle biopsy samples, without any identified causative factor. RESULTS: We identified CAPN3 mutations in the six unrelated patients originally diagnosed with idiopathic EM. INTERPRETATION: Mutations in CAPN3 can cause EM. Thus, a subset of idiopathic EM is genetically determined, with an autosomal recessive mode of inheritance. Patients presented with a triad that appears to be indicative of CAPN3 mutations: (1) EM in the first decade, (2) elevated serum creatine phosphokinase levels (isolated or with little corresponding weakness), and (3) inconstant peripheral hypereosinophilia. However, that EM represents a distinct phenotype associated to CAPN3 mutations or, rather, an early histopathological picture of LGMD2A must be further evaluated. Our findings should be of interest toward further investigating the role of calpain-3 in skeletal muscle. Furthermore, patients with idiopathic EM should undergo calpain-3 protein analysis and be considered for subsequent molecular analysis of the CAPN3 gene.


Assuntos
Calpaína/genética , Eosinofilia/genética , Proteínas Musculares/genética , Miosite/genética , Western Blotting , Calpaína/metabolismo , Criança , Pré-Escolar , Creatina Quinase/sangue , Eosinofilia/metabolismo , Eosinofilia/patologia , Feminino , Predisposição Genética para Doença , Humanos , Imuno-Histoquímica , Masculino , Proteínas Musculares/metabolismo , Mutação , Miosite/metabolismo , Miosite/patologia , Reação em Cadeia da Polimerase
20.
Nat Genet ; 38(5): 525-7, 2006 May.
Artigo em Inglês | MEDLINE | ID: mdl-16642017

RESUMO

Fibrodysplasia ossificans progressiva (FOP) is a rare autosomal dominant disorder of skeletal malformations and progressive extraskeletal ossification. We mapped FOP to chromosome 2q23-24 by linkage analysis and identified an identical heterozygous mutation (617G --> A; R206H) in the glycine-serine (GS) activation domain of ACVR1, a BMP type I receptor, in all affected individuals examined. Protein modeling predicts destabilization of the GS domain, consistent with constitutive activation of ACVR1 as the underlying cause of the ectopic chondrogenesis, osteogenesis and joint fusions seen in FOP.


Assuntos
Receptores de Ativinas Tipo I/genética , Mutação , Miosite Ossificante/genética , Receptores de Ativinas Tipo I/química , Sequência de Aminoácidos , Animais , Cromossomos Humanos Par 2 , Feminino , Humanos , Masculino , Dados de Sequência Molecular , Linhagem , RNA Mensageiro/genética , Homologia de Sequência de Aminoácidos
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