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BACKGROUND AND OBJECTIVES: To determine the genetic cause of the disease in the previously reported family with adult-onset autosomal dominant distal myopathy (myopathy, distal, 3; MPD3). METHODS: Continued clinical evaluation including muscle MRI and muscle pathology. A linkage analysis with single nucleotide polymorphism arrays and genome sequencing were used to identify the genetic defect, which was verified by Sanger sequencing. RNA sequencing was used to investigate the transcriptional effects of the identified genetic defect. RESULTS: Small hand muscles (intrinsic, thenar, and hypothenar) were first involved with spread to the lower legs and later proximal muscles. Dystrophic changes with rimmed vacuoles and cytoplasmic inclusions were observed in muscle biopsies at advanced stage. A single nucleotide polymorphism array confirmed the previous microsatellite-based linkage to 8p22-q11 and 12q13-q22. Genome sequencing of three affected family members combined with structural variant calling revealed a small heterozygous deletion of 160 base pairs spanning the second last exon 10 of the heterogeneous nuclear ribonucleoprotein A1 (HNRNPA1) gene, which is in the linked region on chromosome 12. Segregation of the mutation with the disease was confirmed by Sanger sequencing. RNA sequencing showed that the mutant allele produces a shorter mutant mRNA transcript compared with the wild-type allele. Immunofluorescence studies on muscle biopsies revealed small p62 and larger TDP-43 inclusions. DISCUSSION: A small exon 10 deletion in the gene HNRNPA1 was identified as the cause of MPD3 in this family. The new HNRNPA1-related phenotype, upper limb presenting distal myopathy, was thus confirmed, and the family displays the complexities of gene identification.
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Autosomal recessive mutations in Anoctamin 5 (ANO5/TMEM16E), a member of the transmembrane 16 (TMEM16) family of Ca2+-activated ion channels and phospholipid scramblases, cause adult-onset muscular dystrophies (limb girdle muscular dystrophy 2L (LGMD2L) and Miyoshi Muscular Dystrophy (MMD3). However, the molecular role of ANO5 is unclear and ANO5 knockout mouse models show conflicting requirements of ANO5 in muscle. To study the role of ANO5 in human muscle cells we generated a myoblast line from a MMD3-patient carrying the c.2272C>T mutation, which we find causes the mutant protein to be degraded. The patient myoblasts exhibit normal myogenesis, but are compromised in their plasma membrane repair (PMR) ability. The repair deficit is linked to the poor ability of the endoplasmic reticulum (ER) to clear cytosolic Ca2+ increase caused by focal plasma membrane injury. Expression of wild-type ANO5 or pharmacological prevention of injury-triggered cytosolic Ca2+ overload enable injured patient muscle cells to repair. A homology model of ANO5 shows that several of the known LGMD2L/MMD3 patient mutations line the transmembrane region of the protein implicated in its channel activity. These results point to a role of cytosolic Ca2+ homeostasis in PMR, indicate a role for ANO5 in ER-mediated cytosolic Ca2+ uptake and identify normalization of cytosolic Ca2+ homeostasis as a potential therapeutic approach to treat muscular dystrophies caused by ANO5 deficit.
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BACKGROUND: Anoctaminopathies are muscle diseases caused by recessive mutations in the ANO5 gene. The effects of anoctaminopathy on oxidative capacity have not previously been studied in a controlled setting. OBJECTIVE: To characterize oxidative capacity in a clinically and genetically well-defined series of patients with anoctaminopathy. METHODS: We sequenced the ANO5 gene in 111 Finnish patients with suspected LGMD2. Patients with positive findings underwent close clinical examination, including electromyography, muscle MRI, and, in selected cases, muscle biopsy. Oxidative capacity was analyzed using spiroergometry and compared to age-matched healthy controls. RESULTS: We characterized 12 newly identified and 2 previously identified patients with ANO5 mutations from 11 families. Our material was genetically homogeneous with most patients homozygous for the Finnish founder variant c.2272C>T (p.Arg758Cys). In one family, we found a novel p.Met470Arg variant compound heterozygous with p.Arg758Cys. Lower limb muscle MRI revealed progressive fatty degeneration of specific posterior compartment muscles. Patients' spiroergometric profiles showed that anoctaminopathy significantly impaired oxidative capacity with increasing ventilation. CONCLUSIONS: Our findings support earlier reports that anoctaminopathy progresses slowly and demonstrate that the disease impairs the capacity for aerobic exercise.
Assuntos
Músculo Esquelético/metabolismo , Distrofia Muscular do Cíngulo dos Membros/metabolismo , Consumo de Oxigênio , Adulto , Anoctaminas/genética , Estudos de Casos e Controles , Eletromiografia , Exercício Físico/fisiologia , Teste de Esforço , Feminino , Finlândia , Heterozigoto , Homozigoto , Humanos , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Músculo Esquelético/diagnóstico por imagem , Músculo Esquelético/fisiopatologia , Distrofia Muscular do Cíngulo dos Membros/genética , Distrofia Muscular do Cíngulo dos Membros/fisiopatologiaRESUMO
OBJECTIVE: Several families with characteristic features of hereditary myopathy with early respiratory failure (HMERF) have remained without genetic cause. This international study was initiated to clarify epidemiology and the genetic underlying cause in these families, and to characterise the phenotype in our large cohort. METHODS: DNA samples of all currently known families with HMERF without molecular genetic cause were obtained from 12 families in seven different countries. Clinical, histopathological and muscle imaging data were collected and five biopsy samples made available for further immunohistochemical studies. Genotyping, exome sequencing and Sanger sequencing were used to identify and confirm sequence variations. RESULTS: All patients with clinical diagnosis of HMERF were genetically solved by five different titin mutations identified. One mutation has been reported while four are novel, all located exclusively in the FN3 119 domain (A150) of A-band titin. One of the new mutations showed semirecessive inheritance pattern with subclinical myopathy in the heterozygous parents. Typical clinical features were respiratory failure at mid-adulthood in an ambulant patient with very variable degree of muscle weakness. Cytoplasmic bodies were retrospectively observed in all muscle biopsy samples and these were reactive for myofibrillar proteins but not for titin. CONCLUSIONS: We report an extensive collection of families with HMERF with five different mutations in exon 343 of TTN, which establishes this exon as the primary target for molecular diagnosis of HMERF. Our relatively large number of new families and mutations directly implies that HMERF is not extremely rare, not restricted to Northern Europe and should be considered in undetermined myogenic respiratory failure.
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Doenças Genéticas Inatas/epidemiologia , Doenças Musculares/epidemiologia , Insuficiência Respiratória/epidemiologia , Adulto , Idoso , Conectina/genética , Exoma/genética , Feminino , Doenças Genéticas Inatas/genética , Doenças Genéticas Inatas/patologia , Ligação Genética/genética , Predisposição Genética para Doença/genética , Humanos , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Músculo Esquelético/patologia , Doenças Musculares/genética , Doenças Musculares/patologia , Mutação/genética , Linhagem , Fenótipo , Insuficiência Respiratória/genética , Insuficiência Respiratória/patologiaRESUMO
Congenital myasthenic syndrome shows a wide clinical heterogeneity. However, the unusual pattern of muscle weakness and the presence of variable degree of muscle pathology, subtle electrophysiological abnormalities and lack of circadian variability of symptoms may complicate its recognition. We have previously reported a Palestinian family with suspected congenital muscular dystrophy and linkage to chromosome 4p16.3. As the DOK7 gene is located in this genetic interval, we considered it a potential candidate for this condition. Patients showed a homozygous DOK7 pathogenic mutation (c.957delC). We have re-examined six patients and found permanent limb-girdle weakness, but also episodic crises without clear precipitating factors. Following the revised diagnosis, patients were treated with salbutamol for 8 months with significant improvement in their muscle strength and function. This family needs to be reclassified as congenital myasthenic syndrome rather than congenital muscular dystrophy.
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Proteínas Musculares/genética , Distrofia Muscular do Cíngulo dos Membros/congênito , Distrofia Muscular do Cíngulo dos Membros/genética , Mutação/genética , Síndromes Miastênicas Congênitas/genética , Agonistas de Receptores Adrenérgicos beta 2/farmacologia , Adulto , Albuterol/farmacologia , Diagnóstico Diferencial , Efedrina/farmacologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Força Muscular/efeitos dos fármacos , Força Muscular/fisiologia , Debilidade Muscular/genética , Debilidade Muscular/fisiopatologia , Distrofia Muscular do Cíngulo dos Membros/diagnóstico , Síndromes Miastênicas Congênitas/diagnóstico , Síndromes Miastênicas Congênitas/etnologia , Paquistão , Resultado do TratamentoRESUMO
Anoctaminopathy is a new muscular dystrophy caused by mutations in the ANO5 gene. ANO5 mutations cause distal and proximal phenotypes. We report here a follow-up muscle MRI study on five patients affected by distal form of anoctaminopathy. T1 weighted scans showed subsequent involvement of gastrocnemius medialis and soleus, hip adductors, hamstrings, gastrocnemius lateralis and quadriceps muscles, and later on tensor fascia lata, gluteus minimus and biceps brachii muscles, respectively. The STIR weighted images showed in the early stages widely distributed hyperintense signals, myoedema, in the adductors, hamstrings, and quadriceps muscles, which at that time have normal T1 signals. All patients showed asymmetry of muscle involvement both clinically and on muscle imaging. The progression of muscle involvement was relatively slow. We conclude that the pattern of muscle involvement seen in patients with distal myopathy with anoctamin 5 mutations (MMD3) is typical and can thus be useful during the differential diagnosis process allowing for a more targeted molecular approach.
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Canais de Cloreto/genética , Miopatias Distais/diagnóstico , Miopatias Distais/genética , Predisposição Genética para Doença/genética , Músculo Esquelético/patologia , Mutação/genética , Idoso , Anoctaminas , Análise Mutacional de DNA , Humanos , Processamento de Imagem Assistida por Computador , Imageamento por Ressonância Magnética , Pessoa de Meia-Idade , Estudos RetrospectivosRESUMO
Limb-girdle muscular dystrophy type 1D (LGMD1D) was linked to chromosome 7q36 over a decade ago, but its genetic cause has remained elusive. Here we studied nine LGMD-affected families from Finland, the United States and Italy and identified four dominant missense mutations leading to p.Phe93Leu or p.Phe89Ile changes in the ubiquitously expressed co-chaperone DNAJB6. Functional testing in vivo showed that the mutations have a dominant toxic effect mediated specifically by the cytoplasmic isoform of DNAJB6. In vitro studies demonstrated that the mutations increase the half-life of DNAJB6, extending this effect to the wild-type protein, and reduce its protective anti-aggregation effect. Further, we show that DNAJB6 interacts with members of the CASA complex, including the myofibrillar myopathy-causing protein BAG3. Our data identify the genetic cause of LGMD1D, suggest that its pathogenesis is mediated by defective chaperone function and highlight how mutations in a ubiquitously expressed gene can exert effects in a tissue-, isoform- and cellular compartment-specific manner.
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Proteínas de Choque Térmico HSP40/genética , Chaperonas Moleculares/genética , Distrofia Muscular do Cíngulo dos Membros/genética , Distrofia Muscular do Cíngulo dos Membros/metabolismo , Proteínas do Tecido Nervoso/genética , Proteínas Adaptadoras de Transdução de Sinal/genética , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Animais , Proteínas Reguladoras de Apoptose , Finlândia , Genótipo , Proteínas de Choque Térmico HSP40/metabolismo , Humanos , Itália , Chaperonas Moleculares/metabolismo , Músculo Esquelético/metabolismo , Músculo Esquelético/patologia , Distrofia Muscular do Cíngulo dos Membros/patologia , Mutação de Sentido Incorreto , Proteínas do Tecido Nervoso/metabolismo , Estados Unidos , Peixe-Zebra/embriologia , Peixe-Zebra/genéticaRESUMO
The objective is to refine the clinical and morphological phenotype and the chromosomal region of interest, in the recently reported 7q36 linked autosomal dominant limb-girdle muscular dystrophy (LGMD1 D/E), by describing four new informative Finnish families. Examinations of the patients included serum CK, neurophysiological studies, cardiac and respiratory function examinations, muscle biopsies and muscle imaging. DNA samples were analyzed by genotyping. Patients in all families had very similar phenotypes with onset of muscle weakness in the pelvic girdle muscles between the fourth and sixth decade, later involvement of the shoulder girdle, and marked walking difficulties in the eighth decade. Muscle biopsies showed myopathic and/or dystrophic features. Genotyping confirmed linkage to the same locus at chromosome 7q36 in all families by one identically segregating haplotype. The linked region was narrowed down from <6.3 to <3.4Mb. Sequencing of the genes in the area is ongoing, aiming to identify the genetic defect.
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Cromossomos Humanos Par 7/genética , Saúde da Família , Ligação Genética , Fenótipo , Adolescente , Adulto , Criança , Pré-Escolar , Mapeamento Cromossômico , Creatina Quinase/sangue , Eletrocardiografia , Eletromiografia , Feminino , Finlândia/etnologia , Genótipo , Humanos , Masculino , Biologia Molecular/métodos , Distrofia Muscular do Cíngulo dos Membros/genética , Distrofia Muscular do Cíngulo dos Membros/patologia , Adulto JovemRESUMO
We have been following clinically and with muscle MRI for the past 3-decades a Finnish family with two patients with distal muscular dystrophy. Previously we demonstrated the cellular defect in these patients to be defective membrane repair and more recently have identified the causative gene to be anoctamin 5 (ANO5). The disorder seen in these patients is characterized by onset in the third decade. First symptoms were burning sensation on the calves and later on calf tightness during running. Muscle weakness and wasting were asymmetric and early involving the calf muscles, later spread to the thigh muscles. Biceps brachi was later manifestation. Clinical course was slow. CK levels were high. Muscle biopsy showed dystrophic pattern and multifocal disruption of the sarcolemmal membrane but no subsarcolemmal vesicle accumulation nor active inflammation. We conclude that the disease seen in our cases is a new separate clinical, genetic and histopathologic entity to include within the classification of autosomal recessive distal muscular dystrophies.
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Canais de Cloreto/genética , Miopatias Distais/genética , Músculo Esquelético/patologia , Adulto , Anoctaminas , Miopatias Distais/patologia , Finlândia , Humanos , Masculino , Pessoa de Meia-Idade , Debilidade Muscular/genética , Debilidade Muscular/patologia , Mutação , Linhagem , FenótipoRESUMO
The recently described human anion channel Anoctamin (ANO) protein family comprises at least ten members, many of which have been shown to correspond to calcium-activated chloride channels. To date, the only reported human mutations in this family of genes are dominant mutations in ANO5 (TMEM16E, GDD1) in the rare skeletal disorder gnathodiaphyseal dysplasia. We have identified recessive mutations in ANO5 that result in a proximal limb-girdle muscular dystrophy (LGMD2L) in three French Canadian families and in a distal non-dysferlin Miyoshi myopathy (MMD3) in Dutch and Finnish families. These mutations consist of a splice site, one base pair duplication shared by French Canadian and Dutch cases, and two missense mutations. The splice site and the duplication mutations introduce premature-termination codons and consequently trigger nonsense-mediated mRNA decay, suggesting an underlining loss-of-function mechanism. The LGMD2L phenotype is characterized by proximal weakness, with prominent asymmetrical quadriceps femoris and biceps brachii atrophy. The MMD3 phenotype is associated with distal weakness, of calf muscles in particular. With the use of electron microscopy, multifocal sarcolemmal lesions were observed in both phenotypes. The phenotypic heterogeneity associated with ANO5 mutations is reminiscent of that observed with Dysferlin (DYSF) mutations that can cause both LGMD2B and Miyoshi myopathy (MMD1). In one MMD3-affected individual, defective membrane repair was documented on fibroblasts by membrane-resealing ability assays, as observed in dysferlinopathies. Though the function of the ANO5 protein is still unknown, its putative calcium-activated chloride channel function may lead to important insights into the role of deficient skeletal muscle membrane repair in muscular dystrophies.
Assuntos
Canais de Cloreto/genética , Genes Recessivos/genética , Distrofia Muscular do Cíngulo dos Membros/genética , Mutação/genética , Adulto , Idoso , Anoctaminas , Sequência de Bases , Canadá , Canais de Cloreto/química , Códon sem Sentido/genética , Cicloeximida/farmacologia , Análise Mutacional de DNA , Disferlina , Família , Feminino , Humanos , Masculino , Proteínas de Membrana/genética , Pessoa de Meia-Idade , Dados de Sequência Molecular , Proteínas Musculares/genética , Músculos/efeitos dos fármacos , Músculos/patologia , Músculos/ultraestrutura , Distrofia Muscular do Cíngulo dos Membros/patologia , LinhagemRESUMO
Bent spine, i.e. camptocormia appears in several disease. Segmental dystonia is one of these. A few cases benefiting from botulinum toxin therapy have been described in the literature. We describe a case, in which segmental dystonia is associated with camptocormia, causing the patient to use a wheelchair. The condition fulfilled the criteria of both clinical and electromyographic dystonia. Administration of botulinum toxin into rectus abdominus muscles was started. The response was good: the patient was able to walk in a fairly erect posture assisted by a rolling walker.
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Toxinas Botulínicas Tipo A/uso terapêutico , Distúrbios Distônicos/tratamento farmacológico , Fármacos Neuromusculares/uso terapêutico , Curvaturas da Coluna Vertebral/tratamento farmacológico , Distúrbios Distônicos/complicações , Feminino , Humanos , Curvaturas da Coluna Vertebral/etiologiaRESUMO
Two autosomal recessive muscle diseases, limb girdle muscular dystrophy type 2B (LGMD2B) and Miyoshi myopathy (MM), are caused by mutations in the dysferlin gene. These mutations result in poor ability to repair cell membrane damage, which is suggested to be the cause for this disease. However, many patients who share clinical features with MM-type muscular dystrophy do not carry mutations in dysferlin gene. To understand the basis of MM that is not due to mutations in dysferlin gene, we analyzed cells from patients in one such family. In these patients, we found no defects in several potential candidates - annexin A2, caveolin-3, myoferlin and the MMD2 locus on chromosome 10p. Similar to dysferlinopathy, these cells also exhibit membrane repair defects and the severity of the defect correlated with severity of their disease. However, unlike dysferlinopathy, none of the conventional membrane repair pathways are defective in these patient cells. These results add to the existing evidence that cell membrane repair defect may be responsible for MM-type muscular dystrophy and indicate that a previously unsuspected genetic lesion that affects cell membrane repair pathway is responsible for the disease in the non-dysferlin MM patients.
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Miopatias Distais/genética , Miopatias Distais/metabolismo , Proteínas de Membrana/genética , Proteínas de Membrana/metabolismo , Proteínas Musculares/genética , Proteínas Musculares/metabolismo , Adulto , Anexina A2/genética , Cálcio/metabolismo , Membrana Celular/metabolismo , Células Cultivadas , Disferlina , Exocitose , Feminino , Haplótipos , Humanos , Lisossomos/metabolismo , Masculino , Pessoa de Meia-Idade , Músculo Esquelético/lesões , Músculo Esquelético/metabolismo , Mutação , Linhagem , FenótipoRESUMO
Balance and gait are a consequence of complex coordination between muscles, nerves, and central nervous system structures. The impairment of these functions can pose serious threats to independent living, especially in the elderly. This study was carried out to evaluate the performance of a wireless acceleration sensor network and its capability in balance estimation. The test has been carried out in eight patients and seven healthy controls. The Patients group had larger values in lateral amplitudes of the sensor displacement and smaller values in vertical displacement amplitudes of the sensor. The step time variations for the Patients were larger than those for the controls. A fuzzy logic and clustering classifiers were implemented, which gave promising results suggesting that a person with balance deficits can be recognized with this system. We conclude that a wireless system is easier to use than a wired one and more unobtrusive to the user.
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Aceleração , Inteligência Artificial , Redes de Comunicação de Computadores/instrumentação , Diagnóstico por Computador/instrumentação , Monitorização Ambulatorial/instrumentação , Equilíbrio Postural/fisiologia , Telemetria/instrumentação , Análise por Conglomerados , Diagnóstico por Computador/métodos , Desenho de Equipamento , Análise de Falha de Equipamento , Humanos , Monitorização Ambulatorial/métodos , Reprodutibilidade dos Testes , Sensibilidade e EspecificidadeRESUMO
BACKGROUND: Marinesco-Sjögren syndrome (MSS) is an autosomal recessive multiorgan disorder showing clinical and genetic heterogeneity. The key features of MSS include cerebellar ataxia, early bilateral cataracts, delayed motor development, and varying degrees of mental retardation. Patients with a subtype of MSS with myoglobinuria and neuropathy have been linked to chromosome 18qter, and recently a locus for classical MSS has been localized on chromosome 5q31. OBJECTIVES: To determine the importance of myopathy in this disorder apart from the CNS based disability and to establish the pattern of muscle involvement and degree of its severity. METHODS: Muscle computed tomography (CT) investigations were carried out in nine Finnish MSS patients homozygous for markers around the MSS locus on chromosome 5q31. RESULTS: Patients with severe clinical disability showed severe and generalized muscle degeneration. Muscle CT findings in patients with relatively severe clinical picture were characterized by severe involvement of the posterior thoracic and pelvic muscles, and almost all thigh muscles. In the legs the peronei and posterior compartment muscles were severely degenerated. The group of patients with moderate severity of disease showed the same pattern of involved muscle, albeit with lower degree of muscle degeneration. CONCLUSIONS: Patients with MSS linked to chromosome 5q31 have a severe progressive myopathy, the extent of which may remain largely unrecognized because of the CNS involvement.
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Músculo Esquelético/patologia , Doenças Musculares/patologia , Degenerações Espinocerebelares/patologia , Tomógrafos Computadorizados , Adulto , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Doenças Musculares/complicações , Índice de Gravidade de Doença , Degenerações Espinocerebelares/complicaçõesRESUMO
We identified the gene underlying Marinesco-Sjögren syndrome, which is characterized by cerebellar ataxia, progressive myopathy and cataracts. We identified four disease-associated, predicted loss-of-function mutations in SIL1, which encodes a nucleotide exchange factor for the heat-shock protein 70 (HSP70) chaperone HSPA5. These data, together with the similar spatial and temporal patterns of tissue expression of Sil1 and Hspa5, suggest that disturbed SIL1-HSPA5 interaction and protein folding is the primary pathology in Marinesco-Sjögren syndrome.
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Fatores de Troca do Nucleotídeo Guanina/genética , Proteínas de Choque Térmico/metabolismo , Chaperonas Moleculares/metabolismo , Proteínas/metabolismo , Degenerações Espinocerebelares/genética , Degenerações Espinocerebelares/metabolismo , Chaperona BiP do Retículo Endoplasmático , Finlândia , Deleção de Genes , Fatores de Troca do Nucleotídeo Guanina/análise , Fatores de Troca do Nucleotídeo Guanina/metabolismo , Humanos , Músculo Esquelético/química , Mutação , Dobramento de ProteínaRESUMO
Computed tomography provides a sensitive method for investigating skeletal muscle changes in neuromuscular diseases, but this method has not been applied to mitochondrial myopathies. We characterized the pattern of muscle involvement in patients with the 3243A>G mutation in mitochondrial DNA (mtDNA), the common MELAS (mitochondrial myopathy, encephalopathy, lactic acidosis and stroke-like episodes) mutation. Twenty-four patients, age 19-73 years, with 3243A>G were examined. Clinical evaluation included assessment of muscle strength and functional capacity. All the patients underwent muscle computed tomography, and muscle samples from 17 of them were examined for the presence of ragged red fibres and for the 3243A>G heteroplasmy. Venous blood lactate at rest and serum creatine kinase were determined. Clinical myopathy was found in six patients, while nine showed mild muscle weakness and nine had normal muscle function. The upper and lower limbs were equally affected, but the proximal muscles were more severely affected than the distal ones. CT revealed abnormalities in the muscles of 13 patients (54%; 95% confidence interval, 33-76%), including the six with clinical myopathy and seven without clinical myopathy. Myopathic changes were found most frequently in the pelvic muscles, with predominant involvement of the gluteus maximus. These data show that CT reveals frequent abnormal findings in the muscle of patients with the 3243A>G mtDNA mutation. Muscle CT is a useful adjunct to clinical evaluation in these patients.
Assuntos
DNA Mitocondrial/genética , Síndrome MELAS/patologia , Músculo Esquelético/patologia , Mutação Puntual , Tomógrafos Computadorizados , Adulto , Idoso , Eletromiografia/métodos , Feminino , Humanos , Síndrome MELAS/genética , Masculino , Pessoa de Meia-Idade , Músculo Esquelético/metabolismo , Estatísticas não ParamétricasRESUMO
We recently described a new type of adult onset distal myopathy (MPD3) with autosomal dominant inheritance. The onset of symptoms is around the age of 30 and the characteristic first symptoms include clumsiness of the hands and stumbling. The thenar and hypothenar muscles are involved at the onset. The disease progressed to the intrinsic muscles of the hands, both anterior and posterior muscle compartments of the lower legs, the forearm muscles, and later to the proximal muscles. Dystrophic changes with rimmed vacuoles were observed in the muscle biopsy. We have performed a genome wide scan here in order to identify the MPD3 locus. Unexpectedly, markers on two distinct chromosomal regions 8p22-q11 and 12q13-q22, provided significant evidence for linkage in this family. Multipoint linkage analyses produced equal maximum multipoint LOD score of 3.01 for both chromosomal regions and haplotype analysis showed a specific haplotype segregating with the disease for both loci. It is thus impossible to distinguish between two loci without additional family material. Two obvious regional candidate genes, encoding muscular proteins became subjects for sequence analyses, the gene for myosin light chain 1 slow-twitch muscle A on 12q13 and the muscle specific exons of ankyrin 1 on 8p11. No mutations were identified in the coding sequence.