Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 29
Filtrar
1.
Stereotact Funct Neurosurg ; 97(1): 18-23, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30870851

RESUMO

BACKGROUND: Intrathecal baclofen (ITB) treatment is considered a powerful tool in the management of severe spasticity in neurological conditions such as multiple sclerosis, cerebral palsy, and traumatic spinal cord and brain injury. OBJECTIVES: The objective of this study was to assess the effectiveness of the ITB in patients with inherited ataxia suffering from severe painful spasms and/or spasticity. METHOD: A total of 5 patients with spinocerebellar ataxia 3 or 7 or Friedreich's ataxia were included in this observational multicenter study. The patients were interviewed and completed outcome measures assessing pain (The Brief Pain Inventory), fatigue (Fatigue Severity Scale), and life satisfaction (LiSAT-9) before and 1 year after the treatment. Spasticity (Modified Ashworth Scale) and spasm frequency (SPFS) were measured objectively for each patient. RESULTS: The mean treatment time was 1.9 years. Evaluation of established standard forms revealed symptomatic relief from spasticity, spasms, pain, and fatigue in addition to improved body posture, sleep, and life satisfaction after ITB treatment. CONCLUSIONS: We report the potential beneficial effects of ITB treatment in patients with inherited ataxia who also suffer from spasticity/spasms. ITB treatment indication in neurological disorders allows for extension to the treatment of spasticity/ spasms in patients with hereditary ataxia.


Assuntos
Baclofeno/administração & dosagem , Ataxia de Friedreich/tratamento farmacológico , Relaxantes Musculares Centrais/administração & dosagem , Espasticidade Muscular/tratamento farmacológico , Dor/tratamento farmacológico , Ataxias Espinocerebelares/tratamento farmacológico , Adulto , Idoso , Feminino , Ataxia de Friedreich/diagnóstico , Humanos , Injeções Espinhais , Masculino , Pessoa de Meia-Idade , Espasticidade Muscular/diagnóstico , Dor/diagnóstico , Medição da Dor/efeitos dos fármacos , Medição da Dor/métodos , Ataxias Espinocerebelares/diagnóstico , Resultado do Tratamento
2.
Acta Neurol Scand ; 139(2): 135-142, 2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-30192380

RESUMO

OBJECTIVE: LMNB1-related autosomal dominant leukodystrophy is caused by an overexpression of the protein lamin B1, usually due to a duplication of the LMNB1 gene. Symptoms start in 5th to 6th decade. This slowly progressive disease terminates with death. We studied brain glucose metabolism in this disease using 18 F-fluorodeoxyglucose positron emission tomography (PET). METHODS: We examined 8 patients, aged 48-64 years, in varying stages of clinical symptomatology. Two patients were investigated with quantitative PET on clinical indications after which six more patients were recruited. Absolute glucose metabolism was analyzed with the PVElab software in 6 patients and 18 healthy controls. A semiquantitative analysis using the CortexID software was performed in seven investigations, relating local metabolism levels to global glucose metabolism. RESULTS: The clinical quantitative PET revealed low global glucose metabolism, with the most marked reduction in the cerebellum. In the PVElab analysis, patients presented low mean glucose metabolism in the cerebellum, brainstem and global grey matter. In the semiquantitative analysis, 2 patients showed a decreased metabolism in the cerebellum and 4 patients a relatively higher metabolism in parts of the temporal lobes. Since none of the patients showed an increased metabolism in the quantitative analysis, we interpret these increases as "pseudo-increases" related to a globally reduced metabolism. CONCLUSIONS: Global reduction of grey matter glucose metabolism in this white matter disease most likely depends on a combination of cortical afferent dysfunction and, in later stages, neuronal loss. The lowest metabolism in the cerebellum is consistent with histopathological findings and prominent cerebellar symptoms.


Assuntos
Cerebelo/diagnóstico por imagem , Lamina Tipo B/genética , Doença de Pelizaeus-Merzbacher/diagnóstico por imagem , Tomografia por Emissão de Pósitrons , Cerebelo/metabolismo , Cerebelo/patologia , Feminino , Fluordesoxiglucose F18 , Humanos , Masculino , Pessoa de Meia-Idade , Doença de Pelizaeus-Merzbacher/metabolismo , Doença de Pelizaeus-Merzbacher/patologia , Compostos Radiofarmacêuticos
3.
Ann Neurol ; 78(3): 412-25, 2015 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-26053668

RESUMO

OBJECTIVE: Duplication of the LMNB1 gene encoding lamin B1 causes adult-onset autosomal-dominant leukodystrophy (ADLD) starting with autonomic symptoms, which are followed by pyramidal signs and ataxia. Magnetic resonance imaging (MRI) of the brain reveals characteristic findings. This is the first longitudinal study on this disease. Our objective is to describe the natural clinical and radiological course of LMNB1-related ADLD. METHODS: Twenty-three subjects in two families with LMNB1 duplications were studied over two decades with clinical assessment and MRI of the brain and spinal cord. They were 29 to 70 years old at their first MRI. Repeated MRIs were performed in 14 subjects over a time period of up to 17 years. RESULTS: Pathological MRI findings were found in the brain and spinal cord in all examinations (i.e., even preceding clinical symptoms). MRI changes and clinical symptoms progressed in a definite order. Autonomic dysfunction appeared in the fifth to sixth decade, preceding or together with gait and coordination difficulties. Motor signs developed ascending from spastic paraplegia to tetraplegia and pseudobulbar palsy in the seventh decade. There were clinical, radiological, and neurophysiological signs of myelopathy. Survival lasted more than two decades after clinical onset. INTERPRETATION: LMNB1-related ADLD is a slowly progressive neurological disease. MRI abnormalities of the brain and spinal cord can precede clinical symptoms by more than a decade and are extensive in all symptomatic patients. Spinal cord involvement is a likely contributing factor to early autonomic symptoms and spastic paraplegia.


Assuntos
Encéfalo/diagnóstico por imagem , Lamina Tipo B/genética , Doença de Pelizaeus-Merzbacher/diagnóstico por imagem , Doença de Pelizaeus-Merzbacher/genética , Medula Espinal/diagnóstico por imagem , Adulto , Idoso , Feminino , Humanos , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade , Doença de Pelizaeus-Merzbacher/mortalidade , Radiografia , Taxa de Sobrevida/tendências
4.
Case Rep Neurol ; 6(2): 171-5, 2014 May.
Artigo em Inglês | MEDLINE | ID: mdl-24987361

RESUMO

Susac syndrome is an autoimmune microangiopathy affecting the brain, retina and inner ear (cochlea and semicircular canals), leading to encephalopathy, branch retinal artery occlusions (BRAOs) and asymmetric neurosensory hearing loss, respectively. The natural history and long-term prognosis are variable as the disease has been shown to be monophasic and self-limiting, polycyclic or chronic continuous. We describe a 35-year-old woman who presented with a sudden hearing loss in the left ear in the 37th week of her second pregnancy. She subsequently developed BRAO in the right eye 2.5 months after having given birth. MRI findings included round lesions in the corpus callosum which are pathognomonic for Susac syndrome. Previous patient records documented encephalopathy, sudden deafness of the right ear and visual field defects in the left eye at the age of 12, followed by permanent hearing and visual defects. We expand on the variability in the course of Susac syndrome as recurrence may occur after as long as 23 years. Cases of monophasic self-limiting Susac syndrome may in fact turn polycyclic with an interval of more than 2 decades between the bouts of the disease. In these cases, suspecting the development of exacerbation early is important in order to start the treatment promptly.

6.
Case Rep Neurol ; 5(3): 201-3, 2013.
Artigo em Inglês | MEDLINE | ID: mdl-24348400

RESUMO

We present the case of a 50-year-old female patient with Friedreich ataxia (FA) who was treated successfully with an intrathecal baclofen (ITB)-delivering pump for painful spasms. To our knowledge, this is the second reported case of FA where ITB relieved painful and disabling spasms. We suggest that ITB should be considered in the treatment of disabling spasms in patients with FA.

7.
Sleep ; 36(8): 1257-9, 1259A, 2013 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-23904686

RESUMO

STUDY OBJECTIVES: Autosomal dominant cerebellar ataxia, deafness and narcolepsy (ADCA-DN) is caused by DNMT1 mutations. Diagnosing the syndrome can be difficult, as all clinical features may not be present at onset, HLA-DQB1*06:02 is often negative, and sporadic cases occur. We report on clinical and genetic findings in a 31-year-old woman with cerebellar ataxia, deafness, and narcolepsy, and discuss diagnostic challenges. DESIGN: Clinical and genetic investigation in a patient and family members. SETTING: Ataxia clinic, São Paulo, Brazil. PATIENTS OR PARTICIPANTS: One patient and her family members. INTERVENTIONS: N/A. MEASUREMENTS AND RESULTS: Narcolepsy was supported by polysomnographic and multiple sleep latency testing. HLA-DQB1*06:02 was positive. CSF hypocretin-1 was 191 pg/mL (normal values > 200 pg/mL). Mild brain atrophy was observed on MRI, with cerebellar involvement. The patient, her asymptomatic mother, and 3 siblings gave blood samples for genetic analysis. DNMT1 exons 20 and 21 were sequenced. Haplotyping of polymorphic markers surrounding the mutation was performed. The proband had a novel DNMT1 mutation in exon 21, p.Cys596Arg, c.1786T > C. All 4 parental haplotypes could be characterized in asymptomatic siblings without the mutation, indicating that the mutation is de novo in the patient. CONCLUSIONS: The Brazilian patient reported here further adds to the worldwide distribution of ADCA-DN. The mutation is novel, and illustrates a sporadic case with de novo mutation. We believe that many more cases with this syndrome are likely to be diagnosed in the near future, mandating knowledge of this condition and consideration of the diagnosis.


Assuntos
Ataxia Cerebelar/genética , DNA (Citosina-5-)-Metiltransferases/genética , Surdez/genética , Narcolepsia/genética , Polimorfismo de Nucleotídeo Único/genética , Adulto , Brasil , Ataxia Cerebelar/complicações , DNA (Citosina-5-)-Metiltransferase 1 , DNA (Citosina-5-)-Metiltransferases/fisiologia , Surdez/complicações , Éxons/genética , Éxons/fisiologia , Feminino , Humanos , Narcolepsia/complicações , Polissonografia
8.
Hum Mutat ; 34(8): 1160-71, 2013 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-23649844

RESUMO

Autosomal dominant leukodystrophy (ADLD) is an adult onset demyelinating disorder that is caused by duplications of the lamin B1 (LMNB1) gene. However, as only a few cases have been analyzed in detail, the mechanisms underlying LMNB1 duplications are unclear. We report the detailed molecular analysis of the largest collection of ADLD families studied, to date. We have identified the minimal duplicated region necessary for the disease, defined all the duplication junctions at the nucleotide level and identified the first inverted LMNB1 duplication. We have demonstrated that the duplications are not recurrent; patients with identical duplications share the same haplotype, likely inherited from a common founder and that the duplications originated from intrachromosomal events. The duplication junction sequences indicated that nonhomologous end joining or replication-based mechanisms such fork stalling and template switching or microhomology-mediated break induced repair are likely to be involved. LMNB1 expression was increased in patients' fibroblasts both at mRNA and protein levels and the three LMNB1 alleles in ADLD patients show equal expression, suggesting that regulatory regions are maintained within the rearranged segment. These results have allowed us to elucidate duplication mechanisms and provide insights into allele-specific LMNB1 expression levels.


Assuntos
Duplicação Gênica , Lamina Tipo B/genética , Doença de Pelizaeus-Merzbacher/genética , Adulto , Sequência de Bases , Pontos de Quebra do Cromossomo , Hibridização Genômica Comparativa , DNA/química , DNA/genética , Humanos , Lamina Tipo B/metabolismo , Dados de Sequência Molecular , Conformação de Ácido Nucleico , Doença de Pelizaeus-Merzbacher/metabolismo , RNA Mensageiro/genética , RNA Mensageiro/metabolismo
9.
Hum Mutat ; 34(4): 572-7, 2013 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-23348830

RESUMO

Welander distal myopathy (WDM) is an adult onset autosomal dominant disorder characterized by distal limb weakness, which progresses slowly from the fifth decade. All WDM patients are of Swedish or Finnish descent and share a rare chromosome 2p13 haplotype. We restricted the WDM-associated haplotype followed by whole exome sequencing. Within the conserved haplotype, we identified a single heterozygous mutation c.1150G>A (p.E384K) in T-cell intracellular antigen-1 (TIA1) in all WDM patients investigated (n = 43). The TIA1 protein regulates splicing, and translation through direct interaction with mRNA and the p.E384K mutation is located in the C-terminal Q-rich domain that interacts with the U1-C splicing factor. TIA1 has been shown to prevent skipping of SMN2 exon 7, and we show that WDM patients have increased levels of spliced SMN2 in skeletal muscle cells when compared with controls. Immunostaining of WDM muscle biopsies showed accumulation of TIA1 and stress granulae proteins adjacent to intracellular inclusions, a typical finding in WDM. The combined findings strongly suggest that the TIA1 mutation causes perturbed RNA splicing and cellular stress resulting in WDM. The selection against the mutation is likely to be negligible and the age of the TIA1 founder mutation was calculated to approximately 1,050 years, which coincides with the epoch of early seafaring across the Baltic Sea.


Assuntos
Miopatias Distais/genética , Efeito Fundador , Mutação , Proteínas de Ligação a Poli(A)/genética , Splicing de RNA , Processamento Alternativo , Sequência de Aminoácidos , Sequência de Bases , Miopatias Distais/metabolismo , Exoma , Éxons , Expressão Gênica , Haplótipos , Humanos , Repetições de Microssatélites , Dados de Sequência Molecular , Músculo Esquelético/metabolismo , Músculo Esquelético/patologia , Proteínas de Ligação a Poli(A)/metabolismo , Alinhamento de Sequência , Proteína 2 de Sobrevivência do Neurônio Motor/genética , Antígeno-1 Intracelular de Células T
10.
J Anesth ; 27(1): 128-31, 2013 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-22976939

RESUMO

Rippling muscle disease (RMD) is a disorder that affects striated muscle and involves disturbances in calcium homeostasis. Malignant hyperthermia susceptibility (MHS) is a potentially lethal disorder, characterized by extreme hypermetabolism and muscle rigidity/rhabdomyolysis during anesthesia with potent inhalational agents, in otherwise healthy individuals. The aim of this report was to search for a correlation between RMD and MHS in members of a family in which both disorders were present. Ten members of a large Swedish family segregating RMD were tested for MHS prior to establishing an RMD diagnosis. Results from diagnostic RMD investigations and anesthesia outcomes were collected and cross-referenced to evaluate whether phenotype variations could be predicted by in vitro contracture test (IVCT) results suggestive of MHS. No correlation was found between individual RMD phenotypes and the IVCT results. There were no recorded adverse reactions to anesthesia, and RMD and MHS did not co-segregate. We conclude that RMD patients should not, on the basis of our present knowledge, be classified as having MHS; however, an increased surveillance for MH reactions is recommended in these patients.


Assuntos
Hipertermia Maligna/genética , Doenças Musculares/genética , Anestesia/efeitos adversos , Anestesia Geral/efeitos adversos , Anestésicos Inalatórios/efeitos adversos , Cafeína , Caveolina 3/genética , Creatina Quinase/sangue , Família , Halotano/efeitos adversos , Humanos , Hipertermia Maligna/complicações , Contração Muscular/efeitos dos fármacos , Contração Muscular/fisiologia , Doenças Musculares/complicações , Mutação/genética , Linhagem , Fenótipo , Inibidores de Fosfodiesterase , Resultado do Tratamento
12.
Brain ; 135(Pt 6): 1682-94, 2012 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-22577218

RESUMO

Hereditary myopathy with early respiratory failure and extensive myofibrillar lesions has been described in sporadic and familial cases and linked to various chromosomal regions. The mutated gene is unknown in most cases. We studied eight individuals, from three apparently unrelated families, with clinical and pathological features of hereditary myopathy with early respiratory failure. The investigations included clinical examination, muscle histopathology and genetic analysis by whole exome sequencing and single nucleotide polymorphism arrays. All patients had adult onset muscle weakness in the pelvic girdle, neck flexors, respiratory and trunk muscles, and the majority had prominent calf hypertrophy. Examination of pulmonary function showed decreased vital capacity. No signs of cardiac muscle involvement were found. Muscle histopathological features included marked muscle fibre size variation, fibre splitting, numerous internal nuclei and fatty infiltration. Frequent groups of fibres showed eosinophilic inclusions and deposits. At the ultrastructural level, there were extensive myofibrillar lesions with marked Z-disc alterations. Whole exome sequencing in four individuals from one family revealed a missense mutation, g.274375T>C; p.Cys30071Arg, in the titin gene (TTN). The mutation, which changes a highly conserved residue in the myosin binding A-band titin, was demonstrated to segregate with the disease in all three families. High density single nucleotide polymorphism arrays covering the entire genome demonstrated sharing of a 6.99 Mb haplotype, located in chromosome region 2q31 including TTN, indicating common ancestry. Our results demonstrate a novel and the first disease-causing mutation in A-band titin associated with hereditary myopathy with early respiratory failure. The typical histopathological features with prominent myofibrillar lesions and inclusions in muscle and respiratory failure early in the clinical course should be incentives for analysis of TTN mutations.


Assuntos
Saúde da Família , Proteínas Musculares/genética , Doenças Musculares/genética , Mutação/genética , Polimorfismo de Nucleotídeo Único/genética , Proteínas Quinases/genética , Insuficiência Respiratória/genética , Actinas/metabolismo , Adulto , Idoso , Conectina , Extremidades/patologia , Feminino , Estudos de Associação Genética , Humanos , Imageamento por Ressonância Magnética , Masculino , Microscopia Eletrônica de Transmissão , Pessoa de Meia-Idade , Músculo Esquelético/patologia , Músculo Esquelético/ultraestrutura , Doenças Musculares/complicações , Moléculas de Adesão de Célula Nervosa/metabolismo , Análise de Sequência com Séries de Oligonucleotídeos , Insuficiência Respiratória/complicações , Suécia
13.
Eur J Hum Genet ; 20(9): 984-5, 2012 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-22395865

RESUMO

Using exome sequencing we searched for the genetic cause of autosomal dominant myofibrillar myopathy with arrhythmogenic right ventricular cardiomyopathy (ARVC) in a Swedish family. A heterozygous C-to-T transition, c.1255C>T, p.Pro419Ser in the desmin gene on chromosome 2q35, was identified. Previous studies had demonstrated linkage to chromosome 10q22.3, but no causative mutation had been found in that region. Sanger sequencing of DNA from 17 family members confirmed the heterozygous c.1255C>T desmin mutation in seven out of ten family members that had been classified as affected in the previous study. Our new results demonstrate the usefulness of next-generation sequencing, and the diagnostic difficulties with some forms of dominantly inherited muscle diseases as they can display a wide clinical and morphological variability even within a given family.


Assuntos
Displasia Arritmogênica Ventricular Direita/genética , Desmina/genética , Filamentos Intermediários/genética , Distrofias Musculares/genética , Mutação Puntual , População Branca/genética , Adulto , Displasia Arritmogênica Ventricular Direita/complicações , Displasia Arritmogênica Ventricular Direita/diagnóstico , Cromossomos Humanos Par 2 , Exoma , Feminino , Heterozigoto , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Masculino , Pessoa de Meia-Idade , Distrofias Musculares/complicações , Distrofias Musculares/diagnóstico , Linhagem , Suécia
14.
Hum Mol Genet ; 21(10): 2205-10, 2012 May 15.
Artigo em Inglês | MEDLINE | ID: mdl-22328086

RESUMO

Autosomal dominant cerebellar ataxia, deafness and narcolepsy (ADCA-DN) is characterized by late onset (30-40 years old) cerebellar ataxia, sensory neuronal deafness, narcolepsy-cataplexy and dementia. We performed exome sequencing in five individuals from three ADCA-DN kindreds and identified DNMT1 as the only gene with mutations found in all five affected individuals. Sanger sequencing confirmed the de novo mutation p.Ala570Val in one family, and showed co-segregation of p.Val606Phe and p.Ala570Val, with the ADCA-DN phenotype, in two other kindreds. An additional ADCA-DN kindred with a p.GLY605Ala mutation was subsequently identified. Narcolepsy and deafness were the first symptoms to appear in all pedigrees, followed by ataxia. DNMT1 is a widely expressed DNA methyltransferase maintaining methylation patterns in development, and mediating transcriptional repression by direct binding to HDAC2. It is also highly expressed in immune cells and required for the differentiation of CD4+ into T regulatory cells. Mutations in exon 20 of this gene were recently reported to cause hereditary sensory neuropathy with dementia and hearing loss (HSAN1). Our mutations are all located in exon 21 and in very close spatial proximity, suggesting distinct phenotypes depending on mutation location within this gene.


Assuntos
Ataxia Cerebelar/genética , DNA (Citosina-5-)-Metiltransferases/genética , Surdez/genética , Genes Dominantes , Mutação , Narcolepsia/genética , Sequência de Aminoácidos , DNA (Citosina-5-)-Metiltransferase 1 , Exoma , Éxons , Humanos , Dados de Sequência Molecular , Linhagem , Fenótipo
15.
Neurogenetics ; 12(1): 65-72, 2011 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-21225301

RESUMO

Adult-onset autosomal dominant leukodystrophy (ADLD) with autonomic symptoms features micturition urgency, constipation, erectile dysfunction, and orthostatic hypotension, usually followed by pyramidal signs and ataxia. Peripheral nerve conduction is normal. The disease is often mistaken for multiple sclerosis in the initial phase. There is a characteristic pattern of white matter changes in the brain and spinal cord on magnetic resonance imaging (MRI), mild atrophy of the brain, and a more marked atrophy of the spinal cord. ADLD is associated with duplications of the lamin B1 (LMNB1) gene but the mechanism by which the rearrangement conveys the phenotype is not fully defined. We analyzed four unrelated families segregating ADLD with autonomic symptoms for duplications of the LMNB1 gene. A single nucleotide polymorphism (SNP) array analysis revealed novel duplications spanning the entire LMNB1 gene in probands from each of the four families. We then analyzed the expression of lamin B1 in peripheral leukocytes by Western blot analysis in five patients from two available families. The protein levels of lamin B1 were found significantly increased. These results indicate that the ADLD phenotype associated with LMNB1 duplications is mediated by increased levels of the lamin B1 protein. Furthermore, we show that a molecular diagnosis for ADLD with autonomic symptoms can be obtained by a direct analysis of lamin B1 in peripheral leukocytes.


Assuntos
Doenças do Sistema Nervoso Autônomo/genética , Duplicação Gênica , Doenças Desmielinizantes Hereditárias do Sistema Nervoso Central/genética , Lamina Tipo B/genética , Adulto , Doenças do Sistema Nervoso Autônomo/sangue , Doenças do Sistema Nervoso Autônomo/patologia , Encéfalo/patologia , Estudos de Casos e Controles , Cromossomos Humanos Par 5/genética , Feminino , Expressão Gênica , Genes Dominantes , Doenças Desmielinizantes Hereditárias do Sistema Nervoso Central/sangue , Doenças Desmielinizantes Hereditárias do Sistema Nervoso Central/patologia , Humanos , Lamina Tipo B/sangue , Leucócitos/metabolismo , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Linhagem , Fenótipo , Polimorfismo de Nucleotídeo Único , RNA Mensageiro/sangue , RNA Mensageiro/genética
16.
Neuromuscul Disord ; 21(2): 115-20, 2011 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-21196119

RESUMO

Myopathy with exercise intolerance and deficiency of iron-sulphur cluster proteins is caused by an intronic IVS5+382 G>C mutation in ISCU, the gene encoding the iron-sulphur cluster assembly protein (IscU). The mutation causes alternative splicing resulting in a truncated protein and severely reduced levels of IscU protein in muscle tissue. Disease manifestations include muscle fatigability, dyspnoea, cardiac palpitations and episodic myoglobinuria. Muscle tissue of these patients demonstrates marked histochemical succinate dehydrogenase deficiency and accumulation of iron in muscle fibres, which are morphological hallmarks of the disease. A biopsy specimen from a patient, two months after a severe attack of rhabdomyolysis, revealed regenerating muscle with normal succinate dehydrogenase activity and only minor iron accumulation, whereas another biopsy obtained nine years after the episode showed the typical hallmarks of the disease. The apparent explanation for the normal succinate dehydrogenase activity during regeneration was a markedly increased level of IscU protein in regenerating muscle tissue and an increase in normally spliced ISCU transcripts in the patient. The results have implications for diagnosis of the disease based on muscle biopsy findings and support the concept that an increase of normally spliced ISCU by RNA modulating therapy may be a therapeutic possibility for these patients.


Assuntos
Deficiências Nutricionais/metabolismo , Proteínas Ferro-Enxofre/deficiência , Doenças Musculares/metabolismo , Rabdomiólise/metabolismo , Succinato Desidrogenase/metabolismo , Idoso , Biópsia , Deficiências Nutricionais/genética , Feminino , Humanos , Íntrons/genética , Proteínas Ferro-Enxofre/genética , Músculo Esquelético/patologia , Doenças Musculares/genética , Mutação/genética , Rabdomiólise/patologia , Succinato Desidrogenase/deficiência
17.
Muscle Nerve ; 41(6): 751-7, 2010 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-20229577

RESUMO

Thirty-nine members, ages 1 to 67 years, of a Swedish family with rippling muscle disease (RMD) were investigated to assess genotype-phenotype correlations. Clinical, neurophysiological, and muscle morphological examinations were performed. Genetic analysis was performed in 38 individuals. Twenty-three patients had percussion-induced muscle mounding (PIMM) and percussion-induced rapid contractions (PIRC). Rippling and hyperCKemia were not found in all patients. Weakness was minor or absent. The electromyogram showed absence of electrical activity in ripples and PIMM, and muscle biopsy specimens confirmed caveolin-3 deficiency and absence of caveolae. Genetic analysis revealed a CAV3 c.G136A transition resulting in a p.A46T missense mutation in affected family members. The phenotype in these 23 cases of RMD with this mutation appears to be homogenous, benign, and nonprogressive. The presence of PIMM and PIRC seems to be diagnostic at all ages, whereas the absence of hyperCKemia and rippling does not exclude the diagnosis.


Assuntos
Caveolina 3/genética , Doenças Musculares/genética , Polimorfismo de Nucleotídeo Único , Adolescente , Adulto , Idoso , Criança , Pré-Escolar , Eletromiografia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Doenças Musculares/fisiopatologia , Neurofisiologia , Linhagem , Sistemas Automatizados de Assistência Junto ao Leito , Suécia
18.
Neuromuscul Disord ; 20(1): 53-6, 2010 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-19932619

RESUMO

We report a family with autosomal dominant centronuclear (myotubular) myopathy caused by a novel mutation, p.A618D, in dynamin 2 (DNM2). The 64-year-old mother and 26-year-old daughter had neonatal onset with hypotonia and weak suckling, followed by improvement, then slowly progressive muscle weakness and respiratory restriction. Muscle biopsy showed radial sarcoplasmic strands around the frequent central nuclei. Electrophysiology revealed predominantly myopathic patterns without peripheral nerve involvement. Centronuclear myopathy with neonatal onset caused by a DNM2 mutation in the C-terminal part of the pleckstrin homology domain may have a favorable prognosis and follow a course similar to adult-onset centronuclear myopathy. We advise respiratory follow-up in these patients.


Assuntos
Dinamina II/genética , Miopatias Congênitas Estruturais/genética , Adulto , Idade de Início , Substituição de Aminoácidos , Progressão da Doença , Família , Feminino , Humanos , Lactente , Pessoa de Meia-Idade , Músculo Esquelético/patologia , Músculo Esquelético/fisiopatologia , Miopatias Congênitas Estruturais/patologia , Miopatias Congênitas Estruturais/fisiopatologia , Fenótipo , Análise de Sequência de DNA , Suécia
19.
Amyloid ; 16(4): 208-14, 2009 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-19922332

RESUMO

The number of amyloidogenic transthyretin (TTR) mutations described in the literature is more than 100. However, for several mutations, the phenotype has been described in a few individuals only; thus, the knowledge of the clinical course and the outcome after therapeutical interventions such as liver transplantation is limited. We describe the phenotype associated with five rare amyloidogenic TTR mutations that lately were discovered in Sweden: ATTR Val30Leu, Ala45Ser, Leu55Gln, Gly57Arg and Tyr69His of which ATTR Gly57Arg is previously unknown. The symptoms at onset differed, but cardiomyopathy and peripheral neuropathy were observed in all except the ATTR Tyr69His mutation. Likewise, carpal tunnel syndrome was found or had been present in all cases except the case with the ATTR Val30Leu mutation. The phenotype of the ATTR Tyr69His mutation was characterised by oculo-meningeal symptoms with seizures and a steadily progressing dementia, symptoms rarely found in ATTR amyloidosis, but similar to those previously described for this mutation, where all cases appear to originate from one Swedish family. Two patients with the ATTR Leu55Gln and Ala45Ser mutations have been subjected to liver transplantation, but echocardiographic examination has revealed an increasing cardiomyopathy after transplantation in both cases, the ATTR Leu55Gln patient succumbed 2 years after transplantation from progressive disease.


Assuntos
Amiloidose/genética , Mutação , Pré-Albumina/genética , Adulto , Amiloidose/etiologia , Cardiomiopatias/etiologia , Cardiomiopatias/genética , Feminino , Humanos , Transplante de Fígado , Pessoa de Meia-Idade , Doenças do Sistema Nervoso Periférico/etiologia , Doenças do Sistema Nervoso Periférico/genética , Fenótipo , Suécia , População Branca , Adulto Jovem
20.
Brain ; 132(Pt 8): 2170-9, 2009 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-19567699

RESUMO

Myopathy with deficiency of succinate dehydrogenase and aconitase is a recessively inherited disorder characterized by childhood-onset early fatigue, dyspnoea and palpitations on trivial exercise. The disease is non-progressive, but life-threatening episodes of widespread weakness, severe metabolic acidosis and rhabdomyolysis may occur. The disease has so far only been identified in northern Sweden. The clinical, histochemical and biochemical phenotype is very homogenous and the patients are homozygous for a deep intronic IVS5 + 382G>C splicing affecting mutation in ISCU, which encodes the differently spliced cytosolic and mitochondrial iron-sulphur cluster assembly protein IscU. Iron-sulphur cluster containing proteins are essential for iron homeostasis and respiratory chain function, with IscU being among the most conserved proteins in evolution. We identified a shared homozygous segment of only 405,000 base pair with the deep intronic mutation in eight patients with a phenotype consistent with the original description of the disease. Two other patients, two brothers, had an identical biochemical and histochemical phenotype which is probably pathognomonic for muscle iron-sulphur cluster deficiency, but they presented with a disease where the clinical phenotype was characterized by early onset of a slowly progressive severe muscle weakness, severe exercise intolerance and cardiomyopathy. The brothers were compound heterozygous for the deep intronic mutation and had a c.149 G>A missense mutation in exon 3 changing a completely conserved glycine residue to a glutamate. The missense mutation was inherited from their mother who was of Finnish descent. The intronic mutation affects mRNA splicing and results in inclusion of pseudoexons in most transcripts in muscle. The pseudoexon inclusion results in a change in the reading frame and appearance of a premature stop codon. In western blot analysis of protein extracts from fibroblasts, there was no pronounced reduction of IscU in any of the patients, but the analysis revealed that the species corresponding to mitochondrial IscU migrates slower than a species present only in whole cells. In protein extracted from isolated skeletal muscle mitochondria the western blot analysis revealed a severe deficiency of IscU in the homozygous patients and appearance of a faint new fraction that could represent a truncated protein. There was only a slight reduction of mitochondrial IscU in the compound heterozygotes, despite their severe phenotype, indicating that the IscU expressed in these patients is non-functional.


Assuntos
Proteínas Ferro-Enxofre/genética , Miopatias Mitocondriais/genética , Mutação , Aconitato Hidratase/deficiência , Adolescente , Adulto , Idoso , Sequência de Bases , Biópsia , Células Cultivadas , Criança , Pré-Escolar , Feminino , Genótipo , Humanos , Proteínas Ferro-Enxofre/deficiência , Masculino , Mitocôndrias Musculares/ultraestrutura , Miopatias Mitocondriais/metabolismo , Miopatias Mitocondriais/patologia , Proteínas Mitocondriais/deficiência , Dados de Sequência Molecular , Músculo Esquelético/patologia , Linhagem , Fenótipo , Reação em Cadeia da Polimerase/métodos , Polimorfismo de Nucleotídeo Único , Reação em Cadeia da Polimerase Via Transcriptase Reversa/métodos , Adulto Jovem
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA