RESUMO
Intronic hexanucleotide (G4C2) repeat expansions in C9orf72 are genetically associated with frontotemporal lobar degeneration (FTLD) and amyotrophic lateral sclerosis (ALS). The repeat RNA accumulates within RNA foci but is also translated into disease characterizing dipeptide repeat proteins (DPR). Repeat-dependent toxicity may affect nuclear import. hnRNPA3 is a heterogeneous nuclear ribonucleoprotein, which specifically binds to the G4C2 repeat RNA We now report that a reduction of nuclear hnRNPA3 leads to an increase of the repeat RNA as well as DPR production and deposition in primary neurons and a novel tissue culture model that reproduces features of the C9orf72 pathology. In fibroblasts derived from patients carrying extended C9orf72 repeats, nuclear RNA foci accumulated upon reduction of hnRNPA3. Neurons in the hippocampus of C9orf72 patients are frequently devoid of hnRNPA3. Reduced nuclear hnRNPA3 in the hippocampus of patients with extended C9orf72 repeats correlates with increased DPR deposition. Thus, reduced hnRNPA3 expression in C9orf72 cases leads to increased levels of the repeat RNA as well as enhanced production and deposition of DPR proteins and RNA foci.
Assuntos
Dipeptídeos/metabolismo , Regulação da Expressão Gênica , Ribonucleoproteínas Nucleares Heterogêneas Grupo A-B/metabolismo , Proteínas/genética , RNA Mensageiro/genética , Animais , Encéfalo/metabolismo , Proteína C9orf72 , Fibroblastos , Técnicas de Silenciamento de Genes , Células HeLa , Humanos , Neurônios/metabolismo , Ligação Proteica , Transporte Proteico , Células Piramidais/metabolismo , Transporte de RNA , RNA Interferente Pequeno/genética , RatosRESUMO
OBJECTIVES: Primary lateral sclerosis (PLS) is commonly considered as a motor neuron disease (MND) variant which almost exclusively affects upper motor neurons (UMN). There is still no consensus whether PLS should be regarded as an independent disease entity separate from amyotrophic lateral sclerosis (ALS) or as a comparatively slowly progressive variant of ALS. Given these different views, clinical diagnosis of PLS is a challenge. In this multicenter study, we analyzed clinical features of patients diagnosed with PLS in four specialized MND centers. MATERIAL AND METHODS: We retrospectively analyzed clinical, laboratory, imaging, and electrophysiological data of 76 patients with PLS diagnosed in four specialized ALS centers. We analyzed the concept of the disease based on our findings and an extensive review of the literature. RESULTS: We found that 79% of patients showed asymmetrical symptoms, 60% showed clinical or electrophysiological signs of lower motor neuron (LMN) involvement after a mean of 8.4 ± 5.0 years, and extrapyramidal and/or non-motoric symptoms were frequently observed. Interestingly, none of the patients diagnosed with PLS fulfilled the diagnostic criteria proposed by Pringle et al. in 1992. CONCLUSIONS: Our data show that PLS as a disease entity is still not well enough defined and that there are different concepts about its clinical presentation. We believe that further prospective longitudinal studies are needed in order to refine diagnostic criteria to reflect current clinical practice. Furthermore, neuropathological and neuroimaging approaches might help to arrange PLS in the MND spectrum and its classification.
Assuntos
Esclerose Lateral Amiotrófica/diagnóstico , Adulto , Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Neurônios Motores/fisiologiaRESUMO
OBJECTIVE: To characterize the phenotype of patients with distal myopathy with vocal cord and pharyngeal weakness due to the p.S85C mutation in the matrin-3 gene (MATR3, Mendelian Inheritance in Man 164015). Recently, it has been suggested that patients with this mutation may suffer from familial amyotrophic lateral sclerosis. METHODS: Sixteen patients from 6 families with late onset distal myopathy associated with the p.S85C MATR3 mutation were characterized. RESULTS: Patients had a predominantly distal muscle weakness, most severely affecting ankle and wrist dorsiflexion. Relevant proximal and axial weakness was found in 6 and respiratory impairment in 5 patients. Dysphagia was diagnosed in 6 and mild voice abnormalities were found in 7 patients. However, laryngoscopy revealed normal vocal cord function. Creatine kinase was normal or mildly elevated. Electromyographically, spontaneous activity was found in 10 of 14 patients and complex repetitive discharges in 9 of 14 patients. Magnetic resonance imaging revealed severe fatty degeneration of distal and upper posterior leg and of paraspinal muscles. Histopathology ranged from mild myopathic to severe dystrophic changes including vacuoles. Absence of sarcomeres in the perinuclear region and abnormal invaginations of nuclei were found ultrastructurally. Haplotype analysis showed a common disease-specific haplotype of the 6 families and suggested that these families form a separate cluster. INTERPRETATION: In contrast to the 2 previously reported families, MATR3-related distal myopathy might be associated with relevant axial, proximal, and respiratory muscle weakness but without vocal cord palsy. There were no clinical, electrophysiological, or histopathological signs of lower motor neuron involvement.
Assuntos
Miopatias Distais/genética , Miopatias Distais/patologia , Doenças da Laringe/genética , Doenças da Laringe/patologia , Proteínas Associadas à Matriz Nuclear/genética , Doenças Faríngeas/genética , Doenças Faríngeas/patologia , Proteínas de Ligação a RNA/genética , Adulto , Idade de Início , Transtornos de Deglutição/genética , Transtornos de Deglutição/patologia , Feminino , Alemanha , Haplótipos , Testes de Função Cardíaca , Humanos , Masculino , Pessoa de Meia-Idade , Debilidade Muscular/genética , Debilidade Muscular/patologia , Músculo Esquelético/patologia , Testes de Função Respiratória , Músculos Respiratórios/patologia , Distúrbios da Voz/genética , Distúrbios da Voz/patologia , Adulto JovemRESUMO
OBJECTIVE: The sensory ataxic neuropathy with dysarthria and ophthalmoparesis (SANDO) syndrome is a subgroup of mitochondrial chronic progressive external ophthalmoplegia (CPEO)-plus disorders associated with multiple mitochondrial DNA (mtDNA) deletions. There is no systematic survey on SANDO in patients with CPEO with either single or multiple large-scale mtDNA deletions. METHODS: In this retrospective analysis, we characterised the frequency, the genetic and clinical phenotype of 107 index patients with mitochondrial CPEO (n=66 patients with single and n=41 patients with multiple mtDNA deletions) and assessed these for clinical evidence of a SANDO phenotype. Patients with multiple mtDNA deletions were additionally screened for mutations in the nuclear-encoded POLG, SLC25A4, PEO1 and RRM2B genes. The clinical, histological and genetic data of 11 patients with SANDO were further analysed. RESULTS: None of the 66 patients with single, large-scale mtDNA deletions fulfilled the clinical criteria of SANDO syndrome. In contrast, 9 of 41 patients (22%) with multiple mtDNA deletions and two additional family members fulfilled the clinical criteria for SANDO. Within this subgroup, multiple mtDNA deletions were associated with the following nuclear mutations: POLG (n=6), PEO1 (n=2), unidentified (n=2). The combination of sensory ataxic neuropathy with ophthalmoparesis (SANO) was observed in 70% of patients with multiple mtDNA deletions but only in 4% with single deletions. The combination of CPEO and sensory ataxic neuropathy (SANO, incomplete SANDO) was found in 43% of patients with multiple mtDNA deletions but not in patients with single deletions. CONCLUSION: The SANDO syndrome seems to indicate a cluster of symptoms within the wide range of multisystemic symptoms associated with mitochondrial CPEO. SANO seems to be the most frequent phenotype associated with multiple mtDNA deletions in our cohort but not or is rarely associated with single, large-scale mtDNA deletions.
Assuntos
DNA Mitocondrial/genética , Disartria/epidemiologia , Disartria/genética , Neuropatia Hereditária Motora e Sensorial/epidemiologia , Neuropatia Hereditária Motora e Sensorial/genética , Oftalmoplegia Externa Progressiva Crônica/epidemiologia , Oftalmoplegia Externa Progressiva Crônica/genética , Oftalmoplegia/epidemiologia , Adolescente , Adulto , Idade de Início , Idoso , Biópsia , Criança , Estudos de Coortes , DNA Helicases/genética , DNA Polimerase gama , DNA Polimerase Dirigida por DNA/genética , Feminino , Deleção de Genes , Humanos , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Proteínas Mitocondriais/genética , Músculo Esquelético/patologia , Oftalmoplegia/genética , Estudos Retrospectivos , Síndrome , Adulto JovemRESUMO
INTRODUCTION: Recently, mutations in the MATR3 gene were found to cause late-onset distal myopathy. The frequency and impact of respiratory involvement are not clear. METHODS: Respiratory parameters [maximum vital capacity (VCmax); forced expiratory volume (FEV1 ); peak expiratory flow (PEF), postural drop of VCmax from sitting to supine, maximum inspiratory muscle pressure (PImax), mouth occlusion pressure after 100 ms (P 0.1), peak cough flow, and blood-gas analysis] were monitored prospectively at baseline, and then 6 months and 12 months later in 8 patients with genetically confirmed MATR3 myopathy. RESULTS: All patients showed involvement of respiratory function. Six of 8 reported exertional dyspnea. At the end of follow-up, 5 of 8 had decreased VC, 7 of 8 had reduced PImax, and 5 of 7 had decreased partial pressure of oxygen (PO2 ). Within 12 months, respiratory parameters deteriorated non-significantly. No patient required non-invasive ventilation. CONCLUSIONS: There is a high risk of abnormal respiratory function with progressive worsening in MATR3 myopathy.
Assuntos
Miopatias Distais/complicações , Miopatias Distais/genética , Mutação/genética , Proteínas Associadas à Matriz Nuclear/genética , Proteínas de Ligação a RNA/genética , Transtornos Respiratórios/etiologia , Adulto , Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-IdadeRESUMO
BACKGROUND: The obstetric risk in patients with Pompe disease (glycogen storage disease type II), a mainly skeletal muscle disorder, is unknown. METHODS: The clinical course and the outcome of pregnancy, and the effect of pregnancy on disease manifestations or clinical signs and symptoms in Pompe disease were analyzed retrospectively using a questionnaire. Participating women with Pompe disease were recruited by the German and the UK sections of the International Pompe Association, and by centers associated within the German Pompe Group. The data was compared with information from the German statistical almanac, perinatal registry, and perinatal quality survey. RESULTS: 66 of 136 women responded to the questionnaire (median age: 47 years, range: 18-74). In 10 of 52 women who had been pregnant, the symptoms of Pompe disease were present during pregnancy (n=7 1st, n=1 2nd, n=1 3rd pregnancy). Muscle weakness worsened in 3 women, and first presented in 3 others during the first pregnancy (4.5% each). Respiratory problems deteriorated in 2/10 women during pregnancy. These 10 symptomatic women had 17 pregnancies (15 deliveries, 2 miscarriages, no abortions). The 42 asymptomatic women (63.6%) had 109 pregnancies (72.4% deliveries, 19.3% miscarriages, 7.3% abortions). There were no significant differences between the mean duration of pregnancies or the mean birth weight in symptomatic and asymptomatic women, or compared to the data from the general population. The same was true of pregnancy and delivery complications (including Cesarean section). CONCLUSIONS: Our data show that women with Pompe disease do not appear to have an increased risk of pregnancy or delivery complications. However, muscle weakness and respiratory complications might manifest or worsen during pregnancy in some women.
Assuntos
Doença de Depósito de Glicogênio Tipo II/complicações , Doença de Depósito de Glicogênio Tipo II/epidemiologia , Complicações do Trabalho de Parto/epidemiologia , Complicações na Gravidez/epidemiologia , Resultado da Gravidez/epidemiologia , Adolescente , Adulto , Idoso , Parto Obstétrico/estatística & dados numéricos , Feminino , Alemanha , Doença de Depósito de Glicogênio Tipo II/patologia , Humanos , Pessoa de Meia-Idade , Gravidez , Complicações na Gravidez/fisiopatologia , Estudos Retrospectivos , Inquéritos e Questionários , Reino Unido , Adulto JovemRESUMO
Recessive mutations in the ANO5 gene, encoding anoctamin 5, cause proximal limb girdle muscular dystrophy (LGMD2L), Miyoshi-type distal myopathy (MM3) and asymptomatic hyper- CKemia. We report a woman with exertion-induced myalgia and weakness in the hip girdle manifesting at the age of 40. Creatine kinase (CK) was increased 20-fold. Histologically the dominating feature was necrotizing myopathy, but long-term immunosuppressive therapy did not change CK level or myopathic symptoms. Molecular genetic investigation led to the finding of the homozygous ANO5 c.191dupA mutation. This is a report of a muscular dystrophy due to ANO5 mutation presenting histologically as necrotizing myopathy. For this reason our finding extends the histological spectrum of myopathies due to ANO5 mutations as well as the possible differential diagnoses for necrotizing myopathy.
Assuntos
Distrofia Muscular do Cíngulo dos Membros/diagnóstico , Adulto , Biópsia , Diagnóstico Diferencial , Progressão da Doença , Feminino , Humanos , Imageamento por Ressonância Magnética , Necrose , FenótipoRESUMO
Histological mitochondrial changes are generally found to be associated with late onset myofibrillar myopathies (MFMs). How these changes contribute to the pathogenesis of MFMs is unknown. Mitochondrial changes, including COX-deficient fibers (n = 8), biochemical activities of respiratory chain complexes (n = 7), and multiple mtDNA deletions by long-range PCR (n = 9) were examined in patients with genetically confirmed MFMs [MYOT (n = 2), DES (n = 1), ZASP (n = 2), FLNC (n = 4)] and compared with age and sex matched normal controls (n = 27) and patients with a mitochondrial disorder with multiple mtDNA deletions due to nuclear genetic defects (n = 8). In 2 MFM patients, micro dissected fibers were analyzed for multiple mtDNA deletions by nested long-range PCR. The COX-deficient fibers only partly corresponded with fibers containing myofibrillar accumulations. In total, there was no difference in the percentage of COX-deficient fibers in MFM patients and normal controls. However, the percentage of COX-deficient fibers was significantly higher in 3 MFM patients. Two MFM patients but none of the controls had multiple mtDNA deletions. Nested long-range PCR detected multiple mtDNA deletions only in COX-deficient fibers. Citrate synthase activities in MFM patients were 1.5-fold increased by compared to those in controls, suggesting initiation of mitochondrial alterations. However, it is unclear whether this is a direct consequence of MFM pathology. *both authors contributed equally to the manuscript.
Assuntos
Mitocôndrias Musculares/patologia , Adulto , Idoso , Conectina/genética , Conectina/metabolismo , DNA/genética , DNA Mitocondrial/genética , Transporte de Elétrons/genética , Complexo IV da Cadeia de Transporte de Elétrons/metabolismo , Feminino , Deleção de Genes , Humanos , Imuno-Histoquímica , Masculino , Microdissecção , Proteínas dos Microfilamentos , Pessoa de Meia-Idade , Fibras Musculares Esqueléticas/metabolismo , Miopatias Congênitas Estruturais/patologia , Reação em Cadeia da PolimeraseRESUMO
INTRODUCTION: In patients with myofibrillar myopathies (MFM), myotonic discharges have occasionally been detected by needle electromyography (EMG). Nevertheless, this peculiar type of spontaneous repetitive discharge has not attracted special interest in the genetically heterogeneous MFMs. METHODS: EMG features were analyzed in 6 patients with genetically confirmed MFM (n = 1 MYOT, n = 1 DES, n = 2 ZASP, n = 2 FLNC). RESULTS: Fibrillation potentials, positive sharp waves, and myotonic discharges were found in all 6 patients, and complex repetitive discharges were found in 5. Myotonic discharges were detected in approximately 50% of the analyzed muscles independent of the site, including distal (3/6), proximal limb (4/6), and paravertebral muscles (3/6). Clinical myotonia could not be elicited in any patient. CONCLUSIONS: Myotonic discharges appear to be part of the electrodiagnostic characteristics of myofibrillar myopathy. Along with other appropriate clinical and histological findings, the presence of myotonic discharges supports the diagnosis of myofibrillar myopathy.
Assuntos
Músculo Esquelético/fisiopatologia , Distrofias Musculares/fisiopatologia , Miopatias Congênitas Estruturais/fisiopatologia , Idoso , Idoso de 80 Anos ou mais , Cardiomiopatias/patologia , Cardiomiopatias/fisiopatologia , Eletromiografia , Fenômenos Eletrofisiológicos , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Músculo Esquelético/patologia , Distrofias Musculares/patologia , Miopatias Congênitas Estruturais/patologiaRESUMO
It is not known whether eosinophilic myositis is a specific histopathological feature of limb girdle muscular dystrophy 2A (LGMD2A). Number and location of eosinophils in skeletal muscle biopsies (n=100) was analysed by Giemsa and modified hematoxylin/eosin staining in patients with genetically confirmed myopathies (LGMD2A, LGMD2B, LGMD2L, facioscapulohumeral muscular dystrophy, dystrophinopathy), histologically confirmed idiopathic inflammatory myopathies (sporadic inclusion body myositis (sIBM), dermatomyositis (DM), polymyositis), amyotrophic lateral sclerosis (neurogenic control), and normal controls. The number of eosinophils/mm² was significantly higher in LGMD2A, PM, DM, and sIBM compared to controls but not significantly higher than other myopathies. A large overlap in the number of eosinophils/mm2 between all groups was seen. In all disease groups eosinophils were mainly found endomysially (46- 88%) and intra- and perivascularly (4-37%). There was no correlation between the numbers of eosinophils/mm² and (i) age at biopsy and (ii) the duration of the disease. The extent of myopathic, fibrotic, and inflammatory changes did not differ in samples with high and low eosinophil count. Eosinophils seem to represent an unspecific histological finding in hereditary and inflammatory myopathies, but also amyotrophic lateral sclerosis.
Assuntos
Eosinofilia/genética , Miosite/genética , Adolescente , Adulto , Idoso , Biópsia , Criança , Pré-Escolar , Eosinofilia/epidemiologia , Feminino , Alemanha/epidemiologia , Humanos , Lactente , Masculino , Pessoa de Meia-Idade , Distrofia Muscular do Cíngulo dos Membros , Miosite/epidemiologia , Coloração e RotulagemRESUMO
Congenital fibrosis of the extraocular muscles type 1 (CFEOM1; OMIM #135700) is an autosomal dominant strabismus disorder associated with defects of the oculomotor nerve. We show that individuals with CFEOM1 harbor heterozygous missense mutations in a kinesin motor protein encoded by KIF21A. We identified six different mutations in 44 of 45 probands. The primary mutational hotspots are in the stalk domain, highlighting an important new role for KIF21A and its stalk in the formation of the oculomotor axis.
Assuntos
Variação Genética , Cinesinas/genética , Mutação/genética , Proteínas do Tecido Nervoso/genética , Músculos Oculomotores/patologia , Oftalmoplegia/congênito , Sequência de Aminoácidos , Criança , Feminino , Fibrose , Ligação Genética , Heterozigoto , Humanos , Masculino , Dados de Sequência Molecular , Oftalmoplegia/patologia , Linhagem , Fenótipo , Homologia de Sequência de AminoácidosRESUMO
Respiratory impairment is the most important prognostic factor in patients with adult-onset Pompe disease. The effect of long-term enzyme replacement therapy (ERT) on pulmonary function remains unclear.Respiratory parameters (vital capacity (VCmax); forced expiratory volume (FEV1); peak expiratory flow (PEF); and blood gas analysis) were monitored every 6 months during a treatment period of 48-77 months of ERT in six patients with genetically and biochemically confirmed adult-onset Pompe disease. Postural drop of VCmax from sitting to supine position, maximal inspiratory muscle pressure (PImax), mouth occlusion pressure after 100 ms (P0.1), and peak cough flow (PCF) were measured over a period of 12 months. Mean change to baseline were +8.8 % points for ΔVCmax, +6.2 % points for ΔFEV1, and +6.6 % points for ΔPEF after 48 months of ERT. In one patient, a decrease of respiratory parameters with later stabilization was observed under ERT until month 42, but noninvasive ventilation (NIV) had to be initiated due to nocturnal desaturation. In the final 12 months period, progressive diaphragm weakness was detected in 3/6 patients (median change in VC% drop +8 %).ERT seems to stabilize pulmonary function and may delay the requirement for ventilation in patients with late-onset Pompe disease.
Assuntos
Gasometria , Terapia de Reposição de Enzimas , Glucana 1,4-alfa-Glucosidase/uso terapêutico , Doença de Depósito de Glicogênio Tipo II/tratamento farmacológico , Medidas de Volume Pulmonar , Testes de Função Respiratória , Adulto , Idoso , Feminino , Seguimentos , Humanos , Assistência de Longa Duração , Masculino , Pessoa de Meia-IdadeRESUMO
OBJECTIVES: Glycogen storage disease type 2(GSD2)/Pompe disease is characterized by respiratory and skeletal muscle weakness and atrophy, resulting in functional disability and reduced life span. METHODS: We present an open-label, investigator-initiated observational study of alglucosidase alfa enzyme replacement therapy (ERT) in 38 adult-onset GSD2 patients (20 female, 18 male) with a mean age at disease onset of 36.2 ± 10.5 years. Mean delay between symptom onset and start of ERT was 14.5 ± 7.2 years. Assessments included serial Walton Gardner Medwin scale, arm function tests, timed 10-meter walk tests, 4- stair climb tests, modified Gowers' maneuvers, 6-minute walk test (6MWT), MRC sum score, forced vital capacities (FVC), creatine kinase (CK) levels, and SF-36 selfreporting questionnaires. All tests were performed at baseline and every 12 months for 36 months of ERT. RESULTS: In the 6MWT we found 21 patients able to walk at baseline a mean distance of 312 ± 165.5 m, improving to 344 ± 165.8 m after 12 months (p=0.006), remaining at 356.4 ± 155.9 m at 24 months (p=0.033), and declining to 325.6 ± 174.8 m after 36 months of ERT (p=0.49, n.s.). The mean FVC in 28 patients was 80.27 ± 14.08% of predicted normal at baseline, after 12 months 79.19 ± 13.09%, at 24 months 78.62 ± 16.55%, and 77.19 ± 18.05%after 36 months. Only mean CK levels were significantly decreased by 8.8% (p=0.041). All other tests were statistically nonsignificant changed. CONCLUSION: Our data denote a rather variable course of neuromuscular deficits in chronic adult-onset Pompe patients during 36 months of alglucosidase alfa ERT.
Assuntos
Terapia de Reposição de Enzimas/métodos , Doença de Depósito de Glicogênio Tipo II/tratamento farmacológico , Doença de Depósito de Glicogênio Tipo II/metabolismo , alfa-Glucosidases/uso terapêutico , Adulto , Idade de Início , Idoso , Creatina Quinase/metabolismo , Feminino , Seguimentos , Doença de Depósito de Glicogênio Tipo II/enzimologia , Humanos , Masculino , Pessoa de Meia-Idade , Testes de Função Respiratória/métodos , Resultado do Tratamento , Caminhada , alfa-Glucosidases/efeitos adversosRESUMO
Complex repetitive discharges (CRDs) are poorly understood phenomena in needle electromyography (EMG) recordings. The data presented here suggest that CRDs may mainly be a sign of motor unit reinnervation. EMG "video" data of 108 CRDs from neurogenic (ND, n = 39) and myogenic (MD, n = 14) disorders were retrospectively analyzed for cycle duration, potential-free time intervals, spike components (SC), maximum amplitudes, blockade, and increased jitter. CRD-SC in ND disorders (9.3 ± 7.8) outnumbered those in MD disorders (6.3 ± 6.2). The CRD cycle duration was correlated with SC and silent periods (p each < 0.000001). Blockade was observed in 36% and increased jitter in 27% of the CRDs. A higher number of CRD-SC in ND vs. MD fits the known differences in motor unit dimensions. Blockade and increased jitter are known features of diseased neuromuscular junctions, such as during reinnervation. The SC patterns of single CRD cycles resemble reinnervation potentials. Thus, CRDs may result from myo-axonal re-excitation in sprouting motor units. The purpose of this investigation was to better understand the circumstances under which CRDs may occur and eventually to contribute to the understanding of their pathogenesis.
RESUMO
BACKGROUND: The homozygous c.34C>T mutation in the AMPD1 gene encoding the muscle-specific isoform of AMP deaminase (AMPD) accounts for the vast majority of inherited skeletal muscle AMPD deficiencies. It is controversial (i) whether AMPD deficiency is associated with exercise-induced complaints and (ii) whether an acquired form exists in which an underlying neuromuscular disorder additionally lowers the AMPD activity. DESIGN: c.34C>T mutation (homozygous- TT, heterozygous-CT,wildtype-CC) was screened in 107 healthy blood donors and 294 patients with skeletal muscle biopsy including 200 with exercise-induced complaints. Additional screening for c.468G > T and c.860A > T mutations was performed in all CT.AMPD was analysed histochemically and biochemically. RESULTS: The mutant allele frequency (MAF) was not different in blood donors, patients with muscle biopsy, and the subgroup with exercise-induced complaints (12.9-16.8 %). CT was found in 63 and TT in 13 patients. The c.468G>T mutation was not detected. The c.860A > T mutation was found in 2.8 % blood donors and 1.6% CT. AMPD activities showed a substantial overlap in CC and CT, but not with TT. AMPD activities in TT, CT, and CC did not differ in patients with a defined neuromuscular disorder and those with only exercise-induced complaints. In TT, CT, and CC there were no differences in the frequency of signs and symptoms, hyperCKemia, or myopathological biopsy pattern. CONCLUSION: MAF did not differ in normal and diseased populations. The frequency of exertion-induced complaints was not higher in TT than CC. There was no specific phenotype of TT and no evidence for an acquired form of AMPD deficiency.
Assuntos
AMP Desaminase/deficiência , AMP Desaminase/genética , Músculo Esquelético/enzimologia , Doenças Neuromusculares/enzimologia , Doenças Neuromusculares/genética , Alelos , Biópsia , Análise Mutacional de DNA , Eletrofisiologia , Feminino , Frequência do Gene , Genótipo , Humanos , Masculino , FenótipoRESUMO
OBJECTIVE: Spinal and bulbar muscular atrophy (SBMA) is caused by an abnormal expansion of the CAG repeat in the androgen receptor gene. This study aimed to systematically phenotype a German SBMA cohort (n = 80) based on laboratory markers for neuromuscular, metabolic, and endocrine status, and thus provide a basis for the selection of biomarkers for future therapeutic trials. METHODS: We assessed a panel of 28 laboratory parameters. The clinical course and blood biomarkers were correlated with disease duration and CAG repeat length. A subset of 11 patients was evaluated with body fat MRI. RESULTS: Almost all patients reported muscle weakness (99%), followed by dysphagia (77%), tremor (76%), and gynecomastia (75%) as major complaints. Creatine kinase was the most consistently elevated (94%) serum marker, which, however, did not relate with either the disease duration or the CAG repeat length. Paresis duration and CAG repeat length correlated with dehydroepiandrosterone sulfate after correction for body mass index and age. The androgen insensitivity index was elevated in nearly half of the participants (48%). CONCLUSIONS: Metabolic alterations in glucose homeostasis (diabetes) and fat metabolism (combined hyperlipidemia), and sex hormone abnormalities (androgen insensitivity) could be observed among SBMA patients without association with the neuromuscular phenotype. Dehydroepiandrosterone sulfate was the only biomarker that correlated strongly with both weakness duration and the CAG repeat length after adjusting for age and BMI, indicating its potential as a biomarker for both disease severity and duration and, therefore, its possible use as a reliable outcome measure in future therapeutic studies.
Assuntos
Atrofia Muscular Espinal/metabolismo , Tecido Adiposo/diagnóstico por imagem , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores/sangue , Composição Corporal , Progressão da Doença , Glucose/metabolismo , Hormônios/metabolismo , Humanos , Metabolismo dos Lipídeos , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Músculo Esquelético/fisiopatologia , Atrofia Muscular Espinal/diagnóstico por imagem , Atrofia Muscular Espinal/genética , Expansão das Repetições de TrinucleotídeosRESUMO
BACKGROUND: Congenital fibrosis of the extraocular muscles types 1 and 3 (CFEOM1/CFEOM3) are autosomal dominant strabismus disorders that appear to result from maldevelopment of ocular nuclei and nerves. We previously reported that most individuals with CFEOM1 and rare individuals with CFEOM3 harbor heterozygous mutations in KIF21A. KIF21A encodes a kinesin motor involved in anterograde axonal transport, and the familial and de novo mutations reported to date predictably alter one of only a few KIF21A amino acids--three within the third coiled-coil region of the stalk and one in the distal motor domain, suggesting they result in altered KIF21A function. To further define the spectrum of KIF21A mutations in CFEOM we have now identified all CFEOM probands newly enrolled in our study and determined if they harbor mutations in KIF21A. RESULTS: Sixteen CFEOM1 and 29 CFEOM3 probands were studied. Three previously unreported de novo KIF21A mutations were identified in three CFEOM1 probands, all located in the same coiled-coil region of the stalk that contains all but one of the previously reported mutations. Eight additional CFEOM1 probands harbored three of the mutations previously reported in KIF21A; seven had one of the two most common mutations, while one harbored the mutation in the distal motor domain. No mutation was detected in 5 CFEOM1 or any CFEOM3 probands. CONCLUSION: Analysis of sixteen CFEOM1 probands revealed three novel KIF21A mutations and confirmed three reported mutations, bringing the total number of reported KIF21A mutations in CFEOM1 to 11 mutations among 70 mutation positive probands. All three new mutations alter amino acids in heptad repeats within the third coiled-coil region of the KIF21A stalk, further highlighting the importance of alterations in this domain in the etiology of CFEOM1.
Assuntos
Cinesinas/química , Cinesinas/genética , Mutação/genética , Proteínas do Tecido Nervoso/química , Proteínas do Tecido Nervoso/genética , Estrabismo/genética , Sequência de Aminoácidos , Sequência de Bases , Análise Mutacional de DNA , Feminino , Genes Dominantes , Humanos , Padrões de Herança/genética , Masculino , Dados de Sequência Molecular , Linhagem , Estrutura Terciária de ProteínaRESUMO
The purpose of the study was to investigate whether provoked changes of cerebral perfusion pressure and arterial carbon dioxide tension are able to influence the cerebral metabolism of endothelin-1 (ET-1) in a porcine model. Brain tissue oxygen tension, regional cerebral blood flow and mean arterial blood pressure were monitored in 10 healthy pigs during induced hyperventilation (HV), hypertension (HrT) and hypotension (HoT). ET-1 was determined in the arterial and cerebrovenous blood. Microdialysis samples (lactate, glucose and pyruvate) were taken from brain and subcutaneous tissue. A significant decrease (p<0.05) of the arterial ET-1 (1.46+/-0.33 fmol/mL) compared to the baseline (2.18+/-0.36 fmol/mL) was observed after the HoT-period. We detected a positive correlation between cerebrovenous ET-1 and extracellular cerebral glucose (0.68; p<0.05) after the baseline as well as a negative correlation of -0.81 (p<0.005) between the cerebrovenous ET-1 level and the extracellular cerebral lactate after the HoT-period. These data imply that with increasingly pathological changes of the cerebral metabolism endothelin becomes progressively more important in the regulation of cerebral vascular tone.
Assuntos
Circulação Cerebrovascular/fisiologia , Endotelina-1/metabolismo , Hipertensão/metabolismo , Hiperventilação/metabolismo , Hipotensão/metabolismo , Animais , Tempo de Circulação Sanguínea/métodos , Glicemia , Modelos Animais de Doenças , Líquido Extracelular/metabolismo , Hipertensão/etiologia , Hiperventilação/etiologia , Hipotensão/etiologia , Pressão Intracraniana/fisiologia , Lactatos/metabolismo , Microdiálise/métodos , Fluxo Sanguíneo Regional/fisiologia , Suínos , Fatores de TempoRESUMO
UNLABELLED: Autosomal dominant Emery-Dreifuss muscular dystrophy is caused by mutations in the LMNA gene that code for the nuclear membrane protein lamin A/C. We investigated skeletal muscle fibers from several muscles for cytoplasmic degenerative changes in three patients with genetically confirmed Emery-Dreifuss muscular dystrophy. Methods included quantitative light and electron microscopy and PCR-based mutational analysis. RESULTS: The degenerative pathway was characterized by the gradual replacement of individual myofibers by connective tissue. Early stages of degeneration typically involved only a segment of the cross-sectional area of a myofiber. Intermediate stages consisted of myofiber shrinkage due to "shedding" of peripheral cytoplasmic portions into the endomysial space, and fragmentation of the myofibers by interposed collagen fibrils. Empty basement membrane sheaths surrounded by abundant deposits of extracellular matrix marked the end stage of the degenerative process. The nuclear number-to-cytoplasmic area in myofibers of one patient increased with increasing cross-sectional area, suggesting that satellite cell fusion with myofibers may have compensated for myofiber shrinkage. The pattern of degeneration described herein differs from muscular dystrophies with plasma membrane defects (dystrophinopathy, dysferlinopathy) and explains the frequently found absence of highly elevated serum creatine kinase levels in autosomal dominant Emery-Dreifuss muscular dystrophy.
Assuntos
Fibras Musculares Esqueléticas/patologia , Músculo Esquelético/patologia , Distrofia Muscular de Emery-Dreifuss/patologia , Distrofia Muscular de Emery-Dreifuss/fisiopatologia , Adulto , Criança , Pré-Escolar , Creatina Quinase/sangue , Análise Mutacional de DNA , Humanos , Lamina Tipo A/genética , Masculino , Microscopia Eletrônica de Transmissão , Distrofia Muscular de Emery-Dreifuss/genética , MutaçãoRESUMO
BACKGROUND: Mitochondrial disorders are characterized by an accumulation of lactate and an insufficient oxygen extraction from blood during exercise. Therefore, both parameters (lactate and oxygen saturation) can be used as screening tests in mitochondrial disorders. However, conflicting results regarding sensitivities and specifities of both tests have been reported. METHOD: We examined 27 patients with genetically defined mitochondrial disorders (single deletions n = 15, multiple deletions n = 5, A3243G mutation n = 7), patients with other neuromuscular disorders, and healthy controls. In the first test subjects performed intermittent isometric handgrip exercise (0.5 Hz) at 80% (3 minutes) and 30% (3 and 15 minutes) of maximal contraction force (MCF). Oxygen saturation and partial pressure in cubital venous blood from the exercising arm were measured. In the second test subjects underwent cycle ergometry at 30 W for 15 minutes. Venous lactate at rest, during and 15 minutes postexercise was determined. RESULT: Both tests showed specificities of 92-96%. Sensitivities for changes of venous oxygen partial pressure and oxygen saturation ranged from 21-26% at 80% MCF for 3 minutes to 47-58% at 30% MCF for 15 minutes. Sensitivities for venous resting, peak, and post-exercise lactate was 33%, 58%, and 67%, respectively. The degree of deoxygenation, however,was independent of the intensity and duration of the applied forces. Oxygen desaturation and lactate increase in patients with mitochondrial disorders were not different in patients with and without clinical symptoms of myopathy. There were significant correlations between the heteroplasmy and both the degree of oxygen desaturation and lactate increase in patients with single deletions. In patients who performed both protocols (n = 16) a combination of both tests increased sensitivity up to 87%. CONCLUSION: Oxygen desaturation in forearm exercise tests and lactate increase in cycle ergometry tests show a high specifity but only moderate sensitivity. Combination of the two screening test clearly increases the sensitivity.