RESUMO
Hereditary rippling muscle disease (RMD) is an autosomal dominant human disorder characterized by mechanically triggered contractions of skeletal muscle. Genome-wide linkage analysis has identified an RMD locus on chromosome 3p25. We found missense mutations in positional candidate CAV3 (encoding caveolin 3; ref. 5) in all five families analyzed. Mutations in CAV3 have also been described in limb-girdle muscular dystrophy type 1C (LGMD1C; refs. 6,7), demonstrating the allelism of dystrophic and non-dystrophic muscle diseases.
Assuntos
Caveolinas/genética , Contração Muscular , Músculo Esquelético , Doenças Musculares/genética , Mutação de Sentido Incorreto , Caveolina 3 , Creatina Quinase/sangue , Proteínas do Citoesqueleto/genética , Humanos , Glicoproteínas de Membrana/genética , Distrofias Musculares/genética , Estimulação FísicaRESUMO
The cellular mechanisms of human skeletal muscle adaptation to disuse are largely unknown. The aim of this study was to determine the morphological and biochemical changes of the lower limb soleus and vastus lateralis muscles following 60 days of head-down tilt bed rest in women with and without exercise countermeasure using molecular biomarkers monitoring functional cell compartments. Muscle biopsies were taken before (pre) and after bed rest (post) from a bed rest-only and a bed rest exercise group (n = 8, each). NOS1 and NOS3/PECAM, markers of myofibre 'activity' and capillary density, and MuRF1 (E3 ubiquitin-ligase), a marker of proteolysis, were documented by confocal immunofluorescence and immunoblot analyses. Morphometrical parameters (myofibre cross-sectional area, type I/II distribution) were largely preserved in muscles from the exercise group with a robust trend for type II hypertrophy in vastus lateralis. In the bed rest-only group, the relative NOS1 immunostaining intensity was decreased at type I and II myofibre membranes, while the bed rest plus exercise group compensated for this loss particularly in soleus. In the microvascular network, NOS3 expression and the capillary-to-fibre ratio were both increased in the exercise group. Elevated MuRF1 immunosignals found in subgroups of atrophic myofibres probably reflected accelerated proteolysis. Immunoblots revealed overexpression of the MuRF1 protein in the soleus of the bed rest-only group (> 35% vs. pre). We conclude that exercise countermeasure during bed rest affected both NOS/NO signalling and proteolysis in female skeletal muscle. Maintenance of NO signalling mechanisms and normal protein turnover by exercise countermeasure may be crucial steps to attenuate human skeletal muscle atrophy and to maintain cell function following chronic disuse.
Assuntos
Proteínas Musculares/análise , Músculo Esquelético/metabolismo , Óxido Nítrico Sintase Tipo III/análise , Óxido Nítrico Sintase Tipo I/análise , Ubiquitina-Proteína Ligases/análise , Simulação de Ausência de Peso , Adulto , Repouso em Cama , Biomarcadores/análise , Biópsia por Agulha , Capilares/ultraestrutura , Terapia por Exercício , Feminino , Decúbito Inclinado com Rebaixamento da Cabeça , Humanos , Immunoblotting , Contração Isométrica , Microscopia Confocal , Fibras Musculares Esqueléticas/metabolismo , Músculo Esquelético/fisiopatologia , Atrofia Muscular/metabolismo , Atrofia Muscular/fisiopatologia , Atrofia Muscular/prevenção & controle , Músculo Quadríceps/metabolismo , Músculo Quadríceps/fisiopatologia , Tempo , Proteínas com Motivo Tripartido , Contramedidas de Ausência de PesoRESUMO
In 1965, an adult-onset, autosomal dominant disorder with a peculiar scapuloperoneal distribution of weakness and atrophy was described in a large, multi-generation kindred and named 'scapuloperoneal syndrome type Kaeser' (OMIM #181400). By genetic analysis of the original kindred, we discovered a heterozygous missense mutation of the desmin gene (R350P) cosegregating with the disorder. Moreover, we detected DES R350P in four unrelated German families allowing for genotype-phenotype correlations in a total of 15 patients carrying the same mutation. Large clinical variability was recognized, even within the same family, ranging from scapuloperoneal (n = 2, 12%), limb girdle (n = 10, 60%) and distal phenotypes (n = 3, 18%) with variable cardiac (n = 7, 41%) or respiratory involvement (n = 7, 41%). Facial weakness, dysphagia and gynaecomastia were frequent additional symptoms. Overall and within each family, affected men seemingly bear a higher risk of sudden, cardiac death as compared to affected women. Moreover, histological and immunohistochemical examination of muscle biopsy specimens revealed a wide spectrum of findings ranging from near normal or unspecific pathology to typical, myofibrillar changes with accumulation of desmin. This study reveals that the clinical and pathological variability generally observed in desminopathies may not be attributed to the nature of the DES mutation alone, but may be influenced by additional genetic and epigenetic factors such as gender. In addition, mutations of the desmin gene should be considered early in the diagnostic work-up of any adult-onset, dominant myopathy, even if specific myofibrillar pathology is absent.
Assuntos
Desmina/genética , Miopatias Distais/genética , Mutação de Sentido Incorreto , Adulto , Idoso de 80 Anos ou mais , Biópsia , Análise Mutacional de DNA/métodos , Miopatias Distais/patologia , Feminino , Haplótipos , Humanos , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Fibras Musculares Esqueléticas/patologia , Músculo Esquelético/patologia , Distrofia Muscular do Cíngulo dos Membros/genética , Distrofia Muscular do Cíngulo dos Membros/patologia , Linhagem , Fenótipo , Fatores Sexuais , SíndromeRESUMO
Inclusion body myopathy with Paget disease of bone and frontotemporal dementia (IBMPFD, MIM 167320) is a recently identified autosomal dominant disorder due to mutations in the valosin-containing protein (VCP) that affects muscle, bone and brain. Brain involvement and neuropsychological findings of IBMPFD have not been described in detail. A patient carried a novel heterozygous base pair change, 47832C>T, in the VCP gene that resulted in substitution of an arginine residue by cysteine at position 93 (R93C). He presented first with myopathy while bone involvement remained subclinical. The patient developed behavioral abnormalities in his 60s and showed frank personality change with fluent empty speech at the age of 74 years. This syndrome was best classified as semantic dementia. Magnetic resonance imaging disclosed slight but progressive cerebral atrophy with prominent callosal and frontal white matter loss. Positron emission tomography demonstrated glucose hypometabolism of the frontal and temporal lobes disproportionate to their structural involvement. This first comprehensive clinical and neuroimaging study in IBMPFD may raise the awareness among clinicians as well as basic scientists for this exemplary genetic model of dementia.
Assuntos
Adenosina Trifosfatases/genética , Encéfalo/patologia , Proteínas de Ciclo Celular/genética , Demência/genética , Demência/patologia , Doenças Neurodegenerativas/genética , Doenças Neurodegenerativas/patologia , Idoso , Análise Mutacional de DNA , Demência/fisiopatologia , Predisposição Genética para Doença , Humanos , Imageamento por Ressonância Magnética , Masculino , Músculo Esquelético/patologia , Mutação , Miosite de Corpos de Inclusão/genética , Miosite de Corpos de Inclusão/patologia , Miosite de Corpos de Inclusão/fisiopatologia , Doenças Neurodegenerativas/fisiopatologia , Testes Neuropsicológicos , Osteíte Deformante/genética , Osteíte Deformante/patologia , Osteíte Deformante/fisiopatologia , Reação em Cadeia da Polimerase , Tomografia por Emissão de Pósitrons , Proteína com ValosinaRESUMO
We report on clinical, histological and genetic findings in two patients carrying novel heteroplasmic mutations in the mitochondrial cytochrome c oxidase subunit genes COII and COIII. The first patient, a 35 year-old man had a multisystemic disease, with clinical symptoms of bilateral cataract, sensori-neural hearing loss, myopathy, ataxia, cardiac arrhythmia, depression and short stature and carried a 7970 G>T (E129X) nonsense mutation in COII. A sudden episode of metabolic encephalopathy caused by extremely high blood lactate lead to coma. The second patient developed exercise intolerance and rhabdomyolysis at age 22 years. A heteroplasmic missense mutation 9789 T>C (S195P) was found in skeletal muscle, but not in blood and myoblasts pointing to a sporadic mutation. Our report of two patients with isolated COX deficiency and new mutations in COX subunit genes may help to draw more attention to this type of mtDNA defects and provide new aspects for counselling affected families.
Assuntos
Complexo IV da Cadeia de Transporte de Elétrons/genética , Encefalomiopatias Mitocondriais/genética , Doenças Musculares/genética , Mutação , Adulto , Análise Mutacional de DNA/métodos , Ácido Glutâmico/genética , Humanos , Imuno-Histoquímica/métodos , Masculino , Encefalomiopatias Mitocondriais/enzimologia , Músculo Esquelético/enzimologia , Músculo Esquelético/patologia , Doenças Musculares/enzimologia , Prolina/genética , RNA Mensageiro/biossíntese , Reação em Cadeia da Polimerase Via Transcriptase Reversa/métodos , Rabdomiólise/genética , Rabdomiólise/patologia , Serina/genéticaRESUMO
OBJECTIVE: To determine the cause of sporadic rippling muscle disease (RMD) in a 24-year-old patient. BACKGROUND: RMD is a rare myopathy characterized by percussion-induced rapid muscle contractions (PIRC), muscle mounding, and rippling waves. We have recently found that autosomal dominant RMD is caused by mutations in the caveolin-3 gene (CAV3) on chromosome 3p25. Possibly, increased activity of neuronal nitric oxide synthase (nNOS) contributes to the clinical characteristics of increased mechanical muscle hyperexcitability. METHODS: Clinical examination, mutational analysis, and immunohistochemistry of muscle tissue were performed in a patient with sporadic RMD. RESULTS: The authors observed a de novo CAV3 missense mutation Arg26Gln. Immunohistochemistry showed reduced caveolin-3 surface expression in a muscle biopsy. In addition, the authors found normal sarcolemmal nNOS expression and a reduced expression of alpha-dystroglycan in muscle fibers. CONCLUSIONS: These data confirm that RMD is caused by CAV3 mutations. Moreover, there is evidence that CAV3 mutations may also be found in patients without a positive family history of RMD.
Assuntos
Caveolinas/genética , Músculos/patologia , Doenças Musculares/genética , Doenças Musculares/patologia , Mutação/genética , Adulto , Biópsia , Caveolina 3 , Eletromiografia , Humanos , Imuno-Histoquímica , Masculino , Músculos/fisiopatologia , Doenças Musculares/fisiopatologiaRESUMO
Tenascin-C is a multifunctional extracellular matrix glycoprotein with stimulatory and anti-adhesive or inhibitory properties for axon growth. Its location and discontinuous expression are restricted in innervated muscle tissues. Tenascin-C accumulated interstitially among human denervated muscle fibers and close to normal-sized fibers. To expand our knowledge of the expression of tenascin-C in human neuromuscular disorders, we investigated immunohistologically 20 human muscle specimens with type II myofiber atrophy of children and adults. Tenascin-C immunoreactivity in adult type II atrophy was frequent, and accumulation in children was sparse and weak. In both groups, tenascin-C immunoreactivity was found: 1. Interstitially around normal-sized type II muscle fibers. 2. Around atrophic type II muscle fibers. 3. Around small-caliber myofibers with centrally located nuclei. These results indicate that tenascin-C immunoreactivity: (1) is detectable around early denervated and reinnervated muscle fibers and, therefore, (2) may reflect in part the molecularly ongoing process of denervation and reinnervation in human type II fiber atrophy.
Assuntos
Fibras Musculares de Contração Rápida/patologia , Atrofia Muscular/patologia , Tenascina/análise , Adulto , Idoso , Pré-Escolar , Feminino , Humanos , Imuno-Histoquímica , Lactente , Masculino , Pessoa de Meia-IdadeRESUMO
Soluble guanlylyl cyclase (sGC) seems to be involved in mechanisms for rapid translation of electrical and chemical signals at the neuromuscular junction. To explore the cellular localization of the alpha2, alpha1 and beta1 subunits of sGC, we studied normal and denervated human muscle biopsies immunohistochemically using antibodies directed against the alpha2 and alpha1/beta1 subunits of sGC and performed double labellings with alpha-bungarotoxin. Confocal imaging could localize the alpha2 and alpha1/beta1 subunits of sGC at neuromuscular junctions and vessels and the subunits remained concentrated at neuromuscular junctions following denervation. The presence of sGC at neuromuscular junctions and at vessels suggests sGC could serve as a postsynaptic second messenger for fine tuning of nerve-muscle interaction and dynamic regulation of intramuscular blood flow.
Assuntos
Guanilato Ciclase/metabolismo , Músculo Esquelético/enzimologia , Junção Neuromuscular/enzimologia , Idoso , Bungarotoxinas/farmacologia , Feminino , Humanos , Imuno-Histoquímica , Masculino , Microscopia Confocal , Pessoa de Meia-Idade , Denervação Muscular , Músculo Esquelético/ultraestrutura , Doenças Neuromusculares/enzimologia , Doenças Neuromusculares/patologia , Junção Neuromuscular/ultraestrutura , Sistemas do Segundo Mensageiro/fisiologiaRESUMO
Proteolytic enzyme expression was studied by matrix metalloproteinases (MMP) immunoreactivity (-IR) in muscle biopsies from patients with amyotrophic lateral sclerosis (ALS), spinal muscle atrophy (SMA) and chronic axonal neuropathies (CANP). In normal muscle MMP-2-, MMP-7-, and MMP-9-IR was localized at neuromuscular junctions, in vessels and nerve branches. ALS biopsies of clinically non-affected muscles revealed neither MMP-2, -7-IR nor MMP-9-IR in atrophied myofibers. ALS-affected biopsies revealed MMP-9-IR, and to lesser extent MMP-2- and MMP-7-IR at normal sized and atrophied myofibers. Biopsies of SMA showed MMP-9- and MMP-7-IR at normal sized and atrophic myofibers, while MMP-2-IR was undetectable. In CANP MMP-9-IR was found at normal sized and atrophied myofibers. Distinct expression patterns of MMPs may thus reflect different stages of muscle denervation atrophy.
Assuntos
Metaloproteinase 2 da Matriz/metabolismo , Metaloproteinase 7 da Matriz/metabolismo , Metaloproteinase 9 da Matriz/metabolismo , Denervação Muscular , Músculo Esquelético/metabolismo , Adulto , Idoso , Esclerose Lateral Amiotrófica/enzimologia , Axônios/patologia , Doença Crônica , Humanos , Técnicas Imunoenzimáticas , Pessoa de Meia-Idade , Atrofia Muscular Espinal/enzimologia , Doenças do Sistema Nervoso/enzimologia , Doenças do Sistema Nervoso/patologiaRESUMO
The cytokine leukemia inhibitory factor (LIF) stimulates myoblast proliferation in vitro and vivo and is neurotrophic for motor neurons. In experimentally reinnervated muscle, exogenous LIF application increases muscle mass through myofiber hypertrophy. The goal of this study was to evaluate possible sources of endogenous LIF in human muscle, and whether LIF immunoreactivity (-IR) was detectable in specific myofiber types and/or re-expressed in human denervated muscle. Our study shows that LIF-IR is constitutively detectable in type I myofibers of normal human muscle. In acute and chronically denervated and reinnervated human muscle, LIF-IR is found in all type I myofibers and in addition in some atrophic and almost all angulated atrophic type II myofibers.
Assuntos
Inibidores do Crescimento/metabolismo , Interleucina-6 , Linfocinas/metabolismo , Músculo Esquelético/metabolismo , Adulto , Idoso , Idoso de 80 Anos ou mais , Citosol/ultraestrutura , Feminino , Humanos , Imuno-Histoquímica , Fator Inibidor de Leucemia , Masculino , Pessoa de Meia-Idade , Denervação Muscular , Fibras Musculares Esqueléticas/metabolismo , Músculo Esquelético/citologia , Músculo Esquelético/inervação , Sarcolema/ultraestruturaRESUMO
Cerebral hyperperfusion syndrome after carotid endarterectomy (CEA) is a rare but well-known phenomenon. Percutaneous transluminal angioplasty (PTA) is being widely evaluated for treatment of selected stenoses of the extracranial arteries. Its benefits and risks still need to be established. Hyperperfusion injury (HI) after PTA of cerebral arteries has not been reported. We describe two patients with severe HI, one with a small putaminal haemorrhage and the other with diffuse basal subarachnoid haemorrhage. In both cases, a typical clinical hyperperfusion syndrome with headache, confusion, vomiting and seizures occurred. Patient 1 underwent PTA of the left carotid artery, both subclavian arteries and proximal vertebral arteries, patient 2 had carotid angioplasty only. Transcranial Doppler ultrasound displayed markedly elevated blood-flow velocities. HI may occur after PTA of extracranial arteries. The pathogenesis might be similar to reperfusion injury after CEA. Our findings suggest that: (1) HI may occur after PTA; (2) patients should be monitored after PTA for HI; (3) further risk factors for HI need to be identified.
Assuntos
Angioplastia com Balão/efeitos adversos , Hemorragia Cerebral/etiologia , Traumatismo por Reperfusão/etiologia , Infarto Cerebral/terapia , Feminino , Humanos , Aneurisma Intracraniano/terapia , Masculino , Pessoa de Meia-Idade , Putamen/irrigação sanguínea , Hemorragia Subaracnóidea/etiologiaRESUMO
To substantiate the role of nitric oxide synthase type-I (NOS-I) in neurogenic muscular disorders we investigated human biopsy samples of type-II fiber atrophy and amyotrophic lateral sclerosis (ALS) by NOS-I immunoreactivity (-IR), NOS-associated NADPH-dependent diaphorase activity (NOSaD) and Western blot analysis. In type-II atrophy, loss of NOSaD and reduced NOS-I-IR was apparent in atrophic myofibers. In atrophic fiber groups lacking NOSaD, both NOS-I and dystrophin-IR was decreased while sarcolemmal beta-dystroglycan- and adhalin-IR (markers of the sarcolemmal dystrophin-glycoprotein complex) was normal. In ALS, groups of scattered angulated atrophic fibers revealed partial loss of NOS-I-IR/NOSaD. Atrophied fibers of either type-I or type-II thus revealed differential sarcolemmal NOS/NOSaD pattern thereby reflecting myopathological alterations of the NO-system in human type-II atrophy and ALS.
Assuntos
Esclerose Lateral Amiotrófica/enzimologia , Músculo Esquelético/enzimologia , Atrofia Muscular/enzimologia , NADPH Desidrogenase/metabolismo , Óxido Nítrico Sintase/metabolismo , Adulto , Idoso , Biópsia , Western Blotting , Proteínas do Citoesqueleto/metabolismo , Distroglicanas , Distrofina/metabolismo , Humanos , Imuno-Histoquímica , Glicoproteínas de Membrana/metabolismo , Pessoa de Meia-Idade , SarcoglicanasRESUMO
A case is reported of a patient who experienced sudden onset of severe respiratory failure, shock and coma after first-time intranasal heroin abuse. During the following days full consciousness was restored, revealing persistent oculogyric crises, axial retropulsive dystonia and ataxia. Initially computer tomography (CT) scans of the brain were normal and cerebral spinal fluid examination showed a slight elevation of lactate. Magnetic resonance imaging (MRI) scans of the brain demonstrated diffuse bilateral subcortical white matter hyperintensities, with sparing of the U-fibers, symmetric bilateral hyperintensities of the globus pallidum and very hyperintensive subcortical foci in the right hemisphere. Differential diagnostic assessment, treatment, clinical and MRI course of a 6-month follow-up are discussed.
Assuntos
Distonia/induzido quimicamente , Heroína/intoxicação , Entorpecentes/intoxicação , Insuficiência Respiratória/induzido quimicamente , Administração Intranasal , Adulto , Heroína/administração & dosagem , Humanos , Imageamento por Ressonância Magnética , Masculino , Entorpecentes/administração & dosagem , Transtornos Relacionados ao Uso de Substâncias/etiologia , Tomografia Computadorizada por Raios XRESUMO
Tenascin is a large oligomeric glycoprotein of the extracellular matrix. Its location is innervated muscle tissues. We investigated immunohistologically, using two monoclonal antibodies (mah) against Tenascin, biopsied denervated human muscle of children and adults. Tenascin was present in the interstitial space among denervated muscle fibres. Accumulation of Tenascin in denervated adult muscle tissue was frequent, accumulation in denervated muscle tissue of children was sparse and weak. The two antibodies reacted correspondingly. Tenascin was not only found in the vicinity of atrophic muscle fibres, but also close to normally sized fibres, suggesting an early stage of denervation even before reduction of muscle fibre volume.
Assuntos
Denervação Muscular , Tenascina/análise , Adulto , Idoso , Anticorpos Monoclonais/imunologia , Criança , Pré-Escolar , Feminino , Humanos , Lactente , Recém-Nascido , Masculino , Pessoa de Meia-Idade , Fibras Musculares Esqueléticas/metabolismo , Fibras Musculares Esqueléticas/patologia , Atrofia Muscular/metabolismo , Doenças Neuromusculares/metabolismo , Doenças Neuromusculares/patologia , Atrofias Musculares Espinais da Infância/metabolismo , Atrofias Musculares Espinais da Infância/patologia , Tenascina/imunologiaRESUMO
OBJECT: The effect of increased intracranial pressure (ICP) on cerebral venous blood flow has been the subject of very few clinical and experimental studies. The authors assessed the usefulness of venous transcranial Doppler (TCD) ultrasonography as a noninvasive monitoring tool for predicting raised ICP. METHODS: Serial venous TCD studies of the basal vein of Rosenthal and the straight sinus (SS) were prospectively performed in 30 control volunteers and 25 patients with raised ICP. Correlations with ICP data were calculated using a multivariate regression model. Venous blood flow velocities (BFVs) in the basal vein of Rosenthal showed, within a certain range, a linear relationship between mean ICP and maximal venous BFV (r = 0.645; p<0.002). Moreover, a linear relationship was found for maximal venous BFVs in the SS and mean ICP (r = 0.928; p<0.0003). CONCLUSIONS: Venous TCD studies may provide an additional noninvasive monitoring tool for raised ICP and give further insights into the cerebral venous hemodynamics present during raised ICP.
Assuntos
Veias Cerebrais/fisiopatologia , Circulação Cerebrovascular/fisiologia , Hipertensão Intracraniana/diagnóstico por imagem , Hipertensão Intracraniana/fisiopatologia , Pressão Intracraniana , Adulto , Idoso , Idoso de 80 Anos ou mais , Pressão Sanguínea , Dióxido de Carbono/sangue , Feminino , Frequência Cardíaca , Humanos , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Ultrassonografia Doppler TranscranianaRESUMO
Plasma IL-6 before and 20 min after prolonged muscular exercise for 20 min at the individual aerobic/anaerobic threshold was analyzed in patients with neuromuscular diseases and in controls. Patients were assigned to the following diagnostic categories: Controls (n=18); amyotrophic lateral sclerosis (n=7); peripheral neuropathy (n=6); muscular dystrophy (n=13); mitochondriopathy (n=3); myopathy (others) (n=3); inflammatory myopathy (n=6); mononeuropathy (n=4). The concentrations of IL-6 before exercise were 5.55+/-0.94 pg/ml, and 6.52+/-0.97 pg/ml after exercise (P=0.0001). We introduced the independent variables age, sex and diagnostic category into a stepwise multiple linear regression model. Age emerged as a significant predictor of the IL-6 ratio (IL-6 post exercise/lL-6 before exercise). The regression equation was: IL-6 ratio=0.87+0.009xage (years), R=0.33, P<0.01, simple linear regression model. All IL-1beta concentrations were below the sensitivity of the assay (5 pg/ml). Concerning patients with neuromuscular diseases, the age associated increased IL-6 release after exercise could mean additional muscle damage.
Assuntos
Códon sem Sentido , DNA Mitocondrial/genética , Complexo IV da Cadeia de Transporte de Elétrons/genética , Miopatias Mitocondriais/genética , Adenosina Trifosfatases/metabolismo , Adolescente , Adulto , Idade de Início , Complexo IV da Cadeia de Transporte de Elétrons/metabolismo , Seguimentos , Humanos , Imuno-Histoquímica , Masculino , Miopatias Mitocondriais/enzimologia , Miopatias Mitocondriais/patologia , Músculo Esquelético/metabolismo , Músculo Esquelético/patologia , Polimorfismo de Fragmento de Restrição , Recuperação de Função Fisiológica , Remissão EspontâneaAssuntos
Predisposição Genética para Doença , Miopatias Mitocondriais/genética , Mutação , RNA de Transferência de Alanina/genética , Adulto , Apoptose , Linhagem Celular , Humanos , Masculino , Pessoa de Meia-Idade , Mitocôndrias/ultraestrutura , Miopatias Mitocondriais/diagnóstico , Miopatias Mitocondriais/patologia , Músculo Esquelético/patologia , Músculo Esquelético/ultraestrutura , Mioblastos Esqueléticos/citologia , Distrofia Miotônica/diagnósticoRESUMO
The need for clinical awareness and diagnostic precision of glycogen storage disease type 2 (GSD2) has increased, as enzyme replacement therapy has become available. So far, only small series have reported the muscle pathology of late-onset GSD2. We reassessed 43 muscle biopsies of 38 GSD2 patients. In all patients the diagnosis of GSD2 has been established by biochemistry and/or mutational analysis of the GAA gene. Additionally to the expected morphological features, ultrastructural analysis revealed a high incidence of autophagic vacuoles, lipofuscin debris, structural Z-line disorganization and histological neurogenic-like pattern that were not thoroughly appreciated, previously. Comparing age at onset and morphology, excessive vacuolar and autophagic myopathy and mitochondrial disorganization of virtually all fibres is common in infants. At juvenile onset, a more moderate vacuolization without significant differences in overall morphology is notable. At late-onset, the spectrum of vacuolar myopathy is more divergent, ranging from almost normal to severe. Here pronounced secondary alterations are observed that include lipofuscin debris, autophagic vacuoles with residual lysosomal bodies and granular inclusions, structural mitochondrial and Z-line texture alterations. Moreover, there is a high incidence of subtle neurogenic-like alteration in all subtypes. Nineteen patients were genetically tested; in 15 patients the common leaky splicing mutation c.-45T>G (or IVS1-13T>G) in intron1 of the GAA gene was found on at least one allele, facilitating genetic screening. In our patients, GAA genotype appears not to be associated with secondary alterations such as autophagic vacuoles, structural alterations or neurogenic-like changes. These findings may have implications for our understanding of the pathogenesis of GSD2 and for assessing therapeutic success of enzyme replacement therapy.
Assuntos
Doença de Depósito de Glicogênio Tipo II/genética , Doença de Depósito de Glicogênio Tipo II/patologia , Músculo Esquelético/ultraestrutura , alfa-Glucosidases/genética , Adolescente , Adulto , Fatores Etários , Idade de Início , Idoso , Biópsia , Criança , Pré-Escolar , Análise Mutacional de DNA , Feminino , Genótipo , Doença de Depósito de Glicogênio Tipo II/metabolismo , Humanos , Imuno-Histoquímica , Lactente , Masculino , Microscopia Eletrônica de Transmissão , Pessoa de Meia-Idade , Músculo Esquelético/metabolismo , Mutação , FenótipoRESUMO
The authors reviewed the obstetric histories of 42 women of 37 families with myotonic dystrophy type 2 (DM2). Nine women (21%) had the first symptoms during pregnancy and worsening in subsequent pregnancies. Of 96 pregnancies, 13% ended as early and 4% as late miscarriages. Preterm labor occurred in 50% of pregnancies resulting in 27% preterm deliveries in women with overt DM2 in pregnancy. There was no evidence of a congenital DM2.