RESUMO
BACKGROUND AND PURPOSE: To describe a large series of patients with α, ß, and γ sarcoglycanopathies (LGMD-R3, R4, and R5) and study phenotypic correlations and disease progression. METHODS: A multicentric retrospective study in four centers in the Paris area collecting neuromuscular, respiratory, cardiac, histologic, and genetic data. The primary outcome of progression was age of loss of ambulation (LoA); disease severity was established according to LoA before or after 18 years of age. Time-to-event analysis was performed. RESULTS: One hundred patients (54 γ-SG; 41 α-SG; 5 ß-SG) from 80 families were included. The γ-SG patients had earlier disease onset than α-SG patients (5.5 vs. 8 years; p = 0.022) and ß-SG patients (24.4 years). Axial muscle weakness and joint contractures were frequent and exercise intolerance was observed. At mean follow-up of 22.9 years, 65.3% of patients were wheelchair-bound (66.7% α-SG, 67.3% γ-SG, 40% ß-SG). Dilated cardiomyopathy occurred in all sarcoglycanopathy subtypes, especially in γ-SG patients (p = 0.01). Thirty patients were ventilated and six died. Absent sarcoglycan protein expression on muscle biopsy and younger age at onset were associated with earlier time to LoA (p = 0.021 and p = 0.002). Age at onset was an independent predictor of both severity and time to LoA (p = 0.0004 and p = 0.009). The α-SG patients showed genetic heterogeneity, whereas >90% of γ-SG patients carried the homozygous c.525delT frameshift variant. Five new mutations were identified. CONCLUSIONS: This large multicentric series delineates the clinical spectrum of patients with sarcoglycanopathies. Age at disease onset is an independent predictor of severity of disease and LoA, and should be taken into account in future clinical trials.
Assuntos
Sarcoglicanopatias , Adolescente , Seguimentos , Homozigoto , Humanos , Músculo Esquelético , Estudos Retrospectivos , Sarcoglicanopatias/epidemiologia , Sarcoglicanopatias/genética , Sarcoglicanas/genéticaRESUMO
BACKGROUND AND PURPOSE: The aim was to determine the genetic background of unknown muscular dystrophy in five French families. METHODS: Twelve patients with limb girdle muscular dystrophy or distal myopathy were clinically evaluated. Gene mutations were identified using targeted exon sequencing and mutated DNAJB6 was tested in vitro. RESULTS: Five patients presented with distal lower limb weakness whilst others had proximal presentation with a variable rate of progression starting at the mean age of 38.5 years. Two novel mutations (c.284A>T, p.Asn95Ile, two families; and c.293_295delATG, p.Asp98del, one family) as well as the previously reported c.279C>G (p.Phe93Leu, two families) mutation in DNAJB6 were identified. All showed a reduced capacity to prevent protein aggregation. CONCLUSIONS: The mutational and phenotypical spectrum of DNAJB6-caused muscle disease is larger than previously reported, including also dysphagia. The originally reported c.279C>G (p.Phe93Leu) mutation is now identified in four different populations and appears to be a mutational hotspot. Our report confirms that some DNAJB6 mutations cause distal-onset myopathy and hence DNAJB6 defects should be considered broadly in dominant muscular dystrophy families.
Assuntos
Miopatias Distais/genética , Proteínas de Choque Térmico HSP40/genética , Chaperonas Moleculares/genética , Distrofia Muscular do Cíngulo dos Membros/genética , Mutação , Proteínas do Tecido Nervoso/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Progressão da Doença , Feminino , França , Humanos , Masculino , Pessoa de Meia-Idade , Debilidade Muscular/genética , Linhagem , FenótipoRESUMO
OBJECTIVES: Rhabdomyolysis and myalgia are common conditions, and mutation in the ryanodine receptor 1 gene (RYR1) is suggested to be a common cause. Due to the large size of RYR1, however, sequencing has not been widely accessible before the recent advent of next-generation sequencing technology and limited phenotypic descriptions are therefore available. MATERIAL & METHODS: We present the medical history, clinical and ancillary findings of patients with RYR1 mutations and rhabdomyolysis and myalgia identified in Denmark, France and The Netherlands. RESULTS: Twenty-two patients with recurrent rhabdomyolysis (CK > 10 000) or myalgia with hyperCKemia (>1.5 × ULN) and a RYR1 mutation were identified. One had mild wasting of the quadriceps muscle, but none had fixed weakness. Symptoms varied from being restricted to intense exercise to limiting ADL function. One patient developed transient kidney failure during rhabdomyolysis. Two received immunosuppressants on suspicion of myositis. None had episodes of malignant hyperthermia. Muscle biopsies were normal, but CT/MRI showed muscle hypertrophy in most. Delay from first symptom to diagnosis was 12 years on average. Fifteen different dominantly inherited mutations were identified. Ten were previously described as pathogenic and 5 were novel, but rare/absent from the background population, and predicted to be pathogenic by in silico analyses. Ten of the mutations were reported to give malignant hyperthermia susceptibility. CONCLUSION: Mutations in RYR1 should be considered as a significant cause of rhabdomyolysis and myalgia syndrome in patients with the characteristic combination of rhabdomyolysis, myalgia and cramps, creatine kinase elevation, no weakness and often muscle hypertrophy.
Assuntos
Mialgia/genética , Rabdomiólise/genética , Canal de Liberação de Cálcio do Receptor de Rianodina/genética , Adolescente , Adulto , Criança , Dinamarca , Feminino , França , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Mutação , Mialgia/fisiopatologia , Países Baixos , Fenótipo , Rabdomiólise/fisiopatologia , Síndrome , Adulto JovemRESUMO
We present three members of an Italian family affected by tubular aggregate myopathy (TAM) and congenital miosis harboring a novel missense mutation in ORAI1. All patients had a mild, late onset TAM revealed by asymptomatic creatine kinase (CK) elevation and congenital miosis consistent with a Stormorken-like Syndrome, in the absence of thrombocytopathy. Muscle biopsies showed classical histological findings but ultrastructural analysis revealed atypical tubular aggregates (TAs). The whole body muscle magnetic resonance imaging (MRI) showed a similar pattern of muscle involvement that correlated with clinical severity. The lower limbs were more severely affected than the scapular girdle, and thighs were more affected than legs. Molecular analysis revealed a novel c.290C>G (p.S97C) mutation in ORAI1 in all affected patients. Functional assays in both human embryonic kidney (HEK) cells and myotubes showed an increased rate of Ca2+ entry due to a constitutive activation of the CRAC channel, consistent with a 'gain-of-function' mutation. In conclusion, we describe an Italian family harboring a novel heterozygous c.290C>G (p.S97C) mutation in ORAI1 causing a mild- and late-onset TAM and congenital miosis via constitutive activation of the CRAC channel. Our findings extend the clinical and genetic spectrum of the ORAI1-related TAM.
Assuntos
Mutação , Miopatias Congênitas Estruturais/genética , Proteína ORAI1/genética , Distúrbios Pupilares/congênito , Idade de Início , Canais de Cálcio Ativados pela Liberação de Cálcio/metabolismo , Feminino , Heterozigoto , Humanos , Masculino , Pessoa de Meia-Idade , Miopatias Congênitas Estruturais/fisiopatologia , Proteína ORAI1/metabolismo , Linhagem , Distúrbios Pupilares/genéticaRESUMO
Nemaline myopathy (NM) is one of the most common forms of congenital myopathy. The condition is defined by the histopathological finding of nemaline bodies (rods) on muscle biopsy and is associated with hypotonia and muscle weakness. The clinical spectrum encompasses lethal forms presenting in the neonatal period with profound weakness and less severe congenital diseases of later onset. NM is significantly heterogeneous from a genetic point of view, and its inheritance can be autosomal-dominant (AD), sporadic or autosomal-recessive (AR). To date, 11 genes encoding proteins of skeletal muscle thin filaments, Kelch domain-associated proteins and an unconventional myosin have been implicated in NM. The mechanisms leading to nemaline body formation and muscle weakness are still largely unclear. This report reviews the clinical, histopathological and genetic features of NM, with a focus on some of the recently discovered forms.
Assuntos
Miopatias da Nemalina/genética , Miopatias da Nemalina/terapia , Biópsia , Humanos , Miopatias da Nemalina/patologiaRESUMO
Myofibrillar myopathies (MFM) are mostly adult-onset diseases characterized by progressive morphological alterations of the muscle fibers beginning in the Z-disk and the presence of protein aggregates in the sarcoplasm. They are mostly caused by mutations in different genes that encode Z-disk proteins, including DES, CRYAB, LDB3, MYOT, FLNC and BAG3. A large family of French origin, presenting an autosomal dominant pattern, characterized by cardiac arrhythmia associated to late-onset muscle weakness, was evaluated to clarify clinical, morphological and genetic diagnosis. Muscle weakness began during adult life (over 30 years of age), and had a proximal distribution. Histology showed clear signs of a myofibrillar myopathy, but with unusual, large inclusions. Subsequently, genetic testing was performed in MFM genes available for screening at the time of clinical/histological diagnosis, and desmin (DES), αB-crystallin (CRYAB), myotilin (MYOT) and ZASP (LDB3), were excluded. LMNA gene screening found the p.R296C variant which did not co-segregate with the disease. Genome wide scan revealed linkage to 7q.32, containing the FLNC gene. FLNC direct sequencing revealed a heterozygous c.3646T>A p.Tyr1216Asn change, co-segregating with the disease, in a highly conserved amino acid of the protein. Normal filamin C levels were detected by Western-blot analysis in patient muscle biopsies and expression of the mutant protein in NIH3T3 showed filamin C aggregates. This is an original FLNC mutation in a MFM family with an atypical clinical and histopathological presentation, given the presence of significantly focal lesions and prominent sarcoplasmic masses in muscle biopsies and the constant heart involvement preceding significantly the onset of the myopathy. Though a rare etiology, FLNC gene should not be excluded in early-onset arrhythmia, even in the absence of myopathy, which occurs later in the disease course.
Assuntos
Arritmias Cardíacas/etiologia , Filaminas/genética , Debilidade Muscular/etiologia , Doenças Musculares/complicações , Doenças Musculares/genética , Mutação de Sentido Incorreto/genética , Adolescente , Adulto , Idade de Início , Idoso , Sequência de Aminoácidos , Análise Mutacional de DNA , Família , Feminino , Genoma Humano , Humanos , Imuno-Histoquímica , Masculino , Pessoa de Meia-Idade , Miofibrilas/patologia , Linhagem , Adulto JovemRESUMO
Mitochondrial diseases are a heterogeneous group of pathologies, caused by missense mutations, sporadic large-scale deletions of mitochondrial DNA (mtDNA) or mutations of nuclear maintenance genes. We report the case of a patient in whom extended muscle pathology, biochemical and genetic mtDNA analyses have proven to be essential to elucidate a unique asymmetrical myopathic presentation. From the age of 34 years on, the patient has presented with oculomotor disorders, right facial peripheral palsy and predominantly left upper limb muscle weakness and atrophy. By contrast, he displayed no motor weakness on the right hemi-body, and no sensory symptoms, cerebellar syndrome, hypoacusis, or parkinsonism. Cardiac function was normal. CK levels were elevated (671 UI/L). Electroneuromyography (ENMG) and muscle MRI showed diffuse myogenic alterations, more pronounced on the left side muscles. Biopsy of the left deltoid muscle showed multiple mitochondrial defects, whereas in the right deltoid, mitochondrial defects were much less marked. Extended mitochondrial biochemical and molecular workup revealed a unique mtDNA deletion, with a 63.4% heteroplasmy load in the left deltoid, versus 8.1% in the right one. This case demonstrates that, in mitochondrial myopathies, heteroplasmy levels may drastically vary for the same type of muscle, rising the hypothesis of a new pathophysiological mechanism explaining asymmetry in hereditary myopathies.
Assuntos
Heteroplasmia , Miopatias Mitocondriais , Masculino , Humanos , Adulto , Miopatias Mitocondriais/patologia , DNA Mitocondrial/genética , Atrofia Muscular/patologia , Músculos/patologiaRESUMO
AIMS: To report the clinical, pathological and genetic findings in a group of patients with a previously not described phenotype of congenital myopathy due to recessive mutations in the gene encoding the type 1 muscle ryanodine receptor channel (RYR1). METHODS: Seven unrelated patients shared a predominant axial and proximal weakness of varying severity, with onset during the neonatal period, associated with bilateral ptosis and ophthalmoparesis, and unusual muscle biopsy features at light and electron microscopic levels. RESULTS: Muscle biopsy histochemistry revealed a peculiar morphological pattern characterized by numerous internalized myonuclei in up to 51% of fibres and large areas of myofibrillar disorganization with undefined borders. Ultrastructurally, such areas frequently occupied the whole myofibre cross section and extended to a moderate number of sarcomeres in length. Molecular genetic investigations identified recessive mutations in the ryanodine receptor (RYR1) gene in six compound heterozygous patients and one homozygous patient. Nine mutations are novel and four have already been reported either as pathogenic recessive mutations or as changes affecting a residue associated with dominant malignant hyperthermia susceptibility. Only two mutations were located in the C-terminal transmembrane domain whereas the others were distributed throughout the cytoplasmic region of RyR1. CONCLUSION: Our data enlarge the spectrum of RYR1 mutations and highlight their clinical and morphological heterogeneity. A congenital myopathy featuring ptosis and external ophthalmoplegia, concomitant with the novel histopathological phenotype showing fibres with large, poorly delimited areas of myofibrillar disorganization and internal nuclei, is highly suggestive of an RYR1-related congenital myopathy.
Assuntos
Mutação , Miofibrilas/ultraestrutura , Miopatia da Parte Central/genética , Miopatia da Parte Central/metabolismo , Miopatia da Parte Central/patologia , Canal de Liberação de Cálcio do Receptor de Rianodina/genética , Adolescente , Adulto , Núcleo Celular/metabolismo , Núcleo Celular/ultraestrutura , Criança , Feminino , Genes Recessivos , Humanos , Imuno-Histoquímica , Masculino , Microscopia Eletrônica de Transmissão , Linhagem , Fenótipo , Reação em Cadeia da Polimerase , Adulto JovemRESUMO
Dystrophin, the protein product of the Duchenne muscular dystrophy (DMD) gene, is a cytoskeletal protein tightly associated with a large oligomeric complex of sarcolemmal glycoproteins including dystroglycan, which provides a linkage to the extracellular matrix component, laminin. In DMD, the absence of dystrophin leads to a drastic reduction in all of the dystrophin-associated proteins, causing the disruption of the linkage between the subsarcolemmal cytoskeleton and the extracellular matrix which, in turn, may render muscle cells susceptible to necrosis. The COOH-terminal domains (cysteine-rich and carboxyl-terminal) of dystrophin have been suggested to interact with the sarcolemmal glycoprotein complex. However, truncated dystrophin lacking these domains was reported to be localized to the sarcolemma in four DMD patients recently. Here we report that all of the dystrophin-associated proteins are drastically reduced in the sarcolemma of three DMD patients in whom dystrophin lacking the COOH-terminal domains was properly localized to the sarcolemma. Our results indicate that the COOH-terminal domains of dystrophin are required for the proper interaction of dystrophin with the dystrophin-associated proteins and also support our hypothesis that the loss of the dystrophin-associated proteins in the sarcolemma leads to severe muscular dystrophy even when truncated dystrophin is present in the subsarcolemmal cytoskeleton.
Assuntos
Distrofina/deficiência , Distrofina/genética , Músculos/metabolismo , Distrofias Musculares/genética , Biópsia , Pré-Escolar , Distrofina/análise , Humanos , Imuno-Histoquímica , Lactente , Masculino , Glicoproteínas de Membrana/metabolismo , Modelos Estruturais , Músculos/patologia , Distrofias Musculares/patologia , Valores de Referência , Sarcolema/metabolismo , Sarcolema/ultraestruturaRESUMO
We analysed the clinical, histochemical, ultrastructural and genetic data of patients affected by central core disease (CCD) studied during the last 20 years. From a total series of 86 CCD-families, we have identified 46 CCD families with RYR1 mutations (16 autosomal dominant, 8 autosomal recessive, 17 sporadic cases and 5 de novo mutations). Out of the other 40 CCD families, the RyR1 gene was entirely excluded in 7 families, by cDNA sequencing or linkage analysis, indicating a genetic heterogeneity of CCD.
Assuntos
Miopatia da Parte Central/diagnóstico , Miopatia da Parte Central/genética , Canal de Liberação de Cálcio do Receptor de Rianodina/genética , Humanos , Imuno-Histoquímica , Miopatia da Parte Central/patologiaRESUMO
Primary adhalin (or alpha-sarcoglycan) deficiency due to a defect of the adhalin gene localized on chromosome 17q21 causes an autosomal recessive myopathy. We evaluated 20 patients from 15 families (12 from Europe and three from North Africa) with a primary adhalin deficiency with two objectives: characterization of the clinical phenotype and analysis of the correlation with the level of adhalin expression and the type of gene mutation. Age at onset and severity of the myopathy were heterogeneous: six patients were wheel-chair bound before 15 years of age, whereas five other patients had mild disease with preserved ambulation in adulthood. The clinical pattern was similar in all the patients with symmetric characteristic involvement of trunk and limb muscles, calf hypertrophy, and absence of cardiac dysfunction. Immunofluorescence and immunoblot studies of muscle biopsy specimens showed a large variation in the expression of adhalin. The degree of adhalin deficiency was fairly correlated with the clinical severity. There were 15 different mutations (10 missense, five null). Double null mutations (three patients) were associated with severe myopathy, but in the other cases (null/missense and double missense) there was a large variation in the severity of the disease.
Assuntos
Proteínas do Citoesqueleto/deficiência , Proteínas do Citoesqueleto/genética , Genes Recessivos , Glicoproteínas de Membrana/deficiência , Glicoproteínas de Membrana/genética , Distrofias Musculares/genética , Distrofias Musculares/fisiopatologia , Adolescente , Adulto , Criança , Pré-Escolar , Proteínas do Citoesqueleto/metabolismo , Progressão da Doença , Feminino , Genes , Humanos , Immunoblotting , Imuno-Histoquímica , Masculino , Glicoproteínas de Membrana/metabolismo , Músculos/patologia , Músculos/fisiopatologia , Distrofias Musculares/patologia , Mutação , SarcoglicanasRESUMO
MERRF (Myoclonic Epilepsy and Ragged-Red Fibres) syndrome is one of the maternally inherited diseases for which a mitochondrial DNA (mtDNA) point mutation has recently been identified. The mutation is always heteroplasmic, that is normal and mutant mtDNA coexist within the same individual. We studied mtDNA heteroplasmy in two families with MERRF syndrome, using a denaturing gradient gel electrophoresis technique that avoids the errors in the evaluation of wild/mutant mtDNA ratios caused by restriction enzyme cutting in the situation of amplification of a heteroplasmic DNA. In two patients, the proportion of muscle mutant mtDNA was in agreement with the severity of muscle mitochondrial proliferation, energy defect and fibre type I predominance. In nine patients from three generations of one family, mutant mtDNA proportion in leukocytes was in relative agreement with the clinical severity of the disease. Transmission of mutant mtDNA through these three generations did not show any tendency toward homoplasmy. Homogeneity of the mutant mtDNA proportion among different tissues from one patient was demonstrated in brain, liver, muscle and heart but a possibility of divergence of the mutant mtDNA proportion during mitosis was documented in cultured skin fibroblasts.
Assuntos
DNA Mitocondrial/genética , Síndrome MERRF/genética , Mutação Puntual , Adolescente , Adulto , Idoso , Sequência de Bases , Criança , Análise Mutacional de DNA , Eletroforese/métodos , Feminino , Histocitoquímica , Humanos , Masculino , Dados de Sequência Molecular , Músculos/química , Desnaturação de Ácido Nucleico , FenótipoRESUMO
Two brothers, aged 27 and 20 months, born from consanguineous healthy parents, presented with cardiomyopathy, lactic acidosis and carnitine abnormalities in serum and muscle, without clinical evidence of muscle involvement. The histochemical reaction for cytochrome c oxidase (COX) activity was negative in all muscle fibres, although the holoenzyme and subunits were present at a normal level, as shown by immunocytochemistry. The COX activity was, respectively, 5 and 25% of control values, in muscle biopsies. Partial deficiency of complex IV was confirmed in fresh isolated muscle mitochondria from patient 2 and was associated with a defect of complex I. Patient 1 died at age 3 yr 6 months. Partial improvement of cardiomyopathy in patient 2 was obtained under carnitine therapy, but seizures occurred and CT scan and magnetic resonance imaging (MRI) revealed thalamic hypodensity. Thus, the disorder appears to be progressive despite the clinical stabilization of the cardiomyopathy. This further demonstrates the complexity and clinical heterogeneity of combined respiratory chain complex deficiencies.
Assuntos
Cardiomiopatias/genética , Deficiência de Citocromo-c Oxidase , Mitocôndrias Cardíacas/enzimologia , Mitocôndrias Musculares/metabolismo , Músculos/patologia , NAD(P)H Desidrogenase (Quinona)/deficiência , Biópsia , Cardiomiopatias/enzimologia , Cardiomiopatias/patologia , Carnitina/metabolismo , Consanguinidade , Complexo IV da Cadeia de Transporte de Elétrons/metabolismo , Feminino , Humanos , Lactente , Masculino , Mitocôndrias Musculares/enzimologia , Mitocôndrias Musculares/ultraestrutura , Músculos/ultraestrutura , NAD(P)H Desidrogenase (Quinona)/metabolismo , Consumo de Oxigênio , Valores de Referência , Succinato Desidrogenase/análiseRESUMO
We report two families both presenting with malignant hyperthermia susceptibility and "core" or "core-like" changes in the muscle tissue. Combined analysis of the malignant hyperthermia phenotype and the histochemical findings demonstrates the complexity of their association and highly suggests genetic heterogeneity of malignant hyperthermia and central core diseases.
Assuntos
Cromossomos Humanos Par 19 , Hipertermia Maligna/genética , Músculos/patologia , Doenças Musculares/genética , Adolescente , Adulto , Idoso , Biópsia , Pré-Escolar , DNA/análise , Suscetibilidade a Doenças , Feminino , Ligação Genética , Humanos , Masculino , Hipertermia Maligna/complicações , Hipertermia Maligna/patologia , Pessoa de Meia-Idade , Doenças Musculares/complicações , Doenças Musculares/patologia , LinhagemRESUMO
We report a 6-year-old female patient presenting with a sudden and severe single episode of rhabdomyolysis in which screening for a metabolic disorder was negative. Four months after the episode a muscle biopsy was performed and showed a mild pattern of necrosis/regeneration. Upon immunofluorescence, a mosaic pattern of dystrophin deficiency was found, and in the dystrophin deficient muscle fibres, the four proteins of the sarcoglycan complex were also lacking. Genetic analysis showed a duplication of exons 3 to 17 on one X-chromosome of the proband, but not on the mother's X-chromosome. A clearly skewed X-inactivation (85% of the defective X being active) was found and is consistent with the patient being symptomatic. To our knowledge, a spontaneous rhabdomyolysis in a female Duchenne muscular dystrophy carrier has never been reported.
Assuntos
Mecanismo Genético de Compensação de Dose , Distrofina/genética , Genes Duplicados , Distrofia Muscular de Duchenne/genética , Distrofia Muscular de Duchenne/patologia , Biópsia , Criança , Feminino , Heterozigoto , Humanos , Distrofia Muscular de Duchenne/metabolismo , Rabdomiólise/genética , Rabdomiólise/metabolismo , Rabdomiólise/patologia , Cromossomo XRESUMO
We report a family with an X-linked recessive muscular dystrophy characterised by exercise-induced myalgia, recurrent pigmenturia and mild proximal muscle involvement. Immunocytochemical and immunoblotting analysis in muscle, using the antibody directed against the rod domain of dystrophin, revealed a loss of immunoreactivity, but the immunolabelling using the antibodies directed against the COOH and NH2 domains of dystrophin were almost normal. The immunoreactions for alpha-sarcoglycan, gamma-sarcoglycan and beta-dystroglycan were normal. In the five male patients of this family with increased serum creatine kinase levels (from x8 to x50), mass spectrometry screening of the urine revealed a large increase in glycerol elimination which was quantified by enzymatic assay (from x14 to x39). An in-frame deletion of the dystrophin gene (exons 13-29) was found in the same five males and in three carrier females. All the deleted chromosomes also carried a missense mutation at nucleotide 947 of the Xp glycerol kinase (GK) gene resulting in a Thr to Met substitution at codon 278. These findings indicate that the two mutations cosegregate on the same chromosome in this family. This is the first reported case of two physically independent mutations, within the DMD and GK genes, which are contiguous but several hundred kilobases apart.
Assuntos
Distrofina/genética , Ligação Genética , Glicerol Quinase/genética , Distrofias Musculares/genética , Mutação Puntual , Cromossomo X , Adolescente , Adulto , Criança , Pré-Escolar , Mapeamento Cromossômico , Feminino , Deleção de Genes , Humanos , Masculino , Linhagem , SíndromeRESUMO
We report histochemical, immunocytochemical, biochemical and molecular studies of skeletal muscle from a 23-year-old man with Kearns-Sayre syndrome. Southern blot analysis revealed a 4.7 kb heteroplasmic deletion of the mitochondrial DNA mapping within genes coding for subunits of complexes I, IV and V of the respiratory chain and for tRNA. Cytochrome c oxidase activity was decreased by 30% in isolated muscle mitochondria, without alteration of the Km. Histochemical and immunocytochemical correlation studies for cytochrome c oxidase revealed a lack of activity in 34% of individual muscle fibers including all the typical ragged-red fibers and a low percentage of immunodeficient fibers.
Assuntos
Deficiência de Citocromo-c Oxidase , DNA Mitocondrial/metabolismo , Síndrome de Kearns-Sayre/metabolismo , Músculos/metabolismo , Oftalmoplegia/metabolismo , Adulto , Humanos , Imuno-Histoquímica , Síndrome de Kearns-Sayre/patologia , Masculino , Músculos/patologiaRESUMO
One hundred patients presenting with exercise intolerance or rhabdomyolysis episodes have been examined successively by 31P Nuclear Magnetic Resonance Spectroscopy (MRS) of leg plantar flexor muscles with exercise test. In all cases a muscle biopsy was performed. At the end of investigations, diagnosis of a metabolic myopathy was made in 33 patients: glycogenolysis or glycolysis deficiency in 8 cases, mitochondrial myopathy in 24 cases and CPT II deficiency in one case. Muscular dystrophy or congenital myopathy were diagnosed in 6 cases. No precise etiology could be found in 30 patients with either high CK levels or muscle biopsy abnormalities. Seven patients had rhabdomyolysis related to excessive physical activities. Twenty-four patients had functional symptoms. The principal MRS parameters used for diagnosis were the values of intracellular pH at the end of exercise and the time constant of phosphocreatine resynthesis during recovery. Lack of acidosis after exercise was observed in all patients with blockade of glycogenolysis or glycolysis. A slowing in phosphocreatine resynthesis was found in 66 p.cent of patients with definite mitochondrial myopathy. The specificity of these parameters were respectively 92.4 p.cent and 85.5 p.cent for the two groups. In conclusion (31)P MRS allows the detection of muscular glycogenoses with a sensitivity close to 100 p.cent. However, its sensitivity was lower for the detection of mitochondrial myopathies, as is also known for the other in vivo metabolic investigations, reflecting the heterogeneity of expression of mitochondrial abnormalities in a given muscle. The integration of imaging in the examination protocol may help to orientate towards the diagnostic of a dystrophy in some patients.
Assuntos
Tolerância ao Exercício/fisiologia , Músculo Esquelético/patologia , Rabdomiólise/patologia , Adolescente , Adulto , Idoso , Exercício Físico , Teste de Esforço , Feminino , Glicogênio/metabolismo , Glicólise , Humanos , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Músculo Esquelético/enzimologia , Músculo Esquelético/fisiopatologia , Fosfocreatina/metabolismo , Rabdomiólise/enzimologia , Rabdomiólise/fisiopatologiaRESUMO
OBJECTIVE: In this study we aim to demonstrate the occurrence of adult forms of TK2 mutations causing progressive mitochondrial myopathy with significant muscle mitochondrial DNA (mtDNA) depletion. METHODS: Patients' investigations included serum creatine kinase, blood lactate, electromyographic, echocardiographic, and functional respiratory analyses as well as TK2 gene sequencing and TK2 activity measurement. Mitochondrial activities and mtDNA were analyzed in the patients' muscle biopsy. RESULTS: The 3 adult patients with TK2 mutations presented with slowly progressive myopathy compatible with a fairly normal life during decades. Apart from its much slower progression, these patients' phenotype closely resembled that of pediatric cases including early onset, absence of CNS symptoms, generalized muscle weakness predominating on axial and proximal muscles but affecting facial, ocular, and respiratory muscles, typical mitochondrial myopathy with a mosaic pattern of COX-negative and ragged-red fibers, combined mtDNA-dependent respiratory complexes deficiency and mtDNA depletion. In accordance with the disease's relatively slow progression, the residual mtDNA content was higher than that observed in pediatric cases. That difference was not explained by the type of the TK2 mutations or by the residual TK2 activity. CONCLUSION: TK2 mutations can cause mitochondrial myopathy with a slow progression. Comparison of patients with similar mutations but different disease progression might address potential mechanisms of mtDNA maintenance modulation.