ABSTRACT
INTRODUCTION: In myotonia congenita (MC), activation with exercise or cooling can induce transient changes in compound motor action potential (CMAP) parameters, thus providing a guide to genetic analysis. MATERIAL AND METHODS: We performed the short exercise test (SET) and the short exercise test with cooling (SETC) in 30 patients with genetically confirmed Becker disease (BMC) to estimate their utility in the diagnosis of BMC. RESULTS: Although we observed a significant decrease in CMAP amplitude immediately after maximal voluntary effort in both tests in the whole BMC group, in men this decline was significantly smaller than in women, especially in SET. Clinical implications/future directions: In men with a clinical suspicion of BMC, a small decrease in CMAP amplitude in SET together with a typical decline in SETC does not exclude the diagnosis of BMC. Our results show a sex-specific difference in chloride channel function in BMC, which needs further investigation.
Subject(s)
Myotonia Congenita , Female , Humans , Male , Myotonia Congenita/diagnosis , Myotonia Congenita/genetics , Sex Characteristics , Electromyography , Action Potentials/physiology , MutationABSTRACT
Limb-girdle muscular dystrophy type R1 (LGMDR1) is caused by mutations in CAPN3 and is the most common type of recessive LGMD. Even with the use of whole-exome sequencing (WES), only one mutant allele of CAPN3 is found in a significant number of LGMDR patients. This points to a role of non-coding, intronic or regulatory, sequence variants in the disease pathogenesis. Targeted sequencing of the whole CAPN3 gene including not only intronic, 3' and 5' UTRs but also potential regulatory regions was performed in 27 patients suspected with LGMDR1. This group included 13 patients with only one mutated CAPN3 allele detected previously with exome sequencing. A second rare variant in the non-coding part of CAPN3 was found in 11 of 13 patients with previously identified single mutation. Intronic mutations were found in 10 cases, with c.1746-20C>G variant present in seven patients. In addition, a large deletion of exons 2-8 was found in one patient. In the patients with no causative mutation previously found, we detected rare CAPN3 variants in 5 out of 10 patients and in two of them in a compound heterozygous state. Rare variants within putative regulatory sequences distant from the CAPN3 gene were found in 15 patients, although in 11 of these cases, other variants are deemed causative. The results indicate that intronic mutations are common in Polish LGMDR patients, and testing for non-coding mutations in CAPN3 should be performed in apparently single heterozygous patients.
ABSTRACT
Mitochondrial encephalomyopathies comprise a group of heterogeneous disorders resulting from impaired oxidative phosphorylation (OxPhos). Among a variety of symptoms progressive external ophthalmoplegia (PEO) seems to be the most common. The aim of this study is to present clinical and genetic characteristics of Polish patients with PEO. Clinical, electrophysiological, neuroradiological, and morphological data of 84 patients were analyzed. Genetic studies of mitochondrial DNA (mtDNA) were performed in all patients. Among nuclear DNA (nDNA) genes POLG was sequenced in 41 patients, TWNK (C10orf2) in 13 patients, and RNASEH1 in 2 patients. Total of 27 patients were included in the chronic progressive external ophthalmoplegia (CPEO) group, 24 in the CPEO+ group. Twenty-six patients had mitochondrial encephalomyopathy (ME), six patients Kearns-Sayre syndrome (KSS), and one patient sensory ataxic neuropathy, dysarthria, ophthalmoparesis (SANDO) syndrome. Genetic analysis of nDNA genes revealed the presence of pathogenic or possibly pathogenic variants in the POLG gene in nine patients, the TWNK gene in five patients and the RNASEH1 gene in two patients. Detailed patients' history and careful assessment of family history are essential in the diagnostic work-up. Genetic studies of both mtDNA and nDNA are necessary for the final diagnosis of progressive external ophthalmoplegia and for genetic counseling.
Subject(s)
DNA Helicases/genetics , DNA Polymerase gamma/genetics , Kearns-Sayre Syndrome/genetics , Mitochondrial Diseases/genetics , Mitochondrial Encephalomyopathies/genetics , Mitochondrial Proteins/genetics , Ophthalmoplegia, Chronic Progressive External/genetics , Ribonuclease H/genetics , Adolescent , Adult , Aged , Cerebellum/diagnostic imaging , Cerebellum/metabolism , Cerebellum/pathology , Cerebrum/diagnostic imaging , Cerebrum/metabolism , Cerebrum/pathology , Child , DNA Helicases/metabolism , DNA Polymerase gamma/metabolism , DNA, Mitochondrial/genetics , DNA, Mitochondrial/metabolism , Diagnosis, Differential , Female , Gene Expression , Humans , Kearns-Sayre Syndrome/diagnostic imaging , Kearns-Sayre Syndrome/metabolism , Kearns-Sayre Syndrome/pathology , Male , Middle Aged , Mitochondria/metabolism , Mitochondria/pathology , Mitochondrial Diseases/diagnostic imaging , Mitochondrial Diseases/metabolism , Mitochondrial Diseases/pathology , Mitochondrial Encephalomyopathies/diagnostic imaging , Mitochondrial Encephalomyopathies/metabolism , Mitochondrial Encephalomyopathies/pathology , Mitochondrial Proteins/metabolism , Muscle, Skeletal/metabolism , Muscle, Skeletal/pathology , Ophthalmoplegia, Chronic Progressive External/diagnostic imaging , Ophthalmoplegia, Chronic Progressive External/metabolism , Ophthalmoplegia, Chronic Progressive External/pathology , Pedigree , Poland , Polymorphism, Genetic , Ribonuclease H/metabolism , Sequence DeletionABSTRACT
INTRODUCTION: Myotonia congenita (MC) is caused by pathogenic variants in the CLCN1 gene coding the chloride channel protein. METHODS: To test the hypothesis that needle EMG could be helpful in distinguishing between the recessive and dominant MC, we performed EMG examination in 36 patients (23 men) aged 4-61â¯years with genetically proven MC: in 30 patients with autosomal recessive MC (Becker MC) and in 6 with autosomal dominant MC (Thomsen MC). RESULTS: Myotonic discharges were recorded in 95.8% of examined muscles. For the whole MC group we observed a significant positive correlation between parameters of motor unit activity potentials (MUAPs) in vastus lateralis and tibialis anterior muscles and the duration of the disease. Similar correlation for biceps brachii also was found in Becker MC subgroup only. DISCUSSION: EMG could still be helpful in diagnosis of MC and together with provocative tests might be useful in differentiation between recessive and autosomal MC.
Subject(s)
Electromyography/methods , Evoked Potentials, Motor , Mutation , Myotonia Congenita/physiopathology , Adolescent , Adult , Child , Child, Preschool , Diagnosis, Differential , Female , Genes, Dominant , Genes, Recessive , Humans , Male , Middle Aged , Muscle, Skeletal/physiopathology , Myotonia Congenita/diagnosis , Myotonia Congenita/geneticsABSTRACT
LGMD2L is a subtype of limb-girdle muscular dystrophy (LGMD), caused by recessive mutations in ANO5, encoding anoctamin-5 (ANO5). We present the analysis of five patients with skeletal muscle weakness for whom heterozygous mutations within ANO5 were identified by whole exome sequencing (WES). Patients varied in the age of the disease onset (from 22 to 38 years) and severity of the morphological and clinical phenotypes. Out of the nine detected mutations one was novel (missense p.Lys132Met, accompanied by p.His841Asp) and one was not yet characterized in the literature (nonsense, p.Trp401Ter, accompanied by p.Asp81Gly). The p.Asp81Gly mutation was also identified in another patient carrying a p.Arg758Cys mutation as well. Also, a c.191dupA frameshift (p.Asn64LysfsTer15), the first described and common mutation was identified. Mutations were predicted by in silico tools to have damaging effects and are likely pathogenic according to criteria of the American College of Medical Genetics and Genomics (ACMG). Indeed, molecular modeling of mutations revealed substantial changes in ANO5 conformation that could affect the protein structure and function. In addition, variants in other genes associated with muscle pathology were identified, possibly affecting the disease progress. The presented data indicate that the identified ANO5 mutations contribute to the observed muscle pathology and broaden the genetic spectrum of LGMD myopathies.
Subject(s)
Anoctamins/ultrastructure , Genetic Predisposition to Disease , Muscle, Skeletal/ultrastructure , Muscular Dystrophies, Limb-Girdle/genetics , Adult , Anoctamins/genetics , Chloride Channels/genetics , Computational Biology , Female , Heterozygote , Humans , Male , Muscle, Skeletal/diagnostic imaging , Muscle, Skeletal/pathology , Muscular Dystrophies, Limb-Girdle/diagnostic imaging , Muscular Dystrophies, Limb-Girdle/pathology , Mutation/genetics , Phenotype , Poland/epidemiology , Young AdultABSTRACT
MUNIX method (Motor Unit Number Index) had been not used to assess number of motor neurons in post-polio syndrome in contrary to needle electromyography. OBJECTIVES: To confirm if MUNIX reflects motor unit loss and clinical stage and to assess difference in MUNIX and EMG results between muscles in different stage. METHODS: 132 Muscles (MUNIX) and 96 (EMG) in 12 patients were studied and divided into groups: with normal strength(N), stable weakness and atrophy(S), new weakness and atrophy(W). RESULTS: In PPS group MUNIX global was 561.36⯱â¯282.6 (right 6 muscles) and 561.27⯱â¯281.1 (left) significantly lower than in control group (six muscles 1139.6⯱â¯164.5) (pâ¯<â¯0.05). MUNIX global correlated with MRC global. MUNIX was greater in muscles with normal strength (95-100% of normal values) than in those with stable weakness (48%-0% of normal values) and new weakness (65%-0% of normal values). Respectively to clinical stage of muscle MUP (motor unit potential) amplitude increased to 350% of normal value, from 250% to 110%, and from 300% to 700%. No correlation was found between MUP parameters and MRC values. CONCLUSIONS: MUNIX reflects motor dysfunction and could be a good biomarker for loss of motor neurons in PPS.
Subject(s)
Electromyography , Motor Neurons/physiology , Muscle, Skeletal/physiology , Needles , Postpoliomyelitis Syndrome/physiopathology , Severity of Illness Index , Aged , Biomarkers , Female , Humans , Male , Middle AgedABSTRACT
INTRODUCTION: Clinically oriented diagnostic criteria can be as specific for diagnosis of sporadic inclusion body myositis (sIBM) as pathological criteria, especially at the time of presentation. EMG may provide an convincing proof that a muscle biopsy should be performed. AIMS: To compare the EMG results in patients with sIBM divided into subgroups based on the newest ENMC criteria for sIBM and to obtain the utility of EMG in the diagnostic process at the time of presentation. METHODS: We retrospectively analysed 16 patients with sIBM for motor unit action potential (MUAP) morphology as well as occurrence and distribution of abnormal spontaneous activity (SA) in muscles. RESULTS: Abnormal SA was recorded in 62.5% of sIBM patients. We found statistically significant differences between subgroups in the incidence of polyphasic MUAPs and high amplitude outliers which were more commonly seen in the "clinico-pathologically defined sIBM". Duration of MUAP in the tibialis anterior was significantly shorter in "probable sIBM". DISCUSSION: "Pseudo-neurogenic" MUAPs, mainly in lower limb muscles, are more commonly seen in "clinico-pathologically defined sIBM" while myopathic MUAPs with prominent abnormal SA are recorded in patients diagnosed with "probable sIBM". Both EMG patterns may be suggestive of sIBM and be an indication for further diagnosis.
Subject(s)
Electromyography/methods , Muscle, Skeletal/physiopathology , Myositis, Inclusion Body/diagnosis , Myositis, Inclusion Body/physiopathology , Action Potentials/physiology , Adult , Aged , Female , Humans , Male , Middle Aged , Muscle, Skeletal/pathology , Retrospective StudiesABSTRACT
INTRODUCTION: Migraine is a common neurological disorder characterized by a particular phenotype, complex pathophysiology and a heterogeneous genetic background. Among several heritable forms, familial hemiplegic migraine is the best described one. In the majority of cases it is caused by mutations in one of three different genes. CASE REPORT: Clinical symptoms of a 47 year old proband (and independently described in his 20 year old son) as well as differential diagnosis are discussed in the presented report. The most characteristic were recurrent attacks of blurred vision, paresthesias and hemiparesis often accompanied by speech disturbances and followed by severe headache with vomiting. Advanced morphological and genetic procedures were required to exclude MELAS, CADASIL and Call-Fleming syndrome. Finally, the definite diagnosis was possible after the application of the whole exome sequencing technique. It confirmed, for the first time in the Polish population, a heterozygous T666M mutation (c.1997C>T; p.Thr666Met) in the CACNA1A gene in the proband, the proband's son and in several other family members. CONCLUSION: The presented report provides clinical and genetic insight into familial hemiplegic migraine 1 resulting from a mutation in the CACNA1A gene.
Subject(s)
Calcium Channels/genetics , DNA Mutational Analysis , Migraine with Aura/genetics , Brain/pathology , Diagnosis, Differential , Genetic Carrier Screening , Genome-Wide Association Study , Humans , Magnetic Resonance Imaging , Male , Middle Aged , Migraine with Aura/diagnosis , Pedigree , Poland , Young AdultABSTRACT
INTRODUCTION: Reproducible non-insertional spontaneous activity (SA), with the exception of endplate activity, is an unequivocal sign of abnormality and is one of the most useful findings obtained on electromyography. METHODS: In this retrospective study we analyzed occurrence and distribution of abnormal SA in 151 patients with genetically confirmed myopathies. RESULTS: Complex repetitive discharges (CRDs) occurred more frequently than fibrillation potentials (fibs) and positive sharp waves (PSWs) in centronuclear myopathy (CNM) and limb-girdle muscular dystrophy type 2A (LGMD-2A), whereas fibs/PSWs were observed more often in desminopathy and facioscapulohumeral dystrophy (FSHD). Abnormal SA was commonly found in CNM (66.7%) and desminopathy (61.5%), occasionally in Duchenne (DMD) and Becker muscular dystrophy (BMD) (45.2% and 27.6%, respectively), but rarely in FSHD (14.9%) and LGMD-2A (12.0%). CONCLUSIONS: Abnormal SA probably occurs more frequently in disorders associated with structural changes in muscle fibers. Screening for SA may be a valuable tool for diagnosis of non-myotonic myopathies. Muscle Nerve 56: 427-432, 2017.
Subject(s)
Action Potentials/physiology , Muscle, Skeletal/physiopathology , Muscular Diseases/diagnosis , Muscular Diseases/physiopathology , Adolescent , Adult , Child , Child, Preschool , Electromyography/methods , Female , Humans , Infant , Male , Middle Aged , Muscular Diseases/genetics , Retrospective Studies , Young AdultABSTRACT
Myofibrillar myopathy (MFM) is a group of inherited muscular disorders characterized by myofibrils dissolution and abnormal accumulation of degradation products. So far causative mutations have been identified in nine genes encoding Z-disk proteins, including αB-crystallin (CRYAB), a small heat shock protein (also called HSPB5). Here, we report a case study of a 63-year-old Polish female with a progressive lower limb weakness and muscle biopsy suggesting a myofibrillar myopathy, and extra-muscular multisystemic involvement, including cataract and cardiomiopathy. Five members of the proband's family presented similar symptoms. Whole exome sequencing followed by bioinformatic analysis revealed a novel D109A mutation in CRYAB associated with the disease. Molecular modeling in accordance with muscle biopsy microscopic analyses predicted that D109A mutation influence both structure and function of CRYAB due to decreased stability of oligomers leading to aggregate formation. In consequence disrupted sarcomere cytoskeleton organization might lead to muscle pathology. We also suggest that mutated RQDE sequence of CRYAB could impair CRYAB chaperone-like activity and promote aggregation of lens crystallins.
ABSTRACT
Childhood chronic inflammatory demyelinating polyneuropathy (CIDP) needs to be differentiated from hereditary neuropathy. We aimed to validate existing CIDP nerve conduction study (NCS) criteria in a group of children with demyelinating neuropathies of chronic or subacute onset. Retrospective analysis of clinical and NCS results in 18 children with CIDP, 7 with hereditary neuropathy with pressure palsy (HNPP), and 24 with Charcot-Marie-Tooth 1a (CMT1a). AAN and EFNS electrodiagnostic CIDP criteria were fulfilled in 17 of 18 CIDP, 3 of 7 HNPP, and 23 of 24 CMT1a patients. A distal compound muscle action potential (dCMAP) of >9 ms was observed in 14 of 18 CIDP patients but not in any patients with HNPP. Abnormal median/normal sural SNAP (AMNS) and a 10 m/s difference between conduction velocities (CV) of two corresponding nerves were not observed in any CMT1a patients. NCS in CMT1a, HNPP, and CIDP reflect demyelination. dCMAP duration, sensory AMNS, and a 10 m/s CV difference parameter are most useful in the differential diagnosis of pediatric CIDP.
Subject(s)
Charcot-Marie-Tooth Disease/diagnosis , Electrodiagnosis/methods , Polyradiculoneuropathy, Chronic Inflammatory Demyelinating/diagnosis , Adolescent , Child , Child, Preschool , Diagnosis, Differential , Electrophysiology/methods , Female , Hereditary Sensory and Motor Neuropathy/diagnosis , Humans , Male , Neural Conduction , Retrospective StudiesABSTRACT
BAG3 belongs to BAG family of molecular chaperone regulators interacting with HSP70 and anti-apoptotic protein Bcl-2. It is ubiquitously expressed with strong expression in skeletal and cardiac muscle, and is involved in a panoply of cellular processes. Mutations in BAG3 and aberrations in its expression cause fulminant myopathies, presenting with progressive limb and axial muscle weakness, and respiratory insufficiency and neuropathy. Herein, we report a sporadic case of a 15-years old girl with symptoms of myopathy, demyelinating polyneuropathy and asymptomatic long QT syndrome. Genetic testing demonstrated heterozygous mutation Pro209Leu (c.626C > T) in exon 3 of BAG3 gene causing severe myopathy and neuropathy, often associated with restrictive cardiomyopathy. We did not find a mutation in any known LQT syndrome genes. Analysis of muscle biopsy revealed profound disintegration of Z-discs with extensive accumulation of granular debris and large inclusions within fibers. We demonstrated profound alterations in BAG3 distribution as the protein localized to long filamentous structures present across the fibers that were positively stained not only for α-actinin but also for desmin and filamin indicating that those disintegrated Z-disc regions contained also other sarcomeric proteins. The mutation caused a decrease in the content of BAG3 and HSP70, and also of α-actinin desmin, filamin and fast myosin heavy chain, confirming its severe effect on the muscle fiber morphology and thus function. We provide further evidence that BAG3 is associated with Z-disc maintenance, and the Pro209Leu mutation may occur worldwide. We also provide a summary of cases associated with this mutation reported so far.
Subject(s)
Adaptor Proteins, Signal Transducing/metabolism , Apoptosis Regulatory Proteins/metabolism , Cardiomyopathies/pathology , Long QT Syndrome/metabolism , Long QT Syndrome/pathology , Muscular Diseases/pathology , Polyneuropathies/pathology , Adaptor Proteins, Signal Transducing/genetics , Adolescent , Apoptosis Regulatory Proteins/genetics , Cardiomyopathies/genetics , Cardiomyopathies/metabolism , Female , Humans , Long QT Syndrome/genetics , Muscle, Skeletal/metabolism , Muscle, Skeletal/pathology , Muscular Diseases/genetics , Muscular Diseases/metabolism , Mutation/genetics , Polyneuropathies/genetics , Polyneuropathies/metabolismABSTRACT
INTRODUCTION: Multisystem manifestations of myotonic dystrophies type 1 (DM1) and 2 (DM2) are well known. Peripheral nerve involvement has been reported in DM1 but not in genetically confirmed DM2. The aim of our study was to assess peripheral nerve involvement in DM2 using nerve conduction studies and to compare these results with findings in DM1. METHODS: We prospectively studied patients with genetically confirmed DM2 (n=30) and DM1 (n=32). All patients underwent detailed neurological examination and nerve conduction studies. RESULTS: Abnormalities in electrophysiological studies were found in 26.67% of patients with DM2 and in 28.13% of patients with DM1 but the criteria of polyneuropathy were fulfilled in only 13.33% of patients with DM2 and 12.5% of patients with DM1. The polyneuropathy was subclinical, and no correlation was found between its presence and patient age or disease duration. CONCLUSIONS: Peripheral nerves are quite frequently involved in DM2, but abnormalities meeting the criteria of polyneuropathy are rarely found. The incidence of peripheral nerve involvement is similar in both types of myotonic dystrophy.
Subject(s)
Myotonic Dystrophy/physiopathology , Polyneuropathies/physiopathology , Adolescent , Adult , Child , Female , Humans , Male , Middle Aged , Myotonic Dystrophy/classification , Myotonic Dystrophy/complications , Polyneuropathies/diagnosis , Polyneuropathies/etiology , Young AdultABSTRACT
Myosin VI (MVI) is a unique unconventional myosin translocating, unlike other myosins, towards the minus end of actin filaments. It is involved in numerous cellular processes such as endocytosis, intracellular trafficking, cell migration, and transcription. In mammalian skeletal muscles it localizes mainly to sarcoplasmic reticulum and is also present within the muscle nuclei and at the neuromuscular junction (Karolczak et al. Histochem Cell Biol 2013; 23:219-228). We have also shown that in denervated rat hindlimb muscle the MVI expression level is significantly increased and its localization is changed, indicating an important role of MVI in striated muscle pathology. Here, we addressed this problem by examining the distribution and expression levels of myosin VI in biopsies of skeletal muscles from patients with different myopathies. We found that, particularly in myopathies associated with fiber atrophy, the amount of MVI was enhanced and its localization in affected fibers was changed. Also, since a mutation within the human MVI gene was shown to be associated with cardiomyopathy, we assessed MVI localization and expression level in cardiac muscle using wild type and MLP(-/-) mice, a dilated cardiomyopathy model. No significant difference in MVI expression level was observed for both types of animals. MVI was found at intercalated discs and also at the sarcoplasmic reticulum. In the knockout mice, it was also present in ring-like structures surrounding the nuclei. The data indicate that in striated muscle MVI could be engaged in sarcoplasmic reticulum maintenance and/or functioning, vesicular transport, signal transmission and possibly in gene transcription.
Subject(s)
Cardiomyopathy, Dilated/metabolism , Muscle, Skeletal/metabolism , Muscular Atrophy/metabolism , Myocardium/metabolism , Myosin Heavy Chains/metabolism , Adult , Aged , Animals , Biopsy , Blotting, Western , Cardiomyopathy, Dilated/genetics , Cardiomyopathy, Dilated/pathology , Case-Control Studies , Disease Models, Animal , Female , Humans , Immunohistochemistry , LIM Domain Proteins/deficiency , LIM Domain Proteins/genetics , Male , Mice, Knockout , Middle Aged , Muscle Proteins/deficiency , Muscle Proteins/genetics , Muscle, Skeletal/pathology , Muscular Atrophy/genetics , Muscular Atrophy/pathology , Myocardium/pathology , Sarcoplasmic Reticulum/metabolismABSTRACT
BACKGROUND: One of the most common cardiac tumors is myxoma. Despite its predominantly benign course, diverse cardiological, systemic as well as neurological complications have been reported. CASE REPORT: We are the first from Poland to present the case of a patient with multiple central nervous system metastases associated with the left atrial myxoma. Various diagnostic, neuroradiological and histopathological procedures were described. The patient underwent cardiac surgery. CONCLUSIONS: Follow-up studies excluded the recurrence of the heart tumor and confirmed partial resolution of brain metastases. Nevertheless, subsequent neurological assessment was advised according to the literature data and possible late relapses mainly due to cerebral emboli.
ABSTRACT
Genetic testing is considered the only reliable diagnostic approach in myotonic dystrophy. However it has recently been reported that a considerable number of patients with genetically proven types of the disease have unusual phenotypic presentation. The aim of our study was to evaluate motor unit reorganization reflected by various electrophysiological abnormalities in myotonic dystrophies and to compare findings between type 1 (DM 1) and type 2 myotonic dystrophy (DM2). Quantitative electromyography (EMG) recordings in 63 patients (33 with DM1 and 30 with DM2) from the biceps brachii (BB), rectus femoris (RF), first dorsal interosseus (FDI), and tibialis anterior (TA) muscles were analyzed. Mean amplitude and size index (SI) of motor unit potentials recorded in TA and RF muscles, mean potential duration in TA, and mean SI and the number of outliers with amplitude above the normal range in BB were significantly increased in DM2 as compared to DM1. Myotonic discharges were recorded more frequently in DM1 than in DM2. EMG findings significantly differ between DM1 and DM2. The presence of high amplitude potentials in lower limb muscles in DM2 patients, atypical for myogenic muscle lesions, could be explained by muscle fiber hypertrophy observed in muscle biopsies.
Subject(s)
Electromyography/methods , Muscle, Skeletal/physiology , Myotonic Disorders/physiopathology , Myotonic Dystrophy/physiopathology , Adolescent , Adult , Arm/physiology , Child , Electrophysiological Phenomena , Female , Humans , Leg/physiology , Male , Middle Aged , Muscle Strength , Phenotype , Quadriceps Muscle/physiology , Reproducibility of Results , Young AdultABSTRACT
Mitochondrial diseases may cause a wide range of central and peripheral nervous system disorders, as well as muscle disorders. The diagnostic workup routinely includes electrophysiological, morphological, neuroimaging and genetic studies. In some cases, the diagnosis may be ascertained only when mitochondrial DNA (mtDNA) examination in the muscle is performed. We report on a case of a 24-year-old woman, with a 7-year history of slowly progressive cerebellar syndrome and bilateral ptosis. Mitochondrial encephalomyopathy was suspected, based on the clinical picture and results of examinations, but the typical red ragged fibers were not found in the muscle biopsy. The results of molecular analysis of mtDNA showed a mtDNA deletion in the muscle and, on a level detectable only with polymerase chain reaction method, in blood leukocytes. This case emphasizes the important role of mtDNA studies in muscle in nonspecific multisystem mitochondrial disorders, even without clinical muscle involvement.
Subject(s)
DNA, Mitochondrial/genetics , Mitochondrial Encephalomyopathies/diagnosis , Ataxia/genetics , Ataxia/physiopathology , Base Sequence , Biopsy , DNA Mutational Analysis , Electrodiagnosis , Electroencephalography , Electromyography , Female , Genetic Markers , Humans , Magnetic Resonance Imaging , Mitochondrial Encephalomyopathies/physiopathology , Molecular Sequence Data , Muscle, Skeletal/pathology , Muscle, Skeletal/physiopathology , Neural Conduction , Neurologic Examination , Polymerase Chain Reaction , Young AdultABSTRACT
INTRODUCTION: Standard electromyography (EMG) is useful in the diagnosis of myotonic dystrophy type 1 (DM1) and type 2 (DM2), but it does not differentiate between them. The aim of this study was to estimate the utility of the short exercise test (SET) and short exercise test with cooling (SETC) in differentiating between DM1 and DM2. METHODS: SET and SETC were performed in 32 patients with DM1 (mean age 35.8 ± 12.7 years) and 28 patients with DM2 (mean age 44.5 ± 12.5 years). RESULTS: We observed a significant decline in compound motor action potential (CMAP) amplitude in DM1 with both SET and SETC immediately after effort. In DM2, there was no marked change in CMAP amplitude with either SET or SETC. CONCLUSIONS: SET and SETC may serve as useful tools for clinical differentiation between DM1 and DM2, and they may be used as a guide for molecular testing.
Subject(s)
Diagnostic Tests, Routine/methods , Exercise Test/methods , Exercise/physiology , Myotonic Disorders/diagnosis , Myotonic Dystrophy/diagnosis , Action Potentials/physiology , Adult , Diagnosis, Differential , Electrophysiological Phenomena , Female , Humans , Linear Models , Male , Middle Aged , Muscle, Skeletal/physiopathology , Myotonic Disorders/physiopathology , Myotonic Dystrophy/physiopathologyABSTRACT
Centronuclear myopathies constitute a group of heterogeneous congenital myopathies characterized by the presence of abnormal, centrally located nuclei within muscle fibers. Centronuclear myopathies can be caused by mutations of several different genes, including DNM2, encoding dynamin 2 (DNM2) a large GTPase involved in membrane trafficking and endocytosis. We report a 52-year-old female with slowly progressive muscle weakness, and a family history of the disease. Clinical, morphological, biochemical and genetic analyses of the proband and her family members were performed, including analyses of the proband's muscle biopsy. A novel D614N mutation, located in the C-terminal region pleckstrin-homology (PH) domain of DNM2 was identified in the proband and four family members, who exhibited similar symptoms. The mutation was associated with profound changes in the localization of DNM2 in muscle fibers without significant changes in protein expression. Mutated DNM2 and proteins involved in the membrane trafficking or membrane compartments maintenance were dislocalized within the myofiber, and concentrated at centrally located nuclei. This novel causative mutation (D614N) within the DNM2 gene in a large Polish centronuclear myopathy family with a late age of overt clinical manifestation caused profound changes in DNM2 localization and impaired proper organization of myofibers, and skeletal muscle functioning.
Subject(s)
Dynamin II/genetics , Muscle Weakness/genetics , Muscle, Skeletal/metabolism , Mutation , Myopathies, Structural, Congenital/genetics , Disease Progression , Dynamin II/metabolism , Female , Genetic Testing , Humans , Middle Aged , Muscle Weakness/metabolism , Muscle Weakness/pathology , Muscle, Skeletal/pathology , Myopathies, Structural, Congenital/metabolism , Myopathies, Structural, Congenital/pathology , Pedigree , PhenotypeABSTRACT
Small heat shock proteins prevent abnormal protein folding and accumulation. We analyzed the expression of hsp27 and alphaB-crystallin in skeletal muscle specimens of patients with desminopathies, plectinopathies, myotilinopathy, and other myofibrillar myopathies by means of differential centrifugation, 2D-gel electrophoresis, Western blotting, and mass spectrometry. Hsp27-P82 and -P15 as well as alphaB-crystallin-P59 and -P45 are the major serine phosphorylation isoforms in normal and diseased human skeletal muscle. 2D-gel-electrophoresis revealed spots of hsp27 in a range of pH 5.3-6.4 in samples of all skeletal muscle specimens, except for the seven desminopathies. They indicated a shift of the main hsp27-spot to alkaline pH degrees, which may help to differentiate primary desminopathies from other myopathies with structural pathology of the desmin cytoskeleton.