ABSTRACT
BACKGROUND: The recreational use of nitrous oxide (N2O) has increased in recent years with a noticeable surge in the incidence of nitrous oxide-related myeloneuropathy. OBJECTIVES: To raise awareness of increasing myeloneuropathy due to recreational nitrous oxide misuse in Israel. METHODS: We conducted a case series documenting the clinical and investigative features of eight patients presenting with nitrous oxide-induced myeloneuropathy who were admitted to our departments. RESULTS: Paresthesia was the chief complaint in all patients, with sensory gait ataxia being a common feature, which was often accompanied by Romberg's sign and mild lower limb weakness. Vitamin B12 levels were below the normal range in seven patients, accompanied by elevated homocysteine and methylmalonic acid levels. Magnetic resonance imaging scans revealed hyperintense signals in the dorsal columns of the cervical spine. All patients improved following vitamin B12 injections. CONCLUSIONS: Enhancing awareness, prompting the use of appropriate investigations, and advocating for timely treatment are needed to overcome the risks associated with nitrous oxide misuse.
Subject(s)
Magnetic Resonance Imaging , Nitrous Oxide , Vitamin B 12 , Humans , Nitrous Oxide/adverse effects , Nitrous Oxide/administration & dosage , Male , Adult , Vitamin B 12/administration & dosage , Female , Israel/epidemiology , Magnetic Resonance Imaging/methods , Spinal Cord Diseases/chemically induced , Paresthesia/chemically induced , Paresthesia/diagnosis , Middle Aged , Recreational Drug Use , Gait Ataxia/chemically induced , Gait Ataxia/etiology , Young Adult , Substance-Related Disorders/complications , Vitamin B 12 Deficiency/chemically induced , Vitamin B 12 Deficiency/diagnosisABSTRACT
We report a multiplex family with extended multisystem neurological phenotype associated with a CRYAB variant. Two affected siblings were evaluated with whole exome sequencing, muscle biopsy, laser microdissection, and mass spectrometry-based proteomic analysis. Both patients and their mother manifested a combination of early-onset cataracts, cardiomyopathy, cerebellar ataxia, optic atrophy, cognitive impairment, and myopathy. Whole exome sequencing identified a heterozygous c.458C>T variant mapped to the C-terminal extension domain of the Alpha-crystallin B chain, disrupting its function as a molecular chaperone and its ability to suppress protein aggregation. In accordance with the molecular findings, muscle biopsies revealed subsarcolemmal deposits that appeared dark with H&E and trichrome staining were negative for the other routine histochemical staining and for amyloid with the Congo-red stain. Electron microscopy demonstrated that the deposits were composed of numerous parallel fibrils. Laser microdissection and mass spectrometry-based proteomic analysis revealed that the inclusions are almost exclusively composed of crystallized chaperones/heat shock proteins. Moreover, a structural model suggests that Ser153 could be involved in monomer stabilization, dimer association, and possible binding of partner proteins. We propose that our report potentially expands the complex phenotypic spectrum of alpha B-crystallinopathies with possible effect of a CRYAB variant on the central nervous system.
Subject(s)
Cardiomyopathy, Hypertrophic/genetics , Cataract/genetics , Cerebellar Ataxia/genetics , Cognitive Dysfunction/genetics , Optic Atrophy/genetics , Sarcolemma/ultrastructure , alpha-Crystallin B Chain/genetics , Amino Acid Sequence , Biopsy , Death, Sudden, Cardiac/etiology , Female , Humans , Inclusion Bodies/ultrastructure , Jews/genetics , Male , Middle Aged , Models, Molecular , Muscle Weakness/genetics , Muscle, Skeletal/pathology , Phenotype , Protein Conformation , Exome SequencingABSTRACT
INTRODUCTION: Nerve conduction studies (NCS) and electromyograms (EMG) constitute an expansion of the neurological examination and help to reach the diagnosis or localize the pathological process. Planning the electrophysiological study and drawing conclusions depend on the skills of the examiner, his experience and the time available for the study. The studies carried out within the framework of the community are carried out in part by skilled physicians, but the time and conditions at their disposal do not enable the proper performance of the studies. The main faults in performing NCS are fewer than needed nerve tests, lack of paying attention to conduction blocks, lack of reporting of proximal amplitudes, lack of reporting of the duration and dispersion of the potentials, and lack of display of potential curves in the summary report. The main drawbacks in the EMG studies are missed spontaneous activity due to too short a stay of the needle electrode in the muscle, a subjective assessment of the size of the motor units and the recruitment pattern because of not using the EMG software for this evaluation objectively. Electrophysiological studies have been performed improperly for many years, causing damage to patients and misleading referring physicians. This actuality should be changed.
Subject(s)
Electromyography , Neural Conduction , Humans , Neurologic ExaminationABSTRACT
BACKGROUND: Human skeletal muscles express three major myosin heavy chain (MyHC) isoforms: MyHCIIx (MYH1) in fast type 2B muscle fibers, MyHCIIa (MYH2) in fast type 2A fibers and MyHCI/ß-cardiac MyHC (MYH7) in slow type I skeletal fibers and cardiac ventricles. In line with its expression pattern, MYH7 mutations have been reported in association with hypertrophic or dilated cardiomyopathy, skeletal myopathies or a combination of both. We analyzed the clinical and molecular phenotype of two unrelated families of Jewish Moroccan ancestry that presented with apparently autosomal dominant inheritance of progressive Laing-like distal myopathy with non-specific myopathic changes, but uncommon marked contractures and wasting of the neck extensors. METHODS: Clinical phenotyping, whole exome sequencing and restriction analysis, generation of mutants followed by cell culture transfection and imaging. RESULTS: Using whole exome sequencing we identified in both families two novel heterozygous proline substitutions located in exon 31 of MYH7 within its rod domain: c.4309G>C (p.Ala1437Pro) and c.4301G>C (p.Arg1434Pro). Here we show that the phenotype caused by these mutations includes marked cervical muscle contracture, and report that the severity of the phenotype varies significantly, to the extent of non-penetrance in one of the families. Finally, we provide evidence that both proline substitutions impair myosin self-assembly in non-muscle cells transfected with ß-myosin constructs carrying the mutations, but do not prevent incorporation of the mutant molecules into the sarcomere. CONCLUSIONS: This study expands our clinical and molecular knowledge of MYH7 rod mutations causing skeletal myopathies, and underscores the importance of discussing disease penetrance during genetic counseling.
Subject(s)
Cardiac Myosins/genetics , Contracture/genetics , Distal Myopathies/genetics , Myosin Heavy Chains/genetics , Proline/metabolism , Adult , Aged , Amino Acid Substitution/genetics , Animals , Back/diagnostic imaging , Back/pathology , COS Cells , Chlorocebus aethiops , DNA/chemistry , DNA/isolation & purification , DNA/metabolism , Distal Myopathies/pathology , Female , Heterozygote , Humans , Male , Muscle, Skeletal/metabolism , Muscle, Skeletal/pathology , Neck/diagnostic imaging , Neck/pathology , Phenotype , Polymorphism, Single Nucleotide , Proline/geneticsABSTRACT
GNE Myopathy (GNEM) is a neuromuscular disorder caused by mutations in the GNE gene. It is a slowly progressive distal and proximal muscle weakness sparing the quadriceps. In this study, we applied our model of mutated M743T GNE enzyme skeletal muscle-cultured myoblasts and paired healthy controls to depict the pattern of signaling proteins controlling survival and/or apoptosis of the PI3K/AKT, BCL2, ARTS/XIAP pathways, examined the effects of metabolic changes/stimuli on their expression and activation, and their potential role in GNEM. Immunoblot analysis of the GNEM myoblasts indicated a notable increased level of activated PTEN and PDK1 and a trend of relative differences in the expression and activation of the examined signaling molecules with variability among the cultures. ANOVA analysis showed a highly significant interaction between the level of PTEN and the patients groups. In parallel, the interaction between the level of BCL2, BAX and PTEN with the specific PI3K/AKT inhibitor-LY294002 was highly significant for BCL2 and nearly significant for PTEN and BAX. The pattern of the ARTS/XIAP signaling proteins of GNEM and the paired controls was variable, with no significant differences between the two cell types. The response of the GNEM cells to the metabolic changes/stimuli: serum depletion and insulin challenge, as indicated by expression of selected signaling proteins, was variable and similar to the control cells. Taken together, our observations provide a clearer insight into specific signaling molecules influencing growth and survival of GNEM muscle cells.
Subject(s)
Distal Myopathies/metabolism , Distal Myopathies/pathology , Multienzyme Complexes/genetics , Multienzyme Complexes/metabolism , Mutant Proteins/genetics , Mutant Proteins/metabolism , Myoblasts, Skeletal/metabolism , Myoblasts, Skeletal/pathology , Signal Transduction/physiology , Adult , Apoptosis , Case-Control Studies , Cell Survival , Cells, Cultured , Distal Myopathies/genetics , Female , Humans , Male , Middle Aged , Mutation , PTEN Phosphohydrolase/metabolism , Phosphatidylinositol 3-Kinases/metabolism , Protein Serine-Threonine Kinases/metabolism , Proto-Oncogene Proteins c-akt/metabolism , Proto-Oncogene Proteins c-bcl-2/metabolism , Pyruvate Dehydrogenase Acetyl-Transferring Kinase , Septins/metabolism , X-Linked Inhibitor of Apoptosis Protein/metabolism , Young AdultABSTRACT
Centronuclear myopathy (CNM) is a rare hereditary myopathy characterized by centrally located muscle fiber nuclei. Mutations in the dynamin 2 (DNM2) gene are estimated to account for about 50 % of CNM cases. Electromyographic recordings in CNM may show myopathic motor unit potentials without spontaneous activity at rest. Myotonic discharges, a distinctive electrical activity caused by membrane hyperexcitability, are characteristic of certain neuromuscular disorders. Such activity has been reported in only one CNM case without a known genetic cause. We sequenced the DNM2 gene and the genes associated with myotonia (CLCN1, SCN4A, DMPK and ZNF9) in a sporadic adult patient with CNM and myotonic discharges. Sequencing the entire coding region and exon-intron boundaries revealed a heterozygous c.1106g-a substitution in exon 8, resulting in a R369Q change in the DNM2. Sequencing the CLCN1, SCN4A, DMPK and ZNF9 genes ruled out mutations in these genes. This is the first report of DNM2-related CNM presenting with myotonia. The diagnosis of CNM should be considered in patients with myotonic discharges of an unknown cause.
Subject(s)
Dynamin II/genetics , Myopathies, Structural, Congenital/complications , Myopathies, Structural, Congenital/genetics , Myotonia/complications , Myotonia/genetics , Adult , Base Sequence , Chloride Channels/genetics , DNA Mutational Analysis , Electromyography , Female , Humans , Muscle, Skeletal/pathology , Muscle, Skeletal/physiopathology , Myopathies, Structural, Congenital/pathology , Myopathies, Structural, Congenital/physiopathology , Myotonia/pathology , Myotonia/physiopathology , Myotonin-Protein Kinase/genetics , NAV1.4 Voltage-Gated Sodium Channel/genetics , RNA-Binding Proteins/geneticsABSTRACT
There are scarce reports of riboflavin-responsive lipid storage myopathy in elderly patients with onset in their sixties. We describe three elderly patients with riboflavin-responsive lipid-storage myopathy. All three patients (aged 67-71 years on first examination) had subacute onset of neck extensors and proximal limb weakness progressing to inability to rise from a sitting position or to walk. Muscle biopsies showed vacuoles with lipid content, mainly in type 1 fibers. Genetic analysis failed to identify any pathogenic variant in one patient, identified a heterozygous variant of uncertain significance c.812 A > G; p.Tyr271Cys in the ETFDH gene in the second patient, and revealed a heterozygote likely pathogenic variant c.1286-2 A > C in the ETFDH gene predicted to cause abnormal splicing in the third patient. All patients responded to treatment with riboflavin and carnitine, and regained normal strength. This report emphasizes the importance of muscle biopsy in revealing treatable lipid storage myopathy in elderly patients with progressive myopathy of unidentifiable cause.
Subject(s)
Iron-Sulfur Proteins , Lipid Metabolism, Inborn Errors , Multiple Acyl Coenzyme A Dehydrogenase Deficiency , Muscular Diseases , Muscular Dystrophies , Oxidoreductases Acting on CH-NH Group Donors , Humans , Aged , Muscle, Skeletal/metabolism , Multiple Acyl Coenzyme A Dehydrogenase Deficiency/drug therapy , Multiple Acyl Coenzyme A Dehydrogenase Deficiency/genetics , Electron-Transferring Flavoproteins/genetics , Iron-Sulfur Proteins/genetics , Oxidoreductases Acting on CH-NH Group Donors/genetics , Muscular Diseases/drug therapy , Muscular Diseases/genetics , Muscular Diseases/pathology , Riboflavin/therapeutic use , LipidsABSTRACT
BACKGROUND: Type 1 diabetes in humans is an autoimmune disease in which Tcells target pancreatic islets of Langerhans, leading to the progressive destruction of the insulin-producing beta cells. Both genetic and environmental factors contribute to the development of autoimmune diabetes. The non-obese diabetic (NOD) mouse model of human type 1 diabetes demonstrates two missense mutations in the transient receptor potentialvanilloid receptor-1 (TRPVi) gene. OBJECTIVES: To investigate whether polymorphism in the TRPV1 gene may play a role in the predisposition to human type 1 diabetes. METHODS: We genotyped 146 Ashkenazi Jewish type 1 diabetic patients and 205 Ashkenazi Jewish healthy controls for the rs222747 (M3151), rs224534 (T4691) and rs8065080 (1585V) variants of the TRPV1 gene. RESULTS: There was a significant increase in the rs222747 (M3151) variant of the TRPV1 gene in the type 1 diabetes cohort compared to the control: rs222747 (M3151) homozygous: (61% vs. 48.3%, P = 0.02). Logistic regression analysis revealed that type 1 diabetes was significantly associated with rs222747 (M3151), such that having diabetes increased the odds of rs222747 homozygosity (M3151) by 67.2%, odds ratio 1.6, 95% confidence interval 1.08-2.57, P < 0.02. No difference was found in the rs224534 (T4691) and rs8065080 (1585V) allelic variants. There was no difference in any of the TRPV1 variants by gender, age when type 1 diabetes was diagnosed, body mass index, glycemic control, blood pressure, positive autoantibodies (ICA, GAD, IAA), and other autoimmune diseases. CONCLUSIONS: Our study demonstrates that TRPV1 may be a susceptible gene for type 1 diabetes in an Ashkenazi Jewish population. These results should be replicated in the same ethnic group and in other ethnic groups.
Subject(s)
Diabetes Mellitus, Type 1/genetics , Jews/genetics , TRPV Cation Channels/genetics , Adult , Female , Genetic Predisposition to Disease , Humans , Logistic Models , Male , Polymorphism, Single NucleotideABSTRACT
BACKGROUND: Oculopharyngeal muscular dystrophy (OPMD) produced by the (GCG)13 expansion mutation in the PABPN1 gene is frequent among Uzbek Jews in Israel. OBJECTIVES: To describe the phenotypic and genotypic features in five Bulgarian Jewish patients, from different families, with autosomal dominant OPMD. METHODS: We performed clinical follow-up, electrodiagnostic tests and mutation detection. Blood samples were obtained after informed consent and DNA was extracted; measurement of GCG repeats in both PABPN1 alleles and sequencing of OPMD mutations were performed according to standard techniques. RESULTS: We identified five patients (four females), aged 58 to 71 years, with bilateral ptosis, dysphagia, dysphonia (n = 3) and myopathic motor units by electromyography. In all patients we noticed proximal weakness of the upper limbs with winging scapulae in three of them. All cases shared the (GCG)13-(GCG)10 PABPN1 genotype. CONCLUSIONS: OPMD among Bulgarian Jews is produced by a (GCG)13 expansion, identical to the mutation in Uzbek Jews and French Canadians. In addition to the classical neurological and neuro-ophthalmological features, early shoulder girdle weakness is common in Bulgarian Jewish patients; this is an unusual feature during the early stages of OPMD produced by the same mutation in other populations. We suggest that besides the disease-producing GCG expansion, additional ethnicity-related genetic factors may influence the OPMD phenotype. OPMD is a rare disease, and the identification of five affected families in the rather small Bulgarian Jewish community in Israel probably represents a new cluster; future haplotype studies may elucidate whether a founder effect occurred.
Subject(s)
Muscle Weakness/diagnosis , Muscular Dystrophy, Oculopharyngeal , Poly(A)-Binding Protein I/genetics , Aged , Bulgaria/ethnology , Electromyography/methods , Female , Genetic Predisposition to Disease , Humans , Israel/epidemiology , Jews/genetics , Male , Middle Aged , Muscle Weakness/physiopathology , Muscular Dystrophy, Oculopharyngeal/ethnology , Muscular Dystrophy, Oculopharyngeal/genetics , Muscular Dystrophy, Oculopharyngeal/physiopathology , Mutation , Neurologic Examination/methodsABSTRACT
OBJECTIVE: Amyloidosis due to the transthyretin Ser77Tyr mutation (ATTRS77Y) is a rare autosomal-dominant disorder, characterized by carpal-tunnel syndrome, poly- and autonomic-neuropathy, and cardiomyopathy. However, related symptoms and signs are often nonspecific and confirmatory tests are required. We describe the age and frequency of early symptoms and diagnostic features among individuals of Jewish Yemenite descent in Israel. METHODS: Records of mutation carriers were retrospectively reviewed. ATTRS77Y diagnosis was defined by the presence of amyloid in tissue and/or amyloid-related cardiomyopathy. RESULTS: We identified the Ser77Tyr mutation at the heterozygous state in 19 amyloidosis patients (mean age at diagnosis: 62 ± 5.7 years, range 49-70) and 30 amyloid-negative carriers. The probability for disease diagnosis increased from 4.4% at age 49 to 100% at 70 and occurred earlier in males. Initial symptoms preceded diagnosis by 5 ± 3.8 years (range 0-12) and were commonly sensory changes in the extremities. Erectile dysfunction predated these in 8/13 (62%) males. In two patients cardiac preceded neurological symptoms. Two patients declined symptoms. Electrophysiological studies near the time of diagnosis indicated a median neuropathy at the wrist in 18/19 (95%) and polyneuropathy in 13/19 (68%). Skin biopsy revealed epidermal denervation in 15/16 (94%) patients. Cardiomyopathy was identified in 16/19 (84%). Sensory complaints or epidermal denervations were present in 17/30 (57%) of amyloid-negative carriers and co-occurred in 10/30 (33%). INTERPRETATION: ATTRS77Y symptoms commonly occur after age 50, but may begin earlier. Median neuropathy, skin denervation and cardiomyopathy are frequently identified. Symptoms may be absent in patients and common in amyloid-negative carriers.
Subject(s)
Amyloid Neuropathies, Familial , Cardiomyopathies , Carpal Tunnel Syndrome , Aged , Female , Humans , Male , Middle Aged , Amyloid , Amyloid Neuropathies, Familial/diagnosis , Amyloid Neuropathies, Familial/genetics , Amyloid Neuropathies, Familial/pathology , Israel , Retrospective Studies , Prealbumin/metabolismABSTRACT
McArdle disease is caused by a myophosphorylase deficiency consequent to defects in the PYGM gene. A minority of the over-133 known mutations are associated with ethnicity, occurring mainly in patients from western Europe, the United States, and Japan. We identified a novel mutation, c.632delG, in three unrelated families of Jewish descent originating from the Caucasus region. This possibly ethnicity-associated mutation can significantly facilitate the diagnosis in Jews of the Caucasus and contribute to genetic consultations.
Subject(s)
Glycogen Phosphorylase, Muscle Form/genetics , Glycogen Storage Disease Type V/genetics , Jews/genetics , Adult , Azerbaijan/ethnology , Base Sequence , Dagestan/ethnology , Glycogen Storage Disease Type V/ethnology , Humans , Molecular Sequence Data , Mutation , Young AdultABSTRACT
BACKGROUND: Transthyretin (TTR)-associated familial amyloid polyneuropathy (FAP) is an autosomal dominant multisystem disease with neurological and extra-neurological manifestations. It is caused by various mutations in the TTR gene leading to the formation of insoluble amyloid. OBJECTIVES: To describe the clinical and genetic findings in patients with TTR-associated FAP in Israel. METHODS: We evaluated eight patients clinically and genetically during the years 2006 to 2011. RESULTS: At onset, all the patients exhibited sensory loss of the lower and upper limbs, five patients experienced muscle pain, and one patient had lower limb weakness. Five patients had autonomic nervous system manifestations, and four demonstrated evidence of amyloid cardiomyopathy. Nerve conduction studies showed sensorimotoraxonal neuropathy in all patients. Sural nerve biopsies were obtained in five patients; only three biopsies revealed amyloid deposit. In four patients of Yemenite descent, genetic analysis of the TTR gene demonstrated ser77tyr mutation. One patient of Tunisian descent and one Ashkenazi patient harbored the val30met mutation. One patient of Iranian descent showed val32ala mutation, and another Ashkenazi patient showed phe33leu mutation. CONCLUSIONS: TTR-associated FAP is a progressive and fatal disease that exists in the Israeli population and is unproportionally common among Yemenite Jews. This disease may be under-diagnosed and should be considered in the differential diagnosis of any patient with rapidly progressive neuropathy, especially with autonomic involvement or extra-neural features. The absence of amyloid in nerve biopsy should not rule out the diagnosis.
Subject(s)
Amyloid Neuropathies, Familial/genetics , DNA/genetics , Mutation , Prealbumin/genetics , Aged , Amyloid Neuropathies, Familial/diagnosis , Amyloid Neuropathies, Familial/epidemiology , DNA Mutational Analysis , Female , Follow-Up Studies , Genetic Predisposition to Disease , Genetic Testing , Humans , Israel/epidemiology , Male , Middle Aged , Prealbumin/metabolism , Prevalence , Retrospective StudiesABSTRACT
Mutations in the epsilon subunit of the acetylcholine receptor (AChR) are a common cause of congenital myasthenic syndrome (CMS). Patients are usually treated with acetylcholinesterase inhibitors and 3,4-diaminopyridine with modest clinical benefit. We report 2 patients with CMS due to mutations in the AChR epsilon subunit. The first patient carries two heterozygous frameshift mutations, ε127ins5 and ε1293insG. The second patient is homozygous for the εC142Y mutation that curtails AChR expression to 22% of wild-type in HEK cells. Treatment with pyridostigmine and 3,4-diaminopyridine had a limited beneficial effect in the first patient, and the second patient became wheelchair-bound during therapy. The additional use of albuterol produced dramatic improvement in strength and in activities of daily living in both patients. The efficacy and safety of albuterol in patients who harbor identified low-expressor or null mutations in the epsilon or other subunits of AChR merits a well-designed clinical trial.
Subject(s)
Adrenergic beta-2 Receptor Agonists/therapeutic use , Albuterol/therapeutic use , Myasthenic Syndromes, Congenital/drug therapy , Receptors, Nicotinic/genetics , Adult , Female , Humans , Middle Aged , Mutation , Myasthenic Syndromes, Congenital/genetics , Treatment OutcomeABSTRACT
BACKGROUND: Myotonic dystrophy type 2 (DM2) is an autosomal dominant, multisystem disorder caused by a CCTG tetranucleotide repeat expansion located in intron 1 of the zinc finger protein 9 gene (ZNF9 gene) on chromosome 3q 21.3. OBJECTIVES: To describe the clinical, electrophysiologic and pathologic findings in patients with myotonic dystrophy 2. METHODS: We evaluated 10 patients genetically, clinically and electrophysiologically during the years 2007 to 2008. RESULTS: All patients were of Jewish European ancestry. Among affected individuals, eight patients had symptoms of proximal muscle weakness, two had muscle pain, and two exhibited myotonia. On physical examination six patients had severe weakness of hip flexor muscles. Seven individuals underwent cataract surgery, and cardiac involvement was seen in one case. On the initial electromyographic (EMG) examination five patients demonstrated myotonic discharges; repeated studies showed these discharges in nine cases. Six muscle biopsies showed non-specific pathological changes. Seven patients had an affected first-degree relative with either a diagnosed or an undiagnosed muscular disorder consistent with an autosomal dominant trait. CONCLUSIONS: DM2 may often present with proximal muscle weakness without myotonia. EMG may initially fail to show myotonic discharges, but these discharges may eventually show in most cases on repeated EMG. Thus, DM2 may be underdiagnosed and should be included in the differential diagnosis of adult patients of Jewish European ancestry presenting with proximal lower limb weakness.
Subject(s)
Electromyography/methods , Muscle Weakness/physiopathology , Musculoskeletal Pain/physiopathology , Myotonia/physiopathology , Myotonic Disorders , RNA-Binding Proteins/genetics , Adult , Age of Onset , Aged , Biopsy , Europe/ethnology , Female , Humans , Inheritance Patterns , Israel/epidemiology , Jews , Male , Middle Aged , Muscle, Skeletal/pathology , Muscle, Skeletal/physiopathology , Myotonia/pathology , Myotonic Disorders/diagnosis , Myotonic Disorders/ethnology , Myotonic Disorders/genetics , Myotonic Disorders/physiopathology , Myotonic Dystrophy , PedigreeABSTRACT
ABSTRACT: Glycogen storage disease type III is a rare inherited disease caused by decreased activity of glycogen debranching enzyme. It affects primarily the liver, cardiac muscle, and skeletal muscle. Pure involvement of the skeletal muscle with adult onset is extremely rare. We report on a patient with myopathy due to glycogen storage disease III, and describe the clinical features, and pathologic and genetic findings.
Subject(s)
Glycogen Storage Disease Type III/diagnosis , Muscular Diseases/etiology , Humans , Male , Middle Aged , Muscle, SkeletalABSTRACT
X-linked myopathy with excessive autophagy (XMEA) is a rare disorder characterized by slow progressive muscle weakness and distinctive pathology of excessive autophagic vacuoles on muscle biopsy. Here we report on five patients, in a single family, with proximal lower limb weakness. The proband, a 25-year-old man, presented with 5 years of progressive lower limbs proximal muscle weakness. His maternal grandfather and three of his maternal male cousins had similar clinical findings and were initially suspected to have Becker muscular dystrophy. Muscle biopsy in two affected family members demonstrated autophagic myopathy, and guided the genetic investigations to the identification of a pathogenic mutation, c.272G > C in the VMA21 gene, known to cause XMEA [1]. To the best of our knowledge this is the first identified Israeli Jewish family afflicted by XMEA.
Subject(s)
Genetic Diseases, X-Linked/diagnosis , Muscle Weakness/pathology , Muscular Diseases/diagnosis , Vacuolar Proton-Translocating ATPases , Adult , Autophagy/genetics , Biopsy , Humans , Israel , Lower Extremity/pathology , Male , Muscle, Skeletal/pathology , Mutation , Vacuolar Proton-Translocating ATPases/genetics , Young AdultABSTRACT
Hereditary inclusion body myopathy (HIBM) is an adult onset, slowly progressive distal and proximal myopathy. Although the causing gene, GNE, encodes for a key enzyme in the biosynthesis of sialic acid, its primary function in HIBM remains unknown. To elucidate the pathological mechanisms leading from the mutated GNE to the HIBM phenotype, we attempted to identify and characterize early occurring downstream events by analyzing the genomic expression patterns of muscle specimens from 10 HIBM patients carrying the M712T Persian Jewish founder mutation and presenting mild histological changes, compared with 10 healthy matched control individuals, using GeneChip expression microarrays. When analyzing the expression profile data sets by the intersection of three statistic methods (Student's t-test, TNoM and Info score), we found that the HIBM-specific transcriptome consists of 374 differentially expressed genes. The specificity of the HIBM transcriptome was assessed by the minimal transcript overlap found between HIBM and the transcriptome of nine additional muscle disorders including adult onset limb girdle myopathies, inflammatory myopathies and early onset conditions. A strikingly high proportion (18.6%) of the overall differentially expressed mRNAs of known function were found to encode for proteins implicated in various mitochondrial processes, revealing mitochondria pathways dysregulation. Mitochondrial morphological analysis by video-rate confocal microscopy showed a high degree of mitochondrial branching in cells of HIBM patients. The subtle involvement of mitochondrial processes identified in HIBM reveals an unexpected facet of HIBM pathophysiology which could at least partially explain the slow evolution of this disorder and give new insights in the disease mechanism.
Subject(s)
Mitochondria/genetics , Mitochondria/metabolism , Myositis, Inclusion Body/genetics , Myositis, Inclusion Body/metabolism , Adult , Aged , Cells, Cultured , Female , Humans , Male , Middle Aged , Mitochondria/ultrastructure , Molecular Sequence Data , Muscle, Skeletal/metabolism , Myoblasts/metabolism , Oligonucleotide Array Sequence AnalysisABSTRACT
Sporadic juvenile muscular atrophy of the distal upper extremity or Hirayama's disease (HD) and autosomal dominant motor distal neuronopathy/axonopathy (CMT2D/dSMA-V), produced by glycyl-tRNA synthetase (GARS) gene mutations, share some clinical features including: young age of onset, predilection for the distal upper extremity, asymmetry, sparing of proximal muscles and unusual cold sensitivity. However, incomplete penetrance of GARS gene mutations may account for apparently non-familial cases. In order to inquire whether GARS gene mutations are associated with HD we studied seven patients fulfilling the clinical and electrodiagnostic criteria for HD. All patients underwent MRI of cervical spine that excluded compressive myelopathy in neutral position and intramedullary pathology. Each patient was tested for the presence of mutations in GARS by sequencing all coding exons amplified from genomic DNA. No pathogenic mutations were found, excluding the role of GARS gene as a possible factor in the aetiology of HD in this cohort.
Subject(s)
Glycine-tRNA Ligase/genetics , Magnetic Resonance Imaging , Muscular Atrophy, Spinal/genetics , Muscular Atrophy, Spinal/pathology , Spinal Cord/pathology , Adolescent , Adult , Cervical Vertebrae , Cohort Studies , DNA Mutational Analysis , Electromyography , Follow-Up Studies , Hand , Humans , Male , Muscular Atrophy, Spinal/physiopathology , Neural Conduction , Young AdultABSTRACT
Diagnosis in the early stages of hereditary transthyretin (ATTR) amyloidosis is imperative to support timely treatment to prevent or delay disease progression. Genetic testing in the setting of genetic counselling enables identification of carriers of a TTR gene mutation who are therefore at risk of developing TTR-associated disease. Knowledge of different genotypes and how they manifest in symptomatic disease should facilitate development of a structured and targeted approach to enable diagnosis of symptomatic disease in ATTR amyloidosis mutation carriers on the first manifestation of the earliest detectable sign or symptom. A group of experts from across Europe, Israel and Japan met to reach a consensus on such an approach. The proposed approach involves establishing a baseline for key clinical parameters, determination of the timing and frequency of follow-up in TTR mutation carriers based on a predicted age of disease onset, and recognition of the likely initial clinical signs and symptoms aligned with the phenotype of the specific TTR gene mutation and family history. Minimum criteria for diagnosis of symptomatic disease have been agreed, which it is hoped will ensure diagnosis of ATTR amyloidosis at the earliest possible stage in people with a known TTR mutation.