Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C1762617 (weakness)
 37,932 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Inclusion body myositis (IBM) is a slowly progressive inflammatory myopathy characterized by selective weakness of finger flexors and quadriceps muscles commonly refractory to treatment. Another chronic inflammatory disorder, sarcoidosis, commonly involves muscle. The comorbidity of inclusion body myositis and sarcoid myopathy is rare. We describe clinical and muscle biopsy findings of a patient with sarcoidosis and inclusion body myositis. A 66-year-old man presented with a 6-year history of progressive, asymmetrical and selective weakness of the quadriceps, biceps and finger flexor muscles; he had a remote history of pulmonary sarcoidosis. A quadriceps muscle biopsy revealed a chronic inflammatory myopathy with ubiquitinated inclusion bodies, rimmed vacuoles, expression of major histocompatibility complex class I, numerous COX-negative fibers and TDP-43 cytoplasmic aggregates (features of IBM) and multiple non-necrotizing granulomata (feature of sarcoidosis). Clinical and histopathologic features of the current illness suggested the patient had sarcoidosis with inclusion body myositis overlap. This patient may represent the coincidental occurrence of both idiopathic inflammatory disorders. Alternatively, sarcoidoisis may promote the development of inclusion body myositis by a similar immune-mediated pathophysiologic process.
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PMID:Inclusion body myositis and sarcoid myopathy: coincidental occurrence or associated diseases. 2559 12

HHcy has been implicated in elderly frailty, but the underlying mechanisms are poorly understood. Using C57 and CBS+/- mice and C2C12 cell line, we investigated mechanisms behind HHcy induced skeletal muscle weakness and fatigability. Possible alterations in metabolic capacity (levels of LDH, CS, MM-CK and COX-IV), in structural proteins (levels of dystrophin) and in mitochondrial function (ATP production) were examined. An exercise regimen was employed to reverse HHcy induced changes. CBS+/- mice exhibited more fatigability, and generated less contraction force. No significant changes in muscle morphology were observed. However, there is a corresponding reduction in large muscle fiber number in CBS+/- mice. Excess fatigability was not due to changes in key enzymes involved in metabolism, but was due to reduced ATP levels. A marginal reduction in dystrophin levels along with a decrease in mitochondrial transcription factor A (mtTFA) were observed. There was also an increase in the mir-31, and mir-494 quantities that were implicated in dystrophin and mtTFA regulation respectively. The molecular changes elevated during HHcy, with the exception of dystrophin levels, were reversed after exercise. In addition, the amount of NRF-1, one of the transcriptional regulators of mtTFA, was significantly decreased. Furthermore, there was enhancement in mir-494 levels and a concomitant decline in mtTFA protein quantity in homocysteine treated cells. These changes in C2C12 cells were also accompanied by an increase in DNMT3a and DNMT3b proteins and global DNA methylation levels. Together, these results suggest that HHcy plays a causal role in enhanced fatigability through mitochondrial dysfunction which involves epigenetic changes.
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PMID:Hyperhomocysteinemia associated skeletal muscle weakness involves mitochondrial dysfunction and epigenetic modifications. 2561 94

We report on two novel mtDNA mutations in patients affected with mitochondrial myopathy. The first patient, a 44-year-old woman, had bilateral eyelid ptosis and the m.8305C>T mutation in the MTTK gene. The second patient, a 56-year-old man, had four-limb muscle weakness and the MTTM gene m.4440G>A mutation. Muscle biopsies in both patients showed ragged red fibers and numerous COX-negative fibers as well as a combined defect of complex I, III and IV activities. The two mutations were heteroplasmic and detected only in muscle tissue, with a higher mutation load in COX-negative fibers. Additionally, both mutations occurred in highly conserved mt-tRNA sites, and were not found by an in silico search in 30,589 human mtDNA sequences. Our report further expands the mutational and phenotypic spectrum of diseases associated with mutations in mitochondrial tRNA genes and reinforces the notion that mutations in mitochondrial tRNAs represent hot spots for mitochondrial myopathies in adults.
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PMID:Identification and characterization of the novel m.8305C>T MTTK and m.4440G>A MTTM gene mutations causing mitochondrial myopathies. 2948 11

Introduction: There are several reported cases of patients developing motor and cognitive neurological impairment under treatment with valproic acid (VPA). We describe a woman who developed a subacute encephalopathy after VPA intake, harboring a mitochondrial DNA variant, previously described as causing VPA sensitivity in one pediatric patient. Material and Methods: A 65-year old woman developed a progressive, severe neurological deterioration after a 3 month treatment with valproate sodium, 800 mg daily. Magnetic resonance spectroscopy (MRS), muscle histochemical analysis and assay of mitochondrial enzymatic activities, and mitochondrial DNA sequencing were performed. Results: Neurological examination showed drowsiness, vertical gaze palsy, inability to either stand or walk, diffuse weakness, increased tendon reflexes. Blood lactate was increased, EEG showed diffuse theta and delta activity, MRI subcortical atrophy and leukoencephalopathy, MRS marked reduction of the NAA spectrum, with a small signal compatible with presence of lactate. Muscle biopsy evidenced presence of ragged red fibers (20%) and reduced COX reactivity. Assay of the muscle enzymatic activities showed multiple deficiencies of the electron transport chain and reduced ATP production. The mt.8393C>T variant in the MT-ATP8 gene was found in homoplasmy. The patient considerably improved after valproate withdrawal. Conclusion: The variant we found has been reported both as a polymorphism and, in a single patient, as related to the valproate-induced encephalopathy. The present case is the first bearing this mutation in homoplasmy. In case of neurological symptoms after starting VPA therapy, once hyperammonemia and liver failure have been ruled out, mtDNA abnormalities should be considered.
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PMID:Reversible Valproate-Induced Subacute Encephalopathy Associated With a MT-ATP8 Variant in the Mitochondrial Genome. 3021 24

Although relatively common in children, severe acute lactic acidosis is rare in adults with mitochondrial myopathies. We report here three cases, aged 27, 32 and 32 years, who developed life-threatening metabolic crisis with severe lactic acidosis, requiring hospitalisation in intensive care unit. Plasma lactates were elevated 10 to 15 fold normal values, necessitating extra-renal dialysis. By contrast CK levels were moderately increased (3 to 5N). No triggering factor was identified, but retrospectively all patients reported long-lasting mild muscle fatigability and weakness before their acute metabolic crisis. All of them recovered after prolonged intensive care but resting lactate levels remained elevated. Muscle biopsy showed ragged-red and COX-negative fibers in two patients and mild lipidosis in the third one. Heteroplasmic pathogenic point mutations were detected in MT-TL1 (m.3280G>A;m.3258C>T) and MT-TK (m.8363A>G). Life-threatening lactic acidosis may thus be a major inaugural clinical manifestation in adults with mitochondrial myopathies. Prolonged intensive care may lead to a dramatic and sustained improvement and is mandatory in such cases.
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PMID:Life-threatening lactic acidosis occurring in adults with mitochondrial disorders. 3105 54

Megaconial congenital muscular dystrophy (CMD) is a rare form of congenital muscular dystrophy attributed to an autosomal recessive CHKB mutation. We report two unrelated Chinese girls with Megaconial CMD who harbored the same novel homozygous CHKB mutation but exhibited different phenotypes. Patient 1, who is now 8 years old, has autism, intellectual disabilities, mild girdle weakness, and characteristic muscle biopsy with COX-negative fibers. Patient 2, now 12 years old, has limited intelligence and marked weakness, with scoliosis, hip subluxation and early loss of ambulation. Both exhibited mildly elevated creatine kinase levels, have relative sparing of adductor longus and extensor digitorum longus on MRI leg muscles, and a c.598del (p.Gln200Argfs*11) homozygous CHKB loss-of-function mutation. Their parents are heterozygous carriers. This is the first report of Megaconial CMD in Chinese patients demonstrating the pathogenicity of the identified homozygous CHKB variant. A case review of all previously reported patients of different ethnicities is also included.
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PMID:Megaconial congenital muscular dystrophy: Same novel homozygous mutation in CHKB gene in two unrelated Chinese patients. 3192 38

Mitochondrial dysfunction is known to play a key role in the pathophysiological pathway of neurodegenerative disorders. Nuclear-encoded proteins are involved in mtDNA replication, including DNA polymerase gamma, which is the only known replicative mtDNA polymerase, encoded by nuclear genes Polymerase gamma 1 (POLG) and Polymerase gamma 2 (POLG2). POLG mutations are well-known as a frequent cause of mitochondrial myopathies of nuclear origin. However, only rare descriptions of POLG2 mutations leading to mitochondriopathies exist. Here we describe a 68-year-old woman presenting with a 20-year history of camptocormia, mild proximal weakness, and moderate CK increase. Muscle histology showed COX-negative fibres. Genetic analysis by next generation sequencing revealed an already reported heterozygous c.1192-8_1207dup24 mutation in the POLG2 gene. This is the first report on a POLG2 mutation leading to camptocormia as the main clinical phenotype, extending the phenotypic spectrum of POLG2 associated diseases. This underlines the broad phenotypic spectrum found in mitochondrial diseases, especially in mitochondrial disorders of nuclear origin.
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PMID:Camptocormia as a Novel Phenotype in a Heterozygous POLG2 Mutation. 3199 53

Progressive external ophthalmoplegia is typically associated with single or multiple mtDNA deletions but occasionally mtDNA single nucleotide variants within mitochondrial transfer RNAs (mt-tRNAs) are identified. We report a 34-year-old female sporadic patient with progressive external ophthalmoplegia accompanied by exercise intolerance but neither fixed weakness nor multisystemic involvement. Histopathologically, abundant COX-deficient fibres were present in muscle with immunofluorescence analysis confirming the loss of mitochondrial complex I and IV proteins. Molecular genetic analysis identified a rare heteroplasmic m.15990C>T mt-tRNAPro variant reported previously in a single patient with childhood-onset myopathy. The variant in our patient was restricted to muscle. Single muscle fibre analysis identified higher heteroplasmy load in COX-deficient fibres than COX-normal fibres, confirming segregation of high heteroplasmic load with a biochemical defect. Our case highlights the phenotypic variability typically observed with pathogenic mt-tRNA mutations, whilst the identification of a second case with the m.15990C>T mutation not only confirms pathogenicity but shows that de novo mt-tRNA point mutations can arise in multiple, unrelated patients.
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PMID:Progressive external ophthalmoplegia due to a recurrent de novo m.15990C>T MT-TP (mt-tRNAPro) gene variant. 3230 57


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