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Myopathies Related to Glycogen Metabolism Disorders.

ABSTRACT: Most of the glycogen metabolism disorders that affect skeletal muscle involve enzymes in glycogenolysis (myophosphorylase (PYGM), glycogen debranching enzyme (AGL), phosphorylase b kinase (PHKB)) and glycolysis (phosphofructokinase (PFK), phosphoglycerate mutase (PGAM2), aldolase A (ALDOA), ?-enolase (ENO3)); however, 3 involve glycogen synthesis (glycogenin-1 (GYG1), glycogen synthase (GSE), and branching enzyme (GBE1)). Many present with exercise-induced cramps and rhabdomyolysis with higher-intensity exercise (i.e., PYGM, PFK, PGAM2), yet others present with muscle atrophy and weakness (GYG1, AGL, GBE1). A failure of serum lactate to rise with exercise with an exaggerated ammonia response is a common, but not invariant, finding. The serum creatine kinase (CK) is often elevated in the myopathic forms and in PYGM deficiency, but can be normal and increase only with rhabdomyolysis (PGAM2, PFK, ENO3). Therapy for glycogen storage diseases that result in exercise-induced symptoms includes lifestyle adaptation and carefully titrated exercise. Immediate pre-exercise carbohydrate improves symptoms in the glycogenolytic defects (i.e., PYGM), but can exacerbate symptoms in glycolytic defects (i.e., PFK). Creatine monohydrate in low dose may provide a mild benefit in PYGM mutations.

SUBMITTER: Tarnopolsky MA

PROVIDER: S-EPMC6277299 | biostudies-literature | 2018 Oct

REPOSITORIES: biostudies-literature

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Myopathies Related to Glycogen Metabolism Disorders.

Tarnopolsky Mark A MA

Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics 20181001 4

Most of the glycogen metabolism disorders that affect skeletal muscle involve enzymes in glycogenolysis (myophosphorylase (PYGM), glycogen debranching enzyme (AGL), phosphorylase b kinase (PHKB)) and glycolysis (phosphofructokinase (PFK), phosphoglycerate mutase (PGAM2), aldolase A (ALDOA), β-enolase (ENO3)); however, 3 involve glycogen synthesis (glycogenin-1 (GYG1), glycogen synthase (GSE), and branching enzyme (GBE1)). Many present with exercise-induced cramps and rhabdomyolysis with higher-i ...[more]

PMID: 30397902

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Project description:BackgroundMetabolic myopathies are a heterogenous group of muscle diseases typically characterized by exercise intolerance, myalgia and progressive muscle weakness. Effective treatments for some of these diseases are available, but while our understanding of the pathogenesis of metabolic myopathies related to glycogen storage, lipid metabolism and β-oxidation is well established, evidence linking treatments with the precise causative genetic defect is lacking.ObjectiveThe objective of this study was to collate all published evidence on pharmacological therapies for the aforementioned metabolic myopathies and link this to the genetic mutation in a format amenable to databasing for further computational use in line with the principles of the "treatabolome" project.MethodsA systematic literature review was conducted to retrieve all levels of evidence examining the therapeutic efficacy of pharmacological treatments on metabolic myopathies related to glycogen storage and lipid metabolism. A key inclusion criterion was the availability of the genetic variant of the treated patients in order to link treatment outcome with the genetic defect.ResultsOf the 1,085 articles initially identified, 268 full-text articles were assessed for eligibility, of which 87 were carried over into the final data extraction. The most studied metabolic myopathies were Pompe disease (45 articles), multiple acyl-CoA dehydrogenase deficiency related to mutations in the ETFDH gene (15 articles) and systemic primary carnitine deficiency (8 articles). The most studied therapeutic management strategies for these diseases were enzyme replacement therapy, riboflavin, and carnitine supplementation, respectively.ConclusionsThis systematic review provides evidence for treatments of metabolic myopathies linked with the genetic defect in a computationally accessible format suitable for databasing in the treatabolome system, which will enable clinicians to acquire evidence on appropriate therapeutic options for their patient at the time of diagnosis.

Project description:The term filaminopathy was introduced after a truncating mutation in the dimerization domain of filamin C (FLNc) was shown to be responsible for a devastating muscle disease. Subsequently, the same mutation was found in patients from diverse ethnical origins, indicating that this specific alteration is a mutational hot spot. Patients initially present with proximal muscle weakness, while distal and respiratory muscles become affected with disease progression. Muscle biopsies of these patients show typical signs of myofibrillar myopathy, including disintegration of myofibrils and aggregation of several proteins into distinct intracellular deposits. Highly similar phenotypes were observed in patients with other mutations in Ig-like domains of FLNc that result in expression of a noxious protein. Biochemical and biophysical studies showed that the mutated domains acquire an abnormal structure causing decreased stability and eventually becoming a seed for abnormal aggregation with other proteins. The disease usually presents only after the fourth decade of life possibly as a result of ageing-related impairments in the machinery that is responsible for disposal of damaged proteins. This is confirmed by mutations in components of this machinery that cause a highly similar phenotype. Transfection studies of cultured muscle cells reflect the events observed in patient muscles and, therefore, may provide a helpful model for testing future dedicated therapeutic strategies. More recently, FLNC mutations were also found in families with a distal myopathy phenotype, caused either by mutations in the actin-binding domain of FLNc that result in increased actin-binding and non-specific myopathic abnormalities without myofibrillar myopathy pathology, or a nonsense mutation in the rod domain that leads to RNA instability, haploinsufficiency with decreased expression levels of FLNc in the muscle fibers and myofibrillar abnormalities, but not to the formation of desmin-positive protein aggregates required for the diagnosis of myofibrillar myopathy.

Project description:RYR1 mutations are typically associated with core myopathies and are the most common overall cause of congenital myopathy. Dominant mutations are most often associated with central core disease and malignant hyperthermia, and genotype-phenotype patterns have emerged from the study of these mutations that have contributed to the understanding of disease pathogenesis. The recent availability of genetic testing for the entire RYR1 coding sequence has led to a dramatic expansion in the identification of recessive mutations in core myopathies and other congenital myopathies. To date, no clear patterns have been identified in these recessive mutations, though no systematic examination has yet been performed.In this study, we investigated genotype-phenotype correlations in a large combined cohort of unpublished (n?=?14) and previously reported (n?=?92) recessive RYR1 cases.Overall examination of this cohort revealed nearly 50% of cases to be non-core myopathy related. Our most significant finding was that hypomorphic mutations (mutations expected to diminish RyR1 expression) were enriched in patients with severe clinical phenotypes. We also determined that hypomorphic mutations were more likely to be encountered in non-central core myopathies. With analysis of the location of non-hypomorphic mutations, we found that missense mutations were generally enriched in the MH/CCD hotspots and specifically enriched in the selectivity filter of the channel pore.These results support a hypothesis that loss of protein function is a key predictive disease parameter. In addition, they suggest that decreased RyR1 expression may dictate non-core related pathology though, data on protein expression was limited and should be confirmed in a larger cohort. Lastly, the results implicate abnormal ion conductance through the channel pore in the pathogenesis in recessive core myopathies. Overall, our findings represent a comprehensive analysis of genotype-phenotype associations in recessive RYR1-myopathies.

Dataset Information

Myopathies Related to Glycogen Metabolism Disorders.

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Myopathies Related to Glycogen Metabolism Disorders.

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