Metabolic Myopathies, Rhabdomyolysis and Exercise Intolerance Panel

The metabolic myopathies are a heterogeneous group of disorders caused by defects in muscle energy metabolism that cause inadequate production or maintenance of ATP levels. The effects may be confined specifically to skeletal muscle, or may also be observed in other tissues with significant energy requirements such as the heart, liver, kidney, brain and retina (Kahler. 2017). Typical clinical features include slowly progressive muscle weakness with or without hypotonia, premature fatigue, episodic aches, cramps and myalgia, exercise intolerance with or without a “second wind” phenomenon, rhabdomyolysis which may or may not be accompanied by myoglobinuria, high creatine kinase (CK) levels, and acute renal failure (Wortmann. 2002; Olpin et al. 2015. PubMed ID: 25878327; Kahler. 2017; Toscano et al. 2017. PubMed ID: 28763305; Lilleker et al. 2018. PubMed ID: 29223996). Age of onset is often childhood through teen years, although onset may occur any time from infancy through late adulthood. Symptoms may only occur when the activity level or nutrition state of the patient forces reliance upon the defective metabolic pathway, or may be precipitated by environmental factors such as intercurrent infection, general anesthesia or medications. Headache and nausea that are accompanied by exertional weakness or myalgia are strongly suggestive of a metabolic myopathy (Wortmann. 2002; Olpin et al. 2015. PubMed ID: 25878327) as are recurrent symptomatic episodes (Lilleker et al. 2018. PubMed ID: 29223996).

Early recognition is important as proper intervention can help prevent morbidity and/or mortality caused by the more severe symptoms (generally rhabdomyolysis and renal failure) (Olpin et al. 2015. PubMed ID: 25878327).

This sequencing panel includes genes that have been associated with metabolic myopathies. The genes within the panel can generally be classified in three groups based on the affected area of metabolism: 1) muscle glycogenoses, 2) disorders of lipid metabolism, and 3) mitochondrial respiratory chain disorders (Olpin et al. 2015. PubMed ID: 25878327). It should be noted that this test also includes some genes that may not be typically considered to cause a metabolic myopathy. These genes are associated with disorders that may present with some clinical features that overlap with typical metabolic myopathies, such as other neuromuscular disorders or mitochondrial myopathies.

The metabolic myopathies are genetically heterogeneous. The majority are inherited in an autosomal recessive (AR) manner, though autosomal dominant (AD) and X-linked (XL) disorders are also included. See individual gene test descriptions for information on clinical features, molecular biology of gene products and spectra of pathogenic variants.

Due to the genetic heterogeneity of the metabolic myopathies, the clinical sensitivity of this specific grouping of genes is difficult to estimate. We are currently unaware of any reports in the literature in which these genes have been sequenced together in a patient cohort with suspected metabolic myopathy, rhabdomyolysis or exercise intolerance as the primary indication for testing. The clinical sensitivity of sequencing the individual genes is generally high in patient groups with biochemical, enzymatic and/or histochemical diagnoses of the relevant disorders; details are available on the individual gene test description pages. Analytical sensitivity is expected to be high as the vast majority of variants reported in these genes are detectable via sequencing.

Gross deletions/duplications are a rare form of pathogenic variation among the majority of the genes in this test panel. However, the DYSF, GAA, GBE1, LAMP2, OPA1, SUCLA2, TAFAZZIN, and TANGO2 genes have a higher proportion of reported gross deletions/duplications (Human Gene Mutation Database).

This test is performed using Next-Gen sequencing with additional Sanger sequencing as necessary.

This panel typically provides 99.3% coverage of all coding exons of the genes plus 10 bases of flanking noncoding DNA in all available transcripts along with other non-coding regions in which pathogenic variants have been identified at PreventionGenetics or reported elsewhere. We define coverage as ≥20X NGS reads or Sanger sequencing. PGnome panels typically provide slightly increased coverage over the PGxome equivalent. PGnome sequencing panels have the added benefit of additional analysis and reporting of deep intronic regions (where applicable).

Dependent on the sequencing backbone selected for this testing, discounted reflex testing to any other similar backbone-based test is available (i.e., PGxome panel to whole PGxome; PGnome panel to whole PGnome).