The molecular diagnosis of metabolic myopathies

The metabolic myopathies constitute a large group of heritable disorders that collectively display extensive genetic heterogeneity. This heterogeneity has many possible explanations that go beyond the individual effects of point mutations in the coding regions of affected genes or degrees of heteroplasmy in mtDNA mutations. Contributing factors include the interaction of protein subunits that may be encoded by different genes and have tissue-specificity; the conferring of tissue specificity by means of molecular processes, such as alternative splicing; and the masquerading of one disorder for another (e.g., occult neuromuscular disorders that pose as malignant hyperthermia). Another contributor to genetic heterogeneity is the fact that predictable Mendelian inheritance can become blurred by modifying genetic factors (e.g., the involvement of multiple promoters for one gene- or tissue-specific transcription factor) and environmental factors (e.g., the triggering agents that render heterozygotes symptomatic in autosomal recessive disorders, such as McArdle's disease and CPT II deficiency). Compounding the complexities of metabolic myopathies are the potential problems inherent in the laboratory diagnosis of these disease (e.g., tissue-specificity of isoforms, fresh versus frozen tissue for biochemical analysis, interpretation of ambiguous results, such as partial enzyme deficiencies). As noted in the tables of common disease-causing mutations, specific mutation analysis has evolved in improving the diagnosis of individual disorders, but it does not always offer definitive assurance of a diagnosis no matter how common one or more mutant alleles may be. The lack of a definitive molecular diagnosis is particularly true for the mitochondrial diseases for which a molecular diagnostic yield is only approximately 6%. It is important to choose the appropriate tissue for molecular or biochemical analysis in Mendelian (e.g., the biochemical analysis of McArdle's disease) and mitochondrial disorders (e.g., the molecular analysis of Kearns-Sayre syndrome); and combine all available diagnostic tools, including clinical, histopathologic, biochemical, and molecular findings to arrive at a valid diagnosis.