Muscle Glycogenosis and Mitochondrial Hepatopathy in an Infant With Mutations in Both the Myophosphorylase and Deoxyguanosine Kinase Genes

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Abstract
Objectives To document 2 apparently incongruous clinical disorders occurring in the same infant: congenital myopathy with myophosphorylase deficiency (McArdle disease) and mitochondrial hepatopathy with liver failure and mitochondrial DNA depletion. Methods An infant girl born to consanguineous Moroccan parents had severe congenital hypotonia and hepatomegaly, developed liver failure, and died at 5 months of age. We studied muscle and liver biopsy specimens histochemically and biochemically, and we sequenced the whole coding regions of the deoxyguanosine kinase (dGK) and myophosphorylase (PYGM) genes. Results Muscle biopsy specimens showed subsarcolemmal glycogen accumulation and negative histochemical reaction for phosphorylase. Liver biopsy specimens showed micronodular cirrhosis and massive mitochondrial proliferation. Biochemical analysis showed phosphorylase deficiency in muscle and cytochromecoxidase deficiency in liver. We identified a novel homozygous missense G-to-A mutation at codon 456 in exon 11 ofPYGM, as well as a homozygous 4–base pair GATT duplication (nucleotides 763-766) in exon 6 ofdGK, which produces a frame shift and a premature TGA stop codon at nucleotides 766 to 768, resulting in a truncated 255–amino acid protein. Both mutations were absent in 100 healthy individuals. Conclusions Our data further expand the genetic heterogeneity in patients with McArdle disease; confirm the strong relationship between mitochondrial DNA depletion syndrome, liver involvement, anddGKmutations; and suggest that genetic "double trouble" should be considered in patients with unusual severe phenotypes.

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