Muscle glycogenosis and mitochondrial hepatopathy in an infant with mutations in both the myophosphorylase and deoxyguanosine kinase genes.
OBJECTIVE
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 cytochrome c oxidase deficiency in liver. We identified a novel homozygous missense G-to-A mutation at codon 456 in exon 11 of PYGM, as well as a homozygous 4-base pair GATT duplication (nucleotides 763-766) in exon 6 of dGK, 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, and dGK mutations; and suggest that genetic "double trouble" should be considered in patients with unusual severe phenotypes.
Mancuso
Michelangelo
M
Department of Neurology, Columbia University College of Physicians and Surgeons, New York, NY 10032, USA.
Filosto
Massimiliano
M
Tsujino
Seiichi
S
Lamperti
Costanza
C
Shanske
Sara
S
Coquet
Michéle
M
Desnuelle
Claude
C
DiMauro
Salvatore
S
D015139:Blotting, Southern; D004272:DNA, Mitochondrial / Q000235:genetics; D005260:Female; D024982:Glycogen Phosphorylase, Muscle Form / Q000235:genetics*; D006008:Glycogen Storage Disease / Q000201:enzymology / Q000235:genetics* / Q000473:pathology; D006720:Homozygote; D006801:Humans; D007231:Infant, Newborn; D008099:Liver / Q000473:pathology; D008930:Mitochondria, Liver / Q000201:enzymology / Q000378:metabolism* / Q000473:pathology; D028361:Mitochondrial Diseases / Q000201:enzymology / Q000235:genetics* / Q000473:pathology; D018482:Muscle, Skeletal / Q000473:pathology; D009135:Muscular Diseases / Q000201:enzymology / Q000235:genetics* / Q000473:pathology; D009154:Mutation; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000235:genetics*; D020133:Reverse Transcriptase Polymerase Chain Reaction
D004272:DNA, Mitochondrial; D024982:Glycogen Phosphorylase, Muscle Form; D017853:Phosphotransferases (Alcohol Group Acceptor); C019165:deoxyguanosine kinase