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J Hum Genet. 2015 Sep;60(9):509-13. doi: 10.1038/jhg.2015.57. Epub 2015 May 28.

Compound heterozygous GFM2 mutations with Leigh syndrome complicated by arthrogryposis multiplex congenita.

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Department of Pediatrics, Sapporo Medical University School of Medicine, Sapporo, Japan.
Department of Human Genetics, Yokohama City University Graduate School of Medicine, Yokohama, Japan.
Department of Child Neurology, Hokkaido Medical Center for Child Health and Rehabilitation, Sapporo, Japan.
Department of Metabolism, Chiba Children's Hospital, Chiba, Japan.
Department of Pediatrics, Saitama Medical University, Saitama, Japan.


Defects in the mitochondrial translation apparatus can impair energy production in affected tissues and organs. Most components of this apparatus are encoded by nuclear genes, including GFM2, which encodes a mitochondrial ribosome recycling factor. A few patients with mutations in some of these genes have been reported to date. Here, we present two female siblings with arthrogryposis multiplex congenita, optic atrophy and severe mental retardation. The younger sister had a progressive cerebellar atrophy and bilateral neuropathological findings in the brainstem. Although her cerebrospinal fluid (CSF) levels of lactate and pyruvate were not increased, brain magnetic resonance spectroscopy showed a lactate peak. Additionally, her CSF lactate/pyruvate and serum beta-hydroxybutyrate/acetoacetate ratios were high, and levels of oxidative phosphorylation in skin fibroblasts were reduced. We therefore diagnosed Leigh syndrome. Genomic investigation confirmed the presence of compound heterozygous GFM2 mutations (c.206+4A>G and c.2029-1G>A) in both siblings, causing aberrant splicing with premature stop codons (p.Gly50Glufs*4 and p.Ala677Leufs*2, respectively). These findings suggest that GFM2 mutations could be causative of a phenotype of Leigh syndrome with arthrogryposis multiplex congenita.

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