ATP Synthase Deficiency due to TMEM70 Mutation Leads to Ultrastructural Mitochondrial Degeneration and Is Amenable to Treatment
2015
TMEM70 is involved in the biogenesis of mitochondrial
ATP synthaseand mutations in the TMEM70 gene impair
oxidative phosphorylation. Herein, we report on pathology and treatment of
ATP synthasedeficiency in four siblings. A
consanguineousfamily of Roma (Gipsy)
ethnic origingave birth to 6 children of which 4 were affected presenting with
dysmorphic features,
failureto
thrive, cardiomyopathy, metabolic crises, and 3-methylglutaconic aciduria as clinical symptoms. Genetic testing revealed a homozygous mutation (c.317-2A>G) in the TMEM70 gene. While light microscopy was unremarkable, ultrastructural investigation of muscle tissue revealed accumulation of swollen degenerated mitochondria with lipid crystalloid inclusions,
cristaeaggregation, and exocytosis of mitochondrial material. Biochemical analysis of mitochondrial complexes showed an almost complete
ATP synthasedeficiency. Despite harbouring the same mutation, the clinical outcome in the four siblings was different. Two children died within 60 h after birth; the other two had recurrent life-threatening metabolic crises but were successfully managed with supplementation of anaplerotic amino acids, lipids, and symptomatic treatment during metabolic crisis. In summary, TMEM70 mutations can cause distinct ultrastructural mitochondrial degeneration and almost complete deficiency of
ATP synthasebut are still amenable to treatment.
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