Neuropediatrics 2012; 43 - FV13_01
DOI: 10.1055/s-0032-1307063

Mitochondrial Encephalopathies caused by defective mitochondrial translation

E Wilichowski 1, H Prokisch 2, T Meitinger 2, J Gärtner 1
  • 1Abt. Pädiatrie II, Schwerpunkt Neuropädiatrie, Universitätsmedizin Göttingen, Göttingen, Germany
  • 2Institut für Humangenetik, Helmholtz-Institut München, München, Germany

Aims: Disturbances of oxidative phosphorylation (OXPHOS) causes progressive encephalopathies. Of the ˜90 protein components of the ATP-generating machinery, 13 are encoded by the mitochondrial DNA (mtDNA) and translated within the organelle. In a substantial number of patients with OXPHOS deficiencies, gene analysis fails to identify mutations in mitochondrial and nuclear genes encoding OXPHOS components. Recently, mutations in an increasing number of nuclear genes have been shown to alter mitochondrial translation.

We present a 24 year-old man with Leigh-like syndrome and complex I deficiency. Exome sequencing revealed two novel described mutations in the MTFMT gene encoding mitochondrial methionyl-tRNA formyltransferase.

Methods: At 5 year-of-age, the boy with a developmental delay suffered acute central facial palsy. Since the age of 12 years, the parents complaint fatigue, reduced activities of movement, speech and alertness. With 15 year-of-age, spastic diplegia became evident which slowly progressed to tetraspasticity. At present the patient is wheelchair-bound and shows strabism and optic atrophy. Lactate levels were elevated in serum and CSF. Serial MR imaging showed symmetric lesions in caput nucleus caudatus, white matter and cervical myelon. Muscle biopsy revealed myopathic changes with reduced activities of complex I.

Exome sequencing was performed using next-generation sequencing combined with stepwise filtering of gene variants.

Results: The patient presents with a Leigh-like syndrome and complex I deficiency in muscle. Exome sequencing resulted in the identification of compound heterozygous mutations in the MTFMT gene: c.1977–1978insA, p.R659fs667X; c.1402G>A, p. A468T.

Conclusion: Alterations of mitochondrial translation of mtDNA genes are important causes of mitochondrial encephalopathies. Here we present the third patient known so far with mutations in the MTFMT gene that has a crucial role in the formylation of Met-tRNAmet and thus in the initiation and elongation process of mitochondrial translation. This gene has to be added to the growing list of mitochondrial translation defects.

Mitochondriopathies - Mitochondrial Encephalopathies - Mitochondrial Translation