Recurrent de novo mitochondrial DNA mutations in respiratory chain deficiency.(Short Report)

Starting from a cohort of 50 NADH-oxidoreductase (complex I) deficient patients, we carried out the systematic sequence analysis of all mitochondrially encoded complex I subunits (ND1 to ND6 and ND4L) in affected tissues. This approach yielded the unexpectedly high rate of 20% mutation identification in our series. Recurrent heteroplasmic mutations included two hitherto unreported (T10158C and T14487C) and three previously reported mutations (T10191C, T12706C and A13514G) in children with Leigh or Leigh-like encephalopathy. The recurrent mutations consistently involved T[right arrow]C transitions (p<1[0.sup.-4]). This study supports the view that an efficient molecular screening should be based on an accurate identification of respiratory chain enzyme deficiency.

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J Med Genet 2003;40:896-899

The twofold genetic origin of the mitochondrial respiratory chain, the large number of catalytic and assembly proteins, and the allelic/non-allelic heterogeneity of disease causing mutations make identification of the mutant genotypes in respiratory chain deficiency particularly tedious. However, elucidating the disease mechanism is of particular importance for establishing the mode of inheritance and identifying the recurrence risk in affected families.

Starting from a cohort of 50 NADH-oxidoreductase (complex I) deficient patients, we carried out the systematic sequence analysis of all mitochondrially encoded complex I subunits in affected tissues. This systematic approach yielded the unexpected mutation rate of 20% including recurrent de novo mtDNA mutations in our series. Whatever the mechanism, this high rate of recurrent de novo mutations is important for genetic counselling. In addition, this study gives support to the view that an efficient molecular screening should be based on accurate identification of the respiratory chain deficiency causing the disease.

PATIENTS

Patient 1

A girl was born to unrelated healthy parents after a 38 week pregnancy (weight 3320 g, length 48.5 cm, occipital frontal circumference (OFC) 34 cm). Her elder sister is healthy. Psychomotor development was apparently normal until 4 months of age when poor visual contact, floppiness, and abnormal movements were noted. Elevated plasma (8 mmol/l) and CSF lactate were noted (7 mmol/l, control below 2.2 mmol/l). Magnetic resonance imaging (MRI) showed widespread signal anomalies consistent with the diagnosis of Leigh disease, namely bilateral involvement of the putamen and of the lateral dorsal and dorsomedial thalamic nuclei, pulvinar, substantia nigra, and external globi pallidi, associated with involvement of the spinothalamic tracts and medial lemniscus, and of the reticular formation. A corticosubcortical hypersignal was also seen in the cingular gyri and in the central regions. MR spectroscopy detected a very high peak of lactate in the basal ganglia. The patient died at 5 months of age after a rapid neurological deterioration.

Patient 2

A boy was born to unrelated healthy parents after a 37 week pregnancy (weight 2600 g, length 47 cm, OFC 33 cm). His elder sister is healthy. He was first admitted aged 19 days for jaundice. At 4 weeks, persistent failure to thrive with high plasma (5.4-7.5 mmol/l) and urinary …