New Nuclear Encoded Mitochondrial Mutation Illustrates Pitfalls in Prenatal Diagnosis by Biochemical Methods

Abstract

A frequent etiology of congenital lactic acidosis is disturbed mitochondrial energy metabolism. Affected children generally present with neurologic symptoms, such as myopathy and epilepsy. Parents who have lost a child to mitochondrial disease often ask for prenatal diagnosis in subsequent pregnancies. The large number of possible mitochondrial or nuclear DNA mutations often makes the molecular defect unknown. In these cases, prenatal diagnosis rests solely on biochemical analysis. Here we report a possible pitfall in prenatal diagnosis of mitochondriopathies by biochemical methods that might occur despite all precautions. It is illustrated by a patient with isolated mitochondrial complex I deficiency and her family in the light of a new mutation (632C→T) in 1 of the 36 nuclear encoded genes of complex I ( NDUFV1 ). The girl (II.1 in Fig. 1A⇓ ) was the first child of healthy Caucasian first-degree cousins. Postnatally she showed acrocyanosis, muscular hypotonia, and a pendular nystagmus. Fundoscopy revealed bitemporal retinal depigmentation. The latencies of the visual evoked potentials were pathologically increased. Lactic acidosis (pH 7.19) was noted, with a plasma lactate concentration of 24.1 mmol/L (reference interval, 0.5–2.2 mmol/L), a lactate-to-pyruvate ratio of 57 (reference values <20), plasma alanine of 893 μmol/L (reference interval, 40–500 μmol/L), urine α-ketoglutaric acid of 1852 mmol/mol creatinine (reference interval, 159 ± 137 mmol/mol creatinine), urine lactate of 1713 mmol/mol creatinine (reference interval, 234 ± 165 mmol/mol creatinine), and cerebrospinal fluid lactate of 9.6 mmol/L (reference values <2 mmol/L). Cranial ultrasound and magnetic resonance imaging results were normal. Muscle histology revealed intracytoplasmic accumulation of glycogen. Mitochondria were ultrastructurally normal on electron microscopy. We measured the respiratory chain complex I, II+III, and IV activities in a fresh muscle biopsy specimen and in cultured fibroblasts according to standard procedures (1)(see the data supplement available with the online version of this Technical Brief, at …