Mitochondrial Complex I Deficiency, Nuclear Type 19

A number sign (#) is used with this entry because of evidence that mitochondrial complex I deficiency nuclear type 19 (MC1DN19) is caused by homozygous or compound heterozygous mutation in the FOXRED1 gene (613622) on chromosome 11q24.

For a discussion of genetic heterogeneity of mitochondrial complex I deficiency, see 252010.

Clinical Features

Calvo et al. (2010) reported a patient with mitochondrial complex I deficiency nuclear type 19 manifesting as Leigh syndrome (see 256000). The patient had congenital lactic acidosis, athetoid movements of the limbs in early childhood, hypotonia, and cerebellar atrophy. He lost motor skills and became wheelchair-dependent by his early teens. He also developed seizures. At age 22 years, he was alert, but had no expressive language and needed help with activities of daily living.

Fassone et al. (2010) reported a patient, born to first-cousin Iranian-Jewish parents, with early-onset complex I-deficient encephalomyopathy. The patient presented with neonatal hypotonia, followed by irritability, acquired microcephaly, and cortical blindness. Hearing appeared to be normal. There had never been any voluntary movements. Hypertrophic cardiomyopathy was present. The patient was alive at the age of 10 years.

Molecular Genetics

In a patient with Leigh syndrome due to mitochondrial complex I deficiency nuclear type 19, Calvo et al. (2010) identified compound heterozygosity for 2 mutations in the FOXRED1 gene (Q232X, 613622.0001 and N430S, 613622.0002).

Fassone et al. (2010) described an Iranian-Jewish child with complex I deficiency caused by homozygosity for a missense mutation in FOXRED1 (R354W; 613622.0003). Both parents and 2 sibs were heterozygous for the mutation, while the other 3 sibs were homozygous for the wildtype sequence. Silencing of FOXRED1 in human fibroblasts resulted in reduced complex I steady-state levels and activity, while lentiviral-mediated FOXRED1 transgene expression rescued complex I deficiency in the patient fibroblasts. The authors concluded that this FAD-dependent oxidoreductase is a complex I-specific molecular chaperone.