Mitochondrial Complex I Deficiency, Nuclear Type 16

A number sign (#) is used with this entry because of evidence that mitochondrial complex I deficiency nuclear type 16 (MC1DN16) is caused by homozygous mutation in the NDUFAF5 gene (612360) on chromosome 20p12.

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

Clinical Features

Sugiana et al. (2008) reported a male infant, born of consanguineous Egyptian parents, with lethal neonatal complex I deficiency. The infant had intrauterine growth retardation, minor facial dysmorphism, unusual hair patterning, abnormal toes, and a small sacral pit. Cerebral ultrasound showed agenesis of the corpus callosum and ventricular septation. He also had a congenital left diaphragmatic hernia, adrenal insufficiency, and increased lactate in the blood and CSF. He died of cardiorespiratory arrest due to progressive lactic acidosis on day 7. Prenatal diagnosis identified 2 additional affected fetuses in subsequent pregnancies.

Gerards et al. (2010) reported 2 adult sibs, born of consanguineous Moroccan parents, who developed symptoms of complex I deficiency with Leigh syndrome (see 256000) in early childhood. The phenotype was less severe than that described by Sugiana et al. (2008). The sibs reported by Gerards et al. (2010) were aged 29 and 33 years at the time of the study, but presented with progressive spasticity at age 3, which subsequently developed into an extrapyramidal choreodystonic movement disorder. Delayed mental development also occurred, and both were moderately mentally retarded in their teens. Brain imaging of 1 patient at age 23 showed a small caudate and hyperintense lesions in the basal ganglia. Laboratory studies of 1 sib showed increased lactate in the cerebrospinal fluid, and both sibs had decreased complex I activity in skeletal muscle (36% and 48% of controls, respectively). A third affected sib died at age 36 years.

Saada et al. (2012) reported 5 children from 2 unrelated families of Ashkenazi Jewish origin with Leigh syndrome associated with deficiencies of mitochondrial complexes I and IV. The patients had typical features of complex I deficiency, with infantile-onset of feeding difficulties, failure to thrive, hypotonia, developmental delay, seizures, and abnormal signals on brain imaging.

Molecular Genetics

Sugiana et al. (2008) reported a male infant, born of consanguineous Egyptian parents, with lethal neonatal complex I deficiency due to homozygous mutation in the NDUFAF5 gene (L229P; 612360.0001).

In 2 adult sibs, born of consanguineous Moroccan parents, who developed symptoms of complex I deficiency with Leigh syndrome in early childhood, Gerards et al. (2010) identified a homozygous mutation in the NDUFAF5 gene (L159F; 612360.0002). Electrophoresis studies of patient leukocytes showed a decrease of mature complex I levels to 30 to 40% of normal controls. The clinically unaffected family members who were heterozygous for the mutation had mature complex I levels of 70 to 90% of normal controls.

In 5 children from 2 unrelated families of Ashkenazi Jewish origin with Leigh syndrome associated with deficiencies of mitochondrial complexes I and IV, Saada et al. (2012) identified a homozygous c.749G-T transversion in exon 7 of the NDUFAF5 gene, resulting in a gly250-to-val (G250V) substitution at a conserved residue. The mutations, which were found by homozygosity mapping followed by candidate gene sequencing, segregated with the disorder in the families. Haplotype analysis indicated a founder effect, and 3 heterozygous carriers were found among 869 Ashkenazi Jewish controls, yielding a carrier rate of 1:290 in this population. Transfection of wildtype NDUFAF5 into the fibroblasts of 1 patient restored complex I activity to near normal, while complex IV activity was only partially restored.