Mitochondrial Complex I Deficiency, Nuclear Type 10

A number sign (#) is used with this entry because of evidence that mitochondrial complex I deficiency nuclear type 10 (MC1DN10) is caused by homozygous mutation in the NDUFAF2 gene (609653) on chromosome 5q12.

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

Clinical Features

Ogilvie et al. (2005) reported a patient with mitochondrial complex I deficiency nuclear type 10. The patient presented with a severe childhood-onset progressive encephalopathy leading to death at age 13 years. Features included ataxia, lethargy, nystagmus, hypotonia, optic atrophy, and episodic respiratory insufficiency. Complex I activity was less than 20% of control values. Brain imaging showed lesions in the mamillothalamic tracts, substantia nigra/medial lemniscus, medial longitudinal fasciculus, and spinothalamic tracts. Confluent areas of hyperintense signal were also seen in the cerebellum. Postmortem examination showed spongiform changes throughout the white matter and deep gray matter with relative sparing of the cortex. There was marked atrophy of the pons, medulla, and cerebellum. Microscopic examination of the cerebral cortex, hippocampus, and cerebellum showed extensive and bizarre degeneration of white matter, which was replaced by a glial scar. Ogilvie et al. (2005) noted that the clinical presentation of the patient did not resemble that seen in Leigh syndrome (see 256000), nor did it resemble that of most other patients with mitochondrial disease. The patient shared most of the characteristic diagnostic criteria for leukoencephalopathy with vanishing white matter (603896), which is caused by mutations in various genes encoding cytosolic translation factors.

Barghuti et al. (2008) reported 2 unrelated children, each born of consanguineous parents of Arab Muslim origin, with fatal mitochondrial complex I deficiency. Both patients presented in late infancy with hypotonia, hyporeflexia, and nystagmus associated with episodes of encephalopathy manifest as flaccidity and apnea, and eventually resulting in death. Serum lactate was not increased. One patient had seizures, dysmetria, and ataxia, whereas the other had optic atrophy. Brain imaging in both patients showed T2-weighted lesions in the mamillothalamic tracts, substantia nigra/medial lemniscus, medial longitudinal fasciculus, and spinothalamic tracts, as well mild changes in the cerebellum. Barghuti et al. (2008) noted that the lesions were distinct from those observed in typical Leigh syndrome (see 256000).

Hoefs et al. (2009) reported a girl, born of consanguineous parents, with fatal mitochondrial complex I deficiency. The patient presented at 3 months of age with nystagmus. At age 7 months, she had vomiting, renal tubular acidosis, poor feeding, and evidence of neurologic decline, including hypotonia and delayed motor development. Laboratory studies showed mildly increased blood lactate, and brain imaging showed signal abnormalities in the thalamus, cerebral peduncles, brainstem, and spinal cord. She developed dyskinetic movements and central hyperventilation, resulting in death at 1 year of age.

Herzer et al. (2010) reported a male infant, born of unrelated Austrian parents, with fatal mitochondrial complex I deficiency. The child presented in infancy with delayed development, nystagmus, and severe episodic apnea requiring ventilation. Neuroimaging showed T2-weighted lesions in the upper spinal cord, brainstem, and periaqueductal region with sparing of the basal ganglia, thalamus, corpus callosum, and internal capsule. Plasma lactate was normal or close to normal. The patient died of cardiorespiratory failure at age 27 months. Postmortem examination showed necrosis, spongiform changes, capillary proliferation in the brainstem, optic nerves, and chiasma. Dorsal spinal tracts, spinocerebral tracts, and dorsal spinal nerve roots showed Wallerian degeneration.

Molecular Genetics

In a patient with mitochondrial complex I deficiency nuclear type 10, Ogilvie et al. (2005) identified a homozygous missense mutation in the B17.2L gene (609653.0001).

In 2 sibs with mitochondrial complex I deficiency, Calvo et al. (2010) identified a homozygous 1-bp deletion in the NDUFAF2 gene (609653.0002).

In 2 unrelated children, each born of consanguineous parents of Arab Muslim origin, with fatal mitochondrial complex I deficiency, Barghuti et al. (2008) identified a homozygous missense mutation in the NDUFAF2 gene (M1L; 609653.0003). The mutation, which was found by homozygosity mapping and candidate gene sequencing, segregated with the disorder in 1 of the families; DNA from family members was not available for the other patient.

In a girl, born of consanguineous parents, with fatal mitochondrial complex I deficiency, Hoefs et al. (2009) identified a homozygous nonsense mutation in the NDUFAF2 gene (Y38X; 609653.0004). The mutation was found by homozygosity mapping and candidate gene sequencing.

In a male infant, born of unrelated Austrian parents, with fatal mitochondrial complex I deficiency, Herzer et al. (2010) identified a homozygous nonsense mutation in the NDUFAF2 gene (W3X; 609653.0005).