Lack Of mitochondrial complex I assembly factor NDUFAF2 results in a distinctive infantile onset brainstem neurodegenerative disease with early lethality

Background: Congenital disorders of the mitochondrial respiratory chain are a heterogeneous group of inborn errors of metabolism. Among these, NADH:ubiquinone oxidoreductase (complex I, CI) deficiency is the most common. Bi-allelic pathogenic variants in NDUFAF2 gene, encoding NDUFAF2, a nuclear assembly CI factor, were initially reported to cause progressive encephalopathy beginning in infancy. Since the initial report in 2005 less than a dozen of patients with NDUFAF2 related disease were reported.

Methods: Clinical, biochemical and neuroradiological features were collected from four new patients. Enzymatic activities of the five respiratory chain complexes were determined in isolated fibroblast mitochondria by spectrophotometric methods. Western blot assays were performed with anti-human NDUFAF2 antibody, anti-VDAC1 antibody was used as mitochondrial loading control. Genetic studies were performed by chromosome microarray analysis using Affymetrix CytoScan 750K arrays.

Results: The patients presented with infantile onset growth retardation, strabismus and optic atrophy and progressed with life threatening episodes of apnea triggered by trivial illnesses with gradual loss of acquired developmental milestones. Serial MRI studies showed progressive pattern of abnormal hyperintense signals involving primarily the brainstem, the upper cervical cord, and later the basal ganglia and thalami. MR spectroscopy showed increased lactate peak. Disease progression was marked by ventilatory dependency and early lethality. All the patients harbored a homozygous 142-kb partial interstitial deletion that omits exons 2-4 of the NDUFAF2 gene. Mitochondrial complex I activity was significantly decreased. Western blot analysis showed absent NDUFAF2 protein compared with normal controls.

Conclusions: Bi-allelic NDUFAF2 loss of function mutations result in a distinctive Leigh like phenotype with clinical and neuro radiological features that are attributed to brain stem damage.