Regression

Gene: NDUFAF4

I don't know

3 unrelated families reported with patient-specific functional evidence provided for each. Regression noted in one reported patient. Other reported family had two siblings unwell from birth with a relatively fulminant course. Another large family reported with fulminant neonatal course / longer-term survivors having recurrent decompensation episodes.

PMID: 32949790 - report two siblings with facial dysmorphism and lactic acidosis diagnosed neonatally with subsequent fatal early encephalopathy with apneic episodes, irritability, central hypoventilation, liver involvement and hyperammonemia. Cerebral white matter anomalies reported in one patient and cardiomyopathy in the other. WES identified homozygous nonsense NDUFAF4 variants with absent NDUFAF4 expression in patient fibroblasts. OXPHOS assembly studies demonstrated almost undetectable levels of fully assembled complex I and complex I–containing supercomplexes and an abnormal accumulation of SCIII2IV1 supercomplexes. Morphologically, fibroblasts showed rounder mitochondria and a diminished degree of branching of the mitochondrial network.

PMID: 28853723 - report one patient born at 38 weeks after IOL for IUGR. Presented age 7 months with developmental regression, growth failure and central hypotonia. Brain MRI revealed diffuse bilateral signal alterations in the basal ganglia and thalami and an EEG showed generalized slowing with multifocal spikes consistent with an epileptogenic focus. Homozygous missense NDUFAF4 variants identified. Lentiviral complementation of patient fibroblasts with wild-type NDUFAF4 rescued complex I deficiency and assembly defect

PMID 18179882 - report multiple affected individuals from one family. Most presented soon after birth with severe metabolic acidosis and high plasma lactate levels. Patients who survived longer were repeatedly admitted because of exacerbation of the acidosis during intercurrent infections. One long-term survivor had profound ID. Seizures occurred in 2 individuals during decompensation episodes. Brain MRI of one patient at 16 months of age revealed severe atrophy of both gray and white matter, with demyelination, most prominent at the anterior aspects of the brain, leaving a cortical ribbon. At the occipito-parietal region there were subventricular cysts, emphasizing the ventricular walls. The cerebellum, basal ganglia, pons, and medulla were severely atrophic

Created: 18 Mar 2022, 6:09 a.m. | Last Modified: 18 Mar 2022, 6:12 a.m.

Panel Version: 0.419

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Phenotypes
Mitochondrial complex I deficiency, nuclear type 15 - MIM#618237

Publications

• 32949790
• 28853723
• 18179882