A Case of NDUFAF6-associated Mitochondrial Respiratory Chain Complex I Deficiency in Two Siblings

Background

The NDUFAF6 gene encodes a protein involved in the assembly of mitochondrial complex I, an essential component of OXPHOS. Pathogenic variants in NDUFAF6 have been associated with such phenotypes as Leigh syndrome and mitochondrial complex I deficiency, which presents with movement disorders and respiratory insufficiency.

Case Study/Methods

We present a clinical report of two siblings with compound heterozygous nucleotide variants in the NDUFAF6 gene. Whole genome sequencing was performed for the proband’s sister and variant segregation was validated by Sanger sequencing.

Results

The proband, a female, 2 y. 11 m. of age, was admitted to the hospital for the first time complaining of respiratory problems due to a viral infection. During the examination, elevated lactate (6.2 mmol/L) and a high level of hepatic transaminases were noted. Ultrasound revealed splenomegaly and reactive changes in the liver but the brain MRI showed no changes.
The younger sister of the proband manifested metabolic crises at the age of 2 y. with lactic acidosis and respiratory failure. From the age of 3 y. 6 m. neurological symptoms were noted. Subsequently, hepatosplenomegaly and chronic renal disease were identified, with increased signal in T2W and FLAIR in the subcortical nuclei on the right in the brain MRI. Whole genome sequencing revealed two splicing variants in the NDUFAF6 gene (NM_152416.4) c.298-768TC and c.715-3CG in the sibling, which were also validated in the proband and mother.

Conclusion

We have described a clinical case of mitochondrial respiratory chain complex I deficiency caused by mutations in the NDUFAF6 gene. Both patients had a wide range of phenotypic manifestations involving the nervous system, which can significantly complicate the diagnosis of such a heterogeneous group of diseases.