NDUFV1: Identification of a Homozygous Mutation in a Patient with Leukodystrophy

Introduction: Mutations in the gene NDUFV1 are known as the cause of mitochondriopathies. NDUFV1 encodes a subunit in complex I called NADH-ubiquinone oxidoreductase flavoprotein. Until now, 16 NDUFV1 mutations have been classified in patients with myopathy, encephalopathy, neurodegenerative diseases such as Parkinson disease and Leigh syndrome.¹ These involve lesions in the white matter and the basal ganglia, and can also cause demyelination of peripheral nerves with subsequent muscular atrophy.²

Method: In a patient with leukodystrophy and conspicuously strip-shaped periventricular lesions, clinical exome sequencing was performed. All disease-related genes were analyzed with known phenotypes. This gene panel currently contains 4,813 genes with approximately 62,000 exons.³

Results: MRI showed a very distinctive, in part cystic leukodystrophy which stripped the entire white matter preferring the periventricular region. Clinically, the phenotype was remarkably mild, with discrete tetraparesis and preserved walking ability, mild cognitive impairment, and rare febrile seizures. Examination using clinical exome sequencing revealed a known pathogenic, homozygous mutation, c.1156C> T, in the gene NDUFV1. In this position, to date only heterozygous mutations have been reported that together with other mutations led to a very severe phenotype, HGMD CM08753, rs150966634.⁴

Conclusion: The homozygous mutation p.Arg386Cys in NDUFV1 is responsible for a leukodystrophy with a very characteristic MRT pattern. The comparatively mild clinical symptoms diverge from the very distinctive MRI changes.

• Bibliography

• Varghese F, Atcheson E, Bridges HR, Hirst J.. Characterization of clinically identified mutations in NDUFV1, the flavin-binding subunit of respiratory complex I, using a yeast model system. Hum Mol Genet 2015; 24 (22) 6350-6360 omim.org/entry/25600 https://www.illumina.com/products/by-type/clinical-research-products/trusight-one.html Mutation taster: file:///E:/NGS/TruSight_one/Daten/Flowcell_10/VariantStudio_TSO_FC10/996/Filtered_Variants/ohneGenlist/Im%20Vergleich%20mit%20Fam.Angeh%C3%B6rigen/NDUFV1_67379443.htm