PP6.6 – 1797 Isolated complex I deficiency and atypical clinical courses in three patients due to novel mutations in NDUFS1 and NDUFV1

Abstract

Objectives: To report three patients with atypical clinical course, to add to our understanding of genotype-phenotype correlations in genes encoding complex I electron input module subunits. Materials and methods: Three patients with isolated complex I deficiency. One girl, patient 1, who presented at birth with hypotonia and feeding difficulties, and died at 5 weeks of age. Two sisters, patients 2 and 3, who presented at 6-7 months of age with progressive muscle weakness and delayed motor development, and have since showed a mild clinical course with long life span and normal mental development. Results: Metabolic findings indicated isolated complex I deficiency. Molecular genetic analysis showed compound heterozygosity for two novel point mutations in NDUFS1 for patient 1 and compound heterozygosity for two novel point mutations in NDUFV1 for patients 2 and 3. A literature review of all reported cases of mutations in the affected genes (NDUFS1, 12 patients; NDUFV1, 14 patients) showed that the clinical course of these three patients was atypical with regard to other patients described with mutations in corresponding genes. Conclusions: Genotype-phenotype correlations in patients with mutations affecting the genes that encode the electron input module of complex I vary, but patients with NDUFS1 mutation tend to have a shorter life span than patients with NDUFV1 mutation. Even considering this, the reported patients show that atypical clinical courses occur. Identifying the mutations is of importance for accurate genetic counseling. Compund heterozygosity due to the combination of a null mutation and a milder missense mutation may predict a more severe phenotype compared to the combination of two milder missense mutations.