NDUFS8-related Complex I Deficiency Extends Phenotype from "PEO Plus" to Leigh Syndrome

Abstract

With over 1,000 nuclear genes that could potentially cause a mitochondrial disorder, the current diagnostic approach requires targeted molecular analysis, guided by a combination of clinical and biochemical features. However, the expanding molecular and clinical spectrum means that this approach does not always yield a result. Here we report the unusual clinical presentation of "Progressive External Ophthalmoplegia (PEO) plus" Leigh syndrome in three children from a consanguineous family where exome sequencing identified mutations in NDUFS8. NDUFS8 is a nuclear-encoded structural core protein of complex I, and mutations are expected to cause infantile onset and severe disease. Our patients had a later onset, milder and a clinically distinct phenotype, and this gene would not normally be considered in this context. Being untargeted to specific genes, whole exome analysis has the potential to re-write the phenotype and reveal an unexpected molecular aetiology, as illustrated by this family.

Fig. 1

(a) The picture shows patient 1 (13 years) and patient 2 (12 years). Note external ophthalmoplegia on upgaze in patient 1. (b) Brain MRI of patient 1 at 9 years of age showed hyperintense lesions in the bilateral putamen and nucleus caudatus as well as in the bilateral frontal subcortical region on T2w sequences without enhancement after gadolinium. The lesions in the bilateral putamen and nucleus caudatus were hypointense on T1 images. There was a slight ventricular asymmetry, but the configuration of the cerebellum and brainstem were normal. Brain MRI of patient 2 at 8 years of age showed an abnormal symmetrical signal in the bilateral putamen (hypointense on T1 images, hyperintense on T2 images) but no other malformations of the brain structures. (c) Exome sequencing detected 62 novel homozygous changes shared in both patients; 30 were protein altering and 15 of these were predicted to be disease causing. Only one of these homozygous changes was in a gene encoding a known mitochondrial protein, NDUFS8, a complex I related gene. (d) Localization of the c.160C>T, pArg54Trp mutation in the NDUFS8 gene. 4Fe-4S refers to the iron-sulphur binding domains