Homozygous missense mutation of NDUFV1 as the cause of infantile bilateral striatal necrosis

Abstract

Infantile bilateral striatal necrosis (IBSN) includes a heterogeneous group of disorders, characterized by symmetrical degeneration predominantly of the caudate nucleus and the putamen [1]. The clinical features encompass pyramidal and extrapyramidal signs such as choreoathetosis, dystonia, spasticity, dysarthria, and dysphagia in conjunction with developmental regression or mental retardation, and additional neurological symptoms [1]. The differential diagnosis has to take into account a variety of toxic, infectious, metabolic, and neurodegenerative disorders [1]. In familial cases, mutations in the mitochondrial genes ATP6 and ND6, and in the nuclear encoded genes nucleoporin 62 (NUP62) and mitochondrial thiamine pyrophosphate transporter (SLC25A19), have been described [2]. We report two siblings with IBSN and a mutation in NDUFV1, not yet linked to this condition. The patients’ parents are unrelated, but belong to a population of German settlers immigrating to Russia about 250 years ago (Fig. 1c). In both children, gait and speech difficulties were noticed from age 4 years. Neurological examination at age 9 (F3) and 5 years (F5) revealed dysarthria, muscular hypertonia with cogwheel rigidity, exaggerated deep tendon reflexes, and bilateral Babinski signs, while MRI demonstrated symmetric cystic lesions of the putamen (Fig. 1a, b). The patients were treated with biotin and thiamine before the definite diagnosis was established, and additionally, with creatine, riboflavin, and other vitamins thereafter. This resulted in a distinct and sustained improvement of their neurological status until last examination at age 11 and 7 years, respectively. Both still walk and attend regular schools. Biochemical analysis of a muscle biopsy from patient F3 revealed isolated complex I deficiency (0.08 U/U citrate synthetase; normal 0.17–0.56). Therefore, we sequenced the entire mtDNA including the genes ATP6 and ND6 without detecting pathogenic variants [3, 4].