Mutations in the mitochondrial complex I assembly factor NDUFAF6 cause isolated bilateral striatal necrosis and progressive dystonia in childhood

Abstract

To perform a deep phenotype characterisation in a pedigree of 3 siblings with Leigh syndrome and compound heterozygous NDUFAF6 mutations. Method: A multi-gene panel of childhood-onset basal ganglia neurodegeneration inherited conditions was analysed followed by functional studies in fibroblasts. Results: Three siblings developed gait dystonia in infancy followed by rapid progression to generalised dystonia and psychomotor regression. Brain magnetic resonance showed symmetric and bilateral cytotoxic lesions in the putamen and proliferation of the lenticular-striate arteries, latter spreading to the caudate and progressing to cavitation and volume loss. We identified a frameshift novel change (c.554_558delTTCTT; p.Tyr187AsnfsTer65) and a pathogenic missense change (c.371T > C; p.Ile124Thr) in the NDUFAF6 gene, which segregated with an autosomal recessive inheritance within the family. Patient mutations were associated with the absence of the NDUFAF6 protein and reduced activity and assembly of mature complex I in fibroblasts. By functional complementation assay, the mutant phenotype was rescued by the canonical version of the NDUFAF6. A literature review of 14 NDUFAF6 patients showed a consistent phenotype of an early childhood insidious onset neurological regression with prominent dystonia associated with basal ganglia degeneration and long survival. Interpretation: NDUFAF6-related Leigh syndrome is a relevant cause of childhood onset dystonia and isolated bilateral striatal necrosis. By genetic complementation, we could demonstrate the pathogenicity of novel genetic variants in NDUFAF6.

Management of Leigh syndrome due to NDUFAF6 variants

“…We do not agree with the statement that thiamine is the only compound effective in Leigh-syndrome [1]. In case Leigh syndrome is due to primary coenzyme-Q deficiency, high dose administration of coenzyme-Q can be highly beneficial [2].…”

“…We read with interest the article by Baide-Mairena et al about three siblings with early-onset Leigh syndrome due to compound heterozygous variants in the NDUFAF6 gene [1]. We have the following comments and concerns.…”

“…Since the basal ganglia lesions were not only hyperintense on T2/FLAIR sequences but also on diffusion-weighted images (DWI) [1], we should be informed whether apparent diffusion coefficient (ADC) maps showed a corresponding hyperintense or hypointense signal. This is of relevance since ADC hyperintensity would suggest the presence of a stroke-like lesion (SLL), which is the morphological equivalent of a stroke-like episode (SLE).…”

Spectrum of movement disorders in mitochondrial diseases

“…NDUFAF6 Complex I assembly Dystonia with childhood onset LS Baide-Mairena et al [30] , 2019 SUCLA2 mtDNA depletion Dystonia/ Chorea LS Carrozzo et al [31] , 2007 ATAD3 mtDNA depletion Dystonia Encephalopathy with cerebellar atrophy…”

“…Recently, a mutation in NDUFAF6, a complex I assembly factor, has been described in three siblings with childhood onset dystonia associated with bilateral striatal necrosis, neurological regression, and long survival [30] .…”