Clinical and genetic analysis of Chinese patients with Leigh syndrome caused by biallelic loss-of-function variants of the NDUFAF6 gene.

Leigh syndrome (LS) is the most common pediatric mitochondrial disorder, typically presenting in infancy with developmental regression, neurological dysfunction, and characteristic brain MRI lesions. It is linked to over 110 genes affecting cellular energy production, making it highly genetically heterogeneous, with complex I deficiency being the most frequent cause. Biallelic mutations in NDUFAF6-a key assembly factor of complex I-cause autosomal recessive Leigh syndrome, specifically NDUFAF6-related Leigh syndrome, also designated as mitochondrial complex I deficiency, nuclear type 17 (MC1DN17; OMIM 618239). Herein, we describe two patients with biallelic loss-of-function variants in NDUFAF6. Patient 1 was homozygous for an in-frame duplication (c.362_364dupTGG; p. Val121dup), whereas patient 2 carried this duplication in trans with a novel frameshift variant (c.169_190dup; p. Leu64fs*2). Both patients manifested motor deterioration, dystonia, dysphagia, and elevated blood lactate levels during infancy, along with symmetrical basal ganglia necrosis on brain MRI. A retrospective analysis of all 24 MC1DN17 cases confirmed infantile/childhood onset, psychomotor regression, dystonia, bilateral striatal necrosis with additional features, and hyperlactataemia as universal characteristics. Mortality was low (1/24; 4%), with motor function maintained for longer than in some other LS-associated genetic subtypes. No clear genotype-phenotype correlation was identified, and disease progression remains difficult to predict. There are currently no disease-modifying treatments available; only supportive care can be provided. Our study expands the NDUFAF6 mutational spectrum and consolidates its distinct clinical profile, highlighting the need for long-term data to define natural history and guide therapy.