Novel NDUFV1 variant in progressive cavitating leukodystrophy with microcephaly: a case report

Progressive cavitating leukoencephalopathy (PCL) is a rare mitochondrial neurodegenerative disorder primarily caused by mitochondrial respiratory chain complex Ⅰ deficiency, with NDUFV1 identified as a major pathogenic gene. Typical phenotypes associated with NDUFV1-related PCL include motor regression, dystonia, cognitive impairment, and limb weakness, while microcephaly is extremely rare. The c.749T > A (p.Val250Glu) variant in NDUFV1 has not been documented previously, and its clinical significance remains undetermined. This report describes a case of PCL associated with this novel variant and microcephaly, aiming to investigate the correlation between genotype and phenotype.

A 17-month-old male infant of Chinese ethnicity was admitted to the hospital for assessment of motor skill regression. Physical examination revealed a head circumference of 45.5 cm (below the 3rd percentile for age and sex), hypertonia, and positive pyramidal tract signs. Laboratory tests showed elevated blood lactate levels. Neuroimaging revealed widespread, symmetrical, patchy abnormal signals accompanied by cavitation in the bilateral cerebral white matter, extending to involve the corpus callosum, brainstem, cerebellum, and upper cervical spinal cord. Genetic testing identified compound heterozygous NDUFV1 variants: c.749T>A (p.Val250Glu, paternal, previously unreported) and c.365C>T (p.Pro122Leu, maternal). The analysis of mitochondrial respiratory chain enzyme activity in skin fibroblasts revealed a deficiency in complex I. The patient received oral cocktail therapy combined with rehabilitation training and was followed up for over two years, showing improvements in motor, language, and cognitive functions, normalization of blood lactate levels, and reduction of abnormal MRI signals post-treatment.

Our study describes a case of NDUFV1-associated PCL caused by a novel compound heterozygous variant. This finding expands both the mutational spectrum of NDUFV1 and the phenotypic spectrum of PCL. It thus contributes significantly to the understanding of genotype-phenotype correlations in this disorder. Importantly, it highlights the need for early recognition of clinical features such as developmental delay, motor regression, and microcephaly, followed by diagnostic and therapeutic steps including prompt genetic testing, timely diagnosis, and appropriate intervention, all essential to improve patient outcomes and slow disease progression.