Cystic Leukoencephalopathy due to NDUFV1 mutation—A Report of the Phenotype and Its Rare Co-occurrence with Primary Hyperoxaluria

Abstract The diagnosis of pediatric metabolic disease is complicated and markers of dysfunction are often key in directing appropriate genetic testing. We present a 4-year-old girl with developmental regression following an episode of chicken pox at 7 months. She lost her ability to sit, roll over, or babble. Investigations revealed high plasma lactate at 3.7 mmol/L (normal: < 2 mmol/L). Magnetic resonance imaging of brain at 12 months showed cystic leukoencephalopathy with sparing of basal ganglia, brain stem, and cerebellum. At 16 months, she made developmental progress, spoke a few single words, and was standing with support. Repeat neuroimaging showed the white matter to be more atrophic with well-delineated cysts in the parietal white matter. The clinicoimaging pattern was suspicious of a mitochondrial disorder and a previously reported pathogenic NDUFV1 mutation, predicted to result in mitochondrial complex I deficiency, and was subsequently confirmed by molecular genetic analysis. Coincidentally, she had raised oxalate and glycolate on repeated urine examination with raised urine oxalate: creatinine ratio. Genetic testing confirmed a pathological mutation in AGXT, consistent with primary hyperoxaluria type 1. NDUFV1 mutations result in variable phenotypes including Leigh syndrome, infantile lactic acidosis, cardiomyopathy, leukoencephalopathy, and the majority are described to be progressive and rapidly fatal in some cases. After the initial episode and now aged 4 years, our index case continues to make developmental progress without further episodes of regression, although speech and language delay persists. This case helps broaden our understanding of genotype–phenotype correlations associated with recessively inherited NDUFV1 mutations and highlights that they can be associated with less severe phenotypes. Moreover, there may be coexisting conditions, particularly in consanguineous pedigrees, which careful analysis of their clinical and biochemical data may allude to.

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