Acute profound lactic alkalosis associated with NDUFV1 compound heterozygosity in a previously healthy 6-year-old female

Abstract

NDUFV1 encodes NADH: ubiquinone oxidoreductase core subunit V1, a key component of mitochondrial Complex 1. Biallelic pathogenic variants in this gene produce a broad and variable phenotypic spectrum in affected individuals, including ophthalmoplegia, developmental delays, brain imaging abnormalities, and recurrent episodes of emesis and lactic acidemia. We report female siblings compound heterozygous for two missense variants (Arg40Gln, Val245Met) in NDUFV1 with unusual presentations of this condition. The 6-year-old proband showed normal growth and neurodevelopment until recently when weight loss and recurrent vomiting were noticed and brain imaging abnormalities consistent with Complex 1 deficiency were documented. She developed lactic acidemia without a clear precipitating factor and that, incongruously, was associated with profound alkalosis with blood pH as high as 7.83. We describe management of her acute illness during a hospital admission with aggressive sodium bicarbonate and sodium acetate replacement, and eventual recognition that anxiety-related hyperventilation contributed substantially to her transient profound alkalosis. We review the complex interplay of lactic acidemia due to mitochondrial Complex 1 deficiency, metabolic acidosis from acute loss of bicarbonate, respiratory alkalosis from hyperventilation and hypocapnia, and other concomitant medical issues, as well as her distinctive neuroradiological findings. Her 14-year-old sister was diagnosed retrospectively despite an earlier initial presentation, and manifests greater neurocognitive effects, similar neuroradiological signs, but no history of acute metabolic decompensation. These cases expand the phenotypic spectrum of this rare inherited illness, provide new information about its presentation and intrafamilial variability, and offer insight relevant to management of life-threatening metabolic crises associated with this disorder.