A novel pathogenic variant m.9122T>G in MT-ATP6 presenting with neonatal hypertrophic cardiomyopathy, hyperammonemia and anaemia
2Laboratory of Molecular Medicine Unit of Muscular and Neurodegenerative Disorders Bambino Gesu Children Hospital IRCCS, Italy
Background
Complex V deficiency is a rare mitochondrial disease (MD) primarily caused by maternally inherited variants in MT-ATP6. The heteroplasmic mutant load of pathogenic variants mainly determine the wide phenotype from NARP (Neuropathy, Ataxia, Retinitis Pigmentosa) to Leigh syndrome.
Case study
We report a full-term neonate with a prenatal diagnosis of biventricular hypertrophy presenting at birth with hypoglycaemia and cardiogenic shock. Newborn screening (NBS) showed elevated C3, C5-OH and low C5-OH/citrulline ratio. Metabolic investigations revealed high ammonia, glutamine, alanine and low citrulline, positive allopurinol load test and urinary Krebs cycle intermediates. Axial hypotonia with cortical atrophy and lactate peak at MRS were reported. During the first 6 months, he developed hyperammonaemia, lactic acidosis and hyporegenerative anaemia and at 1 year, epileptic spasms, progressive cortical atrophy with reduced deep/subcortical white matter.
Results
The biochemical profile coupling MD and proximal urea cycle suggested complex V deficiency. Molecular investigation by Sanger sequencing revealed in leukocytes a homoplasmic new missense variant, m.9122T>G p.(Leu199Arg) in MT-ATP6. Using NGS this variant was present in patient’s fibroblasts at 93% of heteroplasmy; while, blood, urine and buccal swab of the mother were negative for this variant. Mitochondria from patient’s fibroblasts showed a reduction of complex V activity with either substrate used (succinate -87%, malate -70%, pyruvate+malate -61%) and a reduction of ATP6 subunit content.
Conclusions
Our study expanded the phenotype and genotype of mutations located in MT-APT6. In fact, the de novo variant m.9122T>G showed a peculiar phenotype with hyperammonemia and anaemia. So far hyperammonemia has been reported with m.8851T>C, m.8528T>C and m.8993T>G variants; while anaemia in mt.8969G>A change. Functional studies confirmed pathogenicity of the new variant with homoplasmic load in all tissues examined.
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