We report the clinical and biochemical findings from two unrelated patients who presented with a novel syndrome: encephalopathy, intellectual disability, severe hypotonia, chorea and optic atrophy. Whole exome sequencing (WES) uncovered a homozygous mutation in the ATP8A2 gene (NM_016529:c.1287G > T, p.K429N) in one patient and compound heterozygous mutations (c.1630G > C, p.A544P and c.1873C > T, p.R625W) in the other. Only one haploinsufficiency case and a family with a homozygous mutation in ATP8A2 gene (c.1128C > G, p.I376M) have been described so far, with phenotypes that differed slightly from the patients described herein. In conclusion, our data expand both the genetic and phenotypic spectrum associated with ATP8A2 gene mutations.

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We describe a West syndrome (WS) patient with unidentified etiology that evolved to Lennox-Gastaut syndrome. The mitochondrial respiratory chain of the patient showed a simple complex I deficiency in fibroblasts. Whole-exome sequencing (WES) uncovered two heterozygous mutations in NDUFV2 gene that were reassigned to a pseudogene. With the WES data, it was possible to obtain whole mitochondrial DNA sequencing and to identify a heteroplasmic variant in the MT-ND1 (MTND1) gene (m.3946G>A, p.E214K). The expression of the gene in patient fibroblasts was not affected but the protein level was significantly reduced, suggesting that protein stability was affected by this mutation. The lower protein level also affected assembly of complex I and supercomplexes (I/III2 /IV and I/III2 ), leading to complex I deficiency. While ATP levels at steady state under stress conditions were not affected, the amount of ROS produced by complex I was significantly increased.