Delineating the phenotype of PNPLA8-related mitochondriopathies

Pathogenic variants in PNPLA8 have been described either with congenital onset displaying congenital microcephaly, early onset epileptic encephalopathy and early lethality or childhood neurodegeneration with progressive microcephaly. Moreover, a phenotype comprising adulthood onset cerebellar ataxia and peripheral neuropa-thy was also reported. To our knowledge, only six patients with biallelic variants in PNPLA8 have been reported so far. Here, we report the clinical and molecular characterizations of three additional patients in whom exome sequencing identified a loss of function variant (c.1231C>T, p.Arg411Ter) in Family I and a missense var-iant (c.1559T>A, p.Val520Asp) in Family II in PNPLA8. Patient 1 presented with the congenital form of the disease while Patients 2 and 3 showed progressive microcephaly, infantile onset seizures, progressive cortical atrophy, white matter loss, bilateral degeneration of basal ganglia, and cystic encephalomalacia. Therefore, our results add the infantile onset as a new distinct phenotype of the disease and suggest that the site of the variant rather than its type is strongly correlated with the disease onset. In addition, these conditions demonstrate some overlapping fea-tures representing a spectrum with clinical features always aligning with different age of onset.

Automated summary

Pathogenic variants in the PNPLA8 gene have been linked to congenital microcephaly, early onset epileptic encephalopathy, neurodegeneration, and cerebellar ataxia. This study identified two new variants in PNPLA8 in three patients, expanding the understanding of the disease phenotype. The findings suggest that the location of the variant, rather than its type, is strongly associated with the onset of the disease.