Delineating the phenotype of PNPLA8‐related mitochondriopathies

• Published in: Clinical genetics Vol. 105; no. 1; pp. 92 - 98
• Main Authors: Abdel‐Hamid, Mohamed S., Abdel‐Salam, Ghada M. H., Abdel‐Ghafar, Sherif F., Zaki, Maha S.
• Format: Journal Article
• Language: English
• Published: Oxford, UK Blackwell Publishing Ltd 01.01.2024
• Subjects: Adult; Atrophy; Basal Ganglia; Cerebellar ataxia; Cerebellar Ataxia - genetics; Cerebellum; Child; Children; Congenital diseases; cystic encephalomalacia; degeneration of basal ganglia; early onset epileptic encephalopathy; Encephalopathy; Epilepsy; Genotype & phenotype; Humans; Lethality; Microcephaly; Microcephaly - genetics; Microencephaly; Mutation, Missense; Neurodegeneration; Peripheral neuropathy; Phenotype; Phenotypes; PNPLA8; Seizures; Substantia alba; microcephaly; degeneration of basal ganglia; early onset epileptic encephalopathy; cystic encephalomalacia; PNPLA8
• ISSN: 0009-9163; 1399-0004
• DOI: 10.1111/cge.14421

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 neuropathy 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 variant (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 features representing a spectrum with clinical features always aligning with different age of onset. Our results add the infantile onset as a new distinct phenotype of the disease showing progressive atrophy, bilateral degeneration of basal ganglia, and cystic encephalomalacia. Further, we suggest that the site of the variant rather than its type is strongly correlated with the disease onset. The clinical phenotypes of PNPLA8, despite being largely distinct from each other, exhibit a clear spectrum with clinical features always aligning with different age of onset.