Cooccurrence of Two Different Genetic Diseases: A Case of Valproic Acid Hepatotoxicity in Nicolaides–Baraitser Syndrome (SMARCA2 Mutation)—Due to a POLG1-Related Effect?

Abstract

Nicolaides–Baraitser syndrome (NCBRS) is a rare disease caused by a mutation in the SMARCA2 gene. Clinical features include craniofacial dysmorphia and abnormalities of the limbs, as well as intellectual disorder and often epilepsy. Hepatotoxicity is a rare complication of the therapy with valproic acid (VPA) and a mutation of the polymerase γ (POLG) might lead to a higher sensitivity for liver hepatotoxicity. We present a patient with the coincidence of two rare diseases, the NCBRS and additionally a POLG1 mutation in combination with a liver hepatotoxicity. The co-occurrence in children for two different genetic diseases is discussed with the help of literature review.

Low‐level germline mosaicism of a novel SMARCA2 missense variant: Expanding the phenotypic spectrum and mode of genetic transmission

“…SMARCA2 is located on chromosome 9p24.3, and it encodes a component of SWI/SNF complexes, which play an important role in chromatin remodeling and regulation of downstream gene expression in neural development (Sokpor et al, 2017). To date, de novo pathogenic variants were previously reported in all affected individuals with NCBRS (Bramswig et al, 2015;Ejaz et al, 2016;Hofmeister et al, 2020;Hu et al, 2019;Ma et al, 2020;Mari et al, 2015;Sethi et al, 2019;Sousa & Hennekam, 2014;Tang et al, 2017). Nearly all disease-causing variants are missense changes and clustered in the highly conserved ATPase domain, which is critical for ATP-binding/hydrolysis and DNAbinding in transcriptional regulation (Bogershausen & Wollnik, 2018).…”

Epilepsy in Nicolaides–Baraitser Syndrome: Review of Literature and Report of 25 Patients Focusing on Treatment Aspects

“…This case has been discussed in a separate case report. 1 Under VPA, another patient showed a decrease of his carnitine level, a third showed toxic VPA blood levels after 4 years of therapy (an increase had been started after 2 years).…”

Response To: Overlapping Phenotype from Double Trouble SMARCA2 and POLG1 Variants c.2556A > C and c.3708G > T, Respectively

“…We thank Prof. Finsterer 1 for the interest in our case report 2 and his valuable comments. The patient we described is part of the doctoral thesis of Benedikt Hofmeister at the Ludwig Maximilian University Munich describing in detail 25 patients with Nicolaides-Baraitser syndrome (NBS) with proven SMARCA2 mutations.…”