Childhood-Onset Neurodegeneration With Progressive Microcephaly (CONPM) due to a DTYMK Homozygous Pathogenic Variant: Outlining the Phenotype of an Ultra-Rare Disease

Abstract

Childhood-onset neurodegeneration with progressive microcephaly (CONPM) is a rare autosomal recessive disorder caused by pathogenic variants in the DTYMK gene. This ultra-rare condition is characterized by progressive neurological regression, epilepsy, severe microcephaly, and global cerebral atrophy. Only four cases have been reported in the literature to date. This paper's objective is to describe the fifth globally reported case of CONPM and the first documented in a Mexican patient, confirmed through whole-exome sequencing (WES), and to compare findings with previously reported cases. Clinical evaluation, neuroimaging studies, and genetic analysis using WES followed by Sanger sequencing were performed. Clinical and genetic data were analyzed in the context of existing literature on CONPM. A 2-year-old male with progressive neurodevelopmental regression presented with severe microcephaly, epilepsy, hypertonia, and cortical and cerebellar atrophy. Genetic analysis identified a homozygous missense variant in DTYMK (NM_012145.4:c.242C>T; p.Pro81Leu). This variant is predicted to disrupt dTMP phosphorylation, a key step in the maintenance of dTTP pools required for genomic stability and neural function. This case expands the known phenotypic and genotypic spectrum of CONPM and underscores the importance of considering DTYMK variants in cases of childhood neurodegeneration with microcephaly. Further functional studies are needed to elucidate the mechanisms linking DTYMK dysfunction to neurodegeneration.