A novel homozygous variant in the POLR1A gene: a complicated hereditary spastic paraplegia (c-HSP) or a hypomyelinating leukodystrophy type-27 (HLD27) phenotype?

backgroundRNA polymerase I enzyme plays a pivotal role in the biosynthesis of 28S, 18S, and 5.8S ribosomal RNAs, which are crucial components of the protein synthesis machinery. The largest subunit of this enzyme, POLR1A, is encoded by the POLR1A gene. Homozygous variants in POLR1A cause an ultra-rare disorder known as hypomyelinating leukodystrophy type-27 (HLD27) with only four families reported worldwide to date. Here, we describe a fifth family harboring a novel homozygous variant in the POLR1A gene, presenting with atypical features and initially suspected of having complicated hereditary spastic paraplegia (c-HSP). In addition, we conducted a systematic review following the PRISMA 2020 guidelines to identify all reported cases with variants in the POLR1A gene.

resultsThe proband's clinical features were characterized in detail. Whole-exome sequencing (WES) identified a novel homozygous variant in the proband, NM_015425.6:c.2357C > T POLR1A:p.(Thr786Ile). This variant co-segregated with the disease status within the family. The systematic review identified a total of 27 variants in the POLR1A gene, three of which were linked to HLD27.

conclusionOur findings further expand the genetic and clinical spectrum of POLR1A-related disorders by identifying a novel variant and a distinct clinical manifestation characterized by a c-HSP-like phenotype, without apparent hypomyelination. Nevertheless, hypomyelination may develop as the disease progresses. Additionally, our findings raise the possibility that POLR1A variants may be related to HSP-like phenotypes. These findings underscore the critical importance of WES in the diagnosis of complicated disorders, particularly in patients with atypical or difficult-to-interpret clinical presentations.