Natural History in Leukodystrophies Related to POLR3A and POLR3B Mutations: A Multicentric Survey of 21 Pediatric Cases

Objectives: POLR3 related leukodystrophy is a hypomyelinating leukodystrophy caused by mutation in POLR3A and POLR3B genes encoding, respectively, the first and second largest subunit of the RNA polymerase III complex. The objective of this study is to summarize the clinical features of these conditions and to evaluate if it is possible to identify different phenotypes and disease progression for different genotypes.

Methods: A retrospective cohort study was performed including 21 patients with POLR3 related leukodystrophy, referred to CRMR Leukofrance. Six patients with POLR3B and 15 with POLR3A mutations from 11 different hospitals were enrolled. An earlier onset of the disease was observed in patients with POLR3B mutations compared to POLR3A (50% motor delays compared to 27%, onset at 1.5 vs. 3.8 years). Progressive ataxia was present in 53% of POLR3A versus 17% of POLR3B, whereas hypotonia and delayed acquisition from the first months of life were more frequent in POLR3B (33 vs. 6.7%). During evolution, spasticity, dystonia, swallowing disorders, and vescicosphincterian disorders were more frequently observed in POLR3A mutated patients. The nonneurological manifestations of this pathology are present in the two groups without significant differences. MRI analysis showed a higher frequency of diffuse hypomyelinization in POLR3B patients, whereas POLR3A patients have preserved more frequently myelinization in the early myelinated regions.

Conclusion: These data seem to underline that when the pathology is induced by mutations in POLR3B gene, it presents a more precocious onset and half of the patients show a pattern of disease evolution more similar to a neurodevelopmental disorder, at a first stage with an abnormal development and then presenting a second phase of stagnation and a third one of degradation. On the contrary, in the disease related to POLR3A gene we find more often a normal neurological development with a later onset of neurological signs and symptoms. These differences suggest that mutations have consequences on RNA’s transcription (transfer RNA, especially ribosomal) in particular, on myelination genes in patients with POLR3B mutation and on myelin retention and stabilization genes in POLR3A mutated patients.