PP12.11 – 2550: Atypical forms of 4H leukodystrophy

Abstract

Objective 4H leukodystrophy (4H) is a rare inherited disorder characterized by hypomyelination, hypodontia and hypogonadotropic hypogonadism, although dental and puberty development may be normal. The disease starts with early-onset ataxia and neurologic deterioration from the second decade. Recessive mutations in either POLR3A or POLR3B, encoding the two largest subunits of the RNA polymerase III complex, cause the disease. Recently, we identified mutation-positive patients without hypomyelination. Aim of this study was to provide further characterization of this subgroup. Methods We performed a multi-institutional cross-sectional observational study of the clinical, radiological and genotypic characteristics of patients carrying POLR3A or POLR3B mutations, but without hypomyelination on brain MRI in our database. Results Six patients from five families with mutations in either POLR3A or POLR3B were identified. We could distinguish two different presentations: three unrelated patients with progressive T2-hyperintense signal abnormalities in the internal capsule and otherwise normal MRI (group 1, mutations in POLR3A) and three patients with cerebellar atrophy and no or only mild signal changes of their supratentorial white matter (group 2, mutations in POLR3A in one family and in POLR3B in a single patient). The patients of group 1 had hypodontia, which led to the suspicion of a 4H-related disorder. The patients of group 2 had no hypodontia, but one of them had early tooth eruption at three weeks of age, prompting targeted genetic analysis. The two remaining patients were identified by whole-exome sequencing. Mutations found in all patients were compound heterozygous and included at least one mutation leading to altered splicing. Conclusion Hypomyelination is not an obligatory feature of mutations in POLR3A or POLR3B. Hypodontia may be helpful in identifying candidates, but is not obligatory, as already known from patients with classical 4H leukodystrophy. Mutations involving aberrant gene splicing seem to play an important role in these atypical presentations.