Objective: Presentation of two patients with different clinical manifestations of a POLR3A-related leukodystrophy (NM_007055.4)

Background: POLR3A related leukodystrophy is an autosomal recessive disease caused by mutation in the POLR3A gene that leads to the manifestation of neurological and non-neurological signs, and it is characterised by a typical pattern of hypomyelinating leukodystrophy on brain MRI.

Method: We present two patients with early-onset disease and clinical manifestations of generalised dystonia in one and parkinsonism in the other. Both patients underwent a comprehensive evaluation including neurological, neuropsychological and other non neurological examinations. Given the unclear aetiology of the disease, we performed genetic analysis by next-generation sequencing (TruSight One panel), which revealed the presence of a biallelic pathogenic variant in POLR3A (NM_007055.4): c.1771-6 C>G, while in the second patient two heterozygous pathological variants were detected: c.1771-6C>G; c.1771-7C>G in the POLR3A gene.

Results: In the first patient, the disease started with foot dystonia, which then developed into a generalised pattern of dystonia. In addition to dystonia, dystonic head tremor are present, as well as gait and limb ataxia. Accompanying neurological signs are cognitive impairment, while short stature is due to non-neurological signs without growth hormone abnormalities. Brain MRI showed T2 hyperintensity in the midbrain. In the second patient, the disease started with instability, while the neurological findings were slowness, hypokinesia, kinetic tremor and gait ataxia with normal brain MRI.

Conclusion: POLR3A related leukodystrophy can present with a wide spectrum of clinical features, ranging from generalised dystonia to parkinsonism without specific dental and endocrine abnormalities, even in the absence of a specific pattern of hypomyelination on brain MRI, broadening the spectrum of this disorder.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/unusual-presentation-of-polr3a-associated-leukodystrophy-two-cases-reported/