Author:
Di Donato Ilaria,Gallo Antonio,Ricca Ivana,Fini Nicola,Silvestri Gabriella,Gurrieri Fiorella,Cirillo Mario,Cerase Alfonso,Natale Gemma,Matrone Federica,Riso Vittorio,Melone Mariarosa Anna Beatrice,Tessa Alessandra,De Michele Giovanna,Federico Antonio,Filla Alessandro,Dotti Maria Teresa,Santorelli Filippo Maria
Abstract
AbstractMutations in POLR3A are characterized by high phenotypic heterogeneity, with manifestations ranging from severe childhood-onset hypomyelinating leukodystrophic syndromes to milder and later-onset gait disorders with central hypomyelination, with or without additional non-neurological signs. Recently, a milder phenotype consisting of late-onset spastic ataxia without hypomyelinating leukodystrophy has been suggested to be specific to the intronic c.1909 + 22G > A mutation in POLR3A. Here, we present 10 patients from 8 unrelated families with POLR3A-related late-onset spastic ataxia, all harboring the c.1909 + 22G > A variant. Most of them showed an ataxic-spastic picture, two a “pure” cerebellar phenotype, and one a “pure” spastic presentation. The non-neurological findings typically associated with POLR3A mutations were absent in all the patients. The main findings on brain MRI were bilateral hyperintensity along the superior cerebellar peduncles on FLAIR sequences, observed in most of the patients, and cerebellar and/or spinal cord atrophy, found in half of the patients. Only one patient exhibited central hypomyelination. The POLR3A mutations present in this cohort were the c.1909 + 22G > A splice site variant found in compound heterozygosity with six additional variants (three missense, two nonsense, one splice) and, in one patient, with a novel large deletion involving exons 14–18. Interestingly, this patient had the most “complex” presentation among those observed in our cohort; it included some neurological and non-neurological features, such as seizures, neurosensory deafness, and lipomas, that have not previously been reported in association with late-onset POLR3A-related disorders, and therefore further expand the phenotype.
Funder
Italian Ministry of Health
Università degli Studi di Siena
Publisher
Springer Science and Business Media LLC
Subject
Psychiatry and Mental health,Neurology (clinical),Dermatology,General Medicine
Cited by
11 articles.
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