POLR3A variants in hereditary spastic paraparesis and ataxia: clinical, genetic, and neuroradiological findings in a cohort of Italian patients.
Cerebellar ataxia
Hereditary spastic paraplegia
Leukodystrophy
POLR3A
Spastic ataxia
Journal
Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology
ISSN: 1590-3478
Titre abrégé: Neurol Sci
Pays: Italy
ID NLM: 100959175
Informations de publication
Date de publication:
Feb 2022
Feb 2022
Historique:
received:
26
03
2021
accepted:
03
07
2021
pubmed:
24
7
2021
medline:
28
1
2022
entrez:
23
7
2021
Statut:
ppublish
Résumé
Mutations 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.
Identifiants
pubmed: 34296356
doi: 10.1007/s10072-021-05462-1
pii: 10.1007/s10072-021-05462-1
pmc: PMC8789690
doi:
Substances chimiques
POLR3A protein, human
EC 2.7.7.6
RNA Polymerase III
EC 2.7.7.6
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
1071-1077Informations de copyright
© 2021. The Author(s).
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