POLR3A variants in hereditary spastic paraparesis and ataxia: clinical, genetic, and neuroradiological findings in a cohort of Italian patients.
Ilaria Di Donato, Antonio Gallo, Ivana Ricca, Nicola Fini, Gabriella Silvestri, Fiorella Gurrieri, Mario Cirillo, Alfonso Cerase, Gemma Natale, Federica Matrone, Vittorio Riso, Mariarosa Anna Beatrice Melone, Alessandra Tessa, Giovanna De Michele, Antonio Federico, Alessandro Filla, Maria Teresa Dotti, Filippo Maria Santorelli
Author Information
Ilaria Di Donato: Department of Medicine, Surgery and Neurosciences, University of Siena, viale Bracci, 16, 50055, Siena, Italy. didonatoila@gmail.com.
Antonio Gallo: Department of Advanced Medical and Surgical Sciences, University of Campania "Luigi Vanvitelli", Naples, Italy.
Ivana Ricca: Molecular Medicine and Neurogenetics, IRCCS Fondazione Stella Maris, via dei Giacinti 2, Calambrone, 56128, Pisa, Italy.
Nicola Fini: Neurology Unit, Department of Neurosciences, Azienda Ospedaliero Universitaria di Modena, Modena, Italy.
Mariarosa Anna Beatrice Melone: Department of Advanced Medical and Surgical Sciences, University of Campania "Luigi Vanvitelli", Naples, Italy.
Alessandra Tessa: Molecular Medicine and Neurogenetics, IRCCS Fondazione Stella Maris, via dei Giacinti 2, Calambrone, 56128, Pisa, Italy.
Giovanna De Michele: Department of Neurosciences, Reproductive and Odontostomatological Sciences, Federico II University, Naples, Italy.
Antonio Federico: Department of Medicine, Surgery and Neurosciences, University of Siena, viale Bracci, 16, 50055, Siena, Italy.
Alessandro Filla: Department of Neurosciences, Reproductive and Odontostomatological Sciences, Federico II University, Naples, Italy.
Maria Teresa Dotti: Department of Medicine, Surgery and Neurosciences, University of Siena, viale Bracci, 16, 50055, Siena, Italy.
Filippo Maria Santorelli: Molecular Medicine and Neurogenetics, IRCCS Fondazione Stella Maris, via dei Giacinti 2, Calambrone, 56128, Pisa, Italy. filippo3364@gmail.com.
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.
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