POLR3A-related spastic ataxia: new mutations and a look into the phenotype

Adolescent-onset spastic ataxia is a proposed novel phenotype in compound heterozygous carriers of an intronic mutation (c.1909 + 22G > A) in the POLR3A gene. Here, we present ten new cases of POLR3A -related spastic ataxia and discuss the genetic, clinical and imaging findings. Patients belonged...

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Veröffentlicht in:Journal of neurology 2020-02, Vol.267 (2), p.324-330
Hauptverfasser: Infante, Jon, Serrano-Cárdenas, Karla M., Corral‐Juan, Marc, Farré, Xavier, Sánchez, Ivelisse, de Lucas, Enrique M., García, Antonio, Martín-Gurpegui, José Luis, Berciano, José, Matilla-Dueñas, Antoni
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container_end_page 330
container_issue 2
container_start_page 324
container_title Journal of neurology
container_volume 267
creator Infante, Jon
Serrano-Cárdenas, Karla M.
Corral‐Juan, Marc
Farré, Xavier
Sánchez, Ivelisse
de Lucas, Enrique M.
García, Antonio
Martín-Gurpegui, José Luis
Berciano, José
Matilla-Dueñas, Antoni
description Adolescent-onset spastic ataxia is a proposed novel phenotype in compound heterozygous carriers of an intronic mutation (c.1909 + 22G > A) in the POLR3A gene. Here, we present ten new cases of POLR3A -related spastic ataxia and discuss the genetic, clinical and imaging findings. Patients belonged to six pedigrees with hereditary spastic paraplegia or cerebellar ataxia of unknown origin. All affected subjects presented with compound heterozygous variants, comprising c.1909 + 22G > A in combination in each pedigree with one of the following novel mutations (Thr596Met, Tyr665LeufsTer11, Glu198Ter, c.646-687_1185 + 844del). The new mutations segregated with the phenotype in all families. The phenotype combined variable cerebellar ataxia, gait and lower limb spasticity, involvement of central sensory tracts and in some cases also intention tremor. The reportedly characteristic hyperintensity along the superior cerebellar peduncle on MRI was observed in ~ 80% of the cases. Our study extends the clinical and molecular phenotype further supporting the pathogenic role of the c.1909 + 22G4A intronic mutation and identifying four novel causative mutations in POLR3A -related spastic ataxia. Certain characteristic MRI features may be useful to guide genetic diagnosis.
doi_str_mv 10.1007/s00415-019-09574-9
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Our study extends the clinical and molecular phenotype further supporting the pathogenic role of the c.1909 + 22G4A intronic mutation and identifying four novel causative mutations in POLR3A -related spastic ataxia. 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subjects Ataxia
Cerebellar ataxia
Cerebellum
Gait
Genetic screening
Genotype & phenotype
Hereditary spastic paraplegia
Magnetic resonance imaging
Medicine
Medicine & Public Health
Mutation
Neurology
Neuroradiology
Neurosciences
Original Communication
Pedigree
Phenotypes
Spasticity
Superior cerebellar peduncle
Tremor
title POLR3A-related spastic ataxia: new mutations and a look into the phenotype
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