POLR3A variants in hereditary spastic paraparesis and ataxia: clinical, genetic, and neuroradiological findings in a cohort of Italian patients

Abstract

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.

Developmental regression and movement disorder as a phenotypic variant of POLR3A Mutation—Case report

“…Our patient had normal dental and gonadal appearance and function. On the contrary, in the 4H syndrome basal ganglia are spared and ataxia is a chief finding, and dystonia is not a predominant feature 12 which differ from our patient.…”

Developmental Regression and Movement Disorder as a Phenotypic Variant of POLR3A Mutation - Case Report

“…Our patient had normal dental and gonadal appearance and function. On the other hand, in the 4H syndrome basal ganglia are spared and ataxia is a chief finding, and dystonia is not a predominant feature (12) which differ from our patient. Di Donato et al reported 10 patients with POLR3A mutations, mostly the c.1909 + 22G > A variant, to describe late-onset spastic ataxia without hypomyelinating leukodystrophy, but they raise other exceptions such as seizures and non-neurological features, and concluded that further expansions of variants and phenotypic presentations should be investigated (12).…”

Skin Conditions and Movement Disorders: Hiding in Plain Sight

“…Eighty-six percent had mutations in mtDNA coding for tRNA lysine (MERRF). In addition to mitochondrial disorders, presence of lipomas and movement disorders has been reported in POLR3A-related disease, 82 discussed in more details above.…”

“…In addition, progeroid changes and movement disorders may be a prominent feature of biallelic POLR3A variants , related to the Wiedemann‐Rautenstrauch syndrome, a rare neonatal progeroid syndrome with growth and developmental retardation, lipoatrophy, a distinctive face, sparse scalp hair, prominent scalp veins, and dental anomalies. Ataxia, tremor and dystonia may be a common manifestation in these individuals 81,82 …”

“…Ataxia, tremor and dystonia may be a common manifestation in these individuals. 81,82 Hartnup disease is an autosomal recessive disorder caused by SLC6A19 mutations leading to impaired functioning of the sodium dependent B0 AT1 neutral amino acid transporter and impaired intestinal uptake and tubular reabsorption of all neutral amino acids. The disorder typically manifests with cutaneous and neurological symptoms, including a typical pellagra-like rash, light-sensitive dermatitis, intermittent cerebellar ataxia and psychiatric symptoms.…”