Mutations, Genes, and Phenotypes Related to Movement Disorders and Ataxias

Abstract

Our clinical series comprises 124 patients with movement disorders (MDs) and/or ataxia with cerebellar atrophy (CA), many of them showing signs of neurodegeneration with brain iron accumulation (NBIA). Ten NBIA genes are accepted, although isolated cases compatible with abnormal brain iron deposits are known. The patients were evaluated using standardised clinical assessments of ataxia and MDs. First, NBIA genes were analysed by Sanger sequencing and 59 patients achieved a diagnosis, including the detection of the founder mutation PANK2 p.T528M in Romani people. Then, we used a custom panel MovDisord and/or exome sequencing; 29 cases were solved with a great genetic heterogeneity (34 different mutations in 23 genes). Three patients presented brain iron deposits with Fe-sensitive MRI sequences and mutations in FBXO7, GLB1, and KIF1A, suggesting an NBIA-like phenotype. Eleven patients showed very early-onset ataxia and CA with cortical hyperintensities caused by mutations in ITPR1, KIF1A, SPTBN2, PLA2G6, PMPCA, and PRDX3. The novel variants were investigated by structural modelling, luciferase analysis, transcript/minigenes studies, or immunofluorescence assays. Our findings expand the phenotypes and the genetics of MDs and ataxias with early-onset CA and cortical hyperintensities and highlight that the abnormal brain iron accumulation or early cerebellar gliosis may resembling an NBIA phenotype.

Pure cerebellar ataxia due to bi‐allelic PRDX3 variants including recurring p.Asp202Asn

“…1 Subsequent reports brought attention to the presence of cerebellar cortical hyperintensity, T2-hyperintense formation reticularis and dentate nucleus, T1hyperintense substantia nigra as well as transversal stripes of the pons. 4,6 The present report further highlights the extent of brainstem degeneration in PRDX3 patients. 9,10 In conclusion, our study reports three novel patients with rare PRDX3-related SCAR, mainly in the Brazilian ataxia population, and hence expands the phenotypic spectrum of the disease, demonstrating that it can present with features suggestive of cerebellar cortical hyperintensities that link to early onset neurodegeneration.…”

“…Subsequently, a novel homozygous PRDX3 variant was reported in a patient with infantile‐onset severe cerebellar ataxia and peripheral neuropathy, expanding the disease's clinical spectrum 4,5 . Martínez‐Rubio et al 5 .…”

“…Subsequently, a novel homozygous PRDX3 variant was reported in a patient with infantile-onset severe cerebellar ataxia and peripheral neuropathy, expanding the disease's clinical spectrum. 4,5 Mart ınez-Rubio et al 5 showed with biochemical analysis of the PRDX3 mutation p.Asp163Glu results in an unstable structure tending to form aggregates that trigger unfolded protein responses via mitochondria and endoplasmic reticulum. More recently, two further families carrying novel homozygous PRDX3 variants were identified, following a screen of >3,500 ataxia exomes.…”

Methodological Approaches to Modeling the Pathology of the Nervous System

“…After 10-15 minutes, ataxia develops. Voluntary movements are preserved, but they are uneven, inaccurate, and the sequence of muscle contractions is disrupted [12]. Deprived of proprioceptive sensitivity, the limb rises too high, and when it descends, it hits the ground with force.…”

“…In large animals, such phenomena are not observed, since due to their significant body weight, they have greater inertia. The described disorders may be compensated for some time after the damage at the expense of other parts of the central nervous system [1,12,23].…”