Search

Background: Although the group of paroxysmal kinesigenic dyskinesia (PKD) genes is expanding, the molecular cause remains elusive in more than 50% of cases. Objective: The aim is to identify the missing genetic causes of PKD. Methods: Phenotypic characterization, whole exome sequencing and association test were performed among 53 PKD cases. Results: We identified four causative variants in KCNJ10, already associated with EAST syndrome (epilepsy, cerebellar ataxia, sensorineural hearing impairment and renal tubulopathy). Homozygous p.(Ile209Thr) variant was found in two brothers from a single autosomal recessive PKD family, whereas heterozygous p.(Cys294Tyr) and p.(Thr178Ile) variants were found in six patients from two autosomal dominant PKD families. Heterozygous p.(Arg180His) variant was identified in one additional sporadic PKD case. Compared to the Genome Aggregation Database v2.1.1, our PKD cohort was significantly enriched in both rare heterozygous (odds ratio, 21.6; P = 9.7 × 10−8) and rare homozygous (odds ratio, 2047; P = 1.65 × 10−6) missense variants in KCNJ10. Conclusions: We demonstrated that both rare monoallelic and biallelic missense variants in KCNJ10 are associated with PKD. © 2024 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society. [ABSTRACT FROM AUTHOR]

Background: Heterozygous GAA expansions in the FGF14 gene have been related to autosomal dominant cerebellar ataxia (SCA27B‐MIM:620174). Whether they represent a common cause of sporadic late‐onset cerebellar ataxia (SLOCA) remains to be established. Objectives: To estimate the prevalence, characterize the phenotypic spectrum, identify discriminative features, and model longitudinal progression of SCA27B in a prospective cohort of SLOCA patients. Methods: FGF14 expansions screening combined with longitudinal deep‐phenotyping in a prospective cohort of 118 SLOCA patients (onset >40 years of age, no family history of cerebellar ataxia) without a definite diagnosis. Results: Prevalence of SCA27B was 12.7% (15/118). Higher age of onset, higher Spinocerebellar Degeneration Functional Score, presence of vertigo, diplopia, nystagmus, orthostatic hypotension absence, and sensorimotor neuropathy were significantly associated with SCA27B. Ataxia progression was ≈0.4 points per year on the Scale for Assessment and Rating of Ataxia. Conclusions: FGF14 expansion is a major cause of SLOCA. Our natural history data will inform future FGF14 clinical trials. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society. [ABSTRACT FROM AUTHOR]

Infantile striatonigral degeneration is caused by a homozygous variant of the nuclear‐pore complex (NPC) gene NUP62, involved in nucleo‐cytoplasmic trafficking. By querying sequencing‐datasets of patients with dystonia and/or Leigh(‐like) syndromes, we identified 3 unrelated individuals with biallelic variants in NUP54. All variants clustered in the C‐terminal protein region that interacts with NUP62. Associated phenotypes were similar to those of NUP62‐related disease, including early‐onset dystonia with dysphagia, choreoathetosis, and T2‐hyperintense lesions in striatum. In silico and protein‐biochemical studies gave further evidence for the argument that the variants were pathogenic. We expand the spectrum of NPC component‐associated dystonic conditions with localized basal‐ganglia abnormalities. ANN NEUROL 2023;93:330–335 [ABSTRACT FROM AUTHOR]

Bi-allelic I PRKN i variants are involved in 34% to 45% of familial recessive early-onset Parkinson's diseases,[[1]] also called PARK-Parkin (MIM #600116).[3] PARK-Parkin differs from idiopathic Parkinson's disease (PD) in the age onset before 45 years, dystonia at presentation, less frequent dementia, slower progression, better levodopa-responsivity, and a limited dopaminergic neuron depletion.[[2], [4]] A vast mutational spectrum in I PRKN i has already been noticed, including all types of CNV (copy number variant) and SNV (single nucleotide variant).[5] Here, we report four affected members of a family carrying two combinations of bi-allelic I PRKN i pathogenic variants. Finally, proband II.2 and siblings II.1 and II.4 carry two different I PRKN i deletions in I trans i , whereas III.1 is compound heterozygous for paternal exon 2 deletion and maternal splicing variant. Observation of asymmetrical parkinsonism around age 55 suggested instead degenerative parkinsonism, which was then confirmed by a severe dopaminergic depletion in the Datscan. [Extracted from the article]

A small but growing body of scientific literature is emerging about clinical findings in patients with 19p13.3 microdeletion or duplication. Recently, a proximal 19p13.3 microduplication syndrome was described, associated with growth delay, microcephaly, psychomotor delay and dysmorphic features. The aim of our study was to better characterize the syndrome associated with duplications in the proximal 19p13.3 region (prox 19p13.3 dup), and to propose a comprehensive analysis of the underlying genomic mechanism. We report the largest cohort of patients with prox 19p13.3 dup through a collaborative study. We collected 24 new patients with terminal or interstitial 19p13.3 duplication characterized by array-based Comparative Genomic Hybridization (aCGH). We performed mapping, phenotype-genotype correlations analysis, critical region delineation and explored three-dimensional chromatin interactions by analyzing Topologically Associating Domains (TADs). We define a new 377 kb critical region (CR 1) in chr19: 3,116,922-3,494,377, GRCh37, different from the previously described critical region (CR 2). The new 377 kb CR 1 includes a TAD boundary and two enhancers whose common target is PIAS4. We hypothesize that duplications of CR 1 are responsible for tridimensional structural abnormalities by TAD disruption and misregulation of genes essentials for the control of head circumference during development, by breaking down the interactions between enhancers and the corresponding targeted gene., (© 2022 Wiley Periodicals LLC.)