1,720,985 research outputs found
Genetic characterization and genotype-phenotype correlation of cerebellar and brainstem congenital defects
Full text linkPhenotypic spectrum of alpha-synuclein mutations. New insights from patients and cellular models
No full textThe identification of the p.A53T mutation in the SNCA gene encoding alpha-synuclein (alpha-syn), as causative of autosomal dominant Parkinson disease (PD) represented a fundamental milestone, which paved the way to the extremely prolific field of PD genetics. Despite being the oldest player in this field and only a rare cause of inherited PD, research on alpha-syn has remained incredibly active over nearly twenty decades, leading to identify alpha-syn aggregation as a key mechanism in PD pathogenesis. The past two years have witnessed new exciting findings, with the discovery of at least three novel pathogenic mutations (p.H50Q, p.G51D and p.A53E) causative of complex parkinsonian phenotypes, and the identification of additional patients carrying "old" SNCA mutations (p.A53T, p.A30P, p.E46K and whole gene multiplications), which has allowed to further expand their phenotypic spectrum. This review aims at providing a clinical and functional update on the most recent findings in alpha-syn genetics, at the same time discussing novel avenues of SNCA research such as those on somatic mutations and epigenetic mechanisms
Very mild features of dysequilibrium syndrome associated with a novel VLDLR missense mutation
No full textDysequilibrium syndrome (DES) is a non-progressive congenital ataxia characterized by severe intellectual deficit, truncal ataxia and markedly delayed, quadrupedal or absent ambulation. Recessive loss-of-function mutations in the very low density lipoprotein receptor (VLDLR) gene represent the most common cause of DES. Only two families have been reported harbouring homozygous missense mutations, both with a similarly severe phenotype. We report an Italian girl with very mild DES caused by the novel homozygous VLDLR missense mutation p.(C419Y). This unusually benign phenotype possibly relates to a less disruptive effect of the mutation, falling within a domain (EGF-B) not predicted as crucial for the protein function
Posterior Cortical Atrophy phenotype in a GBA N370S mutation carrier: a case report
No full textGlucocerebrosidase (GBA) heterozygous variants are the most important genetic risk factor for the development of alpha-synucleinopathies (i.e., Parkinson's disease and Dementia with Lewy Bodies). Herein, we report for the first time on a patient with a clinical diagnosis of Posterior Cortical Atrophy, carrier of the common GBA heterozygous variant N370S (c.1226A > G)
The Contursi family 20 years later: Intrafamilial variability in a kindred with A53T mutation of SCNA gene
No full textProgressive Supranuclear Palsy-Like Phenotype in a GBA E326K Mutation Carrier
Full text linkMutations in the beta‐glucocerebrosidase gene (GBA ), encoding the lysosomal enzyme that is deficient in Gaucher's disease (GD), are important and common risk factors for Parkinson's disease (PD) and Lewy body dementia (LBD; i.e., α‐synucleinopathies). PD patients with GBA mutations have younger age at onset and are more likely to develop cognitive dysfunction. There are approximately 300 known GBA mutations and determining accurate exact genotype‐phenotype correlations is challenging. In general, GBA mutations were found to variably influence PD risk according to their impact on the protein function. The GBA variant, E326K, has long been considered a polymorphism, given that homozygous individuals do not develop GD. However, this variant was found to reduce GBA enzymatic activity in vitro and mildly increase the risk to develop PD (OR:1.7), with frequent development of associated dementia.
The impact of GBA mutations on the risk to develop tauopathies is less defined, given that previous studies failed to report a significant association with PSP and corticobasal degeneration. Yet, more recent data suggest that the clinical phenotype of GBA‐associated neurodegeneration is more heterogeneous than previously assumed, including phenotypes distinct from α‐synucleinopathies.
Herein, we report on a patient with an unusual phenotype characterized by supranuclear vertical gaze palsy at onset with late emergence of postural instability carrier of the GBA E326K variant
Generation of the human induced pluripotent stem cell (hiPSC) line PSMi006-A from a patient affected by an autosomal recessive form of long QT syndrome type 1
No full textWe generated human induced pluripotent stem cells (hiPSCs) from dermal fibroblasts of a 40 years old female patient homozygous for the mutation c.535 G > A p.G179S on the KCNQ1 gene, causing a severe form of autosomal recessive Long QT Syndrome type 1 (AR-LQT1). The hiPSCs, generated using classical approach of the four retroviruses enconding the reprogramming factors OCT4, SOX2, cMYC and KLF4, display pluripotent stem cell characteristics, and differentiate into cell lineages of all three germ layers: endoderm, mesoderm and ectoderm
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