Ann Clin Transl Neurol
October 2021
Whole exome sequencing and linkage analysis were performed in a three generational pedigree of Greek origin with a broad phenotypic spectrum spanning from Parkinson's disease and Parkinson's disease dementia to dementia of mixed type (Alzheimer disease and vascular dementia). We identified a novel heterozygous c.G1135T (p.
View Article and Find Full Text PDFAlzheimers Dement (Amst)
May 2021
Introduction: We investigated the frequency, neuropathology, and phenotypic characteristics of spastic paraplegia (SP) that precedes dementia in presenilin 1 () related familial Alzheimer's disease (AD).
Methods: We performed whole exome sequencing (WES) in 60 probands with hereditary spastic paraplegia (HSP) phenotype that was negative for variants in known HSP-related genes. Where mutation was identified, brain biopsy was performed.
Background: Tay-Sachs disease (TSD) is a rare autosomalrecessive genetic disorder characterized by progressive destruction of nerve cells in the brain and spinal cord. It is caused by genetic variations in the HEXA gene leading to a deficiency of β hexosaminidase A (HEXA) isoenzyme activity. This study aimed to identify causative gene variants in 3 unrelated consanguineous families presented with TSD from Pakistan and Morocco.
View Article and Find Full Text PDFJunctophilin-3 belongs to a triprotein junctional complex implicated in the regulation of neuronal excitability and involved in the formation of junctional membrane structures between voltage-gated ion channels and endoplasmic (ryanodine) reticular receptors. A monoallelic trinucleotide repeat expansion located within the junctophilin-3 gene (JPH3) has been implicated in a rare autosomal dominant (AD) late-onset (and progressive) disorder clinically resembling Huntington disease (HD), and known as HD-like 2 (HDL2; MIM# 606438). Although the exact molecular mechanisms underlying HDL2 has not yet been fully elucidated, toxic gain-of-function of the aberrant transcript (containing the trinucleotide repeat) and loss of expression of (full-length) junctophilin-3 have both been implicated in HDL2 pathophysiology.
View Article and Find Full Text PDFVariants in SETX have been implicated in recessively and dominantly inherited disorders, ataxia with oculomotor apraxia type 2 (AOA2 OMIM# 606002) and amyotrophic lateral sclerosis (ALS4, OMIM# 602433) respectively, in humans. We report two novel bi-allelic pathogenic variants in SETX in patients suffering from ataxia with oculomotor apraxia type 2, extending the allelic spectrum of the gene variants. We also discuss the pathogenicity of SETX variants in relation to the evolutionary conservation status of the affected amino acids.
View Article and Find Full Text PDFBi-allelic loss-of-function variants in genes that encode subunits of the adaptor protein complex 4 (AP-4) lead to prototypical yet poorly understood forms of childhood-onset and complex hereditary spastic paraplegia: SPG47 (AP4B1), SPG50 (AP4M1), SPG51 (AP4E1) and SPG52 (AP4S1). Here, we report a detailed cross-sectional analysis of clinical, imaging and molecular data of 156 patients from 101 families. Enrolled patients were of diverse ethnic backgrounds and covered a wide age range (1.
View Article and Find Full Text PDFHereditary spastic paraplegia (HSP) is a group of heterogeneous inherited degenerative disorders characterized by lower limb spasticity. Fifty percent of HSP patients remain yet genetically undiagnosed. The 100,000 Genomes Project (100KGP) is a large UK-wide initiative to provide genetic diagnosis to previously undiagnosed patients and families with rare conditions.
View Article and Find Full Text PDFAnn Clin Transl Neurol
September 2020
Background: Several European studies examined the role of C9orf72 repeat expansion in patients with Huntington-disease like phenotypes (HD-L). The scope of our study is to investigate the expansion frequency in a Greek HD-L cohort and the meta-analysis of all published cases. This will be of use in genetic counseling of these cases.
View Article and Find Full Text PDFAmyotroph Lateral Scler Frontotemporal Degener
August 2020
Bakground: Hereditary Spastic paraplegias (HSPs) are a clinically and genetically heterogeneous group of degenerative disorders characterized by progressive spasticity and weakness of the lower limbs. This study aimed to identify causative gene variants in two unrelated consanguineous Pakistani families presented with 2 different forms of HSP.
Methods: Whole exome sequencing (WES) was performed in the two families and variants were validated by Sanger sequencing and segregation analysis.
Deficiency of the adaptor protein complex 4 (AP-4) leads to childhood-onset hereditary spastic paraplegia (AP-4-HSP): SPG47 (AP4B1), SPG50 (AP4M1), SPG51 (AP4E1) and SPG52 (AP4S1). This study aims to evaluate the impact of loss-of-function variants in AP-4 subunits on intracellular protein trafficking using patient-derived cells. We investigated 15 patient-derived fibroblast lines and generated six lines of induced pluripotent stem cell (iPSC)-derived neurons covering a wide range of AP-4 variants.
View Article and Find Full Text PDFEmerging data have established links between paroxysmal neurological disorders or psychiatric disorder, such as migraine, ataxia, movement disorders and epilepsy. Common gene signatures such as expression, protein interaction and the associated signalling pathways link genes in these associated disorders, with the object to predict unknown disease or risk genes. In this study, we used gene interaction networks to investigate common gene signatures associated with the above phenotypes.
View Article and Find Full Text PDFMov Disord Clin Pract
November 2018
Background: The C9orf72 hexanucleotide expansion is one of the latest discovered repeat expansion disorders related to neurodegeneration. Its association with the FTD/ALS spectrum disorders is well established, and it is considered to be one of the leading related genes. It has also been reported as a possible cause of several other phenotypes, including parkinsonism and other movement disorders.
View Article and Find Full Text PDFBackground: Autosomal recessive hereditary spastic paraplegia (HSP) due to AP4M1 mutations is a very rare neurodevelopmental disorder reported for only a few patients.
Methods: We investigated a Greek HSP family using whole exome sequencing (WES).
Results: A novel AP4M1A frameshift insertion, and a very rare missense variant were identified in all three affected siblings in the compound heterozygous state (p.