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Inherited ataxia

Ewelina Elert-Dobkowska, Iwona Stepniak, Wioletta Krysa, Karolina Ziora-Jakutowicz, Maria Rakowicz, Anna Sobanska, Jacek Pilch, Dorota Antczak-Marach, Jacek Zaremba, Anna Sulek
Hereditary spastic paraplegias (HSPs) are clinically and genetically heterogeneous neurodegenerative disorders. Numerous genes linked to HSPs, overlapping phenotypes between HSP subtypes and other neurodegenerative disorders and the HSPs' dual mode of inheritance (both dominant and recessive) make the genetic diagnosis of HSPs complex and difficult. Out of the original HSP cohort comprising 306 index cases (familial and isolated) who had been tested according to "traditional workflow/guidelines" by Multiplex Ligation-dependent Probe Amplification (MLPA) and Sanger sequencing, 30 unrelated patients (all familial cases) with unsolved genetic diagnoses were tested using next-generation sequencing (NGS)...
February 19, 2019: Neurogenetics
Dhruv Gohel, Lakshmi Sripada, Paresh Prajapati, Kritarth Singh, Milton Roy, Darshan Kotadia, Flora Tassone, Nicolas Charlet-Berguerand, Rajesh Singh
Fragile X-associated tremor/ataxia syndrome (FXTAS) is an inherited neurodegenerative disorder caused by an expansion of 55 to 200 CGG repeats (premutation) in FMR1. These CGG repeats are Repeat Associated non-ATG (RAN) translated into a small and pathogenic protein, FMRpolyG. The cellular and molecular mechanisms of FMRpolyG toxicity are unclear. Various mitochondrial dysfunctions have been observed in FXTAS patients and animal models. However, the causes of these mitochondrial alterations are not well understood...
February 13, 2019: Biochimica et biophysica acta. Molecular basis of disease
Clévio Nobrega, José M Codesso, Liliana Mendonça, Luis Pereira de Almeida
Machado-Joseph disease (MJD) or spinocerebellar ataxia type 3 (SCA3) is an autosomal dominantly-inherited neurodegenerative disorder caused by the over-repetition of a CAG codon in the MJD1 gene. This expansion translates into a long polyglutamine tract that confers a toxic gain-of-function to the mutant protein - ataxin-3, leading to neurodegeneration in specific brain regions. No treatment able to modify the disease progression is available. However, we and others have previously shown that specific silencing mutant ataxin-3 by RNA interference with viral vectors is a promising therapeutic strategy for MJD...
February 14, 2019: Human Gene Therapy
Ming-Ming Zhao, Liang-Shu Feng, Shuai Hou, Ping-Ping Shen, Li Cui, Jia-Chun Feng
BACKGROUND: Gerstmann-Sträussler-Scheinker (GSS) disease is an inherited prion disease that is clinically characterized by the early onset of progressive cerebellar ataxia. The incidence of GSS is extremely low and it is particularly rare in China. Therefore, clinicians may easily confuse this disease with other diseases that also cause ataxia, resulting in its under-diagnosis or misdiagnosis. CASE SUMMARY: Here, we report the first case of genetically diagnosed GSS disease in Northeast China...
February 6, 2019: World Journal of Clinical Cases
Dana M Bis-Brewer, Matt C Danzi, Stefan Wuchty, Stephan Züchner
Inherited axonopathies represent a spectrum of disorders unified by the common pathological mechanism of length-dependent axonal degeneration. Progressive axonal degeneration can lead to both Charcot-Marie-Tooth type 2 (CMT2) and Hereditary Spastic Paraplegia (HSP) depending on the affected neurons: peripheral motor and sensory nerves or central nervous system axons of the corticospinal tract and dorsal columns, respectively. Inherited axonopathies display an extreme degree of genetic heterogeneity of Mendelian high-penetrance genes...
February 8, 2019: Scientific Reports
Ching-Yu Chuang, Chih-Chao Yang, Bing-Wen Soong, Chun-Ying Yu, Shu-Hwa Chen, Hsiang-Po Huang, Hung-Chih Kuo
Spinocerebellar ataxias 2 and 3 (SCA2 and SCA3) are dominantly inherited neurodegenerative diseases caused by expansion of polyglutamine-encoding CAG repeats in the affected genes. The etiology of these disorders is known to involve widespread loss of neuronal cells in the cerebellum, however, the mechanisms that contribute to cell death are still elusive. Here we established SCA2 and SCA3 induced pluripotent stem cells (iPSCs) and demonstrated that SCA-associated pathological features can be recapitulated in SCA-iPSC-derived neurons...
February 4, 2019: Scientific Reports
Emily Hanson, Mark Sheldon, Brenda Pacheco, Mohammed Alkubeysi, Veena Raizada
Friedreich's ataxia (FRDA), which occurs in 1/50000 live births, is the most prevalent inherited neuromuscular disorder. Nearly all FRDA patients develop cardiomyopathy at some point in their lives. The clinical manifestations of FRDA include ataxia of the limbs and trunk, dysarthria, diabetes mellitus, and cardiac diseases. However, the broad clinical spectrum makes FRDA difficult to identify. The diagnosis of FRDA is based on the presence of suspicious clinical factors, the use of the Harding criteria and, more recently, the use of genetic testing for identifying the expansion of a triplet nucleotide sequence...
January 26, 2019: World Journal of Cardiology
Peter Rudge, Zane Jaunmuktane, Harpreet Hyare, Matthew Ellis, Martin Koltzenburg, John Collinge, Sebastian Brandner, Simon Mead
A common presentation of inherited prion disease is Gerstmann-Sträussler-Scheinker syndrome, typically presenting with gait ataxia and painful dysaesthesiae in the legs evolving over 2-5 years. The most frequent molecular genetic diagnosis is a P102L mutation of the prion protein gene (PRNP). There is no explanation for why this clinical syndrome is so distinct from Creutzfeldt-Jakob disease, and biomarkers of the early stages of disease have not been developed. Here we aimed, first, at determining if quantitative neurophysiological assessments could predict clinical diagnosis or disability and monitor progression and, second, to determine the neuropathological basis of the initial clinical and neurophysiological findings...
January 28, 2019: Brain: a Journal of Neurology
Ivana Ricca, Federica Morani, Giacomo Maria Bacci, Claudia Nesti, Roberto Caputo, Alessandra Tessa, Filippo Maria Santorelli
Autosomal recessive spastic ataxia of Charlevoix-Saguenay (ARSACS) is an early-onset neurodevelopmental disorder characterized by the association of spastic ataxia and sensorimotor neuropathy. Additional features include retinal changes and cognitive impairment. Today, next-generation sequencing (NGS) techniques are allowing the rapid identification of a growing number of missense variants, even in less typical forms of the disease, but the pathogenic significance of these changes is often difficult to establish on the basis of classic bioinformatics criteria and genotype/phenotype correlations...
January 24, 2019: Neurogenetics
Alessandro Corti, Raina Sota, Matteo Dugo, Raffaele A Calogero, Benedetta Terragni, Massimo Mantegazza, Silvana Franceschetti, Michela Restelli, Patrizia Gasparini, Daniele Lecis, Krystyna H Chrzanowska, Domenico Delia
Ataxia Telangiectasia (A-T) is neurodegenerative syndrome caused by inherited mutations inactivating the ATM kinase, a master regulator of the DNA damage response (DDR). What makes neurons vulnerable to ATM loss remains unclear. In this study we assessed on human iPSC-derived neurons whether the abnormal accumulation of DNA-Topoisomerase 1 adducts (Top1ccs) found in A-T impairs transcription elongation, thus favoring neurodegeneration. Furthermore, whether neuronal activity-induced immediate early genes (IEGs), a process involving the formation of DNA breaks, is affected by ATM deficiency...
January 24, 2019: Scientific Reports
Austin Ferro, Carrie Sheeler, Juao-Guilherme Rosa, Marija Cvetanovic
Microglia, the resident macrophages of the central nervous system (CNS), critically influence neural function during development and in adulthood. Microglia are also profoundly sensitive to insults to the brain to which they respond with process of activation that includes spectrum of changes in morphology, function and gene expression. Ataxias are a class of neurodegenerative diseases characterized by motor discoordination and predominant cerebellar involvement. In case of inherited forms of ataxia, mutant proteins are expressed throughout the brain and it is unclear why cerebellum is particularly vulnerable...
January 17, 2019: Journal of Molecular Biology
Carmela Scuderi, Lucia Saccuzzo, Mirella Vinci, Lucia Castiglia, Ornella Galesi, Michele Salemi, Teresa Mattina, Eugenia Borgione, Santina Città, Corrado Romano, Marco Fichera
In recent years, chromosomal microarray analysis has permitted the discovery of rearrangements underlying several neurodevelopmental disorders and still represents the first diagnostic test for unexplained neurodevelopmental disabilities. Here we report a family of consanguineous parents showing psychiatric disorders and their two sons both affected by intellectual disability, ataxia, and behavioral disorder. SNP/CGH array analysis in this family demonstrated in both siblings a biallelic duplication inherited from the heterozygous parents, disrupting the ADGRB3 gene...
January 18, 2019: European Journal of Human Genetics: EJHG
Flávio Moura Rezende Filho, Michael H Parkinson, José Luiz Pedroso, Roy Poh, Ingrid Faber, Charles Marques Lourenço, Wilson Marques Júnior, Marcondes Cavalcante França Junior, Fernando Kok, Juliana M Ferraz Sallum, Paola Giunti, Orlando Graziani Póvoas Barsottini
BACKGROUND: Autosomal recessive spastic ataxia of Charlevoix-Saguenay (ARSACS) is an important form of inherited ataxia with a varied clinical spectrum. Detailed studies of phenotype and genotype are necessary to improve diagnosis and elucidate this disorder pathogenesis. OBJECTIVE AND METHODS: To investigate the clinical phenotype, retinal architecture, neuroimaging features and genetic profile of Brazilian patients with ARSACS, we performed neurological and ophthalmological evaluation in thirteen Brazilian patients with molecularly confirmed ARSACS, and examined their mutation profiles...
December 23, 2018: Parkinsonism & related Disorders
Phillip G D Ward, Ian H Harding, Thomas G Close, Louise A Corben, Martin B Delatycki, Elsdon Storey, Nellie Georgiou-Karistianis, Gary F Egan
BACKGROUND: Friedreich ataxia is a recessively inherited, progressive neurological disease characterized by impaired mitochondrial iron metabolism. The dentate nuclei of the cerebellum are characteristic sites of neurodegeneration in the disease, but little is known of the longitudinal progression of abnormalities in these structures. METHODS: Using in vivo magnetic resonance imaging, including quantitative susceptibility mapping, we investigated changes in iron concentration and volume in the dentate nuclei in individuals with Friedreich ataxia (n = 20) and healthy controls (n = 18) over a 2-year period...
January 9, 2019: Movement Disorders: Official Journal of the Movement Disorder Society
Diana Angelika Olszewska, E M Fallon, G M Pastores, K Murphy, A Blanco, T Lynch, S M Murphy
SCA 17 is a rare, autosomal dominant disorder caused by TBP gene CAG/CAA repeat expansion. Ataxia and dementia are common. The presence of frontal dysfunction at outset of the disease may mimic frontotemporal dementia (FTD). Parkinsonism, chorea, dystonia, and pyramidal signs may occur. We report an Irish family with autosomal dominant partially penetrant frontal dementia with cerebellar atrophy due to SCA17 and present detailed neuropsychological assessment for the first time. A 44-year-old doctor presented with 18-month history of behavioral problems...
January 8, 2019: Cerebellum
Rayssa Leal Borges-Medeiros, Laura Durão Ferreira, João Ricardo Mendes de Oliveira
Primary familial brain calcification (PFBC) is a rare neurodegenerative disorder characterized by symmetrical and bilateral brain calcification. It is typically inherited as an autosomal dominant disorder, and de novo variants have also been described. Interestingly, just recent studies have reported the first autosomal recessive PFBC-causative gene. PFBC patients exhibit high clinical heterogeneity including Parkinsonism, dystonia, ataxia, depression, and migraine. Mice studies, an important research tool, have been a breakthrough in increasing the understanding of PFBC's main signs and symptoms, and many findings reported in these mice have been subsequently reported in patients...
January 3, 2019: Journal of Molecular Neuroscience: MN
Ilse Eidhof, Bart P van de Warrenburg, Annette Schenck
BACKGROUND: Genetic forms of ataxia are a heterogenous group of degenerative diseases of the cerebellum. Many causative genes have been identified. We aimed to systematically investigate these genes to better understand ataxia pathophysiology. METHODS: A manually curated catalogue of 71 genes involved in disorders with progressive ataxias as a major clinical feature was subjected to an integrated gene ontology, protein network and brain gene expression profiling analysis...
December 27, 2018: Journal of Medical Genetics
Tanveer Jilani, Mohammad Perwaiz Iqbal
Mild to moderate vitamin E deficiency because of inadequate consumption of vitamin E-rich foods and intestinal fat malabsorption is common in growing children, women of reproductive age and elderly South Asian population. Severe vitamin E deficiency may lead to peripheral and motor neurodegenerative diseases (e.g ataxia and motor skeletal myopathy), impaired immune response and free radical-induced hemolytic anemias. Vitamin E insufficiency and/or deficiency status in the general Pakistani population has not been sufficiently investigated...
November 2018: Pakistan Journal of Medical Sciences Quarterly
Ankit Chhoda, Lingeng Lu, Barbara M Clerkin, Harvey Risch, James J Farrell
Pancreatic ductal adenocarcinoma (PDAC) has a 5-year survival rate of only 8% and is estimated to be the second leading cause of cancer-related deaths by 2021. Prior convention held that screening for PDAC would not be beneficial; however, a deeper understanding of the carcinogenesis pathway supports a potential window of opportunity among the target population. Screening for PDAC is not a standard practice among the general population because of its low incidence. However, screening may be beneficial for individuals with familial history, chronic diseases with genetic predispositions, or inherited cancer syndromes, such as hereditary breast ovarian cancer syndrome, hereditary pancreatitis, Peutz-Jeghers syndrome, familial atypical multiple mole melanoma, Lynch syndrome (hereditary nonpolyposis colorectal cancer), ataxia telangiectasia, and Li-Fraumeni syndrome, all of which have been associated with an increased risk of developing PDAC...
January 2019: American Journal of Pathology
Cinthia Aguilera, Elisabeth Gabau, Steve Laurie, Neus Baena, Sophia Derdak, Núria Capdevila, Ariadna Ramirez, Veronica Delgadillo, Maria Jesus García-Catalan, Carme Brun, Miriam Guitart, Anna Ruiz
BACKGROUND: Patients affected by Angelman syndrome (AS) present severe intellectual disability, lack of speech, ataxia, seizures, abnormal electroencephalography (EEG), and a characteristic behavioral phenotype. Around 10% of patients with a clinical diagnosis of AS (AS-like) do not have an identifiable molecular defect. Some of these patients harbor alternative genetic defects that present overlapping features with AS. METHODS: Trio whole-exome sequence was performed on patient and parent's DNA extracted from peripheral blood...
December 11, 2018: Molecular Genetics & Genomic Medicine
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