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Hyperkinetic Movement Disorders
Published in Philip B. Gorelick, Fernando D. Testai, Graeme J. Hankey, Joanna M. Wardlaw, Hankey's Clinical Neurology, 2020
Morales-Briceno Hugo, Victor S.C. Fung, Annu Aggarwal, Philip Thompson
Neurodegenerative: Parkinson's disease (PD).Huntington's disease (HD).Spinocerebellar ataxia (SCA1, 2, 3, 6, 17).Dentatorubral-pallidoluysian atrophy (DRPLA).Corticobasal syndrome (CBS).Progressive supranuclear palsy (PSP).Multiple system atrophy (MSA).
Predictive genetic testing
Published in Angus Clarke, Alex Murray, Julian Sampson, Harper's Practical Genetic Counselling, 2019
Even in the triplet repeat diseases, it is highly reassuring to see the molecular confirmation of the family diagnosis in at least one relative. However rare, there will often be other genes in which mutations can lead to similar clinical features and which could therefore cause confusion. To test an at-risk patient for mutation in the wrong gene would obviously be most unhelpful, with a high risk of generating a false-negative result as the ‘wrong’ gene will usually carry no mutation. Further, if a variant in that other gene has been (falsely) identified as disease-causing in the affected parent, then the test result will be irrelevant: there will be a random relationship between the result and the actual risk of disease (if indeed the risk is Mendelian), so that false-positive, false-negative, true-positive and true-negative results will all be equally likely. Thus, testing an individual, who is at risk of dentatorubral-pallidoluysian atrophy (DRPLA), for HD would clearly be both irrelevant and unhelpful.
Caenorhabditis elegans Aging is Associated with a Decline in Proteostasis
Published in Shamim I. Ahmad, Aging: Exploring a Complex Phenomenon, 2017
Polyglutamine (polyQ) disorders are a family of nine different neurodegenerative disorders all of which are caused by an expansion of a polyQ tract, albeit in different proteins, each encoded by a cytosine-adenine-guanine (CAG) trinucleotide repeat in the corresponding gene. As such, these are heritable genetic disorders and include HD, Machado–Joseph disease (MJD), spinobulbar muscular atrophy (SBMA), dentatorubral–pallidoluysian atrophy (DRPLA), and five SCAs. For all of these diseases, the polyQ expansion destabilizes the affected protein thereby disrupting the thermodynamics of folding and causing protein misfolding and aggregation. Outside of the polyQ tract itself, each of the affected proteins in each of these diseases share no common sequences or functions. The key to disease is thus the polyQ tract, such that the age of disease onset and symptom severity is inversely proportional to the length of the polyQ tract [21–23].
Advances in the understanding of hereditary ataxia – implications for future patients
Published in Expert Opinion on Orphan Drugs, 2018
Anna Zeitlberger, Heather Ging, Suran Nethisinghe, Paola Giunti
In the last two decades, conventional sequencing techniques have gradually been replaced by next-generation sequencing (NGS). These new approaches are capable of reading huge amounts of genetic sequences in parallel [6]. NGS has undoubtedly revolutionized the field of ataxia by broadening our knowledge about the phenotypic spectrum of known ataxia-associated genes and exponentially increasing the number of novel gene discoveries (Figure 1 and Figure 2) [7,8]. To date, over 40 different disease-causing gene loci have been mapped in autosomal dominant cerebellar ataxias (ADCA) (Table 1). These genetic loci have been labeled spinocerebellar ataxia (SCA) and numbered in chronological order of their discovery. The group of eight known episodic ataxias and Dentatorubral-pallidoluysian atrophy (DRPLA) are an exception to this nomenclature. In addition, an equally high number of causative genes has been identified in recessive ataxias (Table 2). However, their classification remains a challenge due to a lack of uniform nomenclature and the vast number of recessive neurological diseases presenting with symptoms of ataxia. This is reflected by the marked variability in disorders that are included to the group of hereditary recessive ataxias in literature [9]. Although numerous, both dominant and recessive ataxias belong to the group of rare diseases. The average prevalence is 2.7 in 100,000 and 3.3 in 100,000, respectively [10]. An awareness of the great variation in prevalence of distinctive ataxic disorders that exists in different ethnical groups and geographic regions may facilitate the choice of genetic tests in clinical practice.
New discoveries in progressive myoclonus epilepsies: a clinical outlook
Published in Expert Review of Neurotherapeutics, 2018
Shweta Bhat, Subramaniam Ganesh
Dentatorubral pallidoluysian atrophy (DRPLA) is a rare autosomal dominant neurodegenerative disorder causing a form of PME due to a mutation in the ATN1 gene [111]. Predominant features of the disease are combination of ataxia, choreoathetosis, seizure, myoclonus, dementia, and psychiatric symptoms depending on the mutation dosage and age of onset. DRPLA is mostly seen in Japanese families; however, pedigrees in other parts of the world are also reported [112,113].