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Inherited ataxia

Jingjing Li, Ruihong Liu, Huiyu Feng, Jian Zhang, Dilong Wang, Yiming Wang, Jinsheng Zeng, Yuhua Fan
Objective: Nonconvulsive status epilepticus (NCSE) is an uncommon clinical manifestation in patients with TBC1D24 mutations. In addition, NCSE has not been reported as a syndrome together with cerebellar ataxia and ophthalmoplegia. Methods: We herein report the clinical and genetic features of a four-year-old patient with NCSE, cerebellar ataxia, and ophthalmoplegia caused by hitherto unidentified TBC1D24 mutations. We performed 24-h video electroencephalogram (EEG), magnetic resonance imaging, and gene sequencing on the patient and her parents to determine the diagnosis...
2018: Frontiers in Neurology
Suran Nethisinghe, Maria Lucia Pigazzini, Sally Pemble, Mary G Sweeney, Robyn Labrum, Katarina Manso, David Moore, Jon Warner, Mary B Davis, Paola Giunti
Spinocerebellar ataxia type 1 (SCA1) is an autosomal dominant neurodegenerative disorder caused by an expansion of a polyglutamine tract within the ATXN1 gene. Normal alleles have been reported to range from 6 to 35 repeats, intermediate alleles from 36 to 38 repeats and fully penetrant pathogenic alleles have at least 39 repeats. This distribution was based on relatively few samples and the narrow intermediate range makes the accuracy of the repeat sizing crucial for interpreting and reporting diagnostic tests, which can vary between laboratories...
2018: Frontiers in Cellular Neuroscience
Aoi Nakazono, Naoko Adachi, Hideyuki Takahashi, Takahiro Seki, Daizo Hamada, Takehiko Ueyama, Norio Sakai, Naoaki Saito
Amyloid and amyloid-like protein aggregations are hallmarks of multiple, varied neurodegenerative disorders, including Alzheimer's and Parkinson's diseases. We previously reported that spinocerebellar ataxia type 14 (SCA14), a dominant-inherited neurodegenerative disease that affects cerebellar Purkinje cells, is characterized by the intracellular formation of neurotoxic amyloid-like aggregates of genetic variants of protein kinase Cγ (PKCγ). A number of protein chaperones, including heat shock protein 70 (Hsp70), promote the degradation and/or refolding of misfolded proteins and thereby prevent their aggregation...
August 9, 2018: Journal of Biological Chemistry
Mahmut Aslan, Serkan Kirik, Bilge Özgör, Serdal Güngör
Background Metachromatic leukodystrophy (MLD) is an autosomal recessively (AR) inherited disease caused by the deficiency of the enzyme arylsulfatase A (ARSA). Although MLD is the most common form of hereditary leukoencephalopathy, it is still very rare. More than 200 gene mutations have been identified in the ARSA gene. The most frequently identified mutation is the one located on chromosome 22q13.33. In the present study, new mutations are reported in two siblings of different ages and with different clinical presentations...
July 27, 2018: Journal of Pediatric Endocrinology & Metabolism: JPEM
Rachael C Cvejic, Darren R Hocking, Wei Wen, Nellie Georgiou-Karistianis, Kim M Cornish, David E Godler, Carolyn Rogers, Julian N Trollor
Fragile X-associated tremor ataxia syndrome is an inherited neurodegenerative disorder caused by premutation expansions (55-200 CGG repeats) of the FMR1 gene. There is accumulating evidence to suggest that early cognitive and brain imaging signs may be observed in some premutation carriers without motor signs of FXTAS, but few studies have examined the relationships between subcortical brain volumes and cognitive performance in this group. This study examined the relationships between caudate volume and select cognitive measures (executive function and information processing speed) in men at risk of developing FXTAS and controls with normal FMR1 alleles (<45 CGG repeats)...
July 25, 2018: Brain Imaging and Behavior
Joo Hyun Kim, Abigail Lukowicz, Wenhui Qu, Andrea Johnson, Marija Cvetanovic
Spinocerebellar ataxia type 1 (SCA1) is a fatal, dominantly inherited neurodegenerative disease caused by the expansion of CAG repeats in the Ataxin-1 (ATXN1) gene. SCA1 is characterized by balance and coordination deficits due to the predominant loss of Purkinje neurons in the cerebellum. We previously demonstrated that cerebellar astrogliosis beings during the early stages of SCA1, prior to onset of motor deficits and loss of Purkinje neurons. We communicate here that cerebellar astrogliosis contributes to SCA1 pathogenesis in a biphasic, stage of disease dependent manner...
July 25, 2018: Glia
Alejandro Leal, Sixto Bogantes-Ledezma, Arif B Ekici, Steffen Uebe, Christian T Thiel, Heinrich Sticht, Martin Berghoff, Corinna Berghoff, Bernal Morera, Michael Meisterernst, André Reis
Charcot-Marie-Tooth disease (CMT) represents a heterogeneous group of hereditary peripheral neuropathies. We previously reported a CMT locus on chromosome 19q13.3 segregating with the disease in a large Costa Rican family with axonal neuropathy and autosomal recessive pattern of inheritance (CMT2B2). We proposed a homozygous missense variant in the Mediator complex 25 (MED25) gene as causative of the disease. Nevertheless, the fact that no other CMT individuals with MED25 variants were reported to date led us to reevaluate the original family...
July 24, 2018: Neurogenetics
Paolo Aretini, Chiara Maria Mazzanti, Marco La Ferla, Sara Franceschi, Francesca Lessi, Veronica De Gregorio, Claudia Nesti, Angelo Valetto, Veronica Bertini, Benedetta Toschi, Roberta Battini, Maria Adelaide Caligo
BACKGROUND: Leigh Syndrome (LS, OMIM 256000) is an early-onset, progressive neurodegenerative disorder characterized by broad clinical and genetic heterogeneity; it is the most frequent disorder of mitochondrial energy production in children. LS inheritance is complex because patients may present mutations in mitochondrial DNA (mtDNA) or in nuclear genes, which predominantly encode proteins involved in respiratory chain structure and assembly or in coenzyme Q10 biogenesis. However, during the last 15 years, the discovery of several genetic mutations and improved knowledge of the natural history of LS has significantly increased our understanding of this mitochondrial disorder...
July 20, 2018: BMC Neurology
Renu Kumari, Deepak Kumar, Samir K Brahmachari, Achal K Srivastava, Mohammed Faruq, Mitali Mukerji
Cerebellar ataxias are a group of rare progressive neurodegenerative disorders with an average prevalence ranges from 4.8 to 13.8 in 100,000 individuals. The inherited disorders affect multiple members of the families, or a community that is endogamous or consanguineous. Presence of more than 3000 mutations in different genes with overlapping clinical symptoms, genetic anticipation and pleiotropy, as well as incomplete penetrance and variable expressivity due to modifiers pose challenges in genotype-phenotype correlation...
July 2018: Journal of Genetics
Stéphanie Valence, Emmanuelle Cochet, Christelle Rougeot, Catherine Garel, Sandra Chantot-Bastaraud, Elodie Lainey, Alexandra Afenjar, Marie-Anne Barthez, Nathalie Bednarek, Diane Doummar, Laurence Faivre, Cyril Goizet, Damien Haye, Bénédicte Heron, Isabelle Kemlin, Didier Lacombe, Mathieu Milh, Marie-Laure Moutard, Florence Riant, Stéphanie Robin, Agathe Roubertie, Pierre Sarda, Annick Toutain, Laurent Villard, Dorothée Ville, Thierry Billette de Villemeur, Diana Rodriguez, Lydie Burglen
PURPOSE: To investigate the genetic basis of congenital ataxias (CAs), a unique group of cerebellar ataxias with a nonprogressive course, in 20 patients from consanguineous families, and to identify new CA genes. METHODS: Singleton -exome sequencing on these 20 well-clinically characterized CA patients. We first checked for rare homozygous pathogenic variants, then, for variants from a list of genes known to be associated with CA or very early-onset ataxia, regardless of their mode of inheritance...
July 12, 2018: Genetics in Medicine: Official Journal of the American College of Medical Genetics
Saba Sheikhbahaei, Roya Sherkat, Nadezhda Camacho-Ordonez, Razie Khoshnevisan, Asadollah Kalantari, Mansour Salehi, Seyed Saman Nazemian, Mohammad Hossein Nasr-Esfahani, Christophe Klein
BACKGROUND: Patients with primary immunodeficiency disease (PID) who survive to adulthood and willing to have a child mostly are worried whether their disease affects their fertility and/or pregnancy and also if their child would be predisposed to PID. CASE PRESENTATION: We report the outcome of conception, pregnancy and their management in 9 families with definite diagnosis of PID. A chronic granulomatous disease subject with an uneventful pregnancy developed fungal sacral osteomyelitis few weeks after delivery...
July 11, 2018: BMC Pregnancy and Childbirth
Chiara Marzi, Stefano Ciulli, Marco Giannelli, Andrea Ginestroni, Carlo Tessa, Mario Mascalchi, Stefano Diciotti
BACKGROUND AND PURPOSE: Fractal dimension (FD) is an index of structural complexity of cortical gray matter (GM) and white matter (WM). Application of FD to pontocerebellar degeneration has revealed cerebellar changes. However, so far, possible concurrent cerebral changes and progression of changes in brain complexity have not been investigated. METHODS: We computed FD of cerebellar and cerebral cortex and WM derived from longitudinal brain MRI of patients with spinocerebellar ataxia type 2 (SCA2), which is an inherited cause of pontocerebellar degeneration...
July 5, 2018: Journal of Neuroimaging: Official Journal of the American Society of Neuroimaging
Elisabetta Indelicato, Alessandra Fanciulli, Jean-Pierre Ndayisaba, Wolfgang Nachbauer, Andreas Eigentler, Roberta Granata, Julia Wanschitz, Werner Poewe, Gregor K Wenning, Sylvia Boesch
BACKGROUND: Friedreich ataxia (FRDA) is an inherited movement disorder which manifests with progressive gait instability, sensory loss and cardiomyopathy. Peripheral neuropathy is an established feature of FRDA. At neuropathological examination, a depletion of large, myelinated axons is evident, but also unmyelinated fibers are affected which may result in a variety of sensory and autonomic signs and symptoms. Impaired temperature perception, vasomotor disturbances of lower extremities and a high prevalence of urinary symptoms have been documented in FRDA, but data from autonomic function testing in genetically confirmed cases are lacking...
June 27, 2018: Journal of Neurology
Rui Ban, Jun-Hong Guo, Chuan-Qiang Pu, Qiang Shi, Hua-Xu Liu, Yu-Tong Zhang
Background: Myoclonic epilepsy with ragged red fibers (MERRF) syndrome is characterized by myoclonus, generalized epilepsy, cerebellar ataxia, and ragged red fibers (RRFs) in the muscle. T-to-C transition at nucleotide position 14709 in the mitochondrial tRNA glutamic acid (tRNAGlu ) gene has previously been associated with maternally inherited diabetes and deafness. However, the association between MERRF and mitochondrial T14709C mutation (m.T14709C) has never been reported before. Methods: Clinical information of a 17-year-old patient was collected; muscle biopsy and next-generation sequencing (NGS) of whole mitochondrial and neuromuscular disease panel were then conducted...
July 5, 2018: Chinese Medical Journal
Matthis Synofzik, Katherine L Helbig, Florian Harmuth, Tine Deconinck, Pranoot Tanpaiboon, Bo Sun, Wenting Guo, Ruiwu Wang, Erika Palmaer, Sha Tang, G Bradley Schaefer, Janina Gburek-Augustat, Stephan Züchner, Ingeborg Krägeloh-Mann, Jonathan Baets, Peter de Jonghe, Peter Bauer, S R Wayne Chen, Ludger Schöls, Rebecca Schüle
We explored the clinico-genetic basis of spinocerebellar ataxia 29 (SCA29) by determining the frequency, phenotype, and functional impact of ITPR1 missense variants associated with early-onset ataxia (EOA). Three hundred thirty one patients from a European EOA target cohort (n = 120), US-American EOA validation cohort (n = 72), and early-onset epileptic encephalopathy (EOEE) control cohort (n = 139) were screened for de novo ITPR1 variants. The target cohort was also screened for inherited ITPR1 variants...
June 20, 2018: European Journal of Human Genetics: EJHG
D Heidelberg, S Ronsin, F Bonneville, S Hannoun, C Tilikete, F Cotton
Ataxia is a neurodegenerative disease resulting from brainstem, cerebellar, and/or spinocerebellar tracts impairments. Symptoms onset could vary widely from childhood to late-adulthood. Autosomal cerebellar ataxias are considered as one of the most complex group in neurogenetics. In addition to their genetic heterogeneity, there is an important phenotypic variability in the expression of cerebellar impairment, complicating the genetic mutation research. A pattern recognition approach using brain MRI measures of atrophy, hyperintensities and iron-induced hypointensity of the dentate nuclei, could be therefore helpful in guiding genetic research...
June 18, 2018: Journal of Neuroradiology. Journal de Neuroradiologie
Kishin Koh, Hiroyuki Ishiura, Minako Beppu, Haruo Shimazaki, Yuta Ichinose, Jun Mitsui, Satoshi Kuwabara, Shoji Tsuji, Yoshihisa Takiyama
Hereditary spastic paraplegias (HSPs) are characterized by various inherited disorders in which weakness and spasticity of the lower extremities are the predominant symptoms. Recently, HSP caused by ALDH18A1 mutations has been reported as SPG9 with autosomal dominant (SPG9A) and autosomal recessive (SPG9B) transmission. In this study, we obtained clinical and genetic findings in two Japanese families with SPG9B. One family had a novel compound heterozygous mutation (c.1321 C > T/c.1994G > A) in the ALDH18A1 gene...
June 18, 2018: Journal of Human Genetics
Solveig Montaut, Christine Tranchant, Nathalie Drouot, Gabrielle Rudolf, Claire Guissart, Julien Tarabeux, Tristan Stemmelen, Amandine Velt, Cécile Fourrage, Patrick Nitschké, Bénédicte Gerard, Jean-Louis Mandel, Michel Koenig, Jamel Chelly, Mathieu Anheim
Importance: Movement disorders are characterized by a marked genotypic and phenotypic heterogeneity, complicating diagnostic work in clinical practice and molecular diagnosis. Objective: To develop and evaluate a targeted sequencing approach using a customized panel of genes involved in movement disorders. Design, Setting and Participants: We selected 127 genes associated with movement disorders to create a customized enrichment in solution capture array...
June 18, 2018: JAMA Neurology
Hayley S McLoughlin, Lauren R Moore, Ravi Chopra, Robert Komlo, Megan McKenzie, Kate G Blumenstein, Hien Zhao, Holly B Kordasiewicz, Vikram G Shakkottai, Henry L Paulson
OBJECTIVE: Spinocerebellar ataxia type 3 (SCA3), also known as Machado-Joseph disease, is the most common dominantly inherited ataxia. Despite advances in understanding this CAG repeat/polyglutamine expansion disease, there are still no therapies to alter its progressive fatal course. Here we investigate whether an antisense oligonucleotide (ASO) targeting the SCA3 disease gene, ATXN3, can prevent molecular, neuropathological, electrophysiological and behavioral features of the disease in a mouse model of SCA3...
June 16, 2018: Annals of Neurology
Enrico Bertini, Ginevra Zanni, Eugen Boltshauser
The terminology of nonprogressive congenital ataxia (NPCA) refers to a clinically and genetically heterogeneous group of disorders characterized by congenital or early-onset ataxia, but no progression or even improvement on follow-up. Ataxia is preceded by muscular hypotonia and delayed motor (and usually language) milestones. We exclude children with prenatal, perinatal, and postnatal acquired diseases, malformations other than cerebellar hypoplasia, and defined syndromic disorders. Patients with NPCA have a high prevalence of cognitive and language impairments, in addition to increased occurrence of seizures, ocular signs (nystagmus, strabismus), behavior changes, and microcephaly...
2018: Handbook of Clinical Neurology
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