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Inherited ataxia

Verónica Martínez Cerdeño, Tiffany Hong, Sarwat Amina, Mirna Lechpammer, Jeanelle Ariza, Flora Tassone, Stephen C Noctor, Paul Hagerman, Randi Hagerman
BACKGROUND: Fragile X-associated tremor/ataxia syndrome (FXTAS) is a late-onset neurodegenerative disorder associated with premutation alleles of the FMR1 gene. Expansions of more than 200 CGG repeats give rise to fragile X syndrome, the most common inherited form of cognitive impairment. Fragile X-associated tremor/ataxia syndrome is characterized by cerebellar tremor and ataxia, and the presence of ubiquitin-positive inclusions in neurons and astrocytes. It has been previously suggested that fragile X-associated tremor/ataxia syndrome is associated with an inflammatory state based on signs of oxidative stress-mediated damage and iron deposition...
December 10, 2018: Movement Disorders: Official Journal of the Movement Disorder Society
Emily Bowie, Ryan Norris, Kathryn V Anderson, Sarah C Goetz
Spinocerebellar ataxia type 11 (SCA11) is a rare, dominantly inherited human ataxia characterized by atrophy of Purkinje neurons in the cerebellum. SCA11 is caused by mutations in the gene encoding the Serine/Threonine kinase Tau tubulin kinase 2 (TTBK2) that result in premature truncations of the protein. We previously showed that TTBK2 is a key regulator of the assembly of primary cilia in vivo. However, the mechanisms by which the SCA11-associated mutations disrupt TTBK2 function, and whether they interfere with ciliogenesis were unknown...
December 10, 2018: PLoS Genetics
Alexander S Brown, Pratap Meera, Banu Altindag, Ravi Chopra, Emma M Perkins, Sharan Paul, Daniel R Scoles, Eric Tarapore, Jessica Magri, Haoran Huang, Mandy Jackson, Vikram G Shakkottai, Thomas S Otis, Stefan M Pulst, Scott X Atwood, Anthony E Oro
The genetically heterogeneous spinocerebellar ataxias (SCAs) are caused by Purkinje neuron dysfunction and degeneration, but their underlying pathological mechanisms remain elusive. The Src family of nonreceptor tyrosine kinases (SFK) are essential for nervous system homeostasis and are increasingly implicated in degenerative disease. Here we reveal that the SFK suppressor Missing-in-metastasis (MTSS1) is an ataxia locus that links multiple SCAs. MTSS1 loss results in increased SFK activity, reduced Purkinje neuron arborization, and low basal firing rates, followed by cell death...
December 7, 2018: Proceedings of the National Academy of Sciences of the United States of America
Lorenzo Nanetti, Elisa Sarto, Anna Castaldo, Stefania Magri, Alessia Mongelli, Davide Rossi Sebastiano, Laura Canafoglia, Marina Grisoli, Chiara Malaguti, Francesca Rivieri, Maria Chiara D'Amico, Daniela Di Bella, Silvana Franceschetti, Caterina Mariotti, Franco Taroni
Autosomal recessive cerebellar ataxia type 3 (ARCA3) is a rare inherited disorder caused by mutations in the ANO10 gene. The disease is characterized by slowly progressive spastic ataxia variably associated with motor neuron involvement, epilepsy, and cognitive decline. We performed mutational screening in 80 patients with sporadic or autosomal recessive adult-onset ataxia. We identified 11 ANO10 gene variants in 10 patients from 8 families (10%): 4 mutations were previously described and 7 were novel. Age at onset ranged between 27 and 53 years...
December 4, 2018: Journal of Neurology
Giulia Coarelli, Alexis Brice, Alexandra Durr
Abstract Spinocerebellar ataxias (SCAs) are rare types of cerebellar ataxia with a dominant mode of inheritance. To date, 47 SCA subtypes have been identified, and the number of genes implicated in SCAs is continually increasing. Polyglutamine (polyQ) expansion diseases ( ATXN1 /SCA1, ATXN2 /SCA2, ATXN3 /SCA3, CACNA1A /SCA6, ATXN7 /SCA7, TBP /SCA17, and ATN1 /DRPLA) are the most common group of SCAs. No preventive or curative treatments are currently available, but various therapeutic approaches, including RNA-targeting treatments, such as antisense oligonucleotides (ASOs), are being developed...
2018: F1000Research
Mario Mascalchi, Alessandra Vella
Magnetic resonance imaging (MRI), single photon emission computed tomography (SPECT) and positron emission tomography (PET) are the main instruments for neuroimaging investigation of patients with chronic ataxia. MRI has a predominant diagnostic role in the single patient, based on the visual detection of three patterns of atrophy, namely, spinal atrophy, cortical cerebellar atrophy and olivopontocerebellar atrophy, which correlate with the aetiologies of inherited or sporadic ataxia. In fact spinal atrophy is observed in Friedreich ataxia, cortical cerebellar atrophy in Ataxia Telangectasia, gluten ataxia and Sporadic Adult Onset Ataxia and olivopontocerebellar atrophy in Multiple System Atrophy cerebellar type...
2018: International Review of Neurobiology
David S Lynch, Charles Wade, Anderson Rodrigues Brandão de Paiva, Nevin John, Justin A Kinsella, Áine Merwick, Rebekah M Ahmed, Jason D Warren, Catherine J Mummery, Jonathan M Schott, Nick C Fox, Henry Houlden, Matthew E Adams, Indran Davagnanam, Elaine Murphy, Jeremy Chataway
Adult-onset leukodystrophies and genetic leukoencephalopathies comprise a diverse group of neurodegenerative disorders of white matter with a wide age of onset and phenotypic spectrum. Patients with white matter abnormalities detected on MRI often present a diagnostic challenge to both general and specialist neurologists. Patients typically present with a progressive syndrome including various combinations of cognitive impairment, movement disorders, ataxia and upper motor neuron signs. There are a number of important and treatable acquired causes for this imaging and clinical presentation...
November 22, 2018: Journal of Neurology, Neurosurgery, and Psychiatry
Shamima Rahman, William C Copeland
The POLG gene encodes the mitochondrial DNA polymerase that is responsible for replication of the mitochondrial genome. Mutations in POLG can cause early childhood mitochondrial DNA (mtDNA) depletion syndromes or later-onset syndromes arising from mtDNA deletions. POLG mutations are the most common cause of inherited mitochondrial disorders, with as many as 2% of the population carrying these mutations. POLG-related disorders comprise a continuum of overlapping phenotypes with onset from infancy to late adulthood...
November 19, 2018: Nature Reviews. Neurology
Roberta Passos Palazzo, Laura Bannach Jardim, Alexandre Bacellar, Fernanda Ramos de Oliveira, Flora Troina Maraslis, Carolina Hilgert Jacobsen Pereira, Juliana da Silva, Sharbel Weidner Maluf
Ataxi A-T elangiectasia (AT) is a multisystem, complex and rare disease inherited in an autosomal recessive manner. Homozygous individuals have a variety of pathological manifestations, however, heterozygotes only present a higher risk of developing cancer. We evaluated the background levels of DNA damage (basal damage) and cell response to bleomycin or ionizing radiation using Comet assay and the cytokinesis-block micronucleus (CBMN) test in individuals with AT, their parents and controls. To evaluate DNA repair, the challenge experiment with ionizing radiation was performed using Comet assay, and different recovery times were evaluated...
December 2018: Mutation Research
J van Gaalen, R P P W M Maas, E F Ippel, M W Elting, K Y van Spaendonck-Zwarts, S Vermeer, C Verschuuren-Bemelmans, D Timmann, Bart P van de Warrenburg
BACKGROUND: Spinocerebellar ataxias (SCAs) are a group of autosomal dominantly inherited degenerative diseases. As the pathological process probably commences years before the first appearance of clinical symptoms, preclinical carriers of a SCA mutation offer the opportunity to study the earliest stages of cerebellar dysfunction and degeneration. Eyeblink classical conditioning (EBCC) is a motor learning paradigm, crucially dependent on the integrity of the olivocerebellar circuit, and has been shown to be able to detect subtle alterations of cerebellar function, which might already be present in preclinical carriers...
November 14, 2018: Experimental Brain Research. Experimentelle Hirnforschung. Expérimentation Cérébrale
Liam S Carroll, Thomas H Massey, Mark Wardle, Kathryn J Peall
Background: Dentatorubral-pallidoluysian atrophy (DRPLA) is a rare, autosomal dominantly inherited disorder characterized by myoclonus, epilepsy, ataxia, and dementia. Diagnosis is challenging due to the heterogeneous presentation and symptomatic overlap with other spinocerebellar ataxias. Symptoms vary according to age of onset, with a mean age at onset of 31 years. A CAG repeat expansion in the ATN1 gene results in neuronal intranuclear inclusions, variable neuronal loss, and astrocytosis in the globus pallidus, dentate and red nuclei...
2018: Tremor and Other Hyperkinetic Movements
Deborah Moreira Rangel, Paulo Ribeiro Nóbrega, Maria Luiza Saraiva-Pereira, Laura Bannach Jardim, Pedro Braga-Neto
BACKGROUND: There are few studies reporting characteristics of patients with cerebellar ataxias in the Brazilian population. The aim of this study was to provide a detailed neurological description of patients with hereditary ataxia followed by a neurology outpatient service in Brazil. METHODS: Neurological and clinical evaluation of patients with hereditary ataxia was performed at a neurology service outpatient clinic of a hospital in Northeast Brazil between October 2013 and January 2015...
October 26, 2018: Parkinsonism & related Disorders
Jillian Friedrich, Holly B Kordasiewicz, Brennon O'Callaghan, Hillary P Handler, Carmen Wagener, Lisa Duvick, Eric E Swayze, Orion Rainwater, Bente Hofstra, Michael Benneyworth, Tessa Nichols-Meade, Praseuth Yang, Zhao Chen, Judit Perez Ortiz, H Brent Clark, Gülin Öz, Sarah Larson, Huda Y Zoghbi, Christine Henzler, Harry T Orr
Spinocerebellar ataxia type 1 (SCA1) is a dominantly inherited ataxia caused by expansion of a translated CAG repeat encoding a glutamine tract in the ataxin-1 (ATXN1) protein. Despite advances in understanding the pathogenesis of SCA1, there are still no therapies to alter its progressive fatal course. RNA-targeting approaches have improved disease symptoms in preclinical rodent models of several neurological diseases. Here, we investigated the therapeutic capability of an antisense oligonucleotide (ASO) targeting mouse Atxn1 in Atxn1154Q/2Q-knockin mice that manifest motor deficits and premature lethality...
November 2, 2018: JCI Insight
Yulu Gu, Jikang Shi, Shuang Qiu, Yichun Qiao, Xin Zhang, Yi Cheng, Yawen Liu
BACKGROUND: Ataxia telangiectasia mutated (ATM) gene plays a key role in response to DNA lesions and is related to the invasion and metastasis of malignancy. Epidemiological studies have indicated associations between ATM rs1801516 polymorphism and different types of cancer, but their results are inconsistent. To further evaluate the effect of ATM rs1801516 polymorphism on cancer risk, we conducted this meta-analysis. METHODS: Studies were identified according to specific inclusion criteria by searching PubMed, Web of Science, and Embase databases...
November 1, 2018: BMC Cancer
Jana Buzkova, Joni Nikkanen, Sofia Ahola, Anna H Hakonen, Ksenia Sevastianova, Topi Hovinen, Hannele Yki-Järvinen, Kirsi H Pietiläinen, Tuula Lönnqvist, Vidya Velagapudi, Christopher J Carroll, Anu Suomalainen
Mitochondrial disorders (MDs) are inherited multi-organ diseases with variable phenotypes. Inclusion body myositis (IBM), a sporadic inflammatory muscle disease, also shows mitochondrial dysfunction. We investigated whether primary and secondary MDs modify metabolism to reveal pathogenic pathways and biomarkers. We investigated metabolomes of 25 mitochondrial myopathy or ataxias patients, 16 unaffected carriers, six IBM and 15 non-mitochondrial neuromuscular disease (NMD) patients and 30 matched controls. MD and IBM metabolomes clustered separately from controls and NMDs...
October 29, 2018: EMBO Molecular Medicine
Maria R Bokhari, Faisal Inayat, Javeria Sardar, Syed Rizwan A Bokhari
Van der Knaap disease or megalencephalic leukoencephalopathy with subcortical cysts (MLC) is a rare, inherited, autosomal recessive disorder. It is characterised by macrocephaly and slowly progressive ataxia, spasticity, and cognitive decline. The usual age of onset is described from birth to infancy. MLC predominantly occurs in some ethnicities where consanguinity is common. This disease is caused by mutations in the gene, which encodes a novel protein, MLC1. The characteristic MRI findings include leukodystrophy and subcortical cysts that yield diagnostic clue in most of the cases...
November 2018: Journal of the College of Physicians and Surgeons—Pakistan: JCPSP
Suhas Ganesh, Husayn Ahmed P, Ravi Kumar Nadella, Ravi Prabhakar More, Manasa Sheshadri, Biju Viswanath, Mahendra Rao, Sanjeev Jain, Odity Mukherjee
AIM: Severe Mental Illnesses, such as bipolar disorder and schizophrenia, are highly heritable, and have a complex pattern of inheritance. Genome wide association studies detect a part of the heritability, which can be attributed to common genetic variation. Examination of rare variants with Next Generation Sequencing may add to the understanding of genetic architecture of SMIs. METHODS: We analyzed 32 ill subjects from 8 multiplex families; and 33 healthy individuals by whole exome sequencing...
October 27, 2018: Psychiatry and Clinical Neurosciences
Annalisa Agostini, Daniela Marchetti, Claudia Izzi, Isabella Cocco, Lorenzo Pinelli, Patrizia Accorsi, Rosaria Iascone Maria, Lucio Giordano
We report the case of two siblings presenting with failure to thrive in early years, progressive microcephaly, moderate intellectual disability, developmental delay, ataxic gait and seizures with an identical EEG pattern, and minimal cerebellar atrophy. We ruled out the syndromic and metabolic causes of microcephaly and subsequently conducted a panel of genetic diagnostic tests, including the clinical exome sequencing which revealed compound heterozygous mutations in MED 17 gene in both patients. p.Glu16fs was found to be inherited from the mother and p...
October 22, 2018: American Journal of Medical Genetics. Part B, Neuropsychiatric Genetics
Vaibhav Bhatia, Lourdes Valdés-Sánchez, Daniel Rodriguez-Martinez, Shom Shankar Bhattacharya
Background: Photoreceptors, light-sensing neurons in retina, are central to vision. Photoreceptor cell death (PCD) is observed in most inherited and acquired retinal dystrophies. But the underlying molecular mechanism of PCD is unclear. Photoreceptors are sturdy neurons that survive high oxidative and phototoxic stress, which are known threats to genome stability. Unexpectedly, DNA damage response in mice photoreceptors is compromised; mainly due to loss of crucial DNA repair proteins, ATM and 53BP1. We tried to understand the molecular function of ATM and 53BP1 in response to oxidative stress and how suppression of DNA repair response in mice retina affect photoreceptor cell survival...
2018: F1000Research
Gunay Balta, Turkan Patiroglu, Fatma Gumruk
A unique consanguineous family with 2 genomic instability disorders, Fanconi anemia and ataxia telangiectasia, revealed exceptional combinations of null mutations in the FANCA and ATM genes. Two siblings with Fanconi anemia had novel homozygous consecutive microdeletions (c.1361-1370delCCTCCTTTGG, c.1374delC) adjoined to upstream 65 nucleotide direct tandem repeats and deletion hotspot motifs in the FANCA gene. The sibling with ataxia telangiectasia revealed a homozygous p.Arg2993Stop (c.8977C>T) null mutation in the ATM gene...
October 18, 2018: Journal of Pediatric Hematology/oncology
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