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Pandolfo, Massimo. "Friedreich ataxia: clinical and genetic aspects". Neuromuscular Disorders 7, n.º 6-7 (septiembre de 1997): 465. http://dx.doi.org/10.1016/s0960-8966(97)87318-x.
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Kumar, D. "Genetic aspects of congenital cerebellar ataxia". Indian Journal of Pediatrics 53, n.º 6 (noviembre de 1986): 761–73. http://dx.doi.org/10.1007/bf02748571.
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Martins Junior, Carlos Roberto, Fabrício Castro de Borba, Alberto Rolim Muro Martinez, Thiago Junqueira Ribeiro de Rezende, Iscia Lopes Cendes, José Luiz Pedroso, Orlando Graziani Povoas Barsottini y Marcondes Cavalcante França Júnior. "Twenty-five years since the identification of the first SCA gene: history, clinical features and perspectives for SCA1". Arquivos de Neuro-Psiquiatria 76, n.º 8 (agosto de 2018): 555–62. http://dx.doi.org/10.1590/0004-282x20180080.
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ABSTRACT Spinocerebellar ataxias (SCA) are a clinically and genetically heterogeneous group of monogenic diseases that share ataxia and autosomal dominant inheritance as the core features. An important proportion of SCAs are caused by CAG trinucleotide repeat expansions in the coding region of different genes. In addition to genetic heterogeneity, clinical features transcend motor symptoms, including cognitive, electrophysiological and imaging aspects. Despite all the progress in the past 25 years, the mechanisms that determine how neuronal death is mediated by these unstable expansions are still unclear. The aim of this article is to review, from an historical point of view, the first CAG-related ataxia to be genetically described: SCA 1.
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Tamega, Abdoulaye, Landoure Guida, Seybou Hassane Diallo, Coulibaly Thomas, Toumany Coulibaly, Lassana Cisse, H. Fischbeck Kenneth y O. Cheick Guinto. "Spinocerebellar Ataxia Type 3 (SCA3): Clinical and genetic aspects in Mali". Revue Neurologique 178 (abril de 2022): S48. http://dx.doi.org/10.1016/j.neurol.2022.02.228.
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Capelli, Leonardo Pires, Márcia Rúbia Rodrigues Gonçalves, Claudia C. Leite, Egberto R. Barbosa, Ricardo Nitrini y Angela M. Vianna-Morgante. "The fragile x-associated tremor and ataxia syndrome (FXTAS)". Arquivos de Neuro-Psiquiatria 68, n.º 5 (octubre de 2010): 791–98. http://dx.doi.org/10.1590/s0004-282x2010000500023.
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FXTAS (Fragile X-associated tremor and ataxia syndrome) is a late- onset neurodegenerative disorder affecting mainly men, over 50 years of age, who are carriers of the FMR1 gene premutation. The full mutation of this gene causes the fragile X syndrome (FXS), the most common cause of inherited mental retardation. Individuals affected by FXTAS generally present intention tremor and gait ataxia that might be associated to specific radiological and/or neuropathological signs. Other features commonly observed are parkinsonism, cognitive decline, peripheral neuropathy and autonomic dysfunction. Nearly a decade after its clinical characterization, FXTAS is poorly recognized in Brazil. Here we present a review of the current knowledge on the clinical, genetic and diagnostic aspects of the disease.
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Bertholon, P., S. Chabrier, F. Riant, E. Tournier-Lasserve y R. Peyron. "Episodic ataxia type 2: unusual aspects in clinical and genetic presentation. Special emphasis in childhood". Journal of Neurology, Neurosurgery & Psychiatry 80, n.º 11 (28 de octubre de 2009): 1289–92. http://dx.doi.org/10.1136/jnnp.2008.159103.
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Barca, Emanuele, Valentina Emmanuele, Salvatore DiMauro, Antonio Toscano y Catarina M. Quinzii. "Anti-Oxidant Drugs: Novelties and Clinical Implications in Cerebellar Ataxias". Current Neuropharmacology 17, n.º 1 (5 de diciembre de 2018): 21–32. http://dx.doi.org/10.2174/1570159x15666171109125643.
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Background:Hereditary cerebellar ataxias are a group of disorders characterized by heterogeneous clinical manifestations, progressive clinical course, and diverse genetic causes. No disease modifying treatments are yet available for many of these disorders. Oxidative stress has been recurrently identified in different progressive cerebellar diseases, and it represents a widely investigated target for treatment. </P><P> Objective: To review the main aspects and new perspectives of antioxidant therapy in cerebellar ataxias ranging from bench to bedside. </P><P> Method: This article is a summary of the state-of-the-art on the use of antioxidant molecules in cerebellar ataxia treatments. It also briefly summarizes aspects of oxidative stress production and general characteristics of antioxidant compounds. </P><P> Results: Antioxidants represent a vast category of compounds; old drugs have been extensively studied and modified in order to achieve better biological effects. Despite the vast body of literature present on the use of antioxidants in cerebellar ataxias, for the majority of these disorders conclusive results on the efficacy are still missing.Conclusion:Antioxidant therapy in cerebellar ataxias is a promising field of investigations. To achieve the success in identifying the correct treatment more work needs to be done. In particular, a combined effort is needed by basic scientists in developing more efficient molecules, and by clinical researchers together with patients communities, to run clinical trials in order to identify conclusive treatments strategies.
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Rojas, Pilar, Rosa de Hoz, Manuel Cadena, Elena Salobrar-García, José A. Fernández-Albarral, Inés López-Cuenca, Lorena Elvira-Hurtado et al. "Neuro-Ophthalmological Findings in Friedreich’s Ataxia". Journal of Personalized Medicine 11, n.º 8 (23 de julio de 2021): 708. http://dx.doi.org/10.3390/jpm11080708.
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Friedreich ataxia (FRDA) is a progressive neurodegenerative disease caused by a severe autosomal recessive genetic disorder of the central nervous (CNS) and peripheral nervous system (PNS), affecting children and young adults. Its onset is before 25 years of age, with mean ages of onset and death between 11 and 38 years, respectively. The incidence is 1 in 30,000–50,000 persons. It is caused, in 97% of cases, by a homozygous guanine-adenine-adenine (GAA) trinucleotide mutation in the first intron of the frataxin (FXN) gene on chromosome 9 (9q13–q1.1). The mutation of this gene causes a deficiency of frataxin, which induces an altered inflow of iron into the mitochondria, increasing the nervous system’s vulnerability to oxidative stress. The main clinical signs include spinocerebellar ataxia with sensory loss and disappearance of deep tendon reflexes, cerebellar dysarthria, cardiomyopathy, and scoliosis. Diabetes, hearing loss, and pes cavus may also occur, and although most patients with FRDA do not present with symptomatic visual impairment, 73% present with clinical neuro-ophthalmological alterations such as optic atrophy and altered eye movement, among others. This review provides a brief overview of the main aspects of FRDA and then focuses on the ocular involvement of this pathology and the possible use of retinal biomarkers.
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Di Domenico, Enea Gino, Elena Romano, Paola Del Porto y Fiorentina Ascenzioni. "Multifunctional Role of ATM/Tel1 Kinase in Genome Stability: From the DNA Damage Response to Telomere Maintenance". BioMed Research International 2014 (2014): 1–17. http://dx.doi.org/10.1155/2014/787404.
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The mammalian protein kinase ataxia telangiectasia mutated (ATM) is a key regulator of the DNA double-strand-break response and belongs to the evolutionary conserved phosphatidylinositol-3-kinase-related protein kinases. ATM deficiency causes ataxia telangiectasia (AT), a genetic disorder that is characterized by premature aging, cerebellar neuropathy, immunodeficiency, and predisposition to cancer. AT cells show defects in the DNA damage-response pathway, cell-cycle control, and telomere maintenance and length regulation. Likewise, inSaccharomyces cerevisiae, haploid strains defective in theTEL1gene, the ATM ortholog, show chromosomal aberrations and short telomeres. In this review, we outline the complex role of ATM/Tel1 in maintaining genomic stability through its control of numerous aspects of cellular survival. In particular, we describe how ATM/Tel1 participates in the signal transduction pathways elicited by DNA damage and in telomere homeostasis and its importance as a barrier to cancer development.
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Vinante, Elena, Elena Colombo, Gabriella Paparella, Michela Martinuzzi y Andrea Martinuzzi. "Respiratory Function in Friedreich’s Ataxia". Children 9, n.º 9 (29 de agosto de 2022): 1319. http://dx.doi.org/10.3390/children9091319.
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Background: Friedreich’s ataxia is an inherited, rare, progressive disorder of children and young adults. It is characterized by ataxia, loss of gait, scoliosis, cardiomyopathy, dysarthria and dysphagia, with reduced life expectancy. Alterations of respiratory dynamics and parameters are frequently observed. However, in the literature there are few, dated studies with small cohorts. Our study aims to make an objective analysis of the respiratory condition of both early and late stage FRDA patients, looking for correlations with the motor, skeletal, speech and genetic aspects of this condition. Materials and methods: This retrospective observational study is based on the collection of clinical and instrumental respiratory data of 44 subjects between 13 and 51 years attending a tertiary rehabilitation centre in northern Italy. The analysis was carried out using Pearson’s correlation test, ANOVA test and post hoc tests. Results: Data show the presence of a recurrent pattern of respiratory dysfunction of a restrictive type, with reduction in forced vital capacity and of flow and pressure parameters. The severity of the respiratory condition correlates with the disease severity (measured with disease-specific scales), with pneumophonic alterations and with the severity of the thoracic scoliotic curve. Conclusions: Respiratory function is impaired at various degrees in FRDA. The complex condition of inco-ordination and hyposthenia in FRDA affects daytime and night-time respiratory efficiency. We believe that the respiratory deficit and the inefficiency of cough are indeed a clinical problem deserving consideration, especially in the context of the concomitant postural difficulty and the possible presence of dysphagia. Therefore, the rehabilitation project for the subject with FRDA should also consider the respiratory function.
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Yang, Lili, Xiaoli Shu, Shujiong Mao, Yi Wang, Xiaonan Du y Chaochun Zou. "Genotype–Phenotype Correlations in Angelman Syndrome". Genes 12, n.º 7 (28 de junio de 2021): 987. http://dx.doi.org/10.3390/genes12070987.
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Angelman syndrome (AS) is a rare neurodevelopmental disease that is caused by the loss of function of the maternal copy of ubiquitin–protein ligase E3A (UBE3A) on the chromosome 15q11–13 region. AS is characterized by global developmental delay, severe intellectual disability, lack of speech, happy disposition, ataxia, epilepsy, and distinct behavioral profile. There are four molecular mechanisms of etiology: maternal deletion of chromosome 15q11–q13, paternal uniparental disomy of chromosome 15q11–q13, imprinting defects, and maternally inherited UBE3A mutations. Different genetic types may show different phenotypes in performance, seizure, behavior, sleep, and other aspects. AS caused by maternal deletion of 15q11–13 appears to have worse development, cognitive skills, albinism, ataxia, and more autistic features than those of other genotypes. Children with a UBE3A mutation have less severe phenotypes and a nearly normal development quotient. In this review, we proposed to review genotype–phenotype correlations based on different genotypes. Understanding the pathophysiology of the different genotypes and the genotype–phenotype correlations will offer an opportunity for individualized treatment and genetic counseling. Genotype–phenotype correlations based on larger data should be carried out for identifying new treatment modalities.
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Di Stefano, Vincenzo, Marianna Gabriella Rispoli, Noemi Pellegrino, Alessandro Graziosi, Eleonora Rotondo, Christian Napoli, Daniela Pietrobon, Filippo Brighina y Pasquale Parisi. "Diagnostic and therapeutic aspects of hemiplegic migraine". Journal of Neurology, Neurosurgery & Psychiatry 91, n.º 7 (19 de mayo de 2020): 764–71. http://dx.doi.org/10.1136/jnnp-2020-322850.
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Hemiplegic migraine (HM) is a clinically and genetically heterogeneous condition with attacks of headache and motor weakness which may be associated with impaired consciousness, cerebellar ataxia and intellectual disability. Motor symptoms usually last <72 hours and are associated with visual or sensory manifestations, speech impairment or brainstem aura. HM can occur as a sporadic HM or familiar HM with an autosomal dominant mode of inheritance. Mutations in CACNA1A, ATP1A2 and SCN1A encoding proteins involved in ion transport are implicated. The pathophysiology of HM is close to the process of typical migraine with aura, but appearing with a lower threshold and more severity. We reviewed epidemiology, clinical presentation, diagnostic assessment, differential diagnosis and treatment of HM to offer the best evidence of this rare condition. The differential diagnosis of HM is broad, including other types of migraine and any condition that can cause transitory neurological signs and symptoms. Neuroimaging, cerebrospinal fluid analysis and electroencephalography are useful, but the diagnosis is clinical with a genetic confirmation. The management relies on the control of triggering factors and even hospitalisation in case of long-lasting auras. As HM is a rare condition, there are no randomised controlled trials, but the evidence for the treatment comes from small studies.
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Arruda, Walter O., Luiz F. B. Torres, Anne lombes, Salvatore Dimauro, Belkiss A. Cardoso, Hélio A. G. Teive, Duilton de Paola y Ricardo R. Seixas. "Mitochondrial myopathy and myoclonic epilepsy". Arquivos de Neuro-Psiquiatria 48, n.º 1 (marzo de 1990): 32–43. http://dx.doi.org/10.1590/s0004-282x1990000100006.
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The authors describe a family (mother, son and two daughters) with mitochondrial myopathy. The mother was asymptomatic. Two daughters had lactic acidosis and myoclonic epilepsy, mild dementia, ataxia, weakness and sensory neuropathy. The son suffered one acute hemiplegic episode due to an ischemic infarct in the right temporal region. All the patients studied had hypertension. EEG disclosed photomyoclonic response in the proband patient. Muscle biopsy disclosed ragged-red fibers and abnormal mitochondria by electron microscopy. Biochemical analysis showed a defect of cytochrome C oxidase in mitochondria isolated from skeletal muscle. Several clinical and genetic aspects of the mitochondrial encephalomyopathies are discussed.
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Kumar, D. y W. R. Timperley. "The clinical, pathological and genetic aspects of sporadic late onset cerebellar ataxia: observations on a series of ten patients". Acta Neurologica Scandinavica 77, n.º 3 (marzo de 1988): 181–86. http://dx.doi.org/10.1111/j.1600-0404.1988.tb05892.x.
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Abuhusain, Hazem y Veejay Bagga. "Redefining a Rare CNS Tumour Through Targeted Genetic Sequencing". Neuro-Oncology 24, Supplement_4 (1 de octubre de 2022): iv15—iv16. http://dx.doi.org/10.1093/neuonc/noac200.068.
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Abstract AIMS Isolated cerebellar vermis lesions in adults is a rare location and entity with few literature case reports detailing gangliogliomas and gangliocytomas. Using targeted genetic sequencing, traditional histological diagnosis can be refined further, with a clear impact on prognosis as well as possible genetic counselling implications. METHOD A single case of cerebellar vermis lesion, identified incidentally through imaging of a neck nodule, with subtle features of ataxia and mild impairment of initiation of speech. Sub-total resection of lesion underwent standard histopathological work-up, followed by targeted genetic sequencing to obtain an integrated diagnosis. RESULTS Histological assessment identified atypical ganglion cells labelled with Synaptophysin on immunohistochemistry. Features closely resembled dysplastic cerebellar gangliocytoma (Lhermitte-Duclos Disease). Further targeted sequencing showed no evidence of IDH1, IDH2, TERT promoter, or histone mutation, however, BRAF mutation was present, supporting an alternate diagnosis of ganglioglioma. CONCLUSION Precision medicine is facilitated with advanced diagnostic techniques. This redefines categorisation of some CNS tumours, particularly rare entities. Techniques are especially valuable to individual patient management as they can have a direct impact on aspects of clinical work-up, prognosis, follow-up, and in some cases, genetic counselling.
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Harding, A. E. "Degenerative ataxias: Genetic aspects". Movement Disorders 7, S1 (1992): 5. http://dx.doi.org/10.1002/mds.870070506.
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Rad, Abolfazl, Umut Altunoglu, Rebecca Miller, Reza Maroofian, Kiely N. James, Ahmet Okay Çağlayan, Maryam Najafi et al. "MAB21L1 loss of function causes a syndromic neurodevelopmental disorder with distinctive cerebellar, ocular, craniofacial and genital features (COFG syndrome)". Journal of Medical Genetics 56, n.º 5 (28 de noviembre de 2018): 332–39. http://dx.doi.org/10.1136/jmedgenet-2018-105623.
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BackgroundPutative nucleotidyltransferase MAB21L1 is a member of an evolutionarily well-conserved family of the male abnormal 21 (MAB21)-like proteins. Little is known about the biochemical function of the protein; however, prior studies have shown essential roles for several aspects of embryonic development including the eye, midbrain, neural tube and reproductive organs.ObjectiveA homozygous truncating variant in MAB21L1 has recently been described in a male affected by intellectual disability, scrotal agenesis, ophthalmological anomalies, cerebellar hypoplasia and facial dysmorphism. We employed a combination of exome sequencing and homozygosity mapping to identify the underlying genetic cause in subjects with similar phenotypic features descending from five unrelated consanguineous families.ResultsWe identified four homozygous MAB21L1 loss of function variants (p.Glu281fs*20, p.Arg287Glufs*14 p.Tyr280* and p.Ser93Serfs*48) and one missense variant (p.Gln233Pro) in 10 affected individuals from 5 consanguineous families with a distinctive autosomal recessive neurodevelopmental syndrome. Cardinal features of this syndrome include a characteristic facial gestalt, corneal dystrophy, hairy nipples, underdeveloped labioscrotal folds and scrotum/scrotal agenesis as well as cerebellar hypoplasia with ataxia and variable microcephaly.ConclusionThis report defines an ultrarare but clinically recognisable Cerebello-Oculo-Facio-Genital syndrome associated with recessive MAB21L1 variants. Additionally, our findings further support the critical role of MAB21L1 in cerebellum, lens, genitalia and as craniofacial morphogenesis.
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Angeloni, Cristina, Martina Gatti, Cecilia Prata, Silvana Hrelia y Tullia Maraldi. "Role of Mesenchymal Stem Cells in Counteracting Oxidative Stress—Related Neurodegeneration". International Journal of Molecular Sciences 21, n.º 9 (7 de mayo de 2020): 3299. http://dx.doi.org/10.3390/ijms21093299.
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Neurodegenerative diseases include a variety of pathologies such as Alzheimer’s disease, Parkinson’s disease, Huntington’s disease, amyotrophic lateral sclerosis, and so forth, which share many common characteristics such as oxidative stress, glycation, abnormal protein deposition, inflammation, and progressive neuronal loss. The last century has witnessed significant research to identify mechanisms and risk factors contributing to the complex etiopathogenesis of neurodegenerative diseases, such as genetic, vascular/metabolic, and lifestyle-related factors, which often co-occur and interact with each other. Apart from several environmental or genetic factors, in recent years, much evidence hints that impairment in redox homeostasis is a common mechanism in different neurological diseases. However, from a pharmacological perspective, oxidative stress is a difficult target, and antioxidants, the only strategy used so far, have been ineffective or even provoked side effects. In this review, we report an analysis of the recent literature on the role of oxidative stress in Alzheimer’s and Parkinson’s diseases as well as in amyotrophic lateral sclerosis, retinal ganglion cells, and ataxia. Moreover, the contribution of stem cells has been widely explored, looking at their potential in neuronal differentiation and reporting findings on their application in fighting oxidative stress in different neurodegenerative diseases. In particular, the exposure to mesenchymal stem cells or their secretome can be considered as a promising therapeutic strategy to enhance antioxidant capacity and neurotrophin expression while inhibiting pro-inflammatory cytokine secretion, which are common aspects of neurodegenerative pathologies. Further studies are needed to identify a tailored approach for each neurodegenerative disease in order to design more effective stem cell therapeutic strategies to prevent a broad range of neurodegenerative disorders.
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Liyanage, Marek, Zoë Weaver, Carrolee Barlow, Allen Coleman, Daniel G. Pankratz, Stacie Anderson, Anthony Wynshaw-Boris y Thomas Ried. "Abnormal rearrangement within the α/δ T-cell receptor locus in lymphomas from Atm-deficient mice". Blood 96, n.º 5 (1 de septiembre de 2000): 1940–46. http://dx.doi.org/10.1182/blood.v96.5.1940.
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Abstract Atm-deficient mice (Atm−/−) recapitulate many aspects of the ataxia telangiectasia (AT) syndrome, including the susceptibility to tumors of lymphoid origin. To investigate the mechanism of tumorigenesis, we have examined a panel of 8 thymic lymphomas from Atm−/− mice. AllAtm−/− tumors are of thymic lymphoblastoid origin, display an immature CD3− and CD4+/CD8+ phenotype, and arise coincident with V(D)J recombination. Cytogenetically, all tumors are diploid or near diploid but exhibit multiple chromosome aberrations with an average of 4 abnormal chromosomes per tumor. All the tumors revealed chromosome 14 rearrangements precisely at the T-cell receptorα/δ(Tcrα/δ) locus, suggesting the involvement of V(D)J recombination in these translocations. In addition, 11.5% ofAtm−/− peripheral T cells showed chromosome 14 translocations, suggesting that rearrangements at theTcrα/δ locus occur early during tumor development in the absence of ATM. However, additional genetic aberrations are required for tumorigenesis. For example, translocations involving chromosome 12, often with chromosome 14 (more than 60%), and partial or complete trisomy of chromosome 15, with copy number increases of the c-myc oncogene were frequently observed. These observations suggest that ATM is required for normal rearrangement of the Tcrα/δ locus but not for V(D)J recombination at other loci. The mechanisms that lead to tumorigenesis may be due to the involvement of ATM in monitoring double-stranded DNA breaks.
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Liyanage, Marek, Zoë Weaver, Carrolee Barlow, Allen Coleman, Daniel G. Pankratz, Stacie Anderson, Anthony Wynshaw-Boris y Thomas Ried. "Abnormal rearrangement within the α/δ T-cell receptor locus in lymphomas from Atm-deficient mice". Blood 96, n.º 5 (1 de septiembre de 2000): 1940–46. http://dx.doi.org/10.1182/blood.v96.5.1940.h8001940_1940_1946.
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Atm-deficient mice (Atm−/−) recapitulate many aspects of the ataxia telangiectasia (AT) syndrome, including the susceptibility to tumors of lymphoid origin. To investigate the mechanism of tumorigenesis, we have examined a panel of 8 thymic lymphomas from Atm−/− mice. AllAtm−/− tumors are of thymic lymphoblastoid origin, display an immature CD3− and CD4+/CD8+ phenotype, and arise coincident with V(D)J recombination. Cytogenetically, all tumors are diploid or near diploid but exhibit multiple chromosome aberrations with an average of 4 abnormal chromosomes per tumor. All the tumors revealed chromosome 14 rearrangements precisely at the T-cell receptorα/δ(Tcrα/δ) locus, suggesting the involvement of V(D)J recombination in these translocations. In addition, 11.5% ofAtm−/− peripheral T cells showed chromosome 14 translocations, suggesting that rearrangements at theTcrα/δ locus occur early during tumor development in the absence of ATM. However, additional genetic aberrations are required for tumorigenesis. For example, translocations involving chromosome 12, often with chromosome 14 (more than 60%), and partial or complete trisomy of chromosome 15, with copy number increases of the c-myc oncogene were frequently observed. These observations suggest that ATM is required for normal rearrangement of the Tcrα/δ locus but not for V(D)J recombination at other loci. The mechanisms that lead to tumorigenesis may be due to the involvement of ATM in monitoring double-stranded DNA breaks.
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Honti, Viktor y L�szl� V�csei. "Genetic and molecular aspects of spinocerebellar ataxias". Neuropsychiatric Disease and Treatment 1, n.º 2 (2005): 125–33. http://dx.doi.org/10.2147/nedt.1.2.125.61044.
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Shuvaev, A. N., O. S. Belozor, M. V. Smolnikova, D. A. Yakovleva, Andr N. Shuvaev, O. M. Kazantseva, E. A. Pozhilenkova, O. I. Mozhei y S. Kasparov. "Population genetics of spinoсerebellar ataxias caused by polyglutamine expansions". Vavilov Journal of Genetics and Breeding 23, n.º 4 (7 de julio de 2019): 473–81. http://dx.doi.org/10.18699/vj19.516.
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Hereditary disorders of the neuronal system are some of the most important problems of medicine in the XXI century. The most interesting representatives of this group are highly prevalent polyglutamine spinocerebellar ataxias (SCAs). It has a basement for quick progression of expansion among different groups all over the World. These diseases are SCA1, 2, 3, 6, 7 and 17, which phenotypically belong to one group due to similarities in clinics and genetics. The substrate of these genetic conditions is CAG trinucleotide repeat of Ataxin genes which may expand in the course of reproduction. For this reason a characteristic feature of these diseases is not only an increase in patient numbers, but also a qualitative change in the progression of their neurological symptoms. All these aspects are reflected in the structure of the incidence of polyglutamine SCAs, both at the global level and at the level of individual population groups. However, most scientific reports that describe the population genetics of polyglutamine SCAs are limited to quantitative indicators of a specific condition in a certain area, while the history of the occurrence and principles of the distribution of polyglutamine SCAs are poorly understood. This prevents long-term predictions of the dynamics of the disease and development of strategies for controlling the spread of mutations in the populations. In this paper we make a detailed analysis of the polyglutamine SCAs population genetics, both in the whole world and specifically in theRussian Federation. We note that for a better analysis it would be necessary to cover a wider range of populations in Africa, Asia andSouth America, which will be possible with the development of new methods for molecular genetics. Development of new methods of detection of polyglutamine SCAs will allow the scientists to better understand how they lead to the brain disease, the means of their spread in the population and to develop better methods for therapy and prevention of these diseases.
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Furtado, Sarah, Shyamal Das y Oksana Suchowersky. "A review of the inherited ataxias: recent advances in genetic, clinical and neuropathologic aspects". Parkinsonism & Related Disorders 4, n.º 4 (diciembre de 1998): 161–69. http://dx.doi.org/10.1016/s1353-8020(98)00030-3.
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de Lange, Titia. "Shelterin-Mediated Telomere Protection". Annual Review of Genetics 52, n.º 1 (23 de noviembre de 2018): 223–47. http://dx.doi.org/10.1146/annurev-genet-032918-021921.
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For more than a decade, it has been known that mammalian cells use shelterin to protect chromosome ends. Much progress has been made on the mechanism by which shelterin prevents telomeres from inadvertently activating DNA damage signaling and double-strand break (DSB) repair pathways. Shelterin averts activation of three DNA damage response enzymes [the ataxia-telangiectasia-mutated (ATM) and ataxia telangiectasia and Rad3-related (ATR) kinases and poly(ADP-ribose) polymerase 1 (PARP1)], blocks three DSB repair pathways [classical nonhomologous end joining (c-NHEJ), alternative (alt)-NHEJ, and homology-directed repair (HDR)], and prevents hyper-resection at telomeres. For several of these functions, mechanistic insights have emerged. In addition, much has been learned about how shelterin maintains the telomeric 3′ overhang, forms and protects the t-loop structure, and promotes replication through telomeres. These studies revealed that shelterin is compartmentalized, with individual subunits dedicated to distinct aspects of the end-protection problem. This review focuses on the current knowledge of shelterin-mediated telomere protection, highlights differences between human and mouse shelterin, and discusses some of the questions that remain.
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Paneque, H. M., A. L. Prieto, R. R. Reynaldo, M. T. Cruz, F. N. Santos, M. L. Almaguer, P. L. Velázquez y B. L. Heredero. "Psychological Aspects of Presymptomatic Diagnosis of Spinocerebellar Ataxia Type 2 in Cuba". Public Health Genomics 10, n.º 3 (2007): 132–39. http://dx.doi.org/10.1159/000101754.
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Eveillard, Marion, Myriam Chevalier, Thomas Besnard, Benjamin Cogne, Alice Kuster, Stephane Bezieau, Marie C. Bene y Claire Beneteau. "Polymorphonuclears Display a New Type of Abnormal Cytologic Granules (Chediak Higashi-Like) in a Very Rare Syndrome Linked to a Biallelic Defect of WDR81". Blood 128, n.º 22 (2 de diciembre de 2016): 1331. http://dx.doi.org/10.1182/blood.v128.22.1331.1331.
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Abstract A twelve years-old girl was admitted at the pediatric emergency unit for a severe pleuro-pneumopathy. She had a long history of recurrent infections in a complex neurological context. Since birth, she had suffered from an epileptic encephalopathy with West syndrome, severe microcephaly and spastic tetraplegia. Her neurological development was extremely impaired: she was not able to neither hold her head nor develop any voluntary hand use. Moreover, she had a precocious puberty and a progressive worsening of her neurological status. She is bedridden, has very poor visual contact and does not speak. Brain magnetic resonance imaging (MRI) examination has evidenced a severe microcephaly, without gyral anomalies, cerebral atrophy predominating in the frontal lobes, hypoplasia of the corpus callosum and dysmyelination. Her older sister and parents are healthy and there is no history of consanguinity in the family. During the infection mentioned above, the only anomaly at complete blood count (CBC) was an excess of monocytes. Yet, and although the CBC instrument had not indicated any alarm for neutrophils, abnormal granules were observed microscopically in polymorphonuclears on the blood smear (fig. 1). The coarse and purplish granules were toluidine-negative, myeloperoxidase-positive and only present in the polymorphonuclear lineage. The large vacuoles in these cells, also seen in monocytes, are related to the infectious condition of the patient in this context of pleuro-pneumopathy. There was no anomaly of the lymphocytes, and specifically no image recalling storage disease. Although previous CBC had not led to the identification of these granules, they were systematically investigated for, at high magnification, afterwards, always observed but seemed to increase during each infectious episode. Their appearance suggests a coalescence of smaller granules during infection. A bone marrow aspiration was performed as the patient underwent surgery for severe scoliosis, at distance from any infectious episode. Abnormal granules were present at all stages of neutrophil maturation (fig. 2). Nobody in the family presents these abnormal granules. Yet, investigations were performed in search of a congenital syndrome or storage disease: metabolic balance, amino acids chromatography in blood and urine, functional analyses of polymorphonuclears, karyotype, CGH array. No anomaly was disclosed. A skin biopsy looking for inclusions allowed to exclude lipofuscinose. Several other investigations were performed which excluded a lysosomal storage disease. A whole exome analysis was then decided for the child, parents and sister after obtaining informed consent from the parents. This allowed to discover mutations on both alleles ofthe WDR81 gene in the propositus: a deletion leading to a frame shift in exon 3 and a substitution generating a missense in exon 9 (c.3820_3835del p.Pro1274Thrfs*56 and c.5453G>T p.Gly1818Val respectively). The c.3820_3835del deletion was inherited by the father and the c.5453G>T mutation was inherited by the mother. The mutations were confirmed by Sanger sequencing and segregated with the expected pattern of autosomal-recessive inheritance in all available family members. This gene has previously been shown to be associated with cerebral ataxia, intellectual disability and quadrupedal locomotion in patients with homozygous mutations in consanguineous families. Moreover, a murine model with mutation of this gene showed tremor and ataxic gait. Expression of WDR81 was found in neuron of central nervous system included Purkinje cells, photoreceptor cells. All these aspects are consistent with the clinical features of the patient, the severity of her disease being possibly related to the fact that both alleles of the WDR81 gene carry a different mutation. This also suggests that the double genetic defect observed in the WDR81 in this child is responsible for the peculiar granules appearing early during myeloid maturation. Interestingly, the WDR81 gene contains a BEACH domain on its N terminal portion. This domain was described in the BEIGE protein and the highly homologous CHS protein which are involved in Chediak-Higashi syndromes. Although the patient has none of the phenotypic nor immune characteristics of a Chediak-Higashi syndrome, it is highly likely that involvement of the WDR81 gene is responsible for the formation of such pseudo Chediak abnormal granules. Disclosures No relevant conflicts of interest to declare.
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Ijim, Fadoua, Mehdi El Kourchi y Soukaina Wakrim. "The Molar Tooth Sign of Brain Mri: A Case Report of Joubert Syndrome". Scholars Journal of Medical Case Reports 10, n.º 9 (9 de septiembre de 2022): 879–82. http://dx.doi.org/10.36347/sjmcr.2022.v10i09.006.
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Joubert syndrome is a rare genetic disorder of autosomal recessive inheritance characterized by congenital malformation of the brainstem and agenesis or hypoplasia of the cerebellar vermis resulting in respiratory disorders, nystagmus, hypotonia, ataxia and delayed motor development. Magnetic resonance imaging allows the diagnosis to be made by demonstrating the "molar tooth sign". We report the observation of an infant aged 1 year 4 months, from a 2nd degree consanguineous marriage, hospitalized for seizures. On examination, she presented with hypotonia. She had abnormal eye movements such as nystagmus. The cerebral magnetic resonance image revealed hypoplasia of the cerebellar vermis and enlargement of the superior cerebellar peduncles with a "molar tooth" aspect in favor of a Joubert syndrome. The evolution was marked by the installation of a delay in psychomotor development.
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Veneri, Giacomo, Antonio Federico y Alessandra Rufa. "Evaluating the Influence of Motor Control on Selective Attention through a Stochastic Model: The Paradigm of Motor Control Dysfunction in Cerebellar Patient". BioMed Research International 2014 (2014): 1–13. http://dx.doi.org/10.1155/2014/162423.
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Attention allows us to selectively process the vast amount of information with which we are confronted, prioritizing some aspects of information and ignoring others by focusing on a certain location or aspect of the visual scene. Selective attention is guided by two cognitive mechanisms: saliency of the image (bottom up) and endogenous mechanisms (top down). These two mechanisms interact to direct attention and plan eye movements; then, the movement profile is sent to the motor system, which must constantly update the command needed to produce the desired eye movement. A new approach is described here to study how the eye motor control could influence this selection mechanism in clinical behavior: two groups of patients (SCA2 and late onset cerebellar ataxia LOCA) with well-known problems of motor control were studied; patients performed a cognitively demanding task; the results were compared to a stochastic model based on Monte Carlo simulations and a group of healthy subjects. The analytical procedure evaluated some energy functions for understanding the process. The implemented model suggested that patients performed an optimal visual search, reducing intrinsic noise sources. Our findings theorize a strict correlation between the “optimal motor system” and the “optimal stimulus encoders.”
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OLIVER, Peter L. y Kay E. DAVIES. "Analysis of human neurological disorders using mutagenesis in the mouse". Clinical Science 108, n.º 5 (22 de abril de 2005): 385–97. http://dx.doi.org/10.1042/cs20050041.
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The mouse continues to play a vital role in the deciphering of mammalian gene function and the modelling of human neurological disease. Advances in gene targeting technologies have facilitated the efficiency of generating new mouse mutants, although this valuable resource has rapidly expanded in recent years due to a number of major random mutagenesis programmes. The phenotype-driven mutagenesis screen at the MRC Mammalian Genetics Unit has generated a significant number of mice with potential neurological defects, and our aim has been to characterize selected mutants on a pathological and molecular level. Four lines are discussed, one displaying late-onset ataxia caused by Purkinje cell loss and an allelic series of three tremor mutants suffering from hypomyelination of the peripheral nerve. Molecular analysis of the causative mutation in each case has provided new insights into functional aspects of the mutated proteins, illustrating the power of mutagenesis screens to generate both novel and clinically relevant disease models.
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Frontali, M., A. Novelletto, G. Annesi y C. Jodice. "CAG repeat instability, cryptic sequence variation and pathogeneticity: evidence from different loci". Philosophical Transactions of the Royal Society of London. Series B: Biological Sciences 354, n.º 1386 (29 de junio de 1999): 1089–94. http://dx.doi.org/10.1098/rstb.1999.0464.
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Different aspects of expanded polyglutamine tracts and of their pathogenetic role are taken into consideration here. (i) The (CAG) n length of wild-type alleles of the Huntington disease gene was analysed in instability-prone tumour tissue from colon cancer patients to test whether the process leading to the elongation of alleles towards the expansion range involves single-unit stepwise mutations or larger jumps. The analysis showed that length changes of a single unit had a relatively low frequency. (ii) The observation of an expanded spinocerebellar ataxia (SCA)1 allele with an unusual pattern of multiple CAT interruptions showed that cryptic sequence variations are critical not only for sequence length stability but also for the expression of the disease phenotype. (iii) Small expansions of the (CAG) n sequence at the CACNA1A gene have been reported as causing SCA6. The analysis of families with SCA6 and episodic ataxia type 2 showed that these phenotypes are, in fact, expressions of the same disorder caused either by point mutations or by small (CAG) n expansions. A gain of function has been hypothesized for all proteins containing an expanded polyglutamine stretch, including the α 1A subunit of the voltage-gated calcium channel type P/Q coded by the CACNA1A gene. Because point mutations at the same gene with similar phenotypic consequences are highly unlikely to have this effect, an alternative common pathogenetic mechanism for all these mutations, including small expansions, can be hypothesized.
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Kalasova, Ilona, Richard Hailstone, Janin Bublitz, Jovel Bogantes, Winfried Hofmann, Alejandro Leal, Hana Hanzlikova y Keith W. Caldecott. "Pathological mutations in PNKP trigger defects in DNA single-strand break repair but not DNA double-strand break repair". Nucleic Acids Research 48, n.º 12 (6 de junio de 2020): 6672–84. http://dx.doi.org/10.1093/nar/gkaa489.
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Abstract Hereditary mutations in polynucleotide kinase-phosphatase (PNKP) result in a spectrum of neurological pathologies ranging from neurodevelopmental dysfunction in microcephaly with early onset seizures (MCSZ) to neurodegeneration in ataxia oculomotor apraxia-4 (AOA4) and Charcot-Marie-Tooth disease (CMT2B2). Consistent with this, PNKP is implicated in the repair of both DNA single-strand breaks (SSBs) and DNA double-strand breaks (DSBs); lesions that can trigger neurodegeneration and neurodevelopmental dysfunction, respectively. Surprisingly, however, we did not detect a significant defect in DSB repair (DSBR) in primary fibroblasts from PNKP patients spanning the spectrum of PNKP-mutated pathologies. In contrast, the rate of SSB repair (SSBR) is markedly reduced. Moreover, we show that the restoration of SSBR in patient fibroblasts collectively requires both the DNA kinase and DNA phosphatase activities of PNKP, and the fork-head associated (FHA) domain that interacts with the SSBR protein, XRCC1. Notably, however, the two enzymatic activities of PNKP appear to affect different aspects of disease pathology, with reduced DNA phosphatase activity correlating with neurodevelopmental dysfunction and reduced DNA kinase activity correlating with neurodegeneration. In summary, these data implicate reduced rates of SSBR, not DSBR, as the source of both neurodevelopmental and neurodegenerative pathology in PNKP-mutated disease, and the extent and nature of this reduction as the primary determinant of disease severity.
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Tulli, Susanna, Andrea Del Bondio, Valentina Baderna, Davide Mazza, Franca Codazzi, Tyler Mark Pierson, Alessandro Ambrosi et al. "Pathogenic variants in the AFG3L2 proteolytic domain cause SCA28 through haploinsufficiency and proteostatic stress-driven OMA1 activation". Journal of Medical Genetics 56, n.º 8 (25 de marzo de 2019): 499–511. http://dx.doi.org/10.1136/jmedgenet-2018-105766.
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BackgroundSpinocerebellar ataxia type 28 (SCA28) is a dominantly inherited neurodegenerative disease caused by pathogenic variants in AFG3L2. The AFG3L2 protein is a subunit of mitochondrial m-AAA complexes involved in protein quality control. Objective of this study was to determine the molecular mechanisms of SCA28, which has eluded characterisation to date.MethodsWe derived SCA28 patient fibroblasts carrying different pathogenic variants in the AFG3L2 proteolytic domain (missense: the newly identified p.F664S and p.M666T, p.G671R, p.Y689H and a truncating frameshift p.L556fs) and analysed multiple aspects of mitochondrial physiology. As reference of residual m-AAA activity, we included SPAX5 patient fibroblasts with homozygous p.Y616C pathogenic variant, AFG3L2+/− HEK293 T cells by CRISPR/Cas9-genome editing and Afg3l2−/− murine fibroblasts.ResultsWe found that SCA28 cells carrying missense changes have normal levels of assembled m-AAA complexes, while the cells with a truncating pathogenic variant had only half of this amount. We disclosed inefficient mitochondrial fusion in SCA28 cells caused by increased OPA1 processing operated by hyperactivated OMA1. Notably, we found altered mitochondrial proteostasis to be the trigger of OMA1 activation in SCA28 cells, with pharmacological attenuation of mitochondrial protein synthesis resulting in stabilised levels of OMA1 and OPA1 long forms, which rescued mitochondrial fusion efficiency. Secondary to altered mitochondrial morphology, mitochondrial calcium uptake resulted decreased in SCA28 cells.ConclusionOur data identify the earliest events in SCA28 pathogenesis and open new perspectives for therapy. By identifying similar mitochondrial phenotypes between SCA28 cells and AFG3L2+/− cells, our results support haploinsufficiency as the mechanism for the studied pathogenic variants.
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Argenta, Fernando Froner, Sissy Hobbhahn, Maria Ines Witz, Luiz Cezar Bello Fallavena y Anamaria Telles Esmeraldino. "Hepatite lobular dissecante em dois caninos Golden Retriever não relacionados geneticamente". Acta Scientiae Veterinariae 45 (27 de junio de 2017): 5. http://dx.doi.org/10.22456/1679-9216.86080.
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Background: Lobular dissecting hepatitis (LDH) is a rare condition of unknown etiology occurring in individuals or in litters of young dogs from some breeds, having poor prognosis and short survival time. Clinically, ascites, weight loss, anorexia, diarrhea and acquired portosystemic shunts are present. Hepatic encephalopathy may also occur. Biochemical blood tests usually show elevated ALT levels. Macroscopically, the liver shows changes in volume, color and regeneration nodules. Histologically, dissection of the parenchyma by connective tissue proliferation leads to disorganization of the liver architecture. The aim of this article is report LDH in two Golden Retriever dogs genetically unrelated.Cases: Two dogs genetically unrelated and of different owners - Golden Retriever breed - were referred to the Veterinary Medical Teaching Hospital of the Universidade Luterana do Brasil (ULBRA). The first case was a female with 17 months of age and the second, brought to examination one year later, was a male with nine months of age. The clinical signs, in both animals were similar, consisting in intense prostration, inapetence, caquexia and ascites for approximately two weeks. The female dog presented also ataxia, convulsion and diarrhea. Blood examination showed, for both dogs, arregenerative anemia, normal levels of alanine aminotransferase (ALT) and elevated levels of alkaline phosphatase. Total serum protein and albumin were also reduced. Both dogs were euthanized due to their critical condition. The necropsy showed similar lesions in both animals: approximately one liter of a free red colored fluid was observed in the abdominal cavity and hepatic changes consisting in pale green color, smooth surface, firm consistence, yellowish nodules at the surface and tissue proliferation at the margins. There was also congestion of the abdominal visceral veins (portal shunts). Histopathological examination showed, for both dogs, interstitial diffuse fibrosis causing dissection of the parenchyma and isolating hepatocytes in small groups, marked cholestasis and sinusoidal infiltration of inflammatory cells (mainly lymphocytes and plasma cells).Discussion: Lobular dissecting hepatitis is a rare form of hepatic cirrhosis, being unique only to dogs. Some breeds including German Shepherd, Poodle, Rottweiler, Cocker Spaniel and Golden Retriever are considered susceptible to the disease. The clinical signs, age, breed and macroscopic and microscopic lesions presented by the two dogs were consistent with LDH. In this disease, serum biochemistry analyses generally show hypoalbuminemia and increased levels of hepatic enzymes, mainly the ALT. In both animals herein described, albumin levels were decreased, but ALT levels were normal, indicating that a suspicion of this disease should not be discarded in similar cases. ALT levels, as well as of other hepatic enzymes, may not reflect the severity of chronic hepatopathies like LDH, in which the producer cells of this enzyme are being destroyed. These two animals, in spite of pertaining to the same breed, did not presented any genetic relationship, and were owned by different persons. The disease may have a great number of possible etiologies and historical data from the two dogs herein described did not indicated any relevant aspect which could be implicated as a cause of the condition. As affected animals are generally referred to a veterinary consultation in an advanced condition, the cause is difficult to be determined.
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Cortese, Andrea, Riccardo Curro', Elisa Vegezzi, Wai Yan Yau, Henry Houlden y Mary M. Reilly. "Cerebellar ataxia, neuropathy and vestibular areflexia syndrome (CANVAS): genetic and clinical aspects". Practical Neurology, 13 de agosto de 2021, practneurol—2020–002822. http://dx.doi.org/10.1136/practneurol-2020-002822.
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Cerebellar ataxia, neuropathy and vestibular areflexia syndrome (CANVAS) typically presents in middle life with a combination of neuropathy, ataxia and vestibular disease, with patients reporting progressive imbalance, oscillopsia, sensory disturbance and a dry cough. Examination identifies a sensory neuropathy or neuronopathy and bilaterally impaired vestibulo-ocular reflex. The underlying genetic basis is of biallelic AAGGG expansions in the second intron of replication factor complex subunit 1 (RFC1). The frequency and phenotype spectrum of RFC1 disease is expanding, ranging from typical CANVAS to site-restricted variants affecting the sensory nerves, cerebellum and/or the vestibular system. Given the wide phenotype spectrum of RFC1, the differential diagnosis is broad. RFC1 disease due to biallelic AAGGG expansions is probably the most common cause of recessive ataxia. The key to suspecting the disease (and prompt genetic testing) is a thorough clinical examination assessing the three affected systems and noting the presence of chronic cough.
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Ali, Benomar. "The clinical and genetic aspects of autosomal recessive cerebellar ataxia". Frontiers in Neuroscience 3 (2009). http://dx.doi.org/10.3389/conf.neuro.01.2009.16.113.
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Gorcenco, Sorina, Christin Karremo y Andreas Puschmann. "Patients’ Perspective in Hereditary Ataxia". Cerebellum, 16 de diciembre de 2022. http://dx.doi.org/10.1007/s12311-022-01505-1.
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AbstractHereditary ataxia represents a heterogeneous group of rare disorders with the chronic progression of motor symptoms that often become debilitating. Many forms include additional neurological, cognitive, or other symptoms. Most of these disorders lack specific treatment. We aimed to investigate aspects of patients’ quality of life, experiences, and expectations. Patients with a diagnosis of hereditary ataxia were identified from our center’s diagnostic register, direct referrals, and from a patient organization. We designed a questionnaire with 32 multiple-choice or open-ended questions on disability and impairment of daily life activities, the perceived effect of symptomatic and supportive therapies, coping strategies, and how they used and experienced various sources of information about their neurological disease. We also included the EQ-5D-3L quality-of-life instrument. Results were analyzed statistically for gender, age, and groups with and without a genetic diagnosis, and were compared to published data from the general population. Seventy-five patients returned the questionnaire. Patients reported considerable disease-related disability and impairment and had significantly lower quality-of-life scores than the general population. Physiotherapy and support from family or friends were important for patients’ overall well-being. Patients with a genetic diagnosis had a lower average age at onset and felt more well-informed about their disease than patients without a genetic diagnosis. Patients used internet sources but relied primarily on their doctors to obtain information about their disease. Our study provides insights into hereditary ataxia patients’ experiences that can lead to improvements in medical and nursing care for these patients.
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Chen, Jiannan, Zhe Zhao, Hongrui Shen, Qi Bing, Nan Li, Xuan Guo y Jing Hu. "Genetic origin of patients having spastic paraplegia with or without other neurologic manifestations". BMC Neurology 22, n.º 1 (16 de mayo de 2022). http://dx.doi.org/10.1186/s12883-022-02708-z.
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Abstract Background Hereditary spastic paraplegia (HSP) is a group of neurodegenerative diseases characterized by lower-limb spastic paraplegia with highly genetic and clinical heterogeneity. However, the clinical sign of spastic paraplegia can also be seen in a variety of hereditary neurologic diseases with bilateral corticospinal tract impairment. The purpose of this study is to identify the disease spectrum of spastic paraplegia, and to broaden the coverage of genetic testing and recognize clinical, laboratorial, electrophysiological and radiological characteristics to increase the positive rate of diagnosis. Methods Twenty-seven cases were screened out to have definite or suspected pathogenic variants from clinically suspected HSP pedigrees through HSP-associated sequencing and/or expanded genetic testing. One case was performed for enzyme detection of leukodystrophy without next-generation sequencing. In addition, detailed clinical, laboratorial, electrophysiological and radiological characteristics of the 28 patients were presented. Results A total of five types of hereditary neurological disorders were identified in 28 patients, including HSP (15/28), leukodystrophy (5/28), hereditary ataxia (2/28), methylmalonic acidemia/methylenetetrahydrofolate reductase deficiency (5/28), and Charcot-Marie-tooth atrophy (1/28). Patients in the HSP group had chronic courses, most of whom were lower limbs spasticity, mainly with axonal neuropathy, and thinning corpus callosum, white matter lesions and cerebellar atrophy in brain MRI. In the non-HSP groups, upper and lower limbs both involvement was more common. Patients with homocysteine remethylation disorders or Krabbe’s disease or autosomal recessive spastic ataxia of Charlevoix-Saguenay had diagnostic results in laboratory or imaging examination. A total of 12 new variants were obtained. Conclusions HSP had widespread clinical and genetic heterogeneity, and leukodystrophy, hereditary ataxia, Charcot-Marie-Tooth atrophy and homocysteine remethylation disorders accounted for a significant proportion of the proposed HSP. These diseases had different characteristics in clinical, laboratorial, electrophysiological, and radiological aspects, which could help differential diagnosis. Genetic analysis could ultimately provide a clear diagnosis, and broadening the scope of genetic testing could improve the positive rate of diagnosis.
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Bonventre, Joseph V. "Ataxia Telangiectasia and Rad3-Related Activation by DNA Damage Mitigates Maladaptive Repair after Acute Kidney Injury". Nephron, 14 de octubre de 2021, 1–4. http://dx.doi.org/10.1159/000519447.
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DNA damage is an important consequence of injury to the proximal tubule. The proximal tubule cell responds to this damage by mounting a DNA damage response (DDR). Two protein kinases, ataxia-telangiectasia mutated (ATM) or ataxia telangiectasia and Rad3-related (ATR), play an important role in this DDR. If efficient, the DDR can lead to repair of the DNA, cell renewal, and return to a healthy state. In many cases, however, especially in the setting of baseline kidney injury, there is incomplete repair. In human chronic kidney disease (CKD) and in human kidney organoids exposed to acute injury, there is increased evidence of DNA damage and activation of ATR. This review focuses on 3 aspects of the DNA damage and response to it: (1) DNA damage and the DDR precipitated by acute injury; (2) protection afforded by the DDR kinase, ATR, in multiple mouse models of acute kidney injury; and (3) downstream effects of genetic inhibition of ATR in the proximal tubule, leading to maladaptive repair, fibrosis, and CKD.
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Bonventre, Joseph V. "Ataxia Telangiectasia and Rad3-Related Activation by DNA Damage Mitigates Maladaptive Repair after Acute Kidney Injury". Nephron, 14 de octubre de 2021, 1–4. http://dx.doi.org/10.1159/000519447.
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DNA damage is an important consequence of injury to the proximal tubule. The proximal tubule cell responds to this damage by mounting a DNA damage response (DDR). Two protein kinases, ataxia-telangiectasia mutated (ATM) or ataxia telangiectasia and Rad3-related (ATR), play an important role in this DDR. If efficient, the DDR can lead to repair of the DNA, cell renewal, and return to a healthy state. In many cases, however, especially in the setting of baseline kidney injury, there is incomplete repair. In human chronic kidney disease (CKD) and in human kidney organoids exposed to acute injury, there is increased evidence of DNA damage and activation of ATR. This review focuses on 3 aspects of the DNA damage and response to it: (1) DNA damage and the DDR precipitated by acute injury; (2) protection afforded by the DDR kinase, ATR, in multiple mouse models of acute kidney injury; and (3) downstream effects of genetic inhibition of ATR in the proximal tubule, leading to maladaptive repair, fibrosis, and CKD.
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Rawat, Amit, Madhubala Sharma, Pandiarajan Vignesh, Ankur Kumar Jindal, Deepti Suri, Jhumki Das, Vibhu Joshi et al. "Utility of targeted next generation sequencing for inborn errors of immunity at a tertiary care centre in North India". Scientific Reports 12, n.º 1 (21 de junio de 2022). http://dx.doi.org/10.1038/s41598-022-14522-1.
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AbstractInborn errors of immunity (IEI) are a heterogeneous group of monogenic disorders that include primary immunodeficiency’s and other disorders affecting different aspects of the immune system. Next-Generation Sequencing (NGS) is an essential tool to diagnose IEI. We report our 3-year experience in setting up facilities for NGS for diagnosis of IEI in Chandigarh, North India. We used a targeted, customized gene panel of 44 genes known to result in IEI. Variant analysis was done using Ion Reporter software. The in-house NGS has enabled us to offer genetic diagnoses to patients with IEI at minimal costs. Of 121 patients who were included pathogenic variants were identified in 77 patients. These included patients with Chronic Granulomatous Disease, Severe Combined Immune Deficiency, leukocyte adhesion defect, X-linked agammaglobulinemia, Ataxia Telangiectasia, Hyper-IgE syndrome, Wiskott Aldrich syndrome, Mendelian susceptibility to mycobacterial diseases, Hyper-IgM syndrome, autoimmune lymphoproliferative syndrome, and GATA-2 deficiency. This manuscript discusses the challenges encountered while setting up and running targeted NGS for IEI in our unit. Genetic diagnosis has helped our patients with IEI in genetic counselling, prenatal diagnosis, and accessing appropriate therapeutic options.
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Lupica, Antonino, Rosaria Oteri, Sara Volta, Daniele Ghezzi, Selene Francesca Anna Drago, Carmelo Rodolico, Olimpia Musumeci y Antonio Toscano. "Diagnostic Challenges in Late Onset Multiple Acyl-CoA Dehydrogenase Deficiency: Clinical, Morphological, and Genetic Aspects". Frontiers in Neurology 13 (3 de marzo de 2022). http://dx.doi.org/10.3389/fneur.2022.815523.
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BackgroundMultiple acyl-CoA dehydrogenase deficiency (MADD) is an autosomal recessive disorder of fatty acid oxidation due to deficiency of the mitochondrial electron transfer chain. The late-onset form is characterized by exercise intolerance, muscle weakness, and lipid storage in myofibers. Most MADD patients greatly benefit from riboflavin supplementation.Patients and methodsA retrospective study was conducted on patients with a diagnosis of vacuolar myopathy with lipid storage followed in our neuromuscular unit in the last 20 years. We selected 10 unrelated patients with the diagnosis of MADD according to clinical, morphological, and biochemical aspects. Clinical features, blood tests including serum acylcarnitines, EMG, and ENG were revised. Muscle biopsy was performed in all, and one individual underwent also a sural nerve biopsy. Gene sequencing of ETFA, ETFB, and ETFDH was performed as a first-tier genetic analysis followed by next-generation sequencing of an hyperCKemia gene panel in patients with undefined genotypes.ResultsClinical evaluation at onset in all our patients showed fatigue and muscle weakness; four patients showed difficulties in chewing, three patients complained of dysphagia, two patients had a dropped head, and a patient had an unexpected ataxia with numbness and dysesthesia. Laboratory blood tests revealed a variable increase in serum CK (266–6,500) and LDH levels (500–2,000). Plasma acylcarnitine profile evidenced increased levels of different chains intermediates. EMG was either normal or showed myogenic or neurogenic patterns. NCS demonstrated sensory neuropathy in two patients. Muscle biopsies showed a vacuolar myopathy with a variable increase in lipid content. Nerve biopsy evidenced an axonal degeneration with the loss of myelinated fibers. ETFDH genetic analysis identifies 14 pathogenic variants. Patients were treated with high doses of riboflavin (400 mg/die). All of them showed a rapid muscle strength improvement and normalization of abnormal values in laboratory tests. Neuropathic symptoms did not improve.ConclusionOur data confirmed that clinical features in MADD patients are extremely variable in terms of disease onset and symptoms making diagnosis difficult. Laboratory investigations, such as serum acylcarnitine profile and muscle biopsy evaluation, may strongly address to a correct diagnosis. The favorable response to riboflavin supplementation strengthens the importance of an early diagnosis of these disorders among the spectrum of metabolic myopathies.
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Nóbrega, Paulo Ribeiro, Anderson Moura Bernardes, Rodrigo Mariano Ribeiro, Sophia Costa Vasconcelos, David Augusto Batista Sá Araújo, Vitor Carneiro de Vasconcelos Gama, Helena Fussiger et al. "Cerebrotendinous Xanthomatosis: A practice review of pathophysiology, diagnosis, and treatment". Frontiers in Neurology 13 (23 de diciembre de 2022). http://dx.doi.org/10.3389/fneur.2022.1049850.
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Cerebrotendinous Xanthomatosis represents a rare and underdiagnosed inherited neurometabolic disorder due to homozygous or compound heterozygous variants involving the CYP27A1 gene. This bile acid metabolism disorder represents a key potentially treatable neurogenetic condition due to the wide spectrum of neurological presentations in which it most commonly occurs. Cerebellar ataxia, peripheral neuropathy, spastic paraparesis, epilepsy, parkinsonism, cognitive decline, intellectual disability, and neuropsychiatric disturbances represent some of the most common neurological signs observed in this condition. Despite representing key features to increase diagnostic index suspicion, multisystemic involvement does not represent an obligatory feature and can also be under evaluated during diagnostic work-up. Chenodeoxycholic acid represents a well-known successful therapy for this inherited metabolic disease, however its unavailability in several contexts, high costs and common use in patients at late stages of disease course limit more favorable neurological outcomes for most individuals. This review article aims to discuss and highlight the most recent and updated knowledge regarding clinical, pathophysiological, neuroimaging, genetic and therapeutic aspects related to Cerebrotendinous Xanthomatosis.
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Sleigh, James y David Sattelle. "C. elegans models of neuromuscular diseases expedite translational research". Translational Neuroscience 1, n.º 3 (1 de enero de 2010). http://dx.doi.org/10.2478/v10134-010-0032-9.
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AbstractThe nematode Caenorhabditis elegans is a genetic model organism and the only animal with a complete nervous system wiring diagram. With only 302 neurons and 95 striated muscle cells, a rich array of mutants with defective locomotion and the facility for individual targeted gene knockdown by RNA interference, it lends itself to the exploration of gene function at nerve muscle junctions. With approximately 60% of human disease genes having a C. elegans homologue, there is growing interest in the deployment of lowcost, high-throughput, drug screens of nematode transgenic and mutant strains mimicking aspects of the pathology of devastating human neuromuscular disorders. Here we explore the contributions already made by C. elegans to our understanding of muscular dystrophies (Duchenne and Becker), spinal muscular atrophy, amyotrophic lateral sclerosis, Friedreich’s ataxia, inclusion body myositis and the prospects for contributions to other neuromuscular disorders. A bottleneck to low-cost, in vivo, large-scale chemical library screening for new candidate therapies has been rapid, automated, behavioural phenotyping. Recent progress in quantifying simple swimming (thrashing) movements is making such screening possible and is expediting the translation of drug candidates towards the clinic.
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Tremblay, Marjolaine, Laura Girard-Côté, Bernard Brais y Cynthia Gagnon. "Documenting manifestations and impacts of autosomal recessive spastic ataxia of Charlevoix–Saguenay to develop patient-reported outcome". Orphanet Journal of Rare Diseases 17, n.º 1 (1 de octubre de 2022). http://dx.doi.org/10.1186/s13023-022-02497-1.
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Abstract Background Autosomal recessive cerebellar ataxias (ARCA) are a group of rare inherited disorders characterized by degeneration or abnormal development of the cerebellum. Autosomal recessive spastic ataxia of Charlevoix–Saguenay (ARSACS) is one of the most prevalent in Europe. Objectives The aim of this study is to provide a better understanding of the manifestations and impacts of ARSACS. Methods A systematic review of the literature was conducted, followed by a qualitative study using semistructured interviews and discussion groups to obtain the experience of people affected. Results According to the PROMIS framework, the results show manifestations and impacts in three components of health: physical, mental, and social. Fatigue and struggles with balance and dexterity are the physical manifestations of the disease most often cited by participants. Negative affects such as frustration and depression are among the mental health impacts with some loss in cognitive abilities. Social health is the least documented component; nonetheless, people with the disease report significant impacts in terms of social relationships, activities and work. Conclusions These findings shed new light on the experience of people with recessive ataxia and identify key aspects to assess to improve their overall health.
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Dupré, Mathieu, Ruben Hermann y Caroline Froment Tilikete. "Update on Cerebellar Ataxia with Neuropathy and Bilateral Vestibular Areflexia Syndrome (CANVAS)". Cerebellum, 4 de octubre de 2020. http://dx.doi.org/10.1007/s12311-020-01192-w.
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Abstract The syndrome of cerebellar ataxia with neuropathy and bilateral vestibular areflexia (CANVAS) has emerged progressively during the last 30 years. It was first outlined by the neurootology/neurophysiology community in the vestibular areflexic patients, through the description of patients slowly developing late-onset cerebellar ataxia and bilateral vestibulopathy. The characteristic deficit of visuo-vestibulo-ocular reflex (VVOR) due to the impaired slow stabilizing eye movements was put forward and a specific disease subtending this syndrome was suggested. The association to a peripheral sensory axonal neuropathy was described later on, with neuropathological studies demonstrating that both sensory neuropathy and vestibular areflexia were diffuse ganglionopathy. Clinical and electrophysiological criteria of CANVAS were then proposed in 2016. Besides the classical triad, frequent chronic cough, signs of dysautonomia and neurogenic pains were frequently observed. From the beginning of published cohorts, sporadic as well as familial cases were reported, the last suggestive of an autosomal recessive mode of transmission. The genetic disorder was discovered in 2019, under the form of abnormal biallelic expansion in the replication factor C subunit 1 (RFC1) in a population of late-onset ataxia. This pathological expansion was found in 100% of the familial form and 92% of sporadic ones when the triad was complete. But using the genetic criteria, the phenotype of CANVAS seems to expand, for exemple including patients with isolated neuronopathy. We propose here to review the clinical, electrophysiological, anatomical, genetic aspect of CANVAS in light of the recent discovery of the genetic aetiology, and discuss differential diagnosis, neuropathology and physiopathology.
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Asher, Melissa, Juao-Guilherme Rosa, Orion Rainwater, Lisa Duvick, Michael Bennyworth, Ruo-Yah Lai, Sheng-Han Kuo y Marija Cvetanovic. "Cerebellar contribution to the cognitive alterations in SCA1: evidence from mouse models". Human Molecular Genetics, 7 de noviembre de 2019. http://dx.doi.org/10.1093/hmg/ddz265.
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Abstract Spinocerebellar ataxia type 1 (SCA1) is a fatal neurodegenerative disease caused by abnormal expansion of glutamine (Q) encoding CAG repeats in the gene Ataxin-1 (ATXN1). Although motor and balance deficits are the core symptoms of SCA1, cognitive decline is also commonly observed in patients. While mutant ATXN1 is expressed throughout the brain, pathological findings reveal severe atrophy of cerebellar cortex in SCA1 patients. The cerebellum has recently been implicated in diverse cognitive functions, yet to what extent cerebellar neurodegeneration contributes to cognitive alterations in SCA1 remains poorly understood. Much of our understanding of the mechanisms underlying pathogenesis of motor symptoms in SCA1 comes from mouse models. Reasoning that mouse models could similarly offer important insights into the mechanisms of cognitive alterations in SCA1 we tested cognition in several mouse lines using Barnes maze and fear conditioning. We confirmed cognitive deficits in Atxn1154Q/2Q knock-in mice with brain wide expression of mutant ATXN1 and in ATXN1 null mice. We found that shorter polyQ length and haploinsufficiency of ATXN1 do not cause significant cognitive deficits. Finally, ATXN1[82Q] transgenic mice—with cerebellum limited expression of mutant ATXN1—demonstrated milder impairment in most aspects of cognition compared to Atxn1154Q/2Q mice, supporting the concept that cognitive deficits in SCA1 arise from a combination of cerebellar and extra-cerebellar dysfunctions.
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BAYAZIT, Beray, Gülnihal UÇARKUŞ, Burcu ÇAĞLAR GENÇOSMAN y Mehmet A. BEĞEN. "Meta-Heuristic Algorithms based on Integer Programming for Shelf Space Allocation Problems". European Journal of Science and Technology, 23 de septiembre de 2022. http://dx.doi.org/10.31590/ejosat.1121006.
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Retail shelf space management, which is one of the most complex aspects of retailing, can be defined as determining when, where and in what quantities products will be displayed and dynamically updating the display considering changing market conditions. Although it is an important problem, research papers that study rectangular arrangement of products to optimize profit are limited. In this paper, we determine rectangular facing units of products to maximize profit for shelf space allocation and the display problem. To solve our two-dimensional shelf space allocation problem, we develop two matheuristic algorithms by using integer programming and genetic algorithm (TP-GA) and integer programming and firefly algorithm (TP-ABA) meta-heuristics together. The performances of the mathheuristics were compared with a real-world dataset from a bookstore. TP-GA and TP-ABA methods were able to generate near-optimal solutions with an average of 4.47% and 4.57% GAPs, respectively. We can also solve instances up to 900 products. These matheuristic algorithms, which are successful in the two-dimensional shelf assignment problem, can also be used to solve similar problems such as allocation of books in a bookstore, allocation of product families in a grocery store, or display of advertisements on websites.
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Loesch, Danuta Z., Flora Tassone, Anna Atkinson, Paige Stimpson, Nicholas Trost, Dean L. Pountney y Elsdon Storey. "Differential Progression of Motor Dysfunction Between Male and Female Fragile X Premutation Carriers Reveals Novel Aspects of Sex-Specific Neural Involvement". Frontiers in Molecular Biosciences 7 (12 de enero de 2021). http://dx.doi.org/10.3389/fmolb.2020.577246.
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Expansions of the CGG repeat in the non-coding segment of the FMR1 X-linked gene are associated with a variety of phenotypic changes. Large expansions (>200 repeats), which cause a severe neurodevelopmental disorder, the fragile x syndrome (FXS), are transmitted from the mothers carrying smaller, unstable expansions ranging from 55 to 200 repeats, termed the fragile X premutation. Female carriers of this premutation may themselves experience a wide range of clinical problems throughout their lifespan, the most severe being the late onset neurodegenerative condition called “Fragile X-Associated Tremor Ataxia Syndrome” (FXTAS), occurring between 8 and 16% of these carriers. Male premutation carriers, although they do not transmit expanded alleles to their daughters, have a much higher risk (40–50%) of developing FXTAS. Although this disorder is more prevalent and severe in male than female carriers, specific sex differences in clinical manifestations and progress of the FXTAS spectrum have been poorly documented. Here we compare the pattern and rate of progression (per year) in three motor scales including tremor/ataxia (ICARS), tremor (Clinical Tremor Rating scale, CRST), and parkinsonism (UPDRS), and in several cognitive and psychiatric tests scores, between 13 female and 9 male carriers initially having at least one of the motor scores ≥10. Moreover, we document the differences in each of the clinical and cognitive measures between the cross-sectional samples of 21 female and 24 male premutation carriers of comparable ages with FXTAS spectrum disorder (FSD), that is, who manifest one or more features of FXTAS. The results of progression assessment showed that it was more than twice the rate in male than in female carriers for the ICARS-both gait ataxia and kinetic tremor domains and twice as high in males on the CRST scale. In contrast, sex difference was negligible for the rate of progress in UPDRS, and all the cognitive measures. The overall psychiatric pathology score (SCL-90), as well as Anxiety and Obsessive/Compulsive domain scores, showed a significant increase only in the female sample. The pattern of sex differences for progression in motor scores was consistent with the results of comparison between larger, cross-sectional samples of male and female carriers affected with the FSD. These results were in concert with sex-specific distribution of MRI T2 white matter hyperintensities: all males, but no females, showed the middle cerebellar peduncle white matter hyperintensities (MCP sign), although the distribution and severity of these hyperintensities in the other brain regions were not dissimilar between the two sexes. In conclusion, the magnitude and specific pattern of sex differences in manifestations and progression of clinically recorded changes in motor performance and MRI lesion distribution support, on clinical grounds, the possibility of certain sex-limited factor(s) which, beyond the predictable effect of the second, normal FMR1 alleles in female premutation carriers, may have neuroprotective effects, specifically concerning the cerebellar circuitry.
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Ishiura, Hiroyuki, Shoji Tsuji y Tatsushi Toda. "Recent advances in CGG repeat diseases and a proposal of fragile X-associated tremor/ataxia syndrome, neuronal intranuclear inclusion disease, and oculophryngodistal myopathy (FNOP) spectrum disorder". Journal of Human Genetics, 20 de enero de 2023. http://dx.doi.org/10.1038/s10038-022-01116-y.
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AbstractWhile whole genome sequencing and long-read sequencing have become widely available, more and more focuses are on noncoding expanded repeats. Indeed, more than half of noncoding repeat expansions related to diseases have been identified in the five years. An exciting aspect of the progress in this field is an identification of a phenomenon called repeat motif–phenotype correlation. Repeat motif–phenotype correlation in noncoding repeat expansion diseases is first found in benign adult familial myoclonus epilepsy. The concept is extended in the research of CGG repeat expansion diseases. In this review, we focus on newly identified CGG repeat expansion diseases, update the concept of repeat motif–phenotype correlation in CGG repeat expansion diseases, and propose a clinical concept of FNOP (fragile X-associated tremor/ataxia syndrome, neuronal intranuclear inclusion disease, and oculopharyngodistal myopathy)-spectrum disorder, which shares clinical features and thus probably share some common disease pathophysiology, to further facilitate discussion and progress in this field.
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Bowie, Emily y Sarah C. Goetz. "TTBK2 and primary cilia are essential for the connectivity and survival of cerebellar Purkinje neurons". eLife 9 (14 de enero de 2020). http://dx.doi.org/10.7554/elife.51166.
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Primary cilia are vital signaling organelles that extend from most types of cells, including neurons and glia. These structures are essential for development of many tissues and organs; however, their function in adult tissues, particularly neurons in the brain, remains largely unknown. Tau tubulin kinase 2 (TTBK2) is a critical regulator of ciliogenesis, and is also mutated in a hereditary neurodegenerative disorder, spinocerebellar ataxia type 11 (SCA11). Here, we show that conditional knockout of Ttbk2 in adult mice results in degenerative cerebellar phenotypes that recapitulate aspects of SCA11 including motor coordination deficits and defects to Purkinje cell (PC) integrity. We also find that the Ttbk2 conditional mutant mice quickly lose cilia throughout the brain. We show that conditional knockout of the key ciliary trafficking gene Ift88 in adult mice results in nearly identical cerebellar phenotypes to those of the Ttbk2 knockout, indicating that disruption of ciliary signaling is a key driver of these phenotypes. Our data suggest that primary cilia play an integral role in maintaining the function of PCs in the adult cerebellum and reveal novel insights into mechanisms involved in neurodegeneration.