Auswahl der wissenschaftlichen Literatur zum Thema „Ataxia Genetic aspects“

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.

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.

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.

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.

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.

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.

The spinocerebellar ataxias (SCAs) are a clinically and genetically heterogeneous group of neurodegenerative disorders. To date, ten SCA loci have been described (SCA1-SCA8, SCA10 and SCA11), with six genes having been cloned (SCA1, SCA2, SCA3/MJD, SCA6, SCA7 and SCA8) and shown to contain CAG/CTG repeats.
This study investigated various aspects of the SCA2, SCA6, and SCA7 subtypes. Haplotype analysis in our panel of SCA2 families identified multiple ancestral mutation events to be responsible for disease in this group. Screening for the newly identified SCA6 and SCA7 mutations in our large collection of SCA families and patients revealed that these mutations are rare in our panel, each accounting for less than 1% of our ataxia samples. Finally, the CAG repeat-containing locus hGT1 was found to be associated with residual age at onset variability in our SCA2 families.
Together, these results add to our growing understanding of the SCAs, and bring us a few steps closer to effective diagnoses of, and treatments for, these devastating diseases.

Orientadores: Iscia Lopes-Cendes, Marilisa Mantovani Guerreiro, Fernando Cendes
Dissertação (mestrado) - Universidade Estadual de Campinas, Faculdade de Ciências Médicas
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Resumo: As Epilepsias Mioclônicas Progressivas (EMPs), formam um grupo raro de desordens geneticamente determinadas e freqüentemente familiais. Caracterizam-se por apresentarem a tríade clínica: epilepsia, mioclonias e declínio neurológico progressivo, como demência e ataxia. As cinco principais causas desta síndrome são: doença de Unverricht-Lundborg (DUL), doença de Lafora (DL), as lipofuscinoses ceroides neuronais (LCN), as encefalomiopatias mitocondriais com fibras vermelhas rajadas (MERRF) e as sialidoses. O objetivo principal deste trabalho foi estudar um grupo de pacientes com EMP, visando chegar ao diagnóstico das causas específicas, através da história clínica, exames de propedêutica armada e testes específicos. Tais estratégias pretendiam: a) determinar as causas mais freqüentes da EMP em nosso meio, b) determinar a utilidade, na prática clínica, dos testes empregados em nosso trabalho, c) estabelecer correlações entre o fenótipo (quadro clínico) e o genótipo (identificação de mutações gênicas específicas), e d) propor um algoritmo diagnóstico adequado a nossa realidade. Para atingirmos os objetivos utilizamos: avaliação clínica neurológica, eletroencefalograma (EEG), ressonância magnética de crânio (RNM), exames histopatológicos e a análise molecular de alguns genes candidatos. Estudamos 25 pacientes pertencentes a 21 familias não-relacionadas. Incluímos todos os pacientes com o diagnóstico provável de EMP avaliados em nosso serviço entre outubro de 2000 a agosto de 2002. O critério inclusão foi a presença da tríade clínica. A avaliação diagnóstica foi feita em três níveis: nível diagnóstico I, composto de história clínica, história famílias e exame neurológico; nível diagnóstico II, EEG e a RNM de crânio; nível diagnóstico III, exames específicos, tais como testes bioquímicos, exames histopatológicos e testes moleculares de genes candidatos: Cistatina B, EPM2A, mutação A3243G no DNA mitocondrial (mtDNA), mutação A8344G no mt DNA, HD e SCA7. O nível diagnóstico I, indicou suspeita diagnóstica de DUL em 9 pacientes (6 famílias). Enquanto, DL foi o diagnóstico provável em 5 pacientes. A suspeita clínica de algum tipo de LCN, estava presente em 5 pacientes (4 famílias). Outros 4 pacientes, tiveram a suspeita clínica de algum tipo de encefalomiopatia mitocondrial enquanto 1 paciente teve a suspeita clínica de doença de depósito e 1 paciente com o suspeita de doença de Huntington (DH) juvenil. o nível diagnóstico 11, não avançou na elucidação diagnóstica das causas específicas, porém nos permitiu excluir uma paciente do estudo, por apresentar lesão destrutiva na RNM de crânio. No nível diagnóstico 111,6/9 pacientes com DUL foram submetidos a biópsia de pele e a análise histopatológica foi sugestiva de DUL em 3/9 pacientes. O estudo molecular do gene Cistatina B realizado nos 9 pacientes, conftrmou a presença de mutações em 3 pacientes, pertencentes a uma família. Dos 4 pacientes com suspeita diagnóstica de DL, todos foram submetidos a biópsia de pele e análise molecular do gene EPM2A. Em apenas 2 pacientes, a análise histopatológica demonstrou a presença inequívoca de corpúsculos de Lafora. A análise molecular não evidenciou a presença de mutações deletérias no gene EPM2A. Quatro dos 5 pacientes com suspeita clínica de LCN foram submetidos a biópsia de pele. Dois pacientes apresentaramos achados típicos da forma infantil tardia. Os 4 pacientes com suspeita clínica de encefalomiopatia mitocondrial, foram submetidos a análise molecular para dois pontos de mutação no mt DNA. Dois pacientes demonstraram alterações moleculares, um com a mutação de ponto A3243G (MELAS), e 1 com a mutação A8344G (MERRF). Nestes a biópsia de músculo, confirmou a presença de fibras vermelhas rajadas. Um dos pacientes com suspeita de doença mitocondrial que apresentou resultado molecular negativo para as duas mutações no mtDNA pesquisadas, teve resultado molecular positivo, para uma forma de ataxia espinocerebelar autossômica dominante tipo 7 (SCA-7). O paciente com suspeita clínica de doença de depósito teve o diagnóstico de sialidose confirmado por testes bioquímicos específicos (baixos níveis de sialidase na urina). O único paciente com suspeita clínica de DH teve o teste molecular negativo para DH. Em conclusão, fomos capazes de chegar a causa específica da EMP em 11/25 (43%) dos pacientes ou 9/21 famílias (44%). As causas específicas de EMP mais freqüentes em nosso meio foram: DUL (3 pacientes), DL (2 pacientes), LCN (2 pacientes) e encefalomiopatias mitocondriais (2 pacientes). O diagnóstico definitivo foi possível graças a uma combinação de testes seguindo um algoritmo diagnóstico orientado pela suspeita clínica. Desse modo propomos que: a análise molecular deve ser o procedimento de escolha para a confIrmação diagnóstica da DUL e das encefalomiopatias mitocondriopatias. No entanto, o exame histopatológico (biópsia de pele) ainda é o teste de escolha para o diagnóstico definitivo das LCNs e da DL
Abstract: Progressive Mioclonic Epilepsies (PME) are arare heterogeneous group of genetically determined disorders characterized by epilepsy, mioclonic jerks and progressive neuroIogicaI decline including dementia and ataxia. There are five main disorders which can cause PME: Unverricht-Lundborg disease (ULD) and Lafora disease (LD), ceroides neuronal lipofuscinoses (LCN), mitochondriaI encephalomyopathies and sialidoses. The objective of this work was to establish specific diagnosis in a group of patients with PME.We also intended to: a) determine the most frequent causes of PME in our cohort of patients, b) determine the usefulness of a number of tests in determining the specifc diagnosis, c) establish phenotype-genotype correlation in our patients and d) propose a more appropriate scheme for the diagnosis of specific causes of PME, in our patients. AlI patients included in this work had the probabIe diagnosis of PME.Diagnostic criterion was the presence of the classical symptons. Patients were anaIyzed by neuroIogicaI evaluation, electroencephalogram (EEG), magnetic resonance imaging (MRI), histopathoIogyc exams and moIecuIar analysis. Initially, probable diagnoses of PME, was based exclusively in information obtained by ciínical familiary histories and neurological exam (diagnostic leveI). EEG and MRI (diagnostic level II )were performed in all patients, whose information guided us to more specific tests (biochemicaI and histopathologyc exams). In addition we performed muscle, skin biopsy and molecular analysis of Cistatina B, EPM2A, HD, SCA-7 genes and A3243G, A8344G point mutations in the mitochondrial DNA (diagnostic level III). We have studied a total of belongs to 25 patientsl 21 unrelated families. The probable diagnosis of ULD (diagnostic leveI I) was present in 9 patients (6 families), LD was the probable diagnosis in 5 patients (5 families) and LCN was probably in 5 patient (4 families). Other 4 unrelated patients had probably mitochondrial encephalomyopathies, while 1 patient had probabilly a metabolic disease and 1 patient had the possible diagnosis ofHuntington disease (HD) juvenile form. EEG and MRI (diagnostic leveI TI)were not useful to establish the specific cause of PME; however MRI in one patient allowed to excluded the diagnosis of PME, since her MRI showed the presence of a destructive lesion in the central nervous system. Skin biopsy was performed in 6/9 patients with probable ULD and 9/9 were screened for mutation in the Cistatin B gene (diagnostic leveI ID). Histopathologyc analysis suggest the diagnosis of ULD in 6 patients belongs to 3 families. Molecular analysis confirmed the presence of Cistatin B point mutations in 3 patientes in one only family. Four patients with probable diagnosis LD were submitted to skin biopsy and EPM2A gene. Histopathologyc analysis confumed the presence of Lafora bodies in two patients. Molecular analysis did not revealed the presence of pathogenic mutations in the EPM2A gene, in our cohort of patients. Four patients with probable LCN were submitted to skin biopsy. Ttwo of these patients presented the typical histopathologyc of the late infantile type. AlI patients with probable mitochondrial encephalomyopathies were submitted to molecular analysis of the mtDNA and three of them had muscle biopsy. Two patients demonstrated molecular alterations, one presented a point mutation at positive the A3243G of in mtDNA confirming MELAS and another had the A8344G point mutation that is found in the MERRF. Muscular biopsy confumed the presence of ragged red fibers in these patients. Found in the patient with probable mitochondrial disease had a positive molecular result a type of spinocerebellar ataxia, SCA-7. The patient with clinical a metabolic deposit disease had the diagnosis confumed by specific biochemical tests (low sialidase levels in the urine) the sialidose. The patient of with probable diagnosis of juvenile HD had negative molecular results. In conclusion we established the specific diagnosis of PME in 11/25 patients (43%) or in 9/21 (44%) families. The most frequently causes of PME were: ULD (3 patients), LD (2 patients), LCN (2 patients) and mitocondrial encephalomyopathies (2 patients). Definitive diagnosis was possible combining clínical evaluation and laboratory tests, following a diagnostic scheme: molecular analysis necessary to confirm the diagnosis of ULD and mitocondrial encephalomyopathies; however, skin biopsy is still the gold standart for the diagnosis of LCNs and LD
Mestrado
Neurologia
Mestre em Ciências Médicas

Copy of author's previously published work inserted.
Bibliography: leaves 193-216.
ix, 268 leaves : ill. ; 30 cm.
Title page, contents and abstract only. The complete thesis in print form is available from the University Library.
Thesis which examines in detail the genetics of congental ataxias, and early and late onset ataxias.
Thesis (Ph.D.)--University of Adelaide, Dept. of Paediatrics, 2000

Copy of author's previously published work inserted.
Bibliography: leaves 193-216.
ix, 268 leaves : ill. ; 30 cm.
Thesis which examines in detail the genetics of congental ataxias, and early and late onset ataxias.
Thesis (Ph.D.)--University of Adelaide, Dept. of Paediatrics, 2000

Aniridia (Greek) literally means “absence of iris” (the colored part of the eye); however, this is a misnomer because patients with aniridia always have irises that are rudimentary or not fully developed. Years ago when this eye condition was given the name “aniridia,” it was not known that the name would come to only describe the most physically noticeable aspect of the condition. Today it is known that the lack of iris is only a minor aspect of aniridia, and it does not reflect the more important aspects of aniridia that can cause even more vision loss. Aniridia has been and still is referred to as a “rare” eye condition, even though the eye conditions that make up aniridia are common ones such as glaucoma, cataract, corneal degeneration, and low vision. The “rare” aspect of aniridia is having the combination of these conditions in one individual, affecting his or her vision. Aniridia is a genetic eye condition that is congenital—that is, it is present from birth—and affects various structures of the eye. It occurs when the gene responsible for eye development, the PAX6 gene (located on the eleventh chromosome), does not function correctly. The result is developmental disorders not only of the iris, but also of the cornea, the angle of the eye, the lens, the retina (sensory part of the eye), and the optic nerve (nerve that carries visual impulse to the brain). The degree of maldevelopment differs from one patient to another. Aniridia is a bilateral disease. The incidence of this condition ranges from one in 40,000 to one in 50,000 births. It occurs equally in males and females, and has no racial predilection. Aniridia can be familial or sporadic (occurs spontaneously, not inherited). Familial Aniridia (87%): The Ocular Manifestations Occur in Isolation 85% autosomal dominant 2%autosomal recessive has been observed in the rare Gillespie’s syndrome, in which aniridia is associated with cerebellar ataxia, structural defects in the cerebellum and other parts of the brain, and mental retardation. Patients with Gillespie syndrome are not predisposed to the development of Wilms’ tumor.

Background: X-linked Adrenoleukodystrophy (X-ALD) represents a key inherited metabolic disorder in neurological practice, representing an important differential diagnosis in different neurological contexts. Symptomatic female patients have been scarcely studied in large cohorts. Objectives: Evaluation of clinical, laboratory and genetic findings from a Brazilian cohort of women with X-ALD. Methods, design and setting: We performed a retrospective observational study of clinical, biochemical, genetic, neuroimaging and neurophysiological aspects of 10 Brazilian female patients with X-linked Adrenoleukodystrophy under clinical follow-up at the Neurometabolic Unit, Division of Neuromuscular Diseases, Federal University of São Paulo (UNIFESP), São Paulo, Brazil. Results: Mean age at diagnosis was 46.2 years and at symptom-onset was 39 years. Female patients presented with spastic paraparesis and neurogenic bladder (60%), cognitive decline (50%), demyelinating sensorimotor polyneuropathy (40%), cerebellar ataxia (30%), epilepsy (20%), apraxia and psychotic symptoms (10%). The most common misdiagnosis were Primary Progressive Multiple Sclerosis and Hereditary Spastic Paraplegia. The main neuroimaging findings were corticospinal tract hyperintensity and cervical and thoracic spinal cord atrophy (60%), unspecific white matter changes (40%) and typical parieto-occipital leukodystrophy. All patients had abnormal profiles of plasma very-long chain fatty acids, all with elevated C26 levels and 80% with elevated C24 levels, but all with abnormally raised C26:C22 and C26:C24 ratio. The most common pathogenic variant observed was c.311G>A (p.Arg104His) (60%). Conclusions: Female patients with ABCD1 pathogenic variants must be carefully evaluated for neuropsychiatric disturbances and followed-up until elderly due to the common occurrence of variable motor, autonomic and sensory compromise.