RESUMO
BACKGROUND: To investigate the genetics of early-onset progressive cerebellar ataxia in Iran, we conducted a study at the Children's Medical Center (CMC), the primary referral center for pediatric disorders in the country, over a three-year period from 2019 to 2022. In this report, we provide the initial findings from the national registry. METHODS: We selected all early-onset patients with an autosomal recessive mode of inheritance to assess their phenotype, paraclinical tests, and genotypes. The clinical data encompassed clinical features, the Scale for the Assessment and Rating of Ataxia (SARA) scores, Magnetic Resonance Imaging (MRI) results, Electrodiagnostic exams (EDX), and biomarker features. Our genetic investigations included single-gene testing, Whole Exome Sequencing (WES), and Whole Genome Sequencing (WGS). RESULTS: Our study enrolled 162 patients from various geographic regions of our country. Among our subpopulations, we identified known and novel pathogenic variants in 42 genes in 97 families. The overall genetic diagnostic rate was 59.9%. Notably, we observed PLA2G6, ATM, SACS, and SCA variants in 19, 14, 12, and 10 families, respectively. Remarkably, more than 59% of the cases were attributed to pathogenic variants in these genes. CONCLUSIONS: Iran, being at the crossroad of the Middle East, exhibits a highly diverse genetic etiology for autosomal recessive hereditary ataxia. In light of this heterogeneity, the development of preventive strategies and targeted molecular therapeutics becomes crucial. A national guideline for the diagnosis and management of patients with these conditions could significantly aid in advancing healthcare approaches and improving patient outcomes.
Assuntos
Degenerações Espinocerebelares , Criança , Humanos , Irã (Geográfico)/epidemiologia , Degenerações Espinocerebelares/genética , Testes Genéticos , Fenótipo , Genes RecessivosRESUMO
A pathogenic GAA repeat expansion in the first intron of the fibroblast growth factor 14 gene (FGF14) has been recently identified as the cause of spinocerebellar ataxia 27B (SCA27B). We herein screened 160 Greek index cases with late-onset cerebellar ataxia (LOCA) for FGF14 repeat expansions using a combination of long-range PCR and bidirectional repeat-primed PCRs. We identified 19 index cases (12%) carrying a pathogenic FGF14 GAA expansion, a diagnostic yield higher than that of previously screened repeat-expansion ataxias in Greek LOCA patients. The age at onset of SCA27B patients was 60.5 ± 12.3 years (range, 34-80). Episodic onset (37%), downbeat nystagmus (32%) and vertigo (26%) were significantly more frequent in FGF14 expansion-positive cases compared to expansion-negative cases. Beyond typical cerebellar signs, SCA27B patients often displayed hyperreflexia (47%) and reduced vibration sense in the lower extremities (42%). The frequency and phenotypic profile of SCA27B in Greek patients was similar to most other previously studied populations. We conclude that FGF14 GAA repeat expansions are the commonest known genetic cause of LOCA in the Greek population and recommend prioritizing testing for FGF14 expansions in the diagnostic algorithm of patients with LOCA.
Assuntos
Ataxia Cerebelar , Ataxias Espinocerebelares , Degenerações Espinocerebelares , Humanos , Adulto , Pessoa de Meia-Idade , Idoso , Idoso de 80 Anos ou mais , Ataxia Cerebelar/diagnóstico , Ataxia Cerebelar/genética , Grécia/epidemiologia , Ataxias Espinocerebelares/genética , Degenerações Espinocerebelares/genética , Fenótipo , Expansão das Repetições de Trinucleotídeos/genéticaRESUMO
Spinocerebellar ataxia 19 (SCA19) represents a rare autosomal dominant genetic disorder resulting in progressive ataxia and cerebellar atrophy. SCA19 is caused by variants in the KCND3 gene, which encodes a voltage-gated potassium channel subunit essential for cerebellar Purkinje cell function. We describe six cases from Chile and Mexico, representing the largest report on SCA19 in Latin America. These cases encompass a range of clinical presentations, highlighting the phenotypic variability within SCA19 from an early-onset, severe disease to a late-onset, slowly progressive condition with normal lifespan. While some patients present with pure ataxia, others also show cognitive impairment, dystonia, and other neurological symptoms. The correlations between specific KCND3 variants and phenotypic outcomes are complex and warrant further investigation. As the genomic landscape of spinocerebellar ataxias evolves, comprehensive genetic testing is becoming pivotal in improving diagnostic accuracy. This study contributes to a better understanding of the clinical spectrum of SCA19, laying the groundwork for further genotype-phenotype correlations and functional studies to elucidate the underlying pathophysiology.
Assuntos
Fenótipo , Humanos , Masculino , Feminino , Pessoa de Meia-Idade , Adulto , México/epidemiologia , Chile/epidemiologia , Idoso , Degenerações Espinocerebelares/genética , Ataxias Espinocerebelares/genética , Ataxias Espinocerebelares/epidemiologiaRESUMO
BACKGROUND: Inherited neuromuscular (NMD) and neurodegenerative diseases (NDD) belong to two distinct categories that disturb different components of the nervous system, leading to a variety of different symptoms and clinical manifestations. Both NMD and NDD are a heterogeneous group of genetic conditions. Genetic variations in the SGCA and SIL1 genes have been implicated in causing Limb Girdle Muscular Dystrophy (LGMD), a type of neuromuscular disorder, and Marinesco-Sjögren Syndrome (MSS) which is a neurodegenerative disorder. METHODS: In the present study, we have investigated four patients presenting LGMD and five patients with MSS features. After collecting detailed clinical and family history, necessary laboratory investigations, including estimation of a skeletal muscle marker enzyme serum creatine kinase (CK), nerve conduction study (NCS), electromyography (EMG), echocardiography (Echo), Magnetic resonance imaging (MRI -brain), CT-brain and X-rays were performed. Whole exome followed by Sanger sequencing was employed to search for the disease-causing variants. RESULTS: Physical examination in LGMD patients revealed poor muscle tone and facing difficulty in straightening up from the floor. Clinical history revealed frequent falls and strenuousness in climbing stairs. They started toe-walking in early childhood. Laboratory investigations confirmed elevated CK levels and abnormal NCS and EMG. The MSS patients showed abnormalities in gate and jerking movement, abnormal speech, and strabismus with cataract. MRI-brain showed cerebral atrophy in some MSS patients with elevated CK levels. Whole exome sequencing revealed a nonsense variant [c.C574T, p.(Arg192*)] in the SGCA gene and a frameshift [c.936dupG, p.(Leu313AlaFs*39)] in the SIL1 gene in LGMD and MSS patients, respectively. CONCLUSION: Our study emphasizes the significance of integrating clinical and genetic analyses for precise diagnosis and tailored management strategies in inherited NMD and NDD disorders. To the best of our knowledge, this is the first study documenting SGCA and SIL1 recurrent variants in subcontinent populations with few rare clinical features. The recurrent mutations expanding the global understanding of the mutation's geographic and ethnic distribution and contributing valuable epidemiological data. The study will facilitate genetic counseling for families experiencing similar clinical features, both within Pakistani populations and in other regions.
Assuntos
Sequenciamento do Exoma , Distrofia Muscular do Cíngulo dos Membros , Humanos , Distrofia Muscular do Cíngulo dos Membros/genética , Masculino , Feminino , Adulto , Sequenciamento do Exoma/métodos , Proteínas Musculares/genética , Linhagem , Mutação/genética , Degenerações Espinocerebelares/genética , Criança , Adolescente , Fatores de Troca de Nucleotídeo Guanina Rho/genética , Fatores de Troca do Nucleotídeo Guanina/genética , Adulto Jovem , Exoma/genética , SarcoglicanasRESUMO
Since 1991, several genetic disorders caused by unstable trinucleotide repeats (TNRs) have been identified, collectively referred to as triplet repeat diseases (TREDs). They share a common mutation mechanism: the expansion of repeats (dynamic mutations) due to the propensity of repeated sequences to form unusual DNA structures during replication. TREDs are characterized as neurodegenerative diseases or complex syndromes with significant neurological components. Spinocerebellar ataxia type 17 (SCA17) falls into the former category and is caused by the expansion of mixed CAA/CAG repeats in the TBP gene. To date, a five-unit organization of this region [(CAG)3 (CAA)3] [(CAG)n] [CAA CAG CAA] [(CAG)n] [CAA CAG], with expansion in the second [(CAG)n] unit being the most common, has been proposed. In this study, we propose an alternative organization scheme for the repeats. A search of the PubMed database was conducted to identify articles reporting both the number and composition of GAC/CAA repeats in TBP alleles. Nineteen reports were selected. The sequences of all identified CAG/CAA repeats in the TBP locus, including 67 cases (probands and b relatives), were analyzed in terms of their repetition structure and stability in inheritance, if possible. Based on the analysis of three units [(CAG)3 (CAA)2] [CAA (CAG)n CAA CAG] [CAA (CAG)n CAA CAG], the organization of repeats is proposed. Detailed analysis of the CAG/CAA repeat structure, not just the number of repeats, in TBP-expanded alleles should be performed, as it may have a prognostic value in the prediction of stability/instability during transmission and the possible anticipation of the disease.
Assuntos
Mutação , Proteína de Ligação a TATA-Box , Expansão das Repetições de Trinucleotídeos , Humanos , Alelos , Ataxias Espinocerebelares/genética , Degenerações Espinocerebelares/genética , Proteína de Ligação a TATA-Box/genética , Expansão das Repetições de Trinucleotídeos/genética , Repetições de Trinucleotídeos/genéticaRESUMO
Genetic cerebellar ataxias are still a diagnostic challenge, and yet not all of them have been identified. Very recently, in early 2023, a new cause of late-onset cerebellar ataxia (LOCA) was identified, spinocerebellar ataxia 27B (SCA27B). This is an autosomal dominant ataxia due to a GAA expansion in intron 1 of the FGF14 gene. Thanks to the many studies carried out since its discovery, it is now possible to define the clinical phenotype, its particularities, and the progression of SCA27B. It has also been established that it is one of the most frequent causes of LOCA. The core phenotype of the disease consists of slowly progressive late-onset ataxia with cerebellar syndrome, oculomotor disorders including downbeat nystagmus, and episodic symptoms such as diplopia. Therapeutic approaches have been proposed, including acetazolamide, and 4-aminopyridine, the latter with a better benefit/tolerance profile.
Assuntos
Degenerações Espinocerebelares , Degenerações Espinocerebelares/diagnóstico por imagem , Degenerações Espinocerebelares/genética , Degenerações Espinocerebelares/terapia , Fatores de Crescimento de Fibroblastos , Íntrons , Humanos , Masculino , Feminino , Adulto , Pessoa de Meia-Idade , Idoso , Encéfalo/diagnóstico por imagem , Imageamento por Ressonância MagnéticaRESUMO
Spinocerebellar degeneration (SCD) is a neurodegenerative disorder characterized by cerebellar ataxia and other multisystem manifestations, such as Parkinsonism and pyramidal tract symptoms. No effective treatment is available for SCD. Approximately one-third of the cases of SCD are inherited, and the remaining two-third are sporadic, including multiple system atrophy. This article provides an overview of hereditary SCD, its clinical features, recent treatment advances, biomarkers, role of genomic medicine, and future treatment prospects.
Assuntos
Ataxia Cerebelar , Atrofia de Múltiplos Sistemas , Degenerações Espinocerebelares , Humanos , Degenerações Espinocerebelares/diagnóstico , Degenerações Espinocerebelares/genética , Degenerações Espinocerebelares/terapiaRESUMO
BACKGROUND: Spinocerebellar ataxia 29 (SCA29) is a rare genetic disorder characterized by early-onset ataxia, gross motor delay, and infantile hypotonia, and is primarily associated with variants in the ITPR1 gene. Cases of SCA29 in Asia are rarely reported, limiting our understanding of this disease. METHODS: A female Korean infant, demonstrating clinical features of SCA29, underwent evaluation and rehabilitation at our outpatient clinic from the age of 3 months to the current age of 4 years. Trio-based genome sequencing tests were performed on the patient and her biological parents. RESULTS: The infant initially presented with macrocephaly, hypotonia, and nystagmus, with nonspecific findings on initial neuroimaging. Subsequent follow-up revealed gross motor delay, early onset ataxia, strabismus, and cognitive impairment. Further neuroimaging revealed atrophy of the cerebellum and vermis, and genetic analysis revealed a de novo pathogenic heterozygous c.800C>T, p.Thr267Met missense mutation in the ITPR1 gene (NM_001378452.1). CONCLUSION: This is the first reported case of SCA29 in a Korean patient, expanding the genetic and phenotypic spectrum of ITPR1-related ataxias. Our case highlights the importance of recognizing early-onset ataxic symptoms, central hypotonia, and gross motor delays with poor ocular fixation, cognitive deficits, and isolated cerebellar atrophy as crucial clinical indicators of SCA29.
Assuntos
Receptores de Inositol 1,4,5-Trifosfato , Mutação de Sentido Incorreto , Degenerações Espinocerebelares , Humanos , Feminino , Receptores de Inositol 1,4,5-Trifosfato/genética , Degenerações Espinocerebelares/genética , Degenerações Espinocerebelares/patologia , Pré-Escolar , Ataxia Cerebelar/genética , Ataxia Cerebelar/patologia , Ataxias Espinocerebelares/genética , Ataxias Espinocerebelares/patologia , LactenteRESUMO
ABSTRACT Objective To describe and compare the vestibular findings most evident among the hereditary ataxias, as well as correlate their clinical features with the nervous structures affected in this disease. Methods Seventy-five patients were evaluated and underwent a case history, otorhinolaryngological and vestibular assessments. Results Clinically, the patients commonly had symptoms of gait disturbances (67.1%), dizziness (47.3%), dysarthria (46%) and dysphagia (36.8%). In vestibular testing, alterations were predominantly evident in caloric testing (79%), testing for saccadic dysmetria (51%) and rotational chair testing (47%). The presence of alterations occurred in 87% of these patients. A majority of the alterations were from central vestibular dysfunction (69.3%). Conclusion This underscores the importance of the contribution of topodiagnostic labyrinthine evaluations for neurodegenerative diseases as, in most cases, the initial symptoms are otoneurological; and these evaluations should also be included in the selection of procedures to be performed in clinical and therapeutic monitoring.
RESUMO Objetivo Descrever e comparar os achados vestibulares mais evidentes entre a ataxia hereditária, bem como correlacionar seus aspectos clínicos com o estudo das estruturas nervosas afetadas nesta doença. Métodos 75 pacientes foram avaliados e submetidos aos seguintes procedimentos: anamnese, avaliação otorrinolaringológica e vestibular. Resultados Clinicamente, os pacientes apresentaram sintomas de distúrbios da marcha (67,1%), tonturas (47,3%), disartria (46%) e disfagia (36,8%). No teste vestibular, as alterações foram predominantemente evidentes no teste calórico (79%), dismetria sacádicas (51%) e no teste rotatório (47%). A presença de alterações ocorreu em 87% dos pacientes. A maioria das alterações observadas foram da disfunção vestibular central (69,3%). Conclusão O estudo ressalta a importância da contribuição da avaliação labiríntica no topodiagnóstico para doenças neurodegenerativas, uma vez que, na maioria dos casos, os sintomas iniciais são otoneurológicos, e essas avaliações também devem ser incluídas na seleção de procedimentos a serem realizados no monitoramento clínico e terapêutico.
Assuntos
Humanos , Masculino , Feminino , Adolescente , Adulto , Pessoa de Meia-Idade , Idoso , Adulto Jovem , Degenerações Espinocerebelares/diagnóstico , Degenerações Espinocerebelares/epidemiologia , Doenças Vestibulares/diagnóstico , Doenças Vestibulares/epidemiologia , Testes de Função Vestibular/métodos , Brasil/epidemiologia , Transtornos de Deglutição/fisiopatologia , Transtornos de Deglutição/epidemiologia , Degenerações Espinocerebelares/fisiopatologia , Degenerações Espinocerebelares/genética , Nistagmo Patológico/fisiopatologia , Nistagmo Patológico/epidemiologia , Reação em Cadeia da Polimerase , Prevalência , Estudos Transversais , Estudos Retrospectivos , Distribuição por Sexo , Transtornos Neurológicos da Marcha/fisiopatologia , Transtornos Neurológicos da Marcha/epidemiologia , Tontura/fisiopatologia , Tontura/epidemiologia , Disartria/fisiopatologia , Disartria/epidemiologia , MutaçãoRESUMO
ABSTRACT Hereditary ataxias (HA) represents an extensive group of clinically and genetically heterogeneous neurodegenerative diseases, characterized by progressive ataxia combined with extra-cerebellar and multi-systemic involvements, including peripheral neuropathy, pyramidal signs, movement disorders, seizures, and cognitive dysfunction. There is no effective treatment for HA, and management remains supportive and symptomatic. In this review, we will focus on the symptomatic treatment of the main autosomal recessive ataxias, autosomal dominant ataxias, X-linked cerebellar ataxias and mitochondrial ataxias. We describe management for different clinical symptoms, mechanism-based approaches, rehabilitation therapy, disease modifying therapy, future clinical trials and perspectives, genetic counseling and preimplantation genetic diagnosis.
RESUMO As ataxias hereditárias representam um grupo complexo de doenças neurodegenerativas, e se caracterizam por ataxia cerebelar progressiva, associada a sinais e sintomas extra-cerebelares e sistêmicos, os quais incluem: neuropatia periférica, sinais piramidais, distúrbios do movimento, convulsões e disfunção cognitiva. Não existe um tratamento efetivo para a cura das ataxias hereditárias. Até o momento os tratamentos disponíveis são apenas sintomáticos. Nesta revisão vamos abordar tratamento sintomático das principais ataxias autossômicas recessivas, ataxias autossômicas dominantes, ataxias ligadas ao X e ataxias mitocondriais. Descrevemos os diferentes sintomas, abordagens terapêuticas baseadas no mecanismo fisiopatológico, terapia de reabilitação, terapia modificadora da doença, futuros ensaios clínicos, perspectivas, níveis de evidência, aconselhamento genético e diagnóstico genético pré-implantacional.
Assuntos
Humanos , Degenerações Espinocerebelares/terapia , Degenerações Espinocerebelares/classificação , Degenerações Espinocerebelares/genética , Aconselhamento GenéticoRESUMO
Autosomal recessive cerebellar ataxias are a heterogeneous group of neurological disorders. In 1981, a neurological entity comprised by early onset progressive cerebellar ataxia, dysarthria, pyramidal weakness of the limbs and retained or increased upper limb reflexes and knee jerks was described. This disorder is known as early onset cerebellar ataxia with retained tendon reflexes. In this article, we aimed to call attention for the diagnosis of early onset cerebellar ataxia with retained tendon reflexes as the second most common cause of autosomal recessive cerebellar ataxias, after Friedreich ataxia, and also to perform a clinical spectrum study of this syndrome. In this data, 12 patients from different families met all clinical features for early onset cerebellar ataxia with retained tendon reflexes. Dysarthria and cerebellar atrophy were the most common features in our sample. It is uncertain, however, whether early onset cerebellar ataxia with retained tendon reflexes is a homogeneous disease or a group of phenotypically similar syndromes represented by different genetic entities. Further molecular studies are required to provide definitive answers to the questions that remain regarding early onset cerebellar ataxia with retained tendon reflexes.
.As ataxias cerebelares autossômicas recessivas são um grupo heterogêneo de doenças neurológicas. Em 1981, foi descrita uma entidade neurológica incluindo ataxia cerebelar progressiva de início precoce, disartria, liberação piramidal e manutenção ou aumento dos reflexos tendíneos nos membros superiores e inferiores. Essa síndrome é conhecida como ataxia cerebelar de início precoce com reflexos mantidos. Neste artigo, o objetivo foi chamar a atenção para o diagnóstico de ataxia cerebelar de início precoce com reflexos mantidos como a segunda causa mais comum de ataxia cerebelar autossômica recessiva, após a ataxia de Friedreich, e também realizar um estudo do espectro clínico da síndrome. Doze pacientes de diferentes famílias preencheram os critérios clínicos para ataxia cerebelar de início precoce com reflexos mantidos. Disartria e atrofia cerebelar foram as características mais frequentes. No entanto, não há consenso se a ataxia cerebelar de início precoce com reflexos mantidos é uma doença homogênea ou um grupo de síndromes com fenótipos semelhantes representadas por diferentes entidades genéticas. Estudos moleculares futuros são necessários para fornecer respostas definitivas para as questões pendentes em relação à ataxia cerebelar de início precoce com reflexos mantidos.
.Assuntos
Adulto , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Adulto Jovem , Reflexo de Estiramento , Degenerações Espinocerebelares/diagnóstico , Idade de Início , Imageamento por Ressonância Magnética , Estudos Retrospectivos , Reflexo de Estiramento/genética , Índice de Gravidade de Doença , Síndrome , Degenerações Espinocerebelares/genética , Degenerações Espinocerebelares/fisiopatologiaRESUMO
Chronic ataxias are an heterogeneous group of disorders that affect the child at different ages. Thus, the congenital forms, generally non progressive are observed from first months of life and are expressed by hypotonia and motor delay long before the ataxia became evident. The cerebral magnetic resonance images (MRI) may be diagnostic in some pictures like Joubert syndrome. The group of progressive hereditary ataxias, usually begin after the infant period. The clinical signs are gait instability and ocular apraxia that can be associated with oculocutaneous telangiectasias (ataxia-telangiesctasia) or with sensory neuropathy (Friedreich ataxia). In this review are briefly described congenital ataxias and in more detailed form the progressive hereditary ataxias autosomal recessive, autosomal dominants and mitochondrials. The importance of genetic study is emphasized, because it is the key to obtain the diagnosis in the majority of these diseases. Although now there are no treatments for the majority of progressive hereditary ataxias, some they have like Refsum disease, vitamine E deficiency, Coenzyme Q10 deficiency and others, thus the diagnosis in these cases is even more important. At present the diagnosis of childhood hereditary ataxia not yet treatable is fundamental to obtain suitable handling, determine a precise outcome and to give to the family an opportune genetic counseling.
Assuntos
Ataxia Cerebelar/genética , Degenerações Espinocerebelares/genética , Ataxia Cerebelar/diagnóstico , Ataxia Cerebelar/fisiopatologia , Ataxia/diagnóstico , Ataxia/fisiopatologia , Ataxia/genética , Criança , Debilidade Muscular/diagnóstico , Debilidade Muscular/fisiopatologia , Debilidade Muscular/genética , Degenerações Espinocerebelares/diagnóstico , Degenerações Espinocerebelares/fisiopatologia , Doença Crônica , Doenças Mitocondriais/diagnóstico , Doenças Mitocondriais/fisiopatologia , Doenças Mitocondriais/genética , Feminino , Humanos , Masculino , Ubiquinona/deficiência , Ubiquinona/genéticaRESUMO
Spinocerebellar ataxia type 1 (SCA1), spinocerebellar ataxia type 2 (SCA2) and Machado-Joseph disease or spinocerebellar ataxia type 3 (MJD/SCA3) are three distinctive forms of autosomal dominant spinocerebellar ataxia (SCA) caused by expansions of an unstable CAG repeat localized in the coding region of the causative genes. Another related disease, dentatorubropallidoluysian atrophy (DRPLA) is also caused by an unstable triplet repeat and can present as SCA in late onset patients. We investigated the frequency of the SCA1, SCA2, MJD/SCA3 and DRPLA mutations in 328 Brazilian patients with SCA, belonging to 90 unrelated families with various patterns of inheritance and originating in different geographic regions of Brazil. We found mutations in 35 families (39 percent), 32 of them with a clear autosomal dominant inheritance. The frequency of the SCA1 mutation was 3 percent of all patients; and 6 percent in the dominantly inherited SCAs. We identified the SCA2 mutation in 6 percent of all families and in 9 percent of the families with autosomal dominant inheritance. The MJD/SCA3 mutation was detected in 30 percent of all patients; and in the 44 percent of the dominantly inherited cases. We found no DRPLA mutation. In addition, we observed variability in the frequency of the different mutations according to geographic origin of the patients, which is probably related to the distinct colonization of different parts of Brazil. These results suggest that SCA may be occasionally caused by the SCA1 and SCA2 mutations in the Brazilian population, and that the MJD/SCA3 mutation is the most common cause of dominantly inherited SCA in Brazil.
Assuntos
Humanos , Criança , Adulto , Pessoa de Meia-Idade , Adolescente , Mutação/genética , Degenerações Espinocerebelares/genética , Brasil , Aberrações Cromossômicas/genética , Análise Mutacional de DNA , Genes Dominantes , Doença de Machado-Joseph/genética , Reação em Cadeia da Polimerase , Repetições de TrinucleotídeosRESUMO
Os autores apresentam o estudo realizado em 5 membros afetados de uma família portadora da doença de Machado-Joseph. Säo abordados os diferentes tipos clínicos da doença encontrados, bem como os exames complementares realizaods, em particular os estudos de tomografia craniana, exames neurofisiológicos (eletromiografia, estudo de conduçäo nervosa, estudo de potencial evocado auditivo), biópsias de nervo periferico e de músculo estriado esquelético, com estudo histoquimico
Assuntos
Humanos , Masculino , Adulto , Pessoa de Meia-Idade , Degenerações Espinocerebelares/genética , Crânio , Degenerações Espinocerebelares/diagnóstico , Diagnóstico Diferencial , Linhagem , Tomografia Computadorizada por Raios XRESUMO
Há, até o momento, notícia de 9 famílias näo aparentadas com o diagnóstico clínico de doença de Machado-Joseph (MJD) no Brasil. Esta é a maior família do mundo com doença. É de origem açoriana e contem 622 indivíduos na árvore fenealógica. Destes, 236 foram examinados. Dois examinadores julgaron 39 como afetados. Respectivamente 12, 23 e 4 pacientes tinham os fenôtipos I, II e III da doença, com idades no início variando entre 10-48, 14-54 e 30-55. Doença tipo I de início juvenil näo mostrou atrofia täo severa nas imagens por ressonância magnética (RM) quanto doença tipo II de duraçäo igual, demonstrando que severidade clínica e grau de atrofia näo caminham paralelamente. Nenhum dos 8 pacientes examinados por RM tinha atrofia olivar ou anormalidades no globo pálido. Doze pacientes e 23 sob risco foram submetidos a avaliaçäo neuropsicológica. A atençäo foi normal em todos. Memória verbal estava pior nos doentes com maior decaimento com o tempo que nos sob risco. Ambos os grupos tiveram pontuaçäo abaixo do normal na identificaçäo de silhuetas e praxia construtiva. Memória visual estava bem abaixo do normal para ambos, com muitas rotaçöes, porém sem omissöes ou confabulaçäo. Padräo peculiar de multiplicaçäo dos detalhes internos, que denominamos o "efeito olho de mosca" foi visto em 6 doentes e 8 sob risco. Discriminaçäo defeituosa de cores, quando múltiplas cores eram apresentadas lado a lado, na ausência de anomia ou cegueira a cores, caracterizável como "simultagnosia a cores", surgiu como achado e foi pesquisada em 29 sujeitos 4/10 doentes e 6/19 sob risco mostram esta dificuldade. Conclui-se que disfunçöes cognitivas na esfera visual säo proeminentes nesta família. Se seriam próprias da doença e manifestaçäo precoce daqueles sob risco, está ainda para ser estabelecido. Depressäo foi avaliada com critérios do DSM III-R e com o Montgomery-Asberg Depression Rating Scale. Näo houve diferença entre doentes e sob risco. Entretanto, os pacientes tiveram menos depressäo do que tinham tido antes ou nas fases precoces da doença. A MJD plenamente instalada parecia exercer efeito protetor da depressäo
Assuntos
Humanos , Masculino , Feminino , Criança , Adolescente , Adulto , Pessoa de Meia-Idade , Degenerações Espinocerebelares/genética , Açores/etnologia , Brasil , Degenerações Espinocerebelares/diagnóstico , Exame Neurológico , Testes Neuropsicológicos , Linhagem , Escalas de Graduação Psiquiátrica , Espectroscopia de Ressonância Magnética , Fatores de RiscoRESUMO
As heredoataxias constituem grupo complexo de doenças neurodegenerativas hereditárias, para o qual várias formas de classificaçäo clínica e patológica foram propostas com sucesso variável. O desenvolvimento das tTcnicas de biologia molecular trouxe informaçöes importantes que têm permitido caracterizar geneticamente as ataxias cerebelares hereditárias. O reconhecimento das doenças causadas por expansöes de trinucleotídeos abre novo capítulo para a pesquisa sobre outros mecanismos de doenças, como na ataxia de Friedreich e nas várias formas de ataxia cerebelar autossômica dominante(SCA1 a SCA7), das quais a doença de Machado-Joseph/SCA3 parece ser a mais comum no nosso meio. A deficiência familial de vitamina E (cromossomo 8q) leva a quadro semelhante ao da ataxia de Friedreich (cromossomo 9p), mas responde à reposiçäo oral de tocoferol. Formas familiais de ataxia periódica com (cromossomo 12p) ou sem (cromossomo 19p) mioquimia foram caracterizadas, a primeira resultado de mutaçöes dos gens de canais de potássio. Os portadores do gen da ataxia-teleangiectasia (cromossomo 11q) representam 1-3 por cento da populaç1 e säo suscetíveis aos efeitos oncogânicos da radiaçäo iônica. Sem olvidar da importância da avaliaçäo clínica neurológica, a avaliaçäo genética laboratorial passa a ser valiosa ferramenta para o diagnóstico e aconselhamento genético, além do melhor entendimento da patogênese dessas doenças.
Assuntos
Humanos , Degenerações Espinocerebelares/classificação , Degenerações Espinocerebelares/diagnóstico , Degenerações Espinocerebelares/genéticaRESUMO
The spinocerebellar ataxias (SCAs) are a clinically and genetically heterogeneous group of late onset neurodegenerative disorders. To date, seven different genes causing autosomal dominant SCA have been mapped:SCA1,SCA2, Machado-Joseph disease(MJD)/SCA3,SCA4,SCA5,SCA7 and dentatorubropallidoluysian atrophy (DRPLA). Expansions of an unstable trinucleotide CAG repeat cause three of these disorders: SCA1, MJD/SCA3 and DRPLA. We studied one Brazilian family segregating an autosomal dominant type of SCA. A total of ten individuals were examined and tested for the presence of the SCA1, MJD and DRPLA mutations. Three individuals, one male and two females, were considered affected based on neurological examination; ages at onset were: 32, 36 and 41 years. The first complaint in all three patients was gait ataxia which progressed slowly over the years. Six individuals showed one allele containing an expanded CAG repeat in the SCA1 gene. The mean size of the expanded allele was 48.2 CAG units. Instability of the expanded CAG tract was seen in the two transmissions that were observed in this family. In both occasions there was a contraction of the CAG tract. Our study demonstrates that SCA1 occurs in the Brazilian population. In addition, our results stress the importance of molecular studies in the confirmation of diagnosis and for pre-symptomatic testing in SCAs.