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BACKGROUND: The age at onset (AO) of Machado-Joseph disease (SCA3/MJD), a disorder due to an expanded CAG repeat (CAGexp) in ATXN3, is quite variable and the role of environmental factors is still unknown. Caffeine was associated with protective effects against other neurodegenerative diseases, and against SCA3/MJD in transgenic mouse models. We aimed to evaluate whether caffeine consumption and its interaction with variants of caffeine signaling/metabolization genes impact the AO of this disease. METHODS: a questionnaire on caffeine consumption was applied to adult patients and unrelated controls living in Rio Grande do Sul, Brazil. AO and CAGexp were previously determined. SNPs rs5751876 (ADORA2A), rs2298383 (ADORA2A), rs762551 (CYP1A2) and rs478597 (NOS1) were genotyped. AO of subgroups were compared, adjusting the CAGexp to 75 repeats (p < 0.05). RESULTS: 171/179 cases and 98/100 controls consumed caffeine. Cases with high and low caffeine consumption (more or less than 314.5 mg of caffeine/day) had mean (SD) AO of 35.05 (11.44) and 35.43 (10.08) years (p = 0.40). The mean (SD) AO of the subgroups produced by the presence or absence of caffeine-enhancing alleles in ADORA2A (T allele at rs5751876 and rs2298383), CYP1A2 (C allele) and NOS1 (C allele) were all similar (p between 0.069 and 0.516). DISCUSSION: Caffeine consumption was not related to changes in the AO of SCA3/MJD, either alone or in interaction with protective genotypes at ADORA2A, CYP1A2 and NOS1.
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Background: Spinocerebellar ataxia types 2 (SCA2) and 3 (SCA3/MJD) are diseases due to dominant unstable expansions of CAG repeats (CAGexp). Age of onset of symptoms (AO) correlates with the CAGexp length. Repeat instability leads to increases in the expanded repeats, to important AO anticipations and to the eventual extinction of lineages. Because of that, compensatory forces are expected to act on the maintenance of expanded alleles, but they are poorly understood. Objectives: we described the CAGexp dynamics, adapting a classical equation and aiming to estimate for how many generations will the descendants of a de novo expansion last. Methods: A mathematical model was adapted to encompass anticipation, fitness, and allelic segregation; and empirical data fed the model. The arbitrated ancestral mutations included in the model had the lowest CAGexp and the highest AO described in the literature. One thousand generations were simulated until the alleles were eliminated, fixed, or 650 generations had passed. Results: All SCA2 lineages were eliminated in a median of 10 generations. In SCA3/MJD lineages, 593 were eliminated in a median of 29 generations. The other ones were eliminated due to anticipation after the 650th generation or remained indefinitely with CAG repeats transitioning between expanded and unexpanded ranges. Discussion: the model predicted outcomes compatible with empirical data - the very old ancestral SCA3/MJD haplotype, and the de novo SCA2 expansions -, which previously seemed to be contradictory. This model accommodates these data into understandable dynamics and might be useful for other CAGexp disorders.
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BACKGROUND: The natural history of magnetic resonance imaging (MRI) in pre-ataxic stages of spinocerebellar ataxia type 3/Machado-Joseph disease (SCA3/MJD) is not well known. We report cross-sectional and longitudinal data obtained at this stage. METHODS: Baseline (follow-up) observations included 32 (17) pre-ataxic carriers (SARA < 3) and 20 (12) related controls. The mutation length was used to estimate the time to onset (TimeTo) of gait ataxia. Clinical scales and MRIs were performed at baseline and after a median (IQR) of 30 (7) months. Cerebellar volumetries (ACAPULCO), deep gray-matter (T1-Multiatlas), cortical thickness (FreeSurfer), cervical spinal cord area (SCT) and white matter (DTI-Multiatlas) were assessed. Baseline differences between groups were described; variables that presented a p < 0.1 after Bonferroni correction were assessed longitudinally, using TimeTo and study time. For TimeTo strategy, corrections for age, sex and intracranial volume were done with Z-score progression. A significance level of 5% was adopted. RESULTS: SCT at C1 level distinguished pre-ataxic carriers from controls. DTI measures of the right inferior cerebellar peduncle (ICP), bilateral middle cerebellar peduncles (MCP) and bilateral medial lemniscus (ML), also distinguished pre-ataxic carriers from controls, and progressed over TimeTo, with effect sizes varying from 0.11 to 0.20, larger than those of the clinical scales. No MRI variable showed progression over study time. DISCUSSION: DTI parameters of the right ICP, left MCP and right ML were the best biomarkers for the pre-ataxic stage of SCA3/MJD. TimeTo is an interesting timescale, since it captured the longitudinal worsening of these structures.
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Doença de Machado-Joseph , Ataxias Espinocerebelares , Humanos , Doença de Machado-Joseph/diagnóstico por imagem , Doença de Machado-Joseph/genética , Estudos Transversais , Ataxias Espinocerebelares/patologia , Ataxia , Imageamento por Ressonância MagnéticaRESUMO
BACKGROUND: Spinocerebellar ataxia type 3/Machado-Joseph disease (SCA3/MJD) is a rare disease with diagnosis offered by the Unified Health System in Brazil. Our aim was to investigate the diagnostic delay in an interval of 23 years in a public university hospital, and some potentially determining factors. METHODS: A retrospective review of the medical records of subjects identified at our institution between 1999 and 2017 was carried out, including residents of Rio Grande do Sul. The diagnostic delay was equivalent to the difference between age at onset of symptoms and age at molecular diagnosis. Calendar years, educational level, sex, distance between the household and the clinics, age and being the index case were studied as modifying factors. RESULTS: SCA3/MJD had a median diagnostic delay of 5 years. Index cases had delays of 6 versus 4 years (p<0.001) for subsequent family members. Delay correlated with age (rho=0.346, p<0.001), but not with age at disease onset (rho=0.005, p=0.91). No change was observed with the level of education of individuals or with the distance between household and hospital from 1999 to 2017. DISCUSSION: The diagnostic delay of SCA3/MJD is high in our region, where its occurrence has been reported for years. Failure to change the delay over the years suggests ineffective dissemination to the population, but a smaller lag among younger people can portray the effect of digital inclusion.
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Doença de Machado-Joseph , Ataxias Espinocerebelares , Degenerações Espinocerebelares , Humanos , Diagnóstico Tardio , BrasilRESUMO
Spinocerebellar ataxia type 3 or Machado-Joseph disease (MJD/SCA3) is the most prevalent autosomal dominant cerebellar ataxia worldwide, but its frequency varies by geographic region. We describe MJD/SCA3 patients diagnosed in a tertiary healthcare institution in Peru. In a cohort of 341 individuals (253 probands) with clinical ataxia diagnosis, seven MJD/SCA3 probands were identified and their pedigrees extended, detecting a total of 18 MJD/SCA3 cases. Out of 506 alleles from all probands from this cohort, the 23-CAG repeat was the most common ATXN3 allele (31.8%), followed by the 14-CAG repeat allele (26.1%). Normal alleles ranged from 12 to 38 repeats while pathogenic alleles ranged from 64 to 75 repeats. We identified 80 large normal (LN) alleles (15.8%). Five out of seven families declared an affected family member traced back to foreign countries (England, Japan, China, and Trinidad and Tobago). MJD/SCA3 patients showed ataxia, accompanied by pyramidal signs, dysarthria, and dysphagia as well as abnormal oculomotor movements. In conclusion, ATXN3 allelic distribution in non-MJD/SCA3 patients with ataxia is similar to the distribution in normal individuals around the world, whereas LN allele frequency reinforces no correlation with the frequency of MJD/SCA3. Evidence of any atypical MJD/SCA3 phenotype was not found. Furthermore, haplotypes are required to confirm the foreign origin of MJD/SCA3 in the Peruvian population.
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Doença de Machado-Joseph , Degenerações Espinocerebelares , Humanos , Doença de Machado-Joseph/diagnóstico , Doença de Machado-Joseph/epidemiologia , Doença de Machado-Joseph/genética , Peru/epidemiologia , Ataxina-3/genética , Frequência do Gene , Degenerações Espinocerebelares/genéticaRESUMO
BACKGROUND: Little is known about preclinical stages of Machado-Joseph disease, a polyglutamine disorder characterized by progressive adult-onset ataxia. OBJECTIVE: We aimed to describe the longitudinal progression of clinical and oculomotor variables in the preataxic phase of disease. METHODS: Carriers and noncarriers were assessed at three visits. Preataxic carriers (Scale for Assessment and Rating of Ataxia score < 3) expected to start ataxia in ≤4 years were considered near onset (PAN). Progressions of ataxic and preataxic carriers, considering status at the end of the study, were described according to the start (or its prediction) of gait ataxia (TimeToAfterOnset) and according to the study time. RESULTS: A total of 35 ataxics, 38 preataxics, and 22 noncarriers were included. The "TimeToAfterOnset" timeline showed that Neurological Examination Scale for Spinocerebellar Ataxias (NESSCA; effect size, 0.09), Inventory of Non-Ataxia Symptoms (INAS0.07), and the vestibulo-ocular reflex gain (0.12) progressed in preataxic carriers, and that most slopes accelerate in PAN, turning similar to those of ataxics. In the study time, NESSCA (1.36) and vertical pursuit gain (1.17) significantly worsened in PAN, and 6 of 11 PANs converted to ataxia. For a clinical trial with 80% power and 2-year duration, 57 PANs are needed in each study arm to detect a 50% reduction in the conversion rate. CONCLUSIONS: NESSCA, INAS, vestibulo-ocular reflex, and vertical pursuit gains significantly worsened in the preataxic phase. The "TimeToAfterOnset" timeline unveiled that slopes of most variables are small in preataxics but increase and reach the ataxic slopes from 4 years before the onset of ataxia. For future trials in preataxic carriers, we recommend recruiting PANs and using the conversion rate as the primary outcome. © 2022 International Parkinson and Movement Disorder Society.
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Doença de Machado-Joseph , Ataxias Espinocerebelares , Adulto , Humanos , Doença de Machado-Joseph/diagnóstico , Doença de Machado-Joseph/genética , Movimentos Oculares , Ataxias Espinocerebelares/diagnóstico , Ataxias Espinocerebelares/genética , Heterozigoto , Índice de Gravidade de Doença , Progressão da DoençaRESUMO
Little is known about access of rare disease carriers to health care. To increase this knowledge, the Pan American Hereditary Ataxia Network (PAHAN) conducted an exploratory survey about care for hereditary ataxias in American continents and the Caribbean. A questionnaire was sent to health professionals about the hereditary ataxias identified; access to care; and local teaching and research. The number of ataxics under current care per 100,000 inhabitants was subtracted from the expected overall prevalence of 6/100,000, to estimate the prevalence of uncovered ataxic patients. Local Human Development Indexes (HDI) were used to measure socio-economic factors. Twenty-six sites participated. Twelve sites had very high, 13 had high, and one site had medium HDI. Participants reported on 2239 and 602 patients with spinocerebellar ataxias and recessive forms under current care. The number of patients under current care per inhabitants varied between 0.14 and 12/100,000. The estimated prevalence of uncovered ataxic patients was inversely proportional to HDIs (rho = 0.665, p = 0.003). Access to diagnosis, pre-symptomatic tests, and rehabilitation were associated with HDIs. More and better molecular diagnostic tools, protocols and guidelines, and professional training for ataxia care were the top priorities common to all respondents. Evidence of inequalities was confirmed. Lower HDIs were associated with high potential numbers of uncovered ataxic subjects, and with lack of molecular diagnosis, pre-symptomatic testing, and rehabilitation. More and better diagnostic tools, guidelines, and professional training were priorities to all sites. PAHAN consortium might help with the last two tasks.
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Ataxia Cerebelar , Ataxias Espinocerebelares , Degenerações Espinocerebelares , Humanos , Ataxia , Degenerações Espinocerebelares/epidemiologia , Ataxias Espinocerebelares/diagnóstico , Ataxias Espinocerebelares/epidemiologia , Ataxias Espinocerebelares/genética , Região do Caribe/epidemiologiaRESUMO
Although health-related quality of life (HRQoL) has been increasingly valued in healthcare and in clinical trials, there is scarce information about it in spinocerebellar ataxia type 3/Machado-Joseph disease (SCA3/MJD). This study describes the HRQoL results obtained from ataxic SCA3/MJD subjects, and their non-ataxic offspring included in the BIGPRO (Biomarkers and genetic modifiers in a study of presymptomatic and symptomatic SCA3/MJD carriers) study. Demographic data, clinical scales, and HRQoL instruments EQ-5D-3L and SF-36 were collected. Subjects at 50% risk were genotyped in a double-blind manner. The time left until the onset of the disease was estimated for mutation carriers with a SARA < 3 and combined with disease duration of ataxic subjects (TimeToAfterOnset). Analyses were performed using PASW Statistics version 18.0, R version 4.0.0, and G*Power 3.1, and p < 0.05 was considered statistically significant. Twenty-three ataxic carriers, 33 pre-ataxic carriers, and 21 controls were enrolled. Significant differences between ataxic carriers and controls were seen in EQ-VAS, EQ-5D Index, and in some domains of EQ-5D-3L and SF-36. EQ-5D Index showed the best effect size between ataxic and controls (Cohen's d = 2.423). Stepwise changes were seen in pre-ataxic subjects, although not statistically significant. TimeToAfterOnset correlated with EQ-5D Index, EQ-VAS, and SF-36 Physical functioning, Role Physical, Pain, and General Health. EQ-5D Index and EQ-VAS correlated with clinical scales in the ataxic group. These results suggest that HRQoL worsens among carriers since pre-ataxic stages and that they might encompass the underlying disease process. In this cohort, SF-36 Physical Functioning, SF-36 General health, and especially EQ-5D Index and EQ-VAS were the best HRQoL instruments to be used as ancillary evidence to support biological and social meanings for future interventions.
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Doença de Machado-Joseph , Ataxias Espinocerebelares , Método Duplo-Cego , Humanos , Doença de Machado-Joseph/genética , Qualidade de Vida , Ataxias Espinocerebelares/genética , Inquéritos e QuestionáriosRESUMO
BACKGROUND: Dentatorubral-pallidoluysian atrophy (DRPLA) is a rare autosomal dominant spinocerebellar ataxia caused by pathological expansion of CAG trinucleotide repeats in the ATN1 gene. Most cases were described in patients from Japanese ancestry who presented with adult-onset progressive cerebellar ataxia associated with cognitive impairment, choreoathetosis and other movement disorders. DRPLA has been rarely described in Brazilian patients. METHODS: We performed a retrospective observational multicentric study including six different Neurology Centers in Brazil. All patients with genetically confirmed diagnosis of DRPLA had their medical records evaluated and clinical, genetic and neuroimaging features were analyzed. RESULTS: We describe of eight Brazilian patients (5 male, 3 female) from four nuclear families with genetically confirmed DRPLA. The most common neurological features included cerebellar ataxia (nâ¯=â¯7), dementia (nâ¯=â¯3), chorea (nâ¯=â¯2), psychiatric disturbances (nâ¯=â¯2), progressive myoclonic epilepsy (nâ¯=â¯2) and severe bulbar signs (nâ¯=â¯1). Progressive myoclonic epilepsy was observed in two juvenile-onset cases before 20-year. A large CAG trinucleotide length was observed in the two juvenile-onset cases and genetic anticipation was observed in all cases. Neuroimaging studies disclosed cerebellar atrophy (nâ¯=â¯6), as well as brainstem and cerebellar atrophy (nâ¯=â¯2) and leukoencephalopathy (nâ¯=â¯1). CONCLUSION: The patients described herein reinforce that clinical features of DRPLA are highly influenced by age of onset, genetic anticipation and CAG repetition lengths. There is a large complex spectrum of neurological features associated with DRPLA, varying from pure cerebellar ataxia to dementia associated with other movement disorders (myoclonus, choreoathetosis). DRPLA is an unusual cause of cerebellar ataxia and neurodegeneration in Brazilian patients.