Diagnostic Delay of Hereditary Ataxias in Brazil: the Case of Machado-Joseph Disease.

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.

Machado Joseph-Disease Is Rare in the Peruvian Population.

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.

Founder Effects of Spinocerebellar Ataxias in the American Continents and the Caribbean.

Spinocerebellar ataxias (SCAs) comprise a heterogeneous group of autosomal dominant disorders. The relative frequency of the different SCA subtypes varies broadly among different geographical and ethnic groups as result of genetic drifts. This review aims to provide an update regarding SCA founders in the American continents and the Caribbean as well as to discuss characteristics of these populations. Clusters of SCAs were detected in Eastern regions of Cuba for SCA2, in South Brazil for SCA3/MJD, and in Southeast regions of Mexico for SCA7. Prevalence rates were obtained and reached 154 (municipality of Báguano, Cuba), 166 (General Câmara, Brazil), and 423 (Tlaltetela, Mexico) patients/100,000 for SCA2, SCA3/MJD, and SCA7, respectively. In contrast, the scattered families with spinocerebellar ataxia type 10 (SCA10) reported all over North and South Americas have been associated to a common Native American ancestry that may have risen in East Asia and migrated to Americas 10,000 to 20,000 years ago. The comprehensive review showed that for each of these SCAs corresponded at least the development of one study group with a large production of scientific evidence often generalizable to all carriers of these conditions. Clusters of SCA populations in the American continents and the Caribbean provide unusual opportunity to gain insights into clinical and genetic characteristics of these disorders. Furthermore, the presence of large populations of patients living close to study centers can favor the development of meaningful clinical trials, which will impact on therapies and on quality of life of SCA carriers worldwide.

Mitochondrial DNA haplogroups and age at onset of Machado-Joseph disease/spinocerebellar ataxia type 3: a study in patients from multiple populations.

BACKGROUND AND PURPOSE: Mitochondrial dysfunction has been implicated in the pathogenesis of several neurodegenerative disorders, including Machado-Joseph disease (MJD), an autosomal dominant late-onset polyglutamine ataxia that results from an unstable expansion of a CAG tract in the ATXN3 gene. The size of the CAG tract only partially explains age at onset (AO), highlighting the existence of disease modifiers. Mitochondrial DNA (mtDNA) haplogroups have been associated with clinical presentation in other polyglutamine disorders, constituting potential modifiers of MJD phenotype. METHODS: A cross-sectional study, using 235 unrelated patients from Portugal, Brazil, India and Japan, was performed to investigate if mtDNA haplogroups contribute to AO of MJD. mtDNA haplogroups were obtained after sequencing the mtDNA hypervariable region I. Patients were classified in 15 phylogenetically related haplogroup clusters. RESULTS: The AO was significantly different among populations, implying the existence of other non-CAG factors, which seem to be population specific. In the Portuguese population, patients classified as belonging to haplogroup JT presented the earliest onset (estimated onset 34.6 years of age). Haplogroups W and X seem to have a protective effect, causing a delay in onset (estimated onset 47 years of age). No significant association between haplogroup clusters and AO was detected in the other populations or when all patients were pooled. Although haplogroup JT has already been implicated in other neurodegenerative disorders, no previous reports of an association between haplogroups W and X and disease were found. CONCLUSIONS: These findings suggest that haplogroups JT, W and X modify AO in MJD. Replication studies should be performed in European populations, where the frequency of the candidate modifiers is similar.

Sleep apnea in Machado-Joseph disease: a clinical and polysomnographic evaluation.

OBJECTIVE/BACKGROUND: Machado-Joseph disease (MJD) or spinocerebellar ataxia type 3 (SCA3) is the most common type of autosomal dominant spinocerebellar ataxia (SCA). Sleep disorders have been described as frequent non-motor symptoms in MJD, and with marked impairment on quality of life. However, few studies have evaluated the frequency and characteristics of sleep apnea in MJD. PATIENTS/METHODS: This study analyzed the prevalence of sleep apnea in 47 patients with MJD by using polysomnography. Clinical variables such as age, age at onset of symptoms, duration of symptoms (at time of evaluation), body index mass, ataxia scales severity and CAG repeat length were compared with polysomnographic findings. RESULTS: Thirty four percent of MJD patients had OSAS, and 42.5% had excessive daytime somnolence. There were no differences considering ataxia severity, CAG repetition length or other clinical variable. CONCLUSIONS: Patients with MJD have high frequency of obstructive sleep apnea, and this sleep disorder is not correlated with ataxia severity, CAG repetition length or other clinical variable.

Motivation to perform presymptomatic testing in portuguese subjects at-risk for late-onset genetic diseases

El papel del psicólogo clínico en el contexto del consejo genético incluye brindar apoyo a los sujetos en riesgo en el proceso de toma de decisiones, independientemente de la decisión adoptada por el sujeto (conociendo o no el resultado de las pruebas genéticas). El estudio que se informa aborda la motivación para realizar las pruebas pre-sintomáticas (PPS) de sujetos en situación de riesgo para tres enfermedades: polineuropatía amiloide familiar (PAF), la enfermedad de Huntington (EH) y la enfermedad de Machado-Joseph (EMJ) y comparar con la motivación para realizar las PPS para hemocromatosis (HH). La muestra consistió en 213 sujetos portugueses que tenían riesgo genético para contraer las tres enfermedades y 31 sujetos en situación de riesgo genético para contraer hemocromatosis. Ellos fueron evaluados con una entrevista para obtener datos sociodemográficos y debían responder a una pregunta sobre la motivación para llevar a cabo las pruebas pre-sintomáticas. Se obtuvieron siete categorías principales y las siguientes son las más significativas para PAF, EH y EMJ: razones relacionadas con el futuro, razones relacionadas con los demás y razones relacionadas con la curiosidad y la necesidad de conocer. Para hemocromatosis, las más importantes resultaron ser razones relacionadas con los demás y las relacionadas con las características de la enfermedad. La motivación para realizar el test pre-sintomático (PST) de la PAF, EH y EMJ es externa y sin relación con la enfermedad, mientras que la motivación de los sujetos en situación de riesgo para la HH está relacionada con la enfermedad. Las razones relacionadas con los demás es una motivación común en ambos grupos. A los sujetos también les preocupa la posibilidad de transmitir la enfermedad a sus hijos.

The role of the clinical psychologist in the context of genetic counseling includes support for the process of decision-making for subjects at-risk, regardless of the decision that was made. For this, it is important to know the motivations behind these decisions. What may be considered advant-ageous and justifiable reasons to perform the PST for genetic diseases from the medical and public point of view, i.e., planning for the future, helping in the choice of a profession, family planning, improving quality of life and contributing to health, may not be recognized as such by the individual seeking the PST. This study addresses the motivation to perform the presymptomatic testing (PST) of subjects at-risk for three diseases, Familial Amyloid Polyneuro pathy (FAP), Huntington's disease (HD), and Machado-Joseph disease (MJD), compared with the motivation to perform the PST for Hemochromatosis (HH). FAP, HD and MJD are three genetic (monogenic) autosomal dominant late-onset diseases (LON-Ds) with no cure. FAP is a progressive sensorimotor and autonomic neuropathy of adult hood. HD is characterized by a triad of clinical symptoms of chorea (motor, cognitive and psychiatric symptoms), emotional distress and cognitive decline. MJD is characterized by slowly progressive clumsiness in the arms and legs, a staggering lurching gait, sometimes mistaken for drunkenness, difficulty with speech and swallowing, involuntary eye movements, and may be accompanied by double vision or bulging eyes, and lower limb spasticity. HH is a disease in which too much iron accumulates in parenchymal organs, leading to iron overload and subsequent organ toxicity and failure. The study participants consisted in 213 subjects at genetic risk for FAP, HD, and MJD and 31 subjects at genetic risk for HH, that were assessed through an interview to obtain sociodemographic data and the answer to one question about motivation to perform PST: "Which were the reasons that led you to perform the predictive test? "This study was carried out in Center for Predictive and Preventive Genetics (CGPP), Institute for Molecular and Cell Biology (IBMC), Porto (Portugal). This research used a mixed-method, since qualitative and quantitative techniques of data analysis were used. Before deciding to seek genetic counseling and to know their genetic status, subjects at-risk have naturally considered their motives and it was probably the pro-counseling reasons the ones dictating the motivation to perform the PST. This may suggest that in fact there is a prior self-selection to the test, i.e. only those considering to have emotional skills to go through the process, performing the test. Seven major categories were obtained. The most significant ones for FAP, HD and MJD were reasons related to the future, reasons related to others and reasons related to curiosity and to the need to know. For HH, the most important ones were reasons related to others and reasons related to the characteristics of the disease. The motivation of subjects at-risk to perform the PST for FAP, HD and MJD is external and unrelated to the disease, while the motivation of subjects at-risk to perform the PST for HH is related to the disease. Reasons related to others area common motivation: as subjects at-risk for FAP, HD and MJD, subjects at-risk for HH also chose reasons related to others as one of the most important motivations to carry out the PST. These subjects also care about the fact that they can transmit the disease to their children and care about other family members which are already ill. The category reasons related to others includes sub-categories that identify the person and the situation that led to the decision to perform a PST. Subjects at-risk are also concerned about the fact that they have to decide whether or not to have children and its economic implications.

Spinocerebellar ataxia type 3/Machado-Joseph disease: segregation patterns and factors influencing instability of expanded CAG transmissions.

Controversies about Mendelian segregation and CAG expansion (CAGexp) instabilities during meiosis in spinocerebellar ataxia type 3/Machado-Joseph disease (SCA3/MJD) need clarification. Additional evidence about these issues was obtained from the cohort of all SCA3/MJD individuals living in South Brazil. A survey was carried out to update information registered since 2001. Deaths were checked with the Public Information System, and data was made anonymous. Anticipation and delta-CAGexp from parent-offspring pairs, and delta-CAGexp between siblings were obtained. One hundred and fifty-nine families (94% of the entire registry) were retrieved, comprising 3725 living individuals as of 2015, 625 of these being symptomatic. Minimal prevalence was 6:100,000. Carriers of a CAGexp represented 65.6% of sibs in the genotyped offspring (p < 0.001). Median instability was larger among paternal than maternal transmissions, and instabilities correlated with anticipation (r = 0.38; p = 0.001). Age of the parent correlated to delta-CAGexp among 115 direct parent-offspring CAGexp transmissions (ρ = 0.23, p = 0.014). In 98 additional kindreds, the delta-CAGexp between 269 siblings correlated with their delta-of-age (ρ = 0.27, p < 0.0001). SCA3/MJD was associated with a segregation distortion favoring the expanded allele in our cohort. Instability of expansion during meiosis was weakly influenced by the age of the transmitting parent at the time of conception.

Cervical and ocular vestibular evoked potentials in Machado-Joseph disease: Functional involvement of otolith pathways.

INTRODUCTION: Machado-Joseph disease is defined as an autosomal dominant ataxic disorder caused by degeneration of the cerebellum and its connections and is associated with a broad range of clinical symptoms. The involvement of the vestibular system is responsible for several symptoms and signs observed in the individuals affected by the disease. We measured cervical and ocular vestibular evoked myogenic potentials in a sample of Machado-Joseph disease patients in order to assess functional pathways involved. METHODS: Bilateral measures of cervical and ocular vestibular evoked myogenic potentials (cVEMP and oVEMP) were obtained from 14 symptomatic patients with genetically proven Machado-Joseph disease and compared with those from a control group of 20 healthy subjects. RESULTS: Thirteen (93%) patients showed at least one abnormal test result; oVEMP and cVEMP responses were absent in 17/28 (61%) and 11/28 (39%) measures, respectively; and prolonged latency of cVEMP was found in 3/28 (11%) measures. Of the 13 patients with abnormal responses, 9/13 (69%) patients showed discordant abnormal responses: four with absent oVEMP and present cVEMP, two with absent cVEMP and present oVEMP, and three showed unilateral prolonged cVEMP latencies. CONCLUSION: Both otolith-related vestibulocollic and vestibulo-ocular pathways are severely affected in Machado-Joseph disease patients evaluated by VEMPs.

Epidemiological, clinical, and molecular characterization of Cuban families with spinocerebellar ataxia type 3/Machado-Joseph disease.

BACKGROUND: Spinocerebellar Ataxia Type 3/Machado-Joseph Disease (SCA3/MJD) is a hereditary neurodegenerative disorder resulting from the expansion of CAG repeats in the ATXN3 gene. It is the most common autosomal dominant ataxia in the world, but its frequency prevalence in Cuba remains uncertain. We undertook a national study in order to characterize the ATXN3 gene and to determine the prevalence of SCA3/MJD in Cuba. RESULTS: Twenty-two individuals belonging to 8 non-related families were identified as carriers of an expanded ATXN3 allele. The affected families come from the central and western region of the country. Ataxia of gait was the initial symptom in all of the cases. The normal alleles ranged between 14 and 33 CAG repeats while the expanded ones ranged from 63 to 77 repeats. The mean age at onset was 40 ± 9 years and significantly correlated with the number of CAG repeats in the expanded alleles. CONCLUSIONS: This disorder was identified as the second most common form of spinocerebellar ataxia (SCA) in Cuba based on molecular testing, and showing a different geographical distribution from that of SCA2. This research constitutes the first clinical and molecular characterization of Cuban SCA3 families, opening the way for the implementation of predictive diagnosis for at risk family members.

Brain stem and cerebellum volumetric analysis of Machado Joseph disease patients / Análise volumétrica de cerebelo e tronco cerebral de pacientes com doença de Machado Joseph

Machado-Joseph disease, or spinocerebellar ataxia type 3(MJD/SCA3), is the most frequent late onset spinocerebellar ataxia and results from a CAG repeat expansion in the ataxin-3 gene. Previous studies have found correlation between atrophy of cerebellum and brainstem with age and CAG repeats, although no such correlation has been found with disease duration and clinical manifestations. In this study we test the hypothesis that atrophy of cerebellum and brainstem in MJD/SCA3 is related to clinical severity, disease duration and CAG repeat length as well as to other variables such as age and ICARS (International Cooperative Ataxia Rating Scale). Whole brain high resolution MRI and volumetric measurement with cranial volume normalization were obtained from 15 MJD/SCA3 patients and 15 normal, age and sex-matchedcontrols. We applied ICARS and compared the score with volumes and CAG number, disease duration and age. We found significant correlation of both brain stem and cerebellar atrophy with CAG repeat length, age, disease duration and degree of disability. The Spearman rank correlation was stronger with volumetric reduction of the cerebellum than with brain stem. Our data allow us to conclude that volumetric analysis might reveal progressive degeneration after disease onset, which in turn is linked to both age and number of CAG repeat expansions in SCA 3.

Doença de Machado-Joseph, ou ataxia espinocerebelar tipo 3 (MJD/SCA3) é ataxia espinocerebelar de início tardio mais frequente e resulta de uma expansão da repetição CAG no gene da ataxina-3. Estudos precedentes encontraram correlação entre a atrofia do cerebelo e do tronco cerebral com a idade e número de expansões CAG. Tais correlações não foram encontradas em relação ao tempo de doença ou manifestações clínicas. Neste estudo testamos a hipótese de que a atrofia do cerebelo e do tronco encefálico em MJD/SCA3 está relacionada à gravidade clínica, duração da doença e número de repetições CAG, bem como com outras variáveis como a idade e a ICARS (escala cooperativa internacional de avaliação de ataxias). Foram realizados estudos de imagem pela ressonância magnética de alta resolução e volumetria com normalização de volume craniano de 15 pacientes portadores de MJD/SCA3 e 15 controles pareados por idade e sexo. Nós aplicamos a ICARS e correlacionamos com o escore de volumes e número de CAG, duração da doença e idade. Encontramos correlação significativa entre atrofia de tronco cerebral e cerebelo com duração da doença, repetição CAG, idade e grau de acometimento da doença. O índice de correlação de Spearman foi maior em relação à atrofia de cerebelo do que à atrofia de tronco. Nossos dados permitem concluir que a análise volumétrica pode revelar degeneração progressiva após o início da doença que, por sua vez, está ligada à idade e número de expansões CAG em SCA 3.