Quick viewing(Text Mode)

Trends in the Epidemiology of Spinocerebellar Ataxia Type 3/ Machado-Joseph Disease in the Azores Islands, Portugal

Central JSM Science Bringing Excellence in Open Access

Short Communication *Corresponding author Manuela Lima, Department of Biology, University of the Azores, Rua da Mãe de Deus, 9501-801 Trends in the Epidemiology of Ponta Delgada, São Miguel, Azores, , Tel: +351296650118; Fax: +35196650100; Email:

Spinocerebellar Type 3/ Submitted: 05 July 2016 Accepted: 26 July 2016 Machado-Joseph Disease in the Published: 28 July 2016 Copyright Azores Islands, Portugal © 2016 Lima et al. OPEN ACCESS Maria Andrade de Araújo1#, Mafalda Raposo1-3#, Nadiya Kazachkova1, João Vasconcelos4, Teresa Kay5, and Manuela Keywords • Polyglutamine disease 1-3 Lima * • Prevalence 1Departamento de Biologia, Universidade dos Açores, Portugal • Population isolate 2Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Portugal • Homogeneous cohort 3Instituto de Biologia Molecular e Celular (IBMC), Universidadedo Porto, Portugal 4Serviço de Neurologia, Hospital do Divino Espírito Santo, Portugal 5Departamentode Genética Clínica, Hospital de D. Estefânia, Portugal #Both authors contributed equally to this work

Abstract Spinocerebellar ataxia type 3 (SCA3)/Machado - Joseph disease (MJD) is the most common form of autosomal dominant worldwide. In Portugal, the epidemiological situation of the Azores Islands, known to be a worldwide cluster for this disorder, needs to be regularly monitored. The present work aims to characterize the epidemiological situation of MJD in the Azores Islands, updating values of prevalence and establishing a temporal trend for its evolution from 1980 until the present - day. The prevalence value for the Azores archipelago by the end of 2015 was 39/100 000; prevalence values in the different islands are highly dependent on population size differences within the archipelago. An increase of prevalence from 1981 to 2015 was evidenced in the present study, values ranging from 23 to 39 patient’s per 100 000 habitants, respectively. MJD is recognised worldwide as a ; this study confirms that the Azorean islands still represent an important cluster for this disorder. Given the local burden associated with the high prevalence of SCA3, regional - specific measures need to be reinforced, targeting the improvement of the life - quality of patients and families.

ABBREVIATIONS values of prevalence; the available systematic epidemiological study of MJD in the Azores dates from 1997, reporting 41.6 pa- SCA3: Spinocerebellar Ataxia Type 3; MJD: Machado - Joseph tients per 100000 individuals [4]. The Azorean cluster of MJD pa- Disease; SCA: Spinocerebellar Ataxia; CAG: Cytosine - Adenine - tients is linked to the original descriptions of the disease, which Guanine; PT: Predictive Test; DNA: Deoxyribonucleic Acid; HDES: targeted three distinct families originating from these islands [5- Hospital do Divino Espirito Santo 7]. The extensively studied Azorean pedigrees have allowed the INTRODUCTION development of studies on several aspects of this disease (Table 1). With a pooled average of 2.7 patients per 100000 individu- als, autosomal dominant cerebellar ataxias are globally consid- MJD is an autosomal dominant neurodegenerative disorder ered rare disorders [1]. Amongst the dominant cerebellar ataxias, that involves the cerebellar, ocular, pyramidal, extra pyramidal SCA3/MJD is considered as one of the three most prevalent SCA and peripheral motor systems (revised in [8]); the disease is types [2] http://www.orpha.net/orphacom/cahiers/docs/GB/ characterized by a wide range of clinical manifestations, usually Prevalence_of_rare_diseases_by_alphabetical_list.pdf. In main- starting around 40 years of age, which include ataxia, progressive land Portugal, 56% of all the dominant ataxias correspond to MJD external ophthalmoplegia, pyramidal and extra pyramidal signs, [3], representing a prevalence of 3.1 per 100000 individuals. MJD with rigidity and distal muscular [9,10]. reaches in the Portuguese Islands of the Azores particularly high Survival time for MJD has been reported to be approximately

Cite this article: de Araújo MA, Raposo M, Kazachkova N, Vasconcelos J, Kay T, et al. (2016) Trends in the Epidemiology of Spinocerebellar Ataxia Type 3/ Machado-Joseph Disease in the Azores Islands, Portugal. JSM Brain Sci 1(1): 1001. Lima et al. (2016) Email:

Central Bringing Excellence in Open Access

Table 1: A total of 19 studies were developed based on the Azorean MJD is supportive, as no medication has yet proven effective to either prevent disease or slowdown the progression of symptoms. 1ST AUTHOR & TEAM Double - blind, randomized, placebo controlled clinical trials cohort. Studies are grouped byYEAR scientific theme analyzed.JOURNAL LEADER have been initiated, but those terminated have been inconclusive GENETIC MODIFIERS [18,19]. Noteworthy, several compounds tested in a pre - clinical Raposo M & Lima M 2016 Neuromolecular Medicine setting have been providing promising results [20,21] and are likely candidate for future interventional trials. Raposo M & Lima M 2015 Brain Bettencourt C & Lima M 2011 Archives of The present work aims to characterize MJD’s epidemiological situation in the Azorean islands, by updating values of prevalence BIOMARKERS and establishing a temporal trend for its evolution. Given the Raposo M & Lima M 2015 Movement Disorders impact that MJD has in the Azores Islands, reliable estimates of Raposo M & Lima M 2014 BMC Neurology the overall prevalence of this disease should be important for MOLECULAR MECHANISMS planning and delivering the appropriate provision of health and Journal of Molecular social care to patients and families. In a more global scenario, Bettencourt C & Lima M 2013 Neuroscience MJD in the Azores Islands can provide insights into the paradigm Bettencourt C & Lima M 2012 of population clusters of otherwise rare diseases. Bettencourt C & Lima M 2010 Journal of Human Genetics PATIENTS AND METHODS Bettencourt C & Lima M 2010 Neurogenetics Patients PARTICULAR CLINICAL PRESENTATIONS Individual data on MJD patients was available at the Journal of the Neurological Bettencourt C & Lima M 2013 Sciences Department of Neurology at the HDES. All Azorean pedigrees (which included data from 4generations) were revised and Bettencourt C & Lima M 2011 BMC Neurology updated by the last day of 2015. In all MJD pedigrees considered, PATTERNS OF TRANSMISSION a molecular diagnosis of MJD was available for at least one family Bettencourt C & Lima M 2008 Journal of Human Genetics member. Data concerning a total of 222 patients was compiled: Bettencourt C & Lima M 2008 Journal of Human Genetics for 56% (125/222) of these patients only a clinical diagnosis of MJD was available; for the remaining a clinical as well as a HISTORICAL GENETICS AND EPIDEMIOLOGY molecular diagnosis and the respective genotype were available. Lima M & Coutinho P 2001 Lima M & Abade A 1998 Human Biology The present study is part of a larger project on MJD in Journal of Biosocial Scientific the Azores (PRI - “Projeto Regional Integrado sobre a DMJ”) Lima M & Mayer FM 1998 Archives Neurology approved by the Ethics Committee of the HDES at Ponta Delgada, Lima M & Abade A 1997 Human Biology São Miguel, Azores. PSYCHOLOGY Genetic and clinical variables Genetic Testing and Molecular Gonzalez C & Lima M 2012 Biomarkers For the patients considered in the up - dating of prevalence Gonzalez C & Santos J 2004 Community Genetics (prevalence estimation for 2015), the number of CAG repeats, age at onset and disease duration were available. Furthermore, age at of 20 years (revised in [11]). The causative MJD , ATXN3, onset adjusted for CAG repeats was estimated. The size of the CAG presents a CAG repeat expansion at exon 10 that is polymorphic, tract at ATXN3 was determined as in Bettencourt and colleagues consensually ranging from 13 to 44 CAGs in normal [22], using DNA from blood samples of patients, extracted using [12]. When the CAG tract at the ATXN3 gene contains above 50 repeats [13], the corresponding protein, ataxin-3, gains a toxic the standard procedures. Age at onset was defined as the age of function, triggering a cascade of pathogenic events, including the This information was self - reported by the patients or by the appearance of the first symptoms (normally gait disturbance). formation of aggregates, failure of cellular protein homeostasis, caregivers, during the neurological exam. Disease duration was impairment of axonal transport, transcriptional dysregulation, mitochondrial dysfunction and oxidative stress, as well as age calculated at the time of the present study (last day of 2015). defined as the time elapsed between age at clinical diagnosis and abnormal neuronal signaling (revised in [14]). Epidemiological analysis of MJD in the Azores Based on the determination of the (CAG) length at the n Prevalence update of MJD in the Azores Islands: Patients ATXN3 gene, a direct molecular test is currently available for alive by the last day of 2015 and with known residency in the MJD. Molecular testing warrants differential diagnosis, since Azores were considered in the updating of prevalence. Values in probable MJD patients overlapping of clinical features with for the total Azorean population were obtained from the last other SCAs is widely acknowledged. Testing of healthy at risk population census [23]. individuals is also available, in the context of PT and genetic counselling programs. In the Azores the PT is available in the Temporal trend of prevalence (1981-2015): Patients Azores Islands since 1998 [15-17]. alive by the last day of 1981, 1991, 2001 and 2011 with known residency in the Azores, were considered for prevalence MJD remains an untreatable disorder; patient’s management

JSM Brain Sci 1(1): 1001 (2016) 2/5 Lima et al. (2016) Email:

Central Bringing Excellence in Open Access calculation in each of these years. Values for the total Azorean Island, explains the difference in age at onset between patients population were obtained from the population census of 1981, from these two islands. 1991, 2001 and 2011 [23]. Values of prevalence by island are shown in Figure (1). The Statistical analysis updated overall prevalence of MJD in the Azores (Figure 1) is 39/100 000, a value similar to the previously reported by Lima and Age, CAG repeats number of normal and expanded , age colleagues (1997) [4]. It is known, however, that values presented at onset and disease duration of patients from São Miguel and by Lima et al., (1997) were overestimations; in fact, due to the Flores were compared using the student t-test. Estimated age at onset was calculated by an ANCOVA procedure, in which CAG repeat was treated as covariate. A p-value of 0.05 was considered other spinocerebellar ataxias, clinically undistinguishable from MJD,lack ofwere a molecular included confirmationin the previous until prevalence 1998, cases estimations representing [4]. procedures of the IBM SPSS statistics version 22. Coutinho and colleagues, in 2013, reported values of prevalence as statistically significant. All the analyses were carried out using for mainland Portugal of 3.1 per 100 000 population, although RESULTS AND DISCUSSION Azores was not included (Coutinho et al., 2013). In Azores, Prevalence update of SCA3 in the Azores Islands The 97 MJD patients ascertained by the end of 2015are namelytherefore, Flores the numberIsland as of a identifiedMJD cluster. MJD patients is more than 10 distributed by 7 of the 9 Azorean islands, with a clear times comparatively to mainland Portugal, confirming Azores, concentration of cases in Flores and S. Miguel (Figure 1). For the Prevalence values are highly dependent on population size total cohort, constituted by 51 females and 46 males, the average differences within the archipelago; in the small island of Corvo, age was of 52 ± 15 (mean ± standard deviation) years (Table 2). with only 430 inhabitants, 1 in each 143 is affected (Figure 1). Genetic and clinical data for the sub - group of patients from São Patients from Corvo, however, are originally from the island of Miguel and Flores Islands, representing 78% of the total cohort, are displayed in Table (2). Azorean patients presented earlier this study (633/100 000). Flores, whose particularly high prevalence of MJD is confirmed in age at onset (37 ± 12) when compared to patients from EUROSCA Temporal trend of prevalence (1981-2015) study (N = 403, 40 ± 12), USA (N = 110, 40 ± 11), Japan (N = 126, 41 ± 15) and France (N = 44, 44 ± 12) [24,25]. The number of Data collected allowed the assessment of the number of CAGs repeats in expanded allele in the Azorean cohort was statistically different from all abovementioned cohorts, with 2001, 2011 and 2015. Figure (2) evidences the tendency for the patients in Azores at five different moments - 1981, 1991, exception of the USA cohort [24,25]. In the Azorean cohort, the increase of prevalence. This tendency should be primarily related number of CAGs in the expanded allele explains 68% of the onset with the growing awareness about the disease, both in a medical variance, a value which is 18% higher than that of the EUROSCA and social context, overall allowing a better referral of patients to the clinicians. Furthermore, the availability of the predictive test mixed population sample in the work of Tezenas and colleagues [24],cohort which [24,25]. enrolled This patients finding from could different be related genetic with backgrounds, the use of a carriers. In fact, the adherence to the PT in the Azores was weakening genotype - phenotype correlations. reportedhas, by itself, as being promoted of 20.7%, the early a value identification which is consideredof asymptomatic high, when compared to levels in other similar disorders (16); because Miguel when compared with patients from Flores Island (p < 0.05,Age (Table at onset 2)). wasHowever, significantly taking intolower account for patients as covariate from São in follow - up visits, the time lag between onset and the referral to subjects identified as carriers in the PT are usually engaged in the ANCOVA model the CAG repeats size in the expanded allele; the neurologist is shortened. The large survival time, a common differences of estimated age at onset between São Miguel and feature of MJD patients, should also have contributed to the tendency for the increase of prevalence observed in the Azores size of the CAG tract, which is lower in Flores than in São Miguel in the period analysed. Flores were not statistically significant. Therefore, the average Table 2: Age, CAG repeats size of normal and expanded allele, age at onset, estimated age at onset and disease duration of patients from São Miguel and Flores Islands, the two most representative islands for MJD. N Total N São Miguel N Flores Gender, Female/Male 97 51/46 52 29/23 24 15/9 Age, yrs 97 52 ± 15 [20-85] 52 50 ± 15 [20-85]# 24 59 ± 16 [31-85]# Normal allele, (CAG)n size 86 22 ± 4 [14-29] 47 21 ± 4 [14-28] 20 21 ± 4 [14-27] Mutant allele, (CAG)n size 87 71 ± 3 [64-79] 47 71 ± 3 [65-78]# 21 69 ± 4 [64-79]# Age at onset, years 92 37 ± 11 [16-71] 50 36 ± 1 [16-71] 24 41 ± 12 [18-70] Estimated age at onset*, yrs 86 36 ± 2 47 37 ± 1 21 35±2 Disease duration, yrs 92 14 ± 9 [1-39] 50 14 ± 9 [1-33] 24 18 ± 10 [2-39] Yrs=years; all continuous variables are described as mean ± standard deviation [minimum-maximum], exceptionally for estimated age at onset; *age at onset was estimated (mean ± standard error) using an ANCOVA model, for which the CAG repeats size in mutant allele was set as covariate (71 CAGs); #p-value lower than 0.05

JSM Brain Sci 1(1): 1001 (2016) 3/5 Lima et al. (2016) Email:

Central Bringing Excellence in Open Access

Figure 1 Number of MJD patients and prevalence values calculated by the last day of 2015 for each Azorean island. Circles denote the number of patients by island; shaded areas display values of prevalence.

Figure 2 moments (1981, 1991, 2001, 2011 and 2015). Temporal trend of prevalence in the Azores archipelago, evidencing an increase of prevalence during the last 35 years; values were calculated in five different

CONCLUSION 2. Durr A. Autosomal dominant cerebellar ataxias: polyglutamine expansions and beyond. Lancet Neurol. 2010; 9: 885-894. MJD is recognised, worldwide, as a rare disease; this study 3. Coutinho P, Ruano L, Loureiro JL, Cruz VT, Barros J, Tuna A, et al. Hereditary ataxia and spastic paraplegia in Portugal: a population- for this disorder. Given the fact that Azorean MJD patients share based prevalence study. JAMA Neurol. 2013; 70: 746-755. geneticconfirms and that environmentthe Azorean islands conditions, represent the studyan important of non cluster - CAG factors underlying disease variability should be facilitated. 4. Lima M, Mayer F, Coutinho P, Abade A. Prevalence, geographic distribution, and genealogical investigation of Machado-Joseph More importantly, given the local burden associated with disease in the Azores (Portugal). Hum Biol. 1997; 69: 383-391. reinforced, targeting the improvement of the life - quality of 5. Woods BT, Schaumburg HH. Nigro-spino-dentatal degeneration with nuclear ophthalmoplegia. A unique and partially treatable clinico- patients.the high prevalence, regional - specific measures need to be pathological entity. J Neurol Sci. 1972; 17: 149-166.

REFERENCES 6. Rosenberg RN, Nyhan WL, Bay C, Shore P. Autosomal dominant 1. Ruano L, Melo C, Silva MC, Coutinho P. The global epidemiology of striatonigral degeneration. A clinical, pathologic, and biochemical hereditary ataxia and spastic paraplegia: a systematic review of study of a new . Neurology. 1976; 26: 703-714. prevalence studies. Neuroepidemiology. 2014; 42: 174-183. 7. Nakano KK, Dawson DM, Spence A. Machado disease. A hereditary

JSM Brain Sci 1(1): 1001 (2016) 4/5 Lima et al. (2016) Email:

Central Bringing Excellence in Open Access

ataxia in Portuguese emigrants to Massachusetts. Neurology. 1972; 17. Gonzalez C, Gomes E, Kazachkova N, Bettencourt C, Raposo M, Kay TT, 22: 49-55. 8. mutation.et al. Psychological Genet Test well-being Mol Biomarkers. and family 2012; satisfaction 16: 1363-1368. levels five years descriptions to new perspectives. Orphanet J Rare Dis. 2011; 6: 35. after being confirmed as a carrier of the Machado-Joseph disease Bettencourt C, Lima M. Machado-Joseph Disease: from first 18. Zesiewicz TA, Greenstein PE, Sullivan KL, Wecker L, Miller A, Jahan I, 9. Lima L, Coutinho P. Clinical criteria for diagnosis of Machado-Joseph et al. A randomized trial of varenicline (Chantix) for the treatment of disease: report of a non-Azorena Portuguese family. Neurology. 1980; spinocerebellar ataxia type 3. Neurology. 2012; 78: 545-550. 30: 319-322. 19. Saute JA, de Castilhos RM, Monte TL, Schumacher-Schuh AF, Donis 10. Coutinho P, Andrade C. Autosomal dominant system degeneration KC, D’Ávila R, et al. A randomized, phase 2 clinical trial of lithium in Portuguese families of the Azores Islands. A new genetic disorder carbonate in Machado-Joseph disease. Mov Disord. 2014; 29: 568-573. involving cerebellar, pyramidal, extrapyramidal and motor functions. Neurology. 1978; 28: 703-709. 20. Teixeira-Castro A, Jalles A, Esteves S, Kang S, da Silva Santos L, Silva-Fernandes A, et al. Serotonergic signalling suppresses 11. Paulson HL. Dominantly inherited ataxias: lessons learned from aggregation and neurotoxicity in animal models of Machado-Joseph Machado-Joseph disease/spinocerebellar ataxia type 3. Semin Neurol. disease. Brain. 2015; 138: 3221-3237. 2007; 27: 133-142. 21. Cunha-Santos J, Duarte-Neves J, Carmona V, Guarente L, Pereira de 12. Maciel P, Costa MC, Ferro A, Rousseau M, Santos CS, Gaspar C, et al. Almeida L, Cavadas C. Caloric restriction blocks neuropathology and Improvement in the molecular diagnosis of Machado-Joseph disease. Arch Neurol. 2001; 58: 1821-1827. SIRT1 pathway. Nat Commun. 2016; 7: 11445. 13. Gan SR, Ni W, Dong Y, Wang N, Wu ZY. Population genetics and new motor deficits in Machado-Joseph disease mouse models through 22. Bettencourt C, Fialho RN, Santos C, Montiel R, Bruges-Armas J, Maciel insight into range of CAG repeats of spinocerebellar ataxia type 3 in P, et al. Segregation distortion of wild-type at the Machado- the Han Chinese population. PLoS One. 2015; 10: 0134405. Joseph disease locus: A study in normal families from the Azores 14. Costa Mdo C, Paulson HL. Toward understanding Machado-Joseph islands (Portugal). J Hum Genet. 2008; 53: 333-339. disease. Prog Neurobiol. 2012; 97: 239-257. 23. Instituto Nacional de Estatística 15. Lima M, Kay T, Vasconcelos J, Mota-Vieira L, Gonzalez C, Peixoto A, 24. Tezenas du Montcel S, Durr A, Bauer P, Figueroa KP, Ichikawa Y, et al. Disease knowledge and attitudes toward predictive testing and Brussino A, et al. Modulation of the age at onset in spinocerebellar prenatal diagnosis in families with Machado-Joseph disease from the ataxia by CAG tracts in various . Brain. 2014; 137: 2444-2455. Azores Islands (Portugal). Community Genet. 2001; 4: 36-42. 25. Raposo M, Ramos A, Bettencourt C, Lima M. Replicating studies of 16. Gonzalez C, Lima M, Kay T, Silva C, Santos C, Santos J. Short-term psychological impact of predictive testing for Machado-Joseph cohorts aid? Brain. 2015; 138: 398. disease: and anxiety levels in individuals at risk from the genetic modifiers in spinocerebellar ataxia type 3: can homogeneous Azores (Portugal). Community Genet. 2004; 7: 196-201.

Cite this article de Araújo MA, Raposo M, Kazachkova N, Vasconcelos J, Kay T, et al. (2016) Trends in the Epidemiology of Spinocerebellar Ataxia Type 3/Machado-Joseph Dis- ease in the Azores Islands, Portugal. JSM Brain Sci 1(1): 1001.

JSM Brain Sci 1(1): 1001 (2016) 5/5

Top View