Introduction

Dentatorubro-pallidoluysian atrophy (DRPLA) is an autosomal dominant spinocerebellar ataxia (SCA) caused by an abnormal expansion of a CAG repeat at ATN1 gene that is located on chromosome 12p13 [1]. Expanded CAG tracts (CAGexp) of this gene show 48 or more repeats, and the age of onset and clinical severity is inversely correlated with length of expansion [2]. DRPLA is very rare in Latin America. For instance, frequency of DRPLA was estimated to be 3.1% among SCAs in Venezuela [3], while only one single case has been described so far in Brazil in an individual of Japanese ancestry [4].

Different phenotypes including chorea, cerebellar ataxia, and progressive myoclonic epilepsy have been described in DRPLA, and there is a close relationship with age at onset and CAGexp length. The cardinal feature of juvenile presentation of the disease (<25 years) is a progressive myoclonic epilepsy, whereas in the late-onset DRPLA (>40 years), progressive ataxia, dementia, and chorea are the core findings. DRPLA is one of the several SCAs due to intraneuronal polyglutamine aggregation. As observed in SCA2, SCA3/Machado Joseph disease, and SCA17, phenotype might change substantially according to age at onset [5].

This work aimed to describe the first case of DRPLA among a large cohort of ataxic individuals from Brazil, to estimate its frequency among other SCAs diagnosed by the same laboratory, and to describe ATN1 CAG repeats distribution in the Brazilian population.

Methods

Adult-onset ataxic patients have been recruited from several neurology and neurogenetics centers from Brazil as previously described. They were included in a SCA screening panel when appropriated and following obtaining written informed consent [6]. Relative frequency of DRPLA among SCAs previously investigated by the same laboratory (Rede Neurogenetica, Laboratorio de Identificacao Genetica, Hospital de Clinicas de Porto Alegre) was obtained. Finally, distribution of the CAG repeats at 411 normal ATN1 alleles from other Brazilian individuals was depicted. The present work has been approved by the Ethics Committee from the institution at which the work was performed—Comissão de Ética em Pesquisa do Hospital de Clínicas de Porto Alegre—which follows the Code of ethics of the World Medical Association (Declaration of Helsinki) and the standards established by the author’s Institutional Review Board and granting agency.

Results and Case Report

The proband was a 69-year-old Brazilian woman of mixed (Iberic, Amerindian, and African) ancestry with a 9-year history of progressive gait ataxia. Family history was remarkable for two affected siblings (Fig. 1a). Both had motor and cognitive impairment, but were not evaluated. Neurological examination disclosed a pure cerebellar syndrome, with predominant axial involvement (Video). Scale for the assessment and rating of ataxia (SARA) was 10 and international cooperative ataxia rating scale (ICARS) was 18. Cognition and mental status were normal, without any evidence of psychiatric disturbance. Mini mental state examination was 27/30 and considered normal according to studies of Brazilian population [7]. There were no abnormal involuntary movements. Deep tendon reflexes, cranial nerve, and sensorial examination were normal. Brain magnetic resonance imaging showed mild cerebellar atrophy (Fig. 1b). Genetic investigation was performed for other genetic ataxias, such as Friedreich ataxia, SCA1, SCA2, SCA3, SCA6, SCA7, SCA10, SCA12, SCA17, and Huntington disease, according to methods described elsewhere [6, 8] and results for all this evaluations were negative. Molecular analysis showed that ATN1 alleles presented 14/52 CAG repeats, which confirms DRPLA diagnosis.

Fig. 1
figure 1

Pedigree of the present DRPLA case (a). Brain MRI shows mild cerebellar and global cerebral cortex atrophy (b)

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By June 2016, 700 index cases presenting adult-onset ataxia were investigated in the same laboratory where the diagnosis was accomplish, by studying nucleotide repeats associated to SCA1, SCA2, SCA3/MJD, SCA6, SCA7, SCA10, SCA12, SCA17, and DRPLA. Some index cases presented a clear autosomal dominant inheritance (487/700), while others were isolate, sporadic individuals without a positive family history (213/700). Table 1 depicts the overall results. Geographical origins varied between different parts of the country, with majority coming from South Brazil [6]. Allele distribution of 176 normal CAG repeats at ATN1 in Brazilian individuals has been formerly documented [6]. Following that, additional subjects were added and 410 alleles were measured, with a median (range) of 14 (5–20) repeats (data until June 2016). Only 4.3% of these CAG alleles show more than 17 repeats (Fig. 2).

Table 1 Relative frequency of spinocerebellar ataxias due to expanded repeats, among the present case series of ataxic Brazilian individuals studied by Rede Neurogenetica
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Fig. 2
figure 2

Distribution of CAG repeats at normal ATN1 alleles obtained from 410 Brazilian chromosomes

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Discussion

DRPLA is an extremely rare form of SCA in Brazil. This was our first case diagnosed and, as far as we are aware, the first case from the general Brazilian population. Patient presented a late-onset form of ataxia, and her diagnosis was achieved after excluding all other forms of SCAs due to expanded nucleotide repeats. The only single Brazilian case previously diagnosed was a man of Japanese ancestry that presented progressive myoclonic epilepsy starting at 17 years of age [4]. Other large case series of SCAs from Brazil did not detect DRPLA [9–11]. Curiously, the two DRPLA individuals diagnosed in Brazil showed the two phenotypic extremes, the juvenile- and the late-onset forms, illustrating that clinical manifestations are independent from geographical origins.

A significant proportion of cases of DRPLA among SCAs in general were found in Japan (7–20%), Singapore (6%), and Korea (3%) [12]. Despite being considered a rare disease in non-Asian populations, DRPLA patients have been eventually reported in several countries, particularly in Europe and America. DRPLA was estimated to affect 0.25 to 1% of European patients with sporadic or autosomal dominant cerebellar ataxia from series with 116 to 809 index cases [1, 2, 13]. A large nationwide, population-based survey improved these figures, identifying DRPLA in 4% of Portuguese SCA families [14]. Brazilian population is greatly mixed and it is hard to state that the present DRPLA expansion would have a Portuguese, Amerindian, or African origin. Regarding the prevalence of DRPLA in other countries of South America, we only found an epidemiologic study of SCA in Venezuela describing an estimated prevalence of 3.1% [3].

Isolated, sporadic forms of DRPLA have been described in both Asian and non-Asian families [1, 15]. There are a number of reasons for this, including unknown family history and early death of affected ancestors. The relative contribution of de novo CAG expansions is uncertain [16]. Normal alleles at ATN1 range from 6 to 35 CAG repeats; those with 17 to 35 repeats are uncommon and considered mutable normal alleles (mNA) [17, 18]. Higher frequencies of mNA in a given population have been related to relatively higher rates of DRPLA. For instance, mNA occurred in 24% of Japanese, in 10% of French, and in 4.3% of the present Brazilian chromosomes. Conversely, DRPLA corresponds to 7–2, 0.25, and 0.20% of SCA families in Japan, France, and Brazil, respectively [1, 2, 14].

Clinical presentation is strongly correlated to the length of expanded CAG repeats [18]. Because this relationship was questioned by small non-Asian series, a systematic review evaluated the clinical and genetic profile of 183 non-Asian DRPLA patients. Clinical phenotype and mode of presentation in non-Asian patients were also highly dependent on CAGexp [15]. Asian and non-Asian affected individuals with more than 65 CAGexp present a juvenile onset and epilepsy as the main finding, whereas those with fewer than 65 CAGexp repeats are non-juvenile cases presenting heterogeneous features that include ataxia, dementia, chorea, and psychiatric disease [15, 18]. The CAGexp of our present case—52 repeats—was within the range of late-onset forms. After 9 years from the beginning of symptoms, she presented a pure form of ataxia. Unfortunately, we were unable to examine her ataxic and demented sibs in order to compare their CAGexp lengths and to correlate them with their more severe manifestations.

This is the first report to date on the occurrence of DRPLA in a Brazilian individual without Japanese ancestry, and also the first report on frequency of DRPLA among a large Brazilian series of SCA families and adult-onset isolated cases of ataxia. The phenotype of a late-onset pure ataxia should be considered in non-Asian DRPLA patients. Taken into account this preliminary observation, we recommend that patients with undetermined SCA should be tested for DRPLA.