DRPLA: An unusual disease or an underestimated cause of ataxia in Brazil?

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 (n = 7), dementia (n = 3), chorea (n = 2), psychiatric disturbances (n = 2), progressive myoclonic epilepsy (n = 2) and severe bulbar signs (n = 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 (n = 6), as well as brainstem and cerebellar atrophy (n = 2) and leukoencephalopathy (n = 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.

[Polynucleotide repeat expansion of nine spinocerebellar ataxia subtypes and dentatorubral-pallidoluysian atrophy in healthy Chinese Han population].

OBJECTIVE: To assist the establishment of platform and provide the reference standard for mutation detection in spinocerebellar ataxia (SCA) subtypes 1, 2, 3, 6, 7, 8, 10, 12, 17 and dentatorubral-pallidoluysian atrophy (DRPLA) in Chinese Han population. METHODS: The nucleotide repeat numbers of the 9 SCA subtypes and DRPLA were detected using fluorescence-PCR and capillary gel electrophoresis technique in 300 healthy Chinese Han individuals. RESULTS: Among the 300 healthy controls, the range of the CAG trinucleotide repeat number was 17 to 35 in SCA1, 14-28 in SCA2, 13-41 in SCA3/MJD, 4-16 in SCA6, 5-17 in SCA7, 5-21 in SCA12, 23-41 in SCA17, and 12-33 in DRPLA; and the range of CTA/CTG trinucleotide repeat number on SCA8 locus was 12-43 and the range of ATTCT pentanucleotide repeat number on SCA10 locus was 9-32. Of which, the 12 CTA/CTG repeats of SCA8, 9 ATTCT repeats of SCA10, 23 CAG repeats of SCA17 were the shortest normal repeat number, while the 41 CAG repeats of SCA3/MJD, 32 CAG repeats of SCA10 were the largest normal number that have not been reported. CONCLUSION: The normal ranges of polynucleotide repeats of different subtypes of SCA vary with geographical areas and ethnicities. It might be associated with the genetic and ethnic backgrounds. This is the first normal reference standard of polynucleotide repeat number of these ten SCA subtypes in Chinese Han.

Clinical and genetic characteristics of non-Asian dentatorubral-pallidoluysian atrophy: A systematic review.

Dentatorubral-pallidoluysian atrophy (DRPLA) is an inherited neurodegenerative disorder regarded as found almost exclusively among the Japanese. We have performed as systematic review of published literature to investigate the clinical and genetic characteristics of non-Asian DRPLA. We identified 183 non-Asian patients in 27 families reported with DRPLA with a variable level of clinical information. Mean age at onset was 31 (range 1-67) with epilepsy, ataxia, and chorea common presenting features. A highly significant relationship was identified between repeat length and age at onset with repeat length accounting for 62% of the observed variation in age at onset (P < 0.0001). In addition, a highly significant relationship between repeat length and main presenting complaint was identified (P < 0.001). There was evidence of marked anticipation with a median intergenerational reduction in age at onset of 19 years with a corresponding increase of five repeats per generation. DRPLA is not exclusively found among the Japanese but has been reported worldwide. As such, DRPLA should be considered in the differential diagnosis of a wide spectrum of neurological disease, particularly if there is a dominant family history. Non-Asian DRPLA clinico-genetic phenomenology are similar to Asian series and our study confirms marked genetic anticipation together with a clear association between repeat length and clinical phenotype and disease severity.

Dentatorubral pallidoluysian atrophy in South Wales.

BACKGROUND: Dentatorubral pallidoluysian atrophy (DRPLA) is a rare, autosomal dominant, clinically heterogeneous neurodegenerative disorder characterised clinically by progressive dementia, ataxia, chorea, myoclonic epilepsy and psychiatric disturbance and pathologically by combined degeneration of the dentatorubral and pallidoluysian systems. DRPLA has a marked ethnic predilection, most commonly reported in Japan and thought to be rare in Caucasian populations. METHODS: We describe the clinical and genetic characteristics of 17 patients with DRPLA segregating in four families in South Wales. RESULTS: There was marked clinical heterogeneity with considerable overlap of symptoms and signs between and within families. The age of onset ranged from 34 to 60 years with an earlier onset associated with myoclonic epilepsy and a later onset associated with a Huntington disease-like presentation. We identified a distinct haplotype within one family not present within the other three families, suggesting that the expansion in at least one family did not arise from an immediate common ancestor. Analysis of repeat length polymorphisms in 306 Welsh control patients identified 14 (4.6%) with repeat lengths in the high-normal range, compared with 0% and 7.4% in previously reported north American Caucasian and Japanese control populations, respectively. CONCLUSIONS: DRPLA may not be as geographically or ethnically restricted as previously thought and the diagnosis should be considered in non-Asian patients presenting with a wide spectrum of neurological disease, especially if there is a dominant family history of dementia or movement disorder. The prevalence of high-normal length alleles may account for the relatively high prevalence of DRPLA in Wales.

Portuguese families with dentatorubropallidoluysian atrophy (DRPLA) share a common haplotype of Asian origin.

Dentatorubropallidoluysian atrophy (DRPLA) is an autosomal dominant neurodegenerative disorder characterized by a variable combination of progressive ataxia, epilepsy, myoclonus, choreoathetosis and dementia. This disease is caused by a (CAG)(n) expansion in the DRPLA gene, on chromosome 12p13. DRPLA is prevalent in Japan, but several families of non-Japanese ancestry have already been published. To identify the origin of expanded alleles in Portuguese families with DRPLA, we studied two previously reported intragenic SNPs in introns 1 and 3, in addition to the CAG repeat of the DRPLA gene. The results showed that all four Portuguese DRPLA families shared the same haplotype, which is also common to that reported for Japanese DRPLA chromosomes. This haplotype is also the most frequent in Japanese normal alleles, whereas it was rare in Portuguese control chromosomes. Thus, our findings support that a founder DRPLA haplotype of Asian origin was introduced in Portugal, being responsible for the frequency of the disease in this country.

Dentatorubropallidoluysian atrophy in Chinese.

BACKGROUND: Dentatorubropallidoluysian atrophy (DRPLA) is a rare, autosomal dominant neurodegenerative disease characterized by a range of clinical manifestations, including cerebellar ataxia, epilepsy, myoclonus, choreoathetosis, and dementia. Outside the Japanese population, the prevalence is extremely low worldwide. The reason for different ethnic prevalences of DRPLA is unclear. A previous assumption was that large normal alleles contribute to generation of expanded alleles and the relative frequencies of DRPLA. OBJECTIVES: To describe the clinical, radiological, and genetic features of the first reported Chinese family with DRPLA, to our knowledge, and to compare the size distribution of normal alleles at the DRPLA locus in healthy Chinese individuals with that of other ethnic groups. PATIENTS AND METHODS: Of 80 Chinese kindreds with autosomally dominant spinocerebellar ataxias, 1 pedigree with 2 affected patients was found by polymerase chain reaction to carry the characteristic DRPLA mutation. The allele frequencies of different CAG repeat lengths at the DRPLA locus in 225 healthy Chinese individuals were also analyzed and compared with Japanese, white, and African American distributions. RESULTS: The clinical presentations of the 2 Chinese patients affected with DRPLA are similar to those described in Japanese patients, except that the affected father exhibited myoclonus but not chorea. Although the normal DRPLA allele size is distributed similarly in Chinese and Japanese populations, DRPLA in Chinese individuals is rare. Thus far, to our knowledge, only 1 intermediate-sized allele containing more than 30 CAG repeats has been reported among healthy Chinese individuals, in contrast to 3 among Japanese populations. CONCLUSION: The ethnic prevalence of DRPLA seems to be correlated with the prevalence of intermediate-sized alleles in individual populations.

The first identified French family with dentatorubral-pallidoluysian atrophy.

We report the first French family with dentatorubral-pallidoluysian atrophy (DRPLA) in which three members, a 36-year-old woman (proband), her 34-year-old sister, and 14-year-old brother were affected. There was no family history of DRPLA and their father presented at age 66 with pes cavus but without any other neurologic symptoms. Molecular analysis of the DRPLA gene from blood leukocytes showed CAG repeat sizes to be 68/16 in the proband, 62/15 in her father, and 16/16 in her mother. This study provides support for the variable clinical presentation of this disease with incomplete penetrance in the father and demonstrates that DRPLA can be observed in the French Caucasian population.