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Table of Contents
Year : 2020  |  Volume : 3  |  Issue : 1  |  Page : 60-64

Genetically confirmed first Indian dentatorubral–pallidoluysian atrophy kindred: A case report

1 Genomics and Molecular Medicine Unit, CSIR-Institute of Genomics and Integrative Biology (CSIR-IGIB), New Delhi, India
2 Department of Neurology, All India Institute of Medical Sciences (AIIMS), New Delhi, India
3 Child Neurology Division, Department of Pediatrics, All India Institute of Medical Sciences (AIIMS), New Delhi, India
4 Department of Neuro-Radiology, All India Institute of Medical Sciences (AIIMS), New Delhi, India

Date of Submission21-Dec-2019
Date of Decision02-Jan-2020
Date of Acceptance21-Feb-2020
Date of Web Publication01-Apr-2020

Correspondence Address:
Dr. Mohammed Faruq
Genomics and Molecular Medicine Unit, CSIR-Institute of Genomics and Integrative Biology (CSIR-IGIB), Mall Road, New Delhi 110007.
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/AOMD.AOMD_38_19

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DRPLA (dentatorubral–pallidoluysian atrophy) is a neurodegenerative disorder caused by cytosine-adenine-guanine (CAG) trinucleotide repeat expansion (>48) in ATN1 gene at 12p13.31 locus inherited in an autosomal-dominant manner. The key clinical manifestations of DRPLA are ataxia, dementia, and myoclonic epilepsy and have variable association with intellectual disability, behavioral changes, epileptic seizures, and choreoathetosis. It is most commonly reported in Japanese population with a prevalence of 0.2–0.7/100,000. Here we report a three-generation first Indian family identified to carry a pathogenic CAG expansion in ATN1 and clinical features conformed to its key manifestations.

Keywords: CAG repeats, dentatorubral–pallidoluysian atrophy, Indian population, trinucleotide repeats

How to cite this article:
Sharma P, Shaikh RG, Shamim U, Anand V, Chakrabarty B, Gulati S, Sonakar AK, Ahmad I, Garg A, Srivastava AK, Faruq M. Genetically confirmed first Indian dentatorubral–pallidoluysian atrophy kindred: A case report. Ann Mov Disord 2020;3:60-4

How to cite this URL:
Sharma P, Shaikh RG, Shamim U, Anand V, Chakrabarty B, Gulati S, Sonakar AK, Ahmad I, Garg A, Srivastava AK, Faruq M. Genetically confirmed first Indian dentatorubral–pallidoluysian atrophy kindred: A case report. Ann Mov Disord [serial online] 2020 [cited 2023 Jun 1];3:60-4. Available from: https://www.aomd.in/text.asp?2020/3/1/60/281750

  Introduction Top

CAG repeat expansion in the fifth exon of ATN1 gene (chr12p13.31) was identified as causal genetic defect for DRPLA (dentatorubral–pallidoluysian atrophy) or Haw River Syndrome or Naito–Oyangi disease by Koide et al.[1] in Japanese kindred. The causal CAG repeat expansion mutation is inherited in an autosomal-dominant manner, and through gain of function of polyglutamine (polyQ) repeats, the mutated protein exerts toxicity to neuronal tissue.[1]

Clinically, DRPLA shows a wide range of neuronal phenotype, and ataxia, dementia, and myoclonic epilepsy are the key features.[2] The association of other neurological phenotypes, that is, intellectual disability, behavioral changes, epileptic seizures, and choreoathetosis, is variable and their occurrence depends on the presenting age. Patients of age group <20 years have shown ataxia, intellectual disability, behavioral changes, and myoclonic epilepsy as the main features, whereas adult-onset presentation (>20 years) includes ataxia, choreoathetosis, and dementia.[2],[3],[4] Radiological features of the brain parenchyma include, prominent neuronal loss in dentate nucleus of cerebellum, calcification of globus pallidus and white matter lesions in the centrum semiovale. Genetically, the reported normal range of polyQ (CAG)n stretch is 6–35 repeat units. Mutable normal repeats range from 20 to 35 and ≥48 is the pathogenic threshold for full penetrance alleles for manifestations of DRPLA. The reported age of onset is from infancy to late adulthood with a mean age of 31.5 years.[5]

The occurrence of DRPLA has been observed (in different ataxia cohort) to be high in Japan (7%–20%), Singapore (6%), and South Korea (3%), whereas in European countries, Portugal has shown frequency of 2%–4%. Latin America has 0.14%–3.1% and few families have been reported in the USA.[6],[7],[8],[9],[10],[11],[12] So far, no case of DRPLA with genetically confirmed status has been reported from India. We report here a three-generation Indian kindred with intrafamilial variable neurodegenerative phenotype with positive gene defect at DRPLA loci.

  Case Report Top

Proband, a 56-year-old woman, presented in our clinic with a history of walking instability since the age of 40 years followed by hand incoordination and speech slurring for last 6–7 years. During this period, the patient required support while walking. At the age of 48 years, she developed behavioral problems in the form of increased aggression. She also had difficulties in identifying names of family members and recalling old memories for the last 5–6 years. Her activities of daily living were severely affected and required permanent support of a person for her routine activities. She had a history of seizure episodes starting a month ago. She also had complaint of dysphagia with solids without history of choking or coughing. There was no history of hallucination or any other abnormal behaviors. Her spontaneous speech had reduced for the last 3 years and presently walks with full support and with stooped posture. The patient had undergone thyroidectomy 20 years ago. History of insomnia and loss of appetite were noted. The patient’s family has multiple affected members in subsequent and her own generation [Figure 1]. Her elder (II:3) and younger sibling (II:9) had similar illness but were not available for the examination or no records were available. In the second generation, four of the members had developed disease in their early childhood and had died at early age (<20 years). Proband’s son, a 35-year-old gentleman, had developed ataxia at the age of 30 years and was not available for clinical workup. Proband’s granddaughter, a 12-year-old girl, had a history of progressive gait ataxia since the age of 5 years and had dysarthria and dysphagia [Table 1]. She was initially evaluated in pediatric outpatient department as a suspected case of developmental delay and baseline intellectual disability at the age of 5 years. Later for follow-up, she was referred to our clinic (detailed evaluation report presented in the section “Clinical Report of Childhood Case in the Kindred”). On examination, proband had hypotonia of all limbs, with reduced limb strength (4/5), and hyperreflexia in all limbs with extensor plantar response. Sensory system examination was normal. Both upper limb and lower limb gait ataxia of severe degree was observed with impaired finger–nose test and heel–shin test. Ataxia severity of Scale for the assessment and rating of Ataxia (SARA) was 34/40 (total score = 40). No additional deficit was observed on examinations of cranial nerves. Other clinical details and paraclinical investigation findings are presented briefly in [Table 1]. Radiologically, magnetic resonance imaging (MRI) brain had shown multiple focal hyperintensities in centrum semiovale and peri-paraventricular white matter (proband, [Figure 1]).
Figure 1: Pedigree structure of dentatorubral–pallidoluysian atrophy (DRPLA) CAG expansion positive kindred showing multiple affected individuals and phenomena of anticipation observed (upper panel). Magnetic resonance imaging (MRI) brains, T2, and fluid-attenuated inversion recovery (FLAIR) axial images showing multiple punctuate hyperintensities in centrum semiovale and paraventricular white matter and atrophy of cerebellum and brain stem (lower left panel). Fragment analysis results showing profile of expanded repeats in affected individuals (lower right panel)

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Table 1: Clinical characteristics of patient found carrier of dentatorubral–pallidoluysian atrophy (ATN1) expansion positives

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  Clinical Report of Childhood Case in the Kindred Top

A 12-year-old girl presented with baseline intellectual disability, drug refractory multi-semiology seizures with cognitive decline from 5 years of age and incoordination with abnormal movements since 5.5 years of age progressing to bedridden state from the age of 9 years. There was none to mild associated dysmorphism and no neurocutaneous stigmata, and the findings of her fundus examination were normal. Salient features on neurological examination were dementia, dyskinesia, dystonia, and axial myoclonus. The findings of rest of the systemic and general physical examination were normal. She was born to a non-consanguineously married couple and had no adverse prenatal or neonatal events. The findings of her cranial nerve examination were normal. Her MRI brain showed diffuse cerebellar and brainstem atrophy. Her electroencephalography (EEG) showed abundant multifocal epileptiform discharges with partly organized background. Low photic stimulation at 3 Hz precipitated bursts of generalized spike wave discharges, and at 6 Hz a generalized tonic-clonic seizure was precipitated. She was provisionally diagnosed to have progressive myoclonic epilepsy, possibilities being mitochondrial cytopathy, juvenile NCL (neuronal ceroid lipofuscinosis), Lafora body disease, sialidosis, and DRPLA.

Although a rarer entity, possibility of DRPLA was high up, in view of proband and her granddaughter’s clinical manifestations and also anticipation in age at onset was noted in the family in successive generation.

  Results and Discussion Top

Genetic investigations for spinocerebellar ataxia (SCAs) (SCA1, SCA2, SCA3, SCA6, SCA7, SCA12, and SCA17) and Huntington disease loci were negative. The results of the test for CAG nucleotide repeats for ATN1 were obtained, and CAG repeats were found in pathogenic range; proband had 14/57 CAG, her son (III:4) had 15/58 repeats, and granddaughter (IV:2) had 9/68 CAG repeats in heterozygosity.

DRPLA is a rare genetic disorder with its greater frequency observed in Japan and other Asian and European countries. Clinically, the key features in adult-onset cases are cerebellar ataxia, choreoathetosis, and dementia, whereas juvenile-onset cases manifest myoclonic epilepsy, cerebellar ataxia, and variable degree of mental retardation. Cerebellar atrophy as well as brain stem atrophy, white matter degeneration in the cortical and subcortical structure are observed and occur more frequently in juvenile cases.[12] Postmortem brain studies show atrophy of dentate nuclei, calcification of globus pallidus, and axonal dystrophy in nucleus gracilis and demyelination of centrum semiovale corroborating with the imaging findings.[13] EEG shows features of partial seizures and generalized tonic-clonic seizures, and the former variant is more associated with earlier onset cases.[14]

To the best of our knowledge, no report of genetically confirmed case of DRPLA has been described from India. In this report, we describe, for the first time, a three-generation Indian kindred carrying DRPLA CAG repeat expansion. The clinical manifestations in this kindred majorly conformed to the reported key features of DRPLA phenotype, that is, ataxia, psychocognitive affection, epilepsy, and pyramidal features in the proband (CAG57) who had late-onset manifestations [Table 1]. The phenomenon of anticipation was characteristically observed in this family within three generations. The patient from third generation (IV:2) had inherited gained CAG repeats during vertical transmission (CAG68). The proband’s son was not available for examination and had onset at the age of 30 years despite a very little difference in CAG length (CAG58). The presence of a substantially higher number of repeats in the granddaughter (IV:2; CAG68) as compared to her father (III:4; CAG58) clearly showed the phenomenon of paternal transmission leading to large expanded repeats in the offspring. Furthermore, the expanded allele in III:4 [Figure 1] was inherited from affected mother (II:7; CAG57), which showed a marginal difference in the repeat numbers between the two generations. This is in concordance with earlier reports where paternal transmission has resulted in juvenile onset and increased severity of the disorder.[15],[16]

The patient with CAG68 had manifestations other than ataxias, and had myoclonic epilepsy and frequent epileptic episodes. This patient also had intellectual disability and mild facial dysmorphism. Our proband had developed one episode of seizure at the age of 56 years, which is unusual for the DRPLA phenotype spectrum associated with CAG <65 repeats. Overall, our report represents first case of Indian DRPLA family and warrants consideration of this entity in phenotype-oriented screening of DRPLA in specific cases. A wider gain in the understanding is required for the estimation of the true burden of DRPLA in Indian population through adequate genetic screening.


We are highly thankful to the patient and members of the family who participated in this study.

Financial support and sponsorship

This study was funded by CSIR projects MLP1601 and MLP1802.

Conflicts of interest

There are no conflicts of interest.

  References Top

Koide R, Ikeuchi T, Onodera O, Tanaka H, Igarashi S, Endo K, et al. Unstable expansion of CAG repeat in hereditary dentatorubral–pallidoluysian atrophy (DRPLA). Nature Genet 1994;6:9-13.  Back to cited text no. 1
Hasegawa A, Ikeuchi T, Koike R, Matsubara N, Tsuchiya M, Nozaki H, et al. Long-term disability and prognosis in dentatorubral-pallidoluysian atrophy: A correlation with CAG repeat length. Mov Disord 2010;25:1694-700.  Back to cited text no. 2
Maruyama S, Saito Y, Nakagawa E, Saito T, Komaki H, Sugai K, et al. Importance of CAG repeat length in childhood-onset dentatorubral-pallidoluysian atrophy. J Neurol 2012;259:2329-34.  Back to cited text no. 3
Shimojo Y, Osawa Y, Fukumizu M, Hanaoka S, Tanaka H, Ogata F, et al. Severe infantile dentatorubral pallidoluysian atrophy with extreme expansion of CAG repeats. Neurology 2001;56:277-8.  Back to cited text no. 4
Tsuji S. Dentatorubral-pallidoluysian atrophy. Handb Clin Neurol 2012;103:587-94.  Back to cited text no. 5
Braga-Neto P, Pedroso JL, Furtado GV, Gheno TC, Saraiva-Pereira ML, Jardim LB, et al; Rede Neurogenetica. Dentatorubro-pallidoluysian atrophy (DRPLA) among 700 families with ataxia in Brazil. Cerebellum 2017;16:812-16.  Back to cited text no. 6
Coutinho P, Ruano L, Loureiro JL, Cruz VT, Barros J, Tuna A, et al. Hereditary ataxia and spastic paraplegia in Portugal: A population-based prevalence study. JAMA Neurol 2013;70:746-55.  Back to cited text no. 7
Le Ber I, Camuzat A, Castelnovo G, Azulay JP, Genton P, Gastaut JL, et al. Prevalence of dentatorubral-pallidoluysian atrophy in a large series of white patients with cerebellar ataxia. Arch Neurol 2003;60:1097-9.  Back to cited text no. 8
Filla A, Mariotti C, Caruso G, Coppola G, Cocozza S, Castaldo I, et al. Relative frequencies of CAG expansions in spinocerebellar ataxia and dentatorubropallidoluysian atrophy in 116 Italian families. Eur Neurol 2000;44:31-6.  Back to cited text no. 9
Pujana MA, Corral J, Gratacòs M, Combarros O, Berciano J, Genís D, et al. Spinocerebellar ataxias in Spanish patients: Genetic analysis of familial and sporadic cases: The ataxia study group. Hum Genet 1999;104:516-22.  Back to cited text no. 10
Paradisi I, Ikonomu V, Arias S. Spinocerebellar ataxias in Venezuela: Genetic epidemiology and their most likely ethnic descent. J Hum Genet 2016;61:215-22.  Back to cited text no. 11
Sunami Y, Koide R, Arai N, Yamada M, Mizutani T, Oyanagi K. Radiologic and neuropathologic findings in patients in a family with dentatorubral-pallidoluysian atrophy. AJNR Am J Neuroradiol 2011;32:109-14.  Back to cited text no. 12
Farmer TW, Wingfield MS, Lynch SA, Vogel FS, Hulette C, Katchinoff B, et al. Ataxia, chorea, seizures, and dementia: Pathologic features of a newly defined familial disorder. Arch Neurol 1989;46:774-9.  Back to cited text no. 13
Egawa K, Takahashi Y, Kubota Y, Kubota H, Inoue Y, Fujiwara T, et al. Electroclinical features of epilepsy in patients with juvenile type dentatorubral-pallidoluysian atrophy. Epilepsia 2008;49:2041-9.  Back to cited text no. 14
Uyama E, Kondo I, Uchino M, Fukushima T, Murayama N, Kuwano A, et al. Dentatorubral-pallidoluysian atrophy (DRPLA): Clinical, genetic, and neuroradiologic studies in a family. J Neurol Sci 1995;130:146-53.  Back to cited text no. 15
Nagafuchi S, Yanagisawa H, Sato K, Shirayama T, Ohsaki E, Bundo M, et al. Dentatorubral and pallidoluysian atrophy expansion of an unstable CAG trinucleotide on chromosome 12p. Nat Genet 1994;6:14-18.  Back to cited text no. 16


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  [Table 1]

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