Huntington’s disease: The Indian perspective

Srinivas Raju; Prashanth Kukkle

doi:10.4103/AOMD.AOMD_47_20

REVIEW ARTICLES

Year : 2021 | Volume : 4 | Issue : 1 | Page : 4-9

Huntington’s disease: The Indian perspective

Srinivas Raju¹, Prashanth Kukkle²
¹ Department of Neurology, Columbia Asia Hospital, Bangalore, Karnataka, India
² Center for Parkinson’s Disease and Movement Disorders, Vikram Hospital, Bangalore, Karnataka, India

Date of Submission	21-Sep-2020
Date of Decision	16-Jan-2021
Date of Acceptance	17-Feb-2021
Date of Web Publication	17-Apr-2021

Correspondence Address:
Dr. Prashanth Kukkle
Center for Parkinson’s Disease and Movement Disorders, Vikram Hospital, Bangalore, Karnataka.
India

Source of Support: None, Conflict of Interest: None

DOI: 10.4103/AOMD.AOMD_47_20

Abstract

Understanding of Huntington’s disease (HD) has been evolving since its early descriptions from nineteenth century. Significant breakthroughs into HD pathophysiology and therapeutic targets have been seen in last 50 years. Most of the publications in relation to HD are from European and American continents, indicating geographical higher prevalence. HD in India has been reported since early 1950s in the form of case reports and series, with exception of varying references in ancient Indian literature as “Tandavaroga.” In this review, we have amalgamated the various Indian publications on HD till date.

Keywords: Huntington’s disease, India, review

How to cite this article:
Raju S, Kukkle P. Huntington’s disease: The Indian perspective. Ann Mov Disord 2021;4:4-9

How to cite this URL:
Raju S, Kukkle P. Huntington’s disease: The Indian perspective. Ann Mov Disord [serial online] 2021 [cited 2023 May 30];4:4-9. Available from: https://www.aomd.in/text.asp?2021/4/1/4/313944

Introduction

Huntington’s disease (HD) is an autosomal-dominant neurodegenerative disorder with multisystem involvement. It causes movement, cognitive, and psychiatric disturbances with a wide spectrum of signs and symptoms. Since its official description in nineteenth century, HD has made dramatic progression only in last 50 years. The turning point was the discovery of hot spot of HD patients in small Venezuelan town by Americo Negrette followed by epidemiological work of Nancy Wexler, which led to the discovery of causative gene in the subsequent decade.^[1],[2] This and later work by various groups has brought HD in 2020 at the door steps of possible disease-modifying therapy. Conventionally, India has been considered to have low prevalence of HD. However, there have been no systematic studies on the same. In 1955, the first publication of HD in Indian population was published, and since then various works on HD have been in literature.^[3] In this narrative review, we have collated various Indian clinical works and publications. We have done a PubMed database search with MeSH major topic of “Huntington Disease” and keyword “India” from 1947 to June 2020. Articles published from Indian clinical works on human subjects were shortlisted to include 39 publications for this review [Figure 1].

Figure 1: PRISMA flow chart of articles selection

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Historical Aspects

The ancient Indian description of chorea (and possible Huntington’s disease) dates back to Sharangadhara samhita. Sharangadhara samhita is part of “Laghutrayee” or the lesser triad of Ayurveda along with “Madhava Nidana” and “Bhavaprakasha.” Sharangadhara Samhita is written by Acharya Sharangadhara between thirteenth and fourteenth century AD.^[4],[5],[6] In this treatise, “Tandavaroga” has been described.^[7] “Tandava” means violent gesticulations and frantic dance of Lord Shiva [Figure 2]. The disease is characterized by fleeting type of movements, spreading from one limb to other over the time and leading to difficulty in holding objects, change in facial expression, disturbed intellect, and loss of movements during the sleep. The samhita further describes the ayurvedic approach to treatment of Tandavaroga.^[4]

Figure 2: “Shiva-Tandava” posture of Lord Shiva. This type of dance posture requires high energy, agility, and strength. It shows the violent gesticulations and frantic dance of Lord Shiva. In the Sharangadhara samhita, these flows of movements are metaphorically compared with “Chorea” in the description of “Tandavaroga” (Free Image source: https://wallpapersafari.com/w/xvCuf3)

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Albeit HD-like phenomenology was described with “Tandavaroga,” the specific literature on HD was not seen from India till post-Independence period. The first Indian literature on Huntington’s disease was published in 1955 by Chhuttani, wherein he has described seven clinical patients among whom five had typical features with positive family history and two without family history.^[3] In 1956, there was another case report publication by Ganguli on using procaineamide hydrochloride for HD.^[8] Subsequently, Chhuttani^[9] reported 38 cases from five pedigrees in 1957. Among these five pedigrees, one pedigree was elucidated for 200 years covering 273 individuals, leading to 27 affected members. Based on the above publications, Chuttanni concluded that HD was not uncommon in India. Since then various publications on HD have been periodically published by Indian researchers.

Epidemiology

There have been no epidemiological studies from India, but one of the oldest studies on the prevalence of HD among immigrants from the Indian subcontinent to Britain was estimated to be similar to European populations.^[10] The overall prevalence of HD in Asia was 0.40/100,000, much lower compared with that of 5.70/100,000 in European, North American, and Australia.^[11] It is speculated that 20,000–40,000 people are suspected to be affected with HD in the Indian population, and more than 0.2 million may be at risk.^[12]

Genetics

Indian subcontinent represents one of the most ethnically and genetically diverse regions of the world. In one of the earliest genetic papers of HD from India, Pramanik et al.^[13] from eastern India have looked into 28 clinically unrelated HD subjects of different ethnic backgrounds. CAG repeats in the range of 41–56 were reported in comparison to 11–31 in normal controls. The samples consisted of two predominant alleles: (CCG)₇ and (CCG)₁₀. They further reported one four-repeat CCG allele which has not been reported in any other population. Subsequently, Saleem et al.^[14] in 2002 investigated into polymorphisms linked to HD to understand the origin of HD in India. It was found that the distribution of alleles at the CCG repeats (2642 and D4S27) was similar to western European populations. It was further noted that allele D4S127 locus and 7-2-I haplotype (CCG-D4S127-2642loci) were present in higher frequency in southern India. It was postulated that admixture of British troops located in Southern India during colonization was from regions in UK where high rates of HD have been reported. In 2014, Moily et al.^[12] reported 116 HD subjects with more than 39 CAG repeats. Most of the subjects had paternal inheritance (45%) followed by maternal inheritance (24.5%), sporadic mutations (11%), both parents affected (2%), and unknown in others. They noted that subjects with more than 50 CAG repeats had juvenile onset HD, with youngest subject being of 4 years with 85 repeats. In 2016, Srija et al.^[15] published a review of all HD genetic works done in India and concluded that juvenile HD (JHD) was higher in south Indian cohort. Recently in 2018, Chheda et al.^[16] analyzed HD patients’ samples received to their specialized diagnostic lab over 4 years (2013–2017) from across India. Among the 500 samples analyzed, 241 (47.9%) had full penetrant alleles (>40CAGs), nine each (1.8%) had reduced penetrant (36–39 CAGs) and intermediate alleles (27–35 CAGs). Among these 250 clinical HD subjects, most of the subjects were in 40–45 CAG repeats with mean age at clinical onset of 50 years. They also noted that 58 had 46–55 repeats and 12 had more than 56 repeats with a maximal repeat of 106 in an 8-year-old child. It was also noted that increasing CAG repeats inversely corelated with the age of onset, with youngest affected subject being 6 years with 105 repeats.

Pathophysiology

Imbalance of neurotransmitters in the basal ganglia has been considered major culprit which substantially contributes to the pathophysiology of movement disorders. Kumar and Kurup^[17] reported reduced levels of ubiquinone, glutathione, and free radical scavenging enzymes, as well as increased lipid peroxidation products and nitric oxide were noticed in HD, playing a role in regulating genomic function.

Jamwal and Kumar^[18] have done extensive review of neurotransmitters’ role in HD and support the notion that altered neurotransmitters’ imbalance in the basal ganglia region specifically dopamine, glutamate, GABA, and glutamate are solely responsible for the behavioral and motor deficits. The ability in HTT protein to interact with other proteins and increase neuronal cell death by apoptosis is likely to alter the age of onset in HD. Chattopadhyay et al.^[19] analyzed association of GluR6 with the onset age of HD and indicated that CCG repeats in the HTT gene might modify the onset age in HD patients. Chattopadhyay et al.^[20] from Kolkata, western India, looked into genetic modifiers and that variations in TP53 and hCAD genes might modify the age at onset of HD. Johri et al.^[21] have looked into mitochondrial fission–fusion and trafficking as abnormalities in HD. Huntingtin was now shown to function directly in these processes by binding the mitochondrial fission factor dynamin-related protein-1 (DRP1). Mutant huntingtin binds more tightly to DRP1, leading to increased mitochondrial fission and neuronal death, highlighting DRP1 as a potential therapeutic target in HD.

Clinical Features

The initial clinical data on HD were published in 1955 by Chuttani^[3]; subsequently there have been various case reports with interesting presentations.^{[22],[23],[24],[25],[26],[27],[28],[29]} There have been few large case series from different parts of India [Table 1]. One of the first well-documented case series was from Khosla and Arora^[24] from northern India, describing 35 affected cases and 13 sporadic cases spanning over 11 years. In 2001, Murgod et al.,^[30] from National Institute of Mental Health and Neurosciences (NIMHANS), Bangalore, southern India, described clinical and genetic features in 26 subjects. The mean age at onset varied from 6 to 66 years (mean: 36.9 years) with four of them having JHD. Most of the patients had motor symptoms (88.5%) as initial clinical symptom, followed by 11% with behavioral issues. The CAG repeats varied from 39 to 82 repeats (mean: 48 repeats). Later extension of the same group published by Lenka et al.^[31] reviewed 92 patients with initial behavioral vs. motor symptoms. Various features including CAG repeats were compared and it was noted that maternal inheritance was prominent with initial behavioral onset. Ratna et al.^[32] from the same southern institute looked at psychiatric comorbidity in 144 patients with a mean age cohort at death being 53 years and the duration of illness at the time of death was 7 years. Most individuals (66%) were in total functional capacity (TFC) score stage I and II and the TFC score correlated inversely with a duration of illness. There was a high prevalence of psychiatric morbidity (91%) including suicidal tendency (22%). Hussain et al.^[33] more recently have described 75 HD subjects from Bangur Institute of Neurosciences, Kolkata, eastern India, with a mean age at onset of 37 (range 16–62) years with juvenile onset noted in 5% (n = 4). Clinical manifestations at onset were motor in 81.3% patients, behavioral in 10.7%, and cognitive impairment in 8%, similar to other studies. After chorea, next common movement disorder was dystonia. They found more frequent dystonia and less of bradykinesia in comparison to southern Indian study, probably due to more JHD cases in the latter. Frontal lobe dysfunction was found in 77.3% of the patients. Behavioral disturbances were observed in 77.3% of the patients and commonly manifested as depression, irritable behavior, and anxiety.^[33]

Table 1: Major Indian publications on HD clinical manifestations

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JHD is not uncommon in Indian subcontinent and most of them are either case reports or part of case series. The common thread among all is the prominent paternal inheritance. Pani et al.^[34] reported a rare case of JHD manifesting since the age of 7 years with AD inheritance. Later, Srivastava et al.^[35] presented a case of a 12-year girl, with paternal inheritance and features of hypokinetic rigid form with ocular abnormalities, tremor, and hypereflexia with CT scan findings of atrophy of caudate nucleus with prominence of frontal horn of lateral ventricle. Murgod et al.^[30] in 2001 presented four cases of JHD from a cohort of 26 HD patients (16%), all of them had paternal inheritance. Among them, the fathers of two patients were clinically affected, whereas the fathers of the other two were clinically unaffected but had expanded trinucleotide repeats. As compared to other studies, a higher occurrence of JHD (15.4%) was reported in India when compared with other ethnic communities. Naphade et al.^[36] in 2013 published a study in which a 9-year-old male child had a history of cognitive decline, seizures, imbalance, and frequent falls since two years with positron emission tomography/computed tomography (PET/CT) features of a severe hypometabolism in the striatum. Lenka et al.^[31] in their series reported three patients among 92 subjects with JHD (AAO <21 years). Chheda et al.^[16] came across seven cases of JHD, in which the onset of neurological symptoms was below 20 years of age. The youngest patient was a 6-year-old male with 105 CAG repeats, followed by an 8-year-old male with 106 repeats and a 13-year-old female with 72 CAG repeats. The other four patients were 17, 18, 19, and 20 years of age with 62, 68, 58, and 61 CAG repeats, respectively.^[16] Similarly Hussain et al.^[33] in 2020 reported JHD in four (5.3%) patients out of 75 study group; among them three patients presented with chorea and one with akinetic rigid syndrome, transmitted from father in all.

Diagnostics

Genetic testing is the gold standard for the diagnosis of HD. Genetic testing includes assessment of expanded trinucleotide repeat (CAG) on the short arm of chromosome 4. Normal alleles at this site contain CAG repeats and repeats 40 and above in one of the alleles and are considered as fully penetrant. Incomplete or reduced penetrance may happen with 36–39 repeats, 27–35 repeats are considered normal but mutable, and 10–26 repeats are considered normal.^{[15],[16],[37]} The pre-symptomatic screening of family members is not well accepted due to the absence of disease-modifying therapies and the mental agony associated with a positive diagnosis. Only about 5% of the individuals at risk opt for predictive genetic testing. A study by Muthane et al.^[38] addressed some of the ethical issues with genetic testing which is still relevant in our daily practice; they tried to address the predictive genetic testing and its ethical issues of autonomy not only with the doctor–patient relationship but also the individual’s social network. Legal issues about the right to information and disclosure were thought essential with long-term contact and care being crucial to genetic testing. They also found individuals with knowledge about HD and the test differed in their decision of sharing test results and reproductive choices.

Management

The management of HD experiences in India has been in line with international publications. Early literatures have reported utilization of various medications including procaineamide hydrochloride,^[8] reserpine, phenergan, chlorpromazine without much benefits.^[24] However, there is lack of systematic response analysis to various therapies for HD in India. Danivas et al.^[39] reported three patients with HD in whom lithium prevented the progression of chorea and also helped stabilize mood. Mattoo and Khurana^[27] reviewed alcohol and its effect on HD, contradictory to general beliefs of one of the case reports of a patient with strong family history of HD manifested with movement disorder and behavioral problems under alcohol use and withdrawal, but not while being abstinent shows the different responses to treatment and the need for personalized treatments. There are few studies commenting on the nursing aspects and its effects of individualized care and musical therapy in HD. It has been shown that diversional therapies, short walks, and freedom in activities of daily living do help in alleviating symptoms in these individuals.^[40]

Conclusion

HD is well recognized in all parts of India. Due to limited therapeutic outcomes, there have been very few concrete approaches toward understanding the prevalence, clinical manifestations, and their quality of life. This has been slowly changing over last few years, which is noted by establishment of Huntington’s Disease Society of India^[41] and appearance of specialized HD clinics.^[42] A well-established HD registry will help in understanding this rare disorder and address the needs of the patients and families in the Indian subcontinent.

Acknowledgments

This manuscript has not been funded by any sources.

Financial support and sponsorship

Nil.

Conflicts of interest

The authors have no conflict of interest to report.

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