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International Parkinson and Movement Disorder Society
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        VOLUME 27, ISSUE 2 • JUNE 2023  Full issue »

8th AOPMC Philip Thompson Lectureship Award 

“Young onset parkinsonism: From clinics to genetics and beyond”  

Pramod Pal with Victor Fung (President-Elect of MDS), Francisco Cardoso (Current President of MDS), and Raymond Rosales (Current Chair of MDS-AOS)

Philip Thompson
Past-President of MDS

It was my great honour and pleasure to give the Philip Thompson Lecture at the 8th AOPMC this year at Kolkata, India. Though I have not had the opportunity to meet Prof. Thompson, I have always been impressed by his significant contribution to clinical Movement Disorders, and in particular electrophysiology in Movement Disorders.

The Philip Thompson Lectureship Award was an opportunity to provide a personal view on a topic of my choice.  It was a tough decision to select a topic on which I should speak and which will reflect my interest as well as my contribution. Human motor physiology, in particular electrophysiology of Movement Disorders and transcranial magnetic stimulation, have always been my research interest. However, over the past 25 years, the most important area in my clinical practice are the challenges I faced in the diagnosis and management of Parkinsonism, Parkinson’s Disease (PD), and more specifically Young or Early Onset Parkinson’s Disease in India. Over the past 2 decades, I have seen the changing landscape of diagnosis and management of PD in India, partly influenced by the increasing awareness of PD, recognition of early age of onset in PD, and increased availability of genetic testing for PD. We are increasingly recognizing that the clinico-genotypic profile of early onset PD in India has differences compared to that seen in the Western countries, and the management of these patients still have unique challenges. Therefore I decided to speak on “Young onset Parkinsonism: From Clinics to Genetics and Beyond.”

We are increasingly recognizing that the clinico-genotypic profile of early onset PD in India has differences compared to that seen in the Western countries, and the management of these patients still have unique challenges.”

—Pramod Kumar Pal, MD, DM, FRCP



My talk focused on:

  • Age of onset of PD and higher prevalence of younger onset PD in India compared to Caucasian population 

  • Importance of early recognition of Early Onset Parkinson’s Disease (EOPD) 

  • Unique motor and non-motor features of EOPD 

  • Genetic testing for PD in India 

  • Management issues of EOPD, especially in low- or middle-income countries (LMIC) like India 

  • Social and cultural factors in management of EOPD in India. 

Several terms have been used to categorize Parkinson’s Disease (PD) based on the age at onset (AAO) of motor symptoms, including juvenile onset, young onset, early onset, and late onset PDs. While it is accepted that PD with AAO before 21 years should be referred to as juvenile onset PD, it is controversial as to what should be the upper age limit of AAO for young or early onset PD. Recently a recommendation from the MDS Task Force on Early Onset PD states that AAO of motor symptoms of PD after 21 years but before 50 years (22-49) should be labelled as Early Onset PD (EOPD) [1].  Moreover, it was suggested that the term EOPD should be the preferred term, as the term Young Onset PD (YOPD) might stigmatize younger patients further as being “too young” to develop PD or stigmatize patients who are older than the age cut-off as being old.

PD was once considered to be a disease primarily affecting the elderly. However, over the past few decades, there has been a shift in the demographics of patients with PD who visit our movement disorders clinic. While in the past it was predominantly an older population, we now see a significant number of patients with early onset PD, i.e., below 50 years of age. In fact, we recently observed that the average age at onset of PD in India was 51.03 ± 11.32 years, which is almost a decade younger when compared to many other countries [2]. Moreover, 45.06% of a cohort of 2035 patients had an AAO between 22 to 49 years. This is worrisome, owing to the fact that there is a significant young population in India, and we have come to realize that early onset PD requires a different approach for a majority of aspects related to management.

The average age at onset of PD in India was 51.03 ± 11.32 years, which is almost a decade younger when compared to many other countries

However, there is a lack of awareness among the general public, as well among the medical fraternity, that young patients can have PD. This has resulted in young patients failing to seek or deferring timely and appropriate consultations, and even if diagnosed as PD, they are often not willing to accept the diagnosis due to the stigma associated with the disease. This invariably leads to a loss of several productive years of their lives. Gender discrimination still persists in India, and women frequently face delays in receiving treatment. We recently observed such a scenario when we evaluated a family where three siblings (two brothers and one sister) were affected with early onset PD, and although the sister was the first to be affected, she was the last to be evaluated.   

Unique motor and non-motor manifestations in EOPD that impact the quality of life  

The EOPD patients have unique motor manifestations compared to late-onset PD (LOPD) patients, which include higher prevalence of dystonia and early onset levodopa induced dyskinesias (LIDs).  More importantly, some may have a genetic basis and often have pyramidal signs, ataxia, myoclonus, and peripheral neuropathy. Therefore, management of motor problems, especially LIDs in the low- or middle-income countries where patients cannot afford costly drugs such as dopamine agonists and deep brain stimulation (DBS), is very challenging. 

Furthermore, compared to LOPD, the EOPD patients have challenging non-motor symptoms including impulse control disorders (ICDs), depression, anxiety, and sexual dysfunction. ICDs (e.g., hypersexuality, gambling, excessive spending, etc.), which are often precipitated or worsened by dopamine agonists, are prevalent in early onset PD, and patients may be reluctant to share the presence of them, as they may be deemed culturally inappropriate. Certain genetically determined EOPDs, such as those having mutations of GBA and PLA2G6 genes, can have early cognitive disturbances and psychiatric disturbances, including psychosis. PD patients with GBA mutation have a higher chance of developing ICDs and cognitive decline. Patients with PLA2G6 often have very severe dystonia and psychiatric disturbances.

Certain genetically determined EOPDs, such as those having mutations of GBA and PLA2G6 genes, have a higher chance of symptoms like psychosis

Apart from management problems that are faced even by Movement Disorder specialists, these unique motor and non-motor symptoms in EOPD lead to decreased quality of life. Owing to the age of patients with EOPD and the stage of life at the time of diagnosis, there is a longer disease horizon, which leads to significant interaction of PD symptoms with social life and ability to work, as well as significant caregiver burden and burnout. At the workplace, due to inadequate awareness of PD among the employer and colleagues, patients may occasionally face discrimination, and tend worry about job insecurities. Finally, there is stigmatization, especially in social life and workplace. 

Challenges in diagnosis of EOPD 

While diagnosis of LOPD is essentially clinical and usually does not require more than an MRI of the brain to rule out vascular and structural causes, the diagnosis of EOPD is often difficult. This is partly due to lack of awareness among the inexperienced medical fraternity that in EOPD there can be presence of other motor features in addition to parkinsonism, early neuropsychiatric symptoms, abnormal MRI findings often showing metal deposition, brain atrophy, etc. There are many EOPDs that are labelled as “atypical parkinsonism,” and also many disorders that may mimic PD, at least in initial stages. The latter include disorders such as Wilson’s disease (which is common in India), SCAs (especially SCA1, 2 and 3), hereditary spastic paraplegias, mitochondrial and metabolic disorders, and parkinsonism related to infections. Therefore, often further diagnostic tests are required, including MRI of the brain, nuclear imaging (e.g. TRODAT-SPECT, Fluorodopa-PET scan), metabolic and biochemical screenings, and finally genetic tests. The latter includes targeted or whole exome sequencing, mitochondrial genetics, and in difficult cases, whole genome sequencing. 

Genetics in EOPD: Our experience 

It is now established that patients with EOPD, especially those with a positive family history of PD, may have a genetic cause for PD (10-20%) [3-5]. In the past decade, with the advent of whole exome sequencing (WES), monogenic forms of PD as well as susceptibility genes conferring a higher risk of PD have been described. While most of the data is from Caucasian populations, there are increasing reports of genetic pattern of EOPD in AOS region, which may differ from that described in the Western population. 


Patients with EOPD, especially those with a positive family history of PD, may have a genetic cause for PD (10-20%)

The EOPD-related genes seen most frequently in India vary from those seen in Caucasian populations

In a recent study (preliminary unpublished data) of WES in around 200 patients with EOPD at the National Institute of Mental Health & Neurosciences, Bengaluru, India, we observed that 53% of patients had an identifiable genetic cause: 

  • 34% with monogenic cause of high penetrance 

  • 42% having monogenic cause with variable penetrance 

  • and 24 % with miscellaneous genes causing PD.  

The monogenic group most often included PRKN and PLA2G6, followed by LRRK2, PINK, SYNJ1, and least often SNCA, ATP13A2, and DJ1. Among the susceptibility genes, heterozygous variants in GBA was the most common, followed by EIF4G and GIGYF2.  

We identified 15 patients (13 families) with genetically proven PARK-PRKN. The median age at onset was 29 years, with early onset in 12 patients and juvenile-onset in the remaining three. Tremor, dystonia, hyperreflexia, levodopa-responsiveness, levodopa-induced dyskinesia, and motor fluctuation were frequently noted in more than 50% of cases. WES revealed biallelic exon deletionas the most common mutation type identified (in 7 of 13 families). Ten families carried a homozygous mutation (exon deletion-6, missense-2, splice site-1, stop gain-1), while the remaining 3 were likely compound heterozygous variants (biallelic exon deletion-1, biallelic missense-1, exon deletion, and splice site-1). These clinical and genetic findings agree with the findings of MDSgene review on PARK-PRKN [6]. 

PLA2G6 is perhaps one of the common genetic causes of EOPD in India. In an unpublished data of 9 patients from 7 families with PLA2G6-related parkinsonism at our institute, the mean age at onset of motor symptoms was 24.0 years, with initial levodopa responsive parkinsonism in all. A large number of patients had pyramidal signs and dystonia and almost two-thirds had MRI evidence of deposition of iron in the basal ganglia. The most common variant identified in this cohort was p.Arg741Gln, the most frequently identified variant from the Indian subcontinent. 

In contrast to the Caucasian population, LRRK2 variants were infrequently found in our cohort. Only five patients with EOPD had heterozygous variants in LRRK2. All had non-tremor dominant phenotype with a median age at onset of 40 years. In addition, three patients had dystonia and two had visual hallucinations (drug-induced in one) along with anxiety, depression, and suicidal tendencies. Only one patient had the p.Gly2019Ser variant that is commonly seen in the Caucasian population. In contrast, we identified three novel variants (p.Cys353Tyr, p.Arg1957Gly, p.Phe160Leu in one patient each). Earlier, we had generated iPSC cell lines from a PD patient carrying LRRK2 1le1371Val mutation  [7] and subsequently reported that dopaminergic neurons differentiated from this iPSC cell line displayed a lower yield, α-Synuclein pathology, and functional impairment[8].   

GBA susceptibility gene as a cause of PD, especially EOPD, is being increasingly recognized. In a recent study from our center, 21 out of 200 PD patients (10.5%) who underwent genetic testing for underlying genetic cause were identified to have GBA mutations. The average age at onset (AAO) was 39.33 years, and 91% had AAO <50 years.  Twenty patients had heterozygous variants, whereas one patient had homozygous variant. Eight of the missense mutations were novel mutations. Missense variants most commonly involved Exon-10.  Nineteen percent of the GBA cohort had features of ICD, which supports the recent finding that patients with PD due to GBA mutation have a higher lifetime prevalence of ICD[9]. 

With the advent of facilities of WES in India and many other countries in the AOS region, a large number of EOPD patients are undergoing genetic tests. There is an increased awareness of genetic causes of PD, and often patients request genetic tests with hopes of finding an ultimate cure. There are also several research studies looking into the genetics of EOPD, including GWAS studies. We expect a large genetic data from Asian PD patients in the near future. However, in clinical practice, the interpretation of the results of genetic tests is often difficult and needs further expertise, which is lacking in many countries. Finally, pre- and post- genetic counselling of patients are not routinely done or not available in many Movement Disorders centers, and this needs to be looked into. 

Management issues in India and other low- or middle-income countries

In India, most of the standard therapeutic options for PD are available. However, the final choice is often driven by the patient’s ability to pay. Patients with EOPD, for example, have a propensity for early LIDs, making dopamine agonists the first option. However, these are more costly than levodopa, and the majority of the patients cannot afford such treatment on a long-term basis. Furthermore, management can be complicated by the fact that dopamine agonists tend to worsen ICDs, as mentioned earlier. Financial limitations also hold true for DBS, which, while optimal for certain patients, may be deferred purely due to financial limitations. Lack of adequate medical insurance for most patients often exacerbates this issue; patients may be forced to sell their property to afford the surgery, and even if they undergo the surgery, they may not be able to afford battery replacement. Even though numerous treatment options are available, none are curative, and patients may not be willing to take these medications. They may delay appropriate management to visit multiple doctors or try alternative medicine in the hope of a cure eventually. 

To summarize, in India and in many other low- or middle-income countries, there is a complex relationship and often disparity between availability, accessibility, and finally affordability of the services related to:

  • consultationby neurology/movement disorders specialists
  • diagnostic tools often required for PD such as neuroimaging (MRI, TRODAT-SPECT, Fluorodopa-PET scan, etc.) and genetics

  • therapies for PD including dopaminergic drugs (including LD/CD, dopamine agonists, etc.), functional neurosurgery (DBS, lesioning, MRgFUS), apomorphine, levodopa-carbidopa intestinal gel, etc.

In India, while availability of these services is quite robust in certain urban areas, it is quite meager in the rest of the country, especially in the vast rural population. Even if these are available, they are not often easily accessible. Even if accessible, only a handful of patients can finally afford the costly diagnostic and therapeutic options.

India is the most populated country in the world with one-sixth of the world's population. With a prevalence rate of PD varying between 15-43/100,000 population, India is likely to have the highest absolute number of PD patients in the world, of whom nearly 40-45% have age of onset of motor symptoms between 22-49 years (EOPD).

India is likely to have the highest absolute number of PD patients in the world, of whom nearly 40-45% have age of onset of motor symptoms between 22-49 years (EOPD)

Though there is a dearth of neurologists and Movement Disorder specialists, there has been a steady increase in the awareness of PD among the general population and improvement in the quality of PD care. This is largely due to efforts of dedicated neurologists interested in Movement Disorders and educational and outreach activities conducted by various PD support groups in India, the Movement Disorders Society of India, and the International Parkinson and Movement Disorders Society and its Asian-Oceanian Section. Moreover, in the past decade, several governmental and non-governmental teaching institutes and hospitals have started post-doctoral fellowship programs and training courses in Movement Disorders, which are instrumental in the steady increase of manpower in this subspeciality. It is also encouraging to note that clinicians and basic scientists have started working closely in the area of PD research and genetics through several national and international collaborative projects. Therefore, I am optimistic that early diagnosis, optimum medical and surgical treatment, and social and financial supports will be available for most of our patients with Early Onset PD in the near future, and India will also be able to contribute substantially to the understanding of the etiopathogenesis and genetic architecture of this disorder that is seen more commonly in Asia. 

Finally, I would like to thank the Awards Committee of AOPMC for selecting me to give this prestigious lecture.



  1. Mehanna R, et al. Age Cutoff for Early‐Onset Parkinson's Disease: Recommendations from the International Parkinson and Movement Disorder Society Task Force on Early Onset Parkinson's Disease. Movement Disorders Clinical Practice. 2022 Oct;9(7):869-78. 

  2. Prasad S, Rakesh K, Kamble N, Holla VV, Mailankody P, Lenka A, Naduthota RM, Stezin A, Mahale R, Yadav R, Pal PK. Early onset of Parkinson's disease in India: Complicating the conundrum. Parkinsonism Relat Disord. 2022 Dec;105:111-113. doi: 10.1016/j.parkreldis.2022.11.017. Epub 2022 Nov 15. PMID:36410307. 

  3. R.N. Alcalay, E. Caccappolo, H. Mejia-Santana, M.X. Tang, L. Rosado, B.M. Ross, M. Verbitsky, S. Kisselev, E.D. Louis, C. Comella, Frequency of known mutations in early-onset Parkinson disease: implication for genetic counseling: the consortium on risk for early onset Parkinson disease study, Archives of neurology 67(9) (2010) 1116-1122. 

  4. W. Poewe, K. Seppi, C.M. Tanner, G.M. Halliday, P. Brundin, J. Volkmann, A.-E. Schrag, A.E. Lang, Parkinson disease, Nature reviews Disease primers 3(1) (2017) 1-21. 

  5. J.O. Day, S. Mullin, The genetics of Parkinson’s disease and implications for clinical practice, Genes 12(7) (2021) 1006. 

  6. M. Kasten, C. Hartmann, J. Hampf, S. Schaake, A. Westenberger, E.J. Vollstedt, A. Balck, A. Domingo, F. Vulinovic, M. Dulovic, I. Zorn, H. Madoev, H. Zehnle, C.M. Lembeck, L. Schawe, J. Reginold, J. Huang, I.R. König, L. Bertram, C. Marras, K. Lohmann, C.M. Lill, C. Klein, Genotype-Phenotype Relations for the Parkinson's Disease Genes Parkin, PINK1, DJ1: MDSGene Systematic Review, Mov Disord 33(5) (2018) 730-741. 

  7. I. Datta, S. Jagtap, C. Potdar, R. Yadav, P. Pal, Generation of induced pluripotent stem cells (NIMHi001-A) from a Parkinson's disease patient of East Indian ethnicity carrying LRRK2 I1371V variant, Stem Cell Research 44 (2020) 101768. 

  8. Jagtap S, Potdar C, Yadav R, Pal PK, Datta I. Dopaminergic Neurons Differentiated from LRRK2 I1371V-Induced Pluripotent Stem Cells Display a Lower Yield, α-Synuclein Pathology, and Functional Impairment. ACS Chem Neurosci. 2022 Sep 7;13(17):2632-2645. doi: 10.1021/acschemneuro.2c00297. Epub 2022 Aug 25. PMID: 36006382. 

  9. P. Amami, T. De Santis, F. Invernizzi, B. Garavaglia, A. Albanese, Impulse control behavior in GBA-mutated parkinsonian patients, Journal of the Neurological Sciences 421 (2021) 117291. 


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