Cure for a rare form of migraine could lie with the Parsi community

ldquoWhat happens to you when you get the headacherdquo Dr K Ravishankar asks a patient identified simply as Mr IS in the mp3 recording provided to this paper ldquoPeople become small in my vision and my eyes get swollen My nose is blockedrdquo he tells the consultantincharge of the headache and migraine clinics at Jaslok and Lilavati HospitalsAmong the many genetic traits of the Parsis that The AVESTAGENOME Project is trying to study is longetivity Above is a photograph of a 86yrold from the community who Mumbaibased photographer Kurush Umrigar profiled as part of the Parsee Portrait Project Kicked off last year it aims to document through black and white portraits interesting elderly faces of Indiarsquos Parsis Follow Umrigar on Instagram kurushumrigar PIC copyKurush M Umrigar All Rights ReservedThis strange episode is followed by a headache accompanied by nausea and the inability to bear noise Unable to walk Mr IS must lie still The pain which usually comes on in the mornings sometimes more than once a day can last for up to a week ldquoThis timerdquo he says in the 2006 recording ldquoit has lasted for 15 daysrdquo The Mumbai resident says Ravishankar has been battling migraine with aura for the last three yearsMigraine is a neurological disease characterised by recurrent moderate to severe headaches and affects about 303 million individuals worldwide according to the World Health Organisation Typically the pain occurs on one side of the head is pulsating and debilitating Of the worldrsquos migraineurs 25 per cent to 30 per cent suffer from aura a type of migraine in which the pain is preceded by blind spots and seeing zigzag patterns The percentage of aura patients in India says Ravishankar is between seven and 10 per centWhile there is no foolproof solution yet to Mr ISrsquos malaise the answer to a possible cure and preventive therapy may lie in research that will soon kick off 1000 km away at Avesthagen Limited a Bengalurubased innovation driven life sciences companyProfessor Lyn Griffiths who is collaborating with Dr Villoo MorawalaPatells Avesthagen has been working on migraine genetics for years and is hopeful that a vitamin supplementation therapy will help migraine with aura patientsStudying the Parsi geneFounded as an academic startup in 1998 by Dr Mrs Villoo MorawalaPatell Avesthagen started business activities on March 21 2001 It studies complex biological systems by monitoring the gene protein and informational pathway responses integrating these data and ultimately formulating mathematical models that describe the structure of the system and its response to individual perturbationsIn 2007 she launched The AVESTAGENOME Project which aims to collect biological material from 25000 Parsi individuals with a dual aim mdash firstly preserving the biological heritage of the declining community it is estimated that there are around 69000 Parsis in the country in an archive of blood samples with detailed data on genealogy disease history and dietary social habits And secondly to use the data to discover novel biomarkers and drugs for disease classes including metabolic syndromes autoimmune diseases breast and prostate cancers and neurodegenerative disorders like Alzhiemerrsquos The latter two find high incidence among the community that includes descendents of Zoroastrian refugees who fled from Persia around the 8th century and settled in India The Mumbai Cancer Registry 200204 states that 20 per cent of all cancer cases among the Parsis are to do with the breast as compared to 14 per cent among nonParsisDr Villoo MorawalaPatells life sciences firm has collected blood samples of 4500 Parsis to further disease research including that associated with migraine PicAjeesh F RawtherThe project also hopes to study the Parsi genetic trait of longetivity Interestingly early this year MorawalaPatell decided she would also address migraine one of the most common ailments to baffle specialists struggling to find a cureThis August MorawallaPatell and her research were featured in a podcast titled The Intersection on Audiomatic a site for highquality podcasts from toprated talents see link at end of copy Padamparna Ghosh and Samantha Subramanian who anchor the fortnightly podcast discussed how the Parsis could play a role in ldquohelping the world get rid of its worst headacherdquoWhat makes the Parsis crucial to the research is their endogamous marrying among themselves nature Geographically linguistically and religiously isolated from their neighbours endogamous populations have often been successfully utilised to understand human disease Results obtained from such studies can be extrapolated and validated in other communities in the country of research and around the world Endogamous populations tend to be predisposed to certain diseasesand their low genetic heterogeneity makes studying these diseases easyDue to their endogamous nature and small numbers the low heterogeneity among Parsi genes is beneficial for disease mapping Results obtained from studies conducted on communities such as this can be extrapolated and validated in other communities REPRESENTATION PICDr Lalji Singh pioneering scientist in the field of DNA fingerprinting in India and managing director of Hyderabadbased Genome Foundation says because Parsis are endogamous ldquothere is a high probability that recessive defective genes which may be unique to a particular disease will arise in themrdquo The recessive defective gene that Singh refers to is one that is not expressed and is overriden by the dominant gene unless there are two of them one from each parentIn the past studies have been conducted on other endogamous communities such as the Ashkenazi Jews A 2014 study by Shai Carmi a computer science professor at Columbia University together with a group of medical researchers found that all Ashkenazi Jews can trace their ancestry to just 350 individuals dating back to 600 to 800 years The resulting acute genetic similarities say scientists can help them catalogue nearly all genetic variations from the founding population thereby improving disease mappingDr K RavishankarWhile the Parsis are not the only endogamous population in India that their numbers are small matters ldquoThe prevalence of the caste system in the country ensures that most people marry within their caste However because most castes are defined by large numbers there is greater heterogeneity in their genesrdquo Singh explains Another small endogamous community is that of the Nisads boatmen from Jaunpur in Uttar Pradesh ldquoThey also marry among themselves and there are only a hundred of them leftrdquo Over generations passing on defective genes has given rise to vitiligo in one particular family Which gene That says Singh is not yet known ldquoWhile all genes are known to science every genersquos function isnrsquotrdquo he clarifiesHeachache that wonrsquot healA 29yearold medical professional from Mumbai who didnrsquot wish to be identified says she started experiencing headaches when she was 13 Initially her parents thought that it was related to poor eyesight It was later that her condition was diagnosed as migraine with aura ldquoWhen I started studying for my medical exams stress would be the trigger One episode would last eight hours Getting an attack three times a week was commonrdquo she says She was unable to see clearly and couldnrsquot tolerate bright light Working during an attack she calls a punishment ldquoYou have to take those days off The only thing that helps is going to sleeprdquo After 16 years she is yet to pin point the exact trigger but she has learnt to sleep and eat on time and pop a painkiller when she thinks an attack is on its wayItrsquos a reality that 18 per cent of the worldrsquos female population has to live with Yet like her most patients first head to the ophthalmologist This says Ravishankar is the first obstacle ldquoMigraine is underrecognised underdiagnosed and undertreatedrdquo says the doctor who sees five to eight new patients every working day some of them having suffered attacks for as many as 15 yearsCurrently he adds diagnostic tools donrsquot help confirm whether a patient is in fact a migraine sufferer ldquoIt wonrsquot show up on a CT scan neither is there a widely accepted biomarker that will show up on blood testsrdquo he says What helps then is asking the right set of questions based on criteria outlined by the International Headache Society about the nature of these headaches the duration and the accompanying symptomsRavishankar uses the internationally accepted Migraine Disability Assessment Score MIDAS instrument which provides a measure of productive days lost to disability caused by migraine headaches as well as frequency and severity of attacksCurrent course of medication includes prescribing prophylactics which make the brain less excitable and therefore more resistant to triggersThis is a longterm measure During the attack the patient is prescribed an acute abortive medication that reduces the suffering But even these specific medicines do not work all the time in all the patients says RavishankarThere is a surgical option in which electrodes are placed along the pain nerves with a pacemaker so that when the patient feels an attack coming on she can deliver a current to numb the nerves However since feeling pain is an important function of the body the nerves cannot be permanently numbedItrsquos in the absence of regular pathological biomarkers that finding a genetic connect to migraine becomes imperativeThe Australian breakthroughGenetic research in migraine could then be key to finding a cure because although the cause of the disease hasnrsquot been fully understood it has been agreed that both environment and family history play a roleProfessor Lyn Griffiths is a molecular geneticist at the Institute of Health Biomedical Innovation with Australiarsquos Queensland University of Technology QUT Itrsquos a lab that undertakes research to identify genes involved in common chronic disorders and neurogenetic disorders like migraine in particularDr Lalji SinghldquoWe have been working on migraine genetics for years and have identified a number of genes that play a role in the disorder Wersquove also developed diagnostic tests to identify severe familial migraine subtypes Although there are some very good migraine treatments available they are not effective for all migraine sufferers There is need to develop more targeted treatmentsrdquo she says in an email interviewIn 2005 Griffiths and a team of researchers published a paper that showed how vitamin supplementation reduced migraine severity and frequency and that the presence of the MTHFR gene and its variation in the DNA sequence MTHFRC677T influenced response to this treatment in migraine with aura patientsMTHFRC677T is associated with the function of a vital enzyme in the body that works towards metabolising a highly reactive amino acid called homocysteine The enzyme helps keep homocysteine levels in control thus preventing injury to cells lining the inner surface of blood vessels That researchers claim that migraine pain may be connected to dilation of cerebral bloodvessels makes maintaining optimum levels of homocysteine importantIn 20089 Griffiths conducted Phase 1 of a trial on 52 migraine with aura patients all Caucasian adults from Australia suffering from migraine for more than 20 years and carrying a family history of the ailment The trial was to examine whether a daily supplementation of Vitamins B6 and 12 and folic acid would help lower homocysteine levels and migraine disability One half of the group was put on placebo tablets the others on vitamins She found that the vitamins made the enzyme work better and faster bringing down homocysteine levels by 39 per cent compared with baseline a reduction that was greater than placebo ldquoMore importantly the treatment had a very good effect on migraine mdash reducing frequency of attacks and severity of pain in those on the daily Vitamin B treatmentrdquo says GriffithsThe Phase 2 trial was conducted over six months on 206 female patients aged 18 to 60 all of European ancestry from across Australia suffering from migraine for over five years with a current diagnosis of migraine with aura The findings of this study conducted between 201012 were published in 2012 confirmed that the vitamin supplementation was effective in reducing migraine but also that both the MTHFR and MTRR gene variants were influencing treatment response in female migraineursIn May this year Avesthagen and QUT joined hands to expand the study and bring the therapy to India ldquoI felt there is such an unmet understanding of what migraine is or the various different types of migraines So when I heard that a specific genetic marker had been identified for a particular type of migraine and there was preventive therapy for it I found it could be an interesting opportunity for us for research and businessrdquo says MorawalaPatellFuelling the engineShe calls The AVESTAGENOME Project an engine of discovery spanning years of research and involving multiple laboratories ldquoIt will require significant funding of about 60100 million USD over 10 years and perhaps take 300 global scientists to create an output for Precision Medicinerdquo she says over emailBetween 2007 and 2008 Avesthagen collected blood samples from 4500 Parsi individuals along with details of their genealogical medical social and nutritional histories and habits The samples were collected from across 10 Indian cities including Hyderabad and Secunderabad 437 Navsari 687 Surat 708 and Ahmedabad 560 From Mumbai 1108 samples were collectedldquoWe collected nine samples of 7 ml each from every participant These were to process for genomics transcript analysis proteome analysis matabolome analysis and some for preservation for posterityrdquo she explainsThe team worked closely with the heads of Parsi Anjumans or local institutions that represent the community in various cities That MorawalaPatell belongs to the community helpedBorn in Navsari a town in Gujarat she grew up in Nizamabad of Telangana District after her family migrated along with several others on the invitation of the then Nizam of Hyderabad After her first job at the International Crops Research Institute for Semi Arid Tropics Hyderabad she moved to France in 1989 her young daughters in tow to pursue a PhD in planet molecular biology at University Louis Pasteur Strasbourg Nine months as a postdoc at Ghent University in Belgium and she was back home with the idea behind AvesthagenThat of the 4500 samples already collected 15 belong to migraineurs helps Itrsquos these that will be used for further research with QUT revolving around migraine with aura ldquoDetails of process and protocol have yet to be firmed uprdquo she addsThe scientist warns however that answers and treatment may not be immediately forthcoming ldquoThere is a genetic biomarker for this particular type of migraine The therapy was found to work on patients that carry it We are yet to carry out further detailed research before statements can be maderdquoAlthough Ravishankar warns that the MTHFRC677T genotype has not been found to exist in all patients of migraine with aura and therefore a specific therapy may not extend to all Griffiths clarifies that the treatment works for anyone with the said mutation ldquoand that it is known to occur commonly in several different ethnicitiesrdquo is good newsNone of this comes cheapSo far the funding for the project has been solely done through the finances of Avesthagen LtdIn a proposal that MorawalaPatell submitted to the Indian Council of Medical Research in May 2015 for a research grant to wrap up the first five years of what she calls the largest epidemiological and population genetics studies attempted so far she pegs the funds needed at Rs 39 943 lakhShe hopes the government will come on board as collaborator ldquoGiven the Parsi population is rapidly declining it is imperative that sample collection is urgently completed to be able to mine the genomic uniqueness of the populationrdquoFigure more about Dr Mrs Villoo MorawalaPatell and The AVESTAGENOME project in a podcast The Intersection that aired on Audiomaticin httpwwwaudiomaticinshowtheparsisandacureformigraine