It’s been two years since Mohammad Nazir, 44, petitioned the government that six of his children be euthanised. Nazir and his wife Tabassum’s desperate plea to terminate the lives of their children was preceded by 15 agonising years of watching six of their eight children debilitated by a malevolent disease that destroys their neurons and steadily wastes away their muscles.
Suleim, 19, a once-frisky four-year-old, has legs that have shrivelled to the size of bamboo reeds and are locked into each other at the ankles. Head bloated at the temples and browning teeth, the muscles that control his jaw and throat are flaccid too, making speech impossible. “He understands everything,” says Tabassum, 36. “Look Suleim, who’s come to see...,” she trails off, interrupted by a wail. That’s Shoeb, his 16-year-old brother. He’s lying on a bed in the courtyard and shares his brother’s shrivelled legs though they aren’t yet locked in.
Once propped up, Asim, 14, too can continue sitting against the wall. “He’s the sharpest of all and can recite poetry and verses from the Koran,” says Tabassum, with one eye out for Kasif, 11, who appears the most reticent and the only one of the boys with dark eyes unlike his siblings whose eyes are a light brown. The quivering limbs and the seizures — early signals of the onset of megalencephalic leukoencephalopathy, aka the neurological disease — have set in but so far he can stretch his limbs out and ease the weight of his body on his palms.
Because none of them can stand and there’s no nurse, it’s Tabassum who must attend to everything from taking them to the toilet, feeding and washing them (full-fledged baths are rare). When Nazir comes home for lunch, he helps them with physiotherapy. “Most days it’s me alone… they are heavy. It’s hard for me to lift them,” says Tabassum, who says she’s never left her house for a social function in more than a decade. Nazir was a daily-wage labourer until three years ago and now manages a sweet shop in Agra’s central bazaar.
When he’d written that petition in the summer of 2015 it was, he says, because he had neither hope nor money anymore to spend on doctor visits, physiotherapy, acupuncturists and religious offerings. The petition worked, to the extent that local newspapers carried accounts of the family’s predicament.
Earlier visits to hospitals in Agra and one to the All India Institute of Medical Sciences (AIIMS), Delhi, confirmed that the children suffered from a “rare disease”, and treatment largely consisted of muscle relaxants and for controlling the seizures. “We couldn’t understand our fate. Neither my wife’s siblings nor mine had ever seen anything like this in our families,” says Nazir. To Tabassum, the reason was simple. “My womb is cursed,” she laments. But 200 km away, in Delhi, a group of geneticists read about the Nazir family online and realised that they were peering into a medical jigsaw puzzle.
Decoding the mysterious malady
Unravelling the mysteries of the DNA is the nucleus of research at the CSIR- Institute of Genomics and Integrative Biology (CSIR-IGIB). Nearly a decade ago, resident scientists Sridhar Sivasubbu, 44, and Vinod Scaria, 36, were part of a team that first sequenced the entire genome of an Indian. Six years after a consortium of European and American scientists had first cracked the blueprint of the human genome in 2003, the Indian genome sequencing project had isolated the DNA of a 52-year-old Jharkhand man and mapped the same. While the human genome provides the ultimate reference point of the location and sequence of genes that define humans, the promise of indigenous exercises — bragging rights apart — is to have a reference base of how genes in Indian communities vary from, say, African, West Asian or Caucasian genes and then study the extent of these variations in these genes to understand diseases.
A sequenced genome is like the innards of your computer made transparent. Every cell in the human body consists of strands of nucleic acid called DNA (deoxyribonucleic acid), which are chains of four kinds of molecular bricks or nucleotide bases. These bases form exclusive pairs with each other and their order determines how proteins are made. The creation and execution of every physiological process is determined by proteins functioning stably. The genome, as the bases, DNA and other hereditary molecules are collectively referred to, consists of around 3.1 billion base pairs and 20,000-odd protein-coding genes. Some changes in the base pair sequence, otherwise called mutations, could mean vital proteins are absent or formed in ways that are harmful to health.
Over the years, several projects across the world have sequenced scores of genomes, and geneticists know the sequence of bases that make up a typical Caucasian, Indian or Chinese genome as well as the stretches of genes that make up skin colour, the size of your head, how many fingers you will have and whether you will be lactose-intolerant.
Genes are unevenly distributed in 46 clusters in the cell called chromosomes. We inherit half our chromosomes from each parent. When a sperm fertilises an egg, 22 of 23 chromosome pairs carry one copy of gene each and chance determines which of them is passed on.
While most diseases are caused by several genes going awry, some are the result of a single, aberrant one. When AIIMS professor and paediatric neurologist Sheffali Gulati, who specialises in the neurological disorders affecting children, saw Nazir’s children, the symptoms appeared to fit a pattern of a rare class of genetic disorders called leukodystrophies. While there are several forms, leukodystrophies are marked by the brain gradually losing white matter. White matter helps the brain’s cerebral cortex — the grey matter — communicate with one another and the rest of the body.
Zeroing in on Nalband mutation
The Nalband community, all Muslim, to which Nazir belongs, is about 5,000 strong, and spread across Uttar Pradesh, Haryana, Rajasthan and Pakistan. The name literally translates to ‘makers of horse shoes’ though today, a wide range of professions characterise the members of the community. One of Nazir’s siblings is a local politician, another relative who lives nearby is an Unani doctor. Their father was a carpenter. Despite the internal social stratifications, the family is fairly endogamous. Nazir and Tabassum are first cousins and their siblings are married to each other too.
Shamsudheen K.V., 29, who works with Scaria and Sivasubbu at CSIR-IGIB, is the institute’s point man for GUaRDIAN (Genomics for Understanding Rare Diseases India Alliance Network), which has about 100 clinicians spread across 30 centres across the country. In 2015, while still wrapping up his doctoral dissertation, Shamsudheen chanced upon Nazir’s story online and got in touch with him through the newspaper that wrote about him. Around the same time, Human Welfare Foundation (HWF), a Delhi-based charity, also offered to aid Nazir. “We were appalled,” says Muhammad Arif, a deputy director at HWF, “a man who’s suffering to the extent of wanting his children dead and we were unable to do anything about it.” Shamsudheen and Arif met and agreed to collaborate in rehabilitating the family and then arranging for the logistics and medical expenses at AIIMS.
That also marked Shamsudheen’s two-year tryst with Agra where he would tag along with HWF workers and knock on several doors, give crash courses in genetics and cajole the residents of Nazir’s neighbourhood for blood samples, from where DNA and the tapestry of genetic relatedness in the community could be fleshed out.
While DNA resides in slimy cells and must be extracted by concoctions of chemicals, isolating genes is largely about harnessing powerful computers and writing efficient algorithms to find out the common stretches of base pairs that are present in all who carry the disease but are absent in those free of it. The winnowing process, that can extend over weeks, is a laborious trial-and-error exercise.
Eventually, the CSIR-IGIB team found it. Tucked away on the MLC-1 gene on chromosome 21, the researchers informally call it the “Agra” or “Nalband” mutation. Usually when potential genes — that may be out of step from their normal variants by a single letter or an extra letter — are narrowed down, researchers must test out these combinations of base pairs either in lab-cultivated cells (to see if they indeed trigger awry cell growth) or in animal models such as zebrafish.
In the case of Nazir’s family, there were multiple reasons why the ‘Nalband mutation’ was responsible for the disease. One, the gene, MLC-1, where the mutation was discovered, has previously been known to play a role in neurodegenerative disease. Second, all sick children in Nazir’s, and three others in his extended family, had exactly the same mutation. “The odds of it not being responsible were infinitely small,” says Shamsudheen. The results are in the process of being published in a journal.
Genes and the endogamy trap
Finding mutations isn’t as important to the CSIR-IGIB as using this to tackle rare diseases. A July 2016 Current Science editorial notes that though precise statistics of rare disease were absent in India, extrapolating U.K. estimates of 1 in 20 implied that there were 60 million Indians afflicted with such conditions. Sitting in the CSIR-IGIB lab, Sivasubbu says, “In our conservative estimate, if you can prevent an infant with a rare genetic disorder from being born [through prenatal screening], that’s ₹50-80 lakh saved over a lifetime.” A prenatal screening is useful because a child with two mutated copies of the gene will certainly manifest the disease, according to Scaria. With at least 25,000 endogamous communities estimated, the team has so far worked on 500 families and hopes to find at least 1,000 within the next year.
Disease, as the GUaRDIAN’s quest over the years has revealed, shows that economic liberalisation, migration and digitisation have only glacially changed the practices of several thousands of communities that strictly practise endogamy. On the other hand, it also shows how several Indian communities — antipodes in religion and cuisine — are frequently closely connected to Turks, Iranians, Saudi Arabians and Egyptians in the mutations that they inherit and bequeath. According to Scaria, a report from Iran seemed to suggest that the “Agra mutation” may have been reported in a child in that country. Were you to ask Tabassum or Nazir if they’ve encountered anyone in their extended family expressing the same symptoms as their children, they emphatically deny it.
“But that’s not what the family tree says,” says Scaria, pointing to a PowerPoint slide that shows the genetic relationships among 82 members of the community who live within half a kilometre of Nazir’s family. “This is Nazir’s uncle and it shows that there’s a person here with the disease… and here and here… three more,” says Shamsudheen, pointing to a flow chart with shaded circles that indicated members of the family with and without the disease and their relationships. “So far we’ve seen that 28% of the community are carriers of the disease gene.”
Neither Dr. Gulati nor the researchers at CSIR-IGIB have a plausible explanation for why Nazir specifically is particularly unlucky. To Scaria, it only brings to fore the role of chance in genetics. That Nazir has had several children — all within two years of each other and not enough time to be aware of the disease’s progression that begins only after they are toddlers — partially explains the odds.
However it is precisely for situations like this that genetic tests — still a fairly exotic proposition and accessible only to a fraction of Indians who can afford the necessary ₹10,000-20,000 for each such test — can be relevant to India.
Researchers at the Institute of Genomics and Integrative Biology lab in New Delhi where DNA samples are prepared for analysis.
The importance of genetic tests
The cost of finding a mutation — in the case of Nazir’s family, the genes of two affected children were compared to unaffected siblings (here, the oldest son Khubeb, 21, who assists his father at the sweet shop) — including the man-hours and the logistics would be around ₹2,00,000, according to Sivasubbu, but once a specific mutation is known you can offer a diagnostic test that, even commercially, costs about ₹1,000. Such relatively inexpensive tests can be used to look for specific genes in an entire community and then expecting at-risk couples can be informed by genetic counsellors. “You further have the option of prenatal testing now, where the unborn child’s genes can be tested,” he says.
The researchers, as part of their investigation, have encountered clusters of villages in Maharashtra where hundreds of people — all bearing the same surname — have a disease that strikes men after 35 and makes them immobile. They’ve had people writing to them from communities in Gujarat, Andhra Pradesh where family members speak of diseases — such as flaking skin that peels off and makes wearing most clothes impossible or skins that resemble the scales of a fish — that have been plaguing them for generations. As part of their “odysseys”, as Sivasubbu describes them, they’ve attended weddings, where the chances of meeting several extended members of a clan are highest and — away from the view of guests — collected blood samples to ferret potential mutations. In most cases, there are no cures and even the world over, pharma companies aren’t incentivised to spend billions of research dollars on them because the patients are too few and the disease too challenging. In other cases, once a genetic mutation is identified, it gives doctors the confidence to recommend drugs and medicines that they would otherwise not.
After tracing an errant gene in another family, it emerged that administering a course of vitamin E dramatically improved patients’ quality of life, Sivasubbu recounts. To further their project, the GUaRDIAN programme — that’s funded by the Council of Scientific and Industrial Research — aims to have every medical college in every State with the capacity to conduct genetic screening. “In 2008, the dream of sequencing a genome was if we can we offer personalised genome testing and today, given that these technologies are affordable and a service and discovery arm is in place, it seems possible,” says Sivasubbu.
Between hope and fate
Possibility is what Nazir sees today. After the 11-year-old Kasif, Mohammed has had twins — Teeba and Aban — who are eight years old and both have had seizures and the falls and loss of balance that mark the inception of the disease. Even so, they are able to go to school and seem to be much better than their older siblings were at the same age, according to their father. Because the genetic basis of their disease is apparent, they’ve been put on prophylactics to protect against the seizures and improve their muscle tone. “This will improve the quality of life but they too will eventually manifest the conditions,” says Shamsudheen, who is a regular visitor to the family, “and so far there’s no therapy or medicine even in early trials that offers a cure.”
And then there’s Ulfath, the youngest and a girl of 6. Like her eldest brother, Khubeb, she carries only a single copy of the gene and is therefore free of the disease. Khubeb is already betrothed to his cousin, in line with practices of his family. The bride-to-be, says Shamsudheen, is a carrier. To be sick or healthy, says Nazir, is “the will of Allah”.
