Sudha BhattacharyaThe story of Vikas and Poonam Bhatia.
Sambhav Bhatia In Part 1 we saw how Vikas and Poonam lost their two babies Chahak and Lakshya to an unknown disease that was categorized as an inborn error of metabolism. The parents struggled to get a diagnosis for this disease that took away their babies within days of birth; but the correct diagnosis continued to elude them. Here we shall see how their journey finally culminated in the correct diagnosis, and the birth of an organization (MERD, India) founded by Vikas and Poonam. Their lives are now dedicated to spreading awareness about inborn errors of metabolism (IEMs), and campaigning for compulsory newborn screening in India. Pyruvate Dehydrogenase Complex Deficiency (PDCD) : The suspected culprit
In his quest to find the correct diagnosis, Vikas consulted as many knowledgeable Doctors as he could find. However, in the absence of any tissue samples of Lakshya or Chahak to re-analyze, the Doctors could only reach educated guesses. Analysis of blood samples had shown high levels of lactate which could be related to pyruvate metabolism. Of the two enzymes directly involved with pyruvate metabolism, that is, pyruvate dehydrogenase complex (PDC) and pyruvate carboxylase (PC), the needle of suspicion fell on PDC deficiency, since amongst rare genetic disorders this one is more frequent. Another reason was that both babies happened to be boys; hence an X-linked disorder like PDCD, which appears only in boys, was a possibility. The X-chromosome is present only in a single copy in males. Females have two copies of this chromosome, thereby a normal gene on one X-chromosome compensates for the mutated gene on the other in females.In the absence of the compensatory gene, male babies present with disease. The other possible culprit, pyruvate carboxylase deficiency (PCD) was discounted on the same grounds. PCD is an ultra-rare disease and it affects both girls and boys. By 2008 Vikas had certainly gained a vast amount of knowledge about IEMs, but it was insufficient to help him decide about his future course of action. Finally, it was on the practical advice of a senior, well-respected Doctor at Lucknow that Vikas and Poonam decided to go for another baby. They were advised that in an X-linked disorder they had a 50% chance of a normal baby, and if the gene was not X-linked they had a 75% chance of a normal baby. Besides, Poonam was approaching 40 years of age and further delay could have complications in pregnancy. Another useful advice this Doctor gave was to go to a hospital known for excellent neonatal care. They selected Manipal hospital, Bengaluru based on its high reputation.
Their third baby was conceived in Jaipur. This time they were not leaving anything to chance and were alert from day 1. The progress of the fetus was monitored every month by ultrasound. Everything was normal until the seventh month. The next ultrasound revealed enlargement of lateral ventricles of the brain, raising suspicion of abnormality. Vikas and Poonam moved to Bengaluru for the remaining duration of pregnancy. The next ultrasound again gave the same result and cyst was suspected in the brain. However, the Doctors assured them this was not necessarily a problem. Sambhav Bhatia : Dec 3, 2009 - Feb 12, 2010 Sambhav came into this world under the very watchful eyes of his Doctors and parents. After one hour of birth his blood ammonia and lactate levels were checked, and both were high. With the prime suspect being PDCD, he was started on a ketogenic diet which was recommended for this disease (We shall look into the logic of this in a later section). Vikas had already procured this diet from USA. However, the baby’s weight did not increase. Vikas had read the literature and learnt that the same symptoms could be due to PCD as well. Sambhav’s biochemical report on the 16th day indicated that this, in deed, could be the case. If this was true Vikas knew that the baby needed sugar in his diet. The Doctor accepted this suggestion and from the 16th day they started adding sugar to his keto diet. His condition improved and weight started increasing slightly. They then brought the baby home to Jaipur and continued with the same ketogenic diet mixed with added sugar. Breast feed was also given. Although the baby was gaining weight, his condition fluctuated continuously- good days interspersed with bad days. Gradually the bad days began to increase. Vikas knew that for this incurable disease liver transplant was the last resort. He offered a part of his liver for the baby’s transplant, but for such a small baby it was not considered a feasible proposition. Finally, after illuminating Vikas and Poonam’s life for 72 days, Sambhav bid them farewell. PCD : The correct diagnosis Biochemical tests conducted on Sambhav, not being adequate to distinguish PDCD from PCD, it was left for genetic testing to arrive at the correct diagnosis. Samples of Sambhav, along with those from Vikas and Poonam were sent to Dr. Garry Brown at Oxford University for DNA sequence analysis. This revealed the PCD gene mutation, and showed that both Vikas and Poonam were carriers of the mutation. This autosomal recessive pattern of inheritance has a 75% chance of the baby being healthy. Yet, all the three babies had unfortunately inherited both mutated versions of the gene- a cruel throw of the dice.
Many diseases overlap with PCD in symptoms: the importance of correct diagnosis. Although many diseases have symptoms overlapping with PCD due to shared secondary defects, I will describe two of these diseases to highlight the necessity of correct diagnosis in order to provide the correct treatment to the infant. Pyruvate dehydrogenase complex deficiency (PDCD) The similarity between PDC and PC deficiency arises from the fact that both result in pyruvate accumulation and stall the Krebs’ cycle. The main difference between PC and PDC is that (as I described in part I), PDC converts pyruvate to CoA while PC converts pyruvate to oxaloacetate. For management of PDC deficiency a ketogenic diet, with high fat and low carbohydrate intake is recommended. It works in this case because fat breakdown provides CoA which is in short supply in PDC. With CoA available, the stalled Krebs’ cycle is set back in motion and energy supply is resumed. However, ketogenic diet would not work for PC because in this case CoA production is not affected. Rather the molecule in short supply is oxaloacetate. Here the recommended diet is carbohydrate and protein rich, with frequent feedings, and controlling the acidosis. Supplementation with citrate and aspartic acid, the two molecules that can be converted to oxaloacetate, is recommended to help re-start the Krebs’ cycle. Biotinidase deficiency Biotin is an essential vitamin that we obtain from our diet. It is generally bound to dietary proteins. When food is digested in the intestine, biotin is released from the proteins by the action of biotinidase enzyme. When this enzyme is deficient the body can no longer obtain biotin from diet or by recycling endogenous biotin. The overlap of biotinidase deficiency with PCD happens because PC is one of the proteins to which biotin binds. In the absence of biotin PC loses its enzyme activity, and gives rise to symptoms of PC deficiency, although the primary cause is biotinidase deficiency. If diagnosed correctly, biotinidase deficiency can be treated quite easily by supplementing with free biotin which is readily absorbed by the body. PCD, a Genetic Disease : Did it run in the Bhatia families? Humanity inflicts the worst oppression on itself by drawing boundaries. Vikas and Poonam’s families suddenly found themselves on the wrong side of the boundary when the country was partitioned in 1947. Vikas’s family had to migrate from Dera Ismail Khan and Poonam’s family from Multan (now in Pakistan) to start new lives in Jaipur. They left all their possessions behind, but genetic mutations do not respect boundaries. Vikas’s parents had given birth to seven children, of whom the first three did not survive past infancy. His paternal Uncle had twelve babies, of whom the first five did not survive. In those times of turmoil neonatal care was not sophisticated; nevertheless, such a high rate of infant mortality was unusual, making it likely that the rare PCD mutant allele possibly ran in the family. Although Vikas and Poonam do not belong to the same gotra, and their marriage is not considered consanguineous, they are both drawn from the limited gene pool of western Punjab. This increases the chances of both parents being carriers of the same recessive allele, as was revealed in their case. Vikas and Poonam Bhatia : Life after Sambhav With the confirmed genetic test of PCD, an autosomal recessive disease, Vikas and Poonam knew they had a 75% chance of having a normal baby. But, being a throw of the dice, it could well be the same fate the fourth time around. The thought of making yet another infant suffer a torturous death was more than they could bear. No, it didn’t seem right to go through this again. Further, by now they realized that PCD was an unusually hard disease to treat; but there were many other inborn errors of metabolism which if diagnosed early, could be treated at least to the extent of saving lives. The catch was they needed to be diagnosed early and correctly. One may ask, since the most definitive test is genetic, why not go straight for DNA sequencing. This may well be the case in years to come when DNA sequencing technology becomes even more widespread and affordable. However, currently, getting a DNA test takes time (apart from money), and for most IEMs time is of the essence. Biochemical tests, including enzyme assays, or measuring the levels of metabolites are much more rapid and cost-effective. Hence rapid newborn screening using available technologies is the immediate solution. Many IEMs have relatively simple treatments, involving special diets and supplements. Vikas and Poonam realized that If they could spread this knowledge to other prospective parents they might succeed in saving countless newborn babies. MERD, India Thus it was that in February 2011, a year after they lost Sambhav, Vikas and Poonam set up MERD India Foundation (Metabolic Errors and Rare Disease Organization of India), the first of its kind dedicated to IEMs. The mission of MERD India is to provide moral as well as informative support to parents of children born with IEMs, and to campaign for compulsory newborn screening (NBS) in India. Early detection can save the infant from irreversible damage to vital organs, and allow a better quality of life to the baby. In the past decade NBS programs have been initiated in a few metropolitan centres in India and these models have to be replicated country-wide. MERD India envisages that NBS should be compulsory and should become as routine and commonplace as vaccinations, for which Vikas is tirelessly campaigning with Government agencies, and clinicians. They appeal to gynaecologists to sensitize parents in the last trimester of pregnancy about the benefits of NBS. They are campaigning to spread awareness about NBS at all levels, including the panchayat level, at primary health centres and through the ASHA network. At present they have a network of over 350 parents all over the country. Through timely interventions they have saved the lives of hundreds of babies, many of whom are going to school. Most importantly, they have imbued a sense of confidence in parents of babies with IEMs who had given in to gloom and despair. One can only salute Vikas and Poonam who have turned their personal tragedy into a victory for generations to come. My humble tribute : लक्ष्य होगा, तो ही सम्भव है शिशुओं की मीठी चहक। Acknowledgement : I am extremely grateful to Vikas and Poonam Bhatia for freely sharing their story, including the case files of their babies.