The world doesn’t care when a disease is rare, while a parent doesn’t care, that the disease is rare . Over the ages, it’s parents who have propelled rare disease drug discovery.
Borgny, Harry, Liv and Dag (clockwise). Hello Readers! I am Sudha Bhattacharya, mother of a lovely daughter who got diagnosed with a rare muscle disease, GNE Myopathy, at the age of 26 years when she was a budding corporate lawyer. Suddenly her (and our) world of hopes and dreams came crashing down. The verdict was grim. There was no treatment for this rare disease. Her condition would progressively worsen. She would lose muscle function in her limbs and slowly most skeletal muscles would be affected, leaving her severely disabled.
Once the tide of initial shock, disbelief and confusion ebbed, my husband and I (both of us are molecular cell biologists) realized that, as scientists, we had our task cut out for the rest of our lives. Here was a rare genetic disorder which, like thousands of other genetic disorders, had no treatment. Little was known about disease mechanism and just a handful of labs worldwide were actively researching GNE Myopathy. Yet, new developments in gene delivery, gene editing, stem cell biology and related fields provided compelling reasons to be hopeful that treatments would emerge for rare genetic diseases in the foreseeable future. The task for us was to promote such translational research in India, as indigenous production of such drugs would ensure their availability to our patients at affordable prices.
But, more of that in later blog posts. Today I want to narrate a couple of stories of parents whose unrelenting pursuits to find the cause of their child’s mysterious ailment led to the correct diagnosis of a rare disease and to the formulation of the first medical food. Science owes a debt of gratitude to these parents who helped open a whole new area of scientific investigation.
This is the story of a rare genetic disorder called Phenylketonuria (PKU) which we now know is caused by the abnormal accumulation of an amino acid, phenylalanine. This amino acid is present in our normal diet. The body consumes it for normal growth, and rapidly degrades any excess amount. PKU patients lose the ability to degrade excess phenylalanine. Its accumulation has disastrous consequences. It leads to mental retardation and developmental defects in children. A century ago, this disease existed unidentified, and Doctors had absolutely no clue about its possible cause or mode of treatment. This state of ignorance was to end, due to the dogged persistence of two mothers.
Oslo, Norway - late 1920s
Borgny Egeland and her husband, Harry welcomed their first child, Liv, a bright and happy girl. All seemed normal with Liv except that by 3 years of age she hadn’t learnt to speak. At that time the couple welcomed their second baby, Dag, a healthy boy. However, Dag began to show developmental delay as well. By age six, Liv could hardly speak, and had abnormal gait. By age four, Dag could not even eat or drink on his own. In addition, Borgny noticed a strong musty odour in Dag’s urine when he was a year old, and with time both children emitted a musty body odour. Borgny was witnessing the slow mental decline of her lovely babies before her very eyes, and wondered whether the musty odour had any connection with mental retardation of her children. Doctor after Doctor had no help to offer. Mental disability was considered untreatable, and such individuals had to be relegated to institutions.
Dr. Asbjørn Følling In 1934, Borgny’s husband happened to meet Dr. Asbjørn Følling, a physician-chemist, who had acquired new expertise in metabolic medicine. Borgny made an appointment with Dr. Følling at Oslo University hospital. Dr. Følling had no expectations of providing any help whatsoever but agreed to see the children because Borgny was not giving up. “I examined the children mainly because I did not want to be hostile to the mother,” he later said. As with other Doctors who had examined the kids before, Dr. Følling too did not find anything unusual except their musty body odour and mental slowness. He did the usual chemical tests on the childrens’ urine samples to rule out kidney problems and found nothing. To reassure Borgny that he had tested the children thoroughly, Følling did an additional test on the urine samples. He added acidified ferric chloride solution to the urine. If it turned purple, it would be indicative of diabetes or nutritional starvation. To his utter surprise, the urine turned green, a totally novel finding that had never been reported before. What was the unknown substance in the childrens’ urine that gave the musty odour and this unusual chemical reaction? Was it connected to mental retardation, as Borgny had wondered? Følling was now on a mission. Over a period of two months Borgny supplied 20 litres of the childrens’ urine for Følling’s analysis. He finally identified the substance to be phenylpyruvic acid and correctly concluded that it was derived from dietary phenylalanine. Within months, using the simple urine test Følling tested hundreds of children from mental institutions to answer Borgny’s original query. He established a correlation with mental retardation, and identified eight more patients of this previously unknown disease. In Norway it was called Følling’s disease, and was later christened phenylketonuria. Although Borgny’s efforts helped the correct diagnosis of her childrens’ condition, it did not provide them any treatment. This was left for yet another mother to pursue.
Dr. L. I. Wolff
The Hospital for Sick Children, Great Ormond Street, London; and Children’s Hospital, Birmingham, England; 1949
By now the urine test devised by Følling was helping to diagnose more and more PKU patients. In 1949 L.I.Woolf and David Vulliamy working at the Hospital for Sick Children, Great Ormond Street reported a case of PKU and made some seminal observations. They suggested that the mental retardation was due to toxic effect of phenylalanine on the brain, and that this could be relieved by somehow reducing the amount of phenylalanine in the blood. They made the bold suggestion that this could be achieved by feeding the children a diet with restricted levels of phenylalanine. Woolf knew that phenylalanine could be removed from protein hydrolysates by filtration through charcoal, and that protein hydrolysates were safe for human consumption and cheap to produce. His suggestion, however, had few takers at the hospital for sick children.
At the same time, in 1952, Horst Bickel and John Gerrard working at the Children’s Hospital, Birmingham, diagnosed a new PKU patient using the urine test. This two-year-old girl Sheila Jones could not stand, walk or talk and continuously groaned and banged her head. While Bickel was satisfied at having diagnosed the child, and had no plans to go further with the ‘case’, Sheila’s mother couldn’t bear to see her child suffer, and demanded more. “She awaited me every morning in front of the laboratory asking me impatiently when I would at last find a way to help Sheila,” noted Bickel. Driven thus to ponder over a possible treatment, Bickel went to see Woolf to try out his seemingly improbable formula. Woolf provided him with all details of his proposed artificial diet. The trick was to include just enough phenylalanine to permit normal growth without leaving any excess amounts in the blood. Back in Birmingham, Horst Bickel, with Evelyn Hickmans and John Gerrard tested this diet on Sheila. With trial and error, they arrived at the right amount of phenylalanine to be added to the diet, that finally relieved Sheila of her agony. She no longer banged her head or moan continuously. Although her mental damage could not be reversed, her suffering was markedly diminished. This work laid the foundation of ‘medical foods’ and changed the attitude of Doctors, who had thus far considered genetic disorders to be untreatable.
Evelyn Hickman flanked by Gerard (l) and Bickel (r) receiving the John Scott Award.
The success story at Birmingham finally convinced the hospital for sick children at London to also adopt this dietary method to treat their PKU patients. Wolff perfected the diet by optimizing the phenylalanine concentrations. Remarkably, the other great contribution by Wolff and his team was to drive home the importance of newborn screening. They tested the urine of a 17 days old infant who was PKU positive and she became the first neonate to be treated with the special diet. The results were excellent. The baby grew up with almost normal intelligence, got married and had children. This underscored the vital importance of newborn screening to catch PKU and other related metabolic disorders very early and treat them before damage set in.
Eventually it was the physician scientists who solved the puzzle. Of course. They were the experts. But, left to their own devices they would have left these patients as ‘untreatable’ and moved on- for good reason. It was the constant nudging by parents that forced these Doctors to up their game and deliver the winning shots. Maybe it was too late for their loved ones who were already far along in the disease, but it was these mothers who relieved the suffering of future generations of patients. What’s more, their persistence opened the doors of science for further exploration.
Almost every rare disease that has a treatment today, also has a back story of such parents and caregivers. In later blogs I will narrate the present-day account of parents and caregivers of boys afflicted with Duchene Muscular Dystrophy.
Staying with PKU and other ‘inborn errors of metabolism’ for the moment I would like to mention Mr. Vikas Bhatia, a parent from Rajasthan who lost his dear children to an inherited metabolic disorder. Understanding the value of newborn screening that could have saved his babies, he is now India’s foremost champion of bringing newborn screening to every hospital of the country. His inspiring story will be the subject of my next blog. References 1. doi:10.3390/ijns6030059
2. DOI: 10.1542/peds.105.1.89
3. Messner D. On the Scent: The Discovery of PKU, Distillations, Science History Institute, 2012