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The Indian scenario of rare Lysosomal Storage Disorders, diagnostic and treatment approaches

Dr Vibhuti Jain Rana (VJR), Head, Medical, Neovation Consultancy Services, a global medical affairs pharma partner, recently took the opportunity to initiate a series of thought-provoking discussions on rare Lysosomal Storage Disorders (LSDs) with Professor Atul Mehta, former founder and Director, Lysosomal Storage Disorders Center, Royal Free Hospital. He currently works in private practice and holds charitable, consultant and educational roles

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Considering the experience you have in the field of LSDs, please take us through your journey at the Royal Free Hospital, you are training and educating around LSDs, and the foundation of the LSD Center.

I started my haematology training at Hammersmith Hospital in the early 1980s. I was fortunate to have witnessed the birth of the molecular revolution. Ever since approximately 1982-83, we have been able to identify genes, and I began a research career at the Hammersmith Hospital studying genetics. Genetics was not only important to my work in haematology, where there are common genetic conditions such as haemoglobin disorders or thalassemia disorders, but it also facilitated the study of rare inherited disorders, such as the enzyme deficiencies that underlie LSDs. Molecular medicine has revolutionised our approach to the diagnosis and pathophysiology of these conditions. It has also laid the groundwork for new developments in treatment, for example, treatment with recombinant proteins such as enzyme replacement therapy. These treatments have been translated into cancer and other diseases, treatments that will take us into the future of stem cell transplants and cellular treatments, and of course, gene therapy. It is an exciting time.

Studies in Europe, the United States (US) and Australia suggest an overall birth prevalence for all LSDs of one in 5,000-8,000. Specifically, it could be higher in a couple of populations, such as the Ashkenazi Jewish populations, which show a frequency of one in 850 births for rare lysosomal Gaucher disease. Do you believe this number could be underestimated, and is this scenario expected to differ in Indian settings?

We think of rare diseases as being approximately one in 2,000. We then discuss orphan diseases or ultra-rare diseases, which might be one in 40,000. Gaucher disease is considered the most common form of LSD, one in 40,000, and is rare. However, in some populations such as the Ashkenazi Jewish people, the prevalence is one in 850, which is not rare. Even at one in 40,000, in India, this translates to an astonishing 20,000 given India’s population. Therefore, rare diseases may be individually rare, but, collectively, this is a major healthcare issue. In Europe, there are 30 million patients with rare diseases. This will translate to 100 million in India and 350 million worldwide. Therefore, we cannot ignore rare diseases and simply focus on diabetes, hypertension and cancer, ignoring the fact that there will be 1,000s of adults and children, particularly children, with rare diseases. Fundamentally, diagnosis is easy and straightforward. However, we need to consider raising awareness of the conditions to encourage people to think of these rare diseases.

How can we raise awareness among physicians regarding the diagnosis of rare diseases when patients approach them with common complaints such as neurological or gastrological complaints?

When a paediatrician assesses a child with failure to thrive, the child might be anaemic or suffer from fatigue, growth failure, bruising, bleeding, skeletal changes, enlargement of the liver and spleen, neurologic changes, epileptiform fits, myoclonic jerks, or muscle abnormalities. However, if we see a constellation of these abnormalities presenting to a pediatrician or family physician, often a haematologist, then, we must think beyond anaemia, thalassemia and leukemia, and think of these rare inherited conditions. Sometimes, there is a temptation not to think of them and to dismiss them with the attitude that there is no opportunity cost, as these are untreatable anyway. However, caution must be exercised. These diseases are treatable. And of course, if you cannot treat the condition specifically, by diagnosing the condition, you are empowering the patient, you are empowering the family and allowing them to be alert to the possibility that other family members either are affected or will be affected because these are inherited conditions.

India has also seen a rise in awareness in the last two decades among physicians, their societies, and patient advocacy groups, to collectively work towards a better path for rare disease patients. Do you believe this will contribute considerably to the understanding of the burden of LSDs in India?

Yes. We have statistics in Europe and the UK that it used to take five to 15 years to make a diagnosis of Gaucher disease or Fabry disease. We know this by interviewing the patients at our centre. However, we know from information, particularly in Spain and France, that the interval between the initial presentation and the ultimate diagnosis is shortening across Europe. I hope that the same will also be true in India.

What are the typical diagnostic steps and pathways and what challenges hinder timely diagnosis?

I think that awareness is critical. We have published surveys showing that these patients typically present with fatigue, anaemia, bruising, bleeding and skeletal abnormalities. They typically present either to a family physician or a blood specialist, but often to a paediatrician. Diagnosis is easy once suspected. There is no real reason to think that it is going to be any different in India, and an article published in The Lancet identifies that all of these storage disorders are seen in India. The genetic abnormalities are similar to those observed in other parts of the world. India is a tremendously diverse country, composed of many populations that are not only genetically diverse, but also socially and culturally diverse in terms of their educational attainment and financial capabilities. Therefore, the way these patients are present will be different in various parts of the country. When seeing children with enlargement of the liver or spleen, neurological abnormalities, bruising, bleeding, anaemia, and failure to thrive, we must consider these rare diseases and initiate an appropriate blood test. It could be a Dried Blood Test (DBS) to make both enzymatic and molecular diagnoses.

What are the differences in the journey of a patient in developed countries such as the UK versus emerging countries such as India and other Asian countries?

One of the things that we have been successful in doing in the UK is to establish Centres of Excellence (CoE) where these patients can be referred, assessed and treated. I am also aware tha