Rare but Real: Shining a light on rare diseases

Perhapsrarer than the diseases you will often see referred to in the footnotes of medical textbooks or the conclusion of lectures, is an understanding or proper discourse around these conditions. Such is what Dr. Lucy McKay - Bachelor of Medicine, and Science in Human Genetics - has dedicated her professional career to remedy. As CEO and founder of the non-profit Medics4RareDiseases (M4RD), she is dedicated to changing the attitude towards rare diseases amongst medical students and doctors in training to improve the patient odyssey.

For McKay, rare diseases were a topic of interest long before she attended any university lecture, having lost a brother to mucopolysaccharidoses (MPS) - a lysosomal storage disorder with a prevalence of roughly 1 in 25,000 [1] - before she had even been born. Through the subsequent MPS Society her mother founded, she had frequent contact with people afflicted with this disease, from early on seeing the humans behind the affliction.

While in medical school, she recalls being puzzled by the teaching of rare diseases, remembering knowing more than her lecturer when MPS was brought up. She believes the attitude towards the education of these conditions to be outdated and based on fallacious grounds. Such pleonasms as “common things are common” or “if you hear hooves, think horse not zebra” might be true when thinking about the global population but grossly reductive when considering which portion will frequent the clinician. The medical professional will always see a higher number of sick people than the normal person, and if they see more diseases, they will see more rare diseases as well. On top of that, despite being seemingly counterintuitive, these conditions are cumulatively common, affecting nearly 4% of the population [2] with 70% of these being in children [3].

With these numbers, it is troubling to think that most general practitioners feel inadequately trained to take care [4] of these patients and are actively interested in training to improve their care. To help supply this dearth in the medical formation, M4RD made the online course Rare Disease 101. Easily accessible and free on their website, this 8 lesson module covers what a rare disease is, how to suspect a rare disease, the challenges of the patients who suffer with these conditions and how to support them. McKay hopes this multiplatform collaborative effort will be a proof of concept so a more elaborate approach on rare diseases may be eventually integrated into medical curricula.

As a second-generation rare disease advocate and practising clinician, McKay sees the teaching of rare diseases as too selective of a few conditions and molecular mechanics and not enough on the patient’s point of view. The literature supports this sentiment, showing that not only is patient perspective and cooperation key in bringing funding and meaning to the work of clinicians and researchers [5], but that databases such as the Undiagnosed Disease Network and the Rare Diseases Registry are extremely useful to an evidence-based personalised approach to these cases [6] .

Despite the many strides in rare diseases since the insurgence of M4RD and other rare disease organizations, much work is still left to be done. McKay says her organisation won’t be truly successful until it no longer needs to exist, and though that may be a ways away, we can commend the efforts that have brought us this far. Conversations which weren’t even considered a decade ago are now held on every level of our practice. For that, both doctors and patients alike can be grateful of her proposal to dare to think rare.

Dr. Ari Zimran is a specialist in Internal Medicine, as well as an Associate Professor at the Hadassah School of Medicine, Hebrew University of Jerusalem. Beside this, he works at Shaare Zedek Medical Center in Jerusalem.

It was there that he founded the Gaucher’s Disease Unit, which he directed himself from 1989 to 2018. He is now a senior physician in this unit, which is nothing less than the leading outpatient clinic for people with this rare disease in Israel, as well as the largest referral centre for Gaucher’s disease worldwide, having monitored around 900 patients in its 30 years of existence.

Professor Zimran has also been involved in clinical trials for treatments for this illness, published several hundreds of papers and edited three books on this subject. [1]

He has therefore dedicated his whole life to the treatment and studying of Gaucher’s disease. But what does this rare lysosomal storage disease consist of?

People with Gaucher’s disease have a genetic mutation which causes them to have lower activity levels of a lysosomal enzyme called glucocerebrosidase, which is responsible for breaking down glucocerebroside (a glycolipid present

Ari Zimran, MD

in our cell membranes) into glucose and ceramide. This means that glucocerebroside accumulates in these people’s cells, specifically in their macrophages (since these are heavily involved in phagocytosis and digestion of multiple cell types), causing them to increase in size and lipidic components – they become Gaucher cells. [2]

These bloated cells predominantly infiltrate the bone marrow, the spleen, and the liver. The accumulation of glucocerebroside has metabolic implications as well. All of this leads to symptoms such as: hepatosplenomegaly, bone pain and fragile bones, anaemia and fatigue and inefficient coagulation. Neurological impairment may also be present in more severe types of the disease. [2]

Gaucher’s disease is an autosomal recessive genetic disorder. [2] This means that, for someone to have this disease, that person must inherit two mutated copies (one from each parent) of the GBA1 gene, the gene which encodes glucocerebrosidase. More than 300 different mutations in this gene have been described, and generally they prevent the enzyme from folding properly, therefore preventing it from working adequately.