The Virtual World Conference on

Rare Diseases

In the summer of 1983 my son Brian Berman at aged 3 was diagnosed with Gaucher.

We were told there is no treatment, and that he will die soon.

We were completely devastated, but my mother, had gone to Israel a couple months prior, and had met the Director of the Weitzmann Institute. She called him and he told her that the world expert on Gaucher Disease, Dr. Roscoe Brady, had his lab at the NIH, 10 minutes from our home.

I  called Dr. Brady and asked him, “do you have anything to help my child?”

He said, “if you knew what I had, you would come running to my door”- which is what I did- I gave up my medical practice, and worked gratis for Dr. Brady in his lab. At that time, Dr. Brady, who, in 1964 had discovered the enzyme deficiency that caused the Gaucher Disease syndrome, and had attempted to give native placental derived Glucocerebrosidase to little clinical effect, was developing the mannose terminated version.

My son was very ill, on the edge of high output cardiac failure from a massive spleen, severe anemia and thrombocytopenia.

Dec. 22, 1983, without prior animal studies, he was infused the very first targeted enzyme for a lysosomal disorder.

Over the next 7 weeks, we all witnessed a miracle. His spleen reduced in size, his blood counts, energy, and mobility dramatically improved. Two subsequent on- off cycles demonstrated clear therapeutic efficacy.  Subsequent patient trials led to the FDA approval process in 1991. Dr. Brady’s lab was partnered with the fledging company headed by Henri Termeer. This company became Genzyme Corporation which commercialized the enzyme then called Ceredase. Subsequently, the enzyme was generated utilizing genetic technology followed by two other companies each utilizing unique technology to generate enzyme.

In  coordination with Dr. Ari Zimran we obtained  approval by the Israel Ministry of Health and subsequently global approvals ensued.

Although this series of events could not occur in today’s world, it should empower everyone to realize that our gold standard of the double blind, randomized, placebo controlled trials are not the most powerful way of making big changes in the world of medicine.

Many physicians and scientists go into their respective fields because of personal experience ie the N of one. It is in my view, arrogant and foolish to discount, even scoff at what still too many disdainfully refer as anecdotal or observational data.

Henri Termeer himself said many times, to many audiences, that it was seeing the incredible changes in one little boy that inspired him, against many odds, and many naysayers, to build the company that really put lysosomal storage diseases on the map.

PS- I have 6 children, – by spring I will have 21 grandkids, 15 of whom come from my 3 sons with Gaucher-

Tinatin Tkemaladze1,2,4, Elene Abzianidze1, Irakli Rtskhiladze3, Tamar Ramishvili3, Mariam Ghughunishvili2, Volha Skrahina4, Arndt Rolfs4,5,6
1 Department of Molecular and Medical Genetics, Tbilisi State Medical University, Georgia
2 Givi Zhvania Academic Pediatric Clinic, Tbilisi State Medical University, Georgia
3 Medical Center Mrcheveli, Tbilisi, Georgia
4 Centogene GmbH, Rostock, Germany
5 University Rostock, Medical Faculty, Rostock, Germany
6 Arcensus GmbH, Rostock, Germany

Rare diseases (RD) represent emerging group of conditions that pose particular challenges to the affected patients and their families, treating physicians, researchers, insurance companies and the government who ideally has to take care of these patients. Georgia is a small country with a population of 3.7 mill people and the awareness of rare diseases is still limited among healthcare professionals. Diagnosing and performing molecular-genetic investigations is extremely difficult because of the high cost and the low-middle income of the population.
Our aim was to increase awareness of RD in the country and to enable diagnosis of such patients. From 2018 we initiated clinical study with Centogene. The aim of the study is to identify LC/MRM-Ms based biomarkers for inborn errors of metabolism (IEMs) and for several other non-metabolic conditions. Prior to enrollment the patients are offered free of charge (FOC) testing. In order to promote the study and enable people benefit from testing, we intensively promoted our study in various hospitals as well as in media. We carried out several workshops “Application of Artificial Intelligence in the Diagnosis of Rare Diseases” together with Face2Gene for doctors and medical students. Plus, we initiated “Rare Disease” column in one of Georgia’s largest social media medical groups, where each week information on a particular RD is uploaded in Georgian language.
Consequently, over 2 year period, about 2000 individuals received genetic testing. Interestingly, in a cohort of patients with neurodevelopmental disorders WES had up to 60% diagnostic yield with three PKU patients missed in NBS. For cystic fibrosis, the most common mutation for Georgian population is Tyr515fs* (40%), but not Phe508del, which may indicate that our population is genetically distinct from other European countries.
As a result of the above-mentioned activities, the awareness of RD has significantly increased among the healthcare professionals. Our goal in future is to promote education of doctors and students to recognize RD, support formation of parent’s organizations and patient advocacy groups, negotiate with government to support RD patients and facilitate improvement and extension of national NBS program.

Never miss a treatable condition!
J.M. Saudubray
If You Don’t Think You Won’t Look
If You Don’t Look You Won’t Find
If You Don’t Find You Can’t Treat
A. Rolfs

There are multiple issues unique to Africa which limits the care that rare disease patients receive across the continent. One such way in which FYMCA Medical LTD identified these issues was by its African Taskforce. The African Taskforce was a joint venture set up by FYMCA Medical Ltd and Care Beyond Diagnosis to connect likeminded clinicians, patient groups, and policymakers to firstly identify common problems faced in establishing rare disease programs in resource limited countries across the African continent. Further to this FYMCA Medical LTD has held numerous educational events across Africa (Morocco, Botswana, South Africa) helping to train clinicians and give patient groups an opportunity to speak to clinicians.

During these events and along with the Taskforce we identified amongst many other things that: Only 10 % of delegates had a definition of rare diseases and most used current international definitions rather than continent appropriate definitions; Only 11% had a rare disease policy in place but 100% believed they will have one within 5 years; Access to diagnostic investigations for rare disorders were present in some form in 75% of the countries and all have the ability to send samples out of country but the process to achieve this is complex in many cases.
FYMCA Medical LTD has identified these real-life issues and will share insights gained from having worked with clinicians and patient groups in Africa for multiple years.

Biomarkers are surrogate markers of disease, in the case of inherited lysosomal storage diseases (LSDs) usually being proteins or metabolites secreted by storage cells into the blood or urine. Biomarkers can be employed to assist diagnosis, to monitor disease and to assess correction of storage cells by therapeutic intervention. The discovery and application of biomarkers will be exemplified for Gaucher disease (GD). In this LSD, due to inherited deficiency of glucocerebrosidase, lipid-laden macrophages (Gaucher cells) accumulate in various tissues. Several proteins have been identified that are specifically produced by Gaucher cells and secreted, causing elevated levels in plasma. Examples are chitotriosidase, a chitinase, CCL18, a chemokine, and a soluble fragment of GpNMB. More recently, it has been recognized that Gaucher cells produce and release glucosylsphingosine (GlcSph; aka lysoGL1), deacylated glucosylceramide that is produced by acid ceramidase in lysosomes.  GlcSph levels are markedly increased in plasma and urine of GD patients. The value of plasma biomarkers for the clinic will be discussed. In addition, attention is paid to lipid-laden macrophage derived proteins and deacylated sphingolipids (aka lyso-lipids) as future biomarkers for other sphingolipidoses.

The mucopolysaccharidoses (MPS) are one group of lysosomal storage disorders caused by a deficiency of lysosomal enzymes, that are responsible for the degradation of glycosaminoglycans (GAGs), important components of the connective tissues. This is accomplished by complex pathophysiological cascades and results in a storage of GAGs in the cells. Almost all organs and organ systems are affected. 11 enzyme deficiencies leading to 7 types of MPSs are known.

The accumulation of undegraded GAGs leads to a progressive variety of somatic and neurological symptoms, including skeletal and musculoskeletal and cardiorespiratory complications. Some MPS types show also a mental development decline. Early diagnosis, appropriate management and – in some MPS types available- therapies affect the quality of life of patients and can lead to a slowdown or a prevention of irreversible complications.

Since there is not a typical “MPS-symptom”, but only the sum of many nonspecific and variable symptoms may lead to the diagnosis, in particular in attenuated / milder MPS types, they are often diagnosed late and mistaken for an (uncharacteristically running) rheumatologic disease.

Tatiana Bremova-Ertl, Marc Patterson, Taylor Fields, Mallory Factor, Richard Kay, Michael Strupp, Switzerland

Sonia Gueguen, Jérôme Weinbach, Annick Clement, Serge Amselem, Paul Landais, France

Basil Golding, USA

Genetic diseases represent a large group of diseases in which a molecular defect in a gene, usually encoding a protein, leads to a clinical pathology, manifested as a disease. There are different therapeutic modalities for different types of diseases. However, there is one way to cure a genetic disease, namely by replacing the mutant gene in germ cells. Since such a procedure is out of the scope due to severe ethical issues, the possible way is by introducing a normal gene into somatic cells. This procedure is referred to as Gene Therapy.

In order to treat a recessive disease, the normal gene, encoding the deficient protein, is introduced into the body/cells. In the case of a dominant disease, that results from expression of a mutant protein that exerts a negative gain of function effect, the defective gene is silenced. This can be achieved by introduction of antisense encoding genetic material which will block expression of the disease gene or by gene editing, using the CRISPR/Cas9 technology. Gene editing allows correction of any gene or even introducing the gene to be corrected into another gene sequence.

The correcting DNA sequence is introduced into a carrier, known as a vector. The vectors, mostly use at present, are viral derived vectors. Viral vectors are based on viruses that can infect human cells, however, they are completely non-pathogenic to the cells or the patients. The viral vectors used today in clinical trials are self-complimentary Adeno Associated Virus (scAAV) and the lentivirus. Vectors can be injected directly into the patient’s body or introduced into hematopoietic stem cells, which are introduced into the patient’s body.

All the mentioned procedures will be discussed.