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21 Oct 2021 genetic disorders

Takeda, a global research driven pharmaceutical company recently hosted the GENE Summit to address the diagnostic gap and treatment of rare genetic diseases in the Middle East. With the endorsement of the Oman Society for Genetic Medicine and a focus on Gaucher, Hunter and Fabry diseases, the event brought together genetics experts to discuss regional management of rare genetic diseases. Dr Khalid Said Salim al Thihli, Founding member at the Omani Society for Genetic Medicine and senior consultant, Biochemical Geneticist and Medical Geneticist at Sultan Qaboos University Hospital, who was a panelist at the summit, reviews the scene of genetic disorders with special emphasis on Oman in an exclusive interview with Hubert Vaz. Excerpts:

What factors could be responsible for the high prevalence of genetic disease in the region, especially Oman?
Genetic disorders are not limited to cultures, geographical regions or ethnic groups, and most genetic conditions are pan-ethnic in distribution. However, some genetic conditions are relatively more common in some cultures or regions than in others. Consanguineous marriage, highly practiced in the Arab world including Oman, increases the chance of mating between individuals simultaneously carrying rare genetic variants and hence the chance of having a child/children affected with autosomal recessive conditions that are otherwise rarely encountered. A man carrying one genetic change (mutation) in one of the two gene copies he receives from his parents will not have the manifestations of a recessively inherited genetic condition, but he has a 25% chance of having a child affected with this condition if he marries a woman carrying a mutation in the same gene. Given how rare these mutations are in the general population, and the number of genes we have (~20000), the chance of partners both carrying a rare mutation in the same gene is arguably very low. Consanguineous marriage is one way for this to happen more frequently, but the chance becomes significantly higher also in a specific population if a rare mutation in a specific gene becomes relatively more common in a geographical region when inherited from a common ancestor, even in the absence of a history of consanguinity. This is referred to as ‘founder mutation’ and it is seen in different regions and populations across the globe, including Oman and the region.
It is also important to highlight that attention to diagnostic and preventative strategies of genetic conditions in Oman and the region has been relatively recent, and hence there is apparent clustering of diagnosis of these conditions over a relatively short period of time given the improved diagnostic capability with the implementation of preventative strategies lagging behind. Despite the availability of options for prevention of these conditions like carrier testing and prenatal diagnosis, there has been apparent underutilization of these options due to a number of cultural, social and legislative challenges.

How would you describe the situation in Oman with regard to genetic disease over the past few decades – is there any noticeable trend for the better?
Oman has been going through milestones in relation to delivery of clinical genetics services in Oman. This could be felt in the structure, organisation, and technical and clinical expertise providing care for patients and families affected with genetic disorders in Oman. The Genetic and Developmental Medicine Clinic at Sultan Qaboos University Hospital and the National Genetic Center presently provide care to a large number of families affected or at risk of being affected with genetic disorders. Collaboratively, both centers have contributed significantly to improved diagnostic outcomes, organised multidisciplinary care and mitigation of the tremendous effects of a number of genetic conditions at the individual, family and society levels. Genetic counselling services, prenatal diagnosis, pre-implantation genetic diagnosis and carrier screening have all witnessed improving effective utilisation with resultant notable prevention of some serious and devastating genetic conditions. The stigma related to genetic disorder as an obstacle to effective genetic health services is slowly becoming less prominent over time. Oman will also hopefully soon embark into expansion of new-born screening, a milestone that has long been awaited.

Can you specify the symptoms of Gaucher, Hunter and Fabry diseases?
Gaucher, Hunter and Fabry diseases are all disorders that result from defective function of enzymes in a small organelle in the cell called the lysosome. Patients with Gaucher disease usually present with progressively increasing fullness of the abdomen due to significantly enlarged spleen and liver. The enlarged spleen is accompanied with low platelets, low haemoglobin and low white cell counts. Some patients have bone pain, including severe painful bone crises. Patients with a subtype of the disease may develop squint, seizures and balance trouble over time. A small proportion of patients may present in the first few months of life with hypotonia, delayed development, poor feeding and develop seizures and spasticity with death in the first two years of life. This severe form does not appear to be common.
Hunter disease is a lysosomal storage disease that is X-linked and it typically affects boys. A boy with is condition usually present with recurrent ear infections, snoring, enlarged tonsils and adenoids, and sometimes deafness. Boys may present with irritability and pain secondary to the storage material causing carpal tunnel syndrome. Some of them are noted to have heart murmurs secondary to involvement of the heart valves. The boys face change over time to become coarse with thick skin and they also develop stiff hand joints with limitation of joint extension. Some affected boys may have a large head.
Fabry disease is also an X-linked condition, where typically boys tend to be more severely affected. However, females with Fabry disease can also have severe manifestations of the disease. In early childhood affected patients may have non-specific recurrent abdominal pain that may go undiagnosed. Purple coloured skin lesions maybe noticed if a child is carefully examined. If the patients go untreated, they are at risk of renal failure and end stage kidney disease. They are also at risk of early onset strokes and cerebrovascular accidents. Some patients develop disease heart muscles with enlarged heart muscle walls.

With regard to early diagnosis and access to enzyme and genetic testing, are these factors conducive to enhancing treatment outcomes?
One common feature with most lysosomal storage disorders is that they tend to be progressive over time, with disease complications becoming more prominent as storage materials continue to accumulate over time leading to progressive and sometimes irreversible damage to various organs. This entails that the earlier the diagnosis is established and the earlier treatment is initiated the better are the anticipated therapeutic outcomes. Early access to diagnostic investigations including enzymology and genetic testing is key to improved therapeutic outcomes.

Can education at different levels play any role in bringing down the incidence of genetic disorders?
One of the main obstacles to reducing the incidence of genetic disorders is lack of awareness of the existence and impact of these disorders coupled with misconceptions and inadequate utilisation of effective preventative strategies. Overcoming these obstacles through public education at multiple levels is a good starting point towards empowering the society to take an active part in the overall campaign of reducing the incidence of genetic disorders.

What are the standard treatment approaches that can support patient survival, such as enzyme replacement therapies?
From a therapeutic standpoint, genetic disorders are generally classified into those with existing etiology-specific therapies and those without an existing etiology-specific therapy available. Treatment of genetic disorders take different forms depending on the nature of the etiology. These may include enzyme replacement therapy, substrate reduction therapy, RNA-based therapy, and gene therapy. Patients affected with genetic disorders without existing etiology-specific therapy could still benefit from supportive therapies that could mitigate the impact of these disorders.

Is there adequate research on this matter to support initiatives that could be taken up by the ministry of health?
There are different institution-based research efforts directed largely towards characterisation of various genetic disorders, assessing the burden of various genetic disorders at the population level, and piloting preventative efforts through clinic-based initiatives. There are collaborative efforts between the Genetic and Developmental Medicine Clinic at Sultan Qaboos University and the National Genetic Center to drive research in relation to genetic disorders in Oman. There are certainly many gaps in clinical and basic science research in Oman that could be narrowed further with optimised usage of the existing will and infrastructure.

Your opinion on the importance of compiling data in this regard
Generating reliable, systematic and comprehensive clinical and genomic databases is an important asset that could not only improve genome-based diagnostic outcomes but also help plan and prioritise research needs in the field of genetics while supporting strategic national projects that will eventually lead to improved genetic health at the population level.

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