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Singapore Research Team Reports World’s First Case of Jamuar Syndrome and Uncovers the Genetic Abnormality Behind it

Collaboration between doctors at KK Women’s and Children’s Hospital and geneticists at the Institute of Medical Biology (IMB) of A*STAR led to the diagnosis of the world’s first case of Jamuar Syndrome, a disease with epileptic seizures and developmental delays. The team also elucidated the genetic mutations responsible for Jamuar Syndrome.

Through collaborative efforts, scientists at the Institute of Medical Biology (IMB), Agency for Science, Technology and Research (ASTAR) and doctors from KK Women’s and Children’s Hospital (KKH) in Singapore have established a diagnosis for the first known case of a new genetic syndrome in the world. This study was reported in the January 2020 issue of Nature Communications.

This new genetic condition, known as the Jamuar Syndrome was named after Dr Saumya Jamuar, Senior Consultant of Genetics Service at KKH and Head of SingHealth Duke-NUS Genomic Medicine Centre. Dr Jamuar first reported this condition in two young children, whose family sought help from KKH in 2015 for their condition. The siblings showed a distinctive combination of symptoms which included epileptic seizures and developmental delays. They were registered in the BRIDGES (Bridging Research Innovations for the Diagnosis of Genetic Disease in Singapore) programme, which was set up to examine undetermined diseases presented in young children.

Genetic profiling studies performed by Dr Bruno Reversade, Research Director at IMB, A*STAR and his lab led to the discovery of a peculiar DNA aberration (Ala82Thr) in the UGDH gene, which is crucial for proper human brain development. Although this mutation was not known to cause genetic abnormalities in humans previously, a global search presented 34 other children who showed similar clinical profiles of symptoms and the same UGDH gene mutation as that observed in the two siblings. Another mutation in the UGDH gene, Arg317Gln was more prevalent in the 11 Saudi children who were part of the 36 children identified globally. These 11 Saudi children presented histories of epileptic encephalopathy.

Dr Reversade’s lab identified and categorized the implications of the Ala82Thr and Arg317Gln mutations on brain development, showing that the mutations induce changes in the enzyme encoded by the UGDH gene, thereby affecting the enzyme’s stability, structure, or function. The team also established mini brain models in the lab using skin cells from the siblings as starting materials. The comparative study of these mini brain models and those of healthy controls highlighted key differences between the 2 groups – the brain models from the affected children were smaller and presented a lower number of brain progenitor cells. These results emphasized the importance of the UGDH gene in human brain development.

Taking the existent UGDH gene variations into consideration, mutations in the UGDH gene can explain the occurrence of recessive epileptic encephalopathy, which include symptoms like epileptic seizures and variable degrees of speech and developmental delays.

According to Dr Reversade, “Our discovery of the disease-causing mutations in the UGDH gene could pave the way to finding new therapeutic targets for epilepsies. On a more personal note, having a novel genetic disease named after the discoverer, is a formidable accolade. Dr Jamuar was instrumental in this discovery and this is a well-deserved international recognition for his clinical acumen.” [APBN]