Imagine a disease that strikes in childhood, leaving children with frequent epileptic seizures, delayed intellectual development and movement that sometimes worsens to the point they are unable to walk and eat. These devastating disorders—known as developmental epileptic encephalopathies—are unfortunately real.
Researchers have long believed that developmental epileptic encephalopathies have a genetic basis, but not all genetic underpinnings have been elucidated until now. An international team of researchers has found one underlying genetic cause for this disease: recessive mutations in the gene UDP-glucose 6-dehydrogenase (UGDH).
“Germline mutations of the enzyme UGDH are a common cause of epileptic encephalopathies in children,” said study corresponding author Bruno Reversade, a Research Director at the A*STAR's Institute of Medical Biology (IMB) and Institute of Molecular and Cell Biology (IMCB). “This is evidenced by a large number of subjects found all over the world.”
In a collaborative effort co-led by Ludger Schöls at the University of Tübingen, the researchers arrived at their answer through a process of genetic detective work. The first clue was the knowledge that defects in glycosylation, the process of adding sugar chains to proteins and lipids in the body, can result in symptoms similar to that of developmental epileptic encephalopathies.
With this in mind, the team proposed that UGDH might play a role in the disease. Under normal conditions, the UGDH gene codes for an oxidoreductase enzyme that is involved in the glycosylation process. To confirm these suspicions, the team first looked at a Singaporean family of a pair of siblings with developmental epileptic encephalopathy. Exome sequencing of two of the siblings revealed they both carried a rare recessive loss-of-function variant of the UGDH gene, stemming from a single missense mutation.
They then searched for more individuals with similar mutations in UGDH, discovering 27 other cases from 24 unrelated families across the world. Using these patients’ primary fibroblasts and biochemical assays, they confirmed that the mutations impair UGDH stability, oligomerization or enzymatic activity and established the role of UGDH in the production of extracellular matrix components that are essential for human brain development.
After ten weeks of differentiation, cerebral organoids created from patients’ neural progenitor cells showed marked underdevelopment compared to wildtype or carrier organoids. Not only did this study confirm that UGDH mutations behave as loss-of-function alleles, it also demonstrated that cerebral organoids can serve as a ‘disease-in-a-dish’ model.
The team proposed to name the disease Jamuar Syndrome after Saumya Jamuar, a clinical geneticist at the KK Women’s and Children’s Hospital in Singapore, who cared for the Singaporean family that was the starting point in this discovery.
“Understanding the genetic etiology of human disease is a stepping stone towards thinking about possible therapeutic interventions,” said Reversade. “Being able to pinpoint the genetic origin for an orphan disease allows for families of affected children to end a diagnostic odyssey and reach psychological comfort that a definitive cause has been unveiled.”
The A*STAR-affiliated researchers contributing to this research are from the Institute of Medical Biology (IMB), Institute of Molecular and Cell Biology (IMCB), and Translational Laboratory in Genetic Medicine (TLGM).