A genetic research collaboration between Rambam and colleagues in Germany has provided the explanation for the enigmatic death of three babies in the 1990s.
It sounds like a detective story from a police series: New genetic research conducted by partners from Rambam Health Care Campus and abroad has revealed a new and deadly disease, and provides the explanation for the enigmatic death of three babies in the 1990s. Currently, the Rambam team is following the condition of a child from another family, the only survivor of this illness, and is trying to recruit more patients for a future study.
Everything began with the admission of baby L. to Rambam’s Pediatric Intensive Care Unit; they brought in the team of the Genetics Institute. L. was born with a genetic disorder that causes severe neurological and developmental damage. Since 45 days of age, Rambam’s Genetics Institute has followed her in an effort to identify the cause of her ailment. Despite repeated examinations, the team found no known disease that could be attributed to her symptoms, and the search continued.
Rambam’s genetics team found the answer: a newly diagnosed disease resulting from a dysfunctional gene, essential for normal neurologic function. Amazingly, this discovery solved the mystery involving the deaths of three children from another family that had also been followed at Rambam 15 years ago. This finding recently appeared in the prestigious American Journal of Human Genetics (AJHG).
L.’s symptoms included muscle weakness, breathing difficulties, an undeveloped kneecap, and suspected seizures. Tests to trace a known genetic mutation that could have explained these symptoms, failed. Nevertheless, several of the child’s symptoms seemed to indicate a known disorder called glycine encephalopathy. In this disease, high levels of glycine, an amino acid, are present in both blood and spinal fluid, leading to over-suppression of the nervous system. However, L.’s glycine levels were only slightly higher in the spinal fluid and normal in blood, indicating that a different disease was at fault. As a result, Rambam researchers performed an advanced genomic examination that led to the discovery of the disease-causing gene.
Further exploration by the Rambam researchers noted that similar symptoms had appeared in a family monitored by Rambam’s Metabolic Unit throughout the late 1990’s, under the supervision of Professor Hannah Mandel. Three of the family’s children had been born ill and died young, at the ages of two days, 18 days, and seven months. This unusual disease had not been described in the literature of human medicine.
The genomic test that eventually diagnosed L. was not available 15 years ago, when the three siblings were monitored at Rambam. The new test pinpointed a gene previously unknown to cause disease in humans. However, the gene had been vastly studied in connection with defects in mice and zebra fish. Mice lacking this gene were born weak and died of respiratory failure within hours, while zebra fish with a a mutant gene could not swim spontaneously or in response to trigger.
At this point, researchers at Rambam’s Genetics Institute joined forces with a scientist from Germany, Dr. Eulenburg Volker from the Friedrich Alexander University, who had been studying the mice with the defective gene. He wanted to know if the glycine levels in his mice were similar to those observed in glycine encephalopathy, or to those found in patients from the two families at Rambam. Three groups of mice were tested: healthy animals, mice with the mutated gene in a certain part of their brains, and mice that received a medical compound to block the protein’s activity. “All mice had normal glycine levels in their blood, while the affected mice displayed slightly elevated glycine levels in the spinal fluid compared to healthy animals,” explained Alina Kurolap, a graduate student at the Technion, working at Rambam’s Genetics Institute. “This is how we established the hallmarks of this newly diagnosed disease for the first time in humans , in our young patient, L.”
The discovery of diseases caused by a genetic mutation can help families find closure. When Rambam’s staff at the Genetics Institute conveyed to the family the newly discovered cause for the loss of their three babies the nineties, the parents were deeply moved. They finally understood that they were not to fault for the deaths of their children—rather a genetic disease was the culprit.
L.'s parents are still young, and long to have healthy children. Currently, they are attempting to have another baby with the help of in vitro fertilization (IVF) and preimplantation genetic diagnosis (PGD) in Rambam’s IVF Unit and Genetics Institute. Using PGD, one cell from the eight-cell pre-embryos is tested and only healthy embryos are implanted in the woman's womb.
According to Professor Hagit Baris-Feldman, head of the Genetics Institute and leader of this research, what appears to be the end of the story is really just the beginning. “This is an exciting discovery, but we have much more to learn about this disease,” she says, adding “at this time, we are continuing to monitor our little patient—the only one who still surviving this disease —and we trying to recruit additional patients from Israel and abroad to learn more about this gene and this new disease.”
The ABI 3500 genetic analyzer used in this research was purchased by Rambam Health Care Campus with the generous financial aid of the Wolfson Family Charitable Trust of London.
