• A patient's severe, undiagnosed conditions led to a genetic diagnosis for 30 individuals with similar symptoms.
• Researchers identified the FLVCR1 gene, which plays a key role in red blood cell production and cell membrane integrity.
• The team found 30 patients from 23 unrelated families with rare FLVCR1 variants, causing a range of developmental problems.
• The discovery of the FLVCR1 gene's role in these conditions opens new treatment avenues, including potential choline or ethanolamine supplementation.

In a groundbreaking development, a patient suffering from severe medical conditions for years has provided diagnosis for 30 people whose similar conditions also remained undiagnosed despite numerous tests.

This international team of researchers provided a genetic diagnosis for 30 individuals whose condition was undiagnosed for years despite extensive clinical or genetic testing. The study was conducted by researchers at Baylor College of Medicine, National University of Singapore, and collaborating institutions worldwide.

The patient presented an uncommon combination of problems. The patient had severe developmental conditions, epilepsy, and complete insensitivity to pain, which was very atypical. "The condition had remained undiagnosed despite numerous tests conducted by geneticists and neurologists," said Dr. Daniel Calame, instructor of pediatric neurology and developmental neurosciences at Baylor.

Unraveling the Genetic Mystery

Calame and team re-analyzed the patient's genetic and clinical data and that brought them to a gene, FLVCR1, and a medical mystery to solve. Current evidence indicates that the FLVCR1 protein plays a key role in the production of red blood cells and in the transport of choline and ethanolamine in cells.

Choline and ethanolamine are precursors for phosphatidylcholine and for phosphatidylethanolamine, respectively, which are required for cell membrane integrity needed to support cell division and other essential cellular functions.

Other researchers have found that knocking out the gene in mice was lethal at the embryonic stage. "The embryos have many bone malformations in the head and limbs and defective production of red blood cells, which is reminiscent of Diamond-Blackfan anemia (DBA) in people," Calame said. "But this was different from what we saw in our patient."

Implications for Treatment and Future Research

Patients with DBA also have bone malformations. Interestingly, although the evidence in mice pointed at FLVCR1 as the gene causing DBA, the gene was not identified as playing a role in DBA patients at the time. Other genes were discovered that caused the condition. "We were intrigued.

On one hand, we had a patient with a rare FLVCR1 mutation and severe developmental conditions, epilepsy and complete insensitivity to pain, but on the other hand there were patients with rare mutations on the same gene that presented with a different set of problems," Calame noted.

The team searched for an answer to this mystery and identified 30 patients from 23 unrelated families with rare FLVCR1 variants. Altogether, the findings demonstrate that FLVCR1 variants cause a broad spectrum of developmental problems ranging from severe multiorgan developmental disorders resembling DBA to adult-onset neurodegeneration.

"Our findings also support further studying the potential therapeutic value of choline or ethanolamine supplementation in FLVCR1-related diseases," Calame said. "The 30 patients we identified had not had a diagnosis for years; it was rewarding to be able to provide an explanation for their condition."