New Genetic Clues Explain Long-Mysterious Health Conditions

New Delhi: An international team of researchers conducted a study revealing that FLVCR1-related conditions can result in a wide spectrum of symptoms, ranging from severe developmental issues affecting multiple organs to neurodegenerative diseases that emerge later in life.

The study was conducted by Baylor College of Medicine, the National University of Singapore, and other global institutions and was published in Genetics in Medicine.

“The story of our findings began with one patient I saw in the clinic presenting an uncommon combination of problems,” said Dr Daniel Calame, an author and pediatric neurology instructor at Baylor.

He also said, “The patient had severe developmental issues, epilepsy, and complete insensitivity to pain, which was very unusual. The condition had remained undiagnosed despite numerous tests conducted by geneticists and neurologists.”

Dr Calame included the patient in the BCM GREGoR (Genomics Research to Elucidate the Genetics of Rare Diseases) program. “We reanalyzed the patient’s genetic and clinical data, and that brought us to a gene, FLVCR1, and a medical mystery to solve,” he explained.

The FLVCR1 protein is crucial for producing red blood cells and transporting choline and ethanolamine within cells, essential for cell function. Animal studies had shown that removing the Flvcr1 gene in mice was lethal at an early 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,” said Calame. “But this was different from what we saw in our patient.”

Although FLVCR1 had been studied in relation to conditions like ataxia (poor muscle control) and vision problems, these did not match Calame’s patient’s symptoms.

The team identified 30 patients from 23 families worldwide with rare FLVCR1 gene variants. “We identified 22 gene variants, 20 of which had not been described before,” Calame said.

These patients had a range of serious developmental issues, including profound developmental delay, small head size, brain malformations, and in some cases, premature death. Some shared traits with DBA, such as anemia and bone malformations.

In collaboration with Dr Long Nam Nguyen at the National University of Singapore, the team showed in lab experiments that FLVCR1 variants reduced the transport of choline and ethanolamine in cells. “We propose that disease severity depends on the residual transport activity of the FLVCR1 variants a patient carries,” Calame said.

Choline is vital for brain development, and its deficiency can lead to anemia, liver disease, growth issues, and immune problems. “Neurodevelopment is also disrupted by defective choline uptake, and we showed that the variants in our patients do reduce choline transport,” Calame noted.

The study revealed that FLVCR1 variants can cause a wide range of issues, from severe developmental disorders to adult-onset neurodegeneration. The findings highlight the potential of choline or ethanolamine supplements as a treatment.

“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,” Calame said.

“The 30 severely affected individuals reported here had all undergone clinical or research exome or genome sequencing, which identified the reported FLVCR1 variants, yet in each case the variants were previously felt either non-contributory or of uncertain significance given the apparent mismatch of characteristics among patients,” Dr Calame added.