Gene Mutation May Explain Rare Neurological Disorders

Researchers identified rare genetic mutations that may account for undiagnosed neurodevelopmental disorders, linking the FLVCR1 gene with various neurological symptoms.

Investigating a genetic anomaly

A collaborative study, led by Baylor College of Medicine and the National University of Singapore, has found a genetic diagnosis for 30 individuals who had undiagnosed neurodevelopmental disorders despite extensive testing. The study focused on a rare mutation in the FLVCR1 gene, known to play a role in red blood cell production and the cellular transport of choline and ethanolamine. Prior evidence indicated that these molecules are critical for maintaining cell membrane integrity and supporting cell division.

Initial investigations were prompted by one patient with a severe neurodevelopmental disorder, epilepsy and an unusual lack of pain sensitivity. Despite extensive genetic tests, clinicians could not determine a cause. Enrolling in the Baylor GREGoR (Genomics Research to Elucidate the Genetics of Rare Diseases) research program enabled reanalysis, which pointed to the FLVCR1 gene as a potential source of these symptoms.

The role of FLVCR1 in neurodevelopmental disorders

While some previous studies on the FLVCR1 gene in animals suggested it might contribute to bone malformations and red blood cell issues, it had not been definitively linked to similar human conditions. For instance, mice with Flvcr1 gene knockouts had severe bone and blood cell development issues that paralleled symptoms of Diamond-Blackfan anemia (DBA) in humans. However, DBA has typically been associated with other genes.

FLVCR1 mutations have also been observed in people with ataxia – a neurodegenerative disorder marked by poor muscle control and coordination – accompanied by sensory and vision impairments. This pattern differed from the severe developmental conditions seen in the new patient cases, prompting researchers to question if FLVCR1 mutations might contribute to a broader spectrum of neurological symptoms.

“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. Could it be that those different mutations of FLVCR1 caused not one set but a spectrum of characteristics we observed in all the patients combined?”

Dr. Daniel Calame

Expanding the patient database

To investigate this hypothesis, researchers analyzed large datasets of individuals with undiagnosed neurodevelopmental conditions and identified others with FLVCR1 gene mutations. Through databases such as the Baylor-Hopkins Center for Mendelian Genomics, GeneMatcher, and other clinical sources, they located 30 patients across 23 families with similar symptoms. Within this group, researchers identified 22 unique FLVCR1 gene variants, including 20 that had not been previously documented.

These individuals showed overlapping symptoms with the mouse models, including anemia, brain malformations, and bone deformities. These features suggested FLVCR1 may play a broader role in both human and animal neurodevelopmental disorders than previously understood.

Testing gene function in the laboratory

The research team, in collaboration with the Yoon Long Lin School of Medicine, assessed how different FLVCR1 gene mutations impact choline and ethanolamine transport in cells. Lab testing revealed that these gene variants reduced the transport efficiency of choline and ethanolamine by as much as 50%. This finding supports prior studies indicating that choline is crucial for normal neurodevelopment. Deficiencies in choline have also been associated with anemia, growth delays and immune deficiencies, conditions observed in patients with FLVCR1 mutations.

The results suggest that the severity of neurodevelopmental symptoms may correlate with the degree to which a FLVCR1 variant affects choline transport. This mechanistic insight provides a clearer understanding of how FLVCR1 mutations could result in a spectrum of symptoms from multiorgan developmental disorders to adult-onset neurodegeneration.

Potential implications for diagnosis and treatment

The study highlights the importance of examining multiple data sources when analyzing rare genetic conditions, particularly for genes like FLVCR1 with wide-ranging effects. In these cases, consulting animal models proved valuable, as the mouse studies pointed to similarities with DBA-like symptoms that were not initially linked to FLVCR1 in humans. This broader approach allowed researchers to identify the FLVCR1 gene variants as the likely cause for several long-standing undiagnosed conditions.

“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.”

Dr. Daniel Calame

Furthermore, the findings suggest that choline or ethanolamine supplementation may have potential as a treatment for individuals with FLVCR1-related neurodevelopmental disorders, though further research is needed. For now, the study’s contribution lies in providing a diagnosis for individuals whose conditions had remained a mystery for years.

Reference: Calame DG, Wong JH, Panda P, et al. Biallelic variation in the choline and ethanolamine transporter FLVCR1 underlies a severe developmental disorder spectrum. Genetics Med. 2024:101273. doi: 10.1016/j.gim.2024.101273

This article has been republished from the following materials. Note: material may have been edited for length and content. For further information, please contact the cited source. Our press release publishing policy can be accessed here.

This content includes text that has been generated with the assistance of AI. Technology Networks' AI policy can be found here.