Biallelic variation in the choline and ethanolamine transporter FLVCR1 underlies a pleiotropic disease spectrum from adult neurodegeneration to severe developmental disorders.

FLVCR1 encodes Feline leukemia virus subgroup C receptor 1 (FLVCR1), a solute carrier (SLC) transporter within the Major Facilitator Superfamily. FLVCR1 is a widely expressed transmembrane protein with plasma membrane and mitochondrial isoforms implicated in heme, choline, and ethanolamine transport. While Flvcr1 knockout mice die in utero with skeletal malformations and defective erythropoiesis reminiscent of Diamond-Blackfan anemia, rare biallelic pathogenic FLVCR1 variants are linked to childhood or adult-onset neurodegeneration of the retina, spinal cord, and peripheral nervous system. We ascertained from research and clinical exome sequencing 27 individuals from 20 unrelated families with biallelic ultra-rare missense and predicted loss-of-function (pLoF) FLVCR1 variant alleles. We characterize an expansive FLVCR1 phenotypic spectrum ranging from adult-onset retinitis pigmentosa to severe developmental disorders with microcephaly, reduced brain volume, epilepsy, spasticity, and premature death. The most severely affected individuals, including three individuals with homozygous pLoF variants, share traits with Flvcr1 knockout mice and Diamond-Blackfan anemia including macrocytic anemia and congenital skeletal malformations. Pathogenic FLVCR1 missense variants primarily lie within transmembrane domains and reduce choline and ethanolamine transport activity compared with wild-type FLVCR1 with minimal impact on FLVCR1 stability or subcellular localization. Several variants disrupt splicing in a mini-gene assay which may contribute to genotype-phenotype correlations. Taken together, these data support an allele-specific gene dosage model in which phenotypic severity reflects residual FLVCR1 activity. This study expands our understanding of Mendelian disorders of choline and ethanolamine transport and demonstrates the importance of choline and ethanolamine in neurodevelopment and neuronal homeostasis.

Left Main Coronary Artery Aneurysm With Rare Quadfurcation Anatomy.

Coronary artery aneurysms (CAAs) are found in a small percentage of coronary angiograms, with left main coronary artery (LMCA) aneurysms being the least common. We present a 63-year-old male patient with a history of chest pain and an abnormal nuclear stress test. Cardiac catheterization showed a large LMCA aneurysm with unusual quadfurcation left main (LM) anatomy, but otherwise showed no evidence of obstructive coronary artery disease. The patient remained clinically stable, and a repeat cardiac catheterization 2 years later showed unchanged coronary anatomy. Further medical management with close observation was elected. This case illustrates that in select cases, large LMCA aneurysms can be successfully managed medically without surgical or percutaneous interventions. To our knowledge, this is the first report of LMCA aneurysm with quadfurcation anatomy. In addition to the case description, a review of the literature is provided.