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New Phenotype in Two Siblings with Familial FLVCR1 Mutation: Neurotrophic Keratopathy
Betül Dertsiz Kozan1, Mehmet Fuat Alakuş1, Hamza Polat1
1University of Health Sciences Türkiye, Gazi Yaşargil Training and Research Hospital, Clinic of Ophthalmology, Diyarbakır, Türkiye.
Insights
Novel FLVCR1 gene variants are linked to neurotrophic keratopathy, a previously unreported ocular finding. This discovery expands the known phenotype associated with FLVCR1 mutations, impacting choline transport and corneal health.
Area of Science:
- Genetics and Ophthalmology
- Molecular Biology and Disease Mechanisms
Background:
- The feline leukemia virus subgroup C receptor (FLVCR1) gene is crucial for heme, choline, and ethanolamine transport.
- Pathogenic FLVCR1 variants are associated with macrocytic anemia and neurodegeneration, with known ocular findings including optic atrophy and retinitis pigmentosa.
Purpose of the Study:
- To report neurotrophic keratopathy as a novel ocular manifestation in patients with FLVCR1 variants.
- To characterize the clinical and genetic findings in two siblings with homozygous FLVCR1 variants.
Main Methods:
- Clinical examination of two affected siblings.
- Next-generation sequencing to identify genetic variants.
- Analysis of FLVCR1 gene function related to choline transport and acetylcholine production.
Main Results:
- Two siblings presented with homozygous likely pathogenic variants in the FLVCR1 gene.
- Clinical findings included neurotrophic keratopathy (bilateral corneal leukoma, absent corneal reflexes), optic disc pallor, and peripheral neuropathy.
- A novel homozygous likely pathogenic c.160dup p.Arg54ProfsTer36 variant in FLVCR1 was identified.
Conclusions:
- Neurotrophic keratopathy may be a newly identified phenotypic feature of FLVCR1 variants.
- FLVCR1 mutations disrupting choline transport can lead to acetylcholine deficiency, causing corneal epithelial destruction.
- Further research is needed to fully elucidate the genotype-phenotype correlation of FLVCR1 variants.
Abstract:
The feline leukemia virus subgroup C receptor (FLVCR1) gene plays a role in heme, choline, and ethanolamine transport. In biallelic pathogenic FLVCR1 variants, macrocytic anemia may be associated with childhood- or adult-onset neurodegeneration of the retina, spinal cord, and peripheral nervous system. In patients with FLVCR1 variants, optic atrophy and retinitis pigmentosa are previously described ocular findings, but neurotrophic keratopathy has not been reported. In this study, we describe two patients with homozygous novel likely pathogenic variants in terms of their clinical findings, including neurotrophic keratopathy. On examination, the 2-year-old sister had bilateral central corneal clouding, leukoma, absent corneal reflexes, normal fundus findings, and protruding ears. The 5-year-old sister exhibited significant bilateral corneal leukoma and scarring, optic disc pallor, absent corneal reflexes, and autoamputation-like defects on the fingertips of both hands. Next-generation sequencing analysis of the 5-year-old patient revealed a homozygous likely pathogenic c.160dup p.Arg54ProfsTer36 variant of the FLVCR1 gene that was not listed in the GnomAD, ESP6500, ExAC, or Clinvar databases. FLVCR1 mutations can disrupt choline transport and therefore acetylcholine production. Acetylcholine increases cGMP in the cornea, promoting epithelial growth. A lack of this neurotransmitter in the cornea leads to epithelial destruction. The development of neurotrophic keratopathy in this patient and her sibling may be a new phenotypic feature of this novel variant.
