Clinical spectrum and genotype-phenotype correlations of FLVCR1-related hereditary neuropathies and neurodegeneration

Topic:

Pre-Clinical Research

Poster Number: 229

Author(s):

Daniel Calame, MD, PhD, Baylor College of Medicine, Jovi Hui Xin Wong, National University of Singapore, Puravi Panda, National University of Singapore, Jawid Fatih, Baylor College of Medicine, Zain Dardas, Baylor College of Medicine, Haowei Du, PhD, Baylor College of Medicine, Zeynep Coban-Akdemir, PhD, University of Texas Health Science Center at Houston, Jennifer Posey, MD, PhD, Baylor College of Medicine, Richard Gibbs, PhD, Baylor College of Medicine, Davut Pehlivan, MD, Baylor College of Medicine, Reza Maroofian, PhD, University College London, Long Nguyen Nam, PhD, National University of Singapore, James Lupski, MD, PhD, DSc (hon), Baylor College of Medicine

Feline leukemia virus subgroup C receptor 1 (FLVCR1) is a ubiquitously expressed member of the solute carrier (SLC) superfamily which plays a major role in heme and choline transport. While Flvcr1-/- mice die mid-gestation and have limb and hematological defects reminiscent of Diamond-Blackfan anemia, humans with biallelic pathogenic FLVCR1 variants have neuromuscular and neurodegenerative diseases. To date, only 20 families with biallelic presumed pathogenic FLVCR1 variants have been identified. While neurodegeneration is uniformly seen in FLVCR1-related disorders, the phenotypic spectrum is broad including hereditary sensory and autonomic neuropathy (HSAN), posterior column ataxia with retinitis pigmentosa (PCARP), isolated retinitis pigmentosa (RP), and HSAN plus developmental delay/intellectual disability (HSAN+DD/ID). The molecular underpinnings of this phenotypic diversity remain unclear.

To better understand FLVCR1-related disease and to explore genotype-phenotype correlations, we analyzed clinical and research genomic databases and identified nine previously unreported families with homozygous FLVCR1 variants. Phenotypes included HSAN+DD/ID, PCARP, and RP as well as novel FLVCR1-associated phenotypes including 1) congenital microcephaly and brain atrophy and 2) hereditary spastic paraplegia and neuropathy. The cohort includes the first human FLVCR1 knockout (c.153_154insC, p.Ala52ArgfsTer38), an infant with developmental delay, failure to thrive, hypotonia, and optic atrophy. Pathogenic FLVCR1 missense variants reduced transport activity in an in vitro assay. Several missense mutations also caused mis-localization of the protein in the plasma membrane. Severe phenotypes (HSAN+DD/ID, microcephaly) associated with greater impairment of transport activity than mild phenotypes (RP, PCARP, HSAN). Finally, a weak positive correlation between evolutionary conservation, in silico prediction algorithms (CADD, REVEL), and transport activity was found.

Taken together, our results expand the phenotypic spectrum of FLVCR1-related neuropathies and neurodegeneration. These genetic and functional studies suggest disease severity is a function of residual FLVCR1 transport activity. Pharmacological strategies targeting heme or choline reduction or gene replacement therapies may have therapeutic benefit in FLVCR1-related HSAN and neurodegeneration.