Variables in the ACBD5 Gene Leading to Distinct Phenotypes: A Case Report

Abstract

We report the cases of a father and his daughter, the former diagnosed with retinitis pigmentosa (RP) and the latter with early foveal atrophy; while both shared a novel variant of uncertain significance (VUS) in the ACBD5 gene (variant c.431G>A), they exhibited different clinical profiles and disease manifestations. The father was a 48-year-old man who presented with nyctalopia that had persisted since age seven. He had mild disk pallor, vessel attenuation, retinal pigment epithelium (RPE) changes nasal to the fovea, and few midperipheral bone spicules. Sequencing analysis showed that he carried seven VUS in five genes: ACBD5 c.431G>A (p.Gly144Asp), CYP4V2 c.296T>C (p.Met99Thr), EYS c.1852G>A (p.Gly618Ser), HMCN1 c.280G>A (p.Val94Met), HMCN1 c.8939A>C (p.Asn2980Thr), RP1L1 c.575C>A (p.Pro192His), and RP1L1 c.1375A>C (p.Thr459Pro). He shared only the ACBD5 gene with his 18-year-old daughter. The daughter had 20/20 visual acuity, but further testing showed foveal atrophy and hyperautofluorescence. Intrafamilial phenotypic heterogeneity was detected in our patients. Studies on the role of hormonal factors leading to phenotypic variability are warranted.

ACBD5‐related retinal dystrophy with leukodystrophy due to novel mutations in ACBD5 and with additional features including ovarian insufficiency

“…Both reported individuals were found to have a heterozygous variant of uncertain significance in ACBD5 with clinical features of rod-cone dystrophy and foveal atrophy, respectively (Pappaterra-Rodriguez et al, 2022).…”

“…Although prior cases of ACBD5‐related retinal dystrophy with leukodystrophy have demonstrated an autosomal recessive pattern of inheritance, a recent report of a father–daughter pair has posited that heterozygous variants in ACBD5 may predispose to a more restricted clinical syndrome with isolated retinal features. Both reported individuals were found to have a heterozygous variant of uncertain significance in ACBD5 with clinical features of rod‐cone dystrophy and foveal atrophy, respectively (Pappaterra‐Rodriguez et al, 2022).…”

New insights into the functions of ACBD4/5-like proteins using a combined phylogenetic and experimental approach across model organisms

“…Meanwhile, numerous patients with an ACBD5 deficiency have been identified which present with retinal dystrophy, ataxia, psychomotor delay and a severe leukodystrophy (Carmichael et al, 2022; Abu-Safieh et al, 2013; Ferdinandusse et al, 2017; Yagita et al, 2017; Helman et al, 2020; Bartlett et al, 2021; Gorukmez et al, 2022; Pappaterra-Rodriguez et al, 2022; Hasturk et al, 2024; Rudaks et al, 2024). Loss of ACBD5 leads to an accumulation of VLCFA, due to impaired VLCFA import/β-oxidation in peroxisomes, as well as a reduction in ether-phospholipids (Herzog et al, 2018), which are synthesised cooperatively by peroxisomes and the ER.…”