ACBD5 deficiency causes a defect in peroxisomal very long-chain fatty acid metabolism

LD_0498 was found to have impaired peroxisomal β-oxidation of C26:0 and genome sequencing revealed a homozygous, 7.5kb deletion in ACBD5 causing loss of exons 7 and 8, confirmed by Sanger sequencing.

“LD_0498 was found to have impaired peroxisomal β‐oxidation of C26:0 and genome sequencing revealed a homozygous, 7.5kb deletion in ACBD5 (OMIM:616618) causing loss of exons 7 and 8, confirmed by Sanger sequencing.22”

Cognitive impairments were reported in six ACBD5-deficient patients.

“Beyond motor and sensory deficits, cognitive impairments were reported in six patients (Ferdinandusse et al., 2017; Bartlett et al., 2021; Rudaks et al., 2024; Al Shamsi et al., 2025), and delayed language development in five (Ferdinandusse et al., 2017; Bartlett et al., 2021; Gorukmez et al., 2022; Hasturk et al., 2024; Al Shamsi et al., 2025; Supplementary Table 1).”

Rod-cone or cone-rod dystrophies affecting both photoreceptor types were described in at least nine patients.

“Rod-cone or cone-rod dystrophies, affecting both photoreceptor types, were described in at least nine patients”

All 14 reported patients exhibited reduced psychomotor abilities, which progressed to a complete inability to walk in the following years.

“All 14 reported patients exhibited reduced psychomotor abilities, which progressed to a complete inability to walk in the following years”

Delayed language development was reported in five ACBD5-deficient patients.

“and delayed language development in five (Ferdinandusse et al., 2017; Bartlett et al., 2021; Gorukmez et al., 2022; Hasturk et al., 2024; Al Shamsi et al., 2025; Supplementary Table 1).”

To date, eight publications have reported on 16 patients with ACBD5 deficiency.

“To date, eight publications have reported on 16 patients with ACBD5 deficiency”

Microcephaly was observed in six RDLKD individuals.

“Microcephaly was observed in six individuals (Ferdinandusse et al., 2017; Al Shamsi et al., 2025), while four patients were significantly underweight (Al Shamsi et al., 2025).”

One RDLKD patient was born with a cleft palate.

“Additionally, one patient was born with a cleft palate (Ferdinandusse et al., 2017; Supplementary Table 1).”

ACBD5 is specifically required for β-oxidation of VLCFA.

“reinforcing the notion that ACBD5 is specifically required for β-oxidation of VLCFA”

No abnormalities in phytanic acid α-oxidation were detected in ACBD5-deficient patient fibroblasts.

“No abnormalities in phytanic acid α-oxidation were detected, reinforcing the notion that ACBD5 is specifically required for β-oxidation of VLCFA (Ferdinandusse et al., 2017; Yagita et al., 2017).”

Knockout of ACBD5 in HeLa and other mammalian cells did not affect pexophagy.

“knockout of ACBD5 in HeLa and other mammalian cells did not affect pexophagy (Ferdinandusse et al., 2017; Kors et al., 2024).”

These mouse models validate the impaired peroxisomal β-oxidation capacity previously demonstrated in patient-derived fibroblasts.

“These models thus validate the impaired peroxisomal β-oxidation capacity previously demonstrated in patient-derived fibroblasts (Ferdinandusse et al., 2017; Yagita et al., 2017).”

Other features of ataxia, dysarthria, cleft palate, facial dysmorphisms, progressive microcephaly, and seizures are reported sporadically in ACBD5-related retinal dystrophy with leukodystrophy.

“Other features of ataxia, dysarthria, cleft palate, facial dysmorphisms, progressive microcephaly, and seizures are reported sporadically (Abu-Safieh et al., 2013;Bartlett et al., 2021;Ferdinandusse et al., 2017;Gorukmez et al., 2022).”

Early motor development was normal in this case, but can be variable, with both normal and delayed milestones reported in other cases.

“Early motor development was normal in our case, but can be variable, with both normal and delayed milestones reported in other cases (Abu-Safieh et al., 2013;Bartlett et al., 2021;Ferdinandusse et al., 2017;Gorukmez et al., 2022).”

Only seven cases of ACBD5-related retinal dystrophy with leukodystrophy have been reported to date, including one other case diagnosed in adulthood.

“Only seven cases of ACBD5-related retinal dystrophy have been reported in the literature to date, including one other case diagnosed in adulthood.”

ACBD5-related retinal dystrophy with leukodystrophy is a peroxisomal disorder due to deficiency of ACBD5.

“Acyl-CoA-binding domain-containing protein 5-related retinal dystrophy with leukodystrophy (ACBD5) is a peroxisomal disorder due to deficiency of ACBD5.”

Rod-cone dystrophy, delayed or regression of motor development, progressive cognitive decline, and imaging features of a progressive leukodystrophy are common features of ACBD5-related retinal dystrophy with leukodystrophy.

“Rod-cone dystrophy, delayed or regression of motor development, progressive cognitive decline, and imaging features of a progressive leukodystrophy are common features (Abu-Safieh et al., 2013;Bartlett et al., 2021;Ferdinandusse et al., 2017;Gorukmez et al., 2022).”