Newly defined peroxisomal disease with novel ACBD5 mutation

Abstract

Peroxisomal disorders are a heterogeneous group of diseases caused by mutations in a large number of genes. One of the genetic disorders known to cause this situation is ACBD5 (Acyl-CoA binding-domain-containing-5) gene mutations that have been described in recent years. Here, we report two siblings with a novel homozygous nonsense variation (c.1297C>T, p.Arg433*) in ACBD5 (NM_145698.4) gene using Clinical Exome Sequencing (Sophia Genetics).

ER as master regulator of membrane trafficking and organelle function

“…Indeed, plasmalogen and cholesterol homeostasis was shown to be disrupted when the MCS was compromised ( Hua et al, 2017 ). Not surprisingly, a disruption of the peroxisome–ER contact site is associated with pathologies in mice and humans: loss or mutation of ACBD5 causes retinal dystrophy and white matter disease, which are characterized by an increase in very long-chain fatty acids due to impaired lipid transfer and impaired peroxisomal β-oxidation ( Bartlett et al, 2021 ; Darwisch et al, 2020 ; Ferdinandusse et al, 2017 ; Gorukmez et al, 2022 ; Hua et al, 2017 ; Yagita et al, 2017 ). Interestingly, more levels of regulation of MCS formation are currently identified, such as phosphorylation of FFAT motifs, which can either promote or inhibit contact formation: ACBD5 phosphorylation through GSK3b was shown to negatively regulate the ACBD5–VAP–B interaction and thus peroxisome–ER MCS formation, while phosphorylation of the STARD3 FFAT motif induces contact formation with the MSP domains of VAP–A and –B ( Di Mattia et al, 2020 ; Kors et al, 2022 ).…”

Fission Impossible (?)—New Insights into Disorders of Peroxisome Dynamics

“…The first two patients with an ACBD5 deficiency (OMIM: #618863) were identified in a screen for candidate disease genes in retinal dystrophy patients [ 137 ] ( Appendix A ). During the last five years, five further patients from four families with an ACBD5 deficiency have been reported in the literature [ 76 , 138 , 139 , 140 ], documenting the increasing alertness for this relatively newly described disorder ( Appendix A ). By contrast, no patients with a pathogenic mutation in the ACBD4 gene have been detected to date.…”

“…All ACBD5-deficient patients so far exhibit nonsense mutations in the ACBD5 gene, which result in either premature truncation of translation or nonsense-mediated mRNA decay and therefore lead to a complete absence of the protein. The disease-related alterations observed in the patients point to a predominantly neurological pathology and include a visual dysfunction with nystagmus, progressive and eventually severe motor dysfunction with ataxia and dysarthria, which were reported for all patients, as well as cognitive decline, dysphagia [ 138 ], intentional tremor and seizures [ 139 ]. Correspondent with the neurological pathology, brain MRIs of the patients exhibited signs of hypomyelination in the deep white matter of the telencephalon, brain stem long fiber tracts and cerebellar peduncles [ 76 , 138 , 139 ].…”

“…The disease-related alterations observed in the patients point to a predominantly neurological pathology and include a visual dysfunction with nystagmus, progressive and eventually severe motor dysfunction with ataxia and dysarthria, which were reported for all patients, as well as cognitive decline, dysphagia [ 138 ], intentional tremor and seizures [ 139 ]. Correspondent with the neurological pathology, brain MRIs of the patients exhibited signs of hypomyelination in the deep white matter of the telencephalon, brain stem long fiber tracts and cerebellar peduncles [ 76 , 138 , 139 ]. Furthermore, in the oldest patient reported so far (age 36 years), atrophic alterations, such as diffuse ventricular enlargement, widening of the cerebral sulci and space between cerebellar folia were observed [ 138 ].…”

“… Clinical Features Genotype Mutation Organelle Alterations * Reference Cone-rod dystrophy, spastic paraparesis, leukodystrophy c.1205 + 1G>A (p.G402DfsX5) homozygous Frame shift, truncation No detectable ACBD5 protein Impaired β-oxidation of VLCFA in peroxisomes, normal plasmalogen synthesis [ 137 , 143 ] Retinal dystrophy, progressive leukodystrophy and microcephaly, ataxia, dysarthria, hypomyelination with diffuse abnormality in deep white matter c.626-689_937-234delins936+1075_c.936+1230inv (p.D208VfsX30) homozygous Exon 7/8 deletion No detectable ACBD5 protein Normal presence of import-competent peroxisomes. Increased VLCFA levels, reduced C26:0 β-oxidation, reduced plasmalogen biosynthesis [ 76 , 140 , 142 ] Leukodystrophy, nystagmus, cone-rod dystrophy, spastic paraparesis, psychomotor developmental regression c.1467G>A, (p.W489X) homozygous Nonsense mutation, truncation Elevated C26:0, C24:0/C22:0, and C26:0/C22:0 in plasma, decreased C22:0, C24:0 levels and phytanic acid in plasma [ 138 ] Leukodystrophy, retinal dystrophy, nystagmus c.1297C>T, (p.R433X) homozygous Nonsense mutation, truncation Very little detectable ACBD5 protein Elevated C26:0 in plasma (patient 1), elevated C24:0 and C22:0 in plasma (patient 2) [ 139 ] …”