First reported adult patient with retinal dystrophy and leukodystrophy caused by a novel ACBD5 variant: A case report and review of literature

Abstract

Peroxisomes play an essential role in lipid metabolism via interaction with other intracellular organelles. The information about the role of the Acyl‐CoA‐binding domain containing‐protein 5 (ACBD5) in these interactions in human cells is emerging. Moreover, a few patients with retinal dystrophy and leukodystrophy caused by pathogenic variants in ACBD5 have been recently introduced. Here, we present a 36‐year‐old female with retinal dystrophy, leukodystrophy, and psychomotor regression due to a novel homozygous variant in ACBD5. Our study adds to the growing knowledge of this peroxisomal disorder by providing phenotypic details of the first adult patient.

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 ].…”

“…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 ]. Concerning the visual impairment, all patients from the literature exhibit a severe cone-rod dystrophy.…”

“… 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 ] …”