DO: 0080946;
Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
---|---|---|---|---|---|---|
10p12.1 | Retinal dystrophy with leukodystrophy | 618863 | Autosomal recessive | 3 | ACBD5 | 616618 |
A number sign (#) is used with this entry because of evidence that retinal dystrophy with leukodystrophy (RDLKD) is caused by homozygous mutation in the ACBD5 gene (616618) on chromosome 10p12.
Retinal dystrophy and leukodystrophy (RDLKD) is a peroxisomal enzyme deficiency caused by impaired very long chain fatty acid (VLCFA) metabolism. Patients exhibit ataxia and spastic paraparesis as well as developmental delay, and may show facial dysmorphism (Ferdinandusse et al., 2017).
From a cohort of 149 Saudi families with various retinal dystrophies, Abu-Safieh et al. (2013) reported 3 sibs (family CRSPW) with a mutation in the ACBD5 gene. Clinical information was limited, but sibs were stated to have cone-rod dystrophy, developmental delay, spastic paraparesis, and white matter disease.
Ferdinandusse et al. (2017) studied a girl, born of consanguineous parents from the United Arab Emirates, who had progressive leukodystrophy associated with ataxia, retinal dystrophy, and cleft palate. After an unremarkable first few months of life, with repair of the cleft palate at age 6 months, at age 7 months she presented with abnormal eye movements and was diagnosed with retinal rod-cone dystrophy. Although she walked at age 1 year, her gait was unsteady and progressively abnormal. She spoke in sentences at 2.5 years of age, and cognitive function appeared relatively preserved. However, examination at age 4 years showed limited vocabulary with dysarthric speech, and she had progressive microcephaly with facial dysmorphisms, including hypotelorism, bilateral ptosis, tubular nose, and prominent ears. She exhibited rotatory nystagmus, and her motor dysfunction was marked, with a positive Gowers sign and proximal weakness, as well as increased extrapyramidal and pyramidal tone in her arms and legs. Her gait was wide-based with truncal titubation and waddling, and finger-nose-finger testing was remarkable for mild dysmetria. Brain MRI at the age of 4 years revealed hypomyelination with diffuse T2 signal abnormality in deep white matter with relative sparing of the subcortical U fibers. Signal abnormalities were also noted in the long tracts of the brainstem, including the pyramidal tracts, the medial lemniscus, and the cerebellar peduncles. Over time, her gait became increasingly unbalanced, and by the age of 9 years she could walk only with 2-handed assistance or short distances with a walker.
The transmission pattern of RDLKD in the families reported by Abu-Safieh et al. (2013) and Ferdinandusse et al. (2017) was consistent with autosomal recessive inheritance.
Ferdinandusse et al. (2017) performed metabolic screening in a girl with ataxia and retinal dystrophy, and observed mildly increased plasma levels of VLCFAs, with an increase in C26:0 lysophosphatidylcholine and C26-acylcarnitine levels. Peroxisomal fatty acid oxidation studies in patient fibroblasts showed a reduction in C26:0 beta-oxidation activity to 33% of that of control fibroblasts. In a loading study with deuterium-labeled C22:0 (D3-C22:0), both D3-C26:0 and D3-C28:0 levels were increased compared to controls, and unlabeled C26:0 levels were increased, with an increased C26:0/C22:0 ratio.
By autozygome analysis followed by exome sequencing in 149 families with various retinal dystrophies, Abu-Safieh et al. (2013) identified homozygosity for a splicing mutation in the ACBD5 gene (616618.0001) in 3 sibs from a consanguineous Saudi family (CRSPW) with retinal dystrophy, developmental delay, spastic paraparesis, and white matter disease.
In a girl from the United Arab Emirates with retinal dystrophy and leukodystrophy, who exhibited impaired peroxisomal beta-oxidation of C26:0 but was negative for mutation in the ACOX1 (609751) and ABCD1 (300371) genes, Ferdinandusse et al. (2017) sequenced the candidate gene ACBD5 and identified homozygosity for a deletion/insertion mutation (616618.0002) that segregated with disease in the family. Noting phenotypic similarities between this patient and the Saudi sibs previously reported by Abu-Safieh et al. (2013), Ferdinandusse et al. (2017) suggested that the clinical presentation of ACBD5 deficiency is consistent.
Abu-Safieh, L., Alrashed, M., Anazi, S., Alkuraya, H., Khan, A. O., Al-Owain, M., Al-Zahrani, J., Al-Abdi, L., Hashem, M., Al-Tarimi, S., Sebai, M.-A., Shamia, A., and 9 others. Autozygome-guided exome sequencing in retinal dystrophy patients reveals pathogenic mutations and novel candidate disease genes. Genome Res. 23: 236-247, 2013. [PubMed: 23105016] [Full Text: https://doi.org/10.1101/gr.144105.112]
Ferdinandusse, S., Falkenberg, K. D., Koster, J., Mooyer, P. A., Jones, R., van Roermund, C. W. T., Pizzino, A., Schrader, M., Wanders, R. J. A., Vanderver, A., Waterham, H. R. ACBD5 deficiency causes a defect in peroxisomal very long-chain fatty acid metabolism. J. Med. Genet. 54: 330-337, 2017. [PubMed: 27799409] [Full Text: https://doi.org/10.1136/jmedgenet-2016-104132]