Alternative titles; symbols
SNOMEDCT: 238069004; ORPHA: 2971; DO: 0050797;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 17q25.1 | Peroxisomal acyl-CoA oxidase deficiency | 264470 | Autosomal recessive | 3 | ACOX1 | 609751 |
A number sign (#) is used with this entry because peroxisomal acyl-CoA oxidase deficiency is caused by homozygous mutation in the gene encoding peroxisomal straight-chain acyl-CoA oxidase (ACOX1; 609751) on chromosome 17q25.
Heterozygous mutation in the ACOX1 gene causes Mitchell syndrome (MITCH; 618960).
Peroxisomal acyl-CoA oxidase deficiency is a disorder of peroxisomal fatty acid beta-oxidation. See also D-bifunctional protein deficiency (261515), caused by mutation in the HSD17B4 gene (601860) on chromosome 5q2. The clinical manifestations of these 2 deficiencies are similar to those of disorders of peroxisomal assembly, including Zellweger cerebrohepatorenal syndrome (see 214100) and neonatal adrenoleukodystrophy (see 601539) (Watkins et al., 1995).
Poll-The et al. (1988) reported a brother and sister, born of first-cousin parents, with neonatal hypotonia, seizures, apneic spells, delayed psychomotor development, and neurologic regression after age 2 years. Brain imaging showed progressive white-matter demyelination without cortical malformations. Biochemical analysis showed accumulation of very long chain fatty acids (VLCFA) resulting from an isolated deficiency of peroxisomal fatty acyl-CoA oxidase. The clinical findings resembled neonatal adrenoleukodystrophy, but liver biopsy showed that hepatic peroxisomes were not decreased in number and were enlarged in size. In addition, there was no accumulation of pipecolic acid or bile acid synthesis intermediates, and there was no marked decrease in plasmalogens.
Suzuki et al. (1994) described a Japanese brother and sister, born of consanguineous parents, with isolated peroxisomal acyl-CoA oxidase deficiency determined by complementation analysis. Both patients showed profound hypotonia and dysmorphic features, including hypertelorism, epicanthus, low nasal bridge, low-set ears, and polydactyly. Immunoblot analysis showed some residual acyl-CoA oxidase protein. Suzuki et al. (2002) provided follow-up of the patients reported by Suzuki et al. (1994) and reported a third unrelated affected Japanese child. The 2 sibs showed neurologic regression at ages 34 and 26 months, respectively. At age 11 years, the boy was deaf and needed tube feedings. The sister died at age 4 years from respiratory problems. The third child showed mild hypotonia and nystagmus in the neonatal period, and developed seizures at 2 months of age. Neurologic regression occurred at age 28 months, and she showed severe hypotonia, dysphagia, hyperreflexia of the lower limbs, extensor plantar responses, and retinal degeneration. No dysmorphic features were observed. The child died of respiratory failure at 42 months of age. MRI showed demyelination of the pontomedullary corticospinal tracts and cerebellar white matter, similar to that seen in adult patients with X-linked adrenoleukodystrophy (ALD; 300100).
Watkins et al. (1995) found that patients with acyl-CoA oxidase deficiency had a milder initial course than did those with bifunctional enzyme deficiency. None of the patients had dysmorphic features, but all developed progressive leukodystrophy between 2 and 3 years of age, resulting in blindness, deafness, and spasticity. Patients with acyl-CoA oxidase deficiency had milder elevations of VLCFAs, and lesser impairment of beta-oxidation and alpha-oxidation of phytanic acid in fibroblasts than did patients with bifunctional enzyme deficiency. Watkins et al. (1995) summarized their experience with peroxisomal disorders indicating that 10% of patients initially diagnosed with a disorder of peroxisome assembly were ultimately found to have a deficiency of a peroxisomal beta-oxidation enzyme.
Kurian et al. (2004) reported a 10-month-old girl who showed developmental regression at age 7 months, after which she developed irritability, abnormal stereotypic movements, and excessive startle response to auditory stimuli. Dysmorphic features included brachycephaly, marked frontal bossing, broad, depressed nasal bridge, mild hypertelorism, convergent squint, and bilateral nipple inversion. She had marked axial and peripheral hypotonia, and no eye contact or social interaction. Other features included left subretinal pigmentary retinopathy, bilateral sensorineural hearing loss, and mild hepatomegaly with increased echogenicity suggestive of fatty infiltration. Biochemical analysis showed increased serum VLCFA and markedly reduced acyl-CoA oxidase activity with absence of the protein. At age 2.5 years, MRI showed abnormal white matter signals in the brainstem and cerebellum. Kurian et al. (2004) noted that dysmorphic features have only rarely been reported in acyl-CoA oxidase deficiency.
Ferdinandusse et al. (2007) reported 22 patients with acyl-CoA oxidase deficiency confirmed by genetic analysis. Clinical features included hypotonia, seizures, failure to thrive, visual system failure, impaired hearing and vision, loss of motor achievements, hepatomegaly, dysmorphism, brain white matter abnormalities, and osteopenia. The mean age of developmental regression was 28 months, and the mean age at death was 5 years.
Carrozzo et al. (2008) reported a patient with severe acyl-CoA oxidase deficiency, born of consanguineous parents of Italian ancestry. Two previous pregnancies had resulted in miscarriages. In infancy, the proband showed severe generalized hypotonia and generalized seizures with myoclonic jerks. He had severe psychomotor delay and did not achieve postural control. Spastic tetraplegia and poor response to visual and auditory stimuli were apparent by age 4 years. Language development was virtually absent. Brain MRI at age 5.2 years showed brain atrophy, severe white matter abnormalities and peripheral contrast enhancement, hyperintensty of corticopontine tracts, and thinning of the corpus callosum. Funduscopy showed bilateral optic atrophy, and there was a mild sensorineural hearing defect. Liver enzymes were elevated, and the liver showed hyperechogenicity. Laboratory studies showed increased VLCFAs and lack of ACOX1 activity in fibroblasts. The disorder was progressive, and the child died of respiratory failure at age 5.4 years. Genetic analysis identified a homozygous deletion involving the ACOX1 gene (609751.0007). Analysis of chorionic villus sampling identified the disorder in a fourth pregnancy, which was subsequently terminated at 13 weeks' gestation.
Masson et al. (2016) reported a Pakistani patient who was hypotonic at birth and had neonatal seizures. Interictal EEG showed a disorganized pattern with slow-wave activity in the occipital regions. He had developmental delay. He gained head control at age 12 months and could sit with support at 23 months. Following surgery for undescended testicles at age 27 months and a subsequent infection, he had significant regression and severe generalized hypotonia. He developed vertical nystagmus, progressive deafness, and abnormal vision with a prolonged latency on visual evoked potentials. At age 45 months, he had prolonged periods of reduced responsiveness and generalized seizures. Brain MRI findings changed over time and correlated to clinical disease progression: at 20 days of life, the MRI was normal; at 25 months, it showed bilateral hyperintense foci of the hilus of the dentate nucleus; and at 30 months, it showed progression of the cerebellar abnormalities with white matter involvement of the area surrounding the dentate nuclei and the pontine corticospinal tracts. Abnormal signal was also seen in the bilateral posterior centrum semiovale. MR spectroscopy showed an increased choline/NAA ratio in the cerebellum. Analysis of very long chain fatty acids in patient plasma showed abnormal accumulation of C26:0 and an increased C26:22 ratio, with normal phytanic and pristanic acid levels.
Prenatal Diagnosis
Wanders et al. (1990) reported prenatal diagnosis of acyl-CoA oxidase deficiency by analysis of amniotic fluid taken at 20 weeks' gestation. Plasmalogen synthesis was normal, but beta-oxidation activity was decreased. There was an abnormal accumulation of VLCFAs. Immunoblot analysis showed absence of the acyl-CoA oxidase protein.
Affected sibs in the consanguineous families with acyl-CoA oxidase deficiency reported by Poll-The et al. (1988) and Suzuki et al. (1994) suggested autosomal recessive inheritance.
In 2 sibs with acyl-CoA oxidase deficiency reported by Poll-The et al. (1988), Fournier et al. (1994) identified a large deletion in the ACOX1 gene (609751.0001).
In 2 Japanese sibs with acyl-CoA oxidase deficiency reported by Suzuki et al. (1994), Suzuki et al. (2002) identified a homozygous mutation in the ACOX1 gene (M278V; 609751.0002). A third unrelated affected Japanese child had a different homozygous mutation (G178C; 609751.0003).
Ferdinandusse et al. (2007) identified 20 different mutations in the ACOX1 gene (see, e.g., Q309R, 609751.0004; R148X, 609751.0005) in 22 patients with acyl-CoA oxidase deficiency. One patient, who was clinically and biochemically indistinguishable from the others, had a deletion in exon 3II of the ACOX1 gene (609751.0006).
By direct sequencing of the ACOX1 gene in a Pakistani child, born to consanguineous parents, with acyl-CoA oxidase deficiency, Masson et al. (2016) identified a homozygous frameshift mutation (264470.0009). Analysis of very long chain fatty acids in patient plasma showed abnormal accumulation of C26:0 and an increased C26:22 ratio. The patient also had evolving white matter abnormalities on brain MRI that correlated to clinical disease progression.
Carrozzo, R., Bellini, C., Lucioli, S., Deodato, F., Cassandrini, D., Cassanello, M., Caruso, U., Rizzo, C., Rizza, T., Napolitano, M. L., Wanders, R. J. A., Jakobs, C., Bruno, C., Santorelli, F. M., Dionisi-Vici, C., Bonioli, E. Peroxisomal acyl-CoA-oxidase deficiency: two new cases. Am. J. Med. Genet. 146A: 1676-1681, 2008. [PubMed: 18536048] [Full Text: https://doi.org/10.1002/ajmg.a.32298]
Ferdinandusse, S., Denis, S., Hogenhout, E. M., Koster, J., van Roermund, C. W. T., IJlst, L., Moser, A. B., Wanders, R. J. A., Waterham, H. R. Clinical, biochemical, and mutational spectrum of peroxisomal acyl-coenzyme A oxidase deficiency. Hum. Mutat. 28: 904-912, 2007. [PubMed: 17458872] [Full Text: https://doi.org/10.1002/humu.20535]
Fournier, B., Saudubray, J.-M., Benichou, B., Lyonnet, S., Munnich, A., Clevers, H., Poll-The, B. T. Large deletion of the peroxisomal acyl-CoA oxidase gene in pseudoneonatal adrenoleukodystrophy. J. Clin. Invest. 94: 526-531, 1994. [PubMed: 8040306] [Full Text: https://doi.org/10.1172/JCI117365]
Kurian, M. A., Ryan, S., Besley, G. T. N., Wanders, R. J. A., King, M. D. Straight-chain acyl-CoA oxidase deficiency presenting with dysmorphia, neurodevelopmental autistic-type regression and a selective pattern of leukodystrophy. J. Inherit. Metab. Dis. 27: 105-108, 2004. [PubMed: 15065573] [Full Text: https://doi.org/10.1023/b:boli.0000016687.88818.6d]
Masson, R., Guerra, S., Cerini, R., Pensato, V., Gellera, C., Taroni, F., Simonati, A. Early white matter involvement in an infant carrying a novel mutation in ACOX1. Europ. J. Paediat. Neurol. 20: 431-434, 2016. [PubMed: 26965209] [Full Text: https://doi.org/10.1016/j.ejpn.2016.02.007]
Poll-The, B. T., Roels, F., Ogier, H., Scotto, J., Vamecq, J., Schutgens, R. B. H., Wanders, R. J. A., van Roermund, C. W. T., van Wiljand, M. J. A., Schram, A. W., Tager, J. M., Saudubray, J.-M. A new peroxisomal disorder with enlarged peroxisomes and a specific deficiency of acyl-CoA oxidase (pseudo-neonatal adrenoleukodystrophy). Am. J. Hum. Genet. 42: 422-434, 1988. [PubMed: 2894756]
Suzuki, Y., Iai, M., Kamei, A., Tanabe, Y., Chida, S., Yamaguchi, S., Zhang, Z., Takemoto, Y., Shimozawa, N., Kondo, N. Peroxisomal acyl CoA oxidase deficiency. J. Pediat. 140: 128-130, 2002. [PubMed: 11815777] [Full Text: https://doi.org/10.1067/mpd.2002.120511]
Suzuki, Y., Shimozawa, N., Yajima, S., Tomatsu, S., Kondo, N., Nakada, Y., Akaboshi, S., Iai, M., Tanabe, Y., Hashimoto, T., Wanders, R. J. A., Schutgens, R. B. H., Moser, H. W., Orii, T. Novel subtype of peroxisomal acyl-CoA oxidase deficiency and bifunctional enzyme deficiency with detectable enzyme protein: identification by means of complementation analysis. Am. J. Hum. Genet. 54: 36-43, 1994. [PubMed: 8279468]
Wanders, R. J. A., Schelen, A., Feller, N., Schutgens, R. B. H., Stellaard, F., Jakobs, C., Mitulla, B., Seidlitz, G. First prenatal diagnosis of acyl-CoA oxidase deficiency. J. Inherit. Metab. Dis. 13: 371-374, 1990. [PubMed: 2122103] [Full Text: https://doi.org/10.1007/BF01799398]
Watkins, P. A., McGuinness, M. C., Raymond, G. V., Hicks, B. A., Sisk, J. M., Moser, A. B., Moser, H. W. Distinction between peroxisomal bifunctional enzyme and acyl-CoA oxidase deficiencies. Ann. Neurol. 38: 472-477, 1995. [PubMed: 7668838] [Full Text: https://doi.org/10.1002/ana.410380322]