Acyl-CoA oxidase deficiency

Acyl-CoA oxidase deficiency is a rare disorder that leads to significant damage and deterioration of nervous system functions (neurodegeneration).[1] It is caused by pathogenic variants in ACOX1, which codes for the production of an enzyme called peroxisomal straight-chain acyl-CoA oxidase (ACOX1).[1] This specific enzyme is responsible for the breakdown of very long chain fatty acids (VLCFAs).[2]

Acyl-CoA oxidase deficiency
Other namesACOX1 deficiency
Acyl CoA oxidase enzyme
SpecialtyMedical genetics

Defective function of the ACOX1 enzyme prevents proper breakdown of these VLCFAs, leading to accumulation and interference with the nervous system.[1][2] Acyl-CoA oxidase deficiency affects a person from birth, and most newborns affected with this condition will not survive past early childhood.[1] Affected individuals can be born with hypotonia, seizures, and dysmorphic features, such as widely spaced eyes, a low nasal bridge and low set ears. Polydactyly and hepatomegaly have also been described.[1] Most babies will learn to walk and begin speaking, before experiencing a rapid decline in motor function between the ages of 1 and 3.[3] As the person ages, and the conditions worsens, they begin to experience exaggerated reflexes (hyperreflexia), more severe and frequent seizures, and gradual loss of vision and hearing.[1][2] There is no cure for this condition, however there are a range of symptom-based treatments, used to provide supportive care.

Signs and symptoms

Children are born with this condition and their symptoms can be seen immediately.[2] In the early stages these can appear quite mild; weak muscle tone (often extreme hypotonia), lack of neonatal reflexes, seizures and abnormal (dysmorphic) facial features such as widely spaced eyes, a low nasal bridge, low set ears and an abnormally large forehead.[1][2] Due to the nature of the disease, in the build-up of VLCFAs, symptoms worsen progressively over time.[4] Children can often reach the stage at which they begin to walk and talk, before experiencing a rapid decline in motor skills due to demyelination and subsequent nerve damage.[2][3] A hearing deficit may develop, eyesight and response to visual and physical stimuli begins to diminish and eventually becomes non-existent.[1][2] The life expectancy of an individual with ACOX1 deficiency is 5 years.[2][3]

Genetics

Acyl-CoA oxidase deficiency is an autosomal recessive disorder that is caused by biallelic pathogenic variants in ACOX1.[1][5] This is the gene that codes for the production of an enzyme called peroxisomal straight-chain acyl-CoA oxidase which is responsible for the breakdown of VLCFAs.[1][2] It is not completely clear how the build-up of these VLCFAs causes the symptoms seen with this condition, however research suggests that this abnormal accumulation triggers an inflammation in the nervous system which leads to demyelination.[1] Demyelination leads to the loss of white matter, leukodystrophy, in the brain and spinal cord.[1][5] It is this leukodystrophy that is related to the development of neurological abnormalities in people with Acyl-CoA oxidase deficiency.[5] Acyl-CoA oxidase deficiency is an extremely rare condition.[1]

Diagnosis

Diagnosis can be done both prenatally based on family history and after birth based on clinical suspicion.[1][5] The primary prenatal diagnosis techniques involve the assessment of amniotic fluid for an abnormal elevation in VLCFAs, and a reduced presence (or in some cases complete absence) of acyl-CoA oxidase in fibroblasts. If the causative variants in a family are known, prenatal diagnosis can be performed by molecular testing.[4] After birth, there are a number of diagnostic techniques available for use. A blood sample can be taken, from which the serum levels of VLCFAs and acyl-CoA oxidase activity can be assessed. Analysis of VLCFAs is important for the identification of ACOX1 deficiency, if a leukodystrophy has been identified[5] Since the condition is genetic, and is caused by pathogenic variants in ACOX1, it can be confirmed by sequence or copy number analysis.[1] Due to the rarity of this condition, people who have it may not be diagnosed early in their disease progression. As a result, acyl-CoA oxidase deficiency may be misdiagnosed as similar conditions such as Usher syndrome and neonatal adrenoleukodystrophy.[5][6]

Treatment

There are no cures for ACOX1 deficiency, supportive care is used to manage specific clinical symptoms for affected individuals.[1] Treatment is based upon symptoms, with the aim the provide some relief.[5] Pharmacologic agents are used to help improve muscle tone (management of dystonia) and to block neurological signalling to the muscle. Physical therapy is used to improve movement and function.[5] For the specific treatment of recurrent seizures, there are both pharmaceutical and surgical options.[5]

References
  1. "Peroxisomal acyl-CoA oxidase deficiency". Genetics Home Reference, NIH. October 23, 2018.
  2. Thomas, Janet A.; Lam, Christina; Berry, Gerard T. (2018). "Chapter 23: Lysosomal Storage, Peroxisomal, and Glycosylation Disorders and Smith–Lemli–Opitz Syndrome Presenting in the Neonate". Avery's Diseases of the Newborn (Tenth ed.). Elsevier. pp. 253–272.e3. doi:10.1016/B978-0-323-40139-5.00023-1. ISBN 978-0-323-40139-5.
  3. Aubourg, P; Wanders, R (2013). Peroxisomal disorders. Handbook of Clinical Neurology. Vol. 113. pp. 1593–609. doi:10.1016/B978-0-444-59565-2.00028-9. ISBN 9780444595652. PMID 23622381.
  4. "264470 - Peroxisomal Acyl-CoA Oxidase Deficiency". OMIM, Johns Hopkins University. September 9, 2008. Retrieved 2018-10-25.
  5. Vanderver, Adeline; Tonduti, Davide; Schiffmann, Raphael; Schmidt, Johanna; van der Knaap, Marjo S. (6 February 2014). "Leukodystrophy Overview – RETIRED CHAPTER, FOR HISTORICAL REFERENCE ONLY". Leukodystrophy Overview. GeneReviews. University of Washington, Seattle. PMID 24501781.
  6. Parikh, S; Bernard, G; Leventer, RJ; van der Knaap, MS; van Hove, J; Pizzino, A; McNeill, NH; Helman, G; Simons, C; Schmidt, JL; Rizzo, WB; Patterson, MC; Taft, RJ; Vanderver, A; GLIA, Consortium. (April 2015). "A clinical approach to the diagnosis of patients with leukodystrophies and genetic leukoencephelopathies". Molecular Genetics and Metabolism. 114 (4): 501–515. doi:10.1016/j.ymgme.2014.12.434. PMC 4390485. PMID 25655951.
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