User:Tbas6059/OLES2129/Acyl-CoA oxidase deficiency

Acyl-CoA oxidase deficiency is a rare disorder that leads to significant damage and deterioration of nervous system functions (neurodegeneration) (4) (1). It is caused by a mutation in the ACOX1 gene, which codes for the production of an enzyme called peroxisomal straight-chain acyl-CoA oxidase (4). This specific enzyme is responsible for the breakdown of very long chain fatty acids (VLCFA’s) (2) (5). The mutation of the ACOX1 gene prevents proper breakdown of these VLCFA’s, allowing them to accumulate and interfere with the nervous system (4) (2). Acyl-CoA oxidase deficiency affects the patient from birth, and most new-borns suffering this condition will not survive past early childhood (1). Sufferers are born experiencing symptoms of weak muscle tone (hypotonia), seizures, unusual facial features (i.e. widely spaced eyes, a low nasal bridge, low set ears), extra fingers or toes and some patients have an abnormally enlarged liver (hepatomegaly) (4) (1). These symptoms often arise similarly in other conditions, consequently acyl CoA oxidase deficiency is often misdiagnosed (4). Most babies will learn to walk and begin speaking, before experiencing a rapid decline in motor function between the ages of 1 and 3 (11). As the patient ages, and the condition worsens, they begin to experience exaggerated reflexes (hyperreflexia), more severe and frequent seizures, and gradual loss of vision and hearing (4) (2). At present, there are no cures for this condition however there are a range of symptom-based treatments, both pharmaceutical and physical, which aim to improve patient comfort. There are also a number of tests and trials, on this specific condition and others very similar, which look at the possibility of gene therapy through stem cell research (8) (9).

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) (4). There have also been reports of some children possessing extra fingers and toes at birth (6). Due to the nature of the disease, in the build-up of VLCFA’s, symptoms worsen progressively over time. During the first 1 to 2 years, sufferers may experience stridor, apneic spells, and attacks of upward deviation of the eyes lasting for up to 2 minutes (1). 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 (11) (2). Between the years of 2-5, frequency of epileptic seizures can become almost continuous, there is constant blinking of the eyes, distortion of the mouth and general facial appearance, as well as an increase in shallow breathing (1). A hearing deficit may develop, eyesight and response to visual and physical stimuli begins to diminish and eventually becomes non-existent (1) (2) (4). In later stages, pupillary light responses are completely absent and bilateral optic atrophy can become increasingly evident. Muscle hypotonia increases, especially in muscles related to normal deep tendon reflexes (1) (6). By the age of 4 the sufferer will most likely be reduced to a vegetative state, and a CT scan with contrast will reveal extensive white matter hypodensities (1). A child born with this condition is most likely to be dead before the age of five years old (1) (2) (11).

Symptoms can be easily observed; however, it is not always clear that they point to a deficiency in acyl CoA oxidase (4). With the first visible signs of this condition, significant overlaps can be seen with symptoms of similar disorders. As a result, acyl CoA oxidase deficiency, especially being the rare disorder that it is, can often be mistaken for more common neurological disorders such as Ushers Syndrome and NALD (13) (5). The only way to be sure of the specific disorder is though more in depth testing, discussed in the diagnosis section (3).

Causes
Acyl-CoA oxidase deficiency is an autosomal recessive disorder (1) that is caused by a mutation on the ACOX1 gene (4) (1) (6) (9). 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 VLCFA’s (9) (4) (2). It is not completely clear how the build-up of these VLCFA’s causes the symptoms seen with this condition, however research suggests that this abnormal accumulation triggers an inflammation in the nervous system which leads to the breakdown of myelin (demyelination) (4). This breakdown has an extremely negative effect on the transmission of nerve impulses, preventing nerves from being able to transmit information from the brain to other areas of the body (12). This means the brain is unable to send signals to other parts of the body (ie. limbs), explaining the gradual loss of motor function seen in suffers. Demyelination leads to the loss of white matter (leukodystrophy) in the brain and spinal cord (4) (1) (6). It is this leukodystrophy that is related to the development of neurological abnormalities in Acyl-CoA oxidase deficiency sufferers (6).

Gene Location
The ACOX1 gene is located on the long arm of chromosome 17, at position 25.1. Its cytogenic location is 17q25.1 (14). The responsibilty of this gene is to provide instructions for the production of an enzyme called peroxisomal straight-chain acyl-CoA oxidase, which is found in organelles called peroxisomes (14); hence the condition is known as a peroxisomal disorder (4). These peroxisomes contain a variety of enzymes each responsible for the breakdown of many different substances (14). It is imperative that these enzymes fulfil their roles, so as to prevent accumulation of substances which may be detrimental to health (as seen with acyl CoA oxidase deficiency and the build-up of VLCFA’s) (4).

There are more than 20 ACOX1 identified gene mutations in people suffering Acyl CoA oxidase deficiency, preventing the straight-chain acyl-CoA oxidase enzyme from fulfilling its role of VLCFA breakdown (14).

Infection Rates and Epidemiology
Acyl-CoA oxidase deficiency is an extremely rare condition and only a handful of cases have been observed. Since it was first recognised, a total of only 31 patients have been reported (9), it can therefore be very hard to identify any discernible patterns in the epidemiology. In one of the more notable cases, explored by the American Journal of Human Genetics, the condition appears in a set of twins. Both of the twins have the mutation, and their parents were first cousins. This might suggest a link between closely related sexual partners and the mutation, but without further analysis and examples this is just speculation (1). The age group this condition effects is extremely small, as sufferers will rarely live past the age of 5 (4).

Diagnosis
Diagnosis can be done both prenatally and after birth (6) (3) (4). The primary prenatal diagnosis techniques involve the assessment of amniotic fluid for an abnormal elevation in VLCFA’s, and a reduced presence (or in some cases complete absence) of acyl-CoA oxidase in fibroblasts (3). After birth, there are a number of diagnostic techniques available for use. A blood sample can be taken, from which the serum levels of VLCFA’s and acyl-CoA oxidase activity can be assessed (6) (9). An MRI of the brain will also show abnormal white matter signals, and massive white matter deterioration (made clearly visible through use of contrast in the scan) (1). Since the condition is genetic, and is caused by a mutation on the ACOX1 gene, it can be confirmed by looking at the presence or lack of mutation at said gene (4). Medical and family history will also be obtained, along with a physical and neurological examination (6). Based on its nature and rarity, this condition is often misdiagnosed, as doctors don’t know what to look for in many cases. As a result, acyl-CoA oxidase deficiency may be diagnosed as more common, similar conditions such as Ushers syndrome and NALD (13) (3) (5) (6). These to exhibit primary symptoms of leukodystrophy and demyelination inhibiting nerve impulses and consequently having a significant impact on motor functions (6).

Treatment and management
At present there are no cures for this condition, however there are a number of treatment and management techniques available to the sufferer (4). Treatment is based upon symptoms, with the aim the provide some relief to the patient (6). Pharmacologic agents are used to help improve muscle tone (management of dystonia) and to block neurological signalling to the muscle (chemo denervation). Furthermore, in order to improve mobility and function, patients will undergo a range of physical therapies (6). For the specific treatment of recurrent seizures, there are both pharmaceutical and surgical options (6) (7). There are a number of anti-seizure medications available, and it is a matter of finding out which one is the best suit for the patient (produce good results with limited side effects) (7). In regards to surgery, this will involve the removal of the area of the brain where the seizure begins. Other specific seizure treatment includes; vagus nerve stimulation, responsive neurostimulation and deep brain stimulation (7).

Clinical trials and potential therapies
The most promising area of research trials is within stem cells and gene therapy. For example, a recent study “Effects of hematopoietic stem cell transplantation on acyl-CoA oxidase deficiency: a sibling comparison study” (9) has shown some promising results. Two siblings had the condition, one was given this stem cell transplantation while the other was not. This led to less brain inflammation, cortical atrophy, and neuronal loss on neuroimaging and neuropathology when compared to the other untreated sibling (9). Another recent trial by the Masonic Cancer Centre “Reduced-Intensity Hematopoietic Stem Cell Transplant for High Risk Lysosomal and Peroxisomal Disorders,” (8) investigates the effect of stem cell therapy on a different but very similar condition. It too found promising results in an improvement of patient symptoms. These trials and studies, and others like them, aim to replace a disease causing, faulty gene, with a working version in order to cure a condition or modify its effects (10).