The term peroxisomal disease is used to describe genetic defects that affect the formation of peroxisomes, the transport of proteins or enzymes across the peroxisomal membrane, or the function of peroxisomal enzymes themselves. A great many oxygen-dependent systemically active reactions occur in the peroxisomes. Disruption of metabolic processes, for example, can have serious effects on the nerves, skeleton, retina, and liver, as well as cause severe morphologic abnormalities of the face and head.
What is peroxisomal disease?
Peroxisomal disease refers to genetic disorders related to peroxisome formation or function. A total of 15 different diseases and syndromes are known to fall under the umbrella term peroxisomal disease. Peroxisomes are tiny organelles that perform important functions in the breakdown of oxygen radicals. One of their main abilities is to convert toxic hydrogen peroxide into harmless water and oxygen molecules. This suggests that, developmentally, peroxisomes were the first organelles that enabled multicellular organisms not only to neutralize toxic oxygen, but also to derive energy from the oxidation process. The disease may be a disturbance in the formation and proliferation of peroxisomes or a dysfunction of enzyme transport through the membrane surrounding the peroxisomes. Impairment of the biocatalytic capabilities of the enzymes involved themselves also falls under the heading of peroxisomal disease. The approximately 50 different enzymes that have been identified in peroxisomes already indicate their versatile functions and the complexity of the possible disease forms of peroxisomal disease. All forms of the disease have in common that they are caused by different genetic defects, most of which are known.
Causes
Gene mutations of nonsex-specific genes, or autosomes, are responsible for most manifestations of peroxisomal disease. An exception is adrenoleukodystrophy, also called Addison-Schilder syndrome. The disease is due to an alteration of a gene on the X chromosome at gene locus q28. The gene encodes a specific protein that is required in the membrane of peroxisomes to enable the transport of certain lipids across the membrane. In some other cases, transport proteins also play a role in shuttling certain proteins into the interior of the peroxisome. Because the small organelles do not have ribosomes, the 50 or so different proteins required by the peroxisomes must first be synthesized in the cytosol of the cell before they are subsequently shuttled across the membrane of the organelle.
Symptoms, complaints, and signs
Symptoms and signs of peroxisomal disease depend on which genes are altered and the disease syndromes with which each is associated. Not all forms of the disease are adequately understood. In some cases, serious neurological disorders such as encephalopathy, epilepsy, or deafness become apparent. In other cases, skeletal abnormalities and severe morphologic developmental abnormalities of the head and face may become apparent. Abnormalities of the eyes, especially the retina, and liver dysfunction immediately after birth are also frequently due to peroxisomal disease. Usually, certain symptoms, each based on a defined genetic defect, are combined into a disease syndrome.
Diagnosis and disease progression
Diagnosis is usually made by laboratory testing with detection of certain peroxisomal substances in the blood. Specifically, these are superlong-chain fatty acids such as phytanic acid, a long-chain fatty acid with multiple branches that is normally metabolized by alpha-oxidation in peroxisomes. If peroxisomes are unable to metabolize it due to a lack of phytanic acid oxidase, phytanic acid levels in the blood will increase and deposits will occur in various tissues. Zellweger syndrome is characterized by a complete absence of peroxisomes. Effects of the syndrome are already evident in newborns.Maldevelopments of the head and face as well as severe psychomotor developmental disorders and a number of other symptoms are signs that indicate the disease. Signs that are not immediately visible, such as cysts in the brain, can be detected by MRI. However, differential diagnosis of other genetic abnormalities with similar symptoms should always be compared or excluded. In a culture with fibroblasts and hepatocytes, the absence of organelles can be easily demonstrated. Treatment of this severe metabolic disorder is not possible. The disease is usually fatal within a few months after birth. Adrenoleukodystrophy is the only form of peroxisomal disease that is inherited in an x-linked recessive manner. This type of peroxisomal disease is also accompanied by a poor prognosis. In most cases, the disease ends in death within the first ten years of life.
Complications
All peroximeral diseases have a very poor prognosis. However, in some cases, palliative measures can improve the length of life and quality of life. Severe metabolic abnormalities are seen in all diseases, leading to various complications such as liver dysfunction, skeletal abnormalities, or developmental disorders of the head. A particularly severe form of peroxisomal disease is the Zellweger syndrome. This very rare disease always leads to death within the first months of life. Hydrogen peroxide accumulates in the body. Many different symptoms appear, which cannot be treated at all. For example, irregular skull growth takes place, resulting in skull deformities. Furthermore, malformations of the brain occur. Also the other organs are partly malformed. Thus, heart defects, liver insufficiency with iron storage defects, multicystic kidneys or underdeveloped lungs are observed. Life-threatening complications result, among others, from severe respiratory problems, poisoning due to liver insufficiency or blood formation disorders due to iron storage defects. Another peroximal disease is adrenoleukodystrophy. Here the prognosis is somewhat more favorable. However, this disease also always leads to death by the age of ten. In this form of peroxisomal disease, mainly numerous neurological symptoms occur. Frequent seizures occur as part of this disorder. Some prolongation of life can be achieved by bone marrow transplantation. However, curative treatment is not possible in this case either.
When should you see a doctor?
In this disease, a visit to a doctor is usually always necessary, since there is no self-healing and the symptoms can significantly limit the patient’s daily life and thus also significantly reduce the quality of life. The doctor must be consulted if the patient suffers from deafness or epilepsy. In the event of an epileptic seizure, the emergency physician should be called or the hospital visited immediately to avoid further complications. Furthermore, disorders of the liver may also indicate this disease, so a doctor should be consulted in that case as well. The affected person must also undergo examinations of the internal organs at regular intervals to avoid complications. Likewise, abnormalities of the eyes or sudden visual complaints may indicate the disease and should be examined by a medical professional. The diagnosis of the disease can be made by various medical specialists, and further treatment depends strongly on the symptoms that occur. Whether this will result in reduced life expectancy cannot generally be predicted.
Treatment and therapy
Unfortunately, none of the 15 known manifestations of peroxisomal disease has a therapy that could achieve a cause control that goes beyond mere symptom control. Therefore, the treatment and therapeutic options known to date are aimed at symptom relief. Palliative treatments are also used. An exception is offered by x-linked recessive adrenoleukodystrophy. While unsaturated fatty acids are administered for symptomatic improvement, one option is bone marrow transplantation. Bone marrow transplantation may have a significant life-prolonging effect in some circumstances.
Outlook and prognosis
Peroxisomal disease is a genetic metabolic defect that affects the vital oxygen supply in the body. Fifteen different disorders related to this condition are grouped under the term “peroxisomal disease.” The hereditary component and the location of the disorder already suggest that the prognosis may not include a cure. It is also problematic that some of the disorders belonging to it have not been researched enough. The symptoms and sequelae associated with a disrupted or mutated gene are so varied that no summary prognosis can be given for peroxisomal disease. What is clear is that it is a group of very serious sequelae defects that are often fatal. The only question is whether peroxisomal disease diagnosed by a specialist will lead to death a few months, or a few years after birth. More than curative treatment options do not currently exist for any of the 15 known peroxisomal diseases. The quality of life of those affected usually corresponds to their short life span. It is not very high. In some cases it is possible to improve both parameters by intensive palliative care. The most severe peroxisomal disease is Zellweger syndrome. This leads to death within a short time after birth due to severe malformations. More than symptom-relieving or palliative treatments are not feasible for any known peroxisomal disease.
Prevention
Direct preventive measures to avoid peroxisomal disease do not (yet) exist. Currently (2017), not all gene mutations that are considered to trigger peroxisomal disease are known. If a case of peroxisomal disease is already known within the family, parents should be aware of the likelihood that one of their children may be affected by the disease.
Follow-up
Because peroxisomal disease is based on a genetic defect and is usually fatal within a few months of birth or by the end of the first decade of life at the latest, therapy can only alleviate a few symptoms for a short time without being able to cure the disease completely. For this reason, there is no actual aftercare treatment in this sense, but intensive symptom treatment to alleviate some suffering. In general, affected individuals and their families are advised to adopt a healthy lifestyle with a balanced diet to support the immune system. Furthermore, the parents of the affected infant as well as affected children are recommended to talk to a psychotherapist in order to support the processing of this severe blow of fate. The psychotherapist will also suggest certain relaxation and mental techniques for stabilization, as well as advising as many leisure activities as possible, which should provide the affected family with many enjoyable hours together. Since most children suffer from severely reduced lung function, they are advised to spend at least one hour a day in the fresh air. If the parents, who have already been affected once, harbor a further desire to have children, they are advised to undergo a detailed genetic examination in order to determine in advance the likelihood of having another child with the disease.
What you can do yourself
Dealing with peroxisomal disease in everyday life is not always easy for the affected person as well as for the relatives. For this reason, psychological strengthening of all those affected should take place. Mutual cohesion as well as the promotion of well-being are important in order to be able to register positive developments in the further course. In addition to psychotherapeutic support, mental techniques or relaxation methods can be applied. These methods help to reduce stress in everyday life as well as to stabilize the mind. Leisure activities should be adapted to the health possibilities. They are important so that the focus of attention is directed to the beautiful parts of life. To avoid complications or secondary diseases, a healthy lifestyle is essential. The immune system can be supported with a balanced diet. The intake of harmful substances such as nicotine, alcohol or non-prescribed medications should be refrained from. This places additional stress on the organism as a whole, which contributes to a worsening of the overall situation. If respiratory complaints occur, anxiety can often result.The affected person should inform himself about how to behave optimally in case of an emerging anxiety. In addition, it is important for the patient to exercise in the fresh air for a longer period of time every day. This serves to stabilize the immune system and helps the lungs to function properly.
