A total of 45 different lysosomal storage diseases, which are a heterogeneous group of inborn errors of metabolism, are known. People who suffer from any of these disorders have a genetic defect. All storage diseases have one thing in common: a specific enzyme is absent or only partially functional.
What is a lysosomal storage disease?
These congenital storage diseases occur rarely, affecting fewer than five in 10,000 people. The course of the different diseases varies widely, and symptoms can vary greatly. The best known forms of lysosomal storage disease are Fabry disease, Gaucher disease, Pompe disease and mucopolysaccharidosis (MPS). They are often referred to as the “orphans of medicine” because the road to a definite diagnosis and appropriate therapy can be very long. At times, years can pass before those affected learn what is happening to them.
Causes
Lysosomal storage diseases are characterized by certain forms of hereditary metabolic disorders. Patients lack an important enzyme that ensures smooth metabolic balance. In the less pronounced form, this enzyme is at least not present in sufficient quantities. Enzymes have the task of disposing of harmful and waste substances that accumulate in the human organism via the lysosomes, or of reprocessing them in such a way that complaints do not occur. If there is an enzyme deficiency, this smoothly functioning disposal cycle is no longer guaranteed. The harmful substances settle in the cells and disrupt the metabolic cycle. In the initial phase, the disturbances do not yet have a noticeable effect; there are only a few restrictions. However, if this metabolic disorder as a result of enzyme deficiency remains untreated, the symptoms multiply as there is a severe enlargement of the cells.
Symptoms, complaints, and signs
In the worst case, these perish. The consequences are damage to the bones, nervous system, spleen, kidneys, muscles or heart. Fabry disease causes fatty deposits (globotriaosylceramides, Gb3) in cells due to reduced or absent enzyme activity. These unwanted deposits can lead to severe pain in the toes or fingers, brain stroke, and kidney damage.
Diagnosis and disease progression
This condition affects several systems simultaneously: blood vessels, kidneys, heart, and nervous system. Inherited in an autosomal recessive manner, Gaucher disease causes a mutation of the enzyme “beta-glucocerebrosidase” and leads to an accumulation of substrate within cells, especially in macrophages (phagocytes), which are part of the reticulo-endothelial system. The blood count changes, the liver and spleen are enlarged, and the bones ache. The disease is progressive and is usually ethnic in nature, occurring in most cases in people of Jewish descent. Pompe disease is also known as “acid maltase deficiency”. The clinical picture belongs to the group of glycogeneses type II. Affected individuals lack the enzyme “alpha-1,4-glucosidase” (acid maltase) or it is not present in sufficient quantities. Patients suffer from destruction of muscle cells in the form of sugar storage due to impaired glycogen degradation in the muscles. Mucopolysaccharidosis type I (MPS), also known as Hunter’s disease, leads to various clinical causes. Hurler’s disease is the most severe form of progression and Scheie’s disease is at the end of the clinical patogenesis. Between these two courses are transitions of varying severity. The most prominent feature is the impaired degradation of carbohydrates, which accumulate in the lysosomes of the cells. Hunter’s disease patients may suffer from short stature, enlarged spleen and liver, coarse facial features, thickened skin, enlarged tongue, and respiratory problems. In addition, the skeleton is often altered in the pelvis, spine, hand bones, and skull. Umbilical and [[inguinal]] hernias are possible.
Complications
In most cases, symptoms or complications do not occur until very late in this disease. For this reason, it is diagnosed late, so early treatment is not possible in most cases.Without treatment, this leads to various complaints and damage to the internal organs as the disease progresses. The kidneys, liver and spleen are particularly affected. The heart can also be affected by this disease, leading to cardiac death in the worst case. Furthermore, damage to the kidneys also occurs and those affected not infrequently suffer from pain in their toes or fingers. Paralysis can also occur if the brain has been damaged by this disease. The liver and spleen may be enlarged and cause severe pain as well. It is not uncommon for the bones of the affected person to be brittle and painful as well. Treatment of this disease proves to be difficult. In many cases, the life expectancy of the affected person is significantly reduced. Treatment with medication does not usually lead to any particular complications. However, a positive course of the disease cannot be guaranteed in every case.
When should one go to the doctor?
Hair loss, joint problems, and organ dysfunction are possible signs of lysosomal storage disease. A visit to the doctor is recommended if the symptoms recur or come on quite suddenly without a cause. If the symptoms occur in connection with an already diagnosed enzyme defect or another serious disease, the responsible physician must be consulted. Untreated storage disease can lead to dementia, infertility, neuropathies and other complications, some of which can be life-threatening. Therefore, all conceivable signs of the disease should be investigated, even if there is no specific suspicion yet. Symptoms of lysosomal storage disease may occur in phases or develop insidiously, but always require investigation and treatment. Affected individuals are best advised to speak directly to their family doctor or an internist. The actual therapy usually takes place in a specialist clinic for internal diseases, and depending on the symptom picture, physiotherapy or psychotherapy may be attached. Therapeutic measures in particular are indicated due to the often negative course of the disease.
Treatment and therapy
Depending on how early an adequate diagnosis is made, these hereditary diseases can be treated very well by enzyme replacement therapy, so that the affected individuals have much less discomfort and thus a better quality of life. This replacement therapy is used according to the clinical picture. People suffering from Gaucher’s disease lack the “enzyme ß-glucocerebrosidase”, which is produced biotechnologically and administered to the patient’s organism by infusion. Lysosomes act efficiently and are able to absorb substances from their immediate environment. For this reason, the artificially used enzymes are modified in such a way that they can be supplied to the lysosomes in an ideal way. The macrophages (scavenger cells) break down the glucocerebrosides that have accumulated in the cells. This therapy can be compared to insulin therapy in diabetes mellitus, with the difference that it is not a missing hormone that is supplied, but an enzyme that is not present. The body regularly breaks down all substances, including the supplied artificial enzyme. Because of this regular substance breakdown, patients must undergo this infusion therapy regularly until the end of their lives. Enzyme replacement therapy does not act symptomatically, but directly combats the cause of the hereditary disease. Physicians refer to this therapy as causal. The principles of therapy are applicable to all four common storage diseases mentioned above. Pompe patients are also treated by infusion therapy. In this disease, the non-existent enzyme “acid alfa glucosidase” is infused and helps to break down glycogen that has accumulated in the lysosomes of the muscles. In patients with the disease type “mucopolysaccharidosis type I”, the lysosomal enzyme “alpha-iduronidase” is not present or is present in insufficient amounts. It is one of the rarest storage diseases in which sugar molecules accumulate in organs and tissues. In a normal course, the enzyme degrades mucopolysaccharides. The sugar molecules are long-chain and are involved in the formation of supporting and connective tissue, for example bones, skin, joint fluids and cartilage. If the normal degradation process is disturbed due to the lack of the enzyme, pathological glycosaminoglycans (GAG) accumulate in the individual cells.Future treatment options target tablets.
Outlook and prognosis
The prognosis of storage disease is unfavorable. A genetic predisposition has been identified as the cause of the health disorder. Legal requirements prohibit physicians and scientists from altering human genetics. For this reason, the disease remains lifelong and has no prospect of recovery. The treating physician concentrates on the therapy of the developing symptoms. If left untreated, various symptoms increase over a lifetime. The bone system is damaged and problems of the organs occur. In the worst case, it leads to functional difficulties of the internal organs and ultimately to a failure of organ activity. Thus, the affected person is threatened with premature death. The challenge of the disease lies in the diagnosis. In a large number of patients, notable and strongly perceptible symptoms do not appear until later in life. As a result, the genetic disorder remains unnoticed for a long time and early treatment of the disease is difficult. The later a diagnosis is made, the less favorable the further course of the disease. In an advanced stage of the disease, the internal organs or the joints are already severely damaged. Surgical interventions are required and in the case of an unfavorable course of the disease, only a donor organ can save the life of the affected person. Therefore, early treatment is essential for an improved prognosis.
Prevention
Because it is a congenital genetic defect that prevents the expression of an enzyme, this disease is not preventively treatable. However, recent achievements in genetic engineering may provide an approach in this field.
Follow-up
In this disease, affected individuals suffer from a number of different complications and symptoms. These usually all have a very negative impact on the quality of life of the affected person, so a very early diagnosis should be made. The earlier a doctor is consulted, the better the further course of the disease usually is. The manifestation of this disease can be very different, so that a general prediction is often not possible. Those affected suffer from severe damage to the internal organs. Thus, the kidneys and the heart are primarily affected, so that the child can die in the first days if the symptoms are not corrected in time. Likewise, fat deposits occur in different parts of the body. The fingers and toes are particularly affected, which can lead to a significantly reduced aesthetic appearance of the affected person. As a rule, damage to the kidneys and brain occurs in the further course, so that the affected person dies as a result of this damage. Parents and relatives also often suffer from depression or other psychological upsets due to the disease.
This is what you can do yourself
Lysosomal storage disorders very often require intensive medical care. There are often insufficient self-help options. Parents of affected children often experience severe stress in the home environment because their child requires constant care and attention. The clinical pictures of the individual storage disorders vary. There are both mild and very severe forms. One example is Gaucher’s disease. The parents’ help is often limited to feeding the severely disabled child. In milder cases, life expectancy can be almost normal. Nevertheless, constant medical monitoring is necessary to avert possible complications. Regular physical exercise is one of the accompanying therapies, which can also be performed at home. Furthermore, careful cancer screening must be arranged. This requires parents to make constant visits to the doctor with their child. The same applies to other lysosomal storage diseases. In some diseases, in addition to physical disabilities, there may also be mental disabilities that still require special support. In milder forms of certain diseases, such as Hunter’s disease, only skeletal changes and facial dysmorphia appear at first. Here, however, the affected patient is often capable of an independent life. However, constant medical examinations are also necessary here to rule out possible complications such as heart failure or respiratory diseases.The patient can work through psychological stress due to the physical deformities through psychological counseling.
