GM1 gangliosidosis is one of the lipid storage diseases. It is caused by the storage of sugary lipids called gangliosides. Most gangliosides are deposited in nerve cells.
What is GM1 gangliosidosis?
GM1 gangliosidosis is a degradation disorder of GM1 gangliosides. This results in the accumulation of this sugar-containing lipid. In general, gangliosides consist of two fatty acid residues, which are linked to several sugar residues and an N-acetylneuraminic acid residue via the aminodialcohol sphingosine. Basically, a distinction must be made between GM1 gangliosides and GM2 gangliosides. GM1 gangliosides contain four and GM2 gangliosides three sugar residues. The term gangliosides is derived from the terms ganglion and glycoside. A ganglion represents a nerve node. Gangliosides are mainly found in the membranes of nerve cells. There they account for up to six percent of the lipids present. The hydrophobic part of the molecule with the fatty acid chains protrudes into the membrane, while the hydrophilic part with the sugar residues is located outside the cell. The exact significance of the gangliosides is not yet known. According to present research results, they are supposed to be responsible for neuronal information transmissions. There is a constant build-up and degradation of gangliosides. However, if the degradation is disturbed by an enzyme defect, the gangliosides accumulate in the nerve cells and cause significant health problems. GM1 gangliosidosis occurs in infantile, juvenile, and adult forms.
Causes
GM1 gangliosidosis is genetic. The starting point of the disease is a defect in the enzyme β-galactosidase. β-Galactosidase is responsible for cleaving sugar residues from gangliosides. If this enzymatic step is defective, GM1 gangliosides can also no longer be degraded. The GM1 gangliosides accumulate more and more in the nerve cells of the peripheral and central nervous system. Depending on how severely the enzyme is restricted in its function, the three basic forms of GM1 gangliosidosis are formed. The disease is inherited in an autosomal recessive manner. In this case, the gene encoding β-galactosidase must have been passed on to the offspring from both parents. However, there are multiple mutations of the same gene that can result in a defect or deficiency of β-galactosidase.
Symptoms, complaints, and signs
The courses of the three forms of GM1 gangliosidosis are different. Infantile GM1 gangliosidosis represents the most severe form with the worst prognosis, with adult GM1 gangliosidosis having the best prognosis. However, none of the three forms of the disease can be cured. In each case, it is a progressive disease that can only be treated symptomatically. Infantile GM1 gangliosidosis begins in the first three months of a child’s life. Then, from the sixth month of life, developmental arrest occurs. Such symptoms as muscle hypotonia, drinking weakness, reflux, weak intestinal movements, pathological hypersensitivity to sounds and severe liver enlargement appear. The weakness in drinking intensifies so dramatically that parenteral nutrition becomes necessary. The baby must be fed through IV fluids. Sometimes cerebral seizures also occur. In half of the children, a cherry-red spot develops at the back of the eye. This occurs because ganglioside storage causes the retina to turn whitish, making the macula appear red. The field of vision becomes severely clouded to the point of possible blindness of the child. Furthermore, deafness may also develop. In addition, changes in the bones are also noted. In rare cases, the tongue enlarges. The children usually die before the age of two from organ failure or constant infections. Infantile GM1 gangliosidosis is also known as Norman Landing syndrome. The juvenile form of GM1 gangliosidosis, known as Derry syndrome, does not begin until after the first year of life. Here, hepatosplenomegaly occurs, but it is mild. Hepatosplenomegaly represents both liver and spleen enlargement. Other symptoms include hypotonia, ataxia, convulsions, mental developmental disorders, and spasticity. Furthermore, the facial features coarsen visibly. The children usually die of respiratory diseases before the age of ten.There are only isolated reports of the adult form of GM1 gangliosidosis. The onset of the disease is between the ages of three and thirty. Dysarthria (speech disorders), gait disturbances and cramps occur in these individuals. No precise information is yet available on the further prognosis. The prognosis also depends on the speed of progression of the disease.
Diagnosis
The diagnosis of GM1 gangliosidosis is made by human genetic or enzymatic testing. Thus, the enzyme defect can be detected in fibroblasts, leukocytes, or by organ biopsies. GM1 gangliosidosis must be differentially diagnosed from oligosaccharidoses, sphingolipidoses, and mucopolysaccharidoses.
Complications
Serious complications occur as a result of GM1 gangliosidosis, which can negatively affect the child’s development in particular or even stop it completely. In this case, development usually stops as early as the child’s sixth month of life. There is weakness in drinking and development of reflux disease. Likewise, the patient is very sensitive to common sounds and suffers from a relatively strong enlargement of the liver. The quality of life decreases enormously due to GM1 gangliosidosis and everyday life becomes difficult for the patient. Furthermore, complete loss of hearing and vision may occur if the disease continues to progress. In addition, the patient is more susceptible to infections and inflammations. It is not uncommon for respiratory problems to occur, which in the worst case can lead to complete respiratory failure. The developmental arrest also leads to a reduction in intelligence and only weakly developed motor skills. As a rule, the affected person is then dependent on the help of other people. The relatives and parents also suffer from psychological complaints as a result of GM1 gangliosidosis, sometimes depression occurs. A causal treatment of GM1 gangliosidosis is not possible. Life expectancy is drastically reduced by the disease.
When should you see a doctor?
Parents who notice symptoms such as weakness in drinking, heartburn, muscle hypotonia, and severe sensitivity to sound in their child during the first three months of life should consult their pediatrician. The complaints indicate a serious condition that needs to be clarified and, if necessary, treated. If there is a definite suspicion of GM1 gangliosidosis, a medical examination should be arranged immediately. At the latest, if signs of intestinal disturbance or seizures are noticed, a visit to the doctor is necessary. External symptoms that need to be clarified include the characteristic cherry-red spot at the back of the eye. If visual or hearing disorders are also present, medical advice is also required. In most cases, a specialist for the respective condition must be consulted in order to be able to make a clear diagnosis. Depending on the form of GM1 gangliodise, the above-mentioned symptoms may appear three months after birth or only after a year. Therefore, unusual symptoms should be medically clarified in any case. Especially children of parents who suffer from a genetic disease require comprehensive medical monitoring.
Treatment and therapy
There is no causative treatment for GM1 gangliosidosis. It is a genetic disease that constantly progresses due to further storage of GM1 gangliosides. The disease can only be treated symptomatically and supportively. In late-onset GM1 gangliosidosis, enzymatic treatment is discussed as a possible therapeutic approach. Here, due to the slowness of the disease development, a greater therapeutic scope is given. However, a cure has not yet been found in this case either.
Outlook and prognosis
Because scientists and physicians are not allowed to interfere with human genetics for legal reasons, there is no curability for GM1 gangliosidosis as things stand. The gene disease can only be treated symptomatically by physicians, which often becomes a particular challenge. Overall, the prognosis of the disease is considered unfavorable. Children experience a delay in their development already in the first years of life. In severe cases, premature developmental arrest occurs, with numerous consequences. The quality of life of the affected person is reduced, since in addition to physical impairments, cognitive losses are also possible.It is often not possible for the patient to cope with everyday life without sufficient help and support. In exceptional cases, the patient is threatened with respiratory problems that can lead to sudden cessation of breathing. Therefore, GM1 gangliosidosis can have a fatal course. Without the use of medical care, the prognosis of the disease is further worsened. The average life expectancy is significantly shortened due to the numerous complications. Due to the sometimes very intense symptoms, the affected person’s way of life is immensely restricted. In addition, the close environment is also strongly burdened. Consequential symptoms and mental illnesses are to be expected, which lead to a further impairment of the quality of life and thus a poor overall prognosis.
Prevention
To prevent GM1 gangliosidosis in the offspring of families in which cases of the disease have already occurred, human genetic counseling is useful. The disease is inherited in an autosomal recessive manner. This requires that both parents pass the mutated gene to their children. For example, if both parents are healthy carriers of the mutated gene, their offspring have a 25 percent chance of developing GM1 gangliosidosis.
Follow-up
In most cases of GM1 gangliosidosis, there are no options for follow-up care available to the affected person, as this disease is hereditary and cannot be treated causally. The affected person is therefore entitled to purely symptomatic treatment, which, however, does not always lead to success. If the patient wishes to have children, genetic counseling may be useful to prevent GM1 gangliosidosis from being passed on to offspring. GM1 gangliosidosis is usually treated by the administration of medication. In doing so, the affected person must pay attention to the correct and regular intake of these medications, including proper dosage. In cases of doubt or questions, a doctor should therefore always be consulted. In many cases, those affected by GM1 gangliosidosis are also dependent on intensive treatment and therapy, whereby they must be supported above all by friends and by their own family. In the case of psychological complaints, intensive and empathetic discussions with one’s own family are also very helpful. The parents of those affected also often need psychological treatment in this context. The patient’s life expectancy is usually always limited by GM1 gangliosidosis.
What you can do yourself
It is not possible to treat or support GM1 gangliosidosis by self-help measures. Patients are always dependent on symptomatic treatment, as causal therapy is usually not possible for this disease. Since the disease could also be passed on, the affected person or the parents should undergo genetic testing and counseling when GM1 gangliosidosis occurs in order to avoid passing it on to further generations. Patients are always dependent on outside help in their daily lives. This help should preferably be provided by parents, relatives or friends, as this help always has a positive effect on the course of the disease. Especially in the case of blindness or deafness, help and support in everyday life is necessary. Children should be fully educated about GM1 gangliosidosis. This includes education about the incurability of the disease. In case of psychological complaints, discussions with familiar persons are always helpful. Contact with other people affected by the disease can also have a positive effect on the course of the disease. In some cases, this also leads to an exchange of information and thus to a relief in the patient’s everyday life.
