Sandhoff disease represents a lysosomal storage disorder in which there is storage of GM2 gangliosides in neurons. In this case, the enzyme activity of hexosaminidase A and B is impaired. The prognosis is usually very poor.
What is Sandhoff disease?
Sandhoff disease is one of the lysosomal storage diseases. The disease was first described in 1968 by the German biochemist Konrad Sandhoff. In this syndrome, GM2 gangliosides are accumulated in nerve cells because two ganglioside-degrading enzymes have limited or no functionality. Gangliosides are water-insoluble lipids that are present in the membranes of all cells. Here they determine the structure of the outer part of the membrane. Chemically, they are composed of two fatty acid molecules attached to the aminodialcohol sphingosine. At the other end of the sphingosine molecule is an oligosaccharide consisting of several sugar molecules. The fatty acid residues protrude into the cell membrane toward the cell. This part of the molecule is nonpolar and therefore fat-soluble. The sugar moiety is located at the surface of the cell membrane and interacts with polar molecules such as water. The accumulation of GM2 gangliosides occurs mainly in nerve cells. There, a special function of gangliosides in the transmission of information between nerve cells is assumed. The gray matter of the brain is particularly rich in gangliosides. There they make up about six percent of all lipids. However, new gangliosides are constantly being formed, which normally also have to be broken down again in order to remain in balance. In the case of Sandhoff’s disease, however, the degradation process is disturbed, resulting in an accumulation of gangliosides. The disease is very rare. A prevalence of 1 in 130,000 is reported in Europe.
Causes
The cause of Sandhoff disease is the accumulation of GM2 gangliosides in neurons. Two enzymes responsible for the degradation of gangliosides are limited in their ability to function or are completely nonfunctional. These are the enzymes hexosaminidase A and B. Both enzymes are encoded by the HEXB gene on chromosome 5. The corresponding mutation is located at the site responsible for the coding of both proteins. Consequently, there is a loss of function for both. The hereditary defect is inherited in an autosomal recessive manner. For the disease to develop to its full extent, the corresponding genes of both parents must be defective. As a result of the degradation disorder, more and more gangliosides accumulate in the nerve cells. Eventually, the function of the nerve cells becomes massively impaired as more and more ganglioside molecules are added. The nerve cell becomes more and more enlarged. This effect manifests itself in the gradual swelling of the brain. As a result, the transmission of stimuli between the neurons is disturbed. New connections between neurons can no longer be formed and old connections break. As a result, mental decline sets in.
Symptoms, complaints, and signs
In Sandhoff disease, as in many lysosomal storage diseases, a distinction is made between several degrees of expression. These depend on the particular residual enzyme activity. There is an infantile, a juvenile and an adult form of the disease. In the infantile form, the children develop after an inconspicuous developmental phase from the third month of life [Developmental disorders in children|Developmental delays]]. Muscular hypotonia, frequent startle reactions, and motor disturbances occur. As it progresses, seizures, brain enlargement, and declining vision are added. In late stages, vision is lost altogether. Mental and motor abilities continue to decline. A cherry-red spot forms in the macula at the back of the eye. This form of progression usually ends fatally between the third and fifth year of life. In the juvenile form of progression, the first symptoms begin between the second and fifth year of life. Here, too, the same changes occur. However, the disease process progresses more slowly. Here, the life expectancy is between 15 and 20 years. In the adult form of the disease, there are different symptoms that manifest themselves in neurological and psychiatric abnormalities. Vision and mental development may remain unaffected. The further course depends on the residual activity of the enzymes.
Diagnosis and course of the disease
To diagnose Sandhoff disease, the enzyme activity of hexosaminidase A and B is determined. If both enzymes show decreased activity, Sandhoff disease can be assumed. If there is only a functional impairment of enzyme hexosaminidase A, it is Tay-Sachs disease, which has a similar course. Genetic analysis can confirm the diagnosis.
Complications
Sandhoff disease causes significant developmental limitations and delays, especially in children. Likewise, this disease leads to muscle wasting and further to swallowing difficulties. Due to the swallowing difficulties, a normal intake of food and liquids is usually no longer possible for the affected person. Likewise, Sandhoff’s disease leads to motor disorders. Patients often suffer from cramps and reduced vision. In the worst case, complete blindness occurs. Likewise, the patient’s motor skills decrease significantly as the disease progresses. Life expectancy is significantly reduced by Sandhoff’s disease, so that those affected usually live to a maximum of 20 years. The relatives and parents are also affected by Sandhoff’s disease and suffer from severe psychological complaints or depression. The mental development of the patient is usually not affected by the disease. A causal treatment of Sandhoff’s disease is usually not possible. Some of the symptoms can be limited with the help of therapies and medications. However, a complete cure of the disease is not possible.
When should you see a doctor?
If unusual symptoms occur in early childhood or at an advanced age, the doctor should always be consulted. Genetic analysis should be used to identify and differentiate the disease from similar conditions. Since hereditary Sandhoff’s disease is a neurodegenerative metabolic disease that usually occurs at an early age, the first contacts with a doctor are often already given in affected very young children. The disease, which is not yet treatable, leads to blindness and deterioration. Regular visits to the doctor are unavoidable in Sandhoff’s disease. The progressive lipometabolic disease belongs to the rather rare diseases. Since the affected children usually do not even reach the age of four, only symptomatic help can be offered. The poor prognosis makes it difficult for the parents of such children to deal with the disease. For the children themselves, not too much can be done from the medical side. The degradation disorder causes increasingly serious damage to the nerve cells. The brain is also severely affected. The degree of severity of the disorder can vary, however. This influences the medical options for action. In juvenile Sandhoff’s disease, a life expectancy into puberty or beyond is possible with good treatment. Symptoms progress more slowly. They appear at about two years of age. The adult form of Sandhoff disease is the one with the highest life expectancy. However, this is dependent on various influences in the enzyme field.
Treatment and therapy
Unfortunately, causal therapy of Sandhoff disease is not possible, as the disease is hereditary. Only symptomatic treatments can be performed. There are hopeful therapeutic approaches, but they are all in the early stages. As a rule, the prognosis is very poor. Also, unfortunately, life expectancy cannot be extended today. In the adult form of the disease, however, the life expectancy of those affected is somewhat greater. However, it depends on the residual activity of the enzymes.
Outlook and prognosis
Sandhoff disease is a severe disorder that is associated with severe discomfort for sufferers and leads to death within a few months. Accordingly, the genetic disease offers a relatively poor prognosis. The affected children usually die shortly after birth and suffer from severe physical limitations throughout their lives. On average, most Sandhoff’s disease patients die in the third or fourth year of life. The first symptoms appear twelve to fourteen months before death and usually lead to the child’s death due to severe organ damage or cardiovascular problems. The genetic disease can only be treated symptomatically.If symptoms such as strabismus or nystagmus are adequately treated, the affected children can at least lead a relatively symptom-free life. However, the regular visits to the doctor are associated with a great deal of stress for the relatives and the patients themselves. The quality of life is usually greatly reduced. Currently developed therapies could improve the prognosis in the future. In general, patients should adhere to the physician’s assessments. The physician gives an accurate prognosis with regard to the symptom picture and the therapy options.
Prevention
In families with relatives or kin suffering from Sandhoff disease, prophylaxis against further inheritance of the syndrome consists of extensive human genetic counseling. The disease is subject to autosomal recessive inheritance. This means that only if both parents possess the defective gene is there a 25 percent chance of passing the disease on to the offspring. First, the genetic status of both parents should be determined by genetic testing. If only one partner has the defective gene, there is no risk to the child.
Follow-up
In most cases, the measures and options for direct aftercare in Sandhoff disease are significantly limited or not even available to the affected person. For this reason, the affected person should see a doctor at a very early stage to prevent the occurrence of other complications or complaints, as this also prevents the patient from healing on his or her own. Likewise, a doctor should be consulted if the patient wishes to have children again, so that Sandhoff’s disease does not occur in the children, since it is a hereditary disease. Those affected are dependent on taking medication that can alleviate and limit the symptoms. It is important to follow the doctor’s instructions, and a doctor should also be consulted if there are any questions or if there are severe side effects. Furthermore, the correct dosage and also the regular intake of the medication should be observed. Often, those affected by Sandhoff’s disease are dependent on the help and care of other people in their daily lives. In this context, contact with other patients of the disease can also be very useful, as it is not uncommon for this to result in an exchange of information.
This is what you can do yourself
The disease gives only a few options for action that patients or their relatives can use in everyday life. A cure is not possible for the genetic disease. Neither conventional medicine nor alternative approaches can achieve recovery. Patients with Sandhoff’s disease have a significantly shortened life expectancy. In the field of self-help, the focus is ultimately on improving the quality of life. In everyday life, dealing with the symptoms and the course of the disease is particularly important. The disease poses great challenges not only for the patient, but also for those around him or her. Mental strength needs to be strengthened so that the circumstances can be handled well. In addition to the use of relaxation techniques, psychotherapeutic measures help. In addition, relatives should take sufficient time to meet their own needs. This is the only way to ensure that they have sufficient resources when dealing with the sick child. Contacts with self-help groups or other sufferers are felt to be helpful and supportive. In the exchange, mutual help for self-help takes place, as hints and tips for coping with the situation are given. To stabilize the organism, a healthy lifestyle and a balanced diet are recommended. The joy of life is to be promoted despite all adversities, so that an improvement of the overall situation is achieved.