A deficiency of arylsulfatase A in the body leads to metachromatic leukodystrophy. It is a genetic metabolic disease of the brain and occurs recessively inherited, characterized by numerous mutations and effects in the manifestation, so that there are different symptom names as well as the differences in the course and genotype.
What is metachromatic leukodystrophy?
Metachromatic diseases that primarily affect the central nervous system are referred to in medicine as lipid storage diseases, more specifically as sphingolipidoses. They belong to the group of lysosomal storage diseases, are inherited, and often have defects in specific genes. Metachromatic leukodystophy also belongs to this group. Arylsulfatase A is an enzyme responsible for the cleavage of sulfate from sulfatides. This process takes place in the lysosomes of cells. These are the cell organelles in both animal and plant cells that have versicles enclosed by a biomembrane where acidic pH is present. Lysosomes contain digestive enzymes and they break down biopolymers into monomers. If the activity of this enzyme is absent or occurs in reduced activity, deposits of fatty substances gradually form in the body cells and central nervous system. Glycosphingolipids can no longer be cleaved and lipids can no longer be converted into lysosome. The sulfatide is therefore stored. This in turn leads to a rapid degradation of the myelin sheath. The latter is the lipid-rich layer around the axons of neurons, and the breakdown triggers leukodystrophy.
Causes
The name for the disease is derived from Greek and includes both the words “color,” “white,” “bad,” and “nutrition.” In metachromatic leukodystrophy, there is degeneration of the demyelination, or white matter. In this process, the nerve fibers lose their medulla and the myelin sheath as protection of the nerve cell or axon is destroyed or damaged, respectively, in the central nervous system.
Symptoms, complaints, and signs
As the disease progresses, there are disturbances in movement functions that become progressively worse. Affected individuals also experience changes in their mental abilities. Brain function becomes more and more degraded. The earlier the disease begins, the more favorable the prognosis can be. A common form occurs late-infantile and is then called Greenfield syndrome. Symptoms appear between one and two years of age, while development is initially undisturbed. Even if the child could already speak and move normally, problems with walking suddenly appear, frequent stumbling is the result. Likewise, the linguistic expression deteriorates at first. Dysarthria develops, as well as breathing and swallowing difficulties, which are often associated with this problem. Muscle weaknesses and loss of reflexes are the consequence, as it is a peripheral nerve disease, which after some time also shows spastic paralysis symptoms. Painful muscle tension and pathological reflexes are the first indication of a disorder of the central nervous system. Swallowing itself also causes increasing difficulties, even if the symptoms stabilize periodically. Soon, hearing and vision also diminish and complete blindness may occur. The affected child can no longer move independently and is dependent on care and assistance. The mental abilities decrease and dementia develops. Greenfield syndrome leads to death after a few years, which then occurs at the latest in the 8th year of life by decerebration rigidity, i.e. by a body rigidity in coma, in which the brain stem is interrupted. This shows hyperextension of the limbs and trunk.
Diagnosis and course of the disease
Another form of metachromatic leukodystrophy is Scholz syndrome. This juvenile form usually occurs in children between the ages of four and twelve and is manifested by a slow decline in academic performance and deviations from the usual pattern of behavior. For example, the child begins to take refuge in daydreams with increasing frequency. Other disorders include abnormal posture, difficulty walking, tremors, visual and speech disorders, various seizures, and urinary incontinence.Gallstones also form in the organism, causing colic and gallbladder inflammation. The child quickly becomes in need of care. If the course of the disease is adult, there are more psychological abnormalities. This can lead to depression, but also to schizophrenia. The onset of the disease can fall in puberty, but symptoms can also become noticeable in old age. Personality changes, performance decreases, emotional lability increases. The loss of motor and mental abilities can be gradual and progress over decades. A multiple sulfatase deficiency intensifies the symptoms. Mucosulfatidosis develops, with deposits and storage occurring not only in the central nervous system but also in the spleen, liver, lymph nodes, and skeleton.
Complications
In most cases, various paralyses occur in this disease. Patients also suffer from spastic symptoms and, not infrequently, epileptic seizures. These are usually associated with severe pain, so that those affected also suffer from depression or irritability in their daily lives. Involuntary muscle twitching can occur and make everyday life more difficult. In adolescents and children, this can also lead to bullying or teasing. Furthermore, patients often suffer from a lack of concentration and coordination disorders. Memory loss can also occur, so that the child’s development is considerably restricted by the disease. It is not uncommon for those affected to be dependent on the help of other people or their parents in everyday life. The relatives or parents may also suffer from severe psychological symptoms or depression. A cure for this disease is not possible, so that only the symptoms can be treated symptomatically. Complications usually do not occur. The symptoms can be alleviated with the help of medications and therapies. Whether there is a reduced life expectancy due to the disease can usually not be universally predicted.
When should you see a doctor?
Disorders and irregularities of mobility are signs of impaired health that should be evaluated by a physician. If complaints of mobility increase, a visit to the doctor must be made. Gait unsteadiness, dizziness, an increased risk of accidents, or an inability to coordinate movement normally should be examined and treated. If the child experiences developmental problems, problems with locomotion, or frequent stumbling, there is cause for concern. If the child learns to walk particularly late compared to children of the same age or does not become confident in his or her movements, the observations should be discussed with a physician. Respiratory problems or problems with swallowing are further signs of a disease. If there is an undersupply of oxygen to the organism due to the breathing disorder, a life-threatening condition is imminent. Therefore, a visit to the doctor is advisable in case of pallor of the skin or blue discoloration. If speech is impaired or the person’s ability to express himself is disturbed, the indications should be clarified by a physician. If there is an existing or increasing weakness of muscle strength, pain when tensing the muscles, or a loss of natural reflexes, a physician is needed. Dysfunction of the sensory organs should also be examined and treated by a physician. Decreased vision or hearing can lead to blindness and deafness in the worst cases.
Treatment and therapy
Therapy for metachromatic leukodystrophy is very limited. Rather, palliative measures are resorted to, primarily treating the manifestations, relieving pain and muscle spasms, prescribing physiotherapy for spastic seizures. Antiepileptic drugs are used to reduce the seizures, special diet or special nutrition is one of the conditions of treatment. Also, a longer lasting freedom from symptoms could be achieved by transplanting stem cells or bone marrow. However, this surgical intervention has positive effects only if it takes place in the presymptomatic stage. It is also not without problems and involves risks and side effects.Scientific experiments continue to be carried out on tissue cultures and animals, both to clarify the pathogenesis and to open up new possibilities for a form of therapy. This could be enzyme replacement therapy.
Outlook and prognosis
The prognosis of the disease must be evaluated on an individual basis. In some patients, only a small improvement in health status is seen despite all efforts. In other cases, however, a longer-term period of freedom from symptoms could be achieved with medical care. However, recovery does not occur. The course of the disease depends primarily on the time of diagnosis and the start of treatment. The earlier the disease is detected, the better the prognosis. So far, the best results have been achieved at a pre-symptomatic stage. In some cases, surgical intervention can contribute significantly to improving the situation. Nevertheless, the transplantation of bone marrow or stem cells is associated with numerous risks. If the operation proceeds without further disturbances, the best results are usually achieved. In addition, symptomatic therapy is initiated. This is based on the individual symptoms and in most cases is adapted to developments over time. In addition, the affected person should use a special diet within the framework of self-help. This also leads to an alleviation of the existing health irregularities. Without seeking medical help, an increase in symptoms is to be expected. Cognitive impairment, seizures or psychological sequelae may occur. In these patients, the prognosis is considerably worse.
Prevention
Because it is a hereditary disease, preventive measures are not available. The only alternative remains to recognize the symptoms in time and start treatment as early as possible.
What you can do yourself
Patients with metachromatic leukodystrophy usually suffer from a significantly reduced quality of life and are dependent on the support of others in everyday life, especially in advanced stages of the disease. Even in childhood, those affected suffer from motor disorders that become noticeable, for example, when walking or coordinating movements. To prevent social exclusion in children, attendance at a special school is recommended. This often results in helpful social contacts that improve the patients’ attitude to life. Since in some cases the affected persons suffer from learning difficulties that increase with age, they also receive appropriate educational support in special institutions. The physical symptoms of metachromatic leukodystrophy are partially reduced by disciplined use of prescribed medications, although it is usually a purely symptomatic therapy. To improve the patient’s motor skills, regular appointments with a physiotherapist are appropriate. There, patients also learn physiotherapeutic exercises that can also be performed on their own. As the disease progresses, the patients’ independence decreases, so that they need the help of relatives or caregivers to manage their daily lives. Psychotherapeutic support is sometimes needed.
