Fucosidosis is one of the very rare storage diseases with a progressive and sometimes relapsing course due to a lack of activity of alpha-L-fucosidase, which is classified as one of the oligosaccharidoses or glycopreteinoses. A breakthrough treatment method is not yet in sight, which is why treatment to date has been with allogeneic bone marrow transplantation, which is considered the most advanced method to date.
What is fucosidosis?
It is fucosidosis, also known by the synonym alpha-L-fucosidase deficiency, an extremely rare autosomal recessively inherited lysomal storage disease belonging to the oligosaccharidoses group, which occurs not only in humans but also in dogs. The prevalence is less than 1 in 1,000,000 and the mode of inheritance is autosomal recessive. Of the 100 cases circa known and described to date, 20 affected patients are from southern Italy (Grotteria and Mammola in the Reggio Calabria area). In the southwestern United States (Colorado and New Mexico), a further clustering of this disease has been observed. To an extent of about 40 percent, there is a consanguinity. The founder effect, which results in much lower geno- and phenotypic variability of the offspring, can explain the high prevalence within these populations. The founder effect describes the genetically determined deviation of an isolated population or founder population. The starting point for this deviation is the low number of existing “alleles” of the individuals involved in their founding. Thus, different selection conditions do not come into consideration. A distinction is made between two types with smooth transitions:
Type 1 is considered to be clinically more severe and starts already between the 3rd and 18th month of affected patients. Type 2, with a less progressive course, begins between 12 and 24 months of age. Due to the less progressive nature (2), the life expectancy of type 2 patients is higher than that of patients with type 1 disease. Fucosidosis disease progresses less rapidly and not as massively. Therefore, the opposite of progression, the positive regridience, is spoken of. A third type related to patients in the Netherlands is under discussion. The expression is less severe and the disease presents as a juvenile form without angiokeratomas. These are benign skin lesions. These consist of warty hyperkeratoses combined with telangiectasias and angiomas, respectively.
Causes
The cause of generalized storage of fucose-containing glycolipids as well as oligosaccharides in all tissues is the lack of activity of alpha-L-fucosidase. This in turn is due to nonsense or missense mutations on a gene coding for alpha-L-fucosidase, FUCA 1, which is located on chromosome 1 gene locus p34. This enzyme catalyzes the cleavage of L-fucose and glycolipids and oligosaccharides. Both contain fructose. The substrate fucose is a hexose. However, since the enzyme activity is reduced, unmetabolized fucose or fucose-containing compounds accumulate in the cells of all tissues of the body. The result is damage to the cell as well as to the affected organs. In affected individuals, a pseudogene of Fuca1 is located on chromosome 2. The polymorphic (multigene) Fuca2 gene is located on chromosome 6. Enzyme activity in blood serum and fibroblasts is controlled by the gene product of Fuca 2. 20 different mutations have been found to trigger fucosidosis to date.
Symptoms, complaints, and signs
Typical symptoms of fucosidosis include facial deformities, morphologic disproportions of the head and face that deviate from the norm, and skeletal malformations. Furthermore, severe mental retardation as well as seizures, liver enlargement (hepatomegaly), spleen enlargement (splenomegaly), and heart enlargement (cardiomegaly) have been noted. Furthermore, deafness may occur. Age-related angiokeratomas and dysostosis multiplex have also been observed.
Diagnosis
Chromatographic urinalysis can be used to diagnose fucosidosis. It is not quite as simple to determine the enzyme as accurately as possible in amniotic and trophoblast cells in the laboratory.The findings can be confirmed in the laboratory by determining the activity of alpha-L-fucosidase in the leukocytes. Only sometimes is a genetic test also required.
Complications
Fucosidase usually causes various deformities in the facial area. These deformities can cause both physical and psychological distress to the patient, thereby reducing the quality of life enormously. Those affected suffer from severe psychological discomfort and depression. The parents and relatives of the patient can also be affected by the psychological symptoms. The patient suffers from seizures and retardation. The intelligence decreases and the patient is dependent on the help of other people in his everyday life. There is also an enlargement of the spleen and the heart, which can be life-threatening for the affected person. As a rule, the enlargement of the spleen caused by fucosidase leads to pain. As the disease progresses, loss of hearing also occurs. Unfortunately, it is not possible to treat fucosidase. The symptoms can also only be treated to a very limited extent. The life expectancy of the patient decreases extremely due to fucosidase, in most cases the affected person can only reach the age of ten.
When should you go to the doctor?
Fucosidase is usually detected before the affected child is born. At the latest, the diagnosis can be made at birth based on the typical malformations. Parents should seek medical attention if symptoms increase or if unusual symptoms develop. An emergency physician should be called if seizures or twitching occur. Signs of enlargement of the organs also require prompt evaluation by a specialist. If serious complications develop, the child must be taken to a hospital immediately. In the case of psychological complaints, a therapist should be consulted promptly. This is recommended for both the affected child and the parents, as both parties usually suffer from the serious illness and its effects. If adverse events occur during drug treatment, it is best to talk to the doctor in charge. The patient should also see a physician if there are any wound healing problems, infections, or other complications in the area after surgery.
Treatment and therapy
To date, only one therapy is known. Nonsymptomatic bone marrow transplantation. It is considered a treatment method with a curative approach. Approximately ten patients have been treated with this method to date. A final assessment can therefore not yet be made. By the way, a first test was carried out on dogs. From a purely prognostic point of view, patients can thus now reach the second decade of life, in contrast to the past, when they rarely lived beyond five years.
Outlook and prognosis
Fucosidosis is a serious disease that follows a progressive course. The only treatment option to date, bone marrow transplantation, is fraught with many risks and has been successful in only a few patients. The prognosis is accordingly negative. Typical symptoms such as mental damage and organ dysfunction can usually not be treated effectively and eventually lead to the death of the patient. Prior to this, the quality of life and well-being decreases insidiously as a result of the symptoms. In the further course, serious complications occur, which not only extremely limit the affected person, but also greatly reduce life expectancy. In most cases, patients die of the consequences of fucosidosis before the age of ten. If the bone marrow transplant is successful, further physical and mental symptoms can possibly be avoided. The prerequisite for this is that the treatment is initiated at an early stage and that the patient is not already severely disabled from birth. If these factors are present, progression of fucosidosis can be stopped. Congenital malformations and mental impairments can subsequently be treated by surgery, physiotherapy and medication, among other methods. Despite all measures, the affected child usually cannot lead a completely symptom-free life, since fucosidosis causes health problems even after transplantation. Therefore, sufferers must be medically treated throughout their lives.
Prevention
To date, medical research has not yet succeeded in developing preventive measures. Because medical research has not yet gained any further knowledge beyond the starting points, there are still no ways to counteract an outbreak of this disease when a genetic predisposition is assumed.
Follow-up
In most cases, the options for follow-up care of fucosidase are very limited. In this case, the affected person is primarily dependent on direct medical treatment of the disease by a physician in order to avoid further complications and discomfort. Self-cure cannot occur in this case. In order to prevent the disease from being passed on to descendants, genetic counseling should also be performed if the patient wishes to have children. The treatment itself is usually performed by transplantation of bone marrow. In most cases there are no particular complications or other complaints, although fucosidase can only be cured for a short time. Unfortunately, a complete cure cannot be achieved, so that the life expectancy of the affected person is considerably limited and reduced by this disease. In many cases, patients with fucosidase are also dependent on intensive care and support from their own family and friends. In particular, very loving and empathetic care of the affected person has a positive effect on the further course of the disease. However, medical care by a psychologist may also be necessary in the case of psychological complaints.
What you can do yourself
Fucosidase is a serious disease from which most patients die before reaching the age of ten. The most important therapeutic measure is to relieve the symptoms. This is achieved on the one hand by drug treatment, and on the other hand by physiotherapy and sparing. The affected child usually requires full-time care by a nursing service and the parents. For the parents in particular, this represents a considerable physical and emotional burden. For this reason, an accompanying therapy is useful, in which both the parents and the sick child can participate. In the case of a severe course of the disease, the parents and other relatives usually also need psychological care. Attending a self-help group and talking to other affected parents can also help to understand the disease. The actual treatment can also be supported by a conscious diet. Furthermore, the child must be constantly monitored so that a quick response can be made in the event of any seizures or other complications. In the case of enlargement of the internal organs, various measures must be taken on an individual basis to alleviate the discomfort and allow the child to continue living relatively pain-free.
