The diagnosis of Hurler’s disease is associated with an enormous psychological as well as physical burden not only for the affected person, but also for the parents, because the disease not only has an extremely complex, but also severe symptomatology. According to the current state of medicine, Hurler’s disease cannot be cured. Patients must be treated with bone marrow or hematopoietic stem cell transplantation (BMT) and enzyme replacement therapy in infancy or early childhood. This is the only way to succeed in passing the years of puberty.
What is Hurler disease?
Of the lysosomal storage disease mucopolysaccharidosis type I (MPS I), Hurler disease defines the most severe course. The pediatrician Gertrud Hurler described the course of this rare lysosomal storage disease with skeletal deformities and delayed motor and intellectual development for the first time. The name is derived from her name. Currently, there is an increasing distinction between MPS I including involvement of the central nervous system (CNS) and MPS I without involvement. However, in Hurler’s disease the CNS is always involved. Fortunately, this disease occurs very rarely. The estimate is approximately 1 in 145,000 births. However, Hurler disease occurs most frequently at 1:100,000.
Causes
Hurler disease, also called Hurler-Pfaunder syndrome, is caused by mutations in the IDUA gene that cause a defect or complete loss of activity of the enzyme alpha-L-iduronidase. As a result, glycosaminoglycans (GAG) accumulate and cellular metabolism is impaired. Minoglycans can no longer be cleaved and degraded to a sufficient extent due to the enzyme defect. Instead, they are stored in the lysosomes of the body cells. Dermatan sulfate and heparan sulfate in particular accumulate. This severely impairs cell function, resulting in the symptoms that lead to Hurler’s disease.
Symptoms, complaints, and signs
The symptomatology, the pattern of complaints, is very extensive and usually manifests in infancy. Short stature and recurrent otitis, as well as obstructive and restrictive respiratory symptoms, often associated with pulmonary infections, characterize the clinical picture. Umbilical and inguinal hernias, some of which recur, unilateral or bilateral hip dysplasias, as well as gibbus (pointed hump of the spine) and various joint contractions or joint stiffness are also part of the clinical picture. Compression of the spinal cord in the upper cervical spine (C-spine) at the craniocervical junction is also a common symptom. Carpal tunnel syndrome, often bilateral, often occurs in childhood. The eyes often develop a corneal opacity in the 3rd year of life, the hearing increasingly develops a hearing impairment and the tongue enlarges (macroglossia). In addition, sleep apnea and mental retardation may develop. The head is relatively large and the lips are not infrequently widened. Organomegaly (abnormal enlargement of organs) as well as hernias and hirsutism (increased androgen-dependent hair) may also develop. Cardiomyopathy with valvular dysfunction is also frequently observed. A typical appearance is seen in affected patients. These include a short neck, an enlarged tongue, and a deep nasal bridge. Growth is usually normal up to the third year of life. However, developmental delays may occur between the 12th and 24th months of life. Hydrocephalus can also occur in the 2nd year of life. Growth often ends at a height of 1.20 meters. The gait pattern is also very characteristic due to the malpositions. Not only the already mentioned enlargement of the tongue, but also a narrowing of the airways and the reduced elasticity of the lung tissue are responsible for restricted breathing. Corneal opacification can progressively impair vision over time.
Diagnosis and disease progression
A diagnosis of Hurler disease can be made with a [[blood test|]blood test to determine the enzyme activity of alpha-L-iduronidase. Prenatal diagnosis is also possible enzymatically and molecularly. The clinical picture can be divided into three courses because different mutations underlie the enzyme defect. The three courses are:
- Hurler’s disease in severe expression
- Hurler’s/Sheie’s disease (M. Hurler/Sheie) in a moderately severe form.
- Scheie’s disease (M. Sheie) in mild form
Complications
As a rule, Hurler’s disease causes a number of different complaints and complications. The symptoms of this disease extremely limit the daily life of the affected person, so that in most cases he is also dependent on the help of other people or on the help of parents and caregivers. The quality of life of the affected person and the parents is also significantly reduced and limited. As a rule, the patients suffer from severely pronounced short stature and respiratory complaints. These can further lead to respiratory distress and, in the worst case, death of the patient. The joints are also stiff and usually cannot be moved easily. This results in restricted movement and a severe delay in the child’s development. In most cases, there are also problems with the patient’s vision and hearing, so that in the worst case Hurler’s disease can cause complete blindness or loss of hearing. Furthermore, this disease also leads to retardation, so that the patients are dependent on special support. Unfortunately, the disease itself is not curable, so that only some symptoms can be limited. In many cases, the parents and relatives also need psychological treatment.
When should you go to the doctor?
In Hurler’s disease, children already show clear symptoms of the disease. They need medical help immediately after noticing the first irregularities, as the symptoms are very detrimental to the patient’s quality of life. In case of respiratory problems, frequent infections or short stature, a visit to the doctor is advisable. If a suspension of respiratory function is noticed during night sleep, this should be discussed with a physician. If there are complications with mobility, there is also cause for concern. Joint stiffness, irregularities in movement patterns, and problems with locomotion should be presented to a physician. Visual abnormalities or deformities of the skeletal system are signs of a health disorder. If the functionality of the hand is limited or if there is a clouding of the cornea, a doctor is needed. Reduced development of mental skills, learning disabilities or developmental disorders of speech should be clarified by a doctor. General growth disorders, hydrocephalus, an enlarged tongue or a deep nasal root are characteristic of Hurler’s disease and should be presented to a physician as soon as possible. Normally, the disorders are clearly visible from the second year of life. A limitation of hearing or vision are further indications of a present disorder and must be medically examined.
Treatment and therapy
In any case, treatment should be provided by a multidisciplinary team of physicians and therapists. If the central nervous system is affected, treatment in the form of a bone marrow or hematopoietic stem cell transplant (BMT) is indicated as early as possible. This should be performed by the age of 2.5 years in young children. The transplant contains blood cells that produce the enzyme alpha-L-iduronidase. In return, these cells release a part of the formed and intact enzyme into the environment. This is subsequently taken up by other body cells and transported to the lysosomes. The stored glycosaminoglycans can now be degraded again. Only transplantation can have a positive effect on cognitive development and thus also on life expectancy. In addition, an enzyme replacement therapy is carried out afterwards. The defective enzyme is replaced by a biotechnologically produced form of the human enzyme. Now the pathological storage of glycosaminoglycans can be broken down again. However, due to a blood–brain barrier, the enzyme replacement does not reach the central nervous system. As a consequence, this form of therapy cannot exert any influence on cognitive and motor symptoms. According to the current status, only stem cell transplantation can do this. In the run-up to transplantation, the patient’s general condition can be stabilized or improved with enzyme replacement therapy. It can also support the transplantation and alleviate the symptoms. KMT cannot cure Hurler’s disease.From a purely prognostic standpoint, patients on such therapy may reach early adulthood before dying because of cardiovascular and respiratory complications.
Prospect and prognosis
The disease is an enormous psychological as well as physical burden not only for the affected persons themselves, but furthermore for parents, because Hurler’s disease exhibits not only a complex but also very severe symptomatology. According to current knowledge, the disease is not curable. Patients must be treated in early infancy with a special bone marrow or stem cell transplant, as well as enzyme replacement therapy. This is the only way to prolong life beyond puberty. In most cases, the disease causes many different symptoms as well as complications. The effects of the disease significantly limit the lives of patients, so that they are often dependent on the help of caregivers or family. In addition, the quality of life of those affected and their family is significantly reduced and limited. Sufferers often suffer from very pronounced short stature and have severe respiratory problems. These often lead to respiratory distress and, in extreme cases, to the death of the affected person. In addition, the joints are often stiff and difficult to move without pain. This leads to restricted movement and severe developmental delays in the affected children. Also, complaints often occur in the hearing and vision of the patients, so that they can even go completely blind and lose their hearing due to the disease.
Prevention
Hurler disease is a congenital genetic defect. Because of this, no preventive treatment can be given. However, with regard to genetic engineering, the future should be looked at positively.
Follow-up
Hurler disease is based on a genetic defect and takes a severe course in most cases. Affected individuals can make only very limited contributions to treatment themselves. At the beginning of the disease, self-help measures are usually limited to making use of psychotherapeutic offers that can make it easier for patients to accept the disease. Self-help groups, in which an exchange with other sufferers takes place, often help to discover new perspectives on life and to master everyday life with this serious illness. Furnishing the living environment in a way that is suitable for the disabled allows those affected more freedom of movement. Conversational and behavioral therapies often support the patient’s psychological confrontation with the disease. In the advanced stage of the disease, help from trained nursing staff must often be used. Likewise, of course, the support of relatives and friends can positively influence the lifestyle of the affected person. Moderate exercise, avoidance of psychological stress, and a special diet also help to improve the situation. A symptoms diary can help to identify unusual symptoms and complaints at an early stage in order to prevent life-threatening complications. Constant communication with the attending physician is essential. In the final stage of disease progression, relief measures are limited to the administration of pain-relieving medications to be taken as prescribed by a physician.
What you can do yourself
Hurler’s disease usually takes a severe course and can only be treated to a limited extent by those affected themselves. Accordingly, the most important self-help measure focuses on making use of psychotherapeutic measures. Talking to a therapist, on the one hand, and attending a self-help group, on the other, offer sufferers opportunities to accept the disease. In addition, a new perspective on life can be developed in conversation with other sufferers. In addition, steps must be taken to make life with the disease easier in everyday life. This can be the installation of a handicapped accessible facility, but also behavioral and talk therapies. Individuals who have advanced Hurler’s disease require care from a professional. Friends and relatives can be an important source of support during this time. The doctor will also recommend measures such as a change in diet, exercise and avoiding stress. By doing this and keeping a complaints diary, it is possible to lead a relatively symptom-free life despite the disease.The prerequisite for this is that all symptoms and unusual complaints are reported to the doctor. Otherwise, life-threatening complications may arise that require further treatment measures. In the final stages of the disease, self-help measures focus on taking pain-relieving medications as prescribed by the treating physicians.
