Hunter syndrome

Hunter syndrome is a genetic defect of intracellular carbohydrate catabolism (glycosaminoglycans), which is transmitted to male children through X-linked recessive inheritance and causes abnormalities of the skeleton, internal organs and mental retardation.

This syndrome is also called type II mucopolysaccharidosis and is referred to as lysosomal accumulation diseases. According to ICD-10, this congenital fermentopathy is classified as a metabolic disorder and has code E76.1.

[1], [2], [3], [4]

Epidemiology

According to foreign experts, there are only about two thousand living patients suffering from Hunter syndrome all over the world. 500 of them live in the USA, 70 in Korea, 20 in the Philippines, and 6 in Ireland. One living patient was counted in Chile, Pakistan, India, Palestine, Saudi Arabia, Iran and New Zealand.

A study of morbidity among British men showed that its level is approximately one case per 130,000 boys born alive.

According to other sources, in European countries, Hunter's syndrome is detected in one boy for every 140-156 thousand of live-born male children.

In female children, sporadic cases of this disease are extremely rare.

[5]

Causes of the hunter syndrome

Genetics have established that the causes of Hunter syndrome are the mutations of the IDS gene (located on the X chromosome, locus Xq28), which encodes the I2S enzyme.

Mucopolysaccharides, also known as glycosaminoglycans (GAG), are a carbohydrate component of macromolecules of complex proteins of proteoglycans filling the space between cells and forming a matrix. Matrix surrounds cells and, in fact, is the "skeleton" of tissues. But, like many other biochemical components of the body, proteoglycans undergo metabolism. In particular, from the molecules of two species of GAG-dermatan sulfate and heparan sulfate, sulfate, which is in their composition in the form of sulfated alpha-L-iduronic acid, should be removed with the help of the I2S enzyme.

Deficiency of this enzyme in Hunter syndrome leads to incomplete hydrolysis of dermatan- and heparan sulfate, and they accumulate in lysosomes of cells of virtually all tissues (skin, cartilage, tendons, intervertebral discs, bones, vessel walls, etc.). Such a violation of catabolism of glycosaminoglycans entails pathological changes in the structure of tissues, and this, in turn, causes the formation of anatomical defects and functional disorders of various systems and organs.

[6], [7], [8], [9], [10]

Risk factors

Obvious risk factors for the inheritance of mucopolysaccharidosis type II by a male child: the presence of a defective gene on the mother's X chromosome, which is healthy (it has a second X chromosome that compensates for the gene mutation), but is the carrier of the altered IDS gene.

[11], [12], [13], [14], [15]

Pathogenesis

Investigating the pathogenesis of Hunter syndrome, endocrinologists have revealed in the patients with this disease the lack of one of the intracellular enzymes of the class of lysosomal hydrolases - glucuronate sulfatase (I2S), which provides the process of cleavage of mucopolysaccharides.

[16], [17], [18], [19], [20], [21]

Symptoms of the hunter syndrome

The rate of disease transition from the initial stage to the clinically severe form varies widely, and the symptoms of the Hunter syndrome-that is, their presence and degree of manifestation-vary in each case.

This congenital disease refers to progressive pathologies, even when the diagnosis is formulated as a weakened or mild form. It is obvious that the form of manifestation of mucopolysaccharidosis type II depends on the nature of the genetic mutations and determines both the age of the manifestation of the disease and the severity of the pathology. Signs of severe form of Hunter syndrome (type A) are on average seen at the age of two and a half years and are very rapidly amplified. In patients with a weakened form (type B), symptoms can appear in five to eight years (an average of 4.5 years in statistics) or even in adolescence.

It should be borne in mind that the first signs of the Hunter syndrome at the time of the birth of the child do not manifest themselves, but begin to become noticeable after the first year of life. Symptoms of these nonspecific - frequent infections of the upper respiratory tract, inflammation of the ears, inguinal or umbilical hernia, so it is difficult to diagnose immediately.

As the accumulation of glycosaminoglycans in the cells of various tissues continues, there are such clinical symptoms of Hunter syndrome as:

• enlargement and coarsening of facial features due to multiple dysostoses (full lips, large round cheeks, broad nose with flattened bridge of nose, thickened tongue);
• large head (macrocephaly);
• shortening of the cervical spine;
• enlarged abdomen size;
• low hoarse voice (due to widening of the vocal cords);
• wheezing (wheezing) breathing;
• apnea (stopping breathing in a dream);
• incorrect formation of the dentition (large interdental distances, thickened gums);
• thickening and reduction of skin elasticity;
• papular skin lesions of ivory in the form of a network structure between the shoulder blades on the back, on the sides of the chest, on the hands and feet (these signs are practically pathognomonic for Hunter syndrome);
• progressive hearing impairment;
• enlargement of the liver and spleen (hepatosplenomegaly);
• lag in growth (especially noticeable field of three years);
• leading to ataxia limitation of mobility of joints (flexion contractures due to the deformities of the multiplex and impressions in the structure of cartilage and tendons);
• mental retardation;
• mental disorders in the form of attention deficit, attacks of aggression and anxiety, sleep disorders, compulsive disorders, etc.

[22], [23]

Complications and consequences

The consequences and complications of the further accumulation of GAG in lysosome cells affect:

• function of the heart (due to the thickening of the valves and the myocardium, cardiomyopathies and valvular anomalies develop);
• respiratory tract (development of obstruction due to accumulation of heparan and dermatan sulfate in tracheal tissues);
• hearing (total deafness);
• musculoskeletal system (spinal deformity, pelvic or femoral bone dysplasia, wrist bones, early osteoarthritis, movement problems);
• intellect and cognitive functions (with irreversible regress of mental development);
• CNS and psyche (behavioral problems).

In Hunter's syndrome type B, one organ can be pathologically altered, and intellectual abilities are almost not affected: the most often violated can be mastering verbal skills and learning to read. The average age of the lethal outcome of mild disease is 20-22 years, but there is a life expectancy of about 40 years or more.

Severe form of the syndrome leads to an earlier mortality (12-15 years) - as a result of cardiorespiratory complications.

[24], [25], [26]

Diagnostics of the hunter syndrome

To date, the diagnosis of Hunter syndrome includes:

• Examination and detection of visible signs of the disease;
• analyzes: urine on the level of glycosaminoglycans and blood on the activity of the enzyme I2S;
• skin biopsy for the presence of iduronate sulfatase in fibroblasts and the determination of its functional usefulness.

Genetic analysis (prenatal diagnosis) is carried out in cases of family history of the syndrome, for which puncture of the bladder is made and the enzymatic activity of I2S in the amniotic fluid is investigated. There are also ways to determine the activity of this enzyme in the fetal umbilical cord or in the chorionic villus tissue (by cordocentesis and biopsy).

Instrumental diagnostics is carried out:

• X-ray of all bones (to determine the anomalies of ossification and bone deformities);
• Ultrasound of the abdominal cavity;
• spirometry;
• ECG (for the detection of cardiac disorders);
• EEG, CT and MRI of the brain (to detect cerebral changes).

[27], [28], [29]

Differential diagnosis

Differential diagnosis is intended to distinguish Hunter syndrome from other mucopolysaccharidosis (Hurler, Sheie, Hurler syndromes, etc.), lipochondrodystrophy (gargoilism), multiple sulfatase deficiency (mucosulphatidosis), etc.

Treatment of the hunter syndrome

Because of the inherent nature of the pathology, the treatment of Hunter syndrome focuses on palliative therapy - in order to reduce the effects of deterioration of many body functions. That is, supportive and symptomatic treatment often focuses on cardiovascular complications and problems with the respiratory tract. For example, surgical treatment in the form of tonsils and adenoids can open the child's airways and help alleviate respiratory complications. However, the disease progresses, and the tissues do not become normal, so problems can return.

For a long time, the most effective approach has been transplantation of bone marrow transplant or hematopoietic stem cells - as a new source of the missing enzyme I2S. A bone marrow transplant can improve or stop the progression of some physical symptoms in the initial stages of the disease, but with progressive cognitive dysfunction, this method is useless. Therefore, such operations with Hunter syndrome are rare.

Now the emphasis is on enzyme replacement therapy, that is, long (and in this case lifelong) administration of an exogenous I2S enzyme. The main drug for this syndrome is the preparation Elapraza (ELAPRASE), which contains a similar endogenous recombinant lysosomal enzyme to idursulfase. This drug was clinically tested in 2006 and approved by the FDA.

Patients of childhood and adolescence Elaprazu should be infused into the vein once a week - at a rate of 0.5 mg per kilogram of body weight. Possible side effects are manifested by skin reactions, headaches and dizziness, tremor, hot flashes to the head, irregular blood pressure, impaired heart rate, dyspnea, bronchial spasms, joint and abdominal pain, soft tissue swelling, etc.

An important part of the treatment of Hunter syndrome is physiotherapy: a properly selected complex of exercise therapy promotes the preservation of joint mobility in the early stages of the disease, and electrophoresis and magnetotherapy help to reduce the intensity of joint pain. Symptomatic drugs and vitamins are also prescribed to support the functioning of the cardiovascular system, lungs, liver, intestines, etc.

Prevention

Prevention of congenital syndromes, which include mucopolysaccharidosis, is possible only through prenatal diagnosis, as well as genetic examination of future parents in planning pregnancy and counseling families where there is already a sick child.

For some children with Hunter syndrome, early diagnosis can be the prevention or delay in the development of serious consequences of pathology, although even enzyme replacement therapy can not cure a genetic defect.

[30], [31], [32], [33]

Forecast

Although treatment can increase the life expectancy of children with this pathology and improve its quality, patients with severe Hunter syndrome die before 15 years of age. And in the absence of mental symptoms, such patients with severe disability can live twice as long.