Hurler syndrome is a severe hereditary metabolic metabolic disease from the group of mucopolysaccharidoses, characterized by excessive accumulation of glycosaminoglycans (GAG) in various organs and tissues, which leads to their pronounced dysfunction. The clinical picture is extremely diverse, including delayed psychomotor development, gross deformities of the bones of the skull and skeleton, cardiopulmonary disorders, etc. The diagnosis is based on the determination of the excretion of glycosaminoglycans in urine and the activity of the enzyme alpha-iduronidase in the blood, the data of molecular genetic tests. The treatment consists of enzyme replacement therapy
General information
Hurler syndrome (Pfoundler-Hurler disease, mucopolysaccharidosis IH or type I) refers to lysosomal accumulation diseases with an autosomal recessive type of inheritance, manifested almost from the first months of life. The disease was first described by the Austrian pediatrician Gertrude Hurler. Pathology is considered one of the most common mucopolysaccharidoses, found everywhere. According to various data, Hurler syndrome is detected in 1:40,000-1:100,000 newborns. There are no significant gender statistical differences.
Causes
The occurrence of the disease is associated with heterogeneous mutations (small deletions, defects of the splicing site) of the IDUA gene encoding the synthesis of the enzyme alpha-L-iduronidase. The gene is localized in the short arm of chromosome 4 at the 4p16 locus.3. The most frequent mutations of the gene are Q70X and W402X. The lysosomal enzyme α-L-iduronidase regulates the metabolism of the main structural components of the intercellular matrix of connective tissue – it is responsible for the degradation of glycosaminoglycans heparan sulfate and dermatan sulfate.
Due to a genetically determined defect of the enzyme, excessive accumulation of GAG occurs in the lysosomes of cells. The most significant risk factor for the development of Hurler syndrome is the presence of a close relative suffering from this disease. If one of the parents has a mutant gene, the probability of having a sick child is 25%.
Pathogenesis
As a result of violation of intra–lysosomal hydrolysis and subsequent accumulation of intercellular components of connective tissue, inflammatory mediators are released – nitric oxide, tumor necrosis factor-alpha, organ dysfunction develops. Since connective tissue is more or less part of almost every organ, the lesion is multisystem in nature.
The accumulation of mucopolysaccharides in cartilage tissue causes a violation of bone growth, their gross deformation. Fibrosis develops in the walls of blood vessels, the valvular apparatus of the heart, and the meninges. Pathoanatomic examination reveals an increase in organs, hypercellularity, disorganization. There is a decrease in the number of proteoglycans and collagen fibers.
Symptoms
Clinical signs of the disease begin to appear already in the first month of life. Sometimes from birth there is an increase in the spleen and liver, umbilical, inguinal hernias. Symptoms of damage to the musculoskeletal system are pronounced. Contractures and joint stiffness develop quite quickly, pathological bends of the spine (kyphosis of the lumbar region) are formed.
By the end of the first year of life, the child’s face acquires characteristic features of the “gargoilism” type – protruding frontal bumps, a wide flattened bridge of the nose, ocular hypertelorism, thick lips and tongue, narrowed facial part of the skull. Growth retardation is typical, which almost completely stops by 4-5 years. As the disease progresses, symptoms of damage to the central and peripheral nervous system are added.
There is a noticeable lag in psychomotor development – intelligence is reduced, speech is undeveloped. Speech defects are also promoted by the emerging sensorineural hearing loss. From behavioral disorders, isolation and aggression are noted. Gait is impaired, muscle tone is reduced. Sometimes convulsions occur up to tonic-clonic paroxysms.
Other signs of Hurler syndrome include frequent infectious diseases of the upper respiratory tract, recurrent otitis media, corneal opacity. Due to the accumulation of GAG in the tonsils, trachea and epiglottis, the lumen of the breathing tube gradually narrows, which increases the risk of obstructive sleep apnea.
Complications
Hurler syndrome is a serious disease with a large number of complications. The main causes of death are considered to be progressive chronic heart failure as an outcome of developing heart disease and cardiomyopathy, respiratory failure due to airway obstruction, severe infections (pneumonia, meningitis, tuberculosis).
Hydrocephalus can lead to cerebral edema. Cardiac arrhythmias occur due to fibrotic myocardial damage. With spinal cord compression, tetraplegia or lower paraplegia, deterioration or complete loss of pelvic functions are possible. Sometimes there is a loss of vision and hearing.
Diagnostics
Due to the multi–organ lesion, patients with Hurler syndrome need a multidisciplinary approach, therefore, the curation is carried out by doctors of various specialties – pediatricians, neurologists, cardiac surgeons. Anamnestic data and vivid phenotypic features of the disease help to suspect the presence of pathology. To confirm the diagnosis, an additional examination is prescribed, including:
- Determination of enzymatic activity. In peripheral blood leukocytes, there is a reduced activity of lysosomal α-L-iduronidase.
- Excretion of GAG in the urine. There is an increase in the concentration of glycosaminoglycans in the urine due to dermatan sulfate and heparan sulfate.
- MRI of the brain and spinal cord. On MRI of the brain, thickening of the meninges, signs of hydrocephalus (ventricular expansion, cisterns) are visible, spinal MRI shows compression of the spinal cord.
- Radiography. Radiographic signs of Hurler syndrome include dilation of the diaphyses of the tubular bones, shortening and thickening of the collarbones, and the “paddle-like” shape of the ribs. Radiography of the spine shows its curvature, expansion of the vertebrae, underdevelopment, deformation of the transverse processes.
- Ultrasound of the heart. Echocardiography shows thickening or deformation of the valve flaps, signs of regurgitation, expansion of the heart cavities. With the development of CHF, the ejection fraction of the left ventricle decreases.
- Ultrasound and CT. During ultrasound or CT of the abdominal organs, diffuse enlargement of the liver and spleen is determined.
- Spirometry. When measuring the function of external respiration, obstructive disorders are revealed – a decrease in the forced vital capacity of the lungs, the maximum inspiratory flow.
- ENMG. In some patients, when nerve trunks are compressed, signs of neuropathy are detected on electroneuromyography – block and slowing down of the nerve impulse.
- Audiometry. Conducting audiometry shows a significant increase in the threshold of sound perception. Due to the early age of patients, objective methods of audiometry (computer) are preferred.
- Ophthalmoscopy. Very often, when examining the fundus, edema and stagnation of the optic nerve disc, peripheral retinal dystrophy are determined.
- DNA diagnostics. A molecular genetic study to identify mutations in the IDUA gene is considered crucial in the diagnosis of the disease.
Differential diagnosis of Hurler syndrome is performed with other hereditary metabolic disorders – types II, III mucopolysaccharidosis, gangliosidosis, multiple sulfatase insufficiency. Joint damage should be distinguished from non-infectious arthritis, juvenile rheumatoid arthritis.
Treatment
Conservative therapy
Patients are subject to mandatory hospitalization in a hospital. The main drug pathogenetic treatment is lifelong enzyme replacement therapy (ERT). A recombinant form of human alpha-iduronidase (laronidase) is used. The introduction of this drug promotes the restoration of enzymatic activity sufficient for the hydrolysis of accumulated GAG and preventing their further deposition.
Early use of ERT can slow down the progression of neurological disorders and heart failure, restore active movements in the joints and spine, achieve regression of hepatosplenomegaly, and the disappearance of night apnea. The following symptomatic therapy is also carried out:
- Cardiopreparations. ACE inhibitors (perindopril), beta-adrenergic receptor blockers (bisoprolol), aldosterone antagonists (spironolactone) are prescribed for the treatment of congestive heart failure.
- Anticonvulsants. To prevent the occurrence of seizures, anticonvulsant medications are used – NMDA receptor antagonists (phenytoin), GABA activity stimulators (gabapentin), ion channel regulators.
- Psychotropic drugs. In order to correct behavioral disorders, tranquilizers, sedatives (benzodiazepines) are individually selected together with a neuropsychiatrist.
Surgical treatment
Patients with Hurler syndrome under the age of 2 years are recommended radical treatment to avoid the need for lifelong enzyme therapy – hematopoietic stem cell transplantation (HSCT). Bone marrow or cord blood stem cells from HLA-compatible related donors are being transplanted. HSCT prevents the development of cognitive impairment. ERT and immunosuppressive therapy are pre-prescribed.
If there are appropriate indications, the following types of operations are performed:
- Prosthetics of the heart valve: heart defect (insufficiency or stenosis), leading to significant hemodynamic disorders and progression of CHF.
- Decompression of the spinal cord and nerve trunks: compression of the spinal cord, causing sensorimotor disorders and pelvic disorders.
- Ventriculoperitoneal bypass surgery: hydrocephalus with high pressure of cerebrospinal fluid.
- Herniation: the appearance of inguinal or umbilical hernias (if a hernia is pinched, an emergency operation is necessary).
- Tonsillectomy: pronounced hypertrophy of the tonsils, making it difficult to breathe.
- Prosthetics of the knee or hip joints: the development of gross deformities and contractures that completely restrict active movements.
Rehabilitation
An important part of the treatment is rehabilitation measures, which include two main aspects. Massage and physical therapy are necessary to restore movement in the joints. Psychological and pedagogical assistance in the form of systematic individual classes is aimed at the development of cognitive functions, contributes to the longer preservation of intelligence.
Prognosis and prevention
Hurler syndrome is a severe disabling disease with a high mortality rate. The average life expectancy of patients without timely prescribed pathogenetic treatment is 10 years. The most common causes of death are respiratory and heart failure, severe bacterial infections.
The only effective prevention of the development of pathology is termination of pregnancy, if during prenatal diagnosis low activity of alpha-iduronidase was detected during the study of chorionic villi at 8-10 weeks of pregnancy. In the presence of a close relative who suffers from Hurler syndrome, DNA diagnostics is recommended. To prevent infectious complications, vaccination against pneumococcus, meningococcus, Hemophilus bacillus is prescribed.
