Hurler syndrome

Definition

Hurler syndrome is a severe hereditary metabolic disease of metabolism from the group of mucopolysaccharidoses characterized by excessive accumulation of glycosaminoglycans (GAGs) in various organs and tissues, which leads to their marked dysfunction. The clinical picture is highly diverse, including delayed psychomotor development, gross deformities of the bones of the skull and skeleton, cardiopulmonary abnormalities, and so on. Diagnosis is based on determining glycosaminoglycan excretion with urine and alpha-L-iduronidase enzyme activity in blood, as determined by data from molecular genetic tests. Treatment consists of enzyme replacement therapy.

General information

Hurler syndrome (mucopolysaccharidosis type I) is a lysosomal accumulation disease with autosomal recessive inheritance, manifested practically from the first months of life. The pathology is considered one of the most common mucopolysaccharidoses and occurs universally. According to various data, Hurler syndrome is detected in 1:40,000-1:100,000 newborns. There are no significant gender statistical differences.

Causes of Hurler syndrome

The disease is associated with heterogeneous mutations (small deletions, splice site defects) of the IDUA gene encoding the synthesis of the enzyme alpha-L-iduronidase. 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 in the enzyme, there is an excessive accumulation of GAGs 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 giving birth to a sick child is 25%.

Symptoms

Clinical signs of the disease appear in the first month of life. Sometimes, from birth, there is an increase in the spleen and liver, umbilical and inguinal hernias. The symptoms of musculoskeletal system damage are pronounced. Contractures and stiffness of joints develop quite quickly, and abnormal curves of the spine are formed (lumbar kyphosis).

By the end of the first year of life, the child’s face acquires characteristic features—protruding frontal tubercles, wide, flattened nose bridge, eye hypertelorism, thick lips, and tongue, and narrowed facial part of the skull. Typical is stunted growth, which stops almost completely by 4-5 years of age. As the disease progresses, central and peripheral nervous system damage symptoms are added.

There is a noticeable lag in psychomotor development – intelligence is reduced, and speech is underdeveloped. Speech defects also contribute to the emerging sensorineural hearing loss. Gait is disturbed, and muscle tone is reduced. Sometimes there are convulsions up to tonic-clonic paroxysms.

Other signs of Hurler syndrome include frequent upper respiratory tract infections, recurrent otitis media, and corneal opacity. Due to the accumulation of GAGs in the tonsils, trachea, and epiglottis, the airway lumen gradually narrows, increasing the risk of obstructive sleep apnea.

Diagnosis

Due to multiorgan damage, patients with Hurler syndrome require a multidisciplinary approach, so doctors from different specialties – pediatricians, neurologists, cardiac surgeons – are in charge of treatment. Anamnestic data and striking phenotypic features of the disease help to suspect the presence of pathology. To confirm the diagnosis, additional examination is prescribed, including:

• Determination of enzymatic activity. Reduced activity of lysosomal α-L-iduronidase is noted in peripheral blood leukocytes.
• Excretion of GAGs with urine. An increase in the concentration of glycosaminoglycans in urine is detected due to dermatan sulfate and heparan sulfate.
• MRI of the brain and spinal cord. The brain MRI shows thickening of the brain membranes and signs of hydrocephalus (enlargement of ventricles and cisterns), while the spinal MRI shows spinal cord compression.
• Radiography. Radiographic signs of Hurler syndrome include enlargement of diaphyses of tubular bones, shortening and thickening of clavicles, and “paddle-shaped” ribs. Radiographs of the spine show curvature, vertebral enlargement, underdevelopment, and deformity of the transverse processes.
• Cardiac ultrasound. Echocardiography shows thickening or deformation of valve leaflets, regurgitation signs, and dilation of heart cavities. In the development of congestive heart failure, the left ventricular ejection fraction decreases.
• Ultrasound and CT scan. An ultrasound or CT scan of the abdominal cavity reveals diffuse enlargement of the liver and spleen.
• Spirometry. Measurement of external respiratory function reveals obstructive disorders: a decrease in the lungs’ forced vital capacity and maximum inspiratory flow.
• ENMG. In some patients with nerve trunk compression, electroneuromyography shows signs of neuropathy – block and slowing nerve impulse conduction.
• Audiometry. Audiometry shows a significant increase in the threshold of sound perception. Due to the patient’s early age, objective audiometry methods (computed) are preferred.
• Ophthalmoscopy. Very often, the eye fundus examination determines edema, congestion of the optic disc, and peripheral retinal dystrophy.
• DNA diagnosis. Molecular genetic testing to detect IDUA gene mutations is crucial in diagnosing the disease.

The differential diagnosis of Hurler syndrome is made with other hereditary metabolic disorders—types II and III mucopolysaccharidosis, gangliosidosis, and multiple sulfatase deficiency. Joint involvement should be distinguished from noninfectious arthritis and juvenile rheumatoid arthritis.

Treatment for Hurler syndrome

Conservative therapy

Patients are subject to mandatory hospitalization in an inpatient hospital. The primary drug pathogenetic treatment is lifelong enzyme replacement therapy (ERT). A recombinant form of human alpha-L-iduronidase (laronidase) is used. Administration of this drug promotes restoration of enzymatic activity sufficient to hydrolyze accumulated GAGs and prevent their further deposition.

Early use of ERT allows for the slow progression of neurological disorders and heart failure, the restoration of active movements in the joints and spine, the regression of hepatosplenomegaly, and the disappearance of nocturnal apnea. The following symptomatic therapy is also carried out:

• Cardiac drugs. ACE inhibitors, beta-adrenergic receptor blockers, and aldosterone antagonists are prescribed for the treatment of congestive heart failure.
• Anticonvulsants. Anticonvulsant medications, such as NMDA-receptor antagonists, stimulators of GABA activity, and ion channel regulators, are used to prevent seizures.
• Psychotropic drugs. To correct behavioral disorders, tranquilizers and sedatives are individually selected in conjunction with a psychoneurologist.

Surgical treatment

For patients with Hurler syndrome under two years of age, hematopoietic stem cell transplantation is a radical treatment that avoids the need for lifelong enzyme therapy. Bone marrow or cord blood stem cells from HLA-compatible related donors are transplanted. Stem cell transplantation prevents the development of cognitive impairment. Enzyme replacement and immunosuppressive therapy are prescribed beforehand.

The following types of surgery are performed when indicated:

• Spinal cord and nerve trunk decompression: compression of the spinal cord causing sensorimotor and pelvic disorders.
• Ventriculoperitoneal shunt: hydrocephalus with high cerebrospinal fluid pressure.
• Herniectomy: occurrence of inguinal or umbilical hernias (in case of hernia impingement, emergency surgery is necessary).
• Tonsillectomy: marked hypertrophy of tonsils, making breathing difficult.
• Prosthetic knee or hip joints: development of gross deformities and contractures, completely limiting active movements.

All these treatment options are available in more than 390 hospitals worldwide (https://doctor.global/results/diseases/hurler-syndrome). For example, Cord blood stem cell transplantation can be done in following countries:

China in 4 clinics

Germany in 30 clinics

Israel in 6 clinics

Turkey in 12 clinics

United States in 5 clinics.

Rehabilitation

Rehabilitation is an important part of treatment, and it includes two main aspects. Massage and physical therapy are necessary to restore joint movements. Psychological and pedagogical assistance in the form of systematic individual lessons aimed at developing 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 ten years. The most common causes of death are respiratory and cardiac failure and severe bacterial infections.

The only effective prevention of the pathology is termination of pregnancy if low activity of alpha-L—iduronidase was detected during prenatal diagnosis when chorionic villi were examined at 8-10 weeks of pregnancy. A DNA diagnosis is recommended if a close relative suffers from Hurler syndrome. Vaccination against pneumococcus, meningococcus, and Hemophilus bacillus is prescribed to prevent infectious complications.