Mucopolysaccharidosis, type I: causes, symptoms, diagnosis, treatment

Mucopolysaccharidosis, type I (Synonyms: enzyme deficiency of lysosomal aL-iduronidase, syndromes of Hurler, Gurler-Scheye and Sheie).

Mucopolysaccharidosis, type I - is an autosomal recessive disease resulting from a decrease in the activity of lysosomal aL-iduronidase, which is involved in the metabolism of glycosaminoglycans. The disease is characterized by progressive disorders from the internal organs, the bone system, psychoneurological and cardiopulmonary disorders.

ICD-10 code

• E76 Disorders of glycosaminoglycan metabolism.
• E76.0 Mucopolysaccharidosis, type I.

Epidemiology

Mucopolysaccharidosis I is a panethnic disease with a frequency in the population of an average of 1 per 90 000 live births. The average incidence of the Hurler syndrome in Canada is 1 per 100,000 live births, the Hurler-Scheye syndrome is 1 at 115,000, and the Scheye syndrome is 1 per 500,000.

Classification

Depending on the severity of the clinical symptoms of the disease, there are three forms of mucopolysaccharidosis I: the syndromes of Hurler, Gurler-Scheye and Sheie.

Causes of mucopolysaccharidosis type I

Mucopolysaccharidosis I is an autosomal recessive disease that occurs as a result of mutations in the structural gene of lysosomal alpha-L-iduronidase.

The alpha-L-iduronidase gene- IDUA- is located on the short arm of chromosome 4 at the locus 4p16.3. To date, there are more than 100 different mutations in the IDUA gene . The prevalent number of known mutations are punctate in various exons of the IDUA gene . For Caucasians are characterized by two frequent mutations Q70X and W402X.

The most common mutation among patients from the Russian population is the Q70X mutation . Its frequency is 57%, which is comparable with the frequency of Q70X in the Scandinavian population (62%). The frequency of mutation W402X, which occurs in 48% of cases of mucopolysaccharidosis I in a number of European populations, in the Russian population is 5.3%.

Pathogenesis of type I mucopolysaccharidosis

The enzyme aL-iduronidase participates in the metabolism of two glycosaminoglycans, dermatan-sulfate and heparan sulfate. Since iduronic acid is a part of dermatan sulfate and heparan sulphate, the intralisosomal disintegration of these glycosaminoglycans is disrupted in this disease, which accumulates in lysosomes everywhere: cartilage, tendons, periosteum, endocardium and vascular wall, liver, spleen and nervous tissue. Edema of the mild membrane causes partial occlusion of subarachnoid spaces, which leads to progressive internal and external hydrocephalus.

The cells of the cerebral cortex, thalamus, trunk, anterior horns are affected. The stiffness of the joints is the result of the deformation of the metaphyses, the thickening of the joint capsule is secondary to the deposition of glycosaminoglycans and fibrosis in it. Obstruction of the respiratory tract is a consequence of narrowing of the trachea, thickening of the vocal cords, redundancy of the edematous tissues in the upper respiratory tract.

Symptoms of mucopolysaccharidosis type I

Mucopolysaccharidosis, type IH (Hurler syndrome)

In patients with the Hurler syndrome, the first clinical signs of the disease appear in the first year of life, with a peak of manifestation from 6 to 12 months. In a number of cases, a slight increase in the liver, umbilical or inguinal and scrotal hernia has been observed since birth. Usually the diagnosis is set at the age of 6 to 24 months. Typical changes in facial features by the type of gargoyleism become apparent by the end of the first year of life: a large head, protruding frontal tubercles, a broad bridge of nose, short nasal passages with outturned nostrils, a half-open mouth, a large tongue, thick lips, gingival hyperplasia, irregular teeth. Other frequent manifest symptoms are stiffness of small and large joints, kyphosis of the lumbar spine (lumbar gibus), chronic otitis and frequent infectious diseases of the upper respiratory tract. Practically in all patients with the Hurler syndrome, as well as with other types of mucopolysaccharidosis, the skin is dense to the touch. Hypertrichosis is common. In single patients under the age of 1 year, the disease debuted with the development of acute heart failure caused by endocardial fibroelastosis. As the disease progresses, symptoms are attached that testify to the involvement of internal organs, cardiopulmonary, central and peripheral nervous systems in the pathological process. Leading neurological symptoms - decreased intelligence, delayed speech development, changes in muscle tone, tendon reflexes, cranial nerve damage, combined conductive and sensorineural hearing loss. Progressive ventriculomegaly often leads to the development of communicating hydrocephalus. By the end of the first and at the beginning of the second year of life, there are noises in the heart, later acquired aortic and mitral heart defects. By the end of the second year of life, hepatosplenomegaly and characteristic skeletal disorders are identified by the type of multiple dysostosis: short neck, growth retardation, total platiphondylia, lumbar gibus, stiffness of small and large joints, hip dysplasia, joint valgus deformity, a "clawed" paw ", deformation of the chest in the form of barrel or bell-shaped. Often there is a progressive opacification of the cornea, megalocornea, glaucoma, congestive optic discs and / or their partial atrophy.

Early radiologic signs - deformation of the ribs (by the type of "rowing") and ovoid deformation of the vertebral bodies, excessive trabeculation of diaphysis of long tubular bones in combination with its insufficiency in the metaphyses and epiphyses. As the disease progresses, macrocephaly is formed with a thickening of the bones of the cranial vault, premature closure of the lambdoid and sagittal seams of the skull, a decrease in orbits, and expansion of the back of the Turkish saddle. Patients die usually at the age of up to 10 years from obstruction of the respiratory tract, respiratory infections, heart failure.

Mucopolysaccharidosis, type IH / S (Hurler-Scheye syndrome) The clinical phenotype of the Gurler-Scheye syndrome occupies an intermediate position between the Hurler and Scheye syndromes, it is characterized by slowly progressing disorders from the internal organs, the bone system, slight loss of intelligence or lack thereof. The disease usually debuts at the age of 2-4 years. The main clinical disorders are heart failure and development of obstructive upper respiratory tract syndrome. In some patients, total spondylolisthesis is observed, which can lead to compression of the spinal cord. Most patients live to the third decade of life. The main cause of death is acute cardiovascular and pulmonary insufficiency.

Mucopolysaccharidosis, type IS (Scheye syndrome)

In the initial classification of mucopolysaccharidosis, prior to the discovery of the primary biochemical defect in the Scheye syndrome, it was isolated into a separate type, mucopolysaccharidosis V. The Scheye syndrome is the most mild in the course of the disease among other forms of mucopolysaccharidosis I, characterized by joint stiffness, aortic heart defects, corneal opacity and signs of multiple bone dysostosis. The first symptoms usually appear between the ages of 5 and 15 years. Leading clinical symptoms are skeletal disorders in the form of joint stiffness with the development of carpal tunnel syndrome. Ophthalmic disorders include corneal opacity, glaucoma and retinal pigmentary degeneration. Sensorineural hearing loss is a later complication of the disease. Obstructive upper respiratory tract syndrome often leads to apnea during sleep, which in some cases requires the establishment of a tracheostomy. Myelopathy of the cervical spinal cord is less common than in the Gurler-Scheye syndrome. Often noted stenosis of the aorta with circulatory failure and hepatosplenomegaly. Intellect in this syndrome does not suffer or observe mild cognitive impairment.

Diagnosis of type I mucopolysaccharidosis

Laboratory research

The confirmatory biochemical diagnosis of mucopolysaccharidosis I consists in determining the level of urinary glycosaminoglycan excretion and measurement of the activity of lysosomal aL-iduronidase. The total excretion of Glycosaminoglycans in the urine increases. Also, hyperexcretion of dermatan sulfate and heparan sulfate is observed. The activity of aL-iduronidase is measured in leukocytes or in the culture of skin fibroblasts using artificial fluorogenic or chromogenic substrates.

Prenatal diagnosis is possible by measuring the activity of aL-iduronidase in a chorionic villus sampling at the 9-11th week of pregnancy and / or determining the spectrum of GAG in the amniotic fluid at the 20-22nd week of pregnancy. For families with a known genotype, it is possible to carry out DNA diagnostics.

Functional research

When X-ray in patients with the syndrome, the Hurler shows typical signs of the so-called multiple bone dysostosis. With MRI of the brain, multiple cysts are found in periventricular regions of white matter of the brain, corpus callosum, less often basal ganglia, signs of hydrocephalus; in rare cases - brain malformations in the form of lissencephaly, malformation of the Dandy Walker.

Differential diagnostics

Differential diagnosis is performed both within the mucopolysaccharidosis group and with other lysosomal accumulation diseases: mucolipid doses, galactosialidosis, sialidosis, mannosidosis, fucosidosis, GM1-gangliosidosis.

Treatment of mucopolysaccharidosis type I

In the Gurler syndrome, bone marrow transplantation is shown, which can dramatically change the course of the disease and improve its prognosis, but this procedure has many complications and is carried out in the early stages of the disease, mainly at the age of up to 1.5 years. Currently, a drug has been developed for enzyme replacement therapy of mucopolysaccharidosis I-aldurazim (Aldurazyme, Genzyme), which is registered in Europe, USA, Japan; it is used to treat extra-neural disorders in mucopolysaccharidosis I. The drug is indicated for the correction of soft forms of mucopolysaccharidosis I (the syndromes of Hurler-Scheye and Sheie). The drug is administered weekly, intravenously, drip, slowly, at a dose of 100 units / kg. For treatment of the Hurler syndrome with severe neurologic complications, the drug is less effective, since the enzyme does not penetrate the blood-brain barrier.

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