Mucopolysaccharidosis type I: causes, symptoms, diagnosis, treatment

Mucopolysaccharidosis type I (Synonyms: lysosomal aL-iduronidase deficiency, Hurler, Hurler-Scheie and Scheie syndromes).

Mucopolysaccharidosis type I is an autosomal recessive disorder resulting from decreased activity of lysosomal aL-iduronidase, which is involved in the metabolism of glycosaminoglycans. The disease is characterized by progressive disorders of the internal organs, skeletal 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 an average population incidence of 1 in 90,000 live births. The average incidence of Hurler syndrome in Canada is 1 in 100,000 live births, Hurler-Scheie syndrome is 1 in 115,000, and Scheie syndrome is 1 in 500,000.

Classification

Depending on the severity of the clinical symptoms of the disease, three forms of mucopolysaccharidosis I are distinguished: Hurler, Hurler-Scheie and Scheie syndromes.

Causes of mucopolysaccharidosis type I

Mucopolysaccharidosis I is an autosomal recessive disease resulting from 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 locus 4p16.3. More than 100 different mutations in the IDUA gene are currently known . The predominant number of known mutations are point mutations in different exons of the IDUA gene . Two common mutations are characteristic of Caucasians: Q70X and W402X.

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

Pathogenesis of mucopolysaccharidosis type I

The enzyme aL-iduronidase is involved in the metabolism of two glycosaminoglycans - dermatan sulfate and heparan sulfate. Since iduronic acid is a part of dermatan sulfate and heparan sulfate, in this disease the intralysosomal breakdown of these glycosaminoglycans is impaired, which accumulate in lysosomes everywhere: in cartilage, tendons, periosteum, endocardium and vascular wall, liver, spleen and nervous tissue. Edema of the pia mater causes partial occlusion of the subarachnoid spaces, which leads to progressive internal and external hydrocephalus.

The cells of the cerebral cortex, thalamus, trunk, and anterior horns are affected. Joint stiffness is the result of metaphyseal deformation, and the thickening of the joint capsule is secondary to the deposition of glycosaminoglycans and fibrosis. Airway obstruction is the result of tracheal narrowing, vocal cord thickening, and excess edematous tissue in the upper respiratory tract.

Symptoms of mucopolysaccharidosis type I

Mucopolysaccharidosis, type IH (Hurler syndrome)

In patients with 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 some cases, a slight enlargement of the liver, umbilical or inguinal-scrotal hernias are observed from birth. The diagnosis is usually established between 6 and 24 months of age. Characteristic changes in facial features according to the gargoyilism type become obvious by the end of the first year of life: a large head, prominent frontal tubercles, a wide bridge of the nose, short nasal passages with outwardly turned 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 gibbus), chronic otitis and frequent infectious diseases of the upper respiratory tract. Almost all patients with Hurler syndrome, as well as with other types of mucopolysaccharidosis, have dense skin to the touch. Hypertrichosis is common. In isolated patients under 1 year of age, the disease debuted with the development of acute heart failure caused by endocardial fibroelastosis. As the disease progresses, symptoms are added that indicate the involvement of internal organs, the cardiopulmonary, central and peripheral nervous systems in the pathological process. The leading neurological symptoms are decreased intelligence, delayed speech development, changes in muscle tone, tendon reflexes, damage to the cranial nerves, 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, heart murmurs appear, later acquired aortic and mitral heart defects are formed. By the end of the second year of life, hepatosplenomegaly and characteristic skeletal abnormalities of the multiple dysostosis type are detected: short neck, growth retardation, total platyspondyly, lumbar gibbus, stiffness of small and large joints, hip dysplasia, valgus deformity of the joints, changes in the hands such as a "clawed paw", deformation of the chest in the form of a barrel or bell-shaped. Progressive corneal opacity, megalocornea, glaucoma, congestive optic discs and / or their partial atrophy are often observed.

Early radiographic signs are rib deformation (of the "oar" type) and ovoid deformation of the vertebral bodies, excessive trabeculation of the diaphyses of long tubular bones in combination with its insufficiency in the area of the metaphyses and epiphyses. As the disease progresses, macrocephaly is formed with thickening of the bones of the cranial vault, premature closure of the lambdoid and sagittal sutures of the skull, reduction of the orbits, and expansion of the back of the sella turcica. Patients usually die before the age of 10 from airway obstruction, respiratory infections, and heart failure.

Mucopolysaccharidosis, type IH/S (Hurler-Scheie syndrome) The clinical phenotype of Hurler-Scheie syndrome is intermediate between Hurler and Scheie syndromes, characterized by slowly progressive disorders of the internal organs, skeletal system, mild intellectual disability or absence thereof. The disease usually debuts at the age of 2-4 years. The main clinical disorders are heart damage and the development of obstructive upper respiratory tract syndrome. Some patients have total spondylolisthesis, which can lead to spinal cord compression. Most patients survive into their third decade of life. The main cause of death is acute cardiovascular and pulmonary failure.

Mucopolysaccharidosis, type IS (Scheie's syndrome)

In the initial classification of mucopolysaccharidoses, before the discovery of the primary biochemical defect in Scheie syndrome, it was classified as a separate type - mucopolysaccharidosis V. Scheie syndrome is the mildest in the course of the disease among other forms of mucopolysaccharidosis I, it is 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. The leading clinical symptoms are skeletal disorders in the form of joint stiffness with the development of carpal tunnel syndrome. Ophthalmologic disorders include corneal opacity, glaucoma and pigmentary degeneration of the retina. Sensorineural hearing loss is a late complication of the disease. Obstructive syndrome of the upper respiratory tract often leads to the development of sleep apnea, which in some cases requires the installation of a tracheostomy. Cervical myelopathy is less common than in Hurler-Scheie syndrome. Aortic stenosis with circulatory failure and hepatosplenomegaly are often observed. Intelligence is not affected in this syndrome or mild cognitive impairment is observed.

Diagnosis of mucopolysaccharidosis type I

Laboratory research

Confirmatory biochemical diagnostics of mucopolysaccharidosis I involves determining the level of urinary glycosaminoglycan excretion and measuring the activity of lysosomal aL-iduronidase. Total excretion of Glycosaminoglycans in urine increases. Hyperexcretion of dermatan sulfate and heparan sulfate is also observed. The activity of aL-iduronidase is measured in leukocytes or skin fibroblast culture using artificial fluorogenic or chromogenic substrates.

Prenatal diagnosis is possible by measuring the activity of aL-iduronidase in chorionic villus biopsy at 9-11 weeks of pregnancy and/or determining the GAG spectrum in amniotic fluid at 20-22 weeks of pregnancy. For families with a known genotype, DNA diagnostics are possible.

Functional studies

X-ray examination of patients with Hurler syndrome reveals typical signs of so-called multiple bone dysostosis. MRI of the brain reveals multiple cysts in the periventricular areas of the white matter of the brain, the corpus callosum, and less frequently the basal ganglia, signs of hydrocephalus; in rare cases, brain defects such as lissencephaly and Dandy-Walker malformation.

Differential diagnostics

Differential diagnostics are carried out both within the group of mucopolysaccharidoses and with other lysosomal storage diseases: mucolipidoses, galactosialidosis, sialidosis, mannosidosis, fucosidosis, GM1 gangliosidosis.

Treatment of mucopolysaccharidosis type I

In case of Hurler syndrome, bone marrow transplantation is indicated, which can radically change the course of the disease and improve its prognosis, however, 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 for enzyme replacement therapy of mucopolysaccharidosis I has been created - aldurazyme (Aldurazyme, Genzyme), which is registered in Europe, the USA, Japan; it is used to treat extraneural disorders in mucopolysaccharidosis I. The drug is indicated for the correction of mild forms of mucopolysaccharidosis I (Hurler-Scheie and Scheie syndromes). The drug is administered weekly, intravenously, drip, slowly, at a dose of 100 U/kg. For the treatment of Hurler syndrome with severe neurological complications, the drug is less effective, since the enzyme does not penetrate the blood-brain barrier.

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