| disease | Mucopolysaccharidosis |
| alias | Macopolg Sacrotein MPS |
Mucopolysaccharides (macopolg sacrotein MPS) are one of the main components of the bone matrix and connective tissue. The correct name for mucopolysaccharides should be glycosaminoglycans (GAG), which are repeating sequences formed by disaccharide units composed of uronic acid and acetylated amino sugars or their sulfate esters. Known GAGs in mammals include chondroitin-4-sulfate (C4S), chondroitin-6-sulfate (C6S), dermatan sulfate (SD), keratan sulfate (KS), heparin (HP), heparan sulfate or heparitin sulfate (HS), collectively referred to as heparin-like substances, and hyaluronic acid (HA), totaling seven types. These glycosaminoglycans, when linked to core proteins, form proteoglycans (PG). The old name for proteoglycans is mucoproteins. Glycosaminoglycans are also known as acid mucopolysaccharides (AMPS).
Mucopolysaccharidosis is caused by the deficiency of acid mucopolysaccharide-degrading enzymes, leading to incomplete degradation and accumulation of their products in the body. Due to the different distributions of various components in the body and the deficiency of different enzymes, mucopolysaccharidosis manifests differently clinically. Based on metabolic products and clinical manifestations, it is divided into 8 types, some of which have several subtypes.
Mucopolysaccharidosis (mucopolysacharidosis) is a disorder of proteoglycan (mucoprotein, PG) degradation, leading to the accumulation of different acid mucopolysaccharides in the body and resulting in various pathological changes. Clinically, it is classified into different types, as described below.
Mucopolysaccharides deposit in fibroblasts, staining them into balloon-like cells called Hurler cells, which are found in the reticular cells of the liver, spleen, and lymphoid tissues. Similar accumulations occur in chondrocytes and osteoblasts, the central nervous system and peripheral ganglia, retinal cells, and corneal cells. Deposits in the endocardium form patchy thickening, and deposits are also found in the walls of the aorta, pulmonary artery, coronary arteries, and arteries of the brain, kidneys, liver, spleen, and limbs.
Development is normal after birth, with signs gradually appearing before the age of 1. After 1 year of age, developmental delays become evident, and skeletal deformities gradually worsen. The head is large, with a prominent forehead and a boat-shaped skull deformity. The neck is short, with kyphosis in the lower thoracic and upper lumbar spine. The nasal bridge is flat and broad, the lips are large and everted, the tongue is large and the mouth is open, the teeth are sparse and small, and the gums are thickened. The facial features are coarse, with an indifferent expression and intellectual disability. The hair is often coarse and dark. Most patients have joint contractures, broad and short palms and fingers, genu valgum and hip valgus, and flat feet. The abdomen is distended, with hepatosplenomegaly or hernia, but liver function is normal. Corneal clouding is present. Nasopharyngeal tube deformities, deafness, and susceptibility to otitis media, upper respiratory infections, and pneumonia are common. The chest is deformed. Due to the deposition of mucopolysaccharides in blood vessel walls, sudden coronary artery occlusion or myocardial infarction may occur.bubble_chart Etiology
Mucopolysaccharides deposit within fibroblasts, staining them into balloon-like cells known as Hurler cells, which are found in the reticular cells of the liver, spleen, and lymphoid tissues. Similar accumulations occur in chondrocytes, osteoblasts, the central nervous system, peripheral ganglia, retinal cells, and corneal cells. Deposits in the endocardium form patchy thickenings, and accumulations are also present in the walls of the aorta, pulmonary artery, coronary arteries, as well as the arteries of the brain, kidneys, liver, spleen, and limbs.
I. Mucopolysaccharidosis Type I
Mucopolysaccharidosis Type I has two subtypes, both of which are deficiencies of α-1 iduronidase (α-Iduronidase), caused by mutations in certain alleles of this enzyme.
Mucopolysaccharidosis I-H (MPS-IH), also known as Hurler syndrome, is associated with the Hurler gene located on chromosome 1. In mucopolysaccharides, dermatan sulfate and heparan sulfate contain L-iduronic acid components, the degradation of which requires α-L-iduronidase. Due to the deficiency of this enzyme, the degradation of its precursors is blocked, leading to their accumulation in the body. Dermatan sulfate and heparan sulfate are structural components of the cornea, cartilage, bones, skin, tendons, heart valves, and vascular connective tissues, mostly found in the outer layers of cell membranes. Upon cell death, the accumulated mucopolysaccharides can be released.
Diagnosis can be made based on clinical manifestations and X-ray bone changes, combined with the following laboratory tests.
- Peripheral blood leukocytes, lymphocytes, and bone marrow blood cells may show metachromatic granules of varying sizes and shapes, sometimes appearing vacuolated. These granules, known as Reilly granules, have been confirmed to be mucopolysaccharides.
- Patients excrete large amounts of acidic mucopolysaccharides in their urine, which can exceed 100 mg/24 hours (normal range: 3–25 mg/24h). A definitive diagnosis is confirmed by identifying dermatan sulfate and heparan sulfate in the urine. Patients exhibit a deficiency of α-iduronidase in leukocytes, fibroblasts, liver cells, and urine.
Differential diagnosis should exclude dwarfism caused by skeletal developmental delays, such as cretinism (congenital hypothyroidism) and multiple sulfatase deficiency (characterized by increased urinary sulfides and sulfated cholesterol).
Mucopolysaccharidosis Type II (Hunter syndrome) is an X-linked recessive disorder. The disease is caused by a deficiency of iduronate-2-sulfatase. Clinically, it presents as severe (A) or mild (B) forms. The enzyme deficiency impairs the degradation of dermatan sulfate (DS) and heparan sulfate, leading to their accumulation in the body and excretion in urine at a ratio of 1:1.
Clinically, the severe form resembles MPS-IH, with most patients dying before adolescence. Onset occurs between ages 2–6, featuring distinctive facial features and skeletal deformities, but without the bird-beak spinal deformity. Although mucopolysaccharides deposit in corneal endothelial cells, corneal clouding is absent. The skin shows nodular thickening, particularly on the arms and chest. Hearing impairment begins in early childhood, progressing to deafness, along with retinal degeneration and cardiac enlargement with systolic and diastolic murmurs. The condition may culminate in congestive heart failure or myocardial infarction, often the cause of death. Intellectual impairment varies widely, ranging from severe to grade I. Hepatomegaly and joint stiffness are common. The mild form lacks intellectual disability and has milder clinical symptoms.
Diagnosis is based on a 1:1 ratio of dermatan sulfate to heparan sulfate excretion in urine. Fibroblast culture shows 35S-mucopolysaccharide accumulation, which can be corrected by adding purified Hunter syndrome factor, indirectly confirming iduronate sulfatase deficiency. Direct measurement of serum and intracellular enzyme activity provides definitive diagnosis. Prenatal diagnosis via amniotic fluid cell enzyme activity testing can guide family planning.
III. Mucopolysaccharidosis Type III
Mucopolysaccharidosis type III (Sanfilippo syndrome) is characterized by heterogeneity in type III, with different enzyme deficiencies in each subtype. Type IIIA is caused by a deficiency of sulfamidase (formerly known as heparan-N-sulfatase), type IIIB by a deficiency of α-N-acetylglucosaminidase, type IIIC by a deficiency of N-acetyltransferase, and type IIID by a deficiency of glucosamine-6-sulfatase. These enzymes are all required for the degradation of heparan sulfate (HS), so their deficiencies can lead to the accumulation of heparan sulfate (HS) in the body and increased excretion of HS in the urine. The lack of these enzymes primarily causes varying degrees of damage to the nervous system, including ballooning degeneration of neurons, ventricular enlargement, increased levels of heparan sulfate, glycolipids, and GM-gangliosides in brain tissue, and injury to the basal ganglia.
The clinical manifestations include normal psychomotor development within the first year after birth. At 2–3 years of age, behavioral and language impairments, intellectual disability, coarse facial features, joint stiffness, and excessive hair growth gradually appear. Hepatosplenomegaly is present. Neurological symptoms manifest as progressive athetosis and spastic paralysis of the limbs. There is no difference in clinical manifestations among the four subtypes, except that subtype IIIA progresses more rapidly. This type does not involve corneal clouding or cardiac abnormalities.
Diagnosis is based on increased excretion of heparan sulfate in urine and the toluidine blue test.
bubble_chart Clinical Manifestations
After birth, development was normal, but signs gradually appeared before the age of 1. After the age of 1, developmental delays became evident, and skeletal deformities progressively worsened. The head was large, with a prominent forehead and a boat-shaped skull deformity. The neck was short, with kyphosis in the lower chest and upper lumbar spine. The nasal bridge was flat and wide, the lips were large and everted, the tongue was large with an open mouth, and the teeth were sparse and small with thickened gums. The facial features were coarse, with an indifferent expression and intellectual disability. The hair was often coarse and dark. Most had joint contractures, broad and short palms and fingers, and valgus knees and hips with flat feet. The abdomen was distended, with hepatosplenomegaly or hernia, but liver function was normal. Corneal clouding was present. Nasopharyngeal tube deformities, deafness, and susceptibility to otitis media, upper respiratory infections, and pneumonia were observed. The chest was deformed. Due to the deposition of mucopolysaccharides in blood vessel walls, sudden coronary artery occlusion or myocardial infarction could occur.
bubble_chart Auxiliary Examination
X-ray examination: The skull shows a shoe-shaped sella turcica, with a scaphoid-shaped skull, dense cranial plates, premature closure of cranial sutures, and delayed closure of the anterior fontanel. The paranasal sinuses are underdeveloped with reduced pneumatization. The mandible is short and wide, with small and flat condyles and shallow glenoid fossae. The ribs are slender at the vertebral ends and widened at the sternal ends, appearing "ribbon-like." The thoracolumbar junction of the spine exhibits angular kyphosis. Vertebral anomalies include defects at the upper anterior margins and beak-like bony projections at the lower margins. Some vertebrae are underdeveloped, small, and irregular, with posterior displacement, particularly severe in the first and second lumbar vertebrae.
The changes in the long bone diaphyses are more pronounced in the upper limbs than in the lower limbs, with the diaphyses being thick and short, tapering at both ends, and cortical thinning. The humeral diaphysis shows "proximal dorsal angulation," and the distal ends of the ulna and radius exhibit a "V"-shaped inclination. The femoral neck is slender with coxa valga, and the femoral head is flat, small, and dense. The metacarpals and phalanges are short and thick, with wide distal ends and pointed proximal ends forming a triangular shape, while the distal phalanges are claw-like. Interphalangeal joint contractures are present, and the carpal and tarsal bones show delayed ossification with irregular shapes.
