Mucopolysaccharidosis in children

Introduction to mucopolysaccharide storage disease in children Mucopolysaccharidosis (MPS) is a group of congenital genetic diseases. Due to the lack of mucopolysaccharide degrading enzymes, the acid mucopolysaccharide can not be completely degraded, resulting in the accumulation of mucopolysaccharides in different tissues of the body, resulting in a series of clinical symptoms such as skeletal deformities and mental disorders. And signs. basic knowledge Sickness ratio: 0.001%-0.002% Susceptible people: children Mode of infection: non-infectious Complications: deafness

Causes of mucopolysaccharidosis in children

(1) Causes of the disease

The disease is autosomal recessive or sexually linked recessive inheritance, which is related to the disorder of acid mucopolysaccharide metabolism. In the patient, due to the lack of lysosomal -L-iduronidase, the mucopolysaccharide is Decomposition has obstacles, and there are incompletely decomposed mucopolysaccharide deposits in the cells of the body, which are discharged from the urine. This abnormal deposition involves various organs and tissues, such as heart, brain, liver, spleen, etc., in heart valves, blood vessels, Hurler cells with mucopolysaccharide deposition can be seen in the meninges, cornea, periosteum and other tissues. This is the pathological basis of various clinical manifestations.

(two) pathogenesis

Mucopolysaccharide is a complex macromolecule composed mainly of uronic acid and hexosamine. It is distributed in the matrix of connective tissue and is an important component of cartilage, cornea, blood vessel wall and subcutaneous tissue. After carcinogenesis of mucopolysaccharidosis, cartilage Fibroblasts of collagen tissue such as sarcolemma, tendon, blood vessels, heart valves, muscles, meninges, reticuloendothelial tissues and subcutaneous tissues are swollen, which are filled with mucopolysaccharide particles, liver, spleen, kidney, lymph nodes and certain In the parenchymal cells of the endocrine organs, similar substances are deposited, and the ganglion cells of the central nervous system and peripheral nerves are also swollen, but the filling material is mainly neuroglycosides, and the mucopolysaccharide content has little or no mucopolysaccharide.

It is known that there are 9 kinds of mucopolysaccharides, 3 of which are related to the pathogenesis of mucopolysaccharides, namely sulphuric acid skin, heparan sulfate and keratan sulfate. The release of mucopolysaccharide in normal urine is 5-15 mg per day, of which sulfuric acid skin And heparan sulfate account for about 10%, and keratan sulfate only accounts for a small amount (0.1mg/kg). In mucopolysaccharidosis, there may be one or two mucopolysaccharide urinary excretion associated with metabolic disorders. In infants and children, the amount of mucopolysaccharide in urine is more, but it is not as high as mucopolysaccharidosis. Mucopolysaccharide is also seen in other diseases such as multiple exostosis, rheumatic fever, tumor, horse syndrome, high Blood pressure, cirrhosis, glomerulonephritis and collagen disease, but its mucopolysaccharide composition is different from this disease.

The degradation of polysaccharide chains must be carried out in lysosomes. Normal lysosomes contain many kinds of glycosidases, sulfate lipases and acetate transferases. Different mucopolysaccharides require different lysosomal enzymes for degradation. There are 10 known species. Lysosomal enzymes participate in the degradation process, and any defect of the enzyme will cause the decomposition of aminoglucan chains, accumulate in the lysosomes, and the urinary excretion increases. The activity of the deficient enzymes in children is often only normal. 1% to 10%.

Mucopolysaccharidosis except type II is X-linked recessive inheritance, and the rest are autosomal recessive genetic diseases, and the enzyme defects of various types of mucopolysaccharidosis.

Prevention of mucopolysaccharide storage disease in children

Mucopolysaccharidosis is caused by congenital defects of lysosomal acid hydrolase. In addition to complying with the Marriage Law, avoiding marriage of close relatives and reducing the incidence of genetic diseases in offspring, there is no effective preventive measure.

There are unfamiliar siblings in the family who should be checked regularly for an early diagnosis. If a family needs to have a second child, genetic counseling should be carried out and conditions can be used for prenatal diagnosis. Most of the mucopolysaccharidosis types can be analyzed for amniotic fluid cell cDNA for prenatal diagnosis and termination of pregnancy if necessary.

Pediatric mucopolysaccharide storage complications Complications

1. Growth retardation: Children's age and gender height are lower than the median minus 2 standard deviations compared with the same age and gender reference population criteria; various progressive distortions of bone affect motor function.

2. Smart backwardness, language and behavioral obstacles.

3. Liver, splenomegaly, deafness, oppressive paraplegia and respiratory paralysis in the late stage, congestive heart failure and so on.

Symptoms of mucopolysaccharide storage disease in children Common symptoms Nasal low fragile X syndrome Short neck splenomegaly Joint ankylosis Corneal opacity Deafness Intelligent disorder Paraplegia Heart enlargement

Mucopolysaccharide is the main component of connective tissue. Therefore, mucopolysaccharide metabolism affects the whole body. The patient is usually normal at birth. With the increase of age, the clinical symptoms are gradually obvious. The common feature is that there is growth backwardness in the first year or so, except type IV. In addition to the type VI, the patients are accompanied by intelligent backwardness. Due to the different severity of each type of disease, they also have their own clinical features. They need to be identified in the diagnosis, mainly characterized by short stature and special face, indifferent expression, big head, and ugly face. Small eye cracks, wide eye distance, low flat nose, large nostrils, thick lips, forehead and double hernias, many hairs with low hairline, short neck, most corneal opacity, progressive joint distortion, thoracic deformity, spine Kyphosis or scoliosis, knee valgus, claw-shaped hands, early liver, splenomegaly, deafness, heart enlargement, etc.

At present, enzyme defects causing mucopolysaccharidosis have been identified and are classified into 6 types.

1. Mucopolysaccharidosis type I-H (Hurler syndrome)

This type is the most serious type, often died in the age of 10, due to the lack of -L-iduronidase, resulting in the accumulation of dermatan sulfate and heparin sulfate in the body, whole body organs such as cornea, cartilage , bone, skin, myocardial intima, vascular connective tissue, etc. are affected, clinically low intelligence, ugly face, hepatosplenomegaly, bone lesions, cardiovascular disease, corneal opacity and deafness, peripheral blood leukocytes, lymphocytes can be seen different Dyeing granules of different sizes and shapes, sometimes vacuolated, excreted a large amount of acid mucopolysaccharide (>100mg/d, normal 3~25mg/d).

The disease is an autosomal recessive genetic disease. The -L-iduronidase gene has been identified. It is located on chromosome 4p16.3 and has 14 exons. Many gene mutations have been found in it. Phenotypic and genotypic analysis revealed that the mutation of -L-iduronidase gene resulted in a severe deficiency of enzyme activity called mucopolysaccharidosis type I-H, such as the presence of a stop codon in coding region 70, or 402. Mutations that result in moderate or mild decline in enzyme activity are clinically classified as mucopolysaccharidosis type I-S.

Mucopolysaccharidosis type I-S (Scheie syndrome), originally classified as mucopolysaccharidosis type V, is a moderately serious type of mucopolysaccharidosis, genetic type and pathogenic gene with mucopolysaccharidosis type I-H, intelligent development, Clinical symptoms usually appear after 5 years of age.

2. Mucopolysaccharidosis type II (Hunter syndrome)

The clinical weight is similar to the mucopolysaccharide type I-H. It starts from 2 to 6 years old and has a special face and skeletal deformity. However, the spine has no beak-like malformation, no corneal opacity, and the patient is intelligently backward. It is progressive deafness and can be congested. Sexual heart failure, hepatosplenomegaly.

This type is X-linked recessive inheritance. The cause is the deficiency of iduronate sulfatase, which causes the metabolism of dermatan sulfate and heparin sulfate. The disease-causing gene has been cloned and located in the Xq28 region of the chromosome, near the fragile X syndrome area. There are 9 exons. Genetic analysis found that many patients have large fragment deletions, other forms have a little mutation, small fragments are missing or inserted, and the clinical phenotype is consistent with genotype. There are serious lesions, such as at nucleotide 1129. Insertion of 22 bases or those with gene deletions is more serious, and those with a little mutation are relatively mild clinical manifestations.

3. Mucopolysaccharidosis type III (Sanfilippo syndrome)

Clinically, it can be divided into 4 subtypes, which are caused by 4 different enzyme defects, IIIA is a lack of sulfated amidase, IIIB is a lack of -N-acetylhexosaminidase, and type IIIC is -glucosamine. N-acetyltransferase is deficient, and type IIID is N-acetylglucosamine-6-sulfatase deficiency. The above four enzymes are enzymes required for heparin sulfate degradation. Therefore, when these enzymes are deficient, heparin sulfate is caused. Accumulation in the body, while the amount of urinary discharge increased, the clinical development of children in the first year of age is still normal, and later gradually appear language, behavioral disorders, growth and development, in childhood, neurological degenerative lesions are more obvious, with hepatosplenomegaly , suffocating, ugly face, strong joints and so on.

The disease type 4 is an autosomal recessive hereditary disease, which causes heparin sulfate to accumulate in the body. The IIID-type pathogenic gene glucosamine-6-sulfatase has been cloned and located on chromosome 12q14.

4. Mucopolysaccharidosis type IV (Morquio syndrome)

The clinical features are similar to the mucopolysaccharidosis type I-H, but there is no mental retardation, obvious growth disorders, skeletal deformities, X-ray shows typical mucopolysaccharidosis, the spine has a beak-like prominent change, the vertebrae are flat, and the ribs are floating. Chicken breasts, etc., ugly face, short nose, large mouth, poor tooth development, corneal opacity, normal puberty development, spinal cord compression symptoms with age, oppressive paraplegia and respiratory paralysis.

There are two subtypes of mucopolysaccharidosis type IV, mucopolysaccharidosis type IV A is N-acetylgalactosamine-6-sulfatase deficiency, mucopolysaccharidosis type IV B is -galactosidase deficiency, causing keratan sulfate And chondroitin sulfate degradation disorder, resulting in the accumulation of these substances in cells and tissues, the two subtypes have the same phenotype, are autosomal recessive hereditary diseases, the full length of N-acetylgalactosamine-6-sulfatase The cDNA has been cloned, the gene is located on chromosome 16q24.3, and some mutation sites have been found on this gene. The -galactosidase gene has also been cloned, located on chromosome 3q21.33, and the mutation site was found.

5. Mucopolysaccharidosis type VI (Maroteaux-Lamy syndrome)

The clinical manifestations are similar to those of mucopolysaccharidosis type I-H, but there is no intelligence behind, and a large amount of dermatan sulfate is excreted in the urine. The causative gene is N-acetylgalactosamine-4-sulfatase, and the gene is located on chromosome 5q13-5q14. It is an autosomal recessive hereditary disease.

6. Mucopolysaccharidosis type VII

The clinical manifestations are the same as mucopolysaccharidosis type I-H, but the degree of individual severity is different, the variation is larger, and the lighter can be without intelligence. This type is an autosomal recessive hereditary disease caused by -glucuronidase deficiency. 4/6 chondroitin sulfate was deposited in the body, and the gene was located on chromosome 7q21.11 with 12 exons.

Examination of mucopolysaccharidosis in children

1. Urine mucopolysaccharide determination is usually done by toluidine blue method, and the patient's urine is positive.

2. Acetate fiber membrane electrophoresis can distinguish the type of mucopolysaccharide excreted in the urine and carry out typing.

3. Enzymatic analysis The mucin-polysaccharide disease can be classified according to the determination of specific enzyme activity in leukocytes, fibroblasts, and the type of mucopolysaccharide excreted in the urine.

4. Peripheral white blood cells, lymphocytes and bone marrow blood cells can be seen in different sizes of differently stained, deep-stained particles with different forms, sometimes vacuolated, and the particles are called Reilly particles, which have been confirmed to be mucopolysaccharides.

5. X-ray examination of the bone is loose, the cortical bone is thin, the skull is enlarged, the saddle is enlarged, the kyphosis or scoliosis is present, the vertebral body is wedge-shaped or flat, and the chest and the lower front edge of the lumbar vertebral body are fish-like. The anterior process or the bird's beak is sudden, the rib spine end is small, the sternum end is widened, and it is in the shape of a ribbon. The metacarpal bone is short and thick, the basement is sharpened, the distal end of the phalanx is narrow, and the ossification center of the wrist is delayed.

6. B-ultrasound can be found in the liver, spleen and heart enlargement, myocardial function decline.

7. Electrical audiometry to check hearing loss.

8. EEG shows abnormal brain waves.

9. Intelligence detection has decreased intelligence.

Diagnosis and identification of mucopolysaccharide storage disease in children

diagnosis

1. According to clinical features, special face and signs, X-ray film and urine mucopolysaccharide positive, can make a diagnosis.

2. Family history The family history of patients with mucopolysaccharides is helpful for early diagnosis.

Differential diagnosis

The clinical diagnosis of various types of mucopolysaccharidosis is based on clinical manifestations, mainly X-ray multiple skeletal dysplasia and different mucopolysaccharides excreted in the urine. Considering this disease, the diagnosis must be related to the lack of enzymes, and the disease should be associated with rickets. Congenital hypothyroidism, various types of visceral accumulation disease, mannose accumulation disease, GML ganglioside deposition disease, etc. The clinical manifestations of these diseases are similar to those of mucopolysaccharidosis, but the urinary mucopolysaccharide emissions are not increase.

1. Multiple phospho-esterase deficiency may have very mild clinical manifestations and X-ray features of mucopolysaccharidosis, while intelligence and nervous system damage progress more rapidly than Hurler and Hunter's disease. Dyed leukodystrophy is often suspected to be mucopolysaccharide due to hepatosplenomegaly, and mucopolysaccharides and sulphur lipids are often positive in urine.

2. GML gangliosidosis GML gangliosidosis refers to the general hexose ganglioside ganglioside disease, which is a lipid deposition disease and has similarities with the clinical manifestations of mucopolysaccharidosis. It usually occurs in infancy, with mental retardation, decreased muscle tone, hepatosplenomegaly, and more than 50% of retinal cherry red spots.

3. Mannosidosis (mannosidosis) characterized by psychomotor retardation (psychomotor retardation), but also Hurler disease face, hepatosplenomegaly, low muscle tone and mild multiple bone dystrophy, but no mucopolysaccharide in urine It is a mannose-containing oligosaccharide.

4. Fucosidosis has a rough face, hepatosplenomegaly and severe mental retardation and multiple bone dystrophy. The fructose-containing oligosaccharides are deposited in the tissues and discharged from the urine.

5. Aspartyl Glucosamineuria (aspartylglucosaminuria) is often confused with Hurler and Hunter syndrome. The child is born normally, and soon the progressive face is rough, the nose is wide and flat or concave, the nostrils are forward, and the lips are thick. Short neck, liver and spleen, etc., urine excretion of asparagine glucosamine.

6. Mucolipidosis Mucolipidosis should also be differentiated from mucopolysaccharidosis. The clinical manifestations of mucinous disease type I and type II are similar to those of Hurler syndrome, and the multiple retinal malnutrition is abnormal. Cherry erythema is more common; there are progressive neurodegenerative lesions with myoclonic seizures, muscle atrophy, often danced hand and foot hyperkinetic movements and nystagmus, and urinary excretion of salicylic acid combined with oligosaccharides.

7. Spondylo-epiphyseal dysplasia is often mixed with mucopolysaccharidosis type IV, but the mucopolysaccharide in the urine is negative.

8. The clinical manifestations of Kneist syndrome are very similar to those of mucopolysaccharidosis type IV. Excretion of keratan sulfate in the urine, but the mucopolysaccharidosis type IV deficiency of this syndrome is N-acetyl-galactoside-6-sulfatase and - Galactosidase is normal and its etiology is not clear.

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