Introduction to mucopolysaccharidosis

Introduction

Mucopolysaccharidosis (MPS) is a group of lysosomal accumulation diseases caused by the defects of lysosomal hydrolase, which hinders the degradation of acid mucopolysaccharide (glucosaminoglycan), and the accumulation of mucopolysaccharide in the body causes a A series of clinical symptoms. Patients with mucopolysaccharidosis accumulate in the tissues or organs such as bone and cartilage due to excessive mucopolysaccharide, which affects the normal development of these tissues or organs. Excess mucopolysaccharides are excreted from the urine, and a series of clinical symptoms occur. And imaging performance. Mucopolysaccharidosis is a congenital or primary metabolic syndrome.

Cause

(1) Causes of the disease

1. Mucopolysaccharidosis type I (Hurler syndrome) is a chromosomal recessive disease caused by the lack of α-L-iduronase (α-L-iduronidase), which can be divided into three subtypes. :

(1) Hurler syndrome: that is, MPSIH type.

(2) Scheie syndrome is MPS-IS type, that is, 7 types of Zhongyuan V type (MPS-V type).

(3) Hurler-Sheie syndrome, the change is between the first two types.

2. Mucopolysaccharidosis type II (Hunter syndrome) is a concomitant (X) linked hereditary disease, only found in men, due to the lack of iduronate sulphate in the body, clinical manifestations and X-ray examination MPS-1, but its clinical progress is slower than the former, clinical manifestations are lighter than the former, this type is based on clinical manifestations, and is divided into two subtypes: 1MPSIIA, also known as severe type; 2MPSIIB, also known as mild type.

3. Mucopolysaccharidosis type III (Sanfilippo syndrome) formerly known as polydystrophic oligophrenia, is an autosomal recessive hereditary disease, lack of multiple enzymes in the body, the characteristic clinical manifestations of progressive mental retardation Others, such as face and body changes, vary in severity. According to the lack of enzymes and clinical manifestations, it can be divided into four subtypes, namely MPSIIIA, MPSIIIB, MPSIIIC and MPSIIID.

4. Mucopolysaccharidosis type IV (Morquio syndrome) is a more common mucopolysaccharidosis, which is autosomal recessive. Clinical manifestations are unique. This model is divided into 2 subtypes:

(1) MPSIVA type, the related lack of enzyme is N-acetyl-galactosamine-6-sulfate sulfatase.

(2) MPSIVB type, the lack of enzyme is beta-galactosidase (bata-galactosidase). The severity of the clinical manifestations of the two subtypes may vary greatly, and the type A disease is usually more serious.

5. Mucopolysaccharid storage disease type V is considered to be the Seheie type of mucopolysaccharidosis type I. Unlike Hrular syndrome, there is no serious corneal opacity, and opacity is peripheral, and the patient's intelligence is normal. The body is normal or slightly short, the life is basically normal, but there are hairy, joints and rigidity. The back column and the skull X-ray showed only slight changes.

6. Mucopolysaccharidosis type VI (Maroteaux-Lamy syndrome) or arylsulfatase B deficiency (anglsulfatase B deficiency). For autosomal recessive diseases, the lack of enzymes is aryl sulfatase. This type is basically similar to Hurler syndrome, but the intelligence is normal. Unlike Hurler, some patients still have osteophytes, especially the avascular necrosis of the femoral head. The prognosis of this disease is longer than that of MPSI syndrome. The differential diagnosis with Hurler is mainly based on the longer life span, the intelligence is basically normal, and the osteophytes may have increased dermatan sulfate and heparin sulfate in Hurler urine, while the type VI only increases. In the absence of enzymes, type I lacks α-L-iduronidase, type VI lacks arylsulfatase B.

7. Mucopolysaccharidosis type VII (Sly syndrome) is an autosomal recessive disorder, which is extremely rare. The patient lacks β-glucuronidase, and the patient sees short stature and mental retardation in infancy. Chicken breast, back column and so on. The disease is divided into severe and mild subtypes. The former has early onset and has joint contracture. The latter has a late onset and often has avascular necrosis of the femoral head.

(two) pathogenesis

Except that MPS type II is X-linked recessive inheritance, the inheritance patterns of other types are autosomal recessive inheritance. Defective genes are localized on autosomes, and only homozygous genotypes can develop. Among the children whose parents are heterozygous, the probability of mutation and normality is 25%, and the remaining 50% are carriers of heterozygous genes. Since the defective gene of MPS type II is located on sex chromosome X, only males are ill, and women are genetic carriers. The probability of males becoming sick and females becoming carriers is 50%.

There are many types of genetic mutations that have been confirmed so far, and the differences between different populations are large.

Mucopolysaccharides include 4-sulfate chondroitin, 6-chondroitin sulfate, chondroitin sulfate, heparan sulfate, keratan sulfate, heparin and hyaluronic acid, which are cornea, cartilage, bone, skin, fascia, heart valve and The structural component of vascular connective tissue. The lack of α-iduronidase in the MPSI type, the iduronate sulfatase deficiency in the MPS type II, and the β-glucuronidase deficiency in the MPS VII type all cause degradation of chondroitin sulfate and heparan sulfate. The lack of various enzymes of the MPSIII type can cause degradation of heparan sulfate. The β-galactosidase deficiency of MPSIV type mainly affects the degradation of keratan sulfate. The acyl sulfatase B deficiency of the MPSVI type mainly hinders the degradation of chondroitin sulfate. Various mucopolysaccharide components that cannot be degraded are accumulated in the body and deposited in the above tissues, causing organ damage and dysfunction. At the same time, too much mucopolysaccharide can be continuously discharged from the urine.

symptom

Most of the children are normal at birth, and the growth and development within 1 year of age are basically normal. The age of onset varies with the type of mucopolysaccharidosis. Most of the initial symptoms are ear infections, salivation and colds.

Although the progression of various types of mucopolysaccharidosis differs greatly from the severity of the disease, children have some common characteristics in clinical manifestations, such as short stature, special face and abnormal skeletal system. Most children have joint changes and limited mobility. Multiple organ involvement is seen in all children. Some children have corneal opacity, which can lead to visual impairment or even blindness. Hepatosplenomegaly and cardiovascular involvement are more common. Some children may have progressive mental retardation, umbilical hernia and inguinal hernia, slow growth, hydrocephalus, thickening of the skin, increased hair, chronic salivation, repeated infection of the ear, and hearing damage.

1. Mucopolysaccharide storage disease type I Although there are three subtypes of mucopolysaccharide storage disease I, they are all lack of the same enzyme, but the degree of enzyme deficiency is different. Among them, Hurler syndrome is more common, and the clinical manifestation is the most serious. The symptoms of Scheie syndrome appear later and the disease is the lightest, while Hurler-Scheie syndrome is between the two.

It usually performs normally at birth. After 6 months to 1 year old, the child gradually grows slowly, with a lack of expression, slow response, low intelligence, language childish or even idiot. Large head, forehead protruding into a boat shape, widened eye distance, nasal bridge collapsed or flattened, nostril increased, lip thick and everted, mouth open, tongue large and often extended outside the mouth, teeth small and dull, dentate sparse, irregular . Corneal opacity is common, and severe cases can cause blindness. Otitis media often occurs and causes hearing loss and even deafness. Heart valve and chordae may cause heart enlargement and cardiac insufficiency. Bronchial cartilage lesions can cause narrowing of the respiratory tract and are easily complicated by infection. Abdominal bulging, hepatosplenomegaly, mostly inguinal hernia or umbilical hernia, may have diarrhea or constipation. The hair is thick and thick. Short neck, shrug, short limbs and torso, kyphosis, arched hunchback. Most joints are flexed and tough, with limited mobility, often with deformities such as knees, ankle valgus, and flat feet. The palm and finger are short and short, and carpal tunnel syndrome can occur. Patients with Hurler syndrome often die in childhood, and Scheie syndrome and Hurler-Scheie syndrome can survive to adulthood.

2. Mucopolysaccharide storage disease type II is relatively rare. According to the severity of the disease, it is divided into two subtypes, A and B, of which type A is heavier. All patients were male, with more than 2 to 6 years of age onset. The clinical manifestations were similar to Hurler's syndrome, but it occurred later and progressed slowly. Mental retardation and short stature are not as severe as Hurler syndrome. Severe cases of pigmentary retinitis and optic disc edema from early childhood, but no corneal opacity. Hearing is progressive damage and eventually develops into deafness. Skeletal deformities are mild. Cardiac involvement is more common, mainly manifested as heart valve disease, coronary heart disease and congestive heart failure. Most have obstructive apnea syndrome, hepatosplenomegaly, diarrhea or constipation. Patients often die before the age of 15. Type B patients have milder conditions, and some of the hearing and corneas are normal and there are no skeletal deformities.

3. Mucopolysaccharidosis type III is extremely rare in clinical practice. Although this type can have 4 different enzyme deficiency, its clinical manifestations are very similar, mainly for progressive mental retardation. Among them, the clinical progress of type IIIA of mucopolysaccharidosis is faster. Generally, the intelligence is normal before 4 to 5 years old, and then gradually appears to be unresponsive, mentally retarded, and progressively worse. In severe cases, you can have mental retardation when you are 2 to 3 years old. More hair increases. Other changes, such as special face, short stature, and skeletal deformities, are not serious, and can even be normal. There is usually hearing damage, but no corneal opacity. Generally do not involve the heart. There is no abdominal hernia, and the liver and spleen may have mild swelling. The figure is a little short or basically normal, and very few can be expressed as short stature. There may be limited joint activity, even joint stiffness, and flexion deformities in the hands and other joints.

4. Mucopolysaccharide storage disease type IV prominent manifestations of growth retardation, generally not more than 160cm in adult height. Face and intelligence are normal. The toddler was late, and the gait was unstable when walking. Short neck, shrug. The teething time is later, the dentition is not neat, and the teeth lack luster. Corneal opacity can begin as early as childhood. Hearing is progressive damage. Often there is no heart involvement. The liver and spleen are slightly enlarged and there is no abdominal hernia. Skeletal malformations include frustrations such as chicken breasts, hunchbacks, knee valgus, flat feet, and flexion contractures of the joints, with significant joint relaxation but no joint stiffness. Cervical subluxation can occur, causing spinal cord compression symptoms. Most patients can survive 20 to 30 years of age.

5. Mucopolysaccharid storage disease type V is considered to be the Seheie type of mucopolysaccharidosis type I. Unlike Hrular syndrome, there is no serious corneal opacity, and opacity is peripheral, and the patient's intelligence is normal. The body is normal or slightly short, the life is basically normal, but there are hairy, joints and rigidity. The back column and the skull X-ray showed only slight changes.

6. Mucopolysaccharidosis type VI is extremely rare. The clinical manifestations were similar to those of mucopolysaccharidosis, but the patient's intelligence was normal. Growth retardation usually begins from 2 to 3 years old. Cranial suture closure is early, hydrocephalus can occur, and symptoms of cranial hypertension and spastic hemiplegia are caused. Corneal opacity occurs earlier, with progressive hearing impairment, and severe blindness and deafness. Heart valve disease, hepatosplenomegaly and inguinal hernia are more common. Skeletal malformations are also similar to the MPSI type, but are relatively light, usually with long bones in the upper limbs being more severe than lower limbs. Joint activity is clearly limited. Can have mild joint stiffness. Most patients do not live longer than 10 years.

7. Mucopolysaccharide storage disease type VII is extremely rare. Special faces begin to appear gradually shortly after birth. General intelligence is normal, corneal opacity and hearing damage are more common. Most have hepatosplenomegaly, usually do not involve the heart, no abdominal hernia. Short upper limbs, poor bone development, bone deformities such as chicken chest and knee valgus.

diagnosis

According to medical history, clinical manifestations, laboratory tests and X-ray, CT, magnetic resonance, B-ultrasound, prenatal examination and other means can be diagnosed.

Identification

Sometimes differential diagnosis is required between the various types, mainly based on the clinical characteristics of the child and the related enzymatic examinations. In addition, mucopolysaccharidosis needs to be identified with the following diseases:

1. Multiple sulphate lipase deficiency The clinical manifestations of this disease are similar to those of mucopolysaccharidosis, but mental retardation and neurological symptoms appear faster than mucopolysaccharidosis, often similar to metachromatic white matter atrophy. Patients often have hepatomegaly and fixed skin ichthyosis. Laboratory tests for non-mucopolysaccharide urine and cellular enzyme deficiency.

2. Systemic ganglioside deposition (GML ganglioside) combined with the clinical features of fat and mucopolysaccharide storage disease. Children in the infancy have severe systemic ganglioside deposition, intelligent developmental delay, low muscle tone, hepatosplenomegaly, more than half of the patients have skin macula and safflower red spots.

3. Mannosidosis has mental, motor developmental delay, hearing loss, ugly face, hepatosplenomegaly, low muscle tone, mild multiple bone dysplasia. There are a lot of mannose oligosaccharides in the urine and no mucopolysaccharide urine.

4. Patients with fucososis have ugly face, hepatosplenomegaly, severe mental and motor development retardation, and multiple bone dysplasia. The fucose containing oligosaccharides is excreted in the urine, and no mucopolysaccharide urine is excreted.

5. Asparagine Glucoseuria is easily confused with Hurler syndrome and Hunter syndrome. The child is normal at birth, gradually appearing wide nose, collapsed nose, nostril flexion, thick lips and other ugly face, and has a short neck, asymmetrical head, scoliosis, hepatosplenomegaly, and urine contains a large amount of asparaginyl Glucosamine.

6. The clinical manifestations and X-ray changes of mucolipidosis type I have much in common with Hurler syndrome. However, most of the mucolipid diseases have myoclonic convulsions, muscle atrophy, pulsating movements of the hands and feet, nystagmus, and macula and safflower spots. The uric acid-bound oligosaccharide excretion increased and the mucopolysaccharide levels were normal.

The mental and motor developmental retardation of type II of mucoidosis occurs earlier and develops faster. Early gingival hyperplasia, narrow chest, heart valve disease more common, no corneal opacity, long bone periosteal formation can be seen in about half a year, children often die early. There is no increase in mucopolysaccharide in the urine.

Mucinosis type IV may also have mental retardation, corneal opacity, etc., but no mucopolysaccharide urine.

7. The clinical manifestations of Kneist syndrome are similar to those of Morquio syndrome, including large head, collapse of nasal bridge, cleft palate, short neck, bell-shaped chest, retinal detachment, hearing loss, abdominal hernia, short limbs and trunk, arched humerus, kyphosis, Joint rigidity and so on. The child may also have keratan sulfate, but no N-acetylgalactosidase-6-sulfatase or β-galactosidase deficiency.

complication

Growth backwardness, intelligent backwardness, various progressive distortions of bones affect motor function, liver and splenomegaly, deafness, language and behavioral disorders, oppressive paraplegia and respiratory paralysis in the late stage, congestive heart failure and so on.

treatment

Western medicine treatment

The disease currently lacks a thorough cure. Although some progress has been made in the treatment of mucopolysaccharidosis, most of them are in the research stage and have not been widely used in clinical treatment. The most promising treatment for mucopolysaccharidosis is specific enzyme replacement therapy and gene therapy, which can improve the patient's clinical performance and survival.

Specific enzyme replacement therapy can be in two different forms. One is to directly input the microencapsulated enzyme into the body, which is a direct method. The other is the indirect method, which uses retrovirus to carry out transgenic treatment, so that the patient's autologous peripheral blood lymphocytes or bone marrow hematopoietic progenitor cells are reversely transformed into cells containing normal enzyme genes, or implanted into the patient through bone marrow transplantation. Bone marrow cells containing the normal enzyme gene, so that the patient can synthesize the lack of mucopolysaccharide metabolic enzymes. At present, the above two types of treatment methods are in the clinical research stage. Surgery is mainly used to treat defects in certain bodies and organs, such as replacement of heart valves, corneal transplantation, severe spinal cord compression, and the like.

The above content is for reference only, please consult the relevant physician or relevant medical institution if necessary.

prevention

Mucopolysaccharidosis is a group of congenital mucopolysaccharide metabolic disorders, belonging to lysosomal diseases. There is currently no information on prevention.

Prognosis

1. Mucopolysaccharide storage disease type I patients with progressive development, often died at the age of 15 due to heart disease and repeated respiratory infections. Due to the semi-dislocation of the ring, it oppresses the dorsal or dorsal membrane, causing an increase in intracranial pressure and even life-threatening. Surviving patients have bone and joint dysfunction, and early joint degeneration.

2. Mucopolysaccharidosis type II patients survive longer, generally can survive for 20 to 30 years, the lesions are progressive development, the patient died of severe involvement of the heart and respiratory system.

3. Mucopolysaccharide storage disease type III This disease has progressive mental retardation, bone changes can often be repaired in childhood, and even disappear completely after osteophyte fusion. However, if the bones and joints are abnormal and shaped, they cannot be completely recovered. A small number of patients died as a result of respiratory involvement.

4. Mucopolysaccharidosis type IV rarely died in childhood, most of the disease survived for decades, but the disease is easy to affect the aortic valve and respiratory tract, causing death of cardiopulmonary dysfunction. The patient may also suffer severe damage to the central nervous system due to subluxation of the atlantoaxial joint.

5. Mucopolysaccharide storage disease type VII heavy people often die due to heart disease. The contracture of the joint can affect the normal life of the patient. Survivors can have premature secondary and degenerative osteoarthrosis.

The lifespan of patients with mucopolysaccharidosis is significantly shortened, and the average life expectancy is generally 10 to 20 years old. The main causes of death were coronary and aortic valve damage as well as pulmonary infections. If it can be diagnosed early and effectively reduce the accumulation of mucopolysaccharide in the body, it will help the patient's mental condition to improve, the opaque cornea can be restored transparent, the enlarged liver and spleen can be reduced, and the further development of skeletal deformities can be prevented, thus greatly Improve the quality of life of patients and extend their life.