mucopolysaccharidosis
Introduction
Introduction to mucopolysaccharidosis 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 findings, mucopolysaccharidosis is a congenital or primary metabolic syndrome. basic knowledge The proportion of illness: 0.001% Susceptible people: no special people. Mode of infection: non-infectious Complications: neonatal hepatosplenomegaly congestive heart failure
Cause
Causes of mucopolysaccharidosis
Causes:
Genetic factors (90%):
Mucopolysaccharidosis is a congenital or primary metabolic syndrome: 1. Mucopolysaccharidosis type I (Hurler syndrome): an autosomal recessive disorder due to -L-iduronase Due to the lack of (-L-iduronidase), it 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)
It is a concomitant (X) linked hereditary disease, only found in men, due to the lack of iduronic acid sulphate in the body, clinical manifestations and X-ray examination with MPS-1, but its clinical progress is slower than the former, clinical manifestations 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, it is an autosomal recessive hereditary disease. There are many enzymes in the body. The characteristic clinical manifestations are progressive mental retardation. Others such as appearance, body changes, and severity are different. Lack of enzyme differences and clinical manifestations, etc., can be divided into four subtypes, namely MPSIIIA, MPSIIIB, MPSIIIC and MPSIIID.
4. Mucopolysaccharidosis type IV (Morquio syndrome)
It is a more common mucopolysaccharid storage disease, which is autosomal recessive, and its clinical manifestation is unique. This type is divided into two subtypes:
(1) MPSIVA type, the related lack of enzyme is N-acetyl-galactosamine-6-sulfate sulfatase.
(2) MPSIVB type, the lack of enzyme is -galactosidase (bata-galactosidase), the two subtypes, the severity of clinical manifestations can be quite different, usually type A disease is more serious.
5. Mucopolysaccharid storage disease type V
This type is considered to be the Seheie type of mucopolysaccharidosis type I. It differs from Hrular syndrome in that it has no serious corneal opacity, and turbidity is peripheral. The patient has normal intelligence, normal or slightly short, and has a long life. Normal, but hairy, joint stiffness, back column, head X-ray showed only slight changes.
6. Mucopolysaccharidosis type VI (Maroteaux-Lamy syndrome)
Or arylsulfatase B deficiency, an autosomal recessive genetic disease, lacking an enzyme is an aryl sulfatase enzyme, this type is basically similar to Hurler syndrome, but the intelligence is normal, different from 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 longer lifespan, basic intelligence, and osteophytes. There is an increase in dermatan sulfate and heparin sulfate in the presence of Hurler urine, while the type VI is only increased in the latter. In the absence of enzymes, type I lacks -L-iduronidase and type VI lacks arylsulfatase B.
7. Mucopolysaccharidosis type VII (Sly syndrome)
It is an autosomal recessive genetic disease, which is extremely rare. The patient lacks -glucuronidase. The patient is short stature, mental retardation, chicken breast, dorsal column scoliosis, etc. Two subtypes of the disease, the former is early onset, and there is joint contracture, the latter is late, often with avascular necrosis of the femoral head.
Pathogenesis:
Except that MPS type II is X-linked recessive inheritance, the inheritance of all other types is autosomal recessive, the defective gene is located on the autosome, and only the homozygous genotype will occur. Among the children of zygote, 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 sick, and females are Gene carriers, males in their offspring and women are 50% likely to be carriers.
There are many types of genetic mutations that have been confirmed so far, and the differences between different populations are large.
Mucopolysaccharides include 4-chondroitin sulfate, 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 components of vascular connective tissue, the lack of MPSI-type -iduronidase, the lack of MPSII type iduronic acid sulfatase and the lack of MPS VII -glucuronidase, all lead to chondroitin sulfate and The degradation of heparan sulfate is hindered, and the lack of various enzymes of MPSIII can cause degradation of heparan sulfate. The deficiency of MPSIV -galactosidase mainly affects the degradation of keratan sulfate. The acylsulfatase B of MPSVI type The lack of degradation of chondroitin sulfate is mainly hindered, and 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, excessive mucopolysaccharides can be removed from the urine. Continuously discharged.
Prevention
Mucopolysaccharide storage disease prevention
Mucopolysaccharidosis is a group of congenital mucopolysaccharide metabolic disorders, belonging to lysosomal diseases. High-risk families need to do prenatal diagnosis to prevent the same family from being born again. Actively participate in outdoor physical exercise, enhance their immunity, regularly participate in physical examinations, and find that the disease promptly seek medical treatment.
Complication
Mucopolysaccharide storage complications Complications neonatal hepatosplenomegaly congestive heart failure
Growth is backward, intelligence is backward, and various progressive distortions of bone affect motor function, liver, splenomegaly, deafness, language, behavioral disorder, late-stage oppressive paraplegia and respiratory paralysis, congestive heart failure and so on.
Type II classic patients have milder symptoms than type I. This type is mainly male, and the patient's cornea is not turbid. Type III patients have mental retardation as the main clinical manifestation; type IV patients have loose wrist joints. The thoracic cage protrudes forward, similar to chicken breast; type VI patients have normal intelligence and corneal opacity; VII type patients can have very different clinical manifestations, severe manifestations of fetal edema, and light patients can only have short stature.
Symptom
Symptoms of mucopolysaccharide storage disease Common symptoms Visual dysfunction Hepatosplenomegaly Large ear pus mental retardation Abnormal short corneal opacity appearance gradually becomes thicker and more hairy
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. The initial symptoms are mostly 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 of the children have Joint changes and activities are limited, multiple organ involvement is seen in all children, some children have corneal opacity, and thus can cause visual impairment or even blindness, hepatosplenomegaly and cardiovascular involvement are more common, some children may have intelligence Progressive progression, umbilical hernia and inguinal hernia, slow growth, hydrocephalus, thickening of the skin, increased hair, chronic hooliganism, repeated ear infections, and hearing damage.
Mucopolysaccharide storage disease type I
Although there are three subtypes of mucopolysaccharidosis 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 are more common. Late, the condition is the lightest, and the Hurler-Scheie syndrome is somewhere in between.
Normally, the performance is normal at birth. After 6 months to 1 year old, the child gradually grows slowly, with apathy, slow response, low mental retardation, language childish or even idiot, big head, forehead protruding into a boat shape, widened eye distance, nasal bridge collapse or Flat, nostril enlargement, thick lip and everted, open mouth, large tongue and often extend outside the mouth, teeth are small and dull, dentition is sparse, irregular, corneal opacity is common, severe cases can cause blindness, otitis media often occurs, and Causes hearing loss and even deafness, heart valve and chordae can cause heart enlargement and cardiac insufficiency, bronchial cartilage lesions can cause airway stenosis, easy to concurrent infection, abdominal bulging, hepatosplenomegaly, and more inguinal hernia or umbilical hernia, May have diarrhea or constipation, thick hair, thick black, short neck, shrug, limbs and short trunk, kyphosis, arched hunchback, most joints are flexed and straight, limited activity, often knee, valgus and flat feet Isometric, palm, finger short, can appear carpal tunnel syndrome, Hurler syndrome patients often die in childhood, Scheie syndrome and Hurler-Scheie syndrome can survive to adulthood
2. Mucopolysaccharide storage disease type II
It is rare, according to the severity of the disease, it is divided into two subtypes, A and B. Among them, type A is more serious. All patients are male, more than 2 to 6 years old. The clinical manifestations are similar to Hurler syndrome, but the time is obvious. Later, the progress is slow, the mental retardation and short stature are not as serious as Hurler's syndrome. The severe condition begins with childhood and has retinitis pigmentosa and optic disc edema, but no corneal opacity, hearing is progressive damage, and eventually develops deafness. Skeletal malformation is mild, heart 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 before 15 years old Death, type B patients are milder, some hearing and cornea are normal, and there is no skeletal deformity.
3. Mucopolysaccharide storage disease type III
It 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 4~ Before the age of 5, the intelligence was normal, and then gradually appeared unresponsive, mental retardation, progressive progressive, severe cases of 2-3 years old can have mental retardation, more hair increased, other changes such as special face, short stature and bones Malformation, etc. are not serious, and can even be normal, usually with hearing damage, but no corneal opacity, generally do not involve the heart, no abdominal hernia, liver and spleen may be slightly enlarged, slightly short or basically normal, very few It is characterized by short stature, limited joint movement, and even joint stiffness. The hand and other joints may have flexion deformity.
4. Mucopolysaccharidosis type IV
The outstanding performance is growth retardation. Generally, the height is less than 160cm in adulthood, the face and intelligence are normal, the toddler is late, the gait is unstable when walking, the short neck, the shoulders, the teething time is late, the teeth are not neat, the teeth Lack of luster, corneal opacity can occur as early as childhood, hearing is progressive damage, often without heart involvement, mild swelling of the liver and spleen, no abdominal hernia, skeletal malformations including chicken breast, hunchback, knee valgus, flat feet and joints Deformation such as flexion contracture, and obvious joint relaxation, but no joint stiffness, cervical subluxation can occur, causing spinal cord compression symptoms, most patients can survive 20 to 30 years old.
5. Mucopolysaccharid storage disease type V
This type is considered to be the Seheie type of mucopolysaccharidosis type I. It differs from Hrular syndrome in that it has no serious corneal opacity, and turbidity is peripheral. The patient has normal intelligence, normal or slightly short, and has a long life. Normal, but hairy, joint stiffness, back column, head X-ray showed only slight changes.
6. Mucopolysaccharid storage disease type VI
Extremely rare, the clinical manifestations are similar to the mucopolysaccharidosis type I, but the patient's intelligence is normal, generally starting from 2 to 3 years old, growth retardation, cranial suture closure is early, hydrocephalus can occur, and symptoms of intracranial hypertension and Spastic hemiparesis, corneal opacity appeared earlier, progressive hearing damage, severe blindness and deafness, heart valve disease, hepatosplenomegaly and inguinal hernia are more common, skeletal malformation is similar to MPSI type, but relatively Light, usually the upper limbs are more affected than the lower limbs, the joint activity is obviously limited, and there may be mild joint stiffness, and most patients do not live longer than 10 years old.
7. Mucopolysaccharide storage disease type VII
Very rare, special face gradually appeared soon after birth, general intelligence is normal, corneal opacity and hearing damage are more common, mostly hepatosplenomegaly, usually do not involve the heart, no abdominal hernia, short upper limbs, poor bone development There may be bone deformities such as chicken breasts and knee valgus.
Examine
Examination of mucopolysaccharidosis
Laboratory inspection
Urine check
(1) Determination of mucopolysaccharide:
1 Qualitative test of urinary mucopolysaccharide: the urinary plaque is purple-blue or punctate, and there is no color change in normal urine spots.
Determination of urinary mucopolysaccharide in 224h: the mucopolysaccharide excreted in the urine of normal people is 3~25mg per day, and the mucopolysaccharide in the urine of patients with mucopolysaccharidosis often exceeds 100mg/24h, due to the different enzymes lacking in various types of mucopolysaccharidosis, The mucopolysaccharide content and quantity in urine are different. The mucopolysaccharides in MPSI, MPSII and MPSVII urine are chondroitin sulfate and heparan sulfate, among which Hurler syndrome is the most significant, and MPSIII patients only have sulfuric acid in urine. Heparin, MPSIV type is keratan sulfate, which gradually decreases with age, and MPSVI type is mainly chondroitin sulfate.
(2) Determination of enzyme activity: The activity of various enzymes in urine can be measured, and the respective enzyme activities of various types of mucopolysaccharidosis are reduced.
2. Blood test
(1) Reilly body: all types of mucopolysaccharidosis can be seen in peripheral blood or bone marrow lymphocytes and neutrophils, there are different types of deep purple mucopolysaccharide particles of different sizes, namely Reilly body, In addition to white blood cells, MPSVI can still see Reilly bodies in platelets.
(2) Determination of enzyme activity: Determination of enzyme activity in peripheral blood leukocytes is the main basis for the diagnosis and identification of various types of mucopolysaccharidosis.
Film degree exam
X-ray inspection
(1) MPSI type: In each subtype of MPSI type, the X-ray manifestation of bone changes is also the most serious in Hurler syndrome.
1 skull: basically normal within 6 months after birth, and then cranial suture early closure, anterior sacral closure is delayed, the anteroposterior diameter of the skull is increased, and the thickening of the meninges can cause obstructive hydrocephalus. The skull is further enlarged, the anteroposterior diameter of the saddle is increased, and the supine "J" shape or shoe shape is present; if there is a subarachnoid cyst, the saddle enlargement, the skull plate is dense, the barrier is thickened, the skull base and the skull are thick. The top also has sclerosis, sphenoid sinus, mastoid and paranasal sinus development and poor gasification, mandibular thick and short, hook-like dysplasia, flat or concave, sacral fossa shallow, irregular, small teeth, arranged Sparse, irregular, molars are often located in the mandibular branch.
2 spine: the upper and lower edges of the vertebral body are biconvex or elliptical, the odontoid is short, and there may be a subluxation of the atlantoaxial joint. The lower thoracic and lumbar vertebrae (chest 12, waist 1 or waist 1 and waist 2) are short. The ovoid shape has a sharp front and lower edge, and is a "bird's beak"-like protrusion, and is displaced backward to form a kyphosis.
3 thoracic: the rib spine end is small, the middle to the sternum end gradually widened, showing a "boat paddle"-like change, the inner part of the clavicle is obviously thickened, the outer section is thin and upturned, the position of the scapula is raised, slightly equilateral triangle, The lower corner becomes sharper, the shoulder blade is shallow and small, and even disappears. The humeral head is small, the neck-dry angle becomes small, and even the right angle can be present, and there may be a varus deformity.
4 pelvis: abduction of the humerus, narrowing of the base of the humerus, oval shape of the sciatic hole, widening of the pubic symphysis, slope of the upper rim of the acetabulum, shallowing of the acetabulum, increase of the acetabular angle, The bones are small and dense, the femoral head nucleus is small or irregular, and the appearance time is later, the femoral neck is slender, and the neck-dry angle is increased.
5 long tube bone: upper limb changes are more obvious than the lower limbs. Due to the shaping obstacle of the backbone, the backbone is thick and short, the ends are tapered, the cortical bone is thinner, the marrow cavity is enlarged, and the transverse strip development barrier is visible. The bones are small, irregular, or delayed.
6 short tube bone and wrist: palm (), finger (toe) proximal thickening, distal tip sharpened, warhead-like, distal phalanx (especially the thumb) distal tip is thin, claw-like flexion deformity, The carpal bone is irregular, the ossification is delayed, the ossification center is small, and the number is less than that of children of the same age, the ulnar and the distal end of the humerus are developed, and the wrist joint surface is "V" shaped.
(2) MPS type II: The skeletal system changes similar to Hurler syndrome, but the appearance time is relatively late, the progress is slower, the change is often lighter, the main changes include: long bone backbone widening, multiple bone development disorders, the saddle is " The J" shape is enlarged, the "boat paddle"-like ribs are changed, and the lumbar vertebra is "bird's beak"-like protrusion.
(3) MPS type III: This type of bone is abnormally mild, may have cranial crest, posterior tibial and occipital thickening, poor mastoid gasification; the upper and lower edges of the vertebral body slightly bulged, or oval; widened at the medial end of the clavicle The anterior rib of some patients is widened by "boat paddle"; the humeral wing is abducted, the humerus is short and narrow, and the upper edge of the acetabulum is relatively straight; the tubular bone is short and the dry end is slightly widened, which may be accompanied by The shape of the bone is obstructed, and the bone marrow cavity is narrow and irregular.
(4) MPSIV type: the skull and the sella are normal. The early vertebral body is slightly rounded, and then gradually becomes flat. The front edge has a tongue-like protrusion and the intervertebral space is widened; the odontoid is small or absent, which is easy to cause The atlantoaxial joint is unstable, the anterior and posterior diameter of the thorax is enlarged, the sternum is shortened, and the anterior process is curved, which is chicken-chest; the rib is concave at the front end, and has widened, abducted, the posterior rib end is thinned, and the medial end of the clavicle is widened. The butterfly wing extends outward and upward, the shoulder blade is small, the position is raised, the shoulder blade becomes shallow or disappears, the humerus wing is abducted, the base of the humerus is narrowed, the acetabulum becomes shallow, and the scapula is sloped from the outside to the inside. Change, the ischial and pubic bones are short and thick, the femoral head is swollen, the depression is concave, irregular, the femoral neck-dry angle is enlarged, there may be hip dislocation, the lower end of the femur and the upper end of the humerus are small, and the metaphysis is widened. Double or wavy dense band, the sacral line is narrowed, the ulna, the distal radius of the humerus is small and irregular, and even disappears, the articular surface is sloped; the wrist bone is small and irregular, the long bone is generally short and thick, and the metaphyseal end is irregularly increased. Wide, with pointed horns; thin cortical bone, sparse and irregular trabecular bone, Ischemic necrosis marrow sample may change, metacarpal, phalanges stubby, non metaphysis narrowed.
(5) MPSVI type: similar to Hurler syndrome, some patients may have osteonecrosis of ischemic necrosis, which is more common in femoral skull.
(6) MPSVII type: mainly multiple bone dysplasia, X-ray findings similar to Hurler syndrome.
2. CT and magnetic resonance imaging (MRI) can accurately understand the extent and extent of structural changes including the brain, spine, bone (cartilage), joints, respiratory tract and cardiovascular system, both of which can clearly show skull dysplasia, brain White matter changes, hydrocephalus, subarachnoid stenosis, arachnoid cyst, dural thickening of the cranial and cervical joints, spinal cord compression, etc., but in the examination of white matter, magnetic resonance is more sensitive and reliable than CT, usually, the course of disease The longer the CT and the changes in the magnetic resonance examination, the more obvious.
3. B-mode ultrasound for intrauterine examination, can be found in the fetus with or without bone and joint deformity, hepatosplenomegaly and hydrocephalus.
4. Tissue biopsy Biopsy showed that the activity of mucopolysaccharide metabolic enzymes in hepatocytes, skin or connective tissue fibroblasts was significantly reduced.
5. Prenatal examination is usually not used as a routine examination of normal pregnancy. For women with children with mannosidosis, the concentration of mucopolysaccharide in amniotic fluid and the enzyme activity of amniotic fluid cells may be determined when pregnancy is again. If the concentration of amniotic fluid mucopolysaccharide is significantly increased, The amniotic fluid cell enzyme activity is significantly reduced, and prenatal diagnosis can be determined.
Diagnosis
Diagnosis and identification of mucopolysaccharide storage disease
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.
Differential diagnosis
Sometimes differential diagnosis is required between the various types, mainly based on the clinical characteristics of the child and related enzymological examination. In addition, the mucopolysaccharidosis needs to be identified with the following diseases:
1. Multiple 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 leukosis, patients often have hepatomegaly and fixed skin. Fish scales, laboratory tests for non-mucopolysaccharide urine and cellular enzyme deficiency.
2. Systemic gangliosideosis (GML ganglioside)
It has the clinical characteristics of fat and mucopolysaccharide storage disease. The child has severe systemic ganglioside deposition in infants, intelligent developmental delay, low muscle tone, hepatosplenomegaly, and more than half of the patients have skin macula and Sakura red dot.
3. Mannosidosis
Mental, motor developmental delay, hearing loss, ugly face, hepatosplenomegaly, low muscle tone, mild multiple bone dysplasia, etc., a large amount of mannose oligosaccharides in the urine, no mucopolysaccharide urine.
4. Fucosysis
The patient's face is ugly, hepatosplenomegaly, severe mentality, retarded exercise, multiple bone dysplasia, excretion of oligosaccharide fucose in the urine, and no mucopolysaccharide urine.
5. Asparagine Glucoseuria
It is easy to be confused with Hurler syndrome and Hunter syndrome. The child is normal at birth, gradually appearing wide nose, collapsed nose bridge, nostril flexion, thick lips and other ugly face, and has short neck, head asymmetry, scoliosis, liver The splenomegaly is large, and the urine contains a large amount of asparagine.
6. Mucolipidosis
The clinical manifestations and X-ray changes of type I of mucoidosis have much in common with Hurler syndrome, but most of the mucolipid diseases have myoclonic convulsions, muscle atrophy, pulsatile movements of the hands and feet, nystagmus, and macula. And sakura red spots, urinary citrate combined oligosaccharide excretion increased, mucopolysaccharide levels are normal.
The mental state of mucoidosis type II, early onset of motor development, and rapid development, early gingival hyperplasia, narrow chest, valvular heart disease, no corneal opacity, long bone periosteal formation can be seen in about half a year, children often In the early years, the number of non-mucopolysaccharides in the urine increased.
Mucoidosis type IV may also have mental retardation, corneal opacity, etc., but no mucopolysaccharide urine.
7. Kneist syndrome
Clinical manifestations are similar to Morquio syndrome, including large head, nasal bridge collapse, cleft palate, short neck, bell-shaped chest, retinal detachment, hearing loss, abdominal hernia, short limbs and trunk, arched humerus, kyphosis, joint stiffness, etc. There may also be keratan sulfate urine, but no N-acetylgalactosidase-6-sulfatase or -galactosidase deficiency.
