spinal muscular atrophy
Introduction
Introduction to spinal muscular atrophy Spinal muscle atrophy (SMA) refers to a type of disease that causes muscle weakness and muscle atrophy due to degeneration of the anterior horn cells of the spinal cord. It was first reported by Werdnig (1891) and Hoffmann (1893), so it is also called Werdnig- Hoffmann's disease. According to the age of onset and the degree of disease, the disease can be divided into 4 types: I-III is called child-type SMA, which belongs to autosomal recessive genetic disease, and its population incidence rate is 1/6000~1/10000, which is in infancy. The most common fatal genetic disease. SMA, which is onset from 20 to 30 years old, is classified as type IV and can be expressed in different genetic modes such as autosomal recessive, dominant and X-linked recessive, and its population incidence rate is about 0.32/10000. Due to various clinical and genetic characteristics, it is generally believed that this disease should be separated from motor neuron diseases and become a group of independent diseases. basic knowledge The proportion of illness: 0.006% - 0.007% Susceptible people: infants and young children Mode of infection: non-infectious Complications: multiple lung infections urinary tract infections acne
Cause
Cause of spinal muscular atrophy
genetic factors:
Types I to III are autosomal recessive genetic diseases, which are the most common lethal genetic diseases in infancy. Type IV is autosomal recessive, dominant and X-linked recessive.
Pathogenesis
The etiology and pathogenesis of SMA has always been a difficult problem in neurological research. In recent years, great progress has been made in the study of SMA gene localization. In 1995, different research groups reported three SMA candidate genes, France Lefebvre, etc. The survival motor neuron (SMN) gene was found in the 5q13.1 region. It is about 20 kb in length and contains 8 exons. Its transcript is about 1.7 kb, encoding 294 amino acids. Its function is unknown. There are two copies of this gene, there are 5 base differences between them, called SMNt on the telomere side, and SMNc on the centromere side. Studies have shown that exon 7 and 8 of SMNt are in 98.6% of SMA patients. Homozygous deletion or truncation, and 1.4% of patients have small deletions or point mutations, which strongly supports SMN as an important determinant of SMA. Subsequently, Roy et al. cloned a neuronal apoptosis inhibitory protein (NAIP) in the 5q13 region. Gene, there are 16 exons, full length 70kb, encoding 1232 amino acids, 45% SMA-I and 18% SMAII, type III patients with NAIP gene exon 5, exon 6 deletion, and 2% normal Control is also lacking Loss of exon 5 and 6 suggests that the NAIP gene is also associated with SMA co-occurrence. As for adult SMA, only the deletion of SMN gene is found, suggesting similar genetic alterations with childhood SMA, but gene mapping in most patients. It has not been determined that the pathogenesis is unknown.
The pathological changes are mainly located in the anterior horn of the spinal cord, and the motor cells are significantly reduced, showing degenerative changes. The residual nerve cells are pyknosis, nuclear lysis, fine anterior root axis mutation, axonal peripheral cell swelling, brainstem motor neuron degeneration, The facial nerve, the vagus nerve, and the hypoglossal nerve are more common. The muscle pathological examination is shown in the auxiliary examination section below.
Prevention
Spinal muscular atrophy prevention
Preventing the birth of children is the most effective way to prevent this disease. Recently, some domestic scholars have combined PCR-SSCP, PCR-restriction enzyme digestion and linkage analysis to diagnose SMA prenatal genes with high accuracy and success rate. It is worth further promotion and application.
Complication
Spinal muscular atrophy complications Complications Multiple lung infections Urinary tract infections Acne
Symptoms and signs of different types of SMA can be the manifestations of the disease, can also be regarded as complications of the disease (see above clinical manifestations), in addition, should pay attention to secondary lung infections, urinary tract infections, hemorrhoids and so on.
Symptom
Spinal muscular atrophy symptoms Common symptoms Powerless joint deformity Sensory disturbances Reflexes disappeared Muscle fake hypertrophic muscles Atrophic atrophy Dysphagia Difficulty of spinal muscular atrophy Bow-shaped lingual muscle atrophy
1.SMA-I type
Also known as Werdnig-Hoffmann disease, about 1/3 of the cases occur in the uterus, the mother can notice that the fetal movement is weak, half of the onset within one month of birth, almost all cases within 5 months of onset, the incidence rate is about For 1/10000 births, the incidence of male and female is equal, and the muscle tension is lower than soon after birth. The muscle weakness is mainly affected by the proximal muscles of the extremities, and the trunk muscles are weak. The sucking and swallowing power of the child is weak, and the crying is low. Abdominal activity, shallow chest abnormalities, difficulty in turning over and lifting, sputum reflex disappeared, palpation can be found in muscle atrophy of the limbs, but often covered by subcutaneous fat, normal eye movement, normal sphincter function, visible tongue muscle atrophy and tremor, 10 % of cases may have joint deformity or contracture, and the prognosis of this type is poor, about 95% died 18 months after birth.
2.SMA-II type
The onset is slightly later than the SMA-I type, usually starting within 1 year of age, very less than 1 to 2 years old, the incidence is similar to SMA-I, the early growth of the baby is normal, but the exercise is slow after 6 months. Although they can sit, but the standing and walking have not reached the normal level, more than 1/3 of the children can not walk, 20% to 40% of children still have walking ability before the age of 10, most cases show severe limb proximal muscle weakness, lower limbs More important than the upper limbs, and the respiratory muscles, the swallowing muscles are generally not tired, 1/3 of the cases are affected by facial muscles, more than 50% of cases can be seen in the tongue muscles and other muscle fibrillation, sputum reflexes weakened or disappeared, this type has a relatively benign course, Most can live in childhood and live to adulthood individually.
3.SMA-III type
Also known as Kugelberg-Welander disease, usually from early childhood to adolescence, and most of the onset before the age of 5, onset of insidious, manifested as progressive limb proximal muscle weakness and atrophy, early thigh and hip muscle weakness Significantly, the sick child walks in a duck step, and it is difficult to climb the ladder. The scapular band and the upper limb muscles are gradually involved. The muscles innervated by the brain are usually not affected, but the facial muscles, the soft diaphragm muscles are weak, and the extraocular muscles are normal. About 1/4 of cases are associated with pseudohypertrophy of the gastrocnemius muscle, which is almost common in male patients. Half of the patients can see fasciculation in the early stage, and the arched foot can also be seen. The tendon reflex is weakened or disappeared, and the feeling is normal. The prognosis of this type is good, especially for women. Patients, the survival period can usually reach adulthood, many patients can have a normal life expectancy, the more serious cases are often male patients, this type of serum CPK can be increased to varying degrees, EMG in addition to neurogenic changes can still be associated with myogenic damage Mixed, so attention must be paid to the identification of muscular dystrophy.
4.SMA-IV type
Generally referred to as adult SMA, the age of onset is 15 to 60 years old, more common in the age of 35, the onset and progression are more insidious, but there are also cases of progressive aggravation or relatively static, the prognosis of this type is relatively good, walking ability Often can maintain a lifetime, the incidence rate is less than 0.5 / 100,000, about one-third of the cases of this type of autosomal dominant inheritance, manifested as proximal muscle weakness, a little faster progress, lost running ability after about 5 years, there are Autosomal recessive inheritance type generally shows a more benign course, and the other type is X-linked recessive inheritance, also known as spinal brainstem type SMA (Kennedy's disease), which varies in age of onset, but often before 40 years of age. Onset, early manifestation of painful tendon, can occur in the first few years before muscle weakness, proximal muscle weakness often begins from the lower extremity, gradually affecting the scapular muscle, facial muscles and medulla obligate the muscles, the lower muscles and the lingual muscle can be seen After a few years, dysphagia and convulsions may occur. About 50% of cases have some endocrine dysfunction, which is characterized by male breast and primary testicular lesions.
5. Other types of SMA
(1) distal type SMA: this type accounts for about 10% of SMA, and is an autosomal dominant or recessive inheritance form. The former occurs before the age of 20, the latter is slightly late, and the symptoms are mild, and most patients show slow progress. The lower extremity muscle weakness and atrophy, the tibialis anterior and tibial muscles are particularly susceptible, arched foot and scoliosis are also more common, about half of the cases will be affected sooner or later, but to a lesser extent, no sensory disturbance, Peripheral nerve conduction velocity is normal.
(2) Chronic asymmetric SMA: This type starts from 16 to 45 years old, and male patients are twice as many as female patients, showing one or more limb asymmetry muscle atrophy without pyramidal or medullary involvement, muscle The weakness can be mainly proximal or distal, and the disease is relatively limited to a single limb. The natural course of this type is longer, even more than 30 years.
(3) scapular type SMA: the age of onset is 30 to 40 years old, showing that the scapular muscle and the lower limb distal muscle (especially the gastrocnemius) are obviously weak and atrophic, and the arched foot is also more common.
(4) Single-armed SMA: Some cases have been reported in Japan and India, with different ages of onset, more common in men, relatively faster onset, and then into non-progressive period, due to impaired localized anterior horn cells, multiple manifestations The arm has obvious muscle atrophy, EMG shows strict restriction on the abnormality of a single limb, and the bulbar muscle and other muscles are not invaded. The Japanese literature refers to the young-type single-limb SMA as Hirayama disease.
(5) In addition, there are medullary SMA complicated with deafness (Viatetto-Vanlaere syndrome), children with medullary SMA (Fazio-Londe syndrome), oropharyngeal SMA, facial scapular SMA, aminoglycosidase A deficiency, etc. Types of.
Examine
Examination of spinal muscular atrophy
Serum CPK
The serum CPK of SMA-I type is normal, the type II is occasionally increased, the CPK isoenzyme MB is often increased, the type III CPK level is often increased, sometimes it can reach the normal value more than 10 times, and the isoenzyme changes to MM. Mainly; CPK usually increases with the development of muscle damage, and CPK levels begin to decline when the advanced muscles are severely atrophied.
2. Genetic diagnosis
For children's SMA, the exon 7 and 8 of the SMNt gene can be amplified by PCR and combined with single-strand conformation polymorphism analysis (SSCP) or application: DraI, DdeI for SMNt gene exon 7 and exon. Analyze for diagnosis.
3.CT muscle scan
This contributes to the identification of SMA and various types of muscular dystrophy. SMA exhibits a diffuse low-density change of incomplete contour and loss of muscle tissue reflex; while muscular dystrophy shows a large number of low-density lesions, all muscles are involved, and general pseudo- Hypertrophy is rare in SMA patients.
4. Electrophysiological examination
EMG can reflect the severity and progression of four major types of SMA, but its abnormal changes are similar, including increased amplitude and time of fibrillation potential and compound motor unit action potentials (MUAPs) and reduced interference phase, in SMA-III, IV. In the type of cases, neurogenic and myogenic potentials are sometimes seen, and the mixed muscles are present in the same muscle. The muscle-derived MUAPs can be more prominent in patients with elevated CPK levels. In some cases of SMA-III, muscle biopsy is neurogenic. However, EMG showed myogenic damage, suggesting that EMG can be inconsistent with clinical features. All types of SMA showed fibrillation potential and positive sharp wave, but it was more obvious in SMA-I type. It was found in all patients, while SMA-III only saw 60. %, the tremor potential is about 20% positive in SMA-I type, and 50% positive in type III. A unique manifestation of SMA-I type, that is, spontaneous release of MUAPs of 5-15 Hz can be seen when the limb is relaxed. When exercising at random, all types of SMA showed a decrease in interference phase, especially in SMA-I type, which was only a simple phase, which is evidence of loss of motor unit. In the later cases of SMA-III, type IV, similar to Low amplitude multiphase potential of myogenic damage, this Muscle biopsies secondary myogenic change match.
5. Pathological examination
Muscle biopsy is important for the diagnosis of SMA. Its pathological features are denervation and nerve re-innervation. Each type of SMA also has different muscle pathological features:
(1) SMA-I type: This type of muscle pathological feature is the presence of a large group of round atrophic muscle fibers, often involving the entire muscle bundle; also see that the hypertrophic fibers are scattered in the atrophic fibers, both types of muscle fibers can be involved, and Incomplete homosexual muscle grouping.
(2) SMA-II type: The pathological shape of muscle biopsy is similar to SMA-I, but large group of atrophic muscle fibers are not so common, and homogenous muscle grouping is more prominent.
(3) SMA-III type: This type can have multiple manifestations in muscle pathology. In some cases, only slight changes, such as small group homologous muscle grouping, a small amount of atrophic fiber, etc., are generally normal, most serious cases, The performance of muscle biopsy is related to the disease stage. In early childhood, the small fiber is mainly used, and the same type of muscle group can be seen. In the later stage of the disease, the same type of muscle grouping is the main feature, and the group or bundle of small atrophic muscle fibers are combined. Hypertrophy changes are very prominent, diameter up to 100 ~ 150m, often associated with secondary myogenic damage, including muscle fiber tear, central nuclear changes, NADH staining see worm-like and fingerprint-like fibers, a small amount of necrotic and regenerative fibers, macrophages Infiltration and interstitial fat connective tissue hyperplasia.
(4) SMA-IV type: Muscle pathological changes are similar to SMA-III type.
Diagnosis
Diagnosis and differentiation of spinal muscular atrophy
According to this disease, only the lower motor neurons are involved, the limbs are progressive flaccid paralysis, the proximal end is heavier than the distal end, the lower limb is heavier than the upper limbs, and the clinical manifestations of the cervical or lumbar spine are not consistent with the clinical manifestations, and the muscles. Electrograms, muscle pathological examinations, etc., are generally not difficult to make a diagnosis.
If there is a positive family history, it supports diagnosis. Genetic testing can provide reliable evidence for establishing diagnosis, and then make a classification diagnosis based on clinical characteristics, age of onset, prognosis and genetic mode.
Differential diagnosis
Neonatal myasthenia gravis
The mother is a myasthenia gravis patient, which is related to the anti-Ach receptor antibody in the mother's blood reaching the fetus through the placenta. Generally, it is characterized by difficulty in sucking, weak crying, and decreased limb movement after birth. Most of the children are in 2 Symptoms gradually improved within ~6 weeks and were effective with cholinesterase inhibitors.
2. Congenital dystonia (Oppenheim disease)
There was a decrease in muscle tone after birth, no muscle atrophy, no abnormalities in EMG and muscle biopsy.
3. Progressive muscular dystrophy
In SMA-II, type III children, it is necessary to distinguish between Duchenne type or Becker type muscular dystrophy, which has almost all signs of pseudohypertrophy, and its serum CPK is extremely high, especially in the early stage of the disease, EMG and Muscle biopsy is myogenic damage, so the general identification is not difficult, SMA-IV is easy to be confused with limb-type muscular dystrophy and polymyositis, but from clinical manifestations, serum enzymology, EMG and muscle biopsy, etc. Analysis of the characteristics of the aspect is not difficult to distinguish.
