Pediatric spinal muscular atrophy

Introduction to spinal muscular atrophy in children Spinal muscle atrophy (SMA), progressive spinal muscular atrophy (spontaneous spinal muscular atrophy), spinal muscular atrophy, is a type of spinal cord anterior horn motor neurons and brainstem motor neuron degeneration leading to muscle weakness, muscle atrophy The disease is an autosomal recessive genetic disease, which is not uncommon in clinical practice. According to the age of onset and the severity of myasthenia, it is divided into SMA-I type, SMA-II type, SMA-III type three, namely infant type, juvenile type and intermediate type. The common feature is the anterior horn cell degeneration of the spinal cord. The clinical manifestation is Progressive, symmetrical, extensive flaccid paralysis and muscle atrophy dominated by the proximal extremity. Both mental development and sensation are normal. The difference between the types depends on the age of onset, the speed of progression, the degree of muscle weakness and the length of survival. To date, there is no specific effective treatment for SMA. The main treatment measures are prevention or treatment of complications caused by various severe muscle weakness, such as pneumonia, malnutrition, skeletal malformations, mobility disorders and psychosocial problems. The following focuses on infantile spinal muscular atrophy. basic knowledge The proportion of illness: 0.0021% Susceptible people: children Mode of infection: non-infectious Complications: abnormal gait malnutrition

Causes of spinal muscular atrophy in children

(1) Causes of the disease

The cause is not clear. According to family analysis, most scholars believe that it is autosomal recessive inheritance, and a small part is caused by gene mutation. It is unclear whether there are biochemical defects. The disease type 3 is abnormal for positional genes such as autosome 5q12-14. Men and women can be sick, generally more men than women, the disease is common in children's siblings, due to the presence of genetic defects, embryonic early spinal cord anterior horn cells are normal, the pathological process of apoptosis continues, so that patients after birth motoneurons Degeneration and necrosis.

(two) pathogenesis

1. Pathogenesis: In 1990, Gillian et al reported that the SMA gene locus was on chromosome 5q11.2-11.3. In 1994, Meli et al found that severe SMA (Werdnig-Hoffmann type) patients had large gene mutations in 5q11.2-11.3. Lighter patients (Kugelberg-Welander type) have no genetic mutations or less mutations.

There are two genes related to SMA, namely neuronal apoptosis inhibitory protein (NAIP) and survival motoneuron (SMN). The NAIP gene is located in the 5q13 region, 67%. This gene mutation occurs in SMA patients, compared with 2% in the normal population, and the SMN gene is also located in the 5q13 region. More than 98% of SMA patients develop this gene mutation, and there are 2 SMN alleles in the 5q13 region. : SMN1 and SMN2, only the homozygous deletion of the SMN1 gene leads to SMA, while the homozygous deletion of the SMN2 gene occurs in 5% of the normal population, 96% of SMA patients suggest a SMN1 gene mutation, and 4% does not Of the 5q13-linked, 5q13-linked SMA patients, 96.4% showed homozygous deletions in exon 7 and 8 or exon 7 of SMN1, multiple copies of SMN gene [SMNt (telomeric), SMNc (centromeric)], and different The genetic heterogeneity of exon deletion has brought great challenges to the study of SMA. The correlation between the copy number of SMN gene and the severity of clinical symptoms is still under observation. Every SMNt and SMNc of normal people have 2 alleles, SMNt Mutations in the two alleles may be associated with disease, and mutations in SMNc have little or no association with disease. Current studies have shown that SMNt is converted to SMNc in some patients with SMA-II and SMA-III, meaning SMNc copy number increases the severity of clinical symptoms.

The product of the SMN gene is known to interact with RNA-binding proteins, but its exact function has not been elucidated. Compared with the normal population, the reaction products are deleted in neurons of SMA-I patients, while in SMA-II and SMA-III. The reduction in type, if these studies are further confirmed, will be an important step in understanding the pathogenesis of SMA. It is precisely because of the mutation of the gene that the transformation causes the anterior horn motor neurons of the spinal cord and the brainstem motor nucleus to degenerate, eventually leading to muscle weakness. Muscle atrophy.

2. Pathological changes: various types of SMA have different pathological characteristics:

(1) SMA-I type: Muscle pathological features are 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 fibers can be involved, and Incomplete homotypic muscle grouping, atrophic muscle fibers are similar in appearance to those of immature fibers and developmental disorders in embryonic muscle fibers, which the authors call embryonic or infantile muscle fibers.

(2) SMA-II type: muscle pathological changes are similar to SMA-I type, but large group of atrophic muscle fibers are not common, while homogenous muscle grouping is more prominent, some children who are older and enter a relatively stable period, There may be changes in secondary muscular damage, including increased central nucleus and muscle fiber tear.

(3) SMA-III type: This type can have multiple manifestations in muscle pathology. Some cases show only slight changes, such as group homologous muscle grouping, a small amount of atrophic muscle fibers, etc., its shape is generally normal, most serious cases, muscle The performance of biopsy is related to the disease stage. In early childhood, the shrinking fiber is the main feature, and the same type of muscle grouping 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. Muscle fiber hypertrophy changes are very prominent, diameter up to 100 ~ 150m, often associated with secondary myogenic damage, including fiber tear, central nucleus changes, NADH staining see moths and fingerprint fibers, a small amount of necrotic and regenerated fiber, giant Phagocytic infiltration and interstitial fat connective tissue hyperplasia.

Prevention of spinal muscular atrophy in children

Prenatal diagnosis of SMA is carried out with the deepening of SMA gene research. It has been reported in the domestic use of pregnant women's villi (6 to 10 weeks of pregnancy) to predict fetal disease. The advantage of this method is that in the family that did not obtain the specimen of the proband, Prenatal diagnosis can be performed and the pregnancy should be terminated if necessary.

Pediatric spinal muscular atrophy complications Complications, abnormal gait, malnutrition

Difficulties in feeding and difficulty in breathing, muscle atrophy, abnormal gait, deformation of hands and feet, chest dislocation due to weakness of intercostal muscles, asymmetrical thoracic deformity and dislocation of the humeral head, deformation of the spine, joint flexion, loss of motor function, prone to error Suction, severe pneumonia complications, life-threatening, psychosocial problems can occur, causing malnutrition or eventually dying from respiratory muscle paralysis or systemic failure.

Symptoms of spinal muscular atrophy in children Common symptoms Muscle atrophy gait abnormal limb weakness symmetry muscle weakness joint contracture tremor gait dyspnea muscle tension reduce facial muscle weakness

Most patients with this disease are SMA-I, followed by type II, and type III has the lowest incidence.

1. Infant spinal muscular atrophy: also known as SMA-I or Werdnig-Hoffmann disease, this type is the most serious of type 3, according to foreign reports, the incidence rate is 1/2 million live births, about 1/3 of cases Intrauterine morbidity, fetal movement is weakened, half of which can occur at the time of birth or the first few months after birth, and almost all occur within 5 months, and rarely survive for 1 year. These children have symptoms during the fetal period. Fetal movement is reduced, there are obvious limb weakness after birth, feeding difficulties and breathing difficulties, clinical characteristics:

(1) Symmetrical muscle weakness: First, the lower limbs are involved, progress rapidly, active movement is reduced, the proximal muscles are the most affected, and can not sit alone. Finally, there is still slight activity in the development of hands and feet.

(2) Muscle relaxation, tension is extremely low: when the child is lying, the lower limbs are in the position of the frog leg (Fig. 1), the hip abduction, the special position of the knee flexion, and the tendon reflex is reduced or disappeared.

(3) Muscle atrophy: can affect the limbs, neck, trunk and chest muscles, because the baby has more subcutaneous fat, so muscle atrophy is not easy to find.

(4) intercostal muscle paralysis: mild, may have obvious compensatory abdominal breathing, in addition to severe breathing difficulties in severe cases, invisible sternal depression, that is, chest-type contradiction breathing, diaphragmatic movement is always normal .

(5) motor nerve damage: the most common sublingual nerve involvement, showing tongue muscle atrophy and tremor.

(6) The prognosis is poor, the average life expectancy is 18 months, and most of them die within 2 years of age.

2. juvenile SMA: also known as SMA-II type, intermediate SMA or chronic SMA, the incidence is slightly later than type I, the onset is more than 1 year old, the progress is slow, and the child grows and develops at 6-8 months. Normal, most cases show severe muscle weakness with proximal end, lower limbs than upper limbs; multiple micromyoclonus is the main manifestation; respiratory muscles, swallowing muscles are not tired, facial muscles are not tired, sphincter function is normal, this type has A relatively benign course of disease, with a survival period of more than 4 years, can survive until puberty.

3. Juvenile spinal muscular atrophy: also known as SMA-III, also known as Kugelberg-Welander disease, Wohlfart-Kugelberg-Welander syndrome or mild SMA, is the lightest type of SMA, the disease in children Symptoms appear in late or adolescence, beginning with abnormal gait, weak muscles in the proximal extremities, slowly progressing, gradually spreading to the distal and upper limbs of the lower extremities, and can survive to adulthood, showing neurogenic proximal muscle atrophy, easy limbs Confounding with muscular dystrophy, children with phosphatidylinosine kinase are often elevated, and SMA-III children who can walk can have squat gait, lumbar anterior protrusion, abdominal bulge, and tendon reflexes are optional. The walking time is closely related to the age of onset of muscle weakness. Before the age of 2 years, the patients will not be able to walk around 15 years old. After 2 years of age, the patients can maintain walking ability until the age of 50. A large number of prospective clinical studies have shown that SMA- Type II and III have slow or no progression of myasthenia symptoms within a few years.

In addition, atypical SMA progressive medullary paralysis (Fazio-Londe disease), patients with progressive brain damage nucleus, the number is gradually reduced, causing progressive bulbar palsy, but with or rarely associated with anterior horn motoneurons Impaired, the disease often occurs in the first few years after birth, manifested as obvious facial muscle weakness and other cranial nerve motor nucleus involvement symptoms, usually in the V-nucleus below the cranial nerve, the extraocular muscle is generally not tired .

Recently, molecular biology studies have confirmed that at least some patients with SMA may be associated with joint flexion. Bingham et al found that SMN gene deletion was found in two infants who died of respiratory failure and joint flexion, while the other two infants without joint contracture did not. Deletion of the SMN gene suggests that children with joint flexion and muscle weakness or hypotonia should be tested for SMN gene mutations.

Examination of spinal muscular atrophy in children

1. Genetic diagnosis: Since the discovery of the SMN gene, the diagnostic process of SMA has changed. The SMN gene mutation can be detected by blood DNA analysis to diagnose the disease. Once the SMN gene mutation is found, no additional examination is needed to confirm the diagnosis. For SMA, PCR restriction endonuclease method is used to detect the deletion of exon 7 and 8 of SMN gene, which can rapidly diagnose children's SMA. In addition, PCR-SSCP analysis, haplotype linkage analysis is also an effective method for diagnosing SMA. The combination of the three can be mutually verified and complement each other to improve the accuracy of prenatal genetic diagnosis. Some scholars have used PCR and PCR endonuclease to detect gene deletion in SMA patients. The results show that SMA-I and II can pass. The detection of exon 7 and exon 8 of SMN gene is confirmed. The method is simple and reliable. The deletion rate of SMN gene in type III patients is low. It is necessary to be cautious when detecting the gene of SMN gene 7,8 exon. The NAIP gene is involved in the pathogenesis of SMA. The role is still unclear and needs further study. If there is no SMN gene deletion, the following traditional examination methods are needed to confirm the diagnosis. Serum creatine phosphokinase is detected. (CK) assay; electrophysiological examination includes detection of nerve conduction velocity (NCV) and electromyography (EMG) and muscle biopsy.

2. Serum CPK: SMA-I type is normal, type II is occasionally increased, type III is often increased, isozyme change is mainly MM, and increases with the development of muscle damage. When the muscle atrophy is advanced, CK begins to decline. This is different from muscular dystrophy, which peaks in infants and young children and then gradually declines.

3. Muscle biopsy: Muscle biopsy is of great significance for the diagnosis of SMA. Its pathological features are denervation and nerve re-innervation. Each type of SMA has different muscle pathological features, and the same type of muscle is formed in the early stage. In the advanced stage, there may be muscle fiber necrosis.

The appearance of fibrillation potential in the electromyogram is extremely high in the disease, which is as high as 95% to 100%. When the light contraction, the potential time of the motor unit is prolonged, the amplitude is increased, the number of exercise units is decreased during re-contraction, and the nerve conduction velocity is normal. , suggesting neurogenic damage, electrophysiological (NCV and EMG) examination can reflect the severity and progress of SMA, but the EMG changes are similar, including fibrillation potential, and the composite motion unit potential (MVAPS) amplitude increase time limit And the interference phase is reduced, the fibrillation potential and the positive sharp wave can appear in all types of SMA, but the SMA-I type is more obvious. When the motion is free, all types of SMA see the interference phase decrease, especially the type I SMA is only single. Phase, low-wave multiphase potential similar to myogenic damage can be seen in more advanced type III SMA.

Electrophysiological examination NCV showed that the motor conduction velocity could be slowed down, and type I slowed down, while other types were normal; sensory conduction velocity was normal, and it was difficult to detect infant exercise NCV because the infant's limb was small and the stimulation point and recording electrode were difficult. The distance is short and the test results are often normal conduction rates, or sometimes faster than expected.

Diagnosis and diagnosis of spinal muscular atrophy in children

diagnosis

Generally, those with typical clinical symptoms and family history mentioned above are not difficult to diagnose. The following SMA-I diagnostic criteria are described below (Cobben, 1993):

1. Symmetry Progressive proximal limb and trunk muscle weakness, muscle atrophy, no involvement of facial muscles and extraocular muscles, no hyperreflexia, sensory loss and mental retardation.

2. Family history is consistent with autosomal recessive inheritance.

3. Serum CPK is normal.

4. Electromyography suggests neurogenic damage.

5. Muscle biopsy is consistent with anterior horn cell lesions.

The above conditions 1 to 4 or 1, 3, 4, 5 can confirm the disease.

Differential diagnosis

Spinal muscular atrophy should be differentiated from other diseases characterized by low muscle tone and motor development retardation. It needs to be differentiated from congenital muscle relaxation, progressive malnutrition, and progressive neuromuscular atrophy.

1. Identification with muscular dystrophy: spinal muscular atrophy has abnormal manifestations such as muscle atrophy, muscular dystrophy, gastrocnemius muscle has pseudohypertrophic performance and laboratory test results are easy to identify.

2. Identification of muscle flaccid cerebral palsy: muscle flaccid cerebral palsy should be differentiated from infantile SMA, both of which show low muscle tone, but the former sputum reflex exists, often accompanied by mental retardation, the latter sputum reflex disappears, The intelligence is normal and the EMG indicates neurogenic damage.

3. Others: In addition, the disease should be differentiated from chronic inflammatory demyelinating polyneuropathy (CIDP), congenital myopathy, mitochondrial myopathy, etc. In addition to the clinical features of the respective diseases, electromyography and muscle biopsy results are important diagnostic criteria. .

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