summarize

Spinal muscular atrophy (SMA) is one of the most common infantile autosomal recessive genetic diseases. It is mainly the degeneration of motor neurons in the anterior horn of the spinal cord caused by the mutation of motor neuron survival gene 1. The main clinical manifestations are myasthenia and muscular atrophy. The overall population carrying rate of SMA pathogenic variation in China is 1.2%~2.2%, and the risk of birth defects is high. Tertiary prevention strategies can effectively reduce the incidence of SMA.

In order to further standardize the SMA tertiary prevention in China, the Neurogenetics Group of the Neurology Branch of the Chinese Medical Association led domestic multidisciplinary experts to follow the writing norms of domestic and foreign guidelines, according to the research status quo and the characteristics of patients in China, referring to the latest international research evidence, and drawing on the relevant guidelines, and finally summarized the SMA tertiary prevention guidelines suitable for China's national conditions. The promulgation of the guidelines will play a positive role in the prevention of SMA in China, has important practical significance, and will have a far-reaching impact.

Target population

 Key population

(1) Family members who have been diagnosed with SMA;

(2) SMN1 pathogenic variant carriers (SMA carriers) and their spouses;

(3) Couples who have given birth to SMA children;

(4) Patients with clinical manifestations of SMA.

General population

All people of reproductive age without a clinical event of SMA

SMA tertiary prevention strategy

Primary prevention

Universal carrier screening and intervention to prevent SMA birth defects.

High-risk groups: family members diagnosed with SMA, SMA patients or carriers and their spouses (Level A recommended);

General population: All people of childbearing age without a clinical event of SMA (Grade B recommendation)3. Carrier screening: It is recommended that both spouses be screened at the same time (Grade B recommendation).

Secondary prevention

Reduce the incidence of SMA birth defects through prenatal diagnosis.

● Couples who have given birth to SMA children (Grade A recommended);

● Both spouses are SMA carriers (Level A recommended);

● Children who have given birth to clinically diagnosed SMA, but the child has not undergone genetic diagnosis, and the second child is confirmed by SMNI genetic test to be the husband of SMA carriers (Grade A recommended).

Tertiary prevention

Avoiding or mitigating clinical consequences through neonatal/childhood screening.

 ●Recommend that newborns/children with one or both parents who are carriers be screened for SMA (Level A recommendation);

● Recommended newborn screening for SMA (Grade B recommendation);

● It is recommended for newborns/children with suspected manifestations to detect deformities and defects early through standardized diagnosis and 

treatment procedures (Grade A recommendation);

● It is recommended to conduct differential diagnosis of other diseases with myasthenia as the main symptom for suspected patients with no SMNI biallelic pathogenic variation or with atypical symptoms, or with non-SMA clinical manifestations (grade B recommendation);

●For patients with A clear genetic diagnosis, it is necessary for their parents to undergo SMNI testing (Grade A recommendation);

● When no homozygous deletion of SMNI or complex heterozygous variation is detected in the subject, but there is a clear clinical manifestation of SMNI, especially when the patient's parents are close relatives, complete sequence analysis of the SMNI base country should be performed (Grade B recommendation).

Methods of examination for SMA

◉ Serum creatine kinase test: normal or mildly elevated serum creatine kinase level.

◉ electromyography: Indicates extensive neurogenic damage.

◉ Gene testing: MLPA, qPCR can detect SMN1 gene copy number variation, such as exon 7 or exon 7, 8 homozygous deletion mutation; Nested PCR can detect small variations in the exon and adjacent intron regions of SMN1 gene. Second generation sequencing can be used for SMA differential diagnosis to screen for other myasthenia-related diseases. Third generation sequencing can detect both copy number variation and small variation of SMN1 gene.

SMA diagnosis

● Clinical manifestations: The main manifestations are progressive muscle weakness in the proximal symmetrical limb, the lower limb is heavier than the upper limb, and muscle tremor can be seen on physical examination. Based on age of onset, motor milestones, and progression of the disease, SMA is clinically classified into five types: type 0, type 1, type 2, type 3, and type 4. Among them, type 1 accounts for the most, and type 4 accounts for a relatively small proportion. The clinical manifestations and survival time of different types of SMA are shown in Table 3.

●Auxiliary examination: Serological examination shows normal or slightly elevated creatine kinase values, and electromyography indicates extensive neurogenic damage.

●Genetic diagnosis: Genetic testing shows homozygous deletion mutation or biallelic mutation of SMN1 exon 7, and a positive result can confirm SMA.

● Differential diagnosis: When patients are clinically considered for SMA but the genetic test does not show SMN1 biallelic pathogenic variation, or the clinical symptoms are atypical, or accompanied by non-SMA clinical manifestations, a differential diagnosis is required from other diseases with muscle weakness as the main manifestation. For example, children under 6 months need to be identified with other soft infant syndromes, and children over 6 months need to be identified with other neuromuscular diseases. Second generation sequencing is often used for differential diagnosis.