What is Spinal Muscular Atrophy
Spinal Muscular Atrophy (SMA) is an autosomal recessive disorder with a high prevalence and is the second most common neuromuscular disease clinically after DMD. It is the most common lethal disease of infancy. The causative gene is the SMN gene. Mutations in this gene cause progressive degeneration of the anterior horn motor neurons of the spinal cord, resulting in progressive weakness, incompetence and atrophy of the skeletal muscles. The affected child or patient has normal intelligence.
Carriage and prevalence of the gene in the population
The frequency of the pathogenic SMN mutation is quite high in the population, generally reported in the literature to be about 1/40-60, with a prevalence of ~4/10,000. there is a lack of large-scale population data in mainland China; in Taiwan, the carriage rate is about 1-3%, with a prevalence of 1/10,000.
SMA causative gene
The cause of SMA pathogenicity is located in band 3 of region 1 (5q13) on the long arm of chromosome 5. The human genome contains two highly homologous SMNs, SMN 1 and SMN2, which are arranged in tandem: SMN1 is a functional gene and SMN2 can have multiple copies on the same chromosome, and the number of copies can influence the degree of clinical expression. About 95% of SMA patients have a deletion of a large segment of pure exon 7 of the SMN1 gene, which can be accompanied by a deletion of exon 8, and a few others may have a small mutation in the SMN1 gene.
The vast majority of normal individuals have two (and a few have more than two) SMN1 genes, while carriers have only one SMN1 gene.
Current conventional genetic testing methods can only detect deletions in large segments of the gene, such as exon 7 or/and exon 8 deletions. Small point mutations cannot be detected and require special tools.
Clinical manifestations and typing of SMA
SMA mainly presents with muscle weakness of the trunk extremities, symmetrical; lower extremities are often heavier than upper extremities, distal extremities heavier than proximal segments, and low muscle tone; facial muscles are not involved; tendon reflexes are absent; deep and superficial reflexes are normal; there is no intellectual impairment and no sphincter impairment.
According to the age of onset and the severity of the disease can be simply divided into three types
Type I, severe: the manifestations of muscle weakness often appear within the first 6 months of life and often die before the age of 2 years due to expiratory failure.
Type II, moderate: symptoms such as muscle weakness often appear between 6 months and one and a half years of age, can sit alone, but cannot stand or walk on their own, and most can live to be over 4 years old.
Type 3, mild: Symptoms tend to appear over the age of 1.5 years and can walk on their own, but will often require crutches or a wheelchair as an adult.
What are the ancillary tests that may help in the diagnosis?
The main ones are serum CK test; electromyography. Genetic diagnosis can confirm the diagnosis.
Mode of inheritance of SMA
SMA is an autosomal recessive disorder that follows the inheritance pattern of recessive disorders.
The human chromosomes are paired, so the genes are also paired, one of which is inherited from the father and the other from the mother. These two genes are referred to as a “pair of alleles”. A recessive disorder is a disease that manifests itself when there is a mutation (called a pure or compound heterozygous mutation) in both alleles of the pair. A pure mutation means that the pair of alleles inherited from the parents is identical; a compound heterozygous mutation means that the pair of alleles is different.
For recessive genetic disorders.
Individuals with one disease-causing gene are called carriers and have no abnormal expression, but can pass the disease-causing gene to their children. Therefore, the possibility of having a child with the disease is only possible if both parents are carriers.
The genetic characteristics are as follows.
1. the causative gene is located on the autosomes and is therefore independent of sex, with equal risk of disease in both sexes
2. patients often appear in siblings; patients whose parents do not develop the disease are disseminated in the genealogy or appear intergenerationally.
3. both parents are carriers of the mutation, with a risk of 1/4 (25%) in siblings and 1/2 (50%) in carriers
4. The risk of offspring is significantly higher in consanguineous marriages. The mode of inheritance is shown in the figure below.
Pre-conception screening and prenatal diagnosis
Due to the high frequency of SMA carriage in the population, it is relatively easy to encounter it in population marriages, and the carriers do not show it, so the couple will not find it if they do not have children for life. For couples who do not have children, there is no abnormality in the carrier, so there is no need to know. However, if a couple is planning to have children and both couples happen to be carriers, there is a possibility of having a child with the disease, and there is a 1/4 chance of having a child with the disease in each case.
Because SMA is a serious disease with normal intelligence and there is no treatment available, both the patient and the family members are in great pain. Therefore, in some developed countries and Taiwan Province, couples who intend to have children are offered SMA gene carrier testing. If one spouse is not a carrier of SMA gene mutation, the other spouse does not need to be tested; if one spouse is a carrier, the other spouse must be tested, because if she is also a carrier, there is a possibility of having a child with the disease. In such cases, prenatal genetic diagnosis must be performed to clarify the fetal condition and prevent the birth of a child with the disease.
Genetic testing methods
For general population screening or patient testing, 1~2ml of peripheral venous blood can be taken and DNA extracted for genetic analysis. The methods are PCR electrophoresis, Real time PCR and MLPA. The first method can only diagnose patients, while the latter two methods can detect carriers.
Genetic counseling is recommended for everyone who wishes to be tested. It is emphasized that it is best to go to a unit qualified in genetic testing for genetic testing. If prenatal diagnosis (intrauterine diagnosis of the fetus) is involved, be sure to go to an institution qualified in prenatal diagnosis for testing.