Genetics

SMA is a genetic disease. To understand the inheritance of SMA, let us review some fundamentals of genetics. Our bodies are made of billions of cells. Each cell has a nucleus containing 46 chromosomes. Chromosomes carry the complete set of instructions for directing the form, growth, and function of every cell in our body. Our 46 chromosomes are arranged as 23 pairs. One member of each pair is inherited from each parent at the time of conception. Each chromosome is made up of a long spiral of DNA (deoxyriboneucleic acids). A gene is a particular sequence of DNA, found on a chromosome containing a particular set of instructions. The gene for SMA is called survival motor neuron (SMN) and is located on chromosome 5. SMN encodes instructions for a protein that is necessary for certain nerve cells to continue living and functioning.

Genetic disorders can occur when genes are altered or contain mistakes called mutations. The most common mutation seen in 95% of individuals with SMA is a deletion of one portion of the gene (exon 7). In most individuals with SMA the mutations are inherited from a parent. The mutations are transmitted in an autosomal recessive manner. Autosomal recessive traits require two copies of the gene to be mutated for the disease to manifest itself. A person who inherits one copy of the recessive gene does not develop disease because the normal gene compensates for its non-functioning copy. If only one parent is a carrier, there is a 50 percent chance of passing the mutation to each of his or her children. Children who are carriers do not have any medical problems. When both parents are carriers, there is 25 percent chance that any of their children (boys or girls) will inherit two recessive mutations (one copy from each parent) and develop SMA.

Genetic testing is available to diagnose SMA and determine if parents or other members of the family are carriers for SMA. It is always best to start the genetic testing on the individual with SMA. Once the two mutations are identified in the person with SMA, the parents and/or siblings should be tested for the mutation(s) identified in the SMA patient as well as the most common mutation (exon 7 deletion). Your pediatrician, internist, or OB/GYN should be able to provide you with a referral to a genetics center to have this carrier testing. Genetic testing will require one tube of blood and generally takes approximately 4 weeks until results are available. The cost of carrier testing varies by laboratory but is several hundred dollars. Many insurance plans pay for some or all of the cost testing, but you should check with your insurance company for coverage before testing is sent. If the genetic testing demonstrates that the relative of the patient with SMA is a carrier, the spouse or partner of that family member should then be genetically tested for the common exon 7 deletion. Because SMA is an autosomal recessive condition, both parents must be carriers to have a child with SMA. The genetic test results should be interpreted by a clinical geneticist to accurately determine the risk of having a child with SMA. There are unusual circumstances in which the common exon 7 deletion will not be detected in the general population. Therefore, genetic counseling and interpretation should accompany any genetic testing for SMA.

If both parents are carriers, there is a 25% chance they will have a child with SMA. There are a variety of reproductive options available. Regardless of how many previous children they have had with SMA, each pregnancy is independently at 25% risk of SMA. Prenatal testing with either amniocentesis at 15 weeks of gestation or beyond or chorionic villus sampling at 10 weeks of gestation or beyond is available to genetically test a fetus for SMA. Amniocentesis and chorionic villus sampling are generally safe but carry 0.5% and 1%, respectively, risks of complication or pregnancy loss. Therefore, amniocentesis and chorionic villus sampling should only be performed by experienced obstetricians. Genetic results are usually available within two to four weeks of the procedure. In addition, in vitro fertilization with preimplantation genetic diagnosis is available to genetically test embryos prior to implantation. In vitro fertilization with preimplantation genetic diagnosis allows for reproductive choice prior to pregnancy. Couples who are both carriers for SMA should consult a genetics professional to review these reproductive options prior to conception to review the medical risks and benefits of each procedure.