An information leaflet for patients and families

Transcription

1 Birmingham Women's NHS Foundation Trust Spinal Muscular Atrophy (SMA) An information leaflet for patients and families This is a no smoking hospital

2 What is SMA? Spinal Muscular Atrophy (SMA) is a genetic disease that affects muscle movement. It causes the motor neurons in the spinal cord to deteriorate. Motor neurons are nerve cells in the spinal cord. They send impulses to the muscles, telling them to relax or contract. As the motor neurons deteriorate, the link between the brain and the muscles is broken down. As a result, the muscles used for activities such as crawling, walking, sitting up, moving the head, swallowing and breathing become weaker and shrink (atrophy). Symptoms SMA affects muscles throughout the body, although the proximal (those closest to the shoulders, hips and back) are usually most seriously affected. They are also affected much sooner than the muscles further away from the centre of the body. For example, the muscles of the thighs become weaker than the muscles of the lower legs and feet. This process is gradual and will eventually affect all muscle groups in the body apart from the heart. SMA does not affect intelligence. How many types of SMA are there? SMA is classified into four types, based on the age at which it develops and the severity of symptoms. Type I, II and III develop at different stages of childhood. SMA type I is also known as Werdnig-Hoffman disease, Type I is the most severe form. It can develop before birth (some mothers notice decreased movements of the baby in the final months of their pregnancy) up to six months of age. Babies with Type I have weak, thin muscles that make them limp or floppy and unable to sit without support or to raise their head. They usually have breathing and swallowing problems due to the 2

3 weakness of their chest muscles. These very significant muscle problems lead to a reduced life expectancy and affected children are unlikely to live past their second birthday. Types II and III develop after 6 months of age, again with progressive muscle weakness. Type IV is SMA that starts in adulthood, with symptoms usually beginning over the age of 35. What is the cause? SMA is caused by alterations or deletions in a gene known as SMN1 (Survival Motor Neuron 1 gene) on chromosome 5. This gene is responsible for making the Survival Motor Neuron protein. Without it, motor neuron cells in part of the spinal cord deteriorate and die causing SMA. Genes and chromosomes Inside most cells of our body, we all have about 25,000 genes, which are the instructions that tell our body how to grow and develop. Half of these genes we inherit from our mother and the other half from our father. Therefore, we have two copies of each gene and they are stored on 23 pairs of chromosomes (karyotype). When we have children, we pass on only one copy of each of our genes by passing Figure 1. Karyotype one of each pair of chromosomes. If a gene is altered, it can cause a genetic condition or disease. SMN1 gene located on chromosome 5 3

4 Inheritance SMA is an autosomal recessive condition. This means that, for a child to be affected by SMA, both of their SMN1 genes will be deleted/ altered. In the majority of cases, each parent will have passed on a deleted/altered gene, which does not work. Boys and girls are equally affected. The parents of an affected child usually have one normal copy of the gene and one deleted/altered copy. This is known as being a carrier. Carriers are unaffected and have no muscle problems. They are not at risk of the condition. When both parents are carriers, there is a 25% (1 in 4) chance of having a child with two altered/deleted copies of the gene and thus having SMA for each pregnancy. This also means that there is 75% chance of not having a child with SMA for each pregnancy (see diagram below). About 1 in 50 people carry the deleted/altered gene. This risk figure varies with ethnic group. Figure 2. Autosomal Recessive Inheritance: Both Parents are Carriers carrier father carrier mother unaffected affected carrier unaffected child carrier child carrier child affected child 4

5 Are all gene alterations inherited? No, about 2% of gene alterations are brand new or de novo. A de novo gene alteration occurs for the first time in the individual but it is not present in the parents. This individual can then pass the altered gene on to their children. Sometimes an individual can have 2 copies of SMN1 (non-carrier) in their blood cells but have a de novo altered gene is some of their eggs/sperm. This person will still be at risk of passing the altered gene on to their children & having a child with SMA (if the other parent is a carrier). Carriers People usually have 2 normal copies of the SMN1 gene (one on each chromosome 5), but some can have 3 or more. Having extra copies of the gene doesn t cause any health problems. Figure 3. Normal amount of gene copies - people with 2 or more copies of the SMN1 gene Normal A Normal B 2 copies of the gene on the same chromosome 1 copy on the other chromosome or 1 copy on each chromosome This individual has 3 copies This individual has 2 copies 3 Carriers generally have one working SMN1 gene and one deleted/ altered copy (Fig.4, Carrier C). However, someone who has both of their copies of the SMN1 gene on one chromosome and no copies on the other chromosome 5 is also a carrier (Fig 4, Carrier D). 5

6 Figure 4. Types of Carriers Carrier C or Carrier D This person has 1 copy of the gene on 1 This person has 2 copies of the gene on one Autosomal Recessive Inheritance in SMA outcomes depending on type of carrier Figure 5. Autosomal Recessive Inheritance: Both Parents are Carriers (Carrier D, see figure 4 above) Dad carries 2 copies on one Mum carries 2 copies on one Unaffected child Carrier Child Carrier Child Affected Child 6

7 Figure 6. Autosomal Recessive Inheritance: Both Parents are Carriers (Carrier C, see figure 4 above) Dad carries 1 copy on one Mum carries 1 copy on one Unaffected child Carrier Child Carrier Child Affected Child 7

8 Figure 7. Autosomal Recessive Inheritance: Both Parents are Carriers - carrier C & carrier D see figure 4 above Carrier D carries Dad carries 2 2 copies on one copies on one Carrier C carries Mum carries 1 1 copy on one copy on one Unaffected child Carrier child Carrier child Affected child Carrier testing SMA carriers have 1 or 2 copies of the SMN1 gene on one chromosome and NO copies on the other chromosome 5 (Fig 4). SMA carriers can be identified by a blood test (called dosage analysis), which looks at the number of SMN1 copies. If the test shows one copy of the SMN1 gene, that individual is a carrier (Fig.4, Carrier C). Dosage analysis does not identify 100% of SMA carriers. Usually, for people with 2 copies of SMN1, there is one copy of the gene on each chromosome 5, called 1+1 arrangement (Normal B; fig.3). However, a person can also have 2 copies of the SMN1 on the same chromosome and no copies on the other chromosome, known as 2+0 arrangement (Carrier D; fig.4). An individual with this pattern is also a carrier.

9 Dosage analysis cannot tell the difference between 1+1 and 2+0 arrangement as both are detected as having 2 SMN1 gene copies (Fig. 8). Figure 8. Both people have 2 copies of the gene. One has one copy on each chromosome, whereas the other has both copies on the same chromosome. Dosage analysis cannot tell these people apart as it counts the number of gene copies. Not a carrier (B) Carrier (D) 1+1 Arrangement. Not at increased risk to have a child with SMA 2+0 Arrangement. At increased risk to have a child with SMA We are able to identify if an individual is a carrier for SMA in the majority of cases (82%).However, if your test result shows that you carry 2 SMN1 gene copies, we will not be able to confirm if you are a carrier (D, 2+0 ) or not a carrier (B, 1+1 ). How often a 2+0 arrangement happens depends on your ethnic group. The figures vary but in between % of individuals carrier status cannot be determined. So, an individual s carrier risk may be underestimated depending on their ethnic origin and family history. Is there a cure? At present there is no cure for Spinal Muscular Atrophy and there is no treatment that can repair the motor neurons of the spinal cord or reverse the progressive weakening of the muscles caused by SMA. As a result, treatment for SMA focuses on the symptoms and on supportive care.

10 Options in pregnancy Prior to pregnancy: It is now possible to have PGD (preimplantation genetic diagnosis) for SMA. Invasive prenatal testing, associated with around 1:100 (1%) risk of miscarriage, is also available for couples who may wish to know if their baby may be affected with SMA. -- A chorionic villus sampling test also known as CVS is performed after 11 weeks of pregnancy -- A test called amniocentesis is also available later in pregnancy (from 16 weeks) If you wish to consider any of the tests available in pregnancy it is very important to contact your local Genetics Centre before nine weeks of pregnancy to make arrangements for the test. Questions Can I be SMA carrier? Yes, you could be a carrier of SMA, even if no one in the family has SMA. About 1 in 50 people will carry the deleted/altered gene. This figure can vary depending on your ethnic background, as it is more common in some populations than others. If a relative of yours has SMA, or is known to be a carrier of SMA, your chance of being a carrier is greater based on your family history. How common it is to have 2 copies of the SMN1 gene on the same/on one chromosome? This depends on the ethnic origin of the person. Approximately % of people have 2 SMN1 gene copies on the same chromosome (see Fig. 4 Carrier D). This is more common in some ethnic groups than others. At least 6% of Northern Europeans and around 17.2% of people of Asian descent carry 2 SMN1 gene copies on the same chromosome. I am a carrier, what should I do? If you are considering having children, your partner may wish to be tested. When both parents are carriers, there is a 1 in 4 (25%) chance

11 (with each pregnancy) that their baby may have SMA. If your partner is not a carrier & has no family history of SMA, the chance that your baby will have SMA is very small. Being a carrier also means that some of your relatives may also be carriers. They could be referred to their local genetics centre to find out their carrier status. Will my children be at risk of SMA if I am a carrier? In the majority of cases, individuals are only at risk of SMA if both their parents are carriers. Thus, the risk for your children will depend on whether their other parent is a carrier. Also, if both parents are SMA carriers, there is a 1 in 4 (25%) chance (for each pregnancy) that each of your children will be affected by SMA. This is true even if you already have other children with or without SMA. If you are SMA carrier but your partner is not, the chance of having a child with SMA is extremely small. Your children will each have a 50% chance of being a carrier. If I am a carrier, should my children have the test? This depends on how old your children are. Carriers do not have health problems and there is no medical reason to be tested if your child is healthy. However, if your children are adults (or young adults) and would like to find out for themselves (or are considering having children), then they should ask their GP to be referred to their local genetics centre. What if both my partner and I are carriers and planning a pregnancy? If you are thinking of having children, there are several options available that you can discuss in greater detail with your genetics unit: Accept the level of risk and have children without any testing (in pregnancy) Pre-implantation Genetic Diagnosis Invasive prenatal testing - CVS/Amniocentesis Use donor eggs or sperm Adoption

12 For more information & support Spinal Muscular Atrophy Support UK (formerly the Jennifer Trust) 40 Cygnet Court, Timothy s Bridge Road, Stratford-upon-Avon, Warwickshire CV37 9NW Tel: office@smasupportuk.org.uk Website: If you need more advice about any aspect of SMA please contact: Clinical Genetics Unit Birmingham Women s NHS Foundation Trust Mindelsohn Way, Edgbaston Birmingham B15 2TG Telephone: Fax: genetics.ipt@nhs.net Reference Number GG2 Author: Antoniya Ruseva Genetic Counsellor Reviewed: March 2016 Review date: March 2019