Finding out you or your child has CMD has probably been a diagnostic odyssey. In the past, arriving at the diagnosis usually meant having many other diseases ruled out as possibilities and having a muscle biopsy which somewhat confirmed an underlying dystrophic pattern. Most of us went on living our lives, adapting to physical and at times neurologic impairments knowing that this was the best medicine could offer us.
However, in the last 5 years, a pivotal change has occurred. Not only have we seen an explosion in the understanding of the CMD’s with 12 new genes identified in the last 5 years. We have also seen a shift in treatment options to include repairing the type of underlying genetic defect. An example of such a treatment is PTC 124, a drug currently in Phase 2b clinical trial for both Duchenne muscular dystrophy and cystic fibrosis. PTC 124 should treat nonsense mutations across disease types, but has not yet been studied in disorders other than DMD and CF.
This radical change in treatment options, and the need to register the CMD community not only based on vague muscle biopsy results but with true confirmatory genetic testing, has pushed the need for knowing your genetic mutation to the forefront. In some cases of CMD, it may still not be possible to figure out where the genetic mutation lies, if the mutation is in an undiscovered gene.
The best way to find out where your genetic mutation lies is to work with your neurologist, your local MDA clinic and a genetic counselor. Genetic mutation analysis may require reviewing your muscle biopsy results or specimen or sending a small blood sample. Insurance companies will often pay for some or most of your mutation analysis especially if you are still a minor.
Below are a list of terms you may encounter when you learn about your genetic mutation. For more information about genetic terms go to the NIH genetics division glossary: http://ghr.nlm.nih.gov/
- Autosomal recessive: Most forms of CMD are inherited in an autosomal recessive fashion. This means both parents contribute a mutation in the same gene to their child. The child must have both mutations to have CMD and unaffected. The parents are both carriers of CMD. The child may inherit a different mutation from each parent in the same gene.
- Autosomal dominant: Some forms of CMD, in particular Ullrich and lamin A/C related CMD, may be inherited in an autosomal dominant fashion. Autosomal dominant means you need only one mutation to have the disease. Autosomal dominant diseases usually have an affected parent, because the parent carries one mutated copy of the gene which then gets passed to the child who also has the disease. More often in families with a child affected by CMD, the mutation will be a de novo mutation, meaning it has arisen spontaneously, and the parent does not have it, but the child does.
- Dominant negative: This describes the mechanism by which a dominant mutation can cause disease. A mutation whose gene product adversely affects the normal, wild type gene product within the same cell. The mutated copy may associate with the normal copy and cause dysfunction of both. In some cases, such as collagen (Ullrich CMD), one dominant negative mutation may be more harmful than having one mutation, causing the production of no gene product (null mutation or null alleles), which only cause disease when present in both gene copies to that absolutely no product can be made.
- De novo: Spontaneous new occurrence of a mutation. The mutation is not found in either parent, but in rare cases be present in a proportion of the germ cells of a parent.
- Nonsense mutation: This is a mutation (usually a point mutation, i.e. just changing one of the letters in the code) that transforms the normal protein making code of the gene into a stop sign–as a result an incomplete protein is made by the cell, which is then usually rapidly degraded.
- Missense mutation: This type of mutation (again usually a point mutation) changes the reading code of the gene from one amino acid to another. It then depends on how important that particular amino acid is for the correct function of the protein. If critical, the consequences on protein function can be severe, but if less critical, the consequences may be much milder.
- Deletion: Meaning that a chunk of the gene coding region has gone lost–the consequences depend on what has gone lost and whether the reading frame of the gene has been interrupted.
- Insertion: This means that the mutation has inserted an additional bit of gene sequence that does not belong there, usually meaning that the gene can’t be read properly any more.
- Exon/intron: An exon is the part of the gene that codes for the actual protein. On the chromosome, the exons that make up the coding sequence for the protein are separated by introns. Upon reading of the gene, the cell cuts out the introns and puts the exons together (a process called splicing) so that the exons are now continuous with all the information necessary to make a protein. Mutations usually affect the information in exons or the way they are spliced together.