Myotonic Dystrophy (MD) is the most common form of muscular dystrophy, causing chronic, progressive muscle wasting and weakness. Although it typically begins in adulthood, it can manifest at any age. MD is a systemic condition, affecting multiple organs beyond skeletal muscles, including the heart, eyes, and endocrine system. There are two primary types, Type 1 (DM1) and Type 2 (DM2), which share a similar inheritance pattern but result from mutations in different genes.
The Molecular Basis of the Mutation
Myotonic dystrophy is caused by an abnormal expansion of repetitive DNA segments within a gene, known as a microsatellite expansion. This means a small sequence of nucleotides is repeated far more times than normal. This genetic alteration interferes with the normal function of cells in muscles, the central nervous system, and other tissues.
In Type 1 Myotonic Dystrophy (DM1), the mutation involves a triplet repeat (CTG) in the DMPK gene on chromosome 19. Healthy individuals typically have fewer than 35 CTG repeats, but in DM1, this number can expand to hundreds or thousands. Type 2 Myotonic Dystrophy (DM2) involves a four-nucleotide repeat (CCTG) in the CNBP gene on chromosome 3.
In both types, the expanded repeat is located in a non-coding region of the gene. The expanded DNA sequence is transcribed into an abnormally long RNA molecule that becomes toxic to the cell. This toxic RNA disrupts the function of regulatory proteins, particularly those involved in alternative splicing. This molecular dysfunction leads to the wide range of symptoms seen in myotonic dystrophy.
Understanding Autosomal Dominant Transmission
Myotonic dystrophy is inherited in an autosomal dominant pattern. “Autosomal” means the gene is located on a non-sex chromosome. “Dominant” means a person only needs to inherit one copy of the altered gene to develop the disorder.
A person with MD possesses one normal gene copy and one copy carrying the expanded mutation. Since the mutation is dominant, the single altered copy is sufficient to cause the disease. If one parent has MD, they have a 50% chance of passing the altered gene to any offspring.
This 50% probability applies to each pregnancy individually. Each child has an independent chance of inheriting the mutation, regardless of their siblings or sex. Children who do not inherit the mutated gene will not develop the condition and cannot pass it on.
Genetic Instability and Anticipation
The inheritance of Myotonic Dystrophy is complicated by anticipation. This phenomenon means the disorder’s signs and symptoms appear at an earlier age and become progressively more severe in successive generations. This worsening is directly linked to the physical instability of the expanded DNA repeats.
The expanded CTG repeat sequence in DM1 is genetically unstable and tends to lengthen when passed from parent to child. The DNA repair machinery can “slip” during the formation of eggs or sperm, resulting in the child inheriting a considerably longer repeat sequence. A larger number of repeats correlates with an earlier age of onset and a more severe clinical presentation of DM1.
Extreme expansion often occurs when DM1 is inherited from the mother, leading to Congenital Myotonic Dystrophy. This is the most severe form, present at birth with severe weakness and respiratory distress. DM2 also shows anticipation, but it is less pronounced, and the correlation between repeat length and disease severity is not as strong.
Testing and Reproductive Planning
A definitive diagnosis of myotonic dystrophy requires specialized genetic testing through DNA analysis. This testing typically involves a blood or saliva sample to determine if the characteristic expanded repeat sequence is present in the DMPK or CNBP gene. The test also measures the size of the repeat expansion, which helps predict the severity and potential age of onset, particularly in DM1.
Families affected by MD often seek genetic counseling to understand the risks and discuss family planning. A genetic counselor explains the 50% risk and provides context regarding anticipation.
For couples concerned about passing the mutation, options include preimplantation genetic diagnosis (PGD) with in vitro fertilization (IVF). Embryos are tested for the MD mutation before implantation, allowing only unaffected embryos to be selected. Prenatal diagnosis can also be performed during an ongoing pregnancy using procedures like chorionic villus sampling (CVS) or amniocentesis to test the fetus directly.