Myotonic dystrophy (DM) is the most common late-developing form of muscular dystrophy. (Duchenne is the most common type of MD overall.)

There are two types of myotonic dystrophy, type 1 (DM1) and type 2 (DM2), both of which are caused by genetic mutations and are inherited in an autosomal dominant manner.

Patients with either type of DM typically experience gradually worsening muscle weakness, muscle wasting, and difficulties in relaxing muscles (myotonia). Other parts of the body, including the eyes, heart, and endocrine system are also affected in DM.

DM2 is more rare than DM1 and generally runs a milder course. Although both types of DM share similar symptoms, they are caused by different disease processes.

The CNBP gene

DM2 is caused by a genetic defect known as a CCTG repeat expansion in the CNBP gene (also known as ZNF9) located on chromosome 3. The genetic code is made up of sequences of nucleotides (DNA building blocks). CCTG refers to a four-nucleotide long (tetranucleotide) sequence in the genetic code.

In healthy people, the CCTG sequence is repeated less than 26 times. But people with DM2 have between 75 to 11,000 CCTG repeats. The number of times the CCTG sequence is repeated does not dictate the type or severity of symptoms experienced in DM2.

Unlike DM1, DM2 rarely begins in childhood and does not display what geneticists call anticipation (the onset of disease occurring increasingly earlier and becoming more severe with subsequent generations).

Effects of the CNBP gene mutation

The CNBP gene contains instructions that allow the body to produce the nucleic acid binding protein. This protein is found abundantly in the heart and skeletal muscles (muscles used for movement).

Cells use genetic code instructions to first manufacture a molecule called a messenger RNA, or mRNA, that then goes on to produce the protein coded by the gene. In DM2, the CNBP mutation results in faulty RNA production. These accumulate in the cell, interfering with other cellular functions and eventually leading to the symptoms of DM2.

Modifier gene mutations

Patients with DM2 experience a more varied range of symptoms compared to those with DM1. This is thought to be due to additional changes in modifier genes, or genes that affect the target gene (the target gene in DM2 would be CNBP) and are not necessarily present in all patients with DM2.

Mutations in two modifier genes – the CLCN1 and SCN4A genes – have been identified in DM2. Having defects in either of these genes are thought to exaggerate the clinical presentation of DM2, and results in patients with more severe myotonia and muscle stiffness compared to those with only the CCTG repeat expansion.

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