Genetics - DM1

Patterns:

  • DM1 is caused by the expansion of an unstable CTG repeat sequence in an untranslated, but transcribed, portion of the 3’ untranslated region of the dystrophia myotonica protein kinase (DMPK) gene located on chromosome 19q13.3.

  • The normal number of CTG repeats in this region is 5 to 37. Repeat numbers greater than 50 are considered diagnostic of DM1. Occasionally, individuals are identified as inheriting 37 to 49 CTG repeats. Repeats of this length may be encountered in the side branches of known DM1 families, particularly in the older generations, or occasionally by chance in the general population. Individuals with 37 to 49 CTG repeats have not been reported to date to develop detectable DM1 symptoms. However, such “pre-mutations” can expand into the disease range in subsequent generations, particularly when transmitted by men.

  • A diagnosis of DM1 in one person in a family has implications for other family members, giving rise to questions about whether or not the affected person should tell family members who show no symptoms and then whether or not those family members should be tested. Diagnosis of DM1 in a presymptomatic person (including a child) can have important implications for health monitoring and family planning, but it can also raise the possibility of difficulty in obtaining insurance or encountering prejudice in the workplace.

Symptoms:

  • The diagnosis of DM1 should be suspected in anyone presenting with at least three of the following:

    • Eyelid ptosis.

    • Distal weakness, primarily of the finger and wrist flexors, without contractures.

    • Myotonia or “stiffness” of muscles.

    • Pre-senile cataracts, especially the polychromatic type.

  • The diagnosis of DM1 should be suspected in anyone presenting with any one of the above or a family history and:

    • First-degree heart block.

    • Irritable bowel syndrome (IBS) or elevated liver enzymes.

    • Gallstones at a young age.

    • Prolonged recovery or respiratory arrest following an anesthetic.

    • Insulin resistance or diabetes.

    • Hypogonadotrophic hypogonadism.

    • Excessive daytime sleepiness (EDS).

    • Mild learning difficulty.

Diagnosis:

  • Discuss the following tests with your doctor:

    • While DNA testing, including prenatal and presymptomatic testing, for DM1 is now widely available, there are many potential pitfalls in interpreting the results for the patient and family, making genetic counseling a useful part of the diagnostic process.

    • DM1 test via molecular genetic testing is the first line of investigation for anyone suspected of having DM1. More than 50 CTG repeats in the 3’ untranslated region of the DMPK gene on chromosome 19 are considered to have DM1. False-negative genetic testing results can occur, even in a family with an established DM1 diagnosis; expert referral is recommended.

    • Consider a referral to genetic counseling services or a neurologist with expertise in DM1, even if you don’t desire to have children.

    • For physical findings that are suspicious for a diagnosis of DM1 via physical examination with particular emphasis on neuromuscular, cardiovascular and respiratory assessments, obtain a three generation family history.

Treatment:

  • Refer to:

    • Genetic counseling for those who exhibit clinical signs indicative of DM1, for at-risk family members, in order to enable them to make an informed decision about whether to proceed to genetic testing. Such testing should be done through an accredited laboratory experienced in providing DM1 diagnoses. Individuals with 37 to 49 CTG repeats are deemed very unlikely to develop detectable DM1 symptoms. However, such “premutations” can expand into the disease range in subsequent generations, particularly when transmitted by men. Individuals thus identified should be offered genetic counseling to discuss their risk for transmitting DM1.

    • Neuromuscular disease specialist, most likely a neurologist or clinical geneticist with a particular interest in inherited neuromuscular disease, who can facilitate a primary “wholesystem” evaluation, prioritizing additional symptom-specific referrals, and providing ongoing clinical management of the condition.

    • Cardiologist if significant cardiac symptoms are detected. Anyone suspected of having a diagnosis of DM1 should be immediately advised of the risks of anesthesia and sedation and assessed for possible cardiac complications.

    • Review pedigree annually. Genetic counseling should be repeated when new information or circumstances change the risks for family members.

  • Discuss and convey the complexities of the inheritance patterns observed in this disease, particularly the risk of a minimally affected mother giving birth to a severely affected child, via genetic counseling.

  • Male and female DM1-affected individuals may have difficulty conceiving and that the difficulty increases with age.

  • Mutation carriers should inform their close relatives of the possibility that they may also have inherited the risks and repercussions of DM1, even if they or their children are currently asymptomatic.

  • Preimplantation genetic diagnosis can allow selective implantation of unaffected embryos. Prenatal diagnosis by amniocentesis or chorionic villus sampling can allow for termination of an affected pregnancy. It can also prepare the obstetric team for the birth of a DM1- affected baby.

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