Genetics - CDM

Patterns:

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

  • Repeat size is often large (typically >1000 repeats) but the repeat size cannot absolutely in isolation be used to determine whether a child will have CDM or how severe his/her symptoms will be.

  • Once a family has had a child with CDM, there is an increased risk that the next child with DM1 will have congenital form as well.

Symptoms:

  • Congenital DM1 (CDM) is defined in a child who has one or more of the following features:

    • Physical signs or symptoms attributable to DM1 at birth, or in the first month of life, including one or more of the following features: respiratory failure, feeding problems, weakness and hypotonia, clubfoot, polyhydramnios, and/or reduced fetal movement.

    • Genetic confirmation of expanded CTG repeat size.

    • Need for medical intervention or hospitalization in the first month of life for medical issues specific to myotonic dystrophy. Diagnosis may not necessarily be made in the neonatal period but could be made later in life if the above criteria were demonstrably present.

    • Maternal transmission bias is nearly always maternal and does not appear to be related to the severity of the disease in the mother. The mutated gene is only very rarely inherited from the father in newborns with myotonic dystrophy.

Diagnosis:

  • Discuss the following tests with your doctor:

    • DM1 in the pediatric age range (that do not meet the congenital criteria) are herein referred to as childhood-onset DM1. The diagnosis of childhood-onset DM1 can be made at any age if features of DM1 were demonstrably present during the childhood years but were not medically identified or diagnosed.

    • There are other classification systems in the literature that further subdivide by age of symptom onset, such as the following: mild and severe congenital (age 0-1 years), childhood (1-10 years), and juvenile (10-18 years).

    • Genetic counseling if clinical signs indicative of DM1 are present, to enable that an informed decision is made about whether to proceed to genetic testing. Such testing should be done through an accredited laboratory experienced in providing DM1 diagnoses (see myotonic.org). 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.

    • While DNA testing, including prenatal and presymptomatic testing for DM1 is now available, there are many potential pitfalls in interpreting the results without help, making genetic counseling a useful part of the diagnostic process.

Treatment:

  • In many cases, a child with DM1 will be the first person in the family diagnosed with DM1, due to genetic anticipation. A diagnosis of DM1 in one person in a family has implications for other family members, raising questions about whether other family members who show no symptoms should be informed of the diagnosis and whether those family members should be tested. Genetic counseling for affected families should convey information about:

    • The inheritance pattern of disease (autosomal dominant inheritance).

    • The wide variability in the scope and severity of DM1 symptoms, even within the same family.

    • The possibility of changes in symptom scope and severity over time.

    • The likelihood that the mutation will expand and the disease will become more severe as it is passed from generation to generation (anticipation) and as individuals age.

    • The possibility of a minimally-affected mother giving birth to a severely affected child.

    • Options for family planning.

    • Help mutation carriers 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.

    • Do not use CTG repeat numbers, if available, for genetic advice or prognostication; these need to be discussed with a genetic counselor.

    • Parents who have a child with myotonic dystrophy have a 50% risk of having another child with DM1, and clinical experience suggests that they are likely to have congenital or childhood-onset in future births as well.

    • Suggest that parents consider in vitro fertilization with pre-implantation diagnosis to prevent DM1 transmission, or other alternatives for expanding their family.

    • If the family and physician are considering testing an asymptomatic child, consider that all parties take part in a counseling session before testing, and at the time of the disclosure of the result. The counseling should involve the child, parents, child’s physician, a genetic counselor, and if necessary, a psychologist. This may be cumbersome and deter casual testing; at least consider this approach for critical cases.

    • Once the diagnosis is confirmed, consult an expert multi-disciplinary myotonic dystrophy team to coordinate care, prioritize symptom management and make appropriate additional referrals.

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