Presentation: Patient with muscle cramps and myotonia

A 20-year-old man attends clinic complaining of muscle cramps, mostly in his legs and hands. Sometimes when he first stands up they are so bad that he can’t walk properly. He has a very muscular build. An electromyography (EMG) demonstrates myotonia.

• Genomic testing should be considered in anyone with myotonia recorded by an EMG.
• The majority of individuals with myotonia will have either non-dystrophic myotonia or myotonic dystrophy. Myotonic dystrophy is much more common than non-dystrophic myotonia, and should always be considered as first-line testing in a patient with myotonia. Pure myotonic presentations without other systemic or neuromuscular features are indicative of non-dystrophic myotonia.
• Myotonia can be seen by EMG in some myopathies and in Pompe disease (also known as glycogen storage disorder type II). Consider biochemical testing prior to genomic testing if Pompe disease is a likely diagnosis.
• Unaffected individuals may present with a family history of an adult-onset genetic condition. Where signs and/or symptoms suggestive of that condition are not present in the patient, they should be offered referral to a local clinical genetics service to discuss testing as part of a predictive (presymptomatic) testing pathway.
• A genetic diagnosis may have implications for other family members, and can be particularly relevant during a pregnancy. For some genetic conditions, rapid testing is available for the purposes of pregnancy management. Assessment of symptoms during pregnancy and discussion of the patient’s choices regarding prenatal testing may be offered. If the patient or a close relative is pregnant, you may wish to offer them a referral to a local clinical genetics service for further discussion.

• Consult the National Genomic Test Directory. From here you can access the rare and inherited disease eligibility criteria for information about individual tests and their associated eligibility criteria. You can also access a spreadsheet of all available tests.
  • For information about how to arrange testing in Wales, Scotland or Northern Ireland, see Genomic testing in the devolved nations.
• For information about the genes that are included on different gene panels, see the NHS Genomic Medicine Service (GMS) Signed Off Panels Resource.
• Decide which of the tests best suits the needs of your patient and/or their family. This will depend on whether the clinical phenotype is suggestive of a dystrophic myotonia or a non-dystrophic myotonia.
  • R72 Myotonic dystrophy type 1: This is short tandem repeat (STR) testing of the DMPK gene and is used in patients with a likely diagnosis of myotonic dystrophy type 1.
  • R76 Skeletal muscle channelopathy: This panel tests primarily for non-dystrophic myotonias: myotonia congenita, paramyotonia congenita and sodium channel myotonia. It is a small gene panel, including CLCN1 and SCN4A, to look for gene variants and rearrangements. This panel includes DMPK STR testing for myotonic dystrophy type 1 (see R72) but does not include CNBP STR testing for myotonic dystrophy type 2 (see R410).
  • R410 Myotonic dystrophy type 2 (DM2): This is CNBP STR testing and is used in patients with features suggestive of myotonic dystrophy type 1 in whom genomic testing for that disorder is negative.
• In atypical cases (those with additional signs of myopathy or in whom the above testing is negative), consider:
  • R381 Other rare neuromuscular disorders: This panel should be used if the patient’s clinical features are atypical and a broader range of conditions are under consideration. It includes whole genome sequencing (WGS). Only genes known to cause rare neuromuscular conditions would be analysed.
  • R274 Glycogen storage disease: This involves whole exome sequencing or a medium panel, and will include Pompe disease.
• For tests that do not include WGS, including R72, R76 and R410, you can use your local Genomic Laboratory Hub (GLH) test order and consent (record of discussion) forms.
• For tests that are undertaken using WGS, including R381, you will need to:
  • complete an NHS GMS test order form with details of the affected individual (proband) and their parents, including details of the phenotype (using human phenotype ontology (HPO) terms) and the appropriate panel name(s) with associated R number(s) (see How to complete a test order form for WGS for support);
  • complete an NHS GMS record of discussion (RoD) form for each person being tested – for example, if you are undertaking trio testing of an affected patient and their parents, you will need three RoD forms (see How to complete a RoD form for support); and
  • obtain a consultee form signed by an appropriate relative or advocate if the patient does not have capacity to consent to genomic testing.
• Most tests are DNA based, and an EDTA sample (typically a purple-topped tube) is required. There are a few tests for which a different type of tube is used; see Samples for genomic testing in rare disease.
• If you are discussing genomics concepts with your patients, you may find it helpful to use the visual communication aids for genomics conversations.
• Information about patient eligibility and test indications were correct at the time of writing. When requesting a test, please refer to the National Genomic Test Directory to confirm the right test for your patient.

For clinicians

• GeneReviews: Myotonic dystrophy type 1
• Gene Reviews: Myotonic dystrophy type 2
• NHS England: National Genomic Test Directory
• OMIM: 160900 Myotonic dystrophy 1; DM1
• OMIM: 602668 Myotonic dystrophy 2; DM2

References:

• Fialho D, Holmes S and Matthews E. ‘Skeletal muscle channelopathies: A guide to diagnosis and management’. Practical Neurology 2021: volume 21, issue 3, pages 196–204. DOI: 10.1136/practneurol-2020-002576

For patients

• Muscular Dystrophy UK
• Myotonic Dystrophy Foundation
• Myotonic Dystrophy Support Group
• Unlock NDM