Presentation: Child with progressive muscle weakness or suspected muscular dystrophy

A family attends clinic concerned because their three-year-old son’s development is delayed: he sat at eight months, did not walk until 18 months and still cannot run, jump or climb stairs. He has delayed speech, with first words at two years, and he is not yet using two words together. Pregnancy, early life and family history are all unremarkable.

On examination, he is not dysmorphic, he has prominent calves and uses Gowers’ maneuver to stand. Blood test results show raised alanine transaminase levels and creatine kinase (CK) levels that are 10 times higher than the normal range.

• Genomic testing should be considered if there is a strong clinical suspicion of muscular dystrophy. Clinical features include:
  • elevated creatinine kinase levels;
  • muscle symptoms (weakness, fatigue, pain);
  • speech delay, motor delay or global developmental delay;
  • frequent falls and/or an unusual gait; and
  • isolated alteration in liver enzymes.
• In boys presenting with features of Duchenne or Becker muscular dystrophy (the most common forms), dystrophin gene testing should be prioritised.
• In symptomatic girls, a wider differential should be considered. However, as female carriers of Duchenne muscular dystrophy may manifest symptoms, it is reasonable to first test the dystrophin gene.
• In individuals where dystrophin gene test results are normal, a wider differential diagnosis should be considered, and muscle biopsy and MRI together with extended genomic testing is indicated. The choice of genomic test will depend on the age of the child, together with the pattern of muscle involvement, associated findings (such as dysmorphic features and brain or eye involvement) and any family history.

• Consult the National Genomic Test Directory. From here you can access the rare and inherited disease eligibility criteria, which provides information about individual tests and their associated eligibility criteria. You can also access a spreadsheet containing details of all available tests.
  • For those working within NHS Wales, please consult the All Wales Medical Genomics Service website for information on how to arrange testing.
• To find out which genes are included on different gene panels, see the NHS Genomic Medicine Service (GMS) Signed Off Panels Resource.
• Decide which of the panels best suits the needs of your patient or family.
  • For muscular dystrophies there are a number of available panels, including:
    • R73 to identify point mutations, deletions and duplications in the dystrophin gene (DMD) if you suspect Duchenne or Becker muscular dystrophy;
    • R82 if you suspect limb girdle muscular dystrophy;
    • R74 if you think your patient may have a diagnosis of facioscapulohumeral muscular dystrophy and a DUX4 contraction has not been excluded;
    • R345 if you strongly suspect facioscapulohumeral muscular dystrophy and a DUX4 contraction has been excluded (this encompasses methylation testing of DUX4, SMCDH1 gene sequencing, and extended testing of the 4q locus to look for complex variants);
    • R72 if clinical features are strongly suggestive of myotonic dystrophy;
    • R381 Other rare neuromuscular disorders: To be considered if clinical features are atypical and a broader range of genes are potentially causative (this test includes large gene panel or whole exome sequencing (WES), whole genome sequencing (WGS) and short tandem repeat testing).
    • R89 Ultra rare and atypical monogenic disorders: To be considered if the presentation is unusual and has a wide differential that would require analysis of multiple gene panels, including more than one non-WGS test. This includes large gene panel (such as those available on the non- GMS PanelApp), WES, WGS and microarray.
  • For tests that are undertaken using WGS, including R381 and R89, you will need to:
    • complete an NHS GMS test order form with details of the affected child (proband) and parents, including details of the phenotype (using human phenotype ontology (HPO) terms) and the appropriate panel name(s) with associated R number (see How to complete a test order form for WGS for support in completing WGS-specific forms);
    • 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 child and their parents, you will need three RoD forms (see How to complete a record of discussion form for support); and
    • submit parental samples alongside the child’s sample (this is trio testing) to aid interpretation, especially for the larger WGS panels (where this is not possible, for example because the child is in care or the parents are unavailable for testing, the child may be submitted as a singleton).
  • For tests that do not include WGS, including R73, R82, R74, R345, and R72:
    • you can use your local Genomic Laboratory Hub test order and consent (RoD) forms; and
    • parental samples may be needed for interpretation of the child’s result. Parental samples can be taken alongside that of the child, and their DNA stored, or can be requested at a later date if needed.
  • The majority of tests are DNA-based, and an EDTA sample (purple-topped tube) is required. Exceptions include karyotype testing and DNA repair defect testing (for chromosome breakage), which require lithium heparin (green-topped tube).
• Information about patient eligibility and test indications was 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

• Genomics England: NHS Genomic Medicine Service (GMS) Signed Off Panels Resource
• NHS England: National Genomic Test Directory

References:

• Birnkrant D, Bushby K, Bann CM and others. ‘Diagnosis and management of Duchenne muscular dystrophy, part 1: Diagnosis and neuromuscular, rehabilitation, endocrine and gastrointestinal and nutritional management’. The Lancet Neurology 2018: volume 17, issue 3, pages 251–267. DOI: 10.1016/S1474-4422(18)30024-3
• Mercuri E, Bönnemann CG and Muntoni F. ‘Muscular dystrophies’. The Lancet 2019: volume 394, issue 10,213, pages 2,025–2,038. DOI: 10.1016/S0140-6736(19)32910-1

For patients

• Muscular Dystrophy UK
• NHS England: Whole genome sequencing patient information leaflets