Presentation: Adult with ptosis and ophthalmoplegia

A 55-year-old female is referred to her local neurology clinic with a one-year history of droopy eyelids. She complains of recent general fatigue, aching in her shoulders and thighs on exertion and some double vision. Her GP suspects some restriction of her eye movements. Investigations demonstrate negative myasthenia gravis antibodies and normal orbital and brain imaging, and an electromyography shows no evidence of a neuromuscular junction transmission anomaly.

• Genomic testing should be considered in any patient with:
  • ptosis and ophthalmoplegia, in whom an acquired condition has been ruled out;
  • a family history of ptosis and/or ophthalmoplegia (absence of family history does not mean that there is no possibility of a genetic condition); and
  • clinical or biochemical features of a mitochondrial condition, including:
    • elevated lactate, which is a hallmark of some mitochondrial conditions but is often normal in patients with chronic progressive external ophthalmoplegia (CPEO);
    • additional neurological features such as spastic gait, bladder dysfunction, neuropathy and ataxia;
    • multisystemic symptoms such as diabetes and cardiomyopathy; and
    • dysphagia, which is common in (but not exclusive to) oculopharyngeal muscular dystrophy (OPMD) but can also indicate other neuromuscular conditions, such as congenital myasthenia, congenital myopathy and mitochondrial myopathy, especially if there is additional limb weakness.
• 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. Testing for mitochondrial conditions during pregnancy can be particularly complex. If the patient or a close relative is pregnant, please discuss the case with your local clinical genetics service.

• Consult the National Genomic Test Directory. From here you can access the rare and inherited disease eligibility criteria document for information about individual tests and their associated eligibility criteria. You can also access a spreadsheet containing details of all available tests.
  • For information about how to arrange testing in Wales, Scotland or Northern Ireland, see our dedicated Knowledge Hub resource.
• 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 and/or their family.
  • R300 Possible mitochondrial disorder: This involves whole mitochondrial genome sequencing.
  • R352 Mitochondrial DNA maintenance disorder: This panel will identify the nuclear DNA variants that cause CPEO. Testing is undertaken by whole exome sequencing (WES) or medium panel sequencing.
  • R299 Possible mitochondrial disorder – mitochondrial DNA rearrangement testing: Consider this panel, which uses blood-derived DNA, in people under the age of 20: in most adults over that age, rearrangements can only be detected in muscle DNA.
  • R75 Oculopharyngeal muscular dystrophy: This uses short tandem repeat (STR) testing and will identify a short tandem repeat expansion in the PABPN1 gene, which causes OPMD.
  • R80 Congenital myasthenic syndrome and/or R81 Congenital myopathy: These panels use whole exome sequencing or medium panel sequencing. Prior to testing, the patient should be assessed by a neurologist, typically in parallel with maternal anti-acetylcholine receptor (AChR) antibody testing or following clinical assessment as part of the rare neuromuscular specialised service.
  • R63 Possible mitochondrial disorder – nuclear genes: Mitochondrial testing listed above should be considered first including targeted examination of nuclear genes where possible. Testing is performed via whole exome sequencing or a large panel.
• If you require further advice on testing, including choice of tissue, please contact your local highly specialised service for mitochondrial disease.
• For tests that do not include whole genome sequencing, which includes all of the tests outlined above:
  • you should use your local Genomic Laboratory Hub test order and consent (record of discussion) forms; and
  • bear in mind that, when testing in children, parental samples may be needed for interpretation of the proband’s result (parental samples can be taken alongside that of the proband, and their DNA stored, or can be requested at a later date if needed).
• For DNA-based tests, an EDTA sample (purple-topped tube) is required.
• 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

• NHS England: National Genomic Test Directory
• NHS Rare Mitochondrial Disorders Service
• Online Mendelian Inheritance in Man (OMIM): # 117000, # 157640, # 161800, # 164300, # 251900, # 251950, # 254210, # 254300, # 255160, # 255310, # 255320, # 255995, # 258450, # 500002, # 500009, # 540000, # 551000, # 601462, # 602771, # 603034, # 605637, # 605809, # 608358, # 608930, # 608931, # 609283, # 609284, # 609285, # 609286, # 610131, # 610542, # 611705, # 612540, # 613076, # 613077, # 614399, # 614750, # 615120, # 615156, # 616209, # 616227, # 616228, # 616304, # 616313, # 616314, # 616321, # 616322, # 616323, # 616326, # 616330, # 616479, # 617069, # 617070, # 617336, # 617675, # 618098, # 618414, # 618524, # 618578, # 618654, # 618822, # 618823, # 618975, # 619178, # 619967, # 620161, # 620246, # 620249, # 620265, # 620278, # 620310, # 620326, # 620351, # 620369, # 620460 and # 620964
• Oxford University Hospitals NHS Foundation Trust: Oxford Congenital Myasthenia Service referrals

For patients

• Myaware: Congenital myasthenic syndrome
• NHS Inform: Oculopharyngeal muscular dystrophy (OPMD)
• NHS Rare Mitochondrial Disorders Service: What is mitochondrial disease?
• The Lily Foundation