Presentation: Clinical suspicion of young-onset Parkinson disease

A 28-year-old gentleman attends clinic with a two-year history of progressive upper limb rest tremor. Further questioning reveals exercise-induced dystonic posturing at the right ankle. Clinical examination reveals bilateral upper limb rigidity, with bradykinesia noted in both right upper and lower limbs. There is no family history of any neurological conditions.

• Genomic testing should be considered in a patient presenting with suspected Parkinson disease or complex parkinsonism with either:
  • onset below 50 years of age;
  • a first-degree relative affected at below 50 years of age; or
  • the presence of complex features, including:
    • conditions affecting mobility, including spasticity, ataxia or dyspraxia;
    • cognitive impairment, including intellectual difficulties, cortical sensory loss and/or dementia;
    • gaze palsy;
    • early bulbar failure; and/or
    • brain iron accumulation seen on brain MRI imaging.
• Note that concurrent dystonia is common in early onset Parkinson disease.
• If an acquired cause for the patient’s clinical features is identified (such as cerebral palsy or a structural brain lesion), genomic testing is less likely to be indicated.
• 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 about 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 the 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 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.
• If the clinical phenotype suggests a specific diagnosis of Huntington disease, for which targeted testing is available, please refer to Clinical suspicion of Huntington disease.
• Decide which of the panels best suits the needs of your patient and/or their family. For early onset Parkinson disease or parkinsonism, consider one of the following panels.
  • R58 Adult-onset neurodegenerative disorders. This panel investigates single-gene causes of adult-onset neurodegenerative conditions. It includes whole genome sequencing (WGS), though only genes known to cause adult-onset neurodegenerative conditions (including those associated most commonly with early onset Parkinson disease, as well as those associated with motor neurone disease and inherited dementia syndromes) will be analysed. It also includes short tandem repeat (STR) testing for genes associated with a range of neurodegenerative conditions. This panel may be most relevant to individuals with symptoms typical of Parkinson disease and those with cognitive impairment.
  • R56 Adult-onset dystonia chorea or related movement disorder. This is a gene panel aimed at adult-onset complex movement conditions, including early onset parkinsonism. It includes WGS and STR testing involving genes associated with adult-onset movement conditions such as early onset parkinsonism. It may be most relevant to those with dystonia-predominant symptoms or complex movement conditions in whom cognitive impairment may or may not be present.
  • R57 Childhood-onset dystonia, chorea or related movement disorder. This panel should be considered for cases in which onset of symptoms is below the age of 18. It includes WGS and STR testing.
• The conditions described above are complex, and inclusion of other panels in testing may be relevant.
• For tests that are undertaken using WGS, including R58 and R56, you will need to:
  • complete an NHS GMS test order form with details of the affected individual (proband) and their parents if available, 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);
  • 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 RoD form for support); and
  • obtain a consultee form signed by an appropriate relative or advocate if an adult patient does not have capacity to consent to genomic testing.
• All of the tests outlined above are DNA-based, and 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

• GeneReviews: Parkinson disease
• NHS England: National Genomic Test Directory
• NHS Health A to Z: Parkinson’s disease diagnosis

References:

• Day JO and Mullin S. ‘The genetics of Parkinson’s disease and implications for clinical practice’. Genes 2021: volume 12, issue 7, page 1,006. DOI: 10.3390/genes12071006

For patients

• American Parkinson Disease Association: What is early onset Parkinson’s disease?
• Parkinson’s UK: Young-onset Parkinson’s
• The Michael J Fox Foundation for Parkinson’s Research: Early onset Parkinson’s disease