Presentation: Patient with young-onset dementia

A 45-year-old man attends the neurology clinic with his wife. They are concerned about his increasing short-term memory loss, and his wife has noticed that he is having difficulty managing his finances. Cognitive testing reveals deficits in executive function and memory impairment.

• Genomic testing should be considered if the patient’s clinical features fulfil the criteria for a clinical diagnosis of dementia, and acquired causes – such as stroke or intracranial tumours – have been excluded. In addition, one of the following should be present:
  • onset below 55 years of age;
  • a history of dementia of the same type in a first- or second-degree relative; and/or
  • a family history of motor neurone disease in a first- or second-degree relative.
• 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 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 document for 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 panels best suit the needs of your patient and/or their family. For early onset dementia there are a number of available tests.
  • 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 are analysed, plus short tandem repeat (STR) testing for a number of conditions, including Huntington disease, spinal and bulbar muscular atrophy (also known as Kennedy disease), C9orf72-related frontotemporal dementia and motor neurone disease. A full list of associated STR tests will be available from your local Genomic Laboratory Hub (GLH).
  • R68 Huntington disease. This should be used if Huntington disease is the primary suspected diagnosis.
  • R337 CADASIL. This should be used if the likely diagnosis is cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL).
• For tests that are undertaken using WGS, such as R58, you will need to:
  • complete an NHS GMS test order form with details of the affected individual (proband) and their parents where 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 individual 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.
• For tests that do not include WGS, such as R68 and R337, you should use your local GLH test order and consent (ROD) forms.
• For all the tests outlined above, 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

• FTD UK (an organisation that brings together clinicians and researchers working on frontotemporal dementia and associated conditions)
• GeneReviews: Alzheimer disease overview
• GeneReviews: C9orf72 frontotemporal dementia and/or amyotrophic lateral sclerosis
• NHS England: National Genomic Test Directory
• Practical Neurology: Genetics of dementia

For patients

• Alzheimer’s Society: Young-onset dementia
• Dementia UK: Young onset dementia
• FTD Talk
• Rare Dementia Support