Presentation: Patient with suspected cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL)

A 38-year-old woman is referred to stroke services to investigate a possible transient ischaemic attack (TIA). She has a history of migraine with aura and she is being treated for depression. A brain MRI shows patchy bilateral white matter hyperintensities involving the anterior temporal lobes.

Genomic testing to confirm a suspicion of cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) should be considered in patients with a combination of either:

• recurrent strokes or TIAs under the age of 50 with no acquired cause identified; or
• recurrent strokes or TIAs over the age of 50 with a family history of dementia and/or migraine; and one or more of the following:
  • cognitive impairment with recurrent ischaemic attacks; and/or
  • a typical pattern of CADASIL-related white matter disease seen on MRI, which can include lacunar infarcts, cerebral microbleeds and dilated perivascular spaces. There may be bilateral white matter hyperintensities, with prominent temporal lobe and external capsule involvement being characteristic.
• 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, which 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 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. For white matter conditions, there are several different tests available.
  • R337 NOTCH3 single gene sequencing. This test should be used when the patient’s clinical features appear typical of CADASIL.
  • R62 Adult-onset white matter disorders. This is a gene panel undertaken through whole genome sequencing (WGS). It should be used if, following review by a neuroradiologist, the pattern of white matter involvement indicates a primary white matter condition with a likely genetic cause but without the typical features of CADASIL, or where R337 NOTCH3 testing is negative.
• Other tests that should be considered if the patient’s history or other investigations reveal additional findings include the below.
  • R58 Adult-onset neurodegenerative disorders. This is a gene panel undertaken through WGS. It should be considered if the predominant presentation is dementia, rather than the strokes or vascular dementia that are typical of CADASIL.
  • R64 MELAS or MIDD. This panel should be considered if there are non-neurological or MRI features suggestive of a mitochondrial condition.
  • R335 Fabry disease. This panel should be considered if there are additional features suggestive of this diagnosis.
• For tests that do not use WGS, such as R337, you should use your local Genomic Laboratory Hub test order and consent (record of discussion (RoD)) forms.
• For tests that are undertaken using WGS, such as R62, 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 (please see How to complete a test order form for WGS for support);
  • complete an NHS GMS 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
  • submit a consultee form signed by an appropriate relative or advocate if an adult patient does not have capacity to consent to genomic testing.
• 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

• GeneReviews: CADASIL
• NHS England: National Genomic Test Directory
• OMIM: #125310 Cerebral arteriopathy, autosomal dominant, with subcortical infarcts and leukoencephalopathy, type 1 (CADASIL1)
• Stroke Research Group, University of Cambridge: CADASIL

References:

• Arnold M, Bersano A, Burlina H and others. ‘Monogenic cerebral small-vessel diseases: Diagnosis and therapy consensus recommendations of the European Academy of Neurology’. European Journal of Neurology 2020: volume 27, issue 6, pages 909–927. DOI: 10.1111/ene.14183

For patients

• CADASIL Support UK
• Stroke Research Group, University of Cambridge: CADASIL