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 family history of a possible previous TIA in pregnancy and is being treated for depression. A brain MRI shows evidence of cerebral small vessel disease with patchy bilateral white matter hyperintensities including the anterior temporal lobes.

Genomic testing to confirm a suspicion of cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) should be considered when a patient has:

• experienced a cerebral ischaemic event below the age of 50, or over 50 if there is a family history of dementia/migraine AND:
• • cognitive impairment with recurrent ischaemic attacks; or
  • subcortical lacunar lesions on MRI scan in white matter (or both).

A typical pattern of CADASIL-related white matter disease seen on MRI 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.

Although migraine is a commonly associated with CADASIL, in the absence of typical history or imaging features detailed above, migraine with/without aura alone is not an indication for genomic testing.

• Unaffected individuals may present with a family history of an adult-onset genetic condition. Where signs and/or symptoms characteristic of CADASIL 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. For example, patients seeking clarification following a diagnosis of CADASIL in a relative, who are concerned about a personal history of migraine, should be referred to clinical genetics services to discuss testing.
• 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 for information about individual tests and their associated eligibility criteria. You can also access a spreadsheet of all available tests.
  • For information about how to arrange testing in Wales, Scotland or Northern Ireland, see Genomic testing in the devolved nations.
• For information about the genes that 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.
  • If, following review by a neuroradiologist, the pattern of imaging findings suggests a likely genetic cause but without the typical features of CADASIL, or where R337 NOTCH3 testing is negative, alternative testing includes:
    • R461 Cerebral amyloid angiopathy: This indication should be used when the clinical features and/or family history are in keeping with this diagnosis.
    • R62 Adult-onset white matter disorders: This is a gene panel undertaken through whole genome sequencing (WGS).
• Other tests that should be considered if the patient’s history or other investigations reveal additional findings include:
  • 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 include WGS, including R337, you can use your local Genomic Laboratory Hub (GLH) test order and consent (record of discussion) forms.
• For tests that are undertaken using WGS, including R461 or R62, you will need to:
  • complete an NHS GMS test order form with details of the affected individual (proband) and their parents, including details of the phenotype (using human phenotype ontology (HPO) terms) and the appropriate panel name(s) with associated R number(s) (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 patient 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 the patient does not have capacity to consent to genomic testing.
• Most tests are DNA based, and an EDTA sample (typically a purple-topped tube) is required. There are a few tests for which a different type of tube is used; see Samples for genomic testing in rare disease.
• If you are discussing genomics concepts with your patients, you may find it helpful to use the visual communication aids for genomics conversations.
• 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

• Alex, The Leukodystrophy Charity: A-Z of leukodystrophy
• 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:

• Elahi FM, Meschia JF, Worrall BB and others. ‘Management of inherited CNS small vessel diseases: The CADASIL example: A scientific statement from the American Heart Association‘. Stroke 2023: volume 54, issue 10. DOI: https://doi.org/10.1161/STR.0000000000000444
• 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

• Alex, The Leukodystrophy Charity: CADASIL
• CADASIL Support UK
• Stroke Research Group, University of Cambridge: CADASIL