Presentation: Adult with suspected inherited white matter disorder

A 40-year-old woman is referred to neurology following an atypical brain MRI, which has revealed symmetrical confluent white matter hyperintensities. The scan was originally conducted to investigate migraine.

• There are several diagnostic clues that may suggest an adult-onset leukodystrophy, which are not typically found to have acquired causes:
  • similar history or imaging in a close relative;
  • a likelihood of disease onset in childhood, as suggested by developmental delay or learning disability;
  • rapid clinical progression and/or progressive disease without a history of relapses;
  • negative inflammatory biomarkers (such as absence or disappearance of oligoclonal bands in cerebral spinal fluid) and lack of response to steroid treatment; and
  • multisystem, extra-neurological organ involvement, such as those suggestive of a mitochondrial condition (for example, hearing loss, ophthalmoplegia and/or stroke-like episodes).
• 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, they should be offered a referral to their 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. The following panels should be considered for suspected adult-onset leukodystrophies.
  • R62 Adult-onset leukodystrophy: This panel investigates single-gene causes of adult-onset white matter disorders. It includes whole genome sequencing (WGS), though only genes known to cause inherited white matter disorders (including single-gene causes of monogenic small vessel disease) are analysed.
  • R64 MELAS or MIDD: This panel should be used when considering mitochondrial encephalopathy, lactic acidosis and stroke-like episodes (MELAS) or maternally inherited diabetes and deafness (MIDD). It is a targeted test for a single nucleotide variant (3243A>G) in the MTTL1 gene, the most common cause of MELAS.
  • R300 Possible mitochondrial disorder – whole mitochondrial genome sequencing and/or R63 Possible mitochondrial disorder – nuclear genes: These panels should be considered if there are other clinical features strongly suggestive of a mitochondrial condition and/or biochemical evidence of a mitochondrial condition. R300 will identify single nucleotide variants in the mitochondrial genome, while R63 includes WES or a large panel for possible mitochondrial conditions caused by nuclear genes and to identify copy number variants.
  • R58 Adult-onset neurodegenerative disorder: This panel should be considered if, based on family history or clinical or radiological features, you suspect that the patient’s white matter changes are due to an amyloid angiopathy. It includes WGS and short tandem repeat (STR) testing for adult-onset neurodegenerative conditions.
  • R98 Likely inborn error of metabolism: This panel includes WGS and should be used if there is a likely inborn error of metabolism and targeted testing (based on biochemical testing and/or enzyme analysis) is not possible. It should be considered if a rapid diagnosis will direct the patient’s immediate treatment or medical care. In reality, it is rarely used in adult-onset patients.
• For tests that are undertaken using WGS, 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 (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);
  • submit parental samples alongside that of the individual when offering duo or trio testing (that is, including one or both parents) to aid interpretation (where this is not possible, for example because the parents are unavailable for testing, the patient may be submitted as a singleton); 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 tests that do not include WGS, such as R300:
  • you should use your local Genomic Laboratory Hub test order and consent (record of discussion) forms; and
  • parental samples are not usually required but can be taken alongside that of the patient, and their DNA stored, or can be requested at a later date if needed.
• The tests outlined above are DNA-based, and an EDTA sample (typically a 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

• Alex, the Leukodystrophy Charity (Alex TLC): NHS England patient service and registry (information on the NHS England inherited white matter disorders diagnostic and management service (all ages))
• Alex TLC: For professionals
• Alex TLC: What is leukodystrophy?
• NHS England: National Genomic Test Directory
• NHS England: Service specification: Inherited White Matter Disorders Diagnostic and Management Service (All Ages)

References:

• Houldon H, Murphy E, Williams T and others. ‘How to diagnose difficult white matter disorders’. Practical Neurology 2020: volume 20, issue 4, pages 280–286. DOI: 10.1136/practneurol-2020-002530

For patients

• Alex, the Leukodystrophy Charity (Alex TLC)
• Alex TLC: What is leukodystrophy?