Presentation: Patient with suspected hereditary spastic paraplegia

A young man attends a neurology clinic with a history of trips and falls. He has noticed progressive stiffness in both legs, which started in his early 20s with no clear precipitant. When examined, he appears to have increased tone in both legs with increased reflexes and clonus.

• Hereditary spastic paraplegia (also known as hereditary spastic paraparesis) is a diagnosis of exclusion, and all possible acquired causes of the patient’s paraplegia should be eliminated prior to genomic testing.
• Genomic testing should be considered in those with unexplained spastic paraplegia with or without a family history. Some individuals may have additional features for which further investigations and/or gene panels may be indicated. These can include:
  • ataxia and/or tremors;
  • epilepsy or seizures;
  • cognitive impairment and/or intellectual difficulties; and
  • peripheral neuropathy.
• 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 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 hereditary spastic paraplegia there are two panels, and the choice should depend on the age of onset in your patient.
  • R60 Adult onset hereditary spastic paraplegia: This panel investigates single-gene causes of hereditary spastic paraplegia where onset is in adulthood. It includes whole genome sequencing (WGS) and short tandem repeat (STR) testing for conditions such as spinocerebellar ataxia types 1, 2, 3, 6, 7, 12 and 17 and Friedreich ataxia. A full list of included STRs is available from your local Genomic Laboratory Hub (GLH) on request.
  • R61 Childhood onset hereditary spastic paraplegia: This indication investigates single-gene causes of hereditary spastic paraplegia where onset is in childhood. It includes WGS and STR testing for Friedreich ataxia. A full list of included STRs is available from your local GLH on request.
• For tests that are undertaken using WGS, including R60 and R61, 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 whole genome sequencing 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 record of discussion 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; and
  • when testing in children, parental samples may be helpful for interpretation of the proband’s result. Parental samples can be taken alongside that of the proband, and their DNA stored, or can be requested at a later date if needed.
• 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 was 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: Uncomplicated (pure) hereditary spastic paraplegia overview
• NHS England: National Genomic Test Directory

References:

• Meyyazhagan A and Orlacchio A. ‘Hereditary spastic paraplegia: An update’. International Journal of Molecular Sciences 2022: volume 23, issue 3, page 1,697. DOI: 10.3390/ijms23031697

For patients

• NHS Health A to Z: Hereditary spastic paraplegia
• The Hereditary Spastic Paraplegia Support Group