Presentation: Patient with neuropathy

A 22-year-old presents with a 10-year history of difficulty running and frequent tripping. More recently, he has become aware of reduced dexterity in his hands. He has a bilateral high stepping gait, pes cavus and hammer toes with glove and stocking sensory loss. A sensory motor neuropathy is identified on nerve conduction studies.

• Inherited neuropathies, also known as Charcot-Marie-Tooth diseases, are genetic conditions. In the absence of any acquired cause, testing is indicated in the following scenarios:
  • symptomatic patients with a family history of neuropathy or pain condition;
  • slowly progressive, long-standing neuropathy with muscle wasting and foot deformities; and
  • patients with symptoms of neuropathy from childhood or early adulthood with or without a family history.
• Unaffected individuals may present with a family history of an adult-onset genetic condition. If 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 about 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 of the panels best suits the needs of your patient and/or their family. For individuals with inherited neuropathy, two main panels are indicated.
  • R77 Hereditary neuropathy – PMP22 copy number. This panel should be considered in a patient with a demyelinating neuropathy or in whom hereditary neuropathy with liability to pressure palsies (HNPP) is suspected, before proceeding with a more extensive panel. It uses multiplex ligation-dependent probe amplification (MLPA) to identify PMP22 copy number variants associated with Charcot-Marie-Tooth disease type 1A (CMT1A) and HNPP.
  • R78 Hereditary neuropathy or pain disorder. This panel should be used if PMP22 copy number variants are clinically unlikely (as in purely axonal neuropathy) or have already been excluded. It uses whole genome sequencing (WGS), and it includes RFC1 and SMAX1 short tandem repeat (STR) analysis, though this is currently not optimal. If there is clinical suspicion of cerebellar ataxia, neuropathy and vestibular areflexia syndrome (CANVAS) or spinal and bulbar muscular atrophy (also known as Kennedy disease), please clearly state this during referral to enable additional testing to take place.
• Neuropathy may also be a core presentation in other syndromes, caused by pathogenic variants in genes not included in R78. If one of these syndromes is strongly suspected, depending on the clinical features, consider the following panels.
  • R55 Hereditary ataxia with onset in childhood or R56 Hereditary ataxia with onset in adulthood. These panels include testing for Friedreich ataxia, which may present with neuropathy prior to other symptoms. Where there is a high index of suspicion, refer to Patient presenting with adult-onset ataxia.
  • R204 Hereditary systemic amyloidosis. This is undertaken using a small panel and MLPA. Although the TTR gene is included in R78, it is not TTR MLPA, so if amyloid neuropathy is strongly suspected (in which case you may require TTR MLPA specifically), R204 should be used instead (it is also likely to yield a faster result).
  • R315 POLG-related disorder. POLG is not included in R78, so if a POLG-related condition is suspected you should instead use R315. For more information, see Adult with suspected POLG-related disease.
  • R351 NARP syndrome. This includes a small panel and targeted variant testing. The MT-ATP6 gene is included in R78, but if neurogenic muscle weakness, ataxia and retinitis pigmentosa (NARP) is strongly suspected, R351 is likely to yield a faster result.
• For tests that do not include WGS, including R77, you should use your local Genomic Laboratory Hub test order and consent (record of discussion) forms.
• For tests that are undertaken using WGS, such as R78, 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);
  • bear in mind that, when testing in children, parental samples may be needed for interpretation of the proband’s result, especially for the larger WGS panels (samples can be taken alongside that of the proband, and their DNA stored, or can be requested at a later date if needed); and
  • 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 child and their parents, you will need three RoD forms (see How to complete a RoD form for support);
  • obtain a consultee form signed by an appropriate relative or advocate if an adult patient does not have capacity to consent to genomic testing.
• All of the tests outlined above are DNA-based, and 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

• Charcot-Marie-Tooth UK
• GeneReviews: Charcot-Marie-Tooth hereditary neuropathy
• NHS England: National Genomic Test Directory
• OMIM: #118220 Charcot-Marie-Tooth disease, demyelinating, type 1A
• OMIM: #162500 Neuropathy, hereditary, with liability to pressure palsies

References:

• Cortese A, Curro R, Vegezzi E and others. ‘Cerebellar ataxia, neuropathy and vestibular areflexia syndrome (CANVAS): Genetic and clinical aspects’. Practical Neurology 2022: volume 22, issue 1, pages 14–18. DOI: 10.1136/practneurol-2020-002822

For patients

• Charcot-Marie-Tooth UK