Presentation: Clinical suspicion of spinal muscular atrophy in an adolescent or adult

You are asked to review a 17-year-old male in transition to adult neurology services. He is presenting with progressive weakness and cramping in his legs, which has been going on for the past year. On examination, you notice symmetrical reduced power (which is more pronounced in the lower limbs than the upper), absent reflexes in the lower limbs and mild hand and finger tremors. The cranial nerves are intact but tongue fasciculations are present. The patient also has a mild scoliosis of the spine.

Spinal muscular atrophy (SMA) can present at different ages. Suggestive clinical features in a teenager or adult patient include the below.

• Infancy to childhood:
  • progressive muscle weakness (which is more pronounced in the proximal limbs than the distal limbs);
  • hypotonia with typical lower limb posture;
  • delayed (or loss of) motor milestones, including head control;
  • suck and/or swallowing difficulties;
  • reduced or absent peripheral reflexes;
  • muscle fatigue;
  • tongue fasciculations;
  • finger tremors; and
  • recurrent respiratory infections.
• Adulthood:
  • proximal muscle weakness;
  • muscle fatigue;
  • scoliosis; and
  • contractures.

SMA presenting in the neonatal period or early childhood (often known as type 0, type 1 or type 2) has a more severe phenotype. For more information, see Hypotonic infant.

Prenatal testing for SMA may be considered in a pregnancy with a known family history in either parent, or when both parents are known to be carriers for SMA. For more information, see Pregnancy at risk of spinal muscular atrophy.

SMA is often subdivided into types 0 to 4, depending on clinical features, age of onset and copy number of the modifier gene SMN2.

• SMA type 0 : onset prenatal, severe neonatal hypotonia, areflexia and respiratory failure at birth.
• SMA type 1: onset under six months, the patient is never able to sit unsupported.
• SMA type 2: onset six to 18 months, the patient is able to sit but not stand or walk unsupported.
• SMA type 3: onset over 18 months, the patient achieves ambulation but may lose this ability when older.
• SMA type 4: adult onset, the patient presents with fatigue and proximal muscle weakness.

The SMN1 gene causes all subtypes. Only SMA type 1 is referenced in the National Genomic Test Directory (see below); however, that panel should be requested for suspected cases of all SMA types.

• 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.
• Current testing strategy reflects the fact that the majority of patients with typical features of SMA will have copy number variants in the SMN1 gene. A smaller number will have a combination of deletions and sequence variants in SMN1 (compound heterozygous).
• Decide which of the panels best suits the needs of your patient and/or their family.
  • R70 Spinal muscular atrophy type 1 diagnostic test: This panel should be used first if clinical features are suggestive of any type of SMA and SMN1 copy number has not already been tested. It uses multiplex ligation-dependent probe amplification (MLPA) to test for SMN1 variants and will identify homozygous or heterozygous deletions in this gene (homozygous deletions being the most common cause of SMA).
  • R71 Spinal muscular atrophy type 1 rare variant testing: This panel should be used if the patient has clinical features of SMA but only a single (heterozygous) deletion in SMN1 is found. It uses single gene sequencing to identify whether there is a rare pathogenic sequence variant in the other copy of the SMN1 gene, which cannot be detected through MLPA.
• None of the tests outlined above use whole genome sequencing, so you should use your local Genomic Laboratory Hub test order form and consent (record of discussion, or RoD) form.
• 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

• NHS England: National Genomic Test Directory

References:

• Finkel RS, Mercuri E, Muntoni F and others. ‘Diagnosis and management of spinal muscular atrophy: Part 1: Recommendations for diagnosis, rehabilitation, orthopedic and nutritional care’. Neuromuscular Disorders 2018: volume 28, issue 2, pages 103–115. DOI: 10.1016/j.nmd.2017.11.005

For patients

• NHS Health A to Z: Spinal muscular atrophy
• Spinal Muscular Atrophy UK