Spinal Muscular Atrophy (SMA), OMIM #253300

Background and Standard Service Information

SMA is autosomal recessive, with a frequency of 1 in 10,000 (carrier frequency of approximately 1 in 38). Clinical features include: proximal muscle weakness, floppy baby, poor feeding, absent reflexes, arthrogyphosis, and fasciculation of tongue. SMA results from the degeneration of the anterior horn cells of the spinal cord. Approximately 95% of SMA patients have homozygous absence of exons 7 and 8 (or exon 7 only) of the Survival Motor Neuron 1 (SMN1) gene (i.e. they have no functional copies of the SMN1 gene). The remainder of patients are compound heterozygotes for SMN1 mutations, with a subtle mutation on one chromosome and a deletion or gene conversion on the other. The copy number of the adjacent SMN2 gene has been shown to correlate with disease severity, however prediction of disease severity on this basis may not be accurate. SMA is clinically heterogeneous, classified into 4 types based on clinical severity:

The 4 types of Spinal Muscular Atrophy
SMA Types Age of Onset Prognosis
Type I (Werdnig-Hoffmann) 0 - 6 months most severe, never sit, death in early infancy
Type II < 2 years never stand, death in early twenties
Type III (Kugelberg-Welander) > 2 years muscle wasting, survive into adulthood
Type IV 30-50 years Least severe

Essential referral information

In addition to supplying standard patient identification and referral information, the following should be clearly indicated:

  1. Patient’s symptoms.
  2. Any family history, including names, dates of birth, relationship and genetic test results if available.

It is the responsibility of the referring clinician to ensure consent has been obtained for testing and storage.

Samples required

Generally 5-10ml of EDTA blood (FBC bottle) is required. Blood specimens must be appropriately packaged, and preferably sent by courier to arrive as soon as possible. Do not freeze prior or during postage.

Please note that extracted DNA is stored from patient’s samples at the National Centre for Medical Genetics, and kept indefinitely unless a written request for its disposal is received from the patient or their parent/guardian.

Restrictions on Testing

Carrier testing is only available via a Clinical Geneticist. Please refer your patient to Clinical Genetics if carrier testing for SMA is required. Carrier testing is not offered for minors. This policy is consistent with international guidelines for genetic testing of children. Prenatal or presymptomatic diagnosis is offered for families, only where an index case has previously been identified as either 1) homozygously deleted for the SMN1 gene or 2) hemizygously deleted for the SMN1 gene and with either a 2nd causative mutation identified OR a firm diagnosis of SMA, including a characteristic muscle biopsy.

Tests offered

The SMA P021 MLPA assay is available in the National Centre for Medical Genetics, and is a quantitative test for SMN1 gene copy number, (MLPA website).

Diagnostic:
Molecular confirmation of a suggested clinical diagnosis.
Carrier testing:
A direct test, to confirm carrier status or estimate the risk of being a carrier of the common SMN1 mutation, is available at the NCMG. Referrals are accepted from individuals with a family history of SMA, and partners of such individuals. Carrier testing is only available via a Clinical Geneticist, and is not offered for minors.
Prenatal & Presymptomatic:
Prenatal and presymptomatic diagnosis/exclusion (using MLPA, & additional linkage analysis if required) may be possible in families, but only where an index case has previously been identified as either 1) homozygously deleted for the SMN1 gene or 2) hemizygously deleted for the SMN1 gene, and with a 2nd causative mutation characterised OR a firm diagnosis of SMA, including a characteristic muscle biopsy. Prenatal testing must be arranged in advance with the laboratory, through a Clinical Genetics department if possible.

Diagnostic sensitivity of tests

The SMA MLPA assay is a quantitative test for SMN1 gene copy number, and will not pick up subtle deletions, inversions or point mutations in SMN1- screening for such mutations can be arranged via external laboratories, where relevant. Diagnostic sensitivity of the MLPA assay is additionally influenced by the fact that approximately 4% of the SMN1 alleles in the general population have two SMN1 copies on a single chromosome.

Diagnostic:
Homozygous deletion of the SMN1 gene will be evident in approximately 95% of SMA Type I patients.
Carrier testing:
Carrier status will be confirmed in approximately 96% of SMN1 deletion carriers.
Prenatal & Presymptomatic:
Providing linkage analysis is informative, prenatal & presymptomatic diagnosis should be possible, with an error rate due to recombination of less than 1%.

Interpretation

Results are given in the form of a written interpretative report to the referring clinician.

Diagnostic:
Diagnosis is confirmed where a homozygous deletion of exons 7 and 8 (or exon 7 alone) of the SMN1 gene is indicated. Hemizygous deletion of SMN1 (i.e. 1 copy) reduces the likelihood that a patient is affected with SMA, but does not rule out a diagnosis of SMA. Over 99% of 5q13-linked SMA cases are excluded by an MLPA result which indicates 2 copies of SMN1.
Carrier testing:
Detection of only one copy of the SMN1 gene confirms deletion carrier status. In the absence of a family history, detection of two or three copies of the SMN1 gene indicates a very low risk of carrying a deletion (<1%). Where there is a family history of SMA, detection of two copies of the SMN1 gene indicates an intermediate risk of carrying a deletion (an estimate of this risk will be provided with individual reports), while detection of three copies of the SMN1 gene indicates a very low risk of carrying a deletion (<1%).
Prenatal & Presymptomatic:
For families in which an index case has been identified as homozygously deleted for the SMN1 gene, prenatal/presymptomatic diagnosis is confirmed where a homozygous deletion of exons 7 and 8 (or exon 7 alone) of the SMN1 gene is indicated. The absence of homozygous deletion of SMN1 indicates a low risk of developing SMA (<1%). The clinical severity of SMA cannot be accurately predicted.

Target reporting times

As reporting times are constantly evolving, please refer to molecular genetics, or contact the molecular genetics laboratory, to receive up-to-date information on anticipated reporting times for your referral.

Target reporting times for each category of test offered (information correct as of January 2010):
Diagnostic: 6-8 weeks Routine / 2 weeks Urgent (i.e. a neonate)
Carrier testing: 6-8 weeks Routine / 2 weeks Urgent (i.e. pregnancy)
Prenatal: 2 weeks CVS (4 weeks for amniotic fluid specimens)
  • Please contact the laboratory if you have not received a report within a week of your patient being due back in clinic.
  • Please note it is our policy not to issue verbal results.
  • Request for copies of reports on the day that your patient is in clinic cannot normally be accommodated. We usually require 24 hours notice in which to fax a copy of a report.

Further tests

The SMA MLPA assay is a quantitative test for SMN1 gene copy number, and will not pick up subtle deletions, inversions or point mutations in SMN1- however, screening for such mutations can be arranged by us via external laboratories, where relevant (e.g. in the case of a suspected clinical diagnosis in the presence of a hemizygous deletion of SMN1). Please contact the laboratory for further information.

The NCMG Molecular Genetics laboratory participates in external QA schemes run by the UK NEQAS for Molecular Genetics, the European Molecular Genetics Quality Network (EMQN), and the Cystic Fibrosis European Network. Results of assessments are available for inspection upon request.

Document Number: DOC520, Revision Number 4