SMA is an 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:

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

3 - 5mL of whole blood in an EDTA tube. 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 from patients' samples is kept for at least 12 months, unless a written request for its disposal is received from the patient or their parent/guardian.

Restrictions on Testing

Prenatal or presymptomatic diagnosis is offered for families. Family testing for direct members will be performed prior to prenatal testing.

Tests offered

The SMA MLPA assay is a quantitative test for SMN1 & SMN2 genes copy number, kit used is from MRC-Holland

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 & SMN2 mutations. Referrals are accepted from individuals with a family history of SMA, and partners of such individuals.

Prenatal & Presymptomatic:

Prenatal and presymptomatic diagnosis/exclusion (using MLPA) 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) homizygously deleted for the SMN1 gene, and with a 2^ndcausative mutation characterised OR a firm diagnosis of SMA, including a characteristic muscle biopsy. 

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.