Spinal Muscular Atrophy

BACKGROUND:

Spinal muscular atrophy (SMA) is the second most common autosomal recessive disorder in Caucasians with a carrier frequency of 1/35. It is a progressive neuromuscular disease caused by degeneration of alpha motor neurons in the spinal cord causing atrophy of proximal muscles, paralysis, respiratory failure and early death. Classification based on age of onset and clinical severity is:

Type I

(OMIM 253300 Werdnig-Hoffman)

most severe, lives 11 months or less

Type II

(OMIM 253550)

intermediate, lives 21 months or less

Type III

(OMIM 253400)

least severe, lives 33- 66 months

Two highly homologous genes encoding the spinal motor neuron (SMN) gene product are located on chromosome 5q 13. Absence of the SMN1 gene product is diagnostic of SMA and 94% of affected individuals are homozygous for SMN1 gene deletions. Most of the rest are compound heterozygotes with one SMA1 gene deletion and an intragenic SMN1 mutation. The clinical severity of SMA in affected individuals is correlated with the number of SMN2 genes present. Complete lack of the SMN2 gene in SMA affected patients is not seen, so by inference, lack of both the SMN1 and SMN2 genes is lethal. However, SMN2 fails to provide complete protection from SMA because it contains a polymorphism which compromises the efficiency of an RNA splicing enhancer sequence. The presence of one or two copies of the SMN gene is found in 80% of patients with Type 1 SMA. Increasing numbers of SMN2 gene copies is correlated with less severe disease: 83% of patients with Type 2 SMA have 3 SMN2 gene copies and 94% of Type III patients have 3 or 4 SMN2 genes.

INDICATION FOR TESTING:

Definite or possible diagnosis of infants or children with progressive limb and trunk paralysis and delayed gross motor development.
Presymptomatic sibling of an affected individual with a positive DNA test.
Prenatal diagnosis limited to high risk families in which homozygous SMN deletion has been identified.

SAMPLE REQUIREMENTS:

Blood: Two 5ml purple top (EDTA) vacutainers of whole blood (invert several times to mix.) Forward within 48 hours at room temperature.

INTERPRETATION:

Allele specific PCR reactions are used to selectively amplify the SMN1 or SMN2 genes from patient DNA. Real time quantitative PCR assays determine gene dosage. The first assay determines individuals who are carriers or are affected with SMA: 2 SMN1 alleles = normal, 1 SMN1 allele = carrier, no SMN1 alleles = affected. For affected individuals lacking SMN1 genes, the second assay defines the number of SMN2 genes present and the clinical correlations cited above apply.

COUNSELING ISSUES:

1. 2% of SMN gene mutation carriers have intragenic lesions not detected by the deletion assay. Also, 4% of individuals with a normal SMN1 gene have a second tandem copy of the SMN1 gene as well and will not be detected as carriers by the deletion assay. As a result, 6% of SMA carriers (as well as 8% of the parents of SMA affected children) will be missed by the deletion assay. Therefore, the carrier detection rate is 94%.

2. The correlation between SMN2 copy number and severity of clinical disease among SMA affected individuals is not absolute due to the presence of other SMN2 polymorphisms and incomplete gene copies. The following table describes the probability, derived from Baysean calculations that a child found to have homozygous absence of SMN1 will develop Type I, II, or III based on SMN2 copy number.

POSTERIOR PROBABILITY OF DEVELOPING SMA

# SMN2 Genes	TYPE I	TYPE II	TYPE III
1	99.9%	<0.1%	<0.1%
2	97%	2.6%	0.04%
3	7%	83%	10%
4	1%	15%	84%

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