SMN1 Gene Mutation
Spinal muscular atrophy (SMA) is characterized by degeneration of the anterior horn cells in the spinal cord and motor nuclei in the lower brainstem. These diseases are classified as types 1 through 4 depending upon the age of onset and clinical course. SMA type 1 is the most severe type of SMA and presents during infancy, while type 4 is milder and presents in the second or third decade of life. Patients with all forms of SMA have diffuse symmetric proximal muscle weakness that is greater in the lower than upper limbs and absent or markedly decreased deep tendon reflexes.
SMA is inherited in an autosomal recessive pattern. More than 95% of cases are caused by biallelic deletion of exon 7 in the survival motor neuron 1 (SMN1) gene on chromosome 5q13.2. A few cases are compound heterozygotes for an SMN1 deletion and an SMN1 intragenic mutation. SMN1 gene codes for a full-length survival motor neuron protein necessary for lower motor neuron function.The level of SMN protein correlates with severity of disease.
Molecular genetic testing with targeted mutation analysis can confirm the diagnosis of SMA by detection of homozygous deletions of exon 7 of the SMN1 gene. SMA carrier testing determines the number of exon 7-containing SMN1 copies. If exon 7 is deleted from both copies of SMN1, the diagnosis of SMA is confirmed. If exon 7 is deleted from one copy of SMN1, sequence analysis of all SMN1 exons should be performed to determine if the patient is a compound heterozygote for deletion of exon 7 of SMN1 and an intragenic SMN1 mutation. Other diagnoses should be considered if exon 7 is present in both copies of SMN1.
Differences in disease severity are partly related to a modifying gene, called SMN2. SMN1 and SMN2 genes are more than 99 percent identical and lie within an inverted duplication on chromosome 5q13.2. SMN2 encodes for a survival motor neuron protein that is less stable and cannot fully compensate for the loss of functional SMN1 protein. However, when SMN2 gene copy number is increased, enough functional protein is produced to ameliorate disease severity. The presence of three or more copies of SMN2 is associated with a milder phenotype.
