Wallach's Interpretation of Diagnostic Tests: Pathways to Arriving at a Clinical Diagnosis (449 page)

   SMA carrier testing—gene dosage analysis of SMN1 copy number is performed by measuring the number of exon 7–containing SMN1 copies. However, intragenic mutations will not be detected by this test. In addition, molecular tests will not indicate if the two copies of the normal SMN1 gene are located on one chromosome, making the individual a carrier with no SMN1 gene on another chromosome (approximately 4% of the population). Furthermore, 2% of individuals with SMA have one de novo mutation, meaning that only one parent is a carrier.

   Because of these difficulties in SMA carrier test interpretation, SMA carrier testing should be provided in the context of formal genetic counseling.

   Other Considerations

To help to distinguish SMA from other disorders of nerve or muscle that may look similar to SMA, the following tests may be performed:

   Electromyography (EMG), a test that measures the electrical activity of muscle

   Muscle biopsy, looks for the presence of the specific ultrastructural changes

   Creatine kinase (CK), an elevated level indicates muscle disease

Other rare forms of SMA with different genetic causes:

   Spinal muscular atrophy respiratory distress (SMARD) inherited in an autosomal recessive pattern is caused by mutations in the IGHMBP2 gene.

   Spinal muscular atrophy type V/distal hereditary motor neuropathy, autosomal dominant disorder caused by mutations in the BSCL2 and GARS genes.

   Kennedy disease, X-linked autosomal recessive disease known as X-linked recessive bulbospinal neuropathy or X-linked spinal and bulbar atrophy, is associated with an increase in the number of CAG repeats encoding a polyglutamine stretch within the androgen receptor.

Suggested Readings

http://www.fsma.org/FSMACommunity/UnderstandingSMA/

Prior TW, Russman BS. Spinal muscular atrophy. In: Pagon RA, Adam MP, Bird TD, et al., eds.
GeneReviews
^™
[Internet]
. Seattle, WA: University of Washington, Seattle; 2000:1993–2013 [Updated 2011 Jan 27]. Available from:
http://www.ncbi.nlm.nih.gov/books/NBK1352/

   
PULMONARY SYSTEM

ALPHA-1 ANTITRYPSIN DEFICIENCY (A1ATD)

MIM #613490

   Definition

Alpha-1 antitrypsin deficiency, an autosomal recessive disorder caused by mutations in the protease inhibitor 1 gene, SERPINA1. Mutations in the SERPINA1 gene can lead to a shortage (deficiency) of alpha-1 antitrypsin or an abnormal form of the protein that cannot control neutrophil elastase. Without enough functional alpha-1 antitrypsin, neutrophil elastase destroys alveoli and causes lung disease. Abnormal alpha-1 antitrypsin can accumulate in the liver and cause damage. One of the clinical manifestations of A1ATD is liver disease in childhood and cirrhosis and/or hepatocellular carcinoma (HCC) in adulthood. Alpha-1 antitrypsin deficiency is commonly overlooked cause of lung disease.