What is spinal muscular atrophy?

Risk Factors

SMA has a purely genetic etiology and can occur with or without a family history of the disorder. There are no environmental risk factors reported.

Etiology and Genetics

SMA is transmitted in an autosomal recessive pattern whereby a person simultaneously inherits two copies of the disease-causing gene (called SMN1, for survival of motor neuron) at conception. Carriers remain symptom-free because one working copy of SMN1 produces sufficient SMN protein for motor neuron cells to function.

The second gene implicated with SMA is called SMN2 (survival of motor neuron 2). This gene can range in copy number from zero to five copies in each cell. SMN1 and SMN2
are very similar in their composition, differing by only one nucleotide. This nucleotide difference does not change the amino acid generated but does alter the gene splicing (paring down mRNA by editing out noncoding regions of DNA). Usually the protein produced by SMN1 is longer than SMN2, but splicing is not a perfect process, and at times an equally long protein is produced from SMN2 and functions much like SMN1 protein. Thus, a person with SMA that has a high copy number of SMN2 genes is predicted to have a less severe case than someone who does not have any SMN2 genes.

Symptoms

With the exception of Type 0, most infants with SMA are born seemingly healthy and have no immediate symptoms. There is a tremendous range of severity. Generally earlier onset is predictive of a worse prognosis; thus, Type 0 is most severe, while Type IV is comparatively mild. Type 0 symptoms include a lack of fetal movements (at thirty to thirty-six weeks gestation), as well as joint contractures plus difficulty breathing and swallowing as a newborn. Most infants with Type 0 do not survive longer than two months of age. Type I symptoms begin between birth and six months of age and include hypotonia (low muscle tone and strength), paralysis, and mild joint contractures which result in difficulty sitting without support, breathing, and swallowing. Death occurs most commonly before two years of age, typically caused by complications such as respiratory infections. Type II (onset from six to twelve months) symptoms include an inability to sit, but standing or walking unaided is possible. Type III occurs in childhood (over one year of age) and is considerably more mild. Type IV has adult onset of symptoms that include muscle weakness, tremor,
and twitching. All forms of SMA have normal cognition and a high rate of mortality and morbidity.

Screening and Diagnosis

Screening and diagnostic testing for SMA are readily available through commercial laboratories. Carrier screening involves evaluating the SMN1 gene for mutations and determining the number of SMN2 genes via sequencing and quantitative polymerase chain reaction (PCR), respectively. Diagnostic testing is recommended if an individual is symptomatic and can help confirm a clinical diagnosis. Confirmation of a mutation may also aid in determining if extended family members should pursue carrier screening. Prenatal diagnosis requires testing fetal cells and thus performing an amniocentesis to sample the amniotic fluid or a chorionic villus sampling (CVS) to biopsy a small portion of the placenta.

Treatment and Therapy

There is no cure for SMA, but treatment is available to ease symptoms. Treatment of recurrent pulmonary infections, as well as tracheotomies, may be necessary. Alternative therapies include long-term ventilation, tube feeding, and physical therapy, which can help in prolonging survival. SMA Type I is a fatal condition; thus, palliative care is also provided.

Prevention and Outcomes

SMA is best prevented by carrier screening and other testing services. With two carrier parents, the risk is 25 percent for future pregnancies also being affected with SMA. There is also a 50 percent risk of having a future child that is an asymptomatic carrier. Lastly, there is a 25 percent chance of having a future child that is completely unaffected.

Prenatal diagnosis is available with the option of ending the pregnancy should it be affected. Preimplantation genetic diagnosis (PGD) is available to diagnose embryos prior to implantation if pursuing in vitro fertilization; however, the procedure is rarely pursued because insurance coverage is extremely limited.

Bibliography

Cummings, Michael. Human Heredity: Principles and Issues. 8th ed. Pacific Grove: Brooks/Cole, 2008. Print.

Dunaway, Sally, et al. "Independent Mobility After Early Introduction of a Power Wheelchair in Spinal Muscular Atrophy." Journ. of Child Neurology 28.5 (2013): 576–82. Print.

Firth, Helen V., and Jane A. Hurst. Oxford Desk Reference: Clinical Genetics. Oxford: Oxford UP, 2005. Print.

Harper, Peter S. Practical Genetic Counseling. 6th ed. London: Hodder Arnold, 2004. Print.

Sleigh, J. N., et al. "Spinal Muscular Atrophy at the Crossroads of Basic Science and Therapy." Neurmuscular Disorders 3.1 (2013): 96. Print.

Wokke, John H. J. Neuromuscular Disease: A Case-Based Approach. Cambridge: Cambridge UP, 2013. Print.