Spinal muscular atrophy
Spinal muscular atrophy (SMA) is a progressive neurodegenerative disorder characterized by the loss of motor neurons, leading to muscle atrophy. It manifests in five clinical subtypes, varying in age of onset and severity, with Type I being the most common and severe, affecting approximately 1 in 6,000 to 1 in 10,000 individuals. SMA is primarily genetic, resulting from mutations in the SMN1 gene, which is inherited in an autosomal recessive manner. Individuals with one functioning copy of the gene may remain symptom-free, while those with reduced copies of a related gene, SMN2, may experience milder forms of the disease.
Symptoms often appear in infancy or early childhood and can include hypotonia, difficulty breathing and swallowing, and eventual loss of motor functions. There is currently no cure for SMA, but treatments such as risdiplam, nusinersen, and onasemnogene abeparovec-xioi have been approved to help manage the condition and improve quality of life. Carrier screening and prenatal diagnosis options are available to assess risks for future pregnancies, allowing families to make informed decisions. Despite advances in treatment, SMA remains a serious condition with significant health implications and a high rate of mortality.
Spinal muscular atrophy
ALSO KNOWN AS: Infantile Werdnig-Hoffmann disease; Kugelberg-Welander disease; spinobulbar muscular atrophy (SBMA); Kennedy disease
DEFINITION Spinal muscular atrophy (SMA) is a progressive neurodegenerative disorder caused by the loss of function of motor neurons, which leads to muscular atrophy. There are five clinical subtypes that range in age of onset and the severity of disease. SMA Type I is the most common subtype, which combined with other childhood forms affects an estimated 1 in 6,000 to 1 in 10,000 people.
Risk Factors
SMA has a purely genetic 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 1, telomeric) 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, centromeric). 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 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, tremors, 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 or a chorionic villus sampling (CVS) to biopsy a small portion of the placenta.
Treatment and Therapy
There is no cure for SMA, but in 2020, the US Food and Drug Administration approved the use of risdiplam under the brand name Evrysdi® to treat SMA patients beginning at two months of age. The oral medication was shown to greatly improve the ability of patients to sit, stand, eat, and breathe. It works by addressing the reduced amount of survival motor neuron (SMN) protein that causes SMA. By 2024, more than 15,000 patients in more than 100 countries worldwide had been treated using risdiplam.
Other therapies that are used to treat SMA patients include nusinersen (Spinraza™), a drug administered by lumbar puncture that also increases SMN protein, and onasemnogene abeparovec-xioi (Zolgensma™). Onasemnogene is a gene therapy used for patients under two with Type 1 SMA. It is a gene therapy that replaces the patient's faulty SMN gene to help restore its function.
Risdiplam, nusinersen, and onasemnogene are not cures; they are treatments that help improve the quality and length of life of SMA patients. In addition, treatments are available to ease SMA 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 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. In 2016, the US Food and Drug Administration (FDA) approved the drug Nusinersen, the first of its kind to treat SMA. Three years later, the FDA approve the gene therapy medication Onasemnogene abeparvovec-xioi for the treatment of SMA in children under age two.
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