Spinal Muscular Atrophy
Spinalmuscular atrophy is a disease of progressive muscle wasting and motor weakness. Inspinal muscular atrophy, the alpha motor neurons in the anterior horn of thespinal cord that are responsible for skeletal muscle control deteriorate andare lost over time. Affected individuals are plagued by muscle weakness thatprogresses in a proximal to distal fashion. As the motor neurons deteriorate,muscle wasting ensues. Three major types exist (Table 1) and differ based on ageof onset and clinical severity of symptoms.
Structure and Function
Spinalmuscular atrophy is a genetic disease inherited in an autosomal recessivemanner. It is caused by a mutation in the SMN1 (survival motor neuron) gene on chromosome 5 that codes for the so-called survival motor neuron protein – so-called, because without it, motor neurons do not survive.
Evenif the SMN1 gene is not functional, a similar gene, SMN2, found nearby onchromosome 5, can code for the production of some survival motor neuronprotein. The SMN2 gene is able to produce only about 10-20% of the normalamount of SMN protein (Figure 1). People ordinarily have 2 to 4 copies of theSMN2 gene. The more copies of SMN2 that affected people have, the more SMNprotein they produce and the milder their clinical presentation will be.Nonetheless, even with many copies of the SMN2 gene – and some people have upto 8 – the levels of SMN protein are still below normal if the main SMN1 geneis not functional.
Patientswith spinal muscular atrophy type 1 are the most severely affected, with age ofonset at birth and rapid progression, often leading to respiratory failure anddeath within the first two years of life (Figure 2).
Inthese patients, deep tendon reflexes are absent, and muscle fasciculations may beseen. The spinal musculature is severely affected, leading to poor trunkcontrol, often termed “floppy baby syndrome.”
Patientswith spinal muscular atrophy type 2 present later, between 6-18 months of age,and have a less severe and less rapidly progressive course. The proximalmusculature is affected first, and progresses in a distal manner. Almost allpatients will develop scoliosis as weakness progresses (Figure 3). The curvepattern is usually typical of a neuromuscular curve, but is often very flexiblecompared to scoliotic curves seen in other conditions. Soft tissue contracturesaround the hip, knee, and ankle are common. Hip dislocations (Figure 4) andequinovarus feet are often encountered in these patients as well. Patientsusually do not have the ability to stand independently and rely on the use of awheelchair for mobility. Deep tendon reflexes are absent.
Spinalmuscular atrophy type 3 patients are the least severely affected, and symptomspresent later, during childhood or early adolescence. These children usuallymaintain the ability to stand independently but will usually becomewheelchair-bound as an adult.
The diagnosisis suspected based on clinical signs and symptoms, but since spinal muscularatrophy is caused by a genetic mutation in the SMN1 gene, DNA analysis confirmsthe disease.
Radiographsof the affected spine will show the scoliotic deformity, which is usually along, sweeping curve commonly with associated pelvic obliquity. Hip radiographsreveal dysplasia, signs of acetabular dysplasia ranging from mild uncoveringwith instability to dislocation. Generalized osteopenia may be present innon-ambulatory patients.
Spinalmuscular atrophy, an autosomal recessive genetic disease, is seen in one in10,000 live births. It is the most common cause of death due to a geneticdisease in infants. There is no differential risk based on ethnic group.
Spinalmuscular atrophy may be confused phenotypically with muscular dystrophy, andindeed it wasn’t until the mid-20th century that spinal muscular atrophy wasdistinguished as a separate entity. One classic differentiating factor between musculardystrophy and spinal muscular atrophy is the absence of deep tendon reflexes inspinal muscular atrophy, with maintenance of the reflexes in muscular dystrophy.
Shortness of breath and respiratory distress is a common cause of death in spinal muscular atrophy type 1 infants and may require ventilator support in individuals with type 2 and 3 disease.
Signs of choking and difficulty swallowing is common as the disease progresses, which may require speech therapy support.
Treatment Options and Outcomes
Medicaltreatment of spinal muscular atrophy has evolved over the past few years.Nusinersen, a medication that is injected intrathecally (into the spinal canalsuch that it reaches the cerebrospinal fluid), has been shown to slow theprogression of disease in spinal muscular atrophy patients. Nusinersen acts onthe SMN2 gene to modulate the splicing of the RNA transcript, leading toincreased production of SMN protein.
In2019, a gene therapy treatment option was approved in the United States:onasemnogene abeparvovec (Zolgensma). The adenovirus-like vector is givenintravenously and contains the SMN1 gene. It is currently approved for patientsunder 24 months of age.
Ventilatorsupport is a critical aspect of treatment as spinal muscular atrophy patientssuffer from respiratory muscle atrophy. Much like patients with muscular dystrophy, nighttime ventilation is often required either via tracheostomy or CPAP/BiPAP.
Patientswith spinal muscular atrophy type 2 may develop progressive scoliosis. Bracingis sometimes used in an effort to slow progress but will not halt it. In youngpatients, often those with curves greater than 50 degrees are treatedsurgically to prevent respiratory compromise. Since younger patients still havesubstantial thoracic growth left, surgical strategies often involve placementof some sort of growing rod to allow for support and continued growth of thespine and chest wall. Once the patient reaches adolescence, the spine may bedefinitively fused with posterior spinal fusion. If scoliosis develops duringadolescence, surgical treatment is usually performed for curves greater than 40degrees, for progressive curves, or when lung function deteriorates.
Uniqueto spinal muscular atrophy patients, now that Nusinersen treatment isavailable, is to perform a laminectomy at a single level in the lumbar spine toallow access for future intrathecal administration of the medication. Anteriorrelease is rarely necessary in spinal muscular atrophy patients.
Treatmentof the hip dysplasia in spinal muscular atrophy patients remains controversial.Many advocate for observation, as dislocations tend to be asymptomatic and therecurrence rate after open reduction is higher than for idiopathic hipdislocations. If pain is present, the decision may be made to treat thedislocation surgically, with soft tissue releases and femoral/pelvicosteotomies.
Forsoft tissue contractures of the lower extremity, optimal treatment also remainscontroversial. If the patient is ambulatory, knee flexion contractures maybe addressed with hamstring lengthening, and foot and ankle deformitiesaddressed with tendon lengthening procedures. However, many soft tissuecontractures are left alone and observed, especially in non-ambulatorypatients.
Life expectancyin spinal muscular atrophy varies depending on the subtype. Spinal muscularatrophy type 1 patients usually die by 2 years of age. Type 2 patients may beexpected to live to young adulthood. Type 3 patients have approximately normallife expectancy. Improvements in respiratory care and support have served toincrease the life expectancy of these patients.
Nusinersenleads to improved muscle function while retarding disease progression.Long-term outcomes of the medication wait to be seen, as the medication hasonly been approved for use in spinal muscular atrophy patients within the last4 years.
Risk Factors and Prevention
Because spinal muscular atrophy is inherited in an autosomal recessive manner, if there is no known family history of the disease, parents may be unaware of their carrier status. Accordingly, spinal muscular atrophy was added to the Recommended Uniform Screening Panel for newborns in 2018. (This panel is a list of disorders that the federal government recommends for states to screen as part of their newborn screening programs.)
SpinalMuscular Atrophy, Survivalmotor neuron, Werdnig-Hoffman disease, Nusinersen, Zogensma