11.1.1 Introduction and Epidemiology

Spinal muscular atrophy (SMA) is one of a diverse group of neuromuscular disorders that presents variably from the newborn period to much later in life, even as late as the third or fourth decade. ¹ The disease usually manifests itself as hypotonia and weakness. ¹ This autosomal recessive neurodegenerative disorder occurs in as many as 1 of every 10,000 live births, with a reported carrier frequency between 1.7 and 2.5% of the general population. ¹ Currently, there are no preventative therapies, and the mainstay of treatment after diagnosis is supportive therapy aimed at addressing specific symptoms. ² Currently, an investigational gene therapy that acts to replace the defective gene through intrathecal injections holds promise. ³

11.1.2 Etiology and Genetics

SMA is caused by the degeneration of the alpha motor neurons of the anterior horn cells of the spinal cord as well as the motor nuclei of the brainstem. ⁴ In approximately 99% of patients, the etiology of this degeneration is thought to be a homozygous deletion in the survival motor neuron 1 gene (SMN1), ^{5 ,​ 6} found on chromosome 5q13.2. The most often reported mutation within the SMN1 gene is a deletion of exon 7, with approximately 94% of patients with SMA having a homozygous deletion of exon 7. ⁷ The SMN1 gene codes for a protein which, when produced correctly, inhibits neuronal apoptosis. ⁸ In patients with SMA, it is this loss-of-function mutation that results in the neurodegenerative aspects of the disease process. ⁸

Disease severity seems to be closely related to the levels of SMN1 protein deficiency, although the ability to predict SMA severity from genotype alone is limited and not recommended in clinical practice. ^{6 ,​ 9} There is also evidence that survival motor neuron 2 (SMN2), a gene differing only in the nucleotide change from C to T in exon 7, affects phenotypical expression of disease. ^{4 ,​ 9 ,​ 10} SMN2 codes for the production of survival motor neurons, albeit in smaller numbers than SMN1, and there is evidence that increased levels of SMN2 correlate with less severe forms of SMA ¹¹

There are currently two theories as to how the deletion within SMN1 causes SMA. The first theory asserts that this deletion impairs the assembly of small ribonucleoprotein (RNP) subunits of the spliceosome, resulting in disruption of motor neuron circuitry. ^{6 ,​ 12} A second theory postulates that the SMN1 deletion inhibits mRNA transport within neurons. ^{6 ,​ 13}

11.1.3 Initial Presentation, Diagnosis, and Genetic Screening

A diagnosis of SMA should be entertained in any child presenting with delayed milestones, symmetric proximal muscle weakness (ranging from mild to flaccid paralysis [greater in the lower limbs]), or diminished or absent deep tendon reflexes, with or without fasciculations. ¹⁴ A weak cry, poor suck and swallow reflex resulting in excess secretions, and aspiration may also be indicative of SMA, and should prompt further investigation. ¹⁴

Once clinical suspicion is established, genetic testing for a homozygous deletion in exons 7 and 8 of the SMN1 gene can confirm the diagnosis. ¹³ In most cases, genetic testing alone can make a diagnosis, but if an SMN1 deletion is not found, a diagnosis can be confirmed through the use of electromyography, muscle biopsy, and nerve conduction studies. ^{7 ,​ 13} In those with a family history of SMA, a prenatal diagnosis can be made, although population-wide genetic screening is not currently recommended. ^{1 ,​ 15}

11.1.4 Classification Types and Pathogenesis

Once a diagnosis is made, it is important to determine the subtype of disease. There are currently four subtypes of SMA, which are defined by age on onset and functional disability. ⁶ SMA type I, or Werdnig–Hoffmann disease, is the most severe form of this disorder and presents within the neonatal period, typically before 6 months of age, although some signs may be evident in utero, such as decreased fetal movement. ¹³ Neonates with SMA often present with poor swallowing, loss of deep tendon reflexes, poor head control, tongue atrophy, and fasciculations, as well as intercostal muscle weakness. ⁶ They never develop the ability to sit independently. In the past, this disease has led to very early death, often within the first year of life. ¹⁶ However, advances in treatment, including aggressive respiratory support that often includes tracheostomy and ventilator support, has dramatically increased the life expectancy of these children. ¹³

SMA type II (intermediate) presents between 7 and 18 months. These patients present with delayed milestones, although most develop the ability to sit independently, with the defining characteristic of this subtype being the ability to maintain a sitting position unsupported. ¹³ Some patients with SMA type II are ultimately able to stand with the support of a standing frame or leg braces, although they lack the ability to walk. ¹³ Children with SMA type II also typically suffer from swallowing difficulty due to bulbar weakness and may have trouble gaining weight. ¹³ They also have weak intercostal muscles, resulting in difficulty clearing tracheal secretions. ¹³ Patients also suffer from joint contractures, scoliosis, and pulmonary comorbidities that contribute to a decreased life expectancy. ^{6 ,​ 13}

SMA type III (Kugelberg–Welander disease) presents after 18 months of age. ^{6 ,​ 13} Patients within this subtype achieve independent ambulation, although this may deteriorate throughout life. ¹³ Difficulty with mucociliary clearance and swallowing, while less common than in SMA type II, is also present in patients with SMA type III. ¹³ These patients often have less severe pulmonary manifestations of their disease, and in those who continue to ambulate, life expectancy may often approach that of the general population. ¹⁷ These patients suffer from musculoskeletal overuse syndromes, scoliosis, hip abductor weakness (which causes a Trendelenburg lurch), and increased lumbar lordosis. ⁶

SMA type IV (adult onset), the least severe subtype of this condition, presents within the second or third decade of life and results in similar, albeit less severe, symptomatology as SMA type III. ¹⁶ Patients are able to ambulate without assistance and may experience mild motor impairment but do not typically suffer from respiratory or gastrointestinal manifestations of disease. ¹³

11.1.5 Relevance to Orthopaedics

In all subtypes of SMA, there are significant comorbidities, including pulmonary, gastrointestinal, and orthopaedic complications. Scoliosis, in particular, has been reported in between 60 and 95% of patients with SMA types I–III, with the severity of scoliosis and degree of progression directly related to SMA subtype and age of onset. ^{6 ,​ 18} The prevalence of scoliosis is also highly influenced by the ambulatory status of the patient. ¹⁸ Nearly all patients with SMA types I and II will develop scoliosis, while the incidence is as low as 50% in those with SMA type III. ^{7 ,​ 18} Pelvic obliquity and kyphosis are also associated with SMA, further complicating the clinical picture. ⁶ Hip dislocations are ubiquitous in more involved patients, although, as these patients are not ambulatory, surgical treatment is rarely indicated. Given the extent of orthopaedic complications in SMA, all patients with SMA should be seen regularly by an orthopaedic surgeon with experience treating patients with neuromuscular disease.

11.2.1 Patterns of Deformity

The orthopaedic manifestations of SMA include hip dislocations, joint contractures of the upper and lower extremities, and, perhaps most significantly, scoliosis. While the patterns of deformity are generally similar to those seen in other neuromuscular diseases, there are without question distinct characteristics that are specific to SMA that need to be understood to properly care for this challenging population. These include early age of onset, rapid rate of progression, and the unique severe chest wall deformities.

Spinal Deformity

Scoliosis is nearly ubiquitous in children with SMA types I and II. Not surprisingly, the pattern of deformity does vary with disease involvement. For example, while most cases of scoliosis in this population are long C-shaped thoracolumbar curves (Fig. 11‑1), ¹⁹ as commonly seen in a variety of neuromuscular diseases, ⁶ double major curve patterns are more common in children who are less severely affected. The incidence of double major curves is approximately 33% in children who can sit (type II) and only 12% in those who are unable to sit (type I). ¹⁹ The laterality of the curves varies significantly and is approximately 2:1 left:right for curves in patients with type II, while it is closer to 1:1 in patients with type III. ¹⁹ In addition to the frontal plane deformity, sagittal plane deformities are common as in other paralytic disorders such as Duchenne’s muscular dystrophy. ²⁰

The age of onset of scoliosis for these patients is almost always early in life (4.5 years for type II). ²¹ Pelvic obliquity is common, which affects sitting balance, and is typically proportional to the magnitude of scoliosis. ²² For children with SMA capable of ambulation (type III), the incidence of scoliosis is lower, with the timing of onset typically related to the age at which SMA becomes manifest. Overall, for children with all types of SMA type III, the age of onset of deformity is approximately 10 years. ²¹

Related posts:

7 Scoliosis in Cerebral Palsy 9 The Patient with Spinal Cord Injury: Surgical Considerations 8 Surgical Treatment of Spinal Deformity in Myelomeningocele 12 Other Neuromuscular Conditions: Rett Syndrome, Charcot–Marie–Tooth Disease, and Friedreich’s Ataxia 15 Spinal Deformity Associated with Neurodegenerative Disease in Adults 13 Neurosurgical Causes of Scoliosis

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