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Spinal Muscular Atrophy

Spinal muscular atrophy (SMA) is a rare genetic disease that affects the motor neurons due to a protein deficiency as a consequence of a mutation in the SMN1 gene. When the central nervous system receives a stimulus, it produces an appropriate response to the information processed, which can be endocrine or muscular in nature, depending on the stimulus. The degradation of these important cells results in problems related to movement and muscle pain.

“Spinal muscular atrophy (SMA) is a devastating motor neuron disease that predominantly affects children and represents the most common cause of hereditary infant mortality. The condition results from deleterious variants in SMN1, which lead to depletion of the survival motor neuron protein (SMN). Now, 20 years after the discovery of this genetic defect, a major milestone in SMA and motor neuron disease research has been reached with the approval of the first disease-modifying therapy for SMA by US and European authorities — the antisense oligonucleotide nusinersen. At the same time, promising data from early-stage clinical trials of SMN1 gene therapy have indicated that additional therapeutic options are likely to emerge for patients with SMA in the near future. However, the approval of nusinersen has generated a number of immediate and substantial medical, ethical and financial implications that have the potential to resonate beyond the specific treatment of SMA.”1

 “The predominant clinical features of SMA are muscle weakness and atrophy attributed to motor neuron dysfunction and loss. Weakness is usually symmetric and proximally predominant. The spectrum of severity may range from mild proximal limb weakness noticed in adulthood to severe generalized weakness with respiratory failure in the neonatal period. Lower limbs are more involved than upper limbs, and bulbar and respiratory weakness usually occurs in cases with more severe limb weakness. The onset and progression of weakness is distinct from many other motor neuron disorders in that there is usually a presymptomatic period in all but the most severe cases (type 0), followed by rapidly progressive functional loss and a later relatively static phase with slow progression. Occasionally, some families will even report periods of transient improvement after a period of progression. The reason for this pattern of progression is not understood, nor is the natural history in the earliest stage of disease well defined. During periods of stress such as infection or pregnancy, some patients experience worsening weakness.”2

Depending on the symptoms that the patient presents, we can differentiate between several categories of spinal muscular atrophy.

Type I

Also known as Werdnig-Hoffmann’s disease, the symptoms appear before six months of age. The individual stops developing during the growth stages and presents great muscle weakness (hypotonia). This alteration, together with the abnormal secretion of other substances, causes great difficulty in breathing. The most striking symptom is the position of the legs (called frog legs) that appears with a generalized lack of reflexes. In addition, involuntary jerking of a muscle “

“Spontaneous motility is generally poor and antigravity movements of limbs are not typically observed. In the most severe forms decreased intrauterine movements suggest prenatal onset of the disease and present with severe weakness and joint contractures at birth and has been labeled SMN 0. Some of these children may show also congenital bone fractures and extremely thin ribs.

Within SMA type I at least 3 clinical subgroups can be defined according to the severity of clinical signs: a) severe weakness since birth/neonatal period, head control is never achieved; b) onset of weakness after the neonatal period but generally within 2 months, head control is never achieved; c) onset of weakness after the neonatal period but head control is achieved. Some of these children may be able to sit with support.

Clinically, all children with SMA type I show a combination of severe hypotonia and weakness, with sparing of the facial muscles, invariably associated with a typical respiratory pattern. The weakness is usually symmetrical and more proximal than distal, with lower limbs generally weaker than upper limbs. Deep tendon reflexes are absent or diminished but sensitivity is preserved.

The spared diaphragm, combined with weakened intercostal muscles, results in paradoxical breathing. The involvement of bulbar motorneurons often give tongue fasciculation, poor suck and swallow with increasing swallowing and feeding difficulty over time. Aspiration pneumonia is an important cause of morbidity and mortality.

In the last few years there has been increasing evidence that some cases with severe SMA type I (generally carrying 1 copy of SMN2) may have heart defects, mostly atrial and ventricular septal defects and a possible involvement of the autonomic system that may be responsible for arrhythmia and sudden death.”3

Type II

The symptoms appear between six and eighteen months of age. Subjects have difficulty standing and sitting up but can stay erect or seated on their own; they are not able to walk without assistance. Tremors may appear, especially when the patient extends the fingers.

“Type II SMA (or chronic SMA) generally becomes symptomatic at around 6 to 18 months, but it may emerge earlier. Some patients classified as having type II SMA are able to sit up unaided while others can remain sitting if they are positioned, but cannot sit up unaided. Better developed patients are able to remain standing if provided with support, but will nevertheless be unable to learn to walk. Bulbar weakness, combined with swallowing difficulties, can lead to reduced weight gain in some children. Furthermore, these patients may have problems with coughing and with cleaning secretions from the trachea, may have fine trembling (known as fasciculation) and can suffer from scoliosis and contractures as they age. Life expectancy is around 10 to 40 years.”4

Type III

It is called Kugelber-Welander disease. The symptoms appear between childhood and puberty. Patients can walk and sit on their own but can experience pain when they lean. In some cases, tremors and scoliosis (deviation of the spine) may appear together with alterations in the joints.

“Spinal muscular atrophy type 3 (SMA3), or Kugelberg-Welander disease, is a relatively mild form of spinal muscular atrophy characterized by proximal muscle weakness and hypotonia caused by the degeneration of the lower motor neurons in the spinal cord and the brainstem nuclei. The onset of the disease usually occurs in childhood or adolescence, after ambulation has been acquired, distinguishing two subtypes of the disease: SMA3a (onset <3 years) and SMA3b (onset >3 years). Muscle weakness affects mainly the legs and hip muscles and progresses to the shoulders and arms. Difficulties walking, running, and climbing stairs are common. Finger trembling and scoliosis are also frequent.

SMA3 is caused by deletions in the SMN1 gene, encoding the survival motor neuron protein. The disease severity is inversely correlated with the number of copies of the second SMN2 with patients with SMA3 having three or four SMN2 copies.

The use of wheelchair may be required in some patients during childhood (mainly SMA3a), while others retain the ability to walk into adulthood (mainly SMA3b). SMA3 progresses slowly and life expectancy is usually normal. However, deformities of the vertebral column are frequent, and complications may lead to respiratory restriction.”5

Type IV

Also known as Kennedy’s disease. Symptoms appear during adulthood, usually at the age of 35. The patient experiences weakness of the facial muscles and serious dietary issues. Muscle atrophy extends and aggravates with the passage of time, along with a loss of sensitivity in the hands and feet. Fasciculation is also frequent and other neuropathies can develop.

“Kennedy’s disease, an X-linked spinal and bulbar muscular atrophy, is a neuro degenerative disorder characterized by loss of lower motor neurons. Patients with this disease exhibit progressive proximal and bulbar muscle weakness; atrophy, and fasciculation of limb and facial muscles; speech, swallowing, and walking difficulties; and mild sensory deficits. Gynecomastia and infertility may also be observed. In general, patients live a normal life span, although they may become confined to a wheelchair as the disease progresses.”6

As mentioned before, this disorder has a genetic origin where there is an alteration in the SMN1 gene, this means that the patient is not able to synthesize certain proteins essential for the maintenance of the motor neurons. The degeneration of these correlates to the weakness of the skeletal muscle. For this mutation to be present in the children, both parents must be carriers of the defective gene.

The tests most used to identify this pathology are:

  • A DNA analysis of the patient through the extraction of blood and its examination in the laboratory. This way, the gene in question is observed and identified
  • Electromyography and studies of nerve conduction velocity, which serve to analyze the efficacy of the electrical activity of the central nervous system.
  • A muscle biopsy to detect neuromuscular diseases
  • Other routine tests such as urinalysis to detect metabolic waste abnormalities.

“The diagnostic process for SMA has not changed since the original consensus statement paper but more accurate information on the genetic background has become available. Unless there are previous familial cases, the diagnostic process is generally prompted by the clinical signs. Clinically, these infants present with hypotonia, progressive symmetric and proximal weakness affecting the legs more than the arms, sparing of the facial muscles but often with bulbar muscle weakness. There is also weakness of the intercostal muscles with relative sparing of the diaphragm, which results in the typical ‘bell-shaped’ chest and paradoxical breathing pattern. Childhood onset is similarly characterized by hypotonia and proximal weakness, but with less prominent bulbar and respiratory findings.”7

To this day, no effective cure for this disease has been discovered. Within the therapeutic arsenal used, there are numerous treatments focused on alleviating the symptoms that the patient may present, among them we include medication to control spasms and analgesics that alleviate muscle pain.

Current and Emerging SMA Treatments

“Until recently, management of SMA has consisted primarily of supportive care to slow or prevent respiratory failure, nutritional compromise, scoliosis, and joint contractures. Respiratory care includes the use of devices that improve ventilation, especially during sleep and viral illnesses when hypoventilation is most likely to occur, as well as methods to mechanically augment cough and clearance of respiratory secretions. Nutritional support includes the use of nonoral methods to deliver enteral nutrition, typically through a surgically placed feeding tube or temporary nasal tube, plus medical or surgical interventions to control gastroesophageal reflux. Management of joint contractures and scoliosis involves aggressive physical therapy assessments, daily passive range of motion exercises, and use of bracing to facilitate and maintain optimal positioning of extremities and maintain the spine upright against gravity. Surgical intervention with internal fixation of the spine may also be needed. Over time, these supportive interventions have prolonged life and slowed the natural history of SMA.”8

“Currently, a new therapeutic option became available for patients with SMA. Nusinersen is the first approved drug to treat pediatric and adult patients with SMA. It has received the U.S. Food and Drug Administration approval in late December 2016 after initial clinical trials showing that it is safe, well tolerated and effective. In particular, the unpublished ENDEAR trial showed significant improvement in motor milestones among 40% of the patients treated with Nusinersen while all untreated patients consistently deteriorated. Moreover, no significant major adverse events occurred secondary to the administration of this drug except for few reported cases of respiratory tract infections and constipation. Nusinersen is an antisense oligonucleotide that is designed to increase the expression of the survival motor neuron protein. It is administered by intrathecal injection for four initial loading doses; the first three loading doses are given at 14-day intervals, while the fourth loading dose is given 30 days after the third. Thereafter, a maintenance dose is given once every four months. Despite its cost (around $125.000/dose), treatment with Nusinersen is recommended for most patients when available since it can prevent worsening of the disease and avoid respiratory failure and death.”9

Physiotherapy sessions are also useful to avoid other complications. Some orthopedic devices such as a wheelchair, help the patient to better perform activities of daily life. It is also important to establish control of pulmonary ventilation and appropriate diet. In some cases, individuals must be intubated because they have difficulty swallowing.



(1) Groen, E. J., Talbot, K., & Gillingwater, T. H. (2018). Advances in therapy for spinal muscular atrophy: promises and challenges. Nature Reviews Neurology, 14(4), 214. Available online at

(2) Arnold, W. D., Kassar, D., & Kissel, J. T. (2015). Spinal muscular atrophy: diagnosis and management in a new therapeutic era. Muscle & nerve, 51(2), 157-167. Available online at

(3) D’Amico, A., Mercuri, E., Tiziano, F. D., & Bertini, E. (2011). Spinal muscular atrophy. Orphanet journal of rare diseases, 6(1), 71. Available online at

(4) Baioni, M. T., & Ambiel, C. R. (2010). Spinal muscular atrophy: diagnosis, treatment and future prospects. Jornal de pediatria, 86(4), 261-270. Available online at

(5) Angelini, C. (2014). Spinal Muscular Atrophy Type 3, Kugelberg-Welander Disease. In Genetic Neuromuscular Disorders (pp. 303-305). Springer, Cham. Available online at

(6) Au, K. M., Lau, K. K., Chan, A. Y., Sheng, B., & Li, H. L. (2003). Kennedy’s disease. Hong Kong Medical Journal, 9(3), 217-220. Available online at’s_disease

(7) Mercuri, E., Finkel, R. S., Muntoni, F., Wirth, B., Montes, J., Main, M., … & Bertini, E. (2018). Diagnosis and management of spinal muscular atrophy: Part 1: Recommendations for diagnosis, rehabilitation, orthopedic and nutritional care. Neuromuscular Disorders, 28(2), 103-115. Available online at

(8) Tabet, R., El Bitar, S., Zaidan, J., & Dabaghian, G. (2017). Spinal Muscular Atrophy: The Treatment Approved. Cureus, 9(9). Available online at

(9) Rao, V. K., Kapp, D., & Schroth, M. (2018). Gene Therapy for Spinal Muscular Atrophy: An Emerging Treatment Option for a Devastating Disease. Journal of managed care & specialty pharmacy, 24(12-a Suppl), S3-S16. Available online at


Robert Velasquez
11 September, 2018

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Hello everyone, my name is Robert Velazquez. I am a content marketer currently focused on the medical supply industry. I studied Medicine for 5 years. I have interacted with many patients and learned a more:

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