AUTHOR AND EDITOR INFORMATION

Section 1 of 9  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• References

INTRODUCTION

Section 2 of 9  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• References

Background

Kugelberg Welander spinal muscular atrophy (SMA) is a rare inherited disorder that causes progressive degeneration of the anterior horn cells of the spinal cord. The exact cause of this degeneration is unknown. Loss of these cells results in a purely motor progressive neuropathy without sensory involvement. This neuropathy is manifested as hypotonia, weakness, and progressive paralysis.

Spinal muscular atrophies were first described in the 1890s by Guido Werdnig, a physician from the University of Vienna, who gave a lecture titled "On a Case of Muscular Dystrophy with Positive Spinal Cord Findings." One year later, Professor Johann Hoffmann from Heidelberg University presented a paper describing a syndrome of progressive atrophy, weakness, and death during the early childhood period of siblings with genetically normal parents. Both physicians conducted autopsies on their patients and found severe atrophy of the ventral roots of the spinal cord. They also found histologic evidence of loss of motor neurons in the anterior horn cells of this region. Professor Hoffman called the syndrome spinale muskelatrophie or SMA.

In the early 1960s, Byers and Banker classified SMA into categories based on the severity and age of onset of the symptoms, in an effort to predict prognosis. Their system, summarized below, was the basis for the most widely recognized system used today for classification of SMA.

• Type I
  • Onset of symptoms before age 6 months
  • Also known as infantile onset SMA, or Werdnig-Hoffmann disease

• Type II
  • Onset of symptoms at age 6-18 months
  • Also known as chronic SMA, juvenile SMA, or intermediate SMA

• Type III
  • Onset of symptoms after age 18 months, usually in late childhood or adolescence
  • Also known as Wohlfart-Kugelberg-Welander syndrome or mild SMA

Although Byers and Banker's classification system focuses only on the above 3 categories, many sources refer to a fourth type of SMA.

• Type IV
  • This category is reserved for onset of symptoms during early adulthood.
  • This disorder usually carries a much more favorable prognosis than the other types of SMA.

This article focuses only on SMA types III and IV.

Pathophysiology

SMA is caused by successive motor unit degeneration. Atrophy of muscles, due to progressive loss of the anterior horn cells in the spinal cord, is universal. The motor nuclei in the lower brainstem, usually those of cranial nerves V-XII, also may be involved. Various stages of degeneration can be observed histologically at these sites. As the nerve cells decrease in number, replacement gliosis, pyknosis, and secondary Wallerian degeneration in the roots and peripheral nerves are observed. These processes generally begin at the caudal end of the cord and typically are symmetrical. The lower limbs usually are affected sooner and more profoundly than the upper limbs. This degeneration usually affects the proximal musculature before the distal. Note that, unlike in amyotrophic lateral sclerosis (ALS), no corticospinal tract involvement is seen in SMA.

Frequency

United States

The estimated incidence of SMA is 1 case per 15,000 live births. The genetic carrier prevalence is 1:80.

International

SMA has an estimated incidence of 1 case per 15,000-20,000 live births worldwide.

Mortality/Morbidity

SMA types III and IV, unlike types I and II, are consistent with survival well into adulthood. Significant morbidity occurs from the progressive weakness. Patients may fall frequently or have difficulty with stairs. Most patients use wheelchair mobility by their fourth decade of life. Scoliosis and joint contractures are also extremely common. Morbidity associated with these conditions often can be minimized by spinal surgery, as well as aggressive physical therapy. Respiratory failure is not as common as in SMA types I and II. Respiratory complaints usually can be managed medically, and mechanical ventilation seldom is necessary.

Race

SMA affects all races equally.

Sex

SMA affects both sexes equally; however, disease progression is more severe in males.

Age

Age of onset is discussed above in the Background section.

CLINICAL

Section 3 of 9  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• References

History

• Patients with SMA types III and IV usually present with an insidious onset of weakness, often following a brief period of illness such as with influenza. The illness may have required a short period of bedrest.
• Patients most often report symptoms associated with weakness of the hip extensor and hip abductor muscles and describe difficulty climbing stairs or getting up from a seated position on the floor.
• Some patients also may report a mild tremor and occasional painful muscle cramps.
• Difficulty walking or running also is reported by the patient.
• In younger patients, parents may report delayed developmental milestones or decreased athletic abilities in their children.
• A family history of such disorders also may be elicited.

Physical

• Proximal muscle weakness is seen, with the pelvic girdle being more affected than the shoulder girdle.
• Patients have decreased muscle tone.
• Patients have diminished deep tendon reflexes. Ankle reflexes, however, may be preserved until very late in the disease progression.
• Fasciculations may be present in the tongue or shoulder girdle muscles (especially after manual muscle testing).
• Minipolymyoclonus, a fine, irregular tremor of the outstretched fingers, may be seen. This is the result of denervation followed by reinnervation and the asynchronous firing of restructured and enlarged motor units.
• Calf pseudohypertrophy has occasionally been noted, but muscle wasting of affected musculature is more prominent.
• Patients may have a positive Gower sign and a waddling gait.
• Approximately one third of patients have facial and masseter muscle weakness.
• Sensory examination findings are normal.

Causes

The exact etiology of SMA is unknown. SMA is an inherited disorder that almost always occurs in an autosomal recessive pattern. A few cases of autosomal dominant and X-linked recessive patterns have been reported.

All forms of SMA have been linked to a gene deletion on the long arm of chromosome 5, at band 5q13. The 2 genes associated with SMA are SMN1 and SMN2, which are adjacent to each other on band 5q. The SMN1 (survival motor neuron 1) gene is believed to be the primary disease-causing gene. The presence of 3 or more copies of SMN2 is correlated with a milder phenotype.

Authors of recent studies have hypothesized that a deletion of this gene may be related to disturbances in the metabolism of 3',5'-adenosine monophosphate. Whether or not this disturbance contributes to the neuron degeneration of SMA remains to be seen.

DIFFERENTIALS

Section 4 of 9  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• References

Other Problems to be Considered

Duchenne muscular dystrophy
Myasthenia gravis
Glycolytic or lipid storage myopathy
Lambert-Eaton myasthenic syndrome
Polyneuritis
Polymyositis
Endocrine-related myopathy
Botulism
Muscular hypotonia secondary to Marfan syndrome or Prader-Willi syndrome
Malnutrition
Metabolic disorders (eg, organic aciduria) and mitochondrial disorders
Leukodystrophy
Peripheral neuropathies
Carnitine deficiency
Dermatomyositis
Paraneoplastic encephalomyelitis
Transverse myelitis
Poliomyelitis
Arthrogryposis multiplex congenita
Hodgkin disease associated anterior horn disease
Macroglobulinemia associated anterior horn disease

WORKUP

Section 5 of 9  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• References

Lab Studies

• Molecular genetic testing: Routine diagnostic testing involves targeted mutation analysis to detect deletion of exons 7 and 8 of SMN1. Approximately 95-98% of individuals with a clinical diagnosis of SMA lack exon 7 in both copies of SMN1 (ie, they are homozygous for the deletion). Approximately 2-5% of individuals with a clinical diagnosis of SMA are compound heterozygotes for deletion of SMN1 exon 7 and an intragenic mutation of SMN1. Routine genetic testing only detects patients with the homozygous deletion. However, additional testing is available that includes SMN1 sequence analysis looking for point mutations in the SMN1 gene. Recently developed genetic testing, not yet widely available, uses quantitative polymerase chain reaction to determine the SMN2 gene copy number. The SMN2 gene copy number is variable, ranging from 0-5.
• Other testing: Serum creatine kinase levels may be elevated, but usually not to the extent of the elevations seen in persons with muscular dystrophy. Serum aldolase levels also are commonly elevated in persons with types III and IV SMA.

Imaging Studies

• Ultrasound of the muscles had been used to assess for neurogenic atrophy, but it is fairly nonspecific. Ultrasound has lost favor as a diagnostic tool for SMA. Neuroimaging of patients with SMA reveals no brain abnormalities.

Other Tests

• Muscle biopsy reveals evidence of neurogenic atrophy and chronic reinnervation. Skeletal muscle changes include atrophy with a combination of narrow fibers and large hypertrophic fibers. These fibers are separated by abundant fat and fibrous tissues. Increase in the sarcolemmal nuclei with preservation of striations is observed. The phrenic (C3-C5) and sacral (S2-S4) sphincter motor neurons are spared. Typical findings consistent with neurogenic atrophy also are seen on biopsy and are discussed in the Pathophysiology section above.
• Electromyography (EMG) and nerve conduction studies (NCS) can be very useful for the physician in the diagnosis of SMA. Diffuse abnormalities on EMG are seen in the extremities and bulbar musculature. The findings are consistent with axonal degeneration. Fibrillation potentials, positive sharp waves, and complex repetitive discharges are common. Large motor unit potentials are typical, but small amplitudes also have been seen. Upon recruitment, polyphasic motor unit potentials, decreased recruitment, fast firing, and synchronization of motor units are seen. A marked increase in jitter on EMG often is seen and helps to differentiate SMA types III and IV from ALS. Motor nerve conduction velocities are normal or slightly decreased. Motor unit action potentials (MUAPs) progressively decrease in amplitude. Sensory nerve action potentials (SNAPs) are normal.

TREATMENT

Section 6 of 9  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• References

Rehabilitation Program

Physical Therapy

No cure is known for SMA; thus, most care for the patient with SMA is focused on symptomatic control and preventative rehabilitation. Maintaining the patient's joint mobility is very important, as the goal is to decrease the incidence of contractures. Plantar flexion contractures are the most common.

Ankle foot orthotics, worn at night, may help provide prolonged passive stretch to prevent worsening of ankle plantar flexion contractures.

Stretching and strength training, under the care of an experienced physical therapist, are very important components of the preventative rehabilitation approach. For school-age patients, a physical therapist can provide consultation regarding appropriate or adaptive physical education activities.

Aquatic therapy is an excellent way to maintain mobility, strength, and flexibility.

With the progressive weakness associated with SMA, patients may require the use of a wheelchair on a full-time basis. For these patients, there are multiple assistive devices available that enable them to maintain a level of independence. Patients are encouraged to use manual wheelchairs versus electric wheelchairs, when possible, to maintain cardiovascular fitness and upper body strength.

Occupational Therapy

The occupational therapist plays an essential role in addressing the individual needs of each patient. Occupational therapy is useful for teaching the patient ways to increase his or her independence with activities of daily living (ADL). Fine motor skills may be affected by fatigue. Affected school-age patients may benefit from an occupational therapy consultation to address keyboarding and other ways to avoid fatigue with upper extremity activities in the classroom.

Patients may eventually require the use of a wheelchair on a full-time basis. In addition, multiple assistive devices are available that enable patients to maintain a higher level of independence.

Speech Therapy

A speech therapist may be needed for consultation if dysphagia is present or diet modification is needed.

Medical Issues/Complications

• Orthopedic: A few studies have shown that scoliosis is a major problem in half the patients with SMA type III. However, it occurs less frequently and is less severe than scoliosis in persons with SMA type II. Routine radiography should be performed and a thoracolumbar sacral orthosis (TLSO) or surgery may be necessary. Spinal orthoses have been shown to assist in containing the spinal deformity until instrumentation and fusion can be performed if necessary.
• Respiratory function: Ventilatory failure resulting from neuromuscular restrictive lung disease is rare; however, pulmonary function should be measured on a regular basis. A pulmonary rehabilitation program and noninvasive ventilation may be used if respiratory problems develop.
• Sleep disorders: Questions regarding sleep hygiene and fatigue should be addressed. Patients with SMA type III frequently report fatigue. One case report described a 46-year-old man with SMA type III whose increasing daytime fatigue caused by nocturnal snoring and apnea resolved with nighttime use of continuous positive airway pressure with a nasal mask. Another case report documented the coexistence of sleep-disordered breathing and dilated cardiomyopathy in a 53-year-old patient with SMA type III. Similarly, symptoms were virtually eliminated with nighttime use of continuous positive airway pressure via nasal mask.
• Contractures: Contractures are usually mild as long as patients remain ambulatory.
• Dysphagia

Surgical Intervention

• Spinal instrumentation and fusion may be necessary if scoliosis develops. Some upper extremity function can be lost after fusion.
• Tendon lengthenings may be needed to improve joint position.

Consultations

• Genetic counseling: Parents, patients, and extended family members may benefit from genetic counseling. Carrier detection relies on determining the number of exon 7–containing SMN1 gene copies present in an individual. SMA carrier testing, a polymerase chain reaction–based dosage assay, is available on a limited clinical basis. For a number of reasons, test results can be difficult to interpret and should be provided in the context of formal genetic counseling.
• Vocational rehabilitation counseling: This type of counseling may be beneficial to facilitate transition from secondary school to post-secondary education or for vocational planning.

MEDICATION

Section 7 of 9  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• References

A single study from the Russian literature in 1990 suggested that lithium may have a role in slowing the disease progression, but this has not been corroborated. Further studies are need to investigate this and other possible pharmacologic treatments.

A recent study using thyrotropin-releasing hormone as a treatment for SMA types II and III in children showed promising results. More studies are warranted to further investigate this possible treatment. (See reference article by Tzeng et al, A study of thyrotropin-releasing hormone for the treatment of spinal muscular atrophy: a preliminary report. Am J Phys Med Rehabil 2000 Sep-Oct; 79(5): 435-40.)

Merlini et al performed a multicenter, randomized, controlled trial of gabapentin versus no treatment in 120 patients with type II or III SMA for 12 months. A significant improvement in lower extremity maximum voluntary isometric contraction was seen.

FOLLOW-UP

Section 8 of 9  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• References

Further Outpatient Care

• Patients with SMA should have frequent follow-up care for symptomatic control of their disease. Respiratory function, nutritional state, orthopedic status, and equipment needs should be assessed at each visit. Pain control, preventative medicine, surgical intervention, and physical therapy are all essential parts of the patient's long-term care. The multidisciplinary approach, which includes family members, social workers, therapists, and physicians, is important to assist the patient in maintaining a high quality of life.

Complications

• Scoliosis
• Plantar flexion contractures
• Dysphagia

Prognosis

• Patients experience progressive loss of motor function, usually affecting legs before arms, and proximal muscles before distal.
• Patients who have never climbed stairs without a rail lose walking ability by the mid teens. Patients who develop normal walking skills prior to the onset of muscle weakness can maintain this ability until the third or fourth decade.
• Life expectancy of individuals with SMA type III has been shown to be similar to that of the general population.
• See Mortality/Morbidity section.

REFERENCES

Section 9 of 9

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• References

• Adams RD, Victor M. Principles of Neurology. 5th ed. McGraw-Hill Inc;1993.
• Bradley WG. Neurology in Clinical Practice. 3rd ed. Butterworth-Heinemann;2000.
• Il''ina NA, Antipova RI, Khokhlov AP. [Use of lithium carbonate to treat Kugelberg--Welander spinal amyotrophy]. Zh Nevropatol Psikhiatr Im S S Korsakova. 1980;80(11):1657-60. [Medline].
• Lin LC, Jong YJ. Pulmonary function assessment in patients with spinal muscular atrophy type II and type III. Acta Paediatr Taiwan. Jan-Feb 2004;45(1):15-8.
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• Merlini L, Solari A, Vita G, et al. Role of gabapentin in spinal muscular atrophy: results of a multicenter, randomized Italian study. J Child Neurol. Aug 2003;18(8):537-41.
• Merlini L, Granata C, Bonfiglioli S, et al. Scoliosis in spinal muscular atrophy: natural history and management. Dev Med Child Neurol. Aug 1989;31(4):501-8.
• Moosa A, Dubowitz V. Spinal muscular atrophy in childhood. Two clues to clinical diagnosis. Arch Dis Child. May 1973;48(5):386-8.
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• Puruckherr M, Mehta JB, Girish MR, et al. Severe obstructive sleep apnea in a patient with spinal muscle atrophy. Chest. Nov 2004;126(5):1705-7.
• Rodillo E, Marini ML, Heckmatt JZ, Dubowitz V. Scoliosis in spinal muscular atrophy: review of 63 cases. J Child Neurol. Apr 1989;4(2):118-23.
• Russman BS, Buncher CR, White M, et al. Function changes in spinal muscular atrophy II and III. The DCN/SMA Group. Neurology. Oct 1996;47(4):973-6.
• Swaiman KE, Ashwal S. Pediatric Neurology: Principles and Practice. 3rd ed. Mosby Inc;1999.
• Tachdjian MO. Pediatric Orthopedics. 2nd ed. WB Saunders Co;1990.
• Tzeng AC, Cheng J, Fryczynski H, et al. A study of thyrotropin-releasing hormone for the treatment of spinal muscular atrophy: a preliminary report. Am J Phys Med Rehabil. Sep-Oct 2000;79(5):435-40. [Medline].
• Umphred DA. Neurological Rehabilitation. 3rd ed. Mosby Inc;1995.
• Yasuma F, Kuru S, Konagaya M. Dilated cardiomyopathy in Kugelberg-Welander disease: coexisting sleep disordered breathing and its treatment with continuous positive airway pressure. Intern Med. Oct 2004;43(10):951-4.
• Younger DS, Gordon PH. Diagnosis in Neuromuscular Diseases. Vol 14. Neurologic Clinics;1996.
• Zerres K, Rudnik-Schöneborn S, Forrest E, et al. A collaborative study on the natural history of childhood and juvenile onset proximal spinal muscular atrophy (type II and III SMA): 569 patients. J Neurol Sci. Feb 27 1997;146(1):67-72.
• de Groot IJ, de Witte LP. Physical complaints in ageing persons with spinal muscular atrophy. J Rehabil Med. Jul 2005;37(4):258-62.

Article Last Updated: Jun 22, 2006