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Spinal muscular atrophy

Spinal Muscular Atrophy (SMA) is a term applied to a number of different disorders, all having in common a genetic cause and the manifestation of weakness due to loss of the motor neurons of the spinal cord and brainstem. more...

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Caused by mutation of the SMN gene

The most common form of SMA is caused by mutation of the SMN gene, and manifests over a wide range of severity affecting infants through adults. This spectrum has been divided arbitrarily into three groups by the level of weakness.

  • Infantile SMA - Type 1 or Werdnig-Hoffmann disease (generally 0-6 months). SMA type 1, also known as severe infantile SMA or Werdnig Hoffmann disease, is the most severe, and manifests in the first year of life with the inability to ever maintain an independent sitting position.
  • Intermediate SMA - Type 2 (generally 7-18 months). Type 2 SMA, or intermediate SMA, describes those children who are never able to stand and walk, but who are able to maintain a sitting position at least some time in their life. The onset of weakness is usually recognized some time between 6 and 18 months.
  • Juvenile SMA - Type 3 Kugelberg-Welander disease (generally >18 months). SMA type 3 describes those who are able to walk at some time. It is also known as Kugelberg Welander disease.

Other forms of SMA

Other forms of spinal muscular atrophy are caused by mutation of other genes, some known and others not yet defined. All forms of SMA have in common weakness caused by denervation, i.e. the muscle atrophies because it has lost the signal to contract due to loss of the innervating nerve. Spinal muscular atrophy only affects motor nerves. Heritable disorders that cause both weakness due to motor denervation along with sensory impairment due to sensory denervation are known by the inclusive label Charcot-Marie-Tooth or Hereditary Motor Sensory Neuropathy. The term spinal muscular atrophy thus refers to atrophy of muscles due to loss of motor neurons within the spinal cord.

  • Hereditary Bulbo-Spinal SMA Kennedy's disease (X linked, Androgen receptor)
  • Spinal Muscular Atrophy with Respiratory Distress (SMARD 1) (chromsome 11, IGHMBP2 gene)
  • Distal SMA with upper limb predominance (chromosome 7, glycyl tRNA synthase)


The course of SMA is directly related to the severity of weakness. Infants with the severe form of SMA frequently succumb to respiratory disease due to weakness of the muscles that support breathing. Children with milder forms of SMA naturally live much longer although they may need extensive medical support, especially those at the more severe end of the spectrum.

Although gene replacement strategies are being tested in animals, current treatment for SMA consists of prevention and management of the secondary effect of chronic motor unit loss. It is likely that gene replacement for SMA will require many more years of investigation before it can be applied to humans. Due to molecular biology, there is a better understanding of SMA. The disease is caused by deficiency of SMN (survival motor neuron) protein, and therefore approaches to developing treatment include searching for drugs that increase SMN levels, enhance residual SMN function, or compensate for its loss. The first effective specific treatment for SMA may be only a few years away, as of 2005.


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Severe obstructive sleep apnea in a patient with spinal muscle atrophy
From CHEST, 11/1/04 by Michael Puruckherr

Patients with spinal muscle atrophy (SMA) who survive to adulthood experience a slow, continuous loss of motor function but typically have a normal life expectancy. These patients, however, require vigilance on the part of their health-care providers to reverse treatable disorders to maintain a satisfactory quality of life. We report on a patient with obstructive sleep apnea and type 3 SMA. The treatment of his sleep-disordered breathing resulted in the resolution of symptoms that were initially attributed to his neuromuscular disease.

Key words: continuous positive airway pressure; Kugelberg-Welander syndrome; neuromuscular disease; obstructive sleep apnea; spinal muscle atrophy

Abbreviations: CPAP = continuous positive airway pressure; OSA = obstructive sleep apnea; SMA = spinal muscle atrophy


Spinal muscle atrophies (SMAs) represent a heterogeneous group of hereditary progressive motor neuron disorders. The inheritance pattern is typically autosomal-recessive, but autosomal-dominant variants also have been described, especially for type 3 and 4 SMAs. Each form of SMA is characterized by the selective destruction of a-motor neurons in the anterior horns of the spinal cord without pyramidal tract involvement. The different forms of SMA are classified according to clinical criteria, especially age of onset and motor disabilities. (1,2)

Type 3 SMA, also known as the Kugelberg-Welander syndrome, manifests itself after the age of 18 months. The initial clinical presentation is proximal, symmetrical leg weakness. These patients may have a delay in learning to stand and walk, but eventually they manage independent ambulation. Their ability to walk, however, is usually slowly lost during the course of the disease. Although patients with SMA type 3 experience a slow, continuous loss of muscle function that impinges on their activities of daily living, the individual's life span is often not significantly reduced. (1-3)

Obstructive sleep apnea (OSA) affects 2% of adult women and 4% of adult men in the United States. (4) However, the prevalence of sleep-disordered breathing in patients with neuromuscular diseases is > 40%. OSA occurs in 24% of adults with neuromuscular diseases. (5) Despite these observations, the progressive symptoms of sleep-disordered breathing are often attributed to the untreatable progression of the underlying neuromuscular disease, rather than to the more easily treated sleep-disordered breathing. (5) Our patient underscores the concept that close attention to the patient's complaints and vigilance toward their treatment can improve their quality of life.


A 46-year-old white man with type 3 SMA was referred for the evaluation of progressive fatigue that was interfering with Iris usual activities of daily living. He also admitted to increasing somnolence during the day, morning headaches, and snoring with episodes of apnea while asleep. The patient reported no dyspnea, cough, or sputum production.

At 8 years of age, the patient had received a diagnosis of type 3 SMA. The patient stated that he initially was able to sit and walk independently, even though these occurred later than usual in comparison to other children in his age group. At the age of 5 years, he developed proximal muscle weakness, first in his legs, then later in his upper extremities. By the time of his diagnosis, he was confined to a wheelchair.

The patient was slightly below ideal body weight (body mass index, 17.4 kg/[m.sup.2]), and his weight had been stable for years. The patient was wheelchair-bound and had severe scoliosis. The only residual active muscular movements that were preserved were in his left forearm and neck.

All laboratory parameters, including a CBC count, serum electrolyte measurements, a biochemical survey, a coagulation profile, and a measurement of serum creatinine phosphokinase levels, were normal. His arterial blood gas analysis results were normal (pH, 7.47; p[O.sup.2], 85.6 mm Hg; pC[O.sup.2], 33.8 mm Hg). Pulmonary function tests were consistent with a restrictive ventilatory defect (FVC, 2.36 L/min and 59.1% predicted; FE[V.sup.1], 1.77 L/min and 55.2% predicted). His maximal inspiratory and expiratory pressures were decreased at 35.0 mm Hg (73% predicted) and 45.8 mm Hg (69% predicted), respectively. Electromyography demonstrated the following typical characteristics of type 3 SMA: spontaneous muscle activity with fibrillations and fasciculations, but normal transmission velocity of peripheral sensory nerves.

His polysomnography results documented severe OSA with some apneas lasting as long as 2 min and accompanied by oxyhemoglobin desaturations 40% lower than the patient's baseline (Fig 1). The patient was given treatment with continuous positive airway pressure (CPAP) using a nasal mask. When CPAP therapy was titrated up to 9 cm [H.sub.2]O, all episodes of apnea ceased. After 2 nights of CPAP therapy, the patient's daytime drowsiness resolved. At the end of 1 week of therapy, the patient reported significantly less fatigue and an increased sense of well-being. Polysomnography performed after the patient had received 12 months of CPAP therapy demonstrated the complete normalization of the patient's sleep architecture and no apnea episodes.



We believe that our patient is the first to be reported in the English-language medical literature to have severe OSA in association with type 3 SMA. While our patient lacked the traditionally recognized risk factors for OSA, we cannot exclude SMA as a contributing cause of his sleep-disordered breathing. (5) Furthermore, the involvement of respiratory muscles and the increased work of breathing seen in patients with SMA have been implicated in the development of sleep-disordered breathing. (6,7)

Unfortunately, only supportive therapy for SMA is currently possible. This includes active and passive physical therapy, and the application of lightweight orthopedic braces. (1,2,8) Prompt and aggressive treatment of respiratory infections has been shown to improve survival in patients with SMA. (3) There is also a reasonable hope that gene therapy will be available in the future as a form of therapy for SMA. (19,10)

Our patient's condition improved with CPAP treatment, which resolved his nighttime airway obstruction and relieved his complaints of fatigue. This therapy, however, is often not effective in the treatment of sleep-disordered breathing that is secondary to muscle fatigue associated with neuromuscular disorders. Such patients typically require bilevel positive airway pressure therapy that provides a ventilatory rate, and differential inspiratory and expiratory pressures. Therapy with intermittent positive-pressure ventilation via a nasal mask has also been used successfully in these patients. (7) More severely affected patients may need invasive nocturnal ventilation with an artificial airway. Since our patient responded well to CPAP therapy, we believe that his OSA was the cause of his recent symptomatology, rather than his SMA.


While awaiting progress in adjuvant therapies, the clinician providing care to patients with neuromuscular diseases must be watchful for reversible conditions that are associated with or are a complication of their primary disorder. Our patient highlights the fact that other treatable illnesses, such as OSA, can occur in patients with neuromuscular diseases. Early diagnosis and therapy directed toward these treatable disorders can contribute to an improved quality of life and may lengthen patient survival.


(1) Eng GD, Binder H, Koch B. Spinal muscular atrophy: experience in diagnosis and rehabilitation management of 60 patients. Arch Phys Med Rehabil 1984; 65:549-553

(2) Iannaccone ST. Spinal muscular atrophy. Semin Neurol 1998; 18:19-26

(3) Zerres K, Rudnik-Schoneborn 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 1997; 146:67-72

(4) Young T, Palta M, Dempsey J, et al. The occurrence of sleep disordered breathing in middle-aged adults. N Engl J Med 1993; 328:1230-1235

(5) Labanowski M, Schmidt-Nowara W, Guilleminault C. Sleep and neuromuscular disease: frequency of sleep-disordered breathing in a neuromuscular disease clinic population. Neurology 1996; 47:1173-1180

(6) Cerveri I, Fanfulla F, Zoia MC, et al. Sleep disorders in neuromuscular diseases. Monaldi Arch Chest Dis 1993; 48: 318-321

(7) Ellis E, Bye TP, Bruderer JW, et al. Treatment of respiratory failure during sleep in patients with neuromuscular disease. Am Rev Respir Dis 1987; 135:148-152

(8) Carter GT, Abresch RT, Fowler WM Jr, et al. Profiles of neuromuscular diseases: spinal muscular atrophy. Am J Phys Med Rehabil 1995; 74:S150-S159

(9) Wirth B. Spinal muscular atrophy: state-of-the-art and therapeutic perspectives. Amyotroph Lateral Scler Other Motor Neuron Disord 2002; 3:87-95

(10) Schmalbruch H, Haase G. Spinal muscular atrophy: present state. Brain Pathol 2001; 11:231-247

* From The Veterans Affairs Medical Center, Mountain Home, TN.

Manuscript received January 30, 2004; revision accepted June 23, 2004.

Reproduction of this article is prohibited without written permission from the American College of Chest Physicians (e-mail:

Correspondence to: Ryland P. Byrd, Jr., MD, FCCP, Veterans Affairs Medical Center 111-B, PO Box 4000, Mountain Home, TN 37684-4000; e-mail:

COPYRIGHT 2004 American College of Chest Physicians
COPYRIGHT 2004 Gale Group

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