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Infantile 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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Pathologic quiz case: Male infant with generalized hypotonia and absence of respirations at birth
From Archives of Pathology & Laboratory Medicine, 4/1/01 by Kelly, Nadine P

A 28-year-old woman delivered a full-term male infant without complications bv normal spontaneous vainal delivery. The infant had no spontaneous respirations and generalized hypotonia at birth and was therefore placed on a ventilator. Pregnancy was complicated by polyhydramnios. On day 3 of life, a muscle biopsy was performed to rule out Werdnig-Hoffman disease. Microscopic examination revealed small, uniform muscle fibers with peripherally located nuclei (Figure 1). Modified Gomori trichrome stain showed the presence of red-stained granules or rodlike structures within the cytoplasm (Figure 2). These rods were grouped or scattered, some concentrating around the nuclei. Electron microscopy showed numerous electron-dense intracytoplasmic structures (Figure 3). A high-power view showed the lattice configuration of these structures (Figure 4). Other stains, including adenosine triphosphatase at pH 4.6 and pH 9.4, periodic acid-Schiff, oil red O, and acid phosphatase were negative. On day 5 of life, the infant was removed from the ventilator and he died. An autopsy was performed, which showed atrophic muscle fibers microscopically.

Pathologic Diagnosis: Congenital Nemaline Rod Myopathy

Nemaline myopathy, first described in 1963, is a neuromuscular disorder characterized by generalized muscle weakness and the presence of rodlike structures in the muscle fibers; the disorder occurs at a frequency of 1 in 500 000.1 The differential diagnosis of hypotonia in the neonatal period includes several disease entities: spinal muscular atrophy (type 1, Werdnig-Hoffman disease); congenital myopathies, including nemaline myopathy; congenital muscular dystrophy; congenital myotonic dystrophy; metabolic myopathies; neuropathies; and neonatal myasthenia gravis.2

Nemaline myopathy occurs in 3 forms based on age of onset and severity of clinical symptoms. They are a severe congenital form, the classic childhood form, and an adultonset form. The earlier the age of onset, the more severe the clinical symptoms are. Thus, the congenital form frequently results in early death. The childhood form of nemaline myopathy is the most common form and is usually a slow, nonprogressive disease. The patient presents at birth or during the first year of life with generalized weakness and characteristic myopathic facies with several physical deformities. The adult onset form is the least severe form and has variable presentations, including asymptomatic, minimal childhood muscle weakness, weakness in the third to sixth decades, and cardiomyopathy resulting in congestive heart failure.

Werdnig-Hoffman disease, or infantile spinal muscular atrophy, was the primary clinical diagnosis in this patient. Infantile spinal muscular dystrophy includes 3 subtypes: type 1 (acute, fatal) or Werdnig-Hoffman disease; type 2, intermediate; and type 3, chronic or Kugelberg-Welander disease. Werdnig-Hoffman disease is a neuromuscular disorder caused by loss of anterior horn cells and motor nuclei of cranial nerves V through VIII. Clinically, the infants present in the first 2 to 3 months of life with generalized hypotonia and impaired intercostal muscles without diaphragmatic involvement. Pathognomonic physical findings include "jug-handle" arms and "frog-leg" posture.3 Muscle biopsy demonstrates fiber type grouping, atrophy of types 1 and 2 muscle fibers, and hypertrophy of type 1 muscle fibers. These children generally die within the first year of life secondary to respiratory infection.

Congenital nemaline myopathy has several classic clinical features. Intrauterine findings include decreased fetal movements, polyhydramnios, joint contractures with malpositioned limbs, and preterm labor.4 At birth, the infant is "floppy" and requires immediate respiratory assistance. Sucking and swallowing reflexes are absent, but extraocular muscles are spared. Early death in the first weeks or months of life ensues most commonly as a result of bronchopulmonary infections withdrawal from life support, or, rarely, congestive heart failure resulting from cardiomyopathy. Two patients presenting with the severe congenital form who survived the neonatal period have been described.6 These patients were treated aggressively with endotracheal intubation and occupational and physical therapy. It was hypothesized that clinical improvement was achieved because there was time for muscle maturation.

The gold standard for diagnosis of nemaline myopathy is muscle biopsy. The muscle biopsy demonstrates small, uniform muscle fibers in hematoxylin-eosin-stained sections. The modified Gomori trichrome stain allows visualization of the nemaline rods, which stain as red rods like clumps of bacilli within the muscle fibers. They may be seen concentrated around the nuclei as well. Electron microscopy, however, is essential for diagnosis, demonstrating the rods as electron-dense structures in the sarcoplasm.

The pathogenesis of nemaline myopathy is not well understood. The rods, composed of alpha-actinin and actin, are abnormal extensions of the Z band.7 The rods do not involve all muscle fibers. Furthermore, the number of rods does not correlate with disease severity or age of onset; it has been hypothesized that weakness is due to abnormal fiber distribution, decreased number of muscle cells, and immaturity of muscle fibers.8

The inheritance of nemaline rod myopathy has been identified through autosomal-dominant and -recessive means.9 The autosomal-dominant form has been mapped to chromosome 1 and the autosomal-recessive form has been mapped to chromosome 2. In addition, Laing et al7 described the disease gene, TMP3, in autosomal-dominant nemaline myopathy. The TMP3 mutation is due to a missense mutation from methionine to arginine at the N terminus. This mutation leads to stronger actin binding and weaker contraction of the muscle fibers, as there is decreased sensitivity to calcium by the muscle.10

There is no curative treatment for nemaline rod myopathy. According to North et al,' management is aimed at preserving respiratory function and monitoring cardiac function and scoliosis.


1. North KN, Laing NG, Wallgren-Pettersson C, and the ENMC International Consortium on Nemaline Myopathy. Nemaline myopathy: current concepts. J Med Genet. 1997;34:705-713.

2. Dubowitz V. Muscle Disorders in Childhood. 2nd ed. Philadelphia, Pa: WB Saunders Co Ltd; 1995.

3. Fardeau M, Tome-Fernando MS. Congenital myopathies. In: Engel AG, Franzini-Armstrong C, eds. Myology. New York, NY: McGraw-Hill Inc; 1994:14941500.

4. Vendittelli F, Manciet-Labarchede C, Gilbert-Dussardier B. Nemaline myopathy in the neonate: two case reports. Eur J Pediatr. 1996;155:502-505.

5. Sasaki M, Takeda M, Kobayashi K, Nonaka I. Respiratory failure in nemaline myopathy. Pediatr Neurol. 1997;16:344-346.

6. Banwell BL, Singh NC, Ramsay DA. Prolonged survival in neonatal nemaline rod myopathy. Pediatr Neurol. 1994;10:335-337.

7. Laing NG, Wilton SD, Akkari PA, et al. A mutation in the alpha tropomyosin gene TPM3 associated with autosomal dominant nemaline myopathy. Nature Genet. 1995;9:75-79.

8. Shimomura C, Nonaka I. Nemaline myopathy: comparative muscle histochemistry in the severe neonatal, moderate congenital, and adult-onset forms. Pediatr Neurol. 1989;5:25-31.

9. Wallgren-Pettersson C. Genetics of the nemaline myopathies and the myotubular myopathies. Neuromuscul Disord. 1998;8:401-404.

10. Michele DE, Albayya FP, Metzger JM. A nemaline myopathy mutation in alpha-tropomyosin causes defective regulation of striated muscle force production. J Clin Invest. 1999;104:1575-1581.

Nadine P Kelly, MD; Chinnamma Thomas, MD

Accepted for publication August 3, 2000.

From the Department of Pathology, Loyola University Medical Center, Maywood, Ill.

Reprints not available from the author.

Copyright College of American Pathologists Apr 2001
Provided by ProQuest Information and Learning Company. All rights Reserved

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