Spinal muscular atrophies

Genetic testing








Fig. 2. SMA. Marked generalized muscle atrophy due to slowly progressive disease. Symmetric atrophy of the trapezoid muscles A, mild winging B of the medial borders of the scapula

The spinal muscular atrophies (SMAs) are hereditary motor neuron diseases that Anatomy cause the loss of alpha motor neurons in the spinal cord. At autopsy, the spinal cord is atrophied, showing loss of motor neurons and gliosis. The ventral roots are also atrophied. Muscle atrophy is accompanied with signs of denervation and reinnervation.

The onset and severity of symptoms depends upon the type of SMA the patient Symptoms has.

SMA1 (Werdnig-Hoffmann disease) is the most severe form, with symptoms SMA1 appearing in utero, or up to 3 months post-partum. Infants have severe diffuse weakness that eventually leads to fatal loss of respiration.

SMA2 (late infantile SMA) causes weakness that appears between 18-24 SMA2 months. Although less severe, these children may not be able to stand or walk, and develop scoliosis and respiratory failure.

SMA3 (Kugelberg-Welander disease) has the mildest symptoms, and may not SMA3 present until the teenage years. These patients have proximal, symmetric weakness but can still stand and walk. Deterioration of muscle function is slow and mild.

Signs of lower motor neuron loss (hypotonia, reduced or absent reflexes, Signs fasciculations atrophy as shown in Figs. 2. and 3) are apparent, depending upon the severity of disease.

SMA is caused by mutations in one of two copies of the survival motor neuron Pathogenesis (SMN) gene on chromosome 5q13. Loss of exons 7 and 8 in the telomeric copy of the SMN gene leads to SMA1, the most severe form of the disease. Mutations that convert the telomeric copy of the gene to the centromeric copy cause the less severe forms, SMA2 and 3. SMA is also associated with deletions in the neuronal apoptosis inhibitor protein (NAIP) gene. These mutations occur in up to 65% of SMA patients and may modify the severity of the disease. Both genes are believed to suppress neuronal apoptosis, and thus the loss of motor neurons may be the result of misregulated apoptosis.

Diagnosis Genetic testing in patients with appropriate signs and symptoms can reveal

SMN deletions in 95% of patients. Carrier testing is available. EMG and muscle biopsy show signs of denervation. Nerve conduction studies are normal. While these tests are often done early in the diagnosic process, they are unnecessary if a genetic diagnosis has been established. Cerebrospinal fluid analysis and serum creatine kinase are normal.

Differential diagnosis Infantile botulism must be ruled out in possible cases of SMA1. In botulism, impairment is detected using EMG with high frequency nerve stimulation. Stool examination for botulism can also confirm the diagnosis. SMA2 and 3 can be distinguished from chronic inflammatory demyelinating polyneuropathy by the presence of normal nerve conduction and cerebrospinal fluid protein studies.

SMA3 may resemble hereditary motor sensory neuropathies (Charcot-Marie-Tooth disease), but again the nerve conduction studies are normal in SMA.

There is no treatment for these diseases, although physical therapy and braces are helpful for SMA2 and 3 patients. Surgery may be indicated to correct scoliosis.

Half of infants with SMA1 die from respiratory failure by 7 months; 95% die by 17 months. Respiratory failure also shortens the life span of children with SMA2, although not as early as in SMA1. SMA3 patients survive to adulthood and typically maintain ambulatory function. It is not clear whether SMA3 affects lifespan.

References Dubowitz V (1995) Disorders of the lower motor neurone: the spinal muscular atrophies.

In: Muscle disorders in childhood, 2nd edn. Saunders, London, pp 325-369 Wang CH, Carter TA, Gilliam TC (1997) Molecular and genetic basis of the spinal muscular atrophies. In: Rosenberg RN, Pruisner SB, DiMauro S, Barchi RL (eds) The molecular and genetic basis of neurological disease, 2nd edn. Butterworth-Heinemann, Boston, pp 787796



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