SPINAL MUSCULAR ATROPHY - INTERMEDIATE FORM
 
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SPINAL MUSCULAR ATROPHY - INTERMEDIATE FORM

 

DEFINITION:

A neurological disorder characterized by degeneration of the anterior horn cells of the spinal cord resulting in lower limb proximal muscle weakness.

EPIDEMIOLOGY:

  • incidence: ?
  • age of onset:
    • 6-24 months of age
  • risk factors:
    • familial - autosomal recessive
      • chrom.#: 5
      • gene: neuronal apoptotic inhibitor protein (NAIP)
    • M = F

PATHOGENESIS:

1. Background

  • the Spinal Muscular Atrophies (SMA) are a group of inherited disorders in which there is degeneration of the anterior horn cells in the spinal column resulting in weakness
  • there are 3 clinical variants based on varying degrees of severity and onset:
    • Type I - Infantile Type - Werdnig-Hoffmann Disease (Severe)
    • Type II - Intermediate Form (Intermediate)
    • Type III - Juvenile Type - Kugel-Welander Disease (Mild)
  • SMA may be a polygenic disorder as a second gene has been identified adjacent to the NAIP gene of chromosome 5 and it is hypothesized that the protein products of these two genes interact to form a neuronal apoptotic factor; therefore a mutation in either gene may cause the disease
  • apoptosis means programmed natural cell death and NAIP may act as an inhibitor of programmed neuronal cell death

2. Genetic Defect

  • genetic defect -> NAIP is unable to stop the programmed neuronal death of anterior horn cells -> premature death of anterior horn cells -> muscle weakness

CLINICAL FEATURES:

1. Neurological Manifestations

1. Muscle Weakness

1. Lower Limbs

  • proximal muscle more involved that the distal muscles
  • symmetrical involvement
  • gross motor developmental delay or regression
  • able to sit unsupported but usually not able to stand or walk

2. Upper Limbs

  • less affected than the lower limbs
  • hand tremor with outstretched arms

2. Others

  • fasciculation of the tongue (in 70%)
  • variable intercostal muscle weakness with respiratory problems
  • diminished or absent deep tendon reflexes
  • progressive scoliosis
  • joint laxity and hypermobility especially or the hands and feet
  • flexion contractures
  • normal intelligence and facial muscles

INVESTIGATIONS:

1. Diagnostic

  • atrophy of the anterior horn cells on autopsy
  • ? identification of mutations in the NAIP gene (or adjacent gene) in affected patients

2. Serum

  • normal or moderately elevated CPK

3. Muscle Biopsy

  • characterized bundles of uniformly atrophic fibres with isolated groups of large reinnervated fibres
  • muscle fibre loss with adipose tissue replacement

4. Electrophysiological Studies

1. EMG

  • evidence of denervation and reinnervation

2. Motor Nerve Conduction Velocity

  • ? normal or reduced

MANAGEMENT:

1. Supportive

  • no treatment for underlying disorder
  • multidisciplinary approach:
    • Paediatrics, Neurology, Respirology, Orthopedics, Physiotherapy
    • genetic counselling
  • prevention of scoliosis by early bracing
  • treatment of scoliosis by spinal braces or surgery
  • promotion of standing and ambulation by appropriate orthoses and braces
  • aggressive treatment of pneumonias

2. Experimental

1. Gene Therapy

  • delivery of the NAIP gene to the anterior horn cells via genetically-engineered polio virus vectors

3. Prognosis

  • able to sit but not stand or walk unsupported
  • weakness is usually static and non-progressive although some may show some functional improvement while others become increasingly disabled
  • life span depends upon the respiratory function

 

 

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