WERDNIG-HOFFMANN DISEASE
 
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WERDNIG-HOFFMANN DISEASE

 

DEFINITION:

A neurological disorder characterized by degeneration of the anterior horn cells of the spinal cord resulting in infantile hypotonia and progressive weakness.

EPIDEMIOLOGY:

  • incidence: ?
  • age of onset:
    • in utero -> first few months of life
  • 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 - Kugelberg-Welander Disease (Mild)
  • SMA may be a polygenic disorder as a second gene has been identified adjacent to the NAIP gene on 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 could 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 the anterior horn cells -> premature death of anterior horn cells -> hypotonia and weakness
  • mutations in the NAIP gene have been found in patients with Werdnig-Hoffmann Disease

CLINICAL FEATURES:

1. Neurological Manifestations

1. Infantile Hypotonia

  • reduced movements in utero
  • reduced spontaneous activity
  • poor head control

2. Severe Weakness

  • bulbar weakness with sucking and swallowing difficulties
  • weak cry
  • gross motor developmental delay
  • symmetrical affecting the limbs and axial musculature
  • legs more affected than the arms
  • proximal muscles are more affected than the distal muscles
  • jug-handle position of the arms:
    • flaccid, abducted shoulders and internally-rotated
  • frog position of the legs:
    • abducted hips, flexed knees, externally-rotated feet

3. Others

  • fasciculations of the tongue
  • muscle atrophy
  • reduced or absent tendon reflexes
  • joint contractures
  • normal intelligence, facial movements, sensation, and sphincter function

2. Respiratory Manifestations:

1. Abnormal Chest Shape

  • long, narrow, bell-shaped
  • due to costal recession (involvement of the intercostal muscles) and abdominal distension due to diaphragmatic breathing (sparing of the diaphragm)

2. Others

  • recurrent lower respiratory tract infections and aspiration pneuomonias
  • respiratory distress

INVESTIGATIONS:

1. Diagnostic

  • atrophy of anterior horn cells on autopsy
  • identification of mutations in the NAIP gene in affected patients

2. Serum

  • normal CPK

3. Muscle Biopsy

  • atrophy of whole bundles of fibres (involving all fibre types)
  • isolated or clusters of large type 1 fibres
  • normal muscle enzymes

4. Electrophysiological Studies

1. EMG

  • denervation
  • large amplitude, polyphasic potentials of long duration

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
  • 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

  • never able to sit without support
  • most die of pneuonia within the first 3 years of life

 

Pediatric Database - WERDNIG-HOFFMANN DISEASE

 

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