TAY SACHS DISEASE
 
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TAY SACHS DISEASE

 

DEFINITION:

A lysosomal storage disorder characterized by the accumulation of lipids (GM2 gangliosides) primarily in the central nervous system (CNS) resulting in 3 clinical variants.

EPIDEMIOLOGY:

  • incidence: ?
  • age of onset:
    • infancy (Type I); 2-6 years (Type II); adulthood (Type III)
  • risk factors:
    • familial - autosomal recessive
      • chrom.#: 15q23-24
      • gene: beta-hexosaminidase (alpha-chain)
    • M = F
    • Ashkenazi Jews, French-Canadians, Cajun

PATHOGENESIS:

1. Background

  • beta-hexosaminidase A is a lysosomal enzyme which catalyzes the removal of N-acetyl-galactosamine from GM2 gangliosides - the substrate for this reaction is a complex of GM2 ganglioside + a GM2 activator protein
  • beta-hexosaminidase A isoenzyme is a heterodimer composed of an alpha-chain and a beta-chain
  • the alpha-chain gene (defective in Tay Sachs), has been cloned and is about 1700 bp in length and contains 14 exons
  • multiple mutations have been identified in the gene including splicing, insertional, deletional, nonsense, and missense errors
  • in Ashkenazi Jews, the most common mutations are found in exon 11 and at the junction of exons 12 and 13
  • there are 2 forms of GM2 Gangliosidoses:

1. Tay Sachs Disease

  • defective alpha-chain of beta-hexosaminidase

2. Sandhoff Disease

  • defective beta-chain of beta-hexosaminidase

2. Genetic Defect

  • genetic defects -> decreased expression of the alpha-chain -> deficiency of beta-hexosaminidase activity -> accumulation of GM2 gangliosides in the CNS only -> neurological manifestations
  • three clinical variants:
  • Type I - Infantile Form (Tay Sachs Disease)
  • Type II - Juvenile Form (Bernheimer-Seitelberger Disease)
  • Type III - Adult Form
  • in the infantile form there is a complete deficiency of beta-hexosaminidase activity where in the other forms there is a partial deficiency of the enzyme activity

CLINICAL FEATURES:

1. Type I (Infantile Form)

1. CNS Manifestations

1. Psychomotor Retardation

  • normal development up to 3-6 months of age
  • onset of developmental delay followed by rapid regression by the end of the first year of life
1. Gross Motor
  • progressive hypotonia and motor weakness
    • poor head control
    • failure to turn over, crawl, or sit
    • assumes a frog-like position
    • eventually becomes hypertonic with exaggerated reflexes
2. Social/Behavioural
  • decreasing eye contact and focussing
  • interacts very little with the environment eventually becoming unresponsive to exogenous stimuli reaching a vegetative state

2. Others

1. Hyperacusis
  • initally an exaggerated startle response to sharp sounds eventually becoming unattentive and unresponsive
2. Seizures
  • commonly begin after the first year of life and vary in type and frequency
3. Macrocephaly
  • commonly by 1.5 to 2 years of age due to a reactive cerebral gliosis

2. Ophthalmologic Manifestations

  • cherry red spot of the macula (prominent macular fovea centralis)
  • progressive visual inattention with blindness by the 2nd year of life

2. Type II (Juvenile Form)

1. CNS Manifestations

  • progressive ataxia, choreoathetosis, and dysarthria
  • progressive spasticity leading to decerebrate rigidity by 10-12 years of age
  • progressive dementia -> vegetative state
  • seizures

2. Ophthalmologic Manifestations

  • cherry red spot not a consistent finding
  • optic atrophy
  • retinitis pigmentosa
  • progressive loss of vision -> blindness

3. Type III (Adult Form)

1. CNS Manifestations

  • a wide range of symptoms and abnormal findings
  • symptoms of spinocerebellar and lower motor neuron dysfunction are most prominent:
    • motor weakness
    • tremor
  • personality changes
    • psychoses
    • depression
    • normal intelligence

INVESTIGATIONS:

1. Diagnostic

  • deficiency of beta-hexaminidase A activity in leukocytes and cultured skin fibroblasts
  • prenatal:
    • deficiency of enzyme activity in cultured chorionic villi or amniocytes
    • detection of mutations by PCR

2. Imaging Studies

1. MRI/CT

  • progressive loss of the grey and white matter

3. EEG

  • initially paroxysmal discharges with decreasing activity with progression of the disease

4. Pathology

1. CNS

  • multiple membrane-bound laminated structures found within the cytoplasm of ganglion cells by electron microscopy

MANAGEMENT:

1. Supportive

  • no treatment for underlying disorder
  • multidisciplinary approach
    • Paediatrics, Neurology, Ophthalmology, Orthopedics, etc.
    • genetic counselling

2. Prognosis

  • Type I - relentless progression with death by 4 years of age
  • Type II - relentless progression with death between 10-15 years of age
  • Type III - slower progression with death between 20-60 years of age

 

 

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