SANFILIPPO A SYNDROME
 
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SANFILIPPO A SYNDROME

 

DEFINITION:

A lysosomal storage disorder characterized by the accumulation of acid mucopolysaccharide (heparan sulfate) in the central nervous system (CNS) and peripheral tissue.

EPIDEMIOLOGY:

  • incidence: 1/24,000 births
  • age of onset:
    • 2 to 6 years of age (2/3rd's before age 4 years)
  • risk factors:
    • familial - autosomal recessive
      • chrom. #: ?
      • gene: heparan N-sulfatase
    • M = F
    • frequent in the British population and Cayman Islands

PATHOGENESIS:

1. Background

  • heparan N-sulfatase is a lysosomal enzyme which catalyzes the breakdown of heparan sulfate (HS)
  • disease first described in 1963 by Dr. Sanfilippo at U. of Minn. and is now classified as Mucopolysaccharidosis Type IIIA (MPS-IIIA)

2. Genetic Defect

  • genetic defect -> deficiency of heparan N-sulfatase activity -> incomplete degradation of HS -> accumulation of HS in cells of the CNS and periphery causing severe and progressive CNS damage but only mild somatic disease
  • patients with MPS-III make up a genetically diverse but phenotypically similar group
  • MPS-IIIA is the most severe with earlier onset, more rapid progression of symptoms, and shorter survival
  • MPS-IIIA tends to have 3 main stages:
  • 1. preschool: appearance of developmental delay, hyperactivity, difficult behaviour, and decreasing mentation
  • 2. 5 - 10 years: extreme activity and worsening behaviour
  • 3. >10 years: decreasing activity and ambulation, ataxia

CLINICAL FEATURES:

1. CNS Manifestations

1. Progressive Neurologic Disease

  • progressive ataxia
  • bulbar dysfunction
  • dementia
  • seizures
  • tremor

2. Behavioural Problems

  • hyperactivity
  • aggressive-destructive behaviour (F > M)
  • poor attention span
  • temper tantrums
  • physical aggression

3. Developmental Delay

  • speech and language
  • social and adaptive - insomnia, sleep disturbance

4. Intelligence

  • profound mental retardation (83% before age 6 years)

2. Musculoskeletal Manifestations

1. Facial Features

  • occasional enlargened head and coarse facial features

2. Skeletal Features

  • mild joint stiffness (loss of extension of interphalangeal and elbow joints -> all joints)
  • occasional short stature

3. Other Manifestations

1. Respiratory

  • recurrent upper respiratory tract infections
    • ears, nose, chest

2. Cardiovascular

  • spared

3. Gastrointestinal

  • severe diarrhea/constipation
  • mild hepatomegaly/hepatosplenomegaly
  • failure to thrive (may fall off the growth curve)

4. Ophthalmologic

  • mild corneal opacities

5. ENT

  • severe conductive hearing loss

6. Other

  • coarse hair and hirsutism

INVESTIGATIONS:

1. Diagnostic

  • deficiency of heparan N-sulfatase activity in leukocytes and cultured skin fibroblasts
  • prenatal:
    • deficiency of enzyme activity in cultured choronic villi or amniocytes

2. Urine

  • 24 hour urine collection: elevated HS (high false negative rate)

3. Imaging Studies

1. Skeletal X-Rays

  • mild dysostosis multiplex
  • ovoid dysplasia of the vertebrae

2. CT (Head)

  • mild -> severe cortical atrophy

MANAGEMENT:

1. Supportive

  • no treatment for underlying disease
  • multidisciplinary approach
    • Paediatrics, Neurology, Orthopedics, ENT, Ophthalmology
    • genetic counselling
    • bone marrow transplant is experimental

2. Prognosis

  • life expectancy: 14-20 years

 

 

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