SCHINDLER DISEASE
 
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SCHINDLER DISEASE

 

DEFINITION:

A lysosomal storage disorder characterized by the accumulation of lipids (glycoconjugates) primarily in the central nervous system (CNS) resulting in 2 clinical variants.

EPIDEMIOLOGY:

  • incidence: extremely rare (about 3 cases reported)
  • age of onset:
    • infancy (Type I) -> adulthood (Type II)
  • risk factors:
    • familial - autosomal recessive
      • chrom.#: 22q13->qter
      • gene: alpha-N-acetylgalactosaminidase (alpha-GalNAc)

PATHOGENESIS:

1. Background

  • alpha-GalNAc is a lysosomal hydrolase and a homodimer which catalyzes the removal of alpha-linked galactosaminyl residues from glycoconjugates
  • the endogenous substrate for alpha-GalNAc has not been identified
  • disease first reported by Schindler et al in 1989
  • the alpha-GalNAc gene has been cloned and a single base mutation has been identified where a single G->A transition at nucleotide 973 results in a glutamic acid to lysine substitution in residue 325 producing an immunoreactive polypeptide with no detectable alpha-GalNAc activity
  • the overall nucleotide and amino acid similarities between alpha-GalNAc and alpha-galactosidase are 57 and 48%, respectively, and suggests an evolutionary relationship

2. Genetic Defect

  • genetic defect -> deficiency of alpha-GalNAc -> accumulation of alpha-N-acetylgalactosaminyl-containing glycoconjugates primarily in the CNS -> axonal degeneration
    • the major glycoconjugate accumulating is the blood group A trisaccharide
  • two clinical variants:
  • Type I - Infantile Form
  • Type II - Adult Form

CLINICAL FEATURES:

1. Type I (Infantile Form)

1. CNS Manifestations

1. Psychomotor retardation (3 stages)

  • normal development up to 9-12 months
  • onset of developmental delay followed by rapid regression in the 2nd year of life
  • increasing neurologic impairment and by 3-4 years:
    • hypotonia -> spasticity
    • no voluntary movements
    • decorticate posturing
    • symmetric hyperreflexia
    • profound psychomotor retardation

2. Seizures

  • myoclonic seizures
  • grand mal seizures

3. Severe Mental Retardation

  • loss of contact with environment
  • unresponsive hyperreflexia

2. Ophthalmologic Manifestations

  • bilateral optic atrophy
  • cortical blindness
  • nystagmus
  • strabismus

3. Other Manifestations

1. Respiratory

  • frequent and severe respiratory tract infection

2. Type II (Adult Form)

1. Integument Manifestations

1. Angiokeratomas

  • similar to those seen in Fabry Disease
  • onset in 2nd and 3rd decade of life
  • small dark purple-blue telangiectasia
  • most dense between the chest and perineum

2. Musculoskeletal Manifestations

  • slight shortness of stature
  • slight coarse facial features

INVESTIGATIONS:

1. Diagnostic

  • deficiency of alpha-GalNAc activity in leukocytes and cultured skin fibroblasts
  • prenatal:
    • deficiency of alpha-GalNAc activity in cultured chorionic villi or amniocytes

2. Imaging Studies

1. Skeletal X-Rays

  • diffuse severe osteopenia
  • no dysostosis multiplex

2. CT/MRI

  • generalized atrophy of the brain stem, cerebellum, & cortex

3. EEG

  • abnormal - marked slowing

4. Evoked Potentials

  • brainstem auditory, somatosensory and visual evoked potentials show low amplitude and/or delayed responses

3. Urine

  • elevated O-linked glycopeptides and oligosaccharides with terminal and internal alpha-N-acetylgalactosaminyl residues

4. Pathology

1. Electron Microscopy

1. Infantile Form

  • cytoplasmic inclusions consisting of single membrane-bound organelles (secondary lysosomes) containing tubulovesicular structures as well as lamellar, fibrillar, vesicular, and/or granular material
  • autonomic axon of the myenteric plexus, myelinated axons of cutaneous nerves, brain biopsy
  • WBC's, cultured fibroblasts, secretory cells of eccrine sweat glands
  • similar ultrastructural findings as in Seitelberger Disease, Hallervorden-Spatz Disease, and neuroaxonal dystrophy

2. Adult Form

  • similar ultrastructural findings as in the Infantile Form except that the storage material accumulates primarily in blood vessels leading to disseminated angiokeratomas

MANAGEMENT:

1. Supportive

  • no treatment for underlying disorder
  • multidisciplinary approach
    • Peadiatrics, Neurology, Ophthalmology, Orthopedics
    • Genetic counselling
      • normal sib of an affected patient has a 67% risk of being a carrier

2. Prognosis

  • death within the first decade in the Infantile Form

 

 

 

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