Zellweger's Syndrome

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Opitz (1969) suggested the name Zellweger's Syndrome since Zellweger (1909) first described a sibling pair with the phenotype: craniofacial abnormalities, renal cortical cysts and hepatomegaly with intrahepatic biliary dysgenesis.

  • Also known as Cerebrohepatorenal Syndrome. Goldfischer (1973) suggested a link with peroxisomes.
  • Autosomal recessive Peroxisomal disorder


Zellweger Syndrome is one of four Peroxisome Biogenesis Disorders (PBD). Zellweger is the most severe; it is usually apparent at birth and results in death within the first year.

  • These are part of a larger group: Leukodystrophies.


See also these assocated articles:


Incidence

  • Incidence: estimated 1:50 000 to 1:100 000
  • Age: onset from birth
  • Sex: M=F


Aetiology


Clinical features

Multiple congenital anomalies are present from birth:

  • Typical craniofacial malformations:
    • Large anterior fontanelle
    • High forehead
    • Broad nasal ridge
    • Hypoplastic supra-orbital ridges
    • Micrognathia
    • Abnormal Pinnae
    • Nuchal skin folds


  • Neurological Disorders
    • Profound hypotonia with reduced deep tendon reflexes
    • Intractable neonatal seizures
    • Severe developmental delay
    • Sensorineural hearing loss
    • Retinal degeneration


  • Structural brain abnormalities
    • Neuronal migration disorders
    • Leukodystrophy


  • Renal
    • Cysts (cortical)


  • Hepatic
    • Hepatomegaly, jaundice then cirrhosis
    • decreased peroxisomes


  • Biochemical:
    • Raised VLCFAs, bile acids, phytanic acid, pipecolic acid.
    • Low plasmalogen levels, esp in Red cells.


  • Ophthalmology:
    • Congenital cataracts
    • Glaucoma


  • Other:
    • Epiphyseal stippling (chondroplasia punctata)


Biochemical Testing

The clinical features above would lead you to seek a laboratory diagnosis of Zellweger's Syndrome.


The abscence of peroxisomes leads to abnormal levels of substances which are usually involved in peroxisomal metabolic reactions.

  • High levels of VLCFAs (>C22)
  • Raised, abnormal C27-bile acids
  • Raised dicarboxylic acids and pipecolic acid
  • Raised plasma phytanic acid may be raised (diet dependent)


Platelets:

  • Low activity of acyl-CoA: dihydroxyacetone phosphate acyltransferase


Red blood cells:

  • Decreased plasmalogen in phospholipids (if age < 4 months)


Cultured fibroblasts (skin, chorionic villi or amniotic fluid):

  • Low plasmalogen level
  • Decreased activity of acyl-CoA: dihydroxyacetone phosphate acyltransferase, alkyl dihydroxyacetonephosphate synthase and phytanic acid oxidase.


Prognosis

Treatment is largely symptomatic. Seizure management can be very difficult.

  • Zellweger's Syndrome is usually apparent from birth; death occurs within the first year of life.


References


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