Handbook of Genetic Counseling/Zellweger Syndrome

Zellweger Syndrome

Genetic Etiology

• Mode of inheritance: Autosomal recessive with non-allelic heterogeneity.
• Chromosome location: 2p15, 1q22, 12p13.3, 7q21-q22, 6q23-q24
• Molecular genetics: Phenotype caused by mutation in any of several genes involved: in peroxisome biogenesis (peroxi-1, -2, -3, -5, -6, or -12).
• Peroxisomes are subcellular organelles that play a role in lipid metabolism--these are absent

Incidence and Carrier Frequency

• Incidence is 1 in 40,000. Males and females are affected equally.

Clinical Features

• Craniofacial Features
  • Flat occiput and face
  • Anteverted nares
  • Epicanthal folds
  • Brushfield spots
  • High forehead
  • Large fontanels
  • Shallow orbits
• Ocular Features
  • Cataracts
  • Hypoplastic optic disk
• Auditory Features
  • Abnormal helices
  • Deafness
• Neurological Features
  • Early developmental delay
  • Seizures
  • Brain migrational abnormalities
  • MR in survivors
  • Brain malformations including microgyria, heteropias, subependymal cysts, astrocytosis and gliosis, hypoplastic corpus callosum, hypoplastic olfactory lobes
• Extremities
  • Single palmar creases
  • Joint contractures
  • Stippled epiphyses
  • Camptodactyly
• Cardiovascular Features
  • Cardiac septal defects
  • PDA
• Other Features
  • Hepatomegaly
  • Postnatal growth deficiency and low birth weight
  • Poor suck
  • Albuminuria and cysts of glomeruli in kidneys
  • Elevated serum iron level and evidence of excess iron storage
  • Absent liver peroxisomes

Age of Onset, Natural History, Life Span

• Most babies are born breech and exhibit failure to thrive. Some developed icterus and bloody stool.
• Vast majority of children die within the first year of life. Those who survive have profound mental retardation. Average life span is 12-13 weeks.

Testing

• Diagnosis is made through DNA testing.
• Increase in plasma and fibroblasts of very-long-chain fatty acids and lack of dihydroxyacetone phosphate acyltransferase (DHAP-AT) are biochemical markers for this syndrome

Surveillance, Management, and Treatment Options

• Multidisciplinary early intervention
• Oral administration of plasmalogens
• Restricted phytanic acid intake
• OT, PT, hearing aids, nutrition
• Skeletal surveys (X-rays, CT and MRI)
• Renal and abdominal ultrasounds

Differential Diagnoses

• Down syndrome is the most common

Notes

The information in this outline was last updated in 2002.