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