Knowledge on rare diseases and orphan drugs

The birth prevalence of Peroxisome biogenesis disorder (PBD) is estimated to be around 1/50,000 in North America, and around 1/500,000 in Japan. The highest incidence of Zellweger syndrome (ZS) was reported in the Saguenay-Lac St Jean region of Quebec (around 1/12,000).

Onset is in the neonatal period, reflecting both organ malformations that occurred in utero and progressive disease due to ongoing peroxisome dysfunction. Infants present with characteristic dysmorphic craniofacial features (flattened facies, large anterior fontanel, split sutures, prominent high forehead, flattened occiput, upslanting palpebral fissures, epicanthal folds, and broad nasal bridge), profound hypotonia and seizures. Macrocephaly or microcephaly, high arched palate, micrognathia and redundant neck skin folds may be present. Skeletal abnormalities (chondrodysplasia punctata, most often in the patella and hips) and subcortical renal cysts are frequent. There is often failure to thrive, hepatomegaly, jaundice, and coagulopathy. Eye findings include cataracts, glaucoma, pigmentary retinopathy, nystagmus, corneal clouding and optic nerve atrophy. Visual changes and loss are progressive. Sensorineural hearing loss may be present. Cryptorchidism and hypospadias (male) and clitoromegaly (female) may occur. CNS function is severely affected and infants have profound psychomotor delay.

PBD is caused by mutations in one of 13 PEX genes encoding peroxins. Mutations in these genes lead to abnormal peroxisome biogenesis.

ZS is often suspected on physical examination and confirmed with biochemical evaluation. Plasma very-long-chain fatty acid (VLCFA) levels indicate defects in peroxisomal fatty acid metabolism with elevated plasma concentrations of C26:0 and C26:1 and elevated ratios of C24/C22 and C26/C22. Erythrocyte membrane concentrations of plasmalogens C16 and C18 are reduced. Plasma pipecolic acid levels are increased. Sequence analysis of the 13 PEX genes can be performed. MRI can be used to identify perisylvian polymicrogyria, and other developmental brain malformations.

The main differential diagnoses include Usher syndrome I and II, other PBD disorders (see these terms), single enzyme defects in peroxisome fatty acid beta-oxidation, and disorders that feature severe hypotonia, neonatal seizures, liver dysfunction or leukodystrophy.

Prenatal screening for VLCFA levels and plasmalogen synthesis can be performed on cultured amniocytes and chorionic villus sampling in suspected or high-risk pregnancies. If disease causing alleles in the carrier parents have been identified, prenatal diagnosis by DNA testing can be performed as well as preimplantation genetic diagnosis.

ZS is inherited in an autosomal recessive manner, so genetic counseling is possible.

There is no cure for ZS. Standard epileptic drugs are used for seizure control. Hepatic coagulopathy can be treated with vitamin K supplementation while cholestasis may require the provision of all fat soluble vitamins. A gastrostomy tube may be needed to allow for adequate calorie intake. Foods rich in phytanic acids (i.e. cow's milk) should be restricted. Supplementation of mature bile acids, cholic and chenodeoxycholic acid may help improve liver disease in infants with severe hepatopathy. As ZS patients cannot biosynthesize DHA, it can also be provided.

Regardless of interventions, prognosis is poor with most infants dying within the first year of life secondary to respiratory compromise related to infection or intractable epilepsy.

Last update: December 2012 - Expert reviewer(s): Dr Nancy BRAVERMAN