Zellweger syndrome (ZS) is a rare, hereditary disorder affecting infants and usually resulting in death. Unusual problems in prenatal development, an enlarged liver, high level of iron and copper in the blood and vision disturbances are among the major manifestations of ZS. Mutations in the PEX1 gene cause ZS. ZS belongs to the Zellweger spectrum of peroxisome biogenesis disorders (PDB, ZSS) and is considered the most severe of the PBDs. Infants with ZS also lack muscle tone. Sometimes to the point of being unable to move, and may not be able to suck or swallow. Some babies will be born with glaucoma retinal degeneration and impaired hearing. Jaundice and gastrointestinal bleeding may also occur. Symptoms include: characteristic facial appearance, seizures, inability to feed, liver cysts with hepatic (liver) dysfunction, and chondrodysplasia punctata. The most prominent dysmorphic (abnormal) features include a high forehead, hypoplastic supraorbital ridges, epicanthal folds, midface hypoplasia, and a large fontanel. The head circumference is normal to large. Eye abnormalities include cataracts, glaucoma, corneal clouding, Brushfield spots (gray or pale yellow spots that go around the sides of the iris) optic nerve hypoplasia, and pigmentary retinal degeneration. There are abnormalities in neuronal migration, some of which appear to be unique to this disorder and which may be seen on an MRI of the head. Enlargement of the liver (hepatomegaly) is present in 75 % of the cases; with periportal fibrosis resulting in jaundice, micronodular cirrhosis, and hypoprothrombinemia. Renal cortical cysts are almost universally present pathologically but may be missed on ultrasound study. Skeletal abnormalities include clubbed feet, thumb rotation, and stippled chondral calcification of the patella and acetabulum. Infants with this condition are significantly impaired and usually die during the first year of life, usually having made no developmental progress.
TESTING, PHYSICAL FINDINGS, AND ICD-9-CM CODING
Biochemical abnormalities that are found in the blood and/or urine should be confirmed in cultured fibro blasts. The tests are used to detect accumulation of very long chain fatty acids (VLCFA) levels. Bony stippling (chondrodysplasia punctata) may be present on radiological studies and this is suggestive of ZS in the proper clinical setting. MRI of the brain may identify hypomyelination, cortical gyral abnormalities, and germinolytic cysts that are highly suggestive of ZS. Molecular genetic testing for mutations in the PEX genes.
ONSET AND PROGRESSION
The prognosis for infants with ZS is poor. Most infants do not survive past the first 6 months, and usually death is the result of respiratory failure, gastrointestinal bleeding, or liver failure.
There is no cure for ZS, nor is there a standard course of treatment. Since the metabolic and neurological abnormalities that cause the symptoms of Zellweger syndrome are present during fetal development, treatments to correct these abnormalities after birth will be limited. Most treatments are symptomatic and supportive and may include: gastrostomy to provide adequate calories, hearing aids, cataract removal in infancy, glasses, vitamin supplements, primary bile acid therapy, anti-epileptic drugs and possibly monitoring for hyperoaluria, monitoring for coagulation factors and tests of liver function. Avoidance of cow’s milk products is recommended to reduce exposure to phytanic acid.
Suggested MER for Evaluation: If available in the MER, Plasma VLCFA abnormalities as outlined above or mutations in the PEX genes confirm a diagnosis of one of the PBD’s. If such testing is not available, then a complete review of the clinical history, course, and laboratory studies on which the diagnosis is suspected will be needed for review. To then differentiate the three PBDs and to evaluate the severity of the specific case, a complete physical and neurological examination is needed.