Information on the following diseases can be found in the Related Disorders section of this report:

• Infantile Refsum Disease
• Neonatal Adrenoleukodystrophy

Infants with Zellweger syndrome often exhibit prenatal growth failure in spite of a normal period of gestation. This syndrome can often be recognized at birth due to profound lack of muscle tone; some infants may be unable to move. Other symptoms may include unusual facial characteristics, mental retardation, the inability to suck and/or swallow, and liver enlargement. Vision problems and high levels of iron and copper in the blood may also be present. Congenital heart lesions occur less commonly. Jaundice and/or gastrointestinal bleeding due to deficiency of a coagulation factor in the blood can also occur. Pneumonia or respiratory distress may develop if infections are not prevented or controlled. Symptoms may also include hearing problems and developmental delays.

Zellweger syndrome is inherited as an autosomal recessive trait. Symptoms develop as a result of a deficiency or absence of a part of the cell called the peroxisome. This allows certain waste products to accumulate in tissues of the body. The genetics of this syndrome are complex and not yet fully understood, but it is believed that Zellweger syndrome can be caused by at least ten different gene abnormalities.

Chromosomes, which are present in the nucleus of human cells, carry the genetic information for each individual. Human body cells normally have 46 chromosomes. Pairs of human chromosomes are numbered from 1 through 22 and the sex chromosomes are designated X and Y. Males have one X and one Y chromosome and females have two X chromosomes. Each chromosome has a short arm designated "p" and a long arm designated "q". Chromosomes are further sub-divided into many bands that are numbered. For example, "chromosome 11p13" refers to band 13 on the short arm of chromosome 11. The numbered bands specify the location of the thousands of genes that are present on each chromosome.

Genetic diseases are determined by the combination of genes for a particular trait that are on the chromosomes received from the father and the mother.

Recessive genetic disorders occur when an individual inherits the same abnormal gene for the same trait from each parent. If an individual receives one normal gene and one gene for the disease, the person will be a carrier for the disease, but usually will not show symptoms. The risk for two carrier parents to both pass the defective gene and, therefore, have an affected child is 25% with each pregnancy. The risk to have a child who is a carrier like the parents is 50% with each pregnancy. The chance for a child to receive normal genes from both parents and be genetically normal for that particular trait is 25%. The risk is the same for males and females.

All individuals carry a few abnormal genes. Parents who are close relatives (consanguineous) have a higher chance than unrelated parents to both carry the same abnormal gene, which increases the risk to have children with a recessive genetic disorder.

Zellweger syndrome is apparent at birth. In the United States, clinicians estimate that the incidence of Zellweger syndrome is from 1 in 50,000 to 1 in 100,000 live births. One Australian study found that it occurs about once in approximately 100,000 live births. Because some cases go undiagnosed, the exact incidence is not known.

Zellweger syndrome is sometimes described as part of a spectrum with two other leukodystrophies: infantile Refsum disease and neonatal adrenoleukodystrophy. Of the three disorders, Zellweger syndrome has the most severe impact on the child. Infantile Refsum disease is the mildest of the three, and neonatal adrenoleukodystrophy is intermediate between the other two. All three of these disorders of the "Zellweger spectrum" can be caused by abnormalities of the same genes.

Infantile Refsum disease is characterized by the reduction or absence of peroxisomes and by the accumulation of phytanic acid in blood plasma and tissue. It is characterized by vision problems including retinitis pigmentosa and nystagmus (rapid, involuntary, jerky eye movements), hearing impairment, decreased muscle tone, failure to thrive, developmental delay, ataxia (impaired muscle coordination), enlargement of the liver (hepatomegaly), hypocholesterolemia (an abnormally diminished amount of cholesterol in the blood), and mild facial dysmorphism (abnormalities in the form and structure of the face). This disorder becomes apparent in early infancy.

Neonatal adrenoleukodystrophy (NALD) is characterized by varying degrees of adrenal involvement and destruction of the myelin sheath that protects nerve fibers. It affects both males and females, and is transmitted as an autosomal recessive trait. Neonatal adrenoleukodystrophy closely resembles Zellweger syndrome, and may, in fact, represent a somewhat milder variant of that disorder. This disorder is characterized by severe or profound mental retardation, impaired psychomotor development, possible impaired liver function, and retarded growth.

Diagnosis
Diagnosis involves biochemical tests conducted on blood and/or urine samples. In most instances, tests to determine the level of very long chain fatty acids are performed. Other tests will determine the presence and concentration of other metabolic products.

Molecular genetic testing may be undertaken to determine which one (or more) of the suspect genes is involved in a particular case.

Treatment
Treatment of Zellweger syndrome is symptomatic and supportive. A team approach may be required to evaluate and improve feeding, hearing, vision, liver function and neurological functions.

Genetic counseling can be of benefit to families of patients with this disorder. Infections should be guarded against carefully to delay complications.

Information on current clinical trials is posted on the Internet at www.clinicaltrials.gov. All studies receiving U.S. government funding, and some supported by private industry, are posted on this government web site.

For information about clinical trials being conducted at the NIH Clinical Center in Bethesda, MD, contact the NIH Patient Recruitment Office:

Tollfree: (800) 411-1222
TTY: (866) 411-1010
Email: prpl@cc.nih.gov

For information about clinical trials sponsored by private sources, contact:
www.centerwatch.com

About 25 patients will be selected to participate in a study of bile acids in patients with peroxisomal disorders being sponsored by the FDA Office of Orphan Products Development and the Children’s Hospital Medical Center of Cincinnati. The study will look at the effectiveness of various agents in improving primary bile acid synthesis. More information is available from:

Dr. Kenneth D. Setchell
Professor of Pediatrics
Telephone: 513-636-4548
e-mail: Kenneth.setchell@chmcc.org

McKusick VA, ed. Online Mendelian Inheritance In Man (OMIM). The Johns Hopkins University. Zellweger Syndrome; ZS. Entry Number; 214100: Last Edit Date; 7/20/2004.

TEXTBOOKS
Beers MH, Berkow R., eds. The Merck Manual, 17th ed. Whitehouse Station, NJ: Merck Research Laboratories; 1999:2393t.

Scriver CR, Beaudet AL, Sly WS, et al., eds. The Metabolic Molecular Basis of Inherited Disease. 8th ed. McGraw-Hill Companies. New York, NY; 2001:3181-209.

REVIEW ARTICLES
Wanders RJ. Metabolic and molecular basis of peroxisomal disorders: a review. Am J Med Genet. 2004;126:355-75.

Mandel H, Korman SH. Phenotypic variability (heterogeneity) of peroxisomal disorders. Adv Exp Med Biol. 2003;544:9-30.

Depreter M, Espeel M, Roels F. Human peroxisomal disorders. Microsc Res Tech. 2003;62:203-23.

Brosius U, Gartner J. Cellular and molecular aspects of Zellweger syndrome and other peroxisome biogenesis disorders. Cell Mol Life Sci. 2002;59:1058-69.

Martinez M. Restoring the DHA levels in the brains of Zellweger patients. J Mol Neurosci. 2001;16:309-16; discussion 317-21.

Faust PL, Su HM, Moser A, et al. The peroxisome deficient PEX2 Zellweger mouse: pathological and biochemical correlates of lipid dysfunction. J Mol Neurosci. 2001;16:289-97; discussion 317-21.

Powers JM. Normal and defective neuronal membranes: strcture and function: neuronal lesions in peroxisome disorders. J Mol Neurosci. 2001;16:285-87; discussion 317-21.

Suzuki Y, Shimozawa N, Imamura A, et al. Clinical, biochemical and genetic aspects and neuronal migration in peroxisome biogenesis disorders. J Inherit Metab Dis. 2001;24:152-65.

FROM THE INTERNET
NINDS Zellweger Syndrome Information Page. National Institute of Neurological Disorders and Stroke. Last updated December 03, 2004.2pp.
www.ninds.nih.gov/disorders/Zellweger/zellweger_pr.htm

Zellweger syndrome. Genes and Disease. nd. 2pp.
www.ncbi.nlm.nih.gov/books/bv.fcgi?rid=gnd.section240

Steinberg SJ, Raymond GV, Braverman NE, et al. Peroxisome Biogenesis Disorders, Zellweger Syndrome Spectrum. GENEReviews. Last Revision: 1 October 2004. 23pp.
www.genetests.org

The Zellweger Spectrum of Disease. The Peroxisome Website. The Johns Hopkins University School of Medicine. nd. 3pp.
www.peroxisome.org/Layperson/zstext.html

Chedrawi A, Clark G. Peroxisomal Disorders. emedicine. Last Updated: April 28, 2002. 13pp.
www.emedicine.com/neuro/topic309.htm

Introduction to Leukodystrophy. United Leukodystrophy Foundation. nd. 23pp.
www.ulf.org/ulf/intro/index.htm