You are here: Home / Rare Disease Information / Rare Disease Database

Search Rare Diseases

Enter a disease name or synonym to search NORD's database of reports.

0-9 - A - B - C - D - E - F - G - H - I - J - K - L - M - N - O - P - Q - R - S - T - U - V - W - X - Y - Z

Zellweger Spectrum Disorders

NORD is very grateful to Steven J. Steinberg, PhD, FACMG, Assistant Professor, Department of Neurology and Institute of Genetic Medicine, Johns Hopkins University School of Medicine, for the preparation of this report.

Synonyms of Zellweger Spectrum Disorders

  • Generalized Peroxisomal Disorders
  • Peroxisomal Biogenesis Disorders
  • Zellweger Syndrome Spectrum
  • ZSS

Disorder Subdivisions

  • Cerebrohepatorenal Syndrome
  • Hyperpipecolic acidemia
  • Infantile Refsum Disease
  • IRD
  • NALD
  • Neonatal Adrenoleukodystrophy
  • Zellweger Syndrome
  • ZS

General Discussion

Zellweger spectrum disorders are a group of rare, genetic, multisystem disorders that were once thought to be separate entities. These disorders are now classified as different expressions (variants) of one disease process. Collectively, they form a spectrum or continuum of disease. Zellweger syndrome is the most severe form; neonatal adrenoleukodystrophy is the intermediate form; and infantile Refsum disease is the mildest form. Zellweger spectrum disorders can affect most organs of the body. Neurological deficits, loss of muscle tone (hypotonia), hearing loss, vision problems, liver dysfunction, and kidney abnormalities are common findings. Zellweger spectrum disorders often result in severe, life-threatening complications early during infancy. Some individuals with milder forms have lived into adulthood. Zellweger spectrum disorders are inherited as autosomal recessive traits.

Zellweger spectrum disorders are also known as peroxisome biogenesis disorders (PBDs) - a group of disorders characterized by the failure of the body to produce peroxisomes that function properly. Peroxisomes are very small, membrane-bound structures within the gel-like fluid (cytoplasm) of cells that play a vital role in numerous biochemical processes in the body. PBDs are subdivided into the three Zellweger spectrum disorders and rhizomelic chondrodysplasia punctata.


The symptoms of Zellweger spectrum disorders vary greatly from one individual to another. The specific number and severity of symptoms present in an individual are highly variable and affected infants will not have all of the symptoms discussed below. The most severe form, Zellweger syndrome, is usually noticeable shortly after birth. Infants with Zellweger syndrome often have severe neurological deficits, progressive dysfunction of the liver and kidneys and usually develop life-threatening complications during the first year of life.

Children with neonatal adrenoleukodystrophy and infantile Refsum disease may not develop symptoms until later during infancy. Some of these children reach adolescence or adulthood although most have some degree of mental retardation, hearing loss and vision problems. Some have profound loss of muscle tone (hypotonia or floppiness), but some learn to walk and to speak. Some children with these milder forms of Zellweger spectrum disorders do not have any craniofacial abnormalities or only very mild ones.

In extremely rare cases, affected individuals have gone undetected until adulthood. These individuals have had only mild symptoms such as adult-onset hearing loss or vision problems and/or mild developmental delays.

Many symptoms of Zellweger spectrum disorders are present at birth (congenital). Affected infants often exhibit prenatal growth failure in spite of a normal period of gestation and may also have a profound lack of muscle tone (hypotonia or floppiness). Affected infants may be limp, show little movement (lethargic) and poorly respond to environmental stimuli. Infants may be unable to suck and/or swallow leading to feeding difficulties and failure to gain weight and grow as expected (failure to thrive).

Infants also develop a variety of neurological complications including frequent seizures, poor or absent reflexes, mental retardation, and delays in reaching developmental milestones such as sitting, crawling or walking (developmental delays). Affected infants have various brain abnormalities including defects caused by the abnormal migration of brain cells (neurons). Neurons are created in the center of the developing brain and must travel to other areas of the brain to function properly. In individuals with Zellweger spectrum disorders the neurons fail to migrate properly resulting in a variety of brain abnormalities (neuronal migration defects). Some affected infants also develop progressive degeneration of the nerve fibers (white matter) of the brain (leukodystrophy).

Infants may have distinctive facial features including a flattened appearance to the face, a high forehead, abnormally large "soft spots" (fontanelles) on the skull, broad bridge of the nose, a small nose with upturned nostrils (anteverted nares), an abnormally small jaw (micrognathia), a highly arched roof of the mouth (palate), a small chin, extra (redundant) folds of skin on the neck, and minor malformation of the outer part of the ears. The bony ridges of the eye socket may be abnormally shallow and the back of the head may be abnormally flat (flat occiput).

A variety of eye abnormalities may occur including eyes that are spaced widely apart (hypertelorism), clouding of the lenses of the eyes (cataracts) or the clear (transparent) outer layer of the eye (corneal opacities), degeneration of the nerve that carries visual images from the eye to the brain (optic atrophy), and rapid, involuntary eye movements (nystagmus). Many infants with Zellweger spectrum disorders develop degeneration of the retina, which is the thin layer of nerve cells that sense light and convert it into nerve signals, which are then relayed to the brain through the optic nerve. Glaucoma, a condition characterized by increased pressure within the eye causing a distinctive pattern of visual impairment, may also occur. The various eye abnormalities associated with Zellweger spectrum disorders can cause loss of vision to varying degrees. In addition to vision loss, infants with Zellweger spectrum disorders also experience hearing loss with onset during the first few months of life.

Some infants may have an abnormally large spleen (splenomegaly) and/or liver (hepatomegaly). The liver may also be scarred (fibrotic) and inflamed (cirrhosis), with progressive loss of function resulting in a variety of symptoms such as yellowing of the skin and whites of the eyes (jaundice). Additional findings include small cysts on the kidneys and gastrointestinal bleeding due to deficiency of a coagulation factor in the blood. Some children may develop episodes of exaggerated or uncontrolled bleeding (hemorrhaging) including bleeding within the skull (intracranial bleeding). Eventually, liver failure may occur.

Minor skeletal abnormalities may also be present in Zellweger spectrum disorders including clubfoot, fingers that are fixed or stuck in a bent position and cannot extend or straighten fully (camptodactyly), and chondrodysplasia punctata, a condition characterized by the formation of small, hardened spots of calcium (stippling) on the knee cap (patella) and long bones of the arms and legs.

Certain heart defects may also occur in infants with Zellweger spectrum disorders including septal defects and patent ductus arteriosus. Septal defects are "holes" in the heart, specifically holes in the thin partition (septum) that separates the chambers of the heart. Small septal defects may close on their own; larger defects may cause various symptoms including breathing irregularities and high blood pressure. Patent ductus arteriosus is a condition in which the two large arteries of the body (aorta and pulmonary artery) remain connected by a small blood vessel (ductus arteriosus) that is suppose to close after birth.

In same males infants with Zellweger spectrum disorders, additional symptoms may occur including the abnormal placement of the urinary opening on the underside of the penis (hypospadias) and failure of the testes to descend into the scrotum (cryptorchidism).


Zellweger spectrum disorders develop due to changes (mutations) of one of 12 different genes involved in the creation and proper function of peroxisomes (peroxisome biogenesis). These mutations are inherited as autosomal recessive traits. 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 percent with each pregnancy. The risk to have a child who is a carrier like the parents is 50 percent 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 percent. The risk is the same for males and females.

Peroxisomes are very small, membrane-bound structures within the cytoplasm of cells that are involved in numerous chemical processes required for the proper function of the body. Peroxisomes are found in nearly every cell type of the body, but are larger and more numerous in the kidney and liver. Some cells contain less than one hundred peroxisomes; others may contain more than a thousand. Some processes for which peroxisomes are vital include the proper breakdown (metabolism) of fatty acids and the production of certain lipids important to the nervous system (plasmalogens) or digestion (bile acids). Peroxisomes are essential parts of the body's waste disposal system and help ensure the proper development and function of the brain and central nervous system. Defective peroxisomes can cause numerous problems in the body. For example, since affected individuals lack sufficient levels of the enzymes normally produced by peroxisomes, very long chain fatty acids (VLCFA) accumulate in the cells of the affected organ. (The role of VLCFA and pathogenesis is too complicated to reduce to that sentence)Mutation of any one of 12 different genes involved in the proper creation or function of peroxisomes can result in the development of one of the Zellweger spectrum disorders. These twelve genes contain instructions for creating (encoding) proteins known as peroxins that are essential for the proper development of peroxisomes. Approximately 68 percent of individuals with a Zellweger spectrum disorder have a mutation in the peroxisome biogenesis factor 1 (PEX1) gene located on the long arm of chromosome 7 (7q21-22). 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 7q21-q22" refers to band 21-22 on the long arm of chromosome 7. The numbered bands specify the location of the thousands of genes that are present on each chromosome.

The other genes that cause Zellweger spectrum disorders are PEX2, PEX3, PEX5, PEX6, PEX10, PEX12, PEX13, PEX14, PEX16, PEX19, and PEX26.

Affected Populations

Zellweger spectrum disorders are usually apparent at birth. They affect individuals of all ethnic groups. In the United States, the combined incidence of these disorders is at least 1 in 50,000 live births. Because some cases go undiagnosed, determining these disorders true frequency in the general population is difficult.

Zellweger syndrome was described in the medical literature in 1964 by Dr. Hans Zellweger. Neonatal adrenoleukodystrophy and infantile Refsum disease were described later. As the molecular and biochemical understanding of these disorders improved, it became apparent that they represented variants of one disorder and some researchers started using the term "Zellweger spectrum disorder" to describe these disorders. A fourth disorder known as hyperpipecolic acidemia is also considered part of this spectrum.

Related Disorders

Symptoms of the following disorders can be similar to those of Zellweger spectrum disorders. Comparisons may be useful for a differential diagnosis.

Rhizomelic chondrodysplasia punctata (RCDP) spectrum are a group of rare disorders that are also classified as peroxisomal biogenesis disorders. RCDP is characterized by shortening of the long bone of the arms (humerus) and legs (femur), a condition known as rhizomelia. Additional findings include distinctive facial features, the formation of small, hardened spots of calcium (stippling) on the knee cap (patella) and long bones of the arms and legs (chondrodysplasia punctata), cataracts that are present at birth or shortly thereafter, profound growth deficiency after birth, mental retardation, and seizures. RCDP causes life-threatening complications during the first decade of life and in some cases during the newborn (neonatal) period. Milder forms of RCDP have been identified in which affected individuals have less severe mental deficits and growth deficiency and often no rhizomelia. Many of these disorders are caused by mutations in the PEX7 gene and are inherited as an autosomal recessive trait.

The leukodystrophies are a group of rare, progressive, metabolic, genetic disorders that can affect the brain, spinal cord and often the nerves outside the central nervous system (peripheral nerves). Each type of leukodystrophy is caused by an abnormality affecting a specific gene that results in abnormal development of one of at least 10 different chemicals that make up the white matter of the brain. The white matter is tissue composed of nerve fibers. Many of these nerve fibers are covered by a collection of fats (lipids) and proteins known as myelin. Myelin, which collectively may be referred to as the myelin sheath, protects the nerve fibers, acts as an insulator and increases the speed of transmission of nerve signals. Each type of leukodystrophy affects a different part of the myelin sheath, leading to a range of different neurological problems. (For more information on this disorder, choose "leukodystrophy" as your search term in the Rare Disease Database.)

Refsum disease is one of a family of genetic disorders known as the leukodystrophies in which, as a consequence of the disruption of fat (lipid) metabolism, the myelin sheath that insulates and protects the nerves of the brain fails to grow. It is inherited as an autosomal recessive trait. It is characterized by progressive loss of vision (retinitis pigmentosa); degenerative nerve disease (peripheral neuropathy); failure of muscle coordination (ataxia); and dry, rough, scaly skin (ichthyosis). The disorder is caused by the accumulation of a particular fatty acid (phytanic acid) in blood plasma and tissues. This occurs because of a malfunction of the gene that makes the enzyme that breaks down (metabolizes) this acid. The essential enzyme is absent. Treatment with a diet low in foods that contain phytanic acid can be beneficial. Our bodies cannot make phytanic acid. Instead, it is introduced to the body in certain foods, including dairy products, beef, lamb and some seafood. (For more information on this disorder, choose "Refsum" as your search term in the Rare Disease Database.)

Adrenoleukodystrophy is an X-linked recessive genetic disorder caused by an abnormality in the ABCD1 gene on the X chromosome. This condition affects the white matter of the nervous system and the adrenal cortex. Some affected individuals have adrenal insufficiency, which means that reduced amounts of certain hormones such as adrenaline and cortisol are produced, leading to abnormalities in blood pressure, heart rate, sexual development and reproduction. Some of those affected experience serious neurological problems that can affect mental function and lead to disability and reduced life span. This condition has been categorized into six types based on symptoms and age of onset: childhood cerebral ALD, adolescent cerebral ALD, adrenomyeloneuropathy, adult cerebral ALD, adrenal insufficiency only and ALD that occurs in females. (For more information on this disorder, choose "adrenoleukodystrophy" as your search term in the Rare Disease Database.)

A group of disorders may result from a deficiency of a single peroxisomal enzyme. These disorders include D-bifunctional protein deficiency and pseudo-neonatal adrenoleukodystrophy (acyl-CoA oxidase deficiency). The symptoms of single enzyme peroxisomal disorders vary greatly from one individual to another. Some affect infants have severe complications similar to Zellweger syndrome; others have milder symptoms that resemble neonatal adrenoleukodystrophy or infantile Refsum disease.

Standard Therapies

A diagnosis of a Zellweger spectrum disorder is suspected based upon a thorough clinical evaluation, a detailed patient history and identification of characteristic findings. Tests that measure or detect specific substances in blood or urine samples (biochemical assays) can confirm a diagnosis. For example, detection of elevated levels of very long chain fatty acids in the blood is indicative of Zellweger spectrum disorders. Additional tests on blood and urine samples to detect other substances associated with Zellweger spectrum disorders may be performed.

Biochemical assays can be performed before or after birth (pre- or postnatally). Ultrasonography, a test that uses reflected sound waves to create a picture of internal organs, may be used to detect cysts on the kidneys or an enlarged liver.

No specific treatment for Zellweger spectrum disorders exists. Significant progress has been made in understanding the molecular and biochemical aspects of these disorders, which researchers believe will lead to new research strategies and new therapies in the future.

Current treatment of Zellweger spectrum disorders is directed toward the specific symptoms that are apparent in each individual. Treatment may require the coordinated efforts of a team of specialists. Pediatricians, neurologists, surgeons, specialists who assess and treat hearing problems (audiologists), specialists who assess and treat vision problems (ophthalmologists), specialists who assess and treat skeletal disorders (orthopedists) and other healthcare professionals may need to systematically and comprehensively plan an affect child's treatment.

Infants with Zellweger spectrum disorders may require a feeding (gastrostomy) tube to ensure proper intake of calories. A gastrostomy tube is inserted directly into the stomach. Additional therapies used to treat Zellweger spectrum disorders include hearing aids, vitamin K supplementation to treat bleeding complications due to clotting (coagulation) defects, surgery to treat cataracts, and glasses to improve vision. Anti-epileptic drugs may be used to treat seizures, but seizures may persist and be difficult to control despite such therapy.

Early intervention is important in treating children with Zellweger spectrum disorders. Services that may be beneficial may include special remedial education, physical and orthopedic therapy, special services for children with hearing, and other medical, social, and/or vocational services.

Genetic counseling may be of benefit for affected individuals and their families. Other treatment is symptomatic and supportive.

Investigational Therapies

A variety of therapies have been investigated to treat individuals with Zellweger spectrum disorders including specific dietary modifications or regimens such as a diet low in phytanic acid. Specific dietary modifications have had limited effect on individuals with Zellweger spectrum disorders.

Primary bile acid therapy has been used to improve liver function and sodium-4-phenylbutyrate and other pharmacologic agents have been studied.

Some researchers have studied the use of docosahexaenoic acid (DHA), a compound important in the proper function of the brain and retina. DHA is low in individuals with Zellweger spectrum disorders. More research is necessary to determine the long-term safety and effectiveness of this potential therapy for individuals with Zellweger spectrum disorders.

Information on current clinical trials is posted on the Internet at 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:

Toll-free: (800) 411-1222
TTY: (866) 411-1010

For information about clinical trials sponsored by private sources, contact:

Zellweger Spectrum Disorders Resources

NORD Member Organizations:

(To become a member of NORD, an organization must meet established criteria and be approved by the NORD Board of Directors. If you're interested in becoming a member, please contact Susan Olivo, Membership Manager, at

Other Organizations:


Jones KL. Ed. Smith's Recognizable Patterns of Human Malformation. 6th ed. Elsevier Saunders, Philadelphia, PA; 2006:238-239.

McGuinness MC, Smith KD. Peroxisomal Biogenesis Disorders. In: NORD Guide to Rare Disorders. Lippincott Williams & Wilkins. Philadelphia, PA. 2003:486-487.

Gould SJ, Raymond GV, Valle D. The Peroxisome Biogenesis Disorders. In: Scriver CR, Beaudet AL, Sly WS, et al. Eds. The Metabolic Molecular Basis of Inherited Disease. 8th ed. McGraw-Hill Companies. New York, NY; 2001:3181-3217.

Rowland LP. Ed. Merritt's Neurology. 10th ed. Lippincott Williams & Wilkins. Philadelphia, PA. 2000:537-540.

Lyon G, Adams RD, Kolodny EH. Eds. Neurology of Hereditary Metabolic Diseases in Childhood. 2nd ed. McGraw-Hill Companies. New York, NY; 1996:30-39.

Menkes JH, Pine Jr JW, et al. Eds. Textbook of Child Neurology. 5th ed. Williams & Wilkins. Baltimore, MD; 1995:108-109.

Rosewich H, Ohlenbusch A, Gartner J. Genetic and clinical aspects of Zellweger spectrum patients with PEX1 mutations. J Med Genet. 2005;42:e58.

Crane DI, Maxwell MA, Paton BC. PEX1 mutations in the Zellweger spectrum of the peroxisome biogenesis disorders. Hum Mutat. 2005;26:167-175.

Gootjes J, Schmohl F, Waterham HR, Wanders RJA. Novel mutations in the PEX12 gene of patients with a peroxisome biogenesis disorder. Eur J Hum Genet. 2004;12:115-120.

Wanders RJA, Waterham HR. Peroxisomal biogenesis I: biochemistry and genetics of peroxisome biogenesis disorders. Clin Genet. 2004;67:107-133.

Walter C, Gootjes J, Mooijer PA, et al. Disorders of peroxisome biogenesis due to mutations in PEX1: phenotypes and PEX1 protein levels. Am J Hum Genet. 2001;69:35-48.

McGuinness MC, Wei H, Smith KD. Therapeutic developments in peroxisome biogenesis disorders. Exp Opin Invest Drugs. 2000;9:1985-1992.

Wei HW, Kemp S, McGuinness MC, et al. Pharmacological induction of peroxisomes in peroxisomes biogenesis disorders. Ann Neurol. 2000;47:286-296.

Moser HW. Genotype-phenotype correlations in disorders of peroxisome biogenesis. Mol Genet Metab. 1999;68:316-327.

Steinberg SJ, Raymond GV, Braverman NE, Moser AB, Moser HW. Updated:4/26/2006. Peroxisome Biogenesis Disorders, Zellweger Syndrome Spectrum. In: GeneReviews at GeneTests: Medical Genetics Information Resource (database online). Copyright, University of Washington, Seattle. 1997-2003. Available at

Chedrawi A, Clark GD. Peroxisomal Disorders. Emedicine Journal, March 8, 2007. Available at: Accessed on: May 2, 2008.

National Institute of Neurological Disorders and Stoke. Tarlov Cysts Information Page. February 7, 2006. Available at: Accessed On: April 12, 2007.

McKusick VA., ed. Online Mendelian Inheritance in Man (OMIM). Baltimore. MD: The Johns Hopkins University; Entry No:190450; Last Update:03/17/2004. Available at: Accessed on: April 6, 2007.

The information in NORD’s Rare Disease Database is for educational purposes only. It should never be used for diagnostic or treatment purposes. If you have questions regarding a medical condition, always seek the advice of your physician or other qualified health professional. NORD’s reports provide a brief overview of rare diseases. For more specific information, we encourage you to contact your personal physician or the agencies listed as “Resources” on this report.

Report last updated: 2008/09/15 00:00:00 GMT+0

0-9 - A - B - C - D - E - F - G - H - I - J - K - L - M - N - O - P - Q - R - S - T - U - V - W - X - Y - Z

NORD's Rare Disease Information Database is copyrighted and may not be published without the written consent of NORD.

Copyright ©2015 NORD - National Organization for Rare Disorders, Inc. All rights reserved.
The following trademarks/registered service marks are owned by NORD: NORD, National Organization for Rare Disorders, the NORD logo, RareConnect. .