Zellweger syndrome

Definition

Zellweger syndrome refers to an inherited condition that is present at birth and usually causes death during the first six to twelve months of age. This syndrome is caused by a lack or reduction of peroxisomes, which are specialized organelles that help the body get rid of toxic substances. Zellweger syndrome is a disorder of metabolism. It is one of a group of genetic disorders called the leukodystrophies, diseases that involve abnormal growth of the fatty covering of nerve fibers (myelin sheath).

Description

In 1964, researchers described a similar pattern of multiple birth defects in two unrelated pairs of siblings in Iowa and Maryland. Hans Zellweger identified the cases in Iowa. Passarge and McAdams reported several similar cases and introduced the name cerebro-hepato-renal-syndrome. Opitz reviewed the Bowen report and decided that only the Iowa cases represented the same condition reported by others. To recognize Hans Zellweger's role in identifying the Iowa cases, Opitz proposed the name Zellweger cerebro-hepato-renal syndrome. Most refer to the syndrome as Zellweger syndrome.

Initially, Zellweger syndrome was considered a multiple congenital anomaly disorder. In 1973, researchers reported that individuals who have Zellweger syndrome do not have peroxisomes in their liver and kidneys. Important metabolic processes take place in peroxisomes. Thus, the first evidence that Zellweger syndrome should be reassigned to the metabolic disease category was provided.

Metabolism includes numerous chemical processes involved in both construction (anabolism) and break down (catabolism) of important components. These processes are catalyzed (or helped along) by enzymes. If any enzymes are missing in the process, a build-up of an initial substance, or a missing end-product, can result. Either of these situations can lead to disease.

Peroxisomes are small organelles found in cells, particularly of the liver, kidneys, and brain. Substances that are broken down in peroxisomes include very long chain fatty acids, polyunsaturated fatty acids, dicarboxylic fatty acids, prostaglandins, and the side chain of cholesterol. When peroxisomes are absent or deficient, very long chain fatty acids, and other substances that peroxisomes normally help to catalyze, begin to build up in the body.

Peroxisomes also play a part in the initial reactions in the creation of plasmalogens. Plasmalogens are important components in the structure of myelin, a fatty layer that covers the nerve fibers in the body. This covering helps the nerve signals to move correctly from place to place. Since plasmalogens require peroxisomes for their formation, a lack of functioning peroxisomes causes a deficiency in plasmalogens. Since the plasmalogens are required for the formation of myelin, the myelin is defective.

Bile acid formation also requires peroxisomes. Bile is secreted by the liver and stored in the gallbladder. It is released when fat enters the intestines. Bile then helps to break down these fats to prepare them for further digestion. Bile acid is produced during the breakdown of cholesterol.

Babies with Zellweger syndrome have severe developmental retardation and impairment of their central nervous system. They lack muscle tone (hypotonia), and are often blind or deaf. They have a distinctive facial appearance, an enlarged liver, and may have cysts in their kidneys. They will frequently have jaundice in the newborn period that is more serious and lasts longer than usual. Jaundice is a yellow discoloration of the skin and eyes caused by too much bilirubin in the blood. It may be a symptom of many disorders including liver disease. Healthy newborns frequently have jaundice that resolves after a few days.

Genetic profile

Zellweger syndrome is an autosomal recessive condition. This means that in order to have the condition, an individual needs to inherit one copy of the gene for Zellweger syndrome from each parent. An individual who has only one copy of the gene is called a carrier for the condition and does not have any signs or symptoms of the condition. When two parents are carriers for Zellweger syndrome, they have a 25% chance, with each pregnancy, for having an affected child. They have a 50% chance for having a child who is a carrier for the condition and a 25% chance for having a child who is neither affected nor a carrier for Zellweger syndrome.

Changes or mutations in any of several different genes involved in the creation of peroxisomes (peroxisome biogenesis) can cause Zellweger syndrome. There are many gene mutations that have been identified that are involved with the creation of functioning peroxisomes. The gene located on the long arm of chromosome 7, at 7q21-q22, is in part responsible for the creation of peroxisomes. The gene product is called peroxisome biogenesis factor 1 or Peroxin 1 (PEX 1). When a gene change or mutation occurs in this area that does not allow for normal creation of the peroxisomes, then the peroxisomes are not created, leading to Zellweger syndrome. There are several other genes identified on different chromosomes that will not allow for normal peroxisome development if a gene mutation occurs. These include, but are not limited to, peroxisome biogenesis factor 13 (short arm of chromosome 2 at 2p15), peroxisome biogenesis factor 6 (short arm of chromosome 6 at 6p21), peroxisome assembly factor-1 (long arm of chromosome 8 at 8q21), peroxisomal targeting signal 1 receptor (short arm of chromosome 12 at 12p13), and peroxisome biogenesis factor 10 (chromosome 1).

The cause of Zellweger syndrome is a failure of the peroxisomes to be able to bring newly created peroxisomal proteins into the peroxisomes. Instead, the proteins stay outside of the peroxisomes and are broken down. The peroxisome membranes may be present, but are empty, like the wood frame of an empty house. These empty peroxisomes have been called peroxisome "ghosts."

Demographics

The frequency of this condition is estimated to be 1 in 50,000. There is no reported difference in the incidence in any particular sex or ethnic background.

Signs and symptoms

The characteristic facial features of Zellweger syndrome include:

• high forehead
• widely spaced eyes (hypertelorism)
• low, broad, or flat nasal bridge
• "full" cheeks
• small chin (micrognathia)
• forward tilting (anteverted) nostrils
• vertical fold of skin over the inner corner of the eye (epicanthal fold)
• upslanting eyes
• shallow orbital ridges
• minor ear abnormalities

Other characteristics include, but are not limited to:

• breech presentation at birth (feet first)
• extremely weak muscles (hypotonia)
• weak sucking and swallowing reflexes
• high arched palate
• absent deep tendon reflexes
• seizures
• deafness
• enlarged liver (hepatomegaly)
• enlarged spleen
• gastrointestinal bleeding
• slow growth after birth
• severe mental retardation
• abnormal brain findings
• involuntary, rhythmic movements of the eyes (nystagmus)
• large space between the bones of the skull (fontanel)
• flat back part of the head (occiput)
• tiny white or yellow spots on the colored part of the eyes (brushfield spots)
• redundant skin on neck
• congenital cloudy lenses of the eye (cataracts)
• possible heart defects
• a single crease across the palm of the hands (simian creases)
• fixed, immovable joints (contractures)
• misaligned bones in the front part of the foot/club foot (talipes equinovarus)
• undescended testicles (cryptorchidism)
• underdeveloped thymus (thymus hypoplasia)
• hearing impairment
• failure to thrive
• psychomotor retardation
• high levels of iron or copper in the blood

Diagnosis

Diagnosis is based on clinical characteristics combined with a series of tests to determine the peroxisomal function and structure. Biochemical abnormalities include elevated levels of very long chain fatty acids, a decrease in the levels of a peroxisomal enzyme dihydroxyacetone phosphate acyltransferase (DHAPAT), the presence of abnormal intermediates in bile acid formation, and a lack of plasmalogens in a blood sample. Absence of peroxisomes in liver biopsy specimen is considered essential for the diagnosis of Zellweger syndrome.

Prenatal diagnosis for Zellweger syndrome is possible through chorionic villus sampling (CVS) and amniocentesis . Diagnosis may be made by measuring the synthesis of plasmalogens in cultured CVS or amniotic fluid cells or by measuring the amount of very long chain fatty acids. Other tests may be useful, including measuring the amount of the peroxisomal enzyme DHAPAT in the amniotic fluid.

There are other leukodystrophies, including neonatal adrenoleukodystrophy , infantile Refsum disease , and hyperpipecolic acidemia. The milder diseases may be due to having partial peroxisome function.

Treatment and management

In general there is no cure and no treatment for Zellweger syndrome.

Prognosis

The prognosis for individuals who have Zellweger syndrome is poor. Those with the disease usually only live for a few months after birth. Rarely do individuals who have Zellweger syndrome live longer than one year.

Resources

BOOKS

Jones, Kenneth Lyons, ed. Smith's Recognizable Patterns of Human Malformation. 5th ed. Philadelphia: W.B. Saunders Company, 1997.

ORGANIZATIONS

National Organization for Rare Disorders (NORD). PO Box 8923, New Fairfield, CT 06812-8923. (203) 746-6518 or (800) 999-6673. Fax: (203) 746-6481. <http://www.rarediseases.org>.

United Leukodystrophy Foundation. 2304 Highland Dr., Sycamore, IL 60178. (815) 895-3211 or (800) 728-5483. Fax: (815) 895-2432. <http://www.ulf.org>.

WEBSITES

"NINDS Zellweger Syndrome Information Page." National Institute of Neurological Disorders and Stroke. <http://www.ninds.nih.gov/health_and_medical/disorders/zellwege_doc.htm>.

Renee A. Laux, MS