What Is Zellweger Syndrome?

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Zellweger Syndrome

Zellweger syndrome, also called cerebrohepatorenal syndrome, is a rare congenital disorder characterized by the reduction or absence of functional peroxisomes in the cells of an individual.  It is one of a family of disorders called leukodystrophies. Zellweger syndrome is named after Hans Zellweger (1909–1990), a Swiss-American pediatrician, a professor of pediatrics and genetics at the University of Iowa who researched this disorder.

Zellweger syndrome is the most severe form of a spectrum of conditions called Zellweger spectrum. The signs and symptoms of Zellweger syndrome typically appear during the newborn period and may include poor muscle tone (hypotonia), poor feeding, seizures, hearing loss, vision loss, distinctive facial features, and skeletal abnormalities. Affected children also develop life-threatening problems in other organs and tissues, such as the liver, heart, and kidneys.

Children with Zellweger syndrome usually do not survive beyond the first year of life. Zellweger syndrome is caused by mutations in any one of at least 12 genes; mutations in the PEX1 gene are the most common cause. It is inherited in an autosomal recessive manner. There is no cure for Zellweger syndrome; treatment is generally symptomatic and supportive.

Zellweger syndrome is one of a group of four related diseases called peroxisome biogenesis disorders (PBD). The diseases are caused by defects in any one of 13 genes, termed PEX genes, required for the normal formation and function of peroxisomes. The PBDs are divided into two groups: Zellweger spectrum disorders and Rhizomelic Chondrodysplasia Punctua spectrum.

The Zellweger spectrum is comprised of three disorders that have considerable overlap of features. These include Zellweger syndrome (ZS, the most severe form), neonatal adrenoleukodystrophy (NALD), and Infantile Refsum disease (IRD, the least severe form). Peroxisomes are cell structures that break down toxic substances and synthesize lipids (fatty acids. oils, and waxes) that are necessary for cell function. Peroxisomes are required for normal brain development and function and the formation of myelin, the whitish substance that coats nerve fibers.

What Is Zellweger Syndrome?

What Is Zellweger Syndrome?

They are also required for normal eye, liver, kidney, and bone functions. Zellweger spectrum disorders result from dysfunctional lipid metabolism, including the over-accumulation of very long-chain fatty acids and phytanic acid, and defects of bile acids and plasmalogens–specialized lipids found in cell membranes and myelin sheaths of nerve fibers.

Symptoms of these disorders include an enlarged liver; characteristic facial features such as a high forehead, underdeveloped eyebrow ridges, and wide-set eyes; and neurological abnormalities such as cognitive impairment and seizures. Infants will Zellweger syndrome 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 also may occur.

Signs & Symptoms

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 intellectual disability, 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, intellectual disability, 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 supposed to close after birth.

Due to the lack of muscle tone, laryngomalacia (floppy airway) and other respiratory problems may occur in infants with Zellweger spectrum disorders. Respiratory support may entail the use of a nasal cannula for oxygen to more aggressive forms of support as the disease progresses.

In some 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).

Synonyms

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

Disorder Subdivisions

  • Cerebrohepatorenal Syndrome
  • Hyperpipecolic acidemia
  • Infantile Refsum Disease
  • IRD
  • Neonatal Adrenoleukodystrophy
  • NALD
  • 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, visionproblems, 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.

Diagnosis

A diagnosis of a Zellweger syndrome is usually suspected when characteristic signs and symptoms are present at birth, including the distinctive facial features. Tests that measure or detect specific substances in blood or urine samples can confirm a diagnosis of Zellweger syndrome. For example, detection of elevated levels of very long chain fatty acids (VLCFA) in the blood is the most commonly used screening test.

Additional tests on blood and urine samples to find other substances associated with the condition may be performed. An ultrasound may be used to look for cysts on the kidneys or an enlarged liver. A genetic test to find a mutation in one of the genes associated with Zellweger spectrum disorders may also be used to confirm the diagnosis.

A Zellweger spectrum disorders diagnosis is suspected based upon a thorough clinical evaluation, a detailed patient history and identification of characteristic findings. Zellweger spectrum disorders can be diagnosed by showing peroxisome abnormalities that can be monitored in body fluids.

The primary step in Zellweger spectrum disorders diagnosis involves the detection of elevated very long chain fatty acids. Additional tests on blood and urine samples to detect other substances associated with peroxisome metabolism may be performed. Biochemical testing of skin fibroblasts is useful to confirm the abnormalities seen in the blood and urine and clarify questionable results in body fluids.

Yes. Clinical genetic testing is available for the twelve genes known to cause Zellweger syndrome. Carrier testing for at-risk relatives and prenatal testing are possible if the two disease-causing mutations in the family are known.

The Genetic Testing Registry (GTR) is a centralized online resource for information about genetic tests. The intended audience for the GTR is health care providers and researchers. Patients and consumers with specific questions about a genetic test should contact a health care provider or a genetics professional.

Genetic testing is available for Zellweger spectrum disorders; next generation sequencing methods (sequencing millions of small fragments of DNA at the same time)are being used more frequently as a confirmatory test, and may be required for peroxisome disorders that are difficult to determine by traditional biochemical methods. Additionally, genetic determination of mutations in Zellweger spectrum disorders, in contrast to biochemical tests, will also identify carriers for Zellweger spectrum disorders, which will allow reliable genetic counseling of families and may also assist with eligibility for future clinical trials.

Methods have been developed to detect elevated levels of very long chain fatty acids in newborn screening for X-linked adrenoleukodystrophy, a related peroxisomal disorder. Legislation for X-linked adrenoleukodystrophy newborn screening has passed in many states and screening has begun in New York; continued legislative efforts are expected to expand through movements initiated by patient families and advocacy organizations to lobby their state legislatures.  Recently, the Department of Health and Human Services Advisory Committee for Heritable Disorders for Newborns and Children voted to propose the addition of X-linked adrenoleukodystrophy screening in the Recommend Uniform Screening Panel.  Newborn screening for X-linked adrenoleukodystrophy should increase early diagnosis of Zellweger spectrum disorders and determination of accurate incidence estimates of the disease.

Certain tests (biochemical or genetic) can be performed prenatally in the first or second trimester using chorionic villus sampling or amniocentesis. 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. Preimplantation genetic diagnosis with in vitrofertilization can also be performed when the gene mutations are known.

Inheritance

Zellweger syndrome is inherited in an autosomal recessive manner. This means that a person must have a change (mutation) in both copies of the responsible gene in order to have the condition. The parents of an affected person usually each carry one mutated copy of the gene and are referred to as carriers. Carriers do not have signs or symptoms of the condition. When two carriers of an autosomal recessive condition have children, each child has a 25% (1 in 4) risk to have the condition, a 50% (1 in 2) risk to be a carrier like each of the parents, and a 25% chance to not have the condition and not be a carrier.

Cause

Zellweger syndrome is an autosomal recessive disorder caused by mutations in genes that encode peroxins, proteins required for the normal assembly of peroxisomes. Most commonly, patients have mutations in the PEX1, PEX2, PEX3, PEX5, PEX6, PEX10, PEX12, PEX13, PEX14, PEX16, PEX19, or PEX26 genes.  In almost all cases, patients have mutations that inactivate or greatly reduce the activity of both the maternal and paternal copies of one these aforementioned PEX genes.

Zellweger syndrome is an autosomal recessive condition caused by changes (mutations) in any one of at least 12 different genes that are involved in the creation and proper function of peroxisomes. Peroxisomes are structures in cells that are involved in many chemical processes needed for the body to function properly.

They are vital for the proper breakdown of fatty acids and the production of certain lipids (fats) that are important to the nervous system and digestion. They are also play a role in waste disposal and help with the development and function of the brain. Mutations in the genes responsible for Zellweger syndrome cause dysfunction of peroxisomes, which leads to the signs and symptoms of the condition.

As a result of impaired peroxisome function, an individual’s tissues and cells can accumulate very long chain fatty acids (VLCFA) and branched chain fatty acids (BCFA) that are normally degraded in peroxisomes. The accumulation of these lipids can impair the normal function of multiple organ systems, as discussed above. In addition, these individuals can show deficient levels of plasmalogens, ether-phospholipids that are especially important for brain and lung function.

Almost 70% of individuals with a Zellweger spectrum disorder have a mutation in the PEX1 gene. The other genes associated with the Zellweger spectrum each account for a smaller percentage of cases. To see a list of the genes associated with Zellweger syndrome

Treatment

The malabsorption resulting from lack of bile acid has resulted in elemental formula being suggested, which are low in fat with < 3% of calories derived from long chain triglycerides (LCT). However, reduced very long chain fatty acids (VLCFA) has not been shown to reduce blood VLCFA levels,  likely because humans can endogenously produce most VLCFA. Plasma VLCFA levels are decreased when dietary VLCFA is reduced in conjunction with supplementation of Lorenzo’s oil (a 4:1 mixture of glyceryl trioleate and glyceryl trierucate) in X-ALD patients. Since docosahexaenoic acid (DHA) synthesis is impaired [59], DHA supplementation was recommended, but a placebo-controlled study has since showed no clinical efficacy. Due to the defective bile acid synthesis, fat soluble supplements of vitamins, A, D, E, and K are recommended.

There is no cure for Zellweger syndrome, nor is there a standard course of treatment. Since the metabolic and neurological abnormalities that cause the symptoms of Zellweger syndrome are caused during fetal development, treatments to correct these abnormalities after birth are limited. Most treatments are symptomatic and supportive.

There is currently no cure or effective treatment for Zellweger syndrome. Management is supportive and based on the signs and symptoms present in each person. For example, infants with feeding issues may require placement of a feeding tube to ensure proper intake of calories. Care is usually handled by a team of specialists that may include pediatricians, neurologists, surgeons, audiologists (treat hearing problems), ophthalmologists (treat vision problems), and orthopedists (treat skeletal abnormalities).

Prognosis

Currently, no cure for Zellweger syndrome is known, nor is a course of treatment made standard. Infections should be guarded against to prevent such complications as pneumonia and respiratory distress. Other treatment is symptomatic and supportive. Patients usually do not survive beyond one year of age.

The prognosis for infants with Zellweger syndrome is poor. Most infants do not survive past the first 6 months, and usually succumb to respiratory distress, gastrointestinal bleeding, or liver failure.

The long-term outlook (prognosis) for infants with Zellweger syndrome is very poor. Most infants do not survive past the first 6 months of life, and usually succumb to respiratory distress, gastrointestinal bleeding, or liver failure. Although no specific treatment for Zellweger syndrome currently exists, significant progress has been made in understanding the molecular and biochemical aspects of the condition, which researchers believe will lead to new research strategies and new therapies in the future.

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