What is Zellweger syndrome?

Risk Factors

The ZSS disorders are inherited in an autosomal recessive manner. Individuals
with mutations in both copies of any one of the twelve different
PEX genes known to be associated with ZSS disorders are
affected. Full siblings of these individuals have a 25 percent risk of being
affected, a 50 percent risk of being an asymptomatic carrier, and a 25 percent
chance of being unaffected and not a carrier. Male and female infants are affected
with equal frequency. Cases of ZSS disorders have been observed worldwide; no
particular ethnic preponderance has been noted.

Etiology and Genetics

Peroxisomes are small, membrane-bound organelles found in
cells throughout the body. They are involved in a variety of metabolic processes,
including the breakdown of toxic substances, such as hydrogen peroxide, and the
production of bile acids, necessary for digestion of dietary fats. Peroxisomes are
also involved in degradation of very long chain fatty acids (VLCFAs) in a process
known as beta-oxidation, essential for energy production. Peroxisomes play a role
in the synthesis of certain types of lipids, such as plasmalogens, which are
important components of cell membranes in certain tissues (such as the brain).

Proteins necessary for peroxisome function and membrane formation are made within the cell, then transported into existing peroxisomes. Importing these essential proteins prompts growth and division, resulting in the formation of new peroxisomes. In the ZSS disorders, these proteins are unable to be transported into peroxisomes, resulting in decreased biogenesis and function.

ZSS disorders are caused by mutations in the PEX genes, which
encode these essential proteins, known as peroxins. Though approximately
twenty-nine PEX genes have been identified, ZSS disorders have
been associated with mutations in only twelve (located at the following
chromosomal positions): PEX1 (7q21q22) PEX2 or
PXMP3 (8q21.1), PEX3(6q23q24),
PEX5(12p13.3), PEX6 (6p21.1),
PEX10(1p36.32), PEX12 (17q12),
PEX13(2p15), PEX14(1p36.2), PEX16
(11p12p11.2), PEX19 (1q22), and PEX26
(22q11.2). In some cases, the particular gene involved and the type of mutations
present are predictive of the ultimate effect on biogenesis and can be associated
with clinical severity. Mutations in PEX1 is the most common
cause of ZSS, affecting nearly 70 percent of individuals with the disease.

Symptoms

Though once considered separate entities, it is now known that Zellweger
syndrome (ZS), neonatal adrenoleukodystrophy (NALD), and infantile
Refsum
disease (IRD) share a common etiology and represent differing
degrees of severity along the Zellweger syndrome spectrum. There is little
distinction between these conditions, although historically, severely affected
infants were characterized as having ZS and those surviving more than one year and
making some type of developmental progress were thought to have NALD or IRD.

The ZSS disorder typically appears during childhood; though extremely rare,
presentation in adulthood has been reported. Affected neonates often present with
severe hypotonia, failure to thrive, seizures, and liver dysfunction. Some
are noted to have distinctive facial features and neuronal migration defects. Bony
stippling may also be seen on radiographs. Older children may have additional
issues such as hearing loss and/or retinal dystrophy. Affected individuals are
noted to have decreased levels of docosahexaenoic acid (DHA), thought to be
important in brain development, as well as decreased bile acids, important in
normal digestion. Liver dysfunction can result in coagulation
problems, and renal failure, thought to be due to renal cysts,
can also occur. Severely affected individuals usually make no developmental
progress; individuals with milder disease have a wide range of intellectual
abilities, with most exhibiting developmental delays. Loss of previously acquired
skills occurs in some due to progressive leukodystrophy.

Screening and Diagnosis

Analysis of levels of VLCFAs in the plasma is a useful initial screening test. Affected individuals typically have elevated concentrations of C26:0 and C26:1 and elevated C24/C22 and C26/C22 ratios. Measurements of plasmalogens, phytanic and pristanic acids, pipecolic acid, and plasma bile acids are also helpful in diagnosing ZSS and distinguishing this from other peroxisomal disorders. Confirmation of abnormalities noted on blood samples should be performed on cultured fibroblasts. Documentation of causative mutations in one of the PEX genes associated with ZSS can also further confirm the diagnosis.

Treatment and Therapy

Treatment for ZSS disorders remains largely symptomatic. Supplying an adequate
caloric intake may require the placement of a gastrostomy tube. Supplementation of
vitamin
K and other fat-soluble vitamins is recommended. Hearing aids
are used to address hearing loss. Antiepileptic drugs may be used to control
seizures. Supplementation with bile acids, deficient in ZSS, is currently under
investigation. Supplemental DHA has been proposed as a treatment for ZSS, but its
clinical effects have not been proven. Liver transplantation has been attempted in
few cases, though long-term clinical outcomes are currently unavailable.

Prevention and Outcomes

Most severely affected individuals die before one year of age. Evidence
suggests that of those who survive beyond this point with an apparently stable
course, most will survive through early childhood, and survival into young
adulthood has been documented. Death in older individuals is typically the result
of respiratory complications and/or renal failure.

There is no effective means of prevention for the ZSS disorders. Prenatal
testing is typically available for those in which the causative mutations in the
index case have been identified or the biochemical abnormalities have been
demonstrated on cultured fibroblasts. Individuals with a family history of these
disorders should be offered genetic counseling.

Bibliography

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Crane. "Central Serotonergic Neuron Deficiency in a Mouse Model of Zellweger
Syndrome." Neuroscience 274 (2014): 229–41.
Print.

Steinberg, S., et
al. “Peroxisome Biogenesis Disorders.” Biochimica et Biophysica
Acta 1763 (2006): 1733–1748. Print.

Steinberg, Steven J., et al. "Peroxisome
Biogenesis Disorders, Zellweger Syndrome Spectrum."
GeneReviews. University of Washington, 10 May 2012. Web.
4 Aug. 2014.

Tran, Christel, et al. "Late-Onset Zellweger
Spectrum Disorder Caused by PEX6 Mutations Mimicking X-Linked
Adrenoleukodystrophy." Pediatric Neurology 51.2 (2014):
262–65. Print.

Wanders, R., et al.
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Print.