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The Zellweger spectrum disorders (ZSDs) is one of the
group of devastating human disorders with onset in the newborn period or later
in childhood that resulting frequently in death during childhood or
adolescence. ZSDs constitute a heterogeneous group of genetically
determined disorders caused by a deficiency of functional peroxisomes due to
mutations in 1 of the 13 PEX genes.
Peroxisomal proteins are synthesized on free ribosomes in the cytoplasm and are
imported into the organelle post-translationally. Peroxisomal matrix proteins
are targeted to the organelle via cytoplasmic shuttling receptors, recognizing
the peroxisomal targeting signals (PTS 1 at the C-terminal or PTS 2 at the
N-terminal) (Eckert and Erdmann, 2003). Peroxins (PEX) are proteins that are essential for the assembly of functional
peroxisomes. Mutation of peroxin genes leads to the development of severe human
peroxisome biogenesis disorders (PBD) due to peroxisomal metabolic dysfunction
because of the deficient organelle import. These disorders belong to the
diseases of the Zellweger syndrome spectrum (ZSS) disorders. Initially, ZSDs
are described as three distinct disorders, with Zellweger syndrome being the
most severe form, followed by neonatal adrenoleukodystrophy, and the mildest
form being infantile Refsum’s disease (Braverman et. al., 2013). They are all inherited in an autosomal recessive
way. At conception, each sib of an affected
individual has a 25% chance of being affected, a
50% chance of being an asymptomatic carrier, and a 25% chance of being
unaffected and not a carrier. Several knockout mouse models have
been generated for these diseases and are used to characterize the molecular
pathogenesis of these devastating diseases (Moser 1993). Children with
Zellweger syndrome, also called cerebrohepatorenal syndrome, suffer from
neonatal seizures and general hypotonia and exhibit severe migration defects of
neurons and polycystic kidneys. They develop liver cirrhosis and degeneration
of the adrenal cortex leading to adrenal insufficiency and die frequently
during first year of life (Ahlemeyer et.
al., 2007). Similar to Zellweger syndrome, those with neonatal
adrenoleucodystrophy experience neonatal hypotonia and seizures. They may have
progressive white matter disease, and usually die in late infancy (Wanders et. al., 2006). Patients with infantile
Refsum disease have no neuronal migration defect, but can develop a progressive
white matter defect. Their survival is variable, but most patients survive
beyond infancy and some even reach adulthood (Poll-The BT et. al., 1987).
ZSDs are characterized by multiple biochemical abnormalities, especially
accumulation of very long-chain fatty acids (VLCFAs), phytanic acid, pristanic
acid, pipecolic acid and C27-bile acid
intermediates in plasma and low levels of plasmalogens in erythrocytes (Wanders
et. al., 2006). Clinically, ZSDs are
considered as a spectrum of disorders in which patients can present with a
broad range of signs and symptoms. These sign and symptoms are dysfunction of
liver, developmental delay, sensorineural deafness, vision impairment, adrenal
insufficiency, neurological abnormalities and craniofacial dysmorphism (Klouwer et. al., 2015). 

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