Peroxisome Biogenesis Disorders: Zellweger Syndrome & Beyond - Essay Sample

Introduction

Zellweger syndrome disorder is part of diseases known as the peroxisome biogenesis. These diseases result from problems in any single of the 13 genes of the PEX genes, which are needed for the healthy formation as well as the functioning of the peroxisomes. The peroxisome biogenesis disorders are grouped into two; the Rhizomelic Chondrodysplasia Punctual spectrum and the Zellweger spectrum (1).

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Peroxisomes are the cell structures responsible for the breakdown of harmful substances and the acquisition of lipids, which are needed for proper cell functioning. Peroxisomes are necessary for healthy brain development as well as the formation and functioning of the whitish substance coating nerve fibers; it is often referred to as myelin (1). Peroxisomes are also necessary for the normal functioning of the bones, kidney, liver, and eye.

Notably, the Zellweger spectrum also occurs due to the dysfunctional lipid chemical processes, which involves the over-acquisition of long-chain phytanic and fatty acid coupled with the problems of bile products and plasmalogens which are specialized lipids located in the myelin sheaths and the cell membranes particularly those of a nerve fiber. The Zellweger syndrome does not result from defects in only one gene, although there are several clinical characteristics associated with the disorder (1). Its development and that of other closely related Zellweger syndrome spectrum (ZSS) disorders are associated with at least twelve different loci. The loci include:

• The PEX1 gene found on chromosome 7q21.2; mutations in this gene are the ones commonly associated with the Zellweger syndrome.
• The PEX2 gene found on chromosome 8q21.1; this gene is also called the peroxisomal membrane protein 3, PXMP3.
• The PEX3 gene found on chromosome 6q24.2; it encodes a crucial protein that takes part in the targeting of proteins to the peroxisome membrane.
• The PEX5 gene found on chromosome 12p13.31; the gene encodes the receptor for proteins, which contains a PTS1 sequence for targeting the peroxisomes.
• The PEX6 gene found on chromosome 6p21.1: it functions together with PEX5, encoded proteins in PTS1-which contains protein targeting the peroxisomes.
• The PEX10 gene found on chromosome 1p36.32.
• The PEX12 gene found on chromosome 17q12.
• The PEX13 gene found on chromosome 2p11.
• The PEX14 gene found on chromosome 1p36.22; it functions to interact with PEX5, encoded proteins which are bound to a PTS1-containing protein.
• The PEX16 gene found on chromosome 11p11.2.
• The PEX19 gene found on chromosome 1q23.2.
• The PEX26 gene found on chromosome 22q11.21; it encodes protein anchors PEX1p and PEX6p to the peroxisome membrane.

Chromosome 7q11.

The genes give useful instructions for the formation of a group of proteins called the peroxisomes, which are crucial for the formation and proper functioning of the cell structures known as peroxisomes. Peroxines help in the biogenesis of peroxisomes through the production of a membrane, which aids in the separation of the peroxisomes from the other parts of the cell as well as importing enzymes inside the peroxisome. Mutations in the genes which cause Zellweger spectrum disorder do not allow peroxisomes to form usually (2). Zellweger spectrum disorder and other diseases that interfere with normal formation of peroxisomes are known as peroxisome biogenesis disorders. When the peroxisome production is disrupted, the structures cannot effectively perform their usual functions. The absence of functional peroxisomes within cells results in the signs and symptoms of Zellweger syndrome.

The disorder is primarily caused by mutations in the peroxin-1 gene. The genes exist in about 70 percent of the affected people. Other genes are associated with Zellweger spectrum disorder. However, they only account for a smaller percentage of the condition (2).

The Biochemical Symptoms of the Disorder

Victims of the disorder can be placed into three categories about the stage or age of presentation. The stages include the childhood presentation and an adolescent-adult or late presentation (3). The general overview of the primary symptoms for the groups are as follows:

The Biochemical Neonatal-Infantile Presentation of the Disease

The primary signs and symptoms of Zellweger syndrome victims within this category are based on the following:

• Hepatic dysfunction, as well as profound hypotonia which results in prolonged jaundice and feeding problems.
• Epileptic seizures.
• Characteristic dysmorphic signs, with the most evident being the facial dysmorphic signs.
• Sensorineural deafness, as well as ocular abnormalities such as retinopathy, cataracts, and glaucoma.
• Neocortical dysplasia particularly perisylvian polymicrogyria which can be shown by Brain Magnetic Resonance (MRI)
• Generalized reduction in the white matter volume
• Delayed myelination
• Bilateral ventricular dilation
• Germinolytic cysts
• Presence of Chondrodysplasia punctate

The Childhood Biochemical Presentation of the Disorder

The patients at this stage present more distinct signs and symptoms than those with the neonatal-infantile presentation. They include:

• Delayed development
• Ocular abnormalities are comprising of retinitis pigmentosa, cataract, and glaucoma, which result in early blindness and impaired vision.
• Sensorineural deafness. Its identification is through auditory screening programs.
• Hepatomegaly and hepatic dysfunction with coagulopathy, advanced transaminases as well as hyperbilirubinemia are common
• Epileptic seizures may be developed by some patients.
• Development of renal calcium oxalate stones and adrenal insufficiency.
• The occurrence of early-onset progressive leukodystrophy which may lead to loss of acquired skills in some people
• Progressive demyelination which affects the cerebrum, midbrain, and cerebellum

The Biochemical Adolescent-Adult Presentation

The severity of the symptoms at this stage is less, and diagnosis can occur in late childhood. The occurrence may also occur in adulthood. The most common and consistent symptoms at this level include:

• Ocular abnormalities, as well as a sensorineural deficit.
• Craniofacial dysmorphic features may be present or even totally absent
• Significant variability in terms of developmental delay and other patients may still have normal intelligence
• Common primary adrenal insufficiency which may probably be underdiagnosed.
• Presence of other neurological abnormalities such as cerebellar ataxia, pyramidal tract signs together with signs of peripheral neuropathy.

The Biochemical Inheritance of the Disease Syndrome

Zellweger syndrome is inherited from one person to another in an autosomal recessive pattern. For an individual to have the condition, there must exist mutation in both copies of the responsible gene. Each parent of the affected individual always carries a single mutated copy of the gene. The parents are, therefore, referred to as the carriers, and they do not possess any signs or symptoms of the disorder (4). In case two carriers of an autosomal recessive condition give birth to children, each child will have a 50 percent risk to have the condition.

The Biochemical Effects of Mutations in the affected Genes

A mutation in any of the genes is what results in the Zellweger syndrome. The mutations bring about a dysfunctional protein that is useful for an individual's cells to be in a position of importing proteins which are newly-synthesized into tiny cytoplasmic organelles referred to as the peroxisomes. A total absence of or a decrease in the number of peroxisomes is what characterizes the syndrome. Key enzymes found within peroxisomes play various crucial roles during chemical reactions, especially oxidation. Therefore, as already opined in the case of Zellweger syndrome, it very evident that abnormalities that may result in the structure and functionality of peroxisomes ignite the development of a disease (6).

An individual's liver and kidney are where peroxisomes are commonly found. Those with Zellweger syndrome do not have peroxisomes in these organs; hence, they are affected by the ailment. Due to lack of peroxisomes, toxic substances that can find their way into an individual's bloodstream may not get detoxified. Peroxisomes are also useful for organic formation of essential compounds as well as taking part in various vital roles that relate to chemical reactions in a human's body (7). Zellweger syndrome and the mutations in various genes which affect the functioning of peroxisomes comprise of peroxin-1, peroxin-2, peroxin-3, peroxin-5, peroxin-6, as well as peroxin-12. Every gene location is biochemically and genetically unique.

The Biochemical Alterations in the Proteins Function

Just like the lysosomes, peroxisomes are organelles with only one membrane, and they are primarily found in all eukaryotic cells. Peroxins are those proteins that take part in and are required for proper peroxisome biogenesis. Humans have at least 15 peroxin genes. Enzymes containing peroxisome targeting sequences (PTS) are the ones targeted to the peroxisomes. PTS has either of the two amino acid consensus elements, as illustrated below. PTS1 has a C-terminal consensus arrangement of -[S/A/C][K/R/H][L/M]. This is called the SKL motif. A cytosolic PTS1 receptor, which is encoded by the peroxin-5 gene, is useful in the identification of the SKL sequence element. In humans, the two isoforms of peroxin-5 encoded proteins are Pex5pS and Pex5pL. Inside the Pex5pL protein, there is about 37 amino acid insertions.

PTS2 has an N-terminal consensus arrangement of -[R/K][L/V/I/Q]XX[L/V/I/H/Q][L/S/G/A/K]X[H/Q][L/A/F]-. The X represents any amino acid. The membrane of the peroxisome targets those proteins containing a consensus arrangement recognized as a peroxin-19 binding site. The membrane protein receptor encoded by the peroxin-19 gene can recognize the site. Pex5pS, Pex5L, as well as Pex7p freely mingle with target proteins, which are newly synthesized in the cytosol hence directing them to the peroxisome. Peroxin-14 gene known as Pex14p is a component on the membrane of the peroxisome that is useful in protein importation. Bound to a protein that contains a PTS1 sequence with Pex14p, the PTS1 containing protein is then transferred into the peroxisome after interaction of Pex5pS or Pex5pL (8). Proxisome protein importation activity of the Pex7p also requires Pex5pL. Together with Pex5pL, PTS2 containing proteins mingles with Pex7p.The resulting complex interacts with Pex14p, and the PTS2 containing protein is, therefore, transferred into the peroxisome. Most proteins do not contain a PTS2 sequence.

The Biochemical Alteration of Cellular Physiology

Hepatic cysts and general hepatic dysfunctions leading to the increment of copper and iron in the bloodstream characterizes the engagement of the liver in the Zellweger syndrome. As a result, the functioning of the kidney is also greatly impaired. Very long-chain fatty acids, as well as other branched-chain fatty acids, accumulate in tissues thereby impairing their functions. This results from the lack of proper peroxisomal lipid metabolism. There will also be progressive impairment of neuronal migration, neuronal positioning, and reduced myelin production. This is because peroxisomes are useful components in the synthesis of either phospholipid or plasmogen which are essential elements in the brain (9). Myelin loss may result in leukodystrophy as well as the optic nerve dysplasia in infants. Other physiological alterations include increased levels of cerotic and a hexacosenic acid especially in the plasma of very-long-chain fatty acids. Another physiological indicator of a defect in the proximal fatty acid metabolism is the increase in the ratios of C24/C22 and C26/C22 fatty acids (10).

Conclusion

In summary, it is evident from the above discussion...