\u2019<\/em><\/span>).<\/p>\n[\/vc_column_text][\/vc_column][\/vc_row][vc_row el_id=”blog-scroll-point-1″][vc_column][vc_custom_heading text=”What are peroxisomes?”][vc_column_text single_style=””]<\/p>\n
Eukaryotic cells have specialized subcellular organelles<\/strong> that play distinctive roles in cellular metabolism. The membrane structure and the suborganelle content of these structures are unique in order to carry out their different roles. These organelles are essentially the nucleus, endoplasmic reticulum (ER), Golgi apparatus, mitochondria, lysosomes, and peroxisomes<\/strong> (see Figure 1<\/strong>).<\/p>\n[\/vc_column_text][vc_column_text single_style=””]<\/p>\n
Peroxisomes contain enzymes that oxidize<\/strong> <\/em>certain biomolecules normally found in the cell, particularly fatty acids<\/strong> and amino acids<\/strong>. Those oxidation reactions generate hydrogen peroxide (H2<\/sub>O2<\/sub><\/strong>), which is the basis of the name \u201cperoxisome,\u201d a type of microbody (peroxide + soma \u2013 \u201cbody\u2019). However, hydrogen peroxide is potentially toxic to the cell since it has the ability to react with many other biomolecules. As a result, peroxisomes also contain enzymes such as catalase<\/strong> <\/em>that convert hydrogen peroxide to water (H2<\/sub>O<\/strong>) and oxygen (O2<\/sub><\/strong>), thus neutralizing the toxicity. In that way peroxisomes provide a safe compartment for the oxidative metabolism of certain biomolecules.<\/p>\n[\/vc_column_text][vc_column_text single_style=””]<\/p>\n
In order to better appreciate these inborn errors of metabolisms<\/strong> (IEMs) causing peroxisomal diseases, it is essential to gain knowledge of the function and cell biology of peroxisomes. Peroxisomes are cell organelles that consist of a protein-rich matrix surrounded by a single membrane; and were discovered by Belgian biochemist Christian de Duve in 1965, 10 years after he discovered lysosomes<\/em><\/span> [1].<\/p>\n[\/vc_column_text][vc_column_text single_style=””]<\/p>\n
Current knowledge dictates that the mechanism of peroxisome biogenesis involves the following essential features (see Figure 2<\/strong>) [2, 3]:<\/p>\n\n- Peroxisomes are not autonomously multiplying organelles but are derived from the endoplasmic reticulum (ER);<\/strong><\/li>\n
- All peroxisomal proteins, including peroxisomal matrix <\/strong>and membrane proteins,<\/strong> are encoded by the nuclear genome and synthesized on free polyribosomes;<\/li>\n
- The newly synthesized proteins are post-translationally imported from the cytosol into preexisting peroxisomes; and<\/li>\n
- Import of new peroxisomal proteins into peroxisomes leads to an expansion of the size of peroxisomes, which makes them grow until a critical size is attained.<\/li>\n<\/ul>\n
Subsequently, the peroxisomes divide into two daughter peroxisomes<\/strong> that can then undergo the same cycle of events.[\/vc_column_text][\/vc_column][\/vc_row][vc_row][vc_column][vc_single_image image=”5623″ img_size=”full”][vc_column_text single_style=””]<\/p>\nFigure 2. Mechanism of Peroxisome Biogenesis<\/strong>. Schematic illustrating the mechanism of peroxisome biogenesis. Current knowledge dictates that peroxisome can originate from pre-existing peroxisome<\/strong> by division of one peroxisome into two daughter cells but can also be derived de novo<\/em> from the endoplasmic reticulum (ER)<\/strong> in the form of a pre-peroxisome. They subsequently develop into mature, metabolically active peroxisomes through the subsequent import of peroxisomal membrane proteins<\/em> (PMPs)<\/strong>, followed by the uptake of peroxisomal matrix proteins<\/strong><\/em>, containing either a PTS1 or PTS2 signal<\/strong>. The division of peroxisomes involves three distinct sequential steps: elongation of peroxisomes, membrane construction, and fission of peroxisomes.<\/p>\n[\/vc_column_text][\/vc_column][\/vc_row][vc_row el_id=”blog-scroll-point-2″][vc_column][vc_custom_heading text=”Metabolic and Molecular Bases of Peroxisomal Disorders” el_id=”blog-scroll-point-2″][vc_column_text single_style=””]<\/p>\n
Peroxisomes contain more than 50 different matrix enzymes<\/strong><\/em> that are essential for various anabolic and catabolic processes.<\/strong> In contrast to lysosomes, which are rich in enzymes that require an acidic environment, peroxisomal enzymes are most efficient in the oxidative surroundings.<\/p>\n[\/vc_column_text][vc_column_text single_style=””]<\/p>\n
Peroxisomes are found in all human cells, except in erythrocytes (RBCs)<\/strong>. Depending upon their tissue type, their number in a human cell varies considerably from about 100 to 1,000<\/strong>. The highest numbers may be found in hepatocytes (liver cells) and kidney tubular cells, where peroxisomes are involved in the synthesis of bile acids and in detoxification processes (see Figure 3, 4<\/strong>).<\/p>\n[\/vc_column_text][vc_column_text single_style=””]<\/p>\n
Most crucially, in the brain<\/strong>, peroxisomes have a critical role in the generation of intermediate of complex lipids that are incorporated into myelin, as well as in the synthesis of docosahexaenoic acid (DHA), an omega-3 fatty acid<\/strong> that is a primary structural component of the cerebral cortex. Consequently, the altered function of peroxisomes in the brain invariably leads to severe neurological disorders [4].<\/p>\n[\/vc_column_text][vc_column_text single_style=””]<\/p>\n
All peroxisomal proteins, including membrane proteins and enzymes, are nuclearly encoded and synthesized in the cytosol and then imported into peroxisomes. The peroxisomal enzymes are transported into the peroxisomes by peroxins<\/strong>, which are encoded by PEX<\/strong><\/em> genes. In humans, there are at least 16 PEX<\/em> genes identified, thus far. Mutations in PEX<\/em> genes lead to absent or empty peroxisomes resulting in peroxisomal dysfunction. These are collectively known as peroxisomal biogenesis disorders (PBDs)<\/strong>.<\/p>\n[\/vc_column_text][vc_single_image image=”5619″ img_size=”full”][vc_column_text single_style=””]<\/p>\n
Figure 3. Functions of Peroxisomes and Related Disorders.<\/strong> Peroxisomes catalyze a number of essential metabolic functions. The most important, at least in human beings, are: (i)<\/strong> fatty acid \u03b1-oxidation; (ii)<\/strong> fatty acid \u03b2-oxidation; (iii)<\/strong> etherphospholipid biosynthesis; (iv)<\/strong> glyoxylate detoxification, and (v)<\/strong> hydrogen peroxide (H2<\/sub>O2<\/sub><\/strong>) metabolism. Based on the extent of the inherited deficit, peroxisomal disorders can be divided into: (a)<\/strong> the peroxisomal biogenesis disorders (PBDs)<\/strong><\/em>, where all peroxisomal functions are altered, and (b)<\/strong> the single<\/strong> <\/em>peroxisomal enzyme deficiencies (PEDs)<\/em>,<\/strong> with dysfunction of a single enzyme or transporter. [FA, fatty acid; VLCFA, very long-chain fatty acids; ROS, reactive oxygen species; G3P, glycerol-3-phosphate; DHAP, dihydroxyacetone phosphate]<\/p>\n[\/vc_column_text][vc_column_text single_style=””]<\/p>\n
Based on the extent of the inherited deficit, peroxisomal disorders can be divided into [5]:<\/p>\n
\n- the peroxisomal biogenesis disorders (PBDs), where all peroxisomal functions are altered,<\/em><\/strong> and<\/li>\n
- the single peroxisomal enzyme deficiencies (PEDs), with dysfunction of a single enzyme or transporter.<\/strong><\/em><\/li>\n<\/ol>\n
[\/vc_column_text][vc_column_text single_style=””]<\/p>\n
Conditions classified as PBDs are, for example:<\/p>\n
\n- Zellweger syndrome (ZS)<\/strong><\/li>\n
- Neonatal adrenoleukodystrophy (NALD)<\/b><\/li>\n
- Infantile Refsum disease (IRD)<\/strong><\/li>\n
- Rhizomelic chondrodysplasia punctata (RCDP)<\/strong> type 1<\/li>\n<\/ol>\n
[\/vc_column_text][vc_column_text single_style=””]<\/p>\n
Currently, ZS, NALD, and IRD are considered to be various clinical manifestations of the same biochemical disorder (also known as Zellweger syndrome spectrum<\/strong>, or PBD-ZSS<\/strong>), with ZS having the most severe disease intensity, with complete absence of peroxisomes and IRD the mildest (see Figure 3, 4<\/strong>).<\/p>\n[\/vc_column_text][vc_column_text single_style=””]<\/p>\n
The single peroxisomal enzyme deficiencies category is further classified according to 5 various affected peroxisomal metabolic pathways:<\/p>\n
\n- Peroxisomal \u03b1-oxidation<\/li>\n
- Peroxisomal \u03b2-oxidation<\/li>\n
- Ether phospholipid synthesis<\/li>\n
- Glyoxylate detoxification<\/li>\n
- Hydrogen peroxide (H2<\/sub>O2<\/sub>) metabolism<\/li>\n<\/ol>\n
[\/vc_column_text][vc_column_text single_style=””]<\/p>\n
The majority of peroxisomal disorders are inherited in an autosomal recessive manner<\/strong><\/em>. The exception is X-linked adrenoleukodystrophy<\/strong><\/em> (due to mutations in the ABCD1 transporter), which is predominantly affecting males, while females are mostly asymptomatic carriers.<\/p>\n[\/vc_column_text][vc_column_text single_style=””]<\/p>\n
In PBDs, severe damage to the central nervous system (CNS) occurs early in utero during the growth phase due to the defect in neuronal migration. Early death and severe form of mental retardation are the consequence in the majority of these cases. Those children who do survive beyond the first year of life manifest, for example:<\/p>\n
\n- dysmorphic facial features,<\/li>\n
- oculomotor dysfunction,<\/li>\n
- motor and speech impairment (athetosis, dystonia, ataxia), and<\/li>\n
- severe neurological developmental delays.<\/li>\n<\/ul>\n
[\/vc_column_text][\/vc_column][\/vc_row][vc_row el_id=”blog-scroll-point-3″][vc_column][vc_custom_heading text=”Main Biochemical Pathways in Peroxisomes”][vc_column_text single_style=””]<\/p>\n
In order to fully grasp the laboratory findings in PBD and peroxisomal enzyme\/transport defects, one should step back and learn the major biochemical pathways compartmentalized in time and space within specific subcellular organelles, especially in peroxisomes.<\/p>\n
[\/vc_column_text][vc_column_text single_style=””]<\/p>\n
Peroxisomes play an important role in a number of anabolic and catabolic pathways (see Figure 3, 4<\/strong>).<\/p>\n[\/vc_column_text][vc_column_text single_style=””]<\/p>\n
\n- Catabolic pathways<\/strong> include, for example, beta-oxidation and alpha-oxidation of fatty acids.<\/li>\n
- Anabolic pathways<\/strong> involve, for instance, biosynthesis of bile acids and plasmalogen, which can protect cells from reactive oxygen species (ROS)<\/strong> and are found mostly in nervous, cardiovascular, and immune systems.<\/li>\n
- As well as the presqualene segment of the cholesterol\/isoprenoid biosynthetic pathways<\/strong> also occurs in peroxisomes.<\/li>\n
- Finally, as its name suggests, peroxisomes are an important organelle, especially in liver, for detoxification of various toxic molecules including alcohol<\/strong> through peroxidation reaction.<\/li>\n<\/ul>\n
[\/vc_column_text][vc_single_image image=”5620″ img_size=”full”][vc_column_text single_style=””]<\/p>\n
Figure 4. Main Functions of Peroxisomes in Humans. (i)<\/strong> Fatty acid alpha-oxidation; (ii)<\/strong> fatty acid beta-oxidation; (iii)<\/strong> etherphospholipids (plasmalogen) biosynthesis, and (iv)<\/strong> glyoxylate detoxification.<\/p>\n[\/vc_column_text][\/vc_column][\/vc_row][vc_row el_id=”blog-scroll-point-4″][vc_column][vc_custom_heading text=”Fatty Acid \u03b2-Oxidation”][vc_column_text single_style=””]<\/p>\n
\n- Peroxisomal enzymes for beta-oxidation overlap in function with those in mitochondria<\/strong><\/em> besides their selectivity for different lengths of fatty acids\u00a0 \u00a0 \u00a0 \u00a0 \u00a0 \u00a0 \u00a0 \u00a0 \u00a0 \u00a0 \u00a0 \u00a0 (see Figure 3, 4<\/strong>).<\/li>\n
- Peroxisomal enzymes oxidize very long-chain fatty acids<\/strong><\/em> (VLCFA)<\/strong>, that is those\u00a0 \u00a0 \u00a0 \u00a0 22-26 carbons in length, to medium-chain fatty acids<\/strong><\/em>, which are then transported to the mitochondria for further complete oxidation to CO2<\/sub> and H2<\/sub>O.<\/li>\n
- \u03b2-oxidation in the peroxisomes is also important for pristanic acid metabolism<\/strong><\/em>, which is the product generated after \u03b1-oxidation of phytanic acid<\/strong><\/em>, a branched-chain amino acid commonly found in the diet though the consumption of dairy products and fats from ruminant animals, for example, goats, sheep, cattle, as well as certain fish.<\/strong><\/em><\/li>\n
- Consequently, any defect in peroxisomal \u03b2-oxidation, either due to PBD or single gene abnormalities, characteristically manifests with elevated VLCFA and phytanic acid<\/strong><\/em>.<\/li>\n
- For example, X-linked adrenoleukodystrophy (X-ALD)<\/strong><\/em> is the most prevalent peroxisomal disorder. It affects \u03b2-oxidation of VLCFA due to the defective transport of these fatty acids into the peroxisomes because of mutations in the ABCD1 transporter gene.<\/li>\n
- In X-ALD, the accumulation of VLCFAs may potentially be toxic to the adrenal cortex and myelin by triggering inflammatory response in the brain inducing demyelination, i.e., breakdown of myelin.<\/li>\n<\/ul>\n
[\/vc_column_text][\/vc_column][\/vc_row][vc_row el_id=”blog-scroll-point-5″][vc_column][vc_custom_heading text=”Fatty Acid \u03b1-Oxidation”][vc_column_text single_style=””]<\/p>\n
\n- Phytanic acid<\/strong><\/em>, the most notorious branched-chain fatty acid, cannot be metabolized by \u03b2-oxidation as it has a methyl group at the \u03b2-position (viz., C-3). Rather, it first undergoes alpha-oxidation to remove the terminal carboxyl group as CO2<\/sub> (see Figure 3, 4<\/strong>).<\/li>\n
- Once pristane<\/strong> <\/em>is formed by \u03b1-oxidation, it goes through the \u03b2-oxidation.<\/li>\n
- The key enzyme in \u03b1-oxidation is phytanoyl-CoA hydroxylase<\/strong><\/em>.<\/li>\n
- For example<\/strong>, in adult Refsum disease<\/strong><\/em> the phytanoyl-CoA hydroxylase is deficient, leading to accumulation of phytanic acid.<\/li>\n
- Refsum disease can be successfully treated with diet by avoiding consumption of dairy-related products, and likewise fats from ruminant animals, which contains phytanic acid.<\/li>\n
- Refsum disease if left untreated, eventually will manifest as retinitis pigmentosa, cerebellar ataxia, and neuropathy.<\/li>\n<\/ul>\n
[\/vc_column_text][\/vc_column][\/vc_row][vc_row el_id=”blog-scroll-point-6″][vc_column][vc_custom_heading text=”Zellweger Syndrome (ZS)\/
\nNeonatal Adrenoleukodystrophy (NALD)\/
\nInfantile Refsum Disease (IRD)”][vc_column_text single_style=””]<\/p>\n
These group of disorders are 3 expressions of a disease continuum, from most (ZS) to least <\/span> (IRD) severe. The responsible genetic defect occurs in 1 of at least 12 genes<\/strong><\/em> that are involved in peroxisomal formation or protein import, the so-called PEX gene family<\/em>[2, 6]. <\/span><\/strong><\/p>\n[\/vc_column_text][vc_column_text single_style=””]<\/p>\n
Clinical manifestations include hypotonia, poor feeding, facial dysmorphism (distinctive facies), brain malformations, demyelination, neonatal seizures, hepatosplenomegaly, cystic kidneys, cholestasis, and hepatic dysfunction, short limbs with stippled epiphyses (chondrodysplasia punctata), cataracts, retinopathy, hearing deficit, psychomotor delay, and peripheral neuropathy.<\/p>\n
[\/vc_column_text][vc_column_text single_style=””]<\/p>\n
Diagnosis is suspected when elevated blood levels of very-long-chain and branched-chain fatty acids, phytanic acid, bile acid intermediates, and pipecolic acid are detected (see Figure 5<\/strong>). Fasting serum analysis by gas chromatography-mass spectrometry (GC-MS) is essential. Findings, such as elevation of C26:0 and C26:1<\/strong> and the increased ratios C24:C22 and C26\/C22<\/strong> are consistent with a defect in peroxisomal fatty acid metabolism. This is the most informative initial screen. The diagnosis of Zellweger disorder spectrum is positively established after molecular genetic testing of PEX<\/em> genes<\/strong>. Additionally, functional testing in fibroblasts<\/strong> may also be used to confirm molecular and biochemical results<\/span>.<\/p>\n[\/vc_column_text][vc_column_text single_style=””]<\/p>\n
There is currently no specific treatment protocols for these disorders. Management is primarily symptomatic.<\/p>\n
[\/vc_column_text][\/vc_column][\/vc_row][vc_row el_id=”blog-scroll-point-7″][vc_column][vc_custom_heading text=”Rhizomelic Chondrodysplasia Punctata (RCDP)”][vc_column_text single_style=””]<\/p>\n
This disorder of peroxisomal biogenesis is caused by PEX7 gene mutations<\/em><\/strong> and characterized by skeletal changes that include strikingly proximal limbs (dwarfism), midface hypoplasia, frontal bossing, small nares. Vertebral clefts are also common. As well as cataracts, ichthyosis, and profound psychomotor retardation.<\/p>\n[\/vc_column_text][vc_column_text single_style=””]<\/p>\n
Diagnosis of RCDP is suspected by x-ray findings, elevation of serum phytanic acid, and low RBC plasmalogen levels; VLCFA levels are normal. Confirmation by genetic testing. There is no specific treatment of RCDP, the extent of affected vital organs and heavy disease burden significantly impact the life expectancy of patients with RCDP and cause substantial death rates even at neonatal age.<\/strong><\/em><\/p>\n[\/vc_column_text][\/vc_column][\/vc_row][vc_row el_id=”blog-scroll-point-8″][vc_column][vc_custom_heading text=”X-Linked Adrenoleukodystrophy (X-ALD)”][vc_column_text single_style=””]<\/p>\n
X-ALD is the most common single peroxisomal disorder, with a minimum incidence of\u00a0 \u00a0 \u00a0 1 in 21,000<\/strong> males in the United States and 1 in 15,000<\/strong> males in France. This disorder is caused by deficiency of the peroxisomal membrane transporter ALDP<\/strong>, which is coded for by the gene ABCD1<\/strong><\/em>. This is an X-linked gene and thus the disorder manifests primarily in males. So far, greater than 900 mutations have been identified.<\/strong><\/em><\/p>\n