[References]

The Peroxisomal Disorders

DISCLAIMER: The purpose of this page is to sketch, in a general and non-technical manner, the current state of knowledge on the nature and functions of the peroxisome, and the diseases resulting from peroxisomal dysfunction. This information is drawn from a range of medical literature, and is intended to reflect areas in which there is prevailing consensus of opinion. It is believed that the concepts and models discussed represent the best available, and most widely accepted, understanding of the subject.
The author of this page has no medical background and the content is targeted toward a similar readership, typically the parents of affected children. I hope that it may also be of some benefit to health care workers who are not specialists in the field and other professionals working with these children.
HOWEVER, it is hereby expressly stated that the following discussion is NOT to be considered medical advice, or as having any particular relevance to any particular case, or as representing all possible schools of thought. In particular, the subjects of therapy and diet are not within its scope, except in passing mention.
IT'S REAL SIMPLE: If you need medical advice you need to be consulting with a physician. Go. Now. We'll still be here.

OVERVIEW
    The peroxisome is one of several types of organelles present in almost all eukaryotic cells (cells having a nucleus), both plant and animal, an organelle being a specialized structure within a cell where particular chemical and metabolic functions take place. Close metabolic interrelationships exist between the peroxisomes and the other organelles of the cell, the chemical result of one organelle's process often being the raw material of the next. The precise means by which these transports occur is not fully understood; it is surmised from the chemistry involved, but usually not accessible to direct observation. This is true for much of the understanding of the peroxisomes.
    A peroxisome is a round or oval body with an average diameter of 0.5 micron. A cell will contain not one, or even several, peroxisomes but possibly several hundred. The peroxisome is bound by a membrane composed of lipids and proteins, and its interior (called the matrix) is made up of various proteins which function as enzymes in metabolic processes.
    Peroxisomes are especially abundant, and larger in size, in the cells that make up the liver and kidneys of humans and other mammals. Although all peroxisomes are biochemically active, those in liver and kidney perform the majority of peroxisomal function. In a developing fetus and (in humans) for a few weeks after birth, peroxisomes are also abundant in the oligodendrocytes, the cells which surround the developing central nervous system, act to guide its growth, and synthesize the myelin sheath which insulates it.
    The peroxisome was "discovered" in 1954 by a doctor named Rhodin, and over the next ten years some of its more basic functions were determined. This was in large part the work of another doctor named de Duve. The name peroxisome derives from the early observation of the role of this organelle in cellular respiration, a process involving both the generation and decomposition of hydrogen peroxide. Catalase, the enzyme which breaks down hydrogen peroxide, is the necessary identifying marker of the peroxisome: by definition, a peroxisome must contain it and a subcellular structure not containing catalase is not considered a peroxisome.
    It is now known that approximately fifty different biochemical reactions occur entirely or partially within the peroxisome. Some of the processes are anabolic, meaning constructive, and lead to the synthesis of essential biochemicals: bile acids, cholesterol, ether-phospholipids (plasmologens), and docosahexaenoic acid. Some of the processes are catabolic, meaning destructive, and lead to the decomposition of certain fatty acids, particularly very long chain fatty acids (VLCFAs) and others such as phytanic acid, pipecolic acid, and the prostaglandins. Most of these processes involve coordinated interactions between the peroxisomes and other organelles, and each metabolic step is dependent upon the successful completion of the previous. For example, the decomposition of the VCLFAs and phytanic acid is a process shared by the peroxisomes and the mitochondria, the correct functioning of the peroxisomal steps being essential to the overall success of the process. Likewise, the final steps in the synthesis of the plasmologens occur in the endoplasmic reticulum, but the process depends on precursors which are synthesized in the peroxisomes.

PEROXISOMAL BIOGENESIS
     A peroxisome doesn't last very long. Its "life span" is just a day or two, so there has to be a constant process of replacement, the formation of new peroxisomes. This process, referred to as peroxisomal biogenesis or peroxisomal assembly, goes like this:
1) The proteins which will make up the peroxisome's membrane and matrix are synthesized by free ribosomes, another type of organelle. The ribosome is the site at which messenger RNA, bringing genetic information from the DNA in the cell nucleus, is translated into the variety of proteins which make up the cell and its organelles. (Some organelles, notably the mitochondria, also contain their own DNA and ability to synthesize some proteins internally. This has led to the hypothesis that the mitochondria (and possibly also the peroxisomes, which however do not contain their own DNA) were originally independent life forms that have evolved into a complex symbiosis with their host, the cell. At any rate, the vast majority of the proteins necessary to the cell and its organelles are synthesized on the ribosomes from nuclear genetic coding.)
2) The completed proteins enter the cytosol, which is (roughly speaking) that portion of the cell's interior that isn't either the nucleus or an organelle.
3) From the cytosol, the peroxisomal membrane and matrix proteins are imported into pre-existing peroxisomes, which exist either singly or in a network called a peroxisomal reticulum. These expand with the upload of the new material and at a certain point new peroxisomes are formed either by division or budding from the reticulum.
    The various proteins are directed to their correct positions in the peroxisome - either incorporated into the membrane or passing through it into the matrix - by means of peroxisomal targeting signals (PTSs). A PTS is a sequence of amino acids usually at or near an end of the protein, synthesized along with it on the ribosome. This sequence is not properly a part of the actual protein but is a tag essentially identifying it to a second protein known as a PTS receptor. A PTS receptor is a mobile protein which repeatedly shuttles between the cytsol - recognizing and binding the PTS protein - and the peroxisome, separating from it and leaving it for import.
     About half of the peroxisomal matrix proteins are identified by a sequence known as PTS1 (SKL, serine-lysine-leucine, or certain variants), and several more by a sequence known as PTS2, occuring at opposite ends of the protein. There are also proteins which have both the PTS1 and PTS2. Other known matrix proteins have neither the PTS1 nor the PTS2, so it is assumed that there must also be a PTS3 and possibly others, trickier to identify as they don't occur at the ends of the protein, but internally. The proteins which are components of the peroxisomal membrane (integral membrane proteins, IMP) also have a type of internal PTS.
     The receptors for PTS1 and PTS2 have been closely studied, both the functioning proteins and the genes which code for them. Their role in peroxisome biogenesis is well-understood, and there is known correlation between mutuations of these genes and some of the peroxisomal diseases, the biogenesis disorders.
     There are about fifteen other proteins known to be necessary to the correct assembly of a peroxisome. For the most part the genes which code for them have been identified, although the exact function of the protein may be only more or less understood. In addition to the PTS1 and PTS2 receptors (and presumably the PTS3 receptor not yet identified), there are proteins known as chaperones (heat shock proteins) which go along for the shuttle ride and somehow mediate between the PTS-protein and the PTS-receptor. Others known as gatekeepers are possibly involved in the separation of the protein from the receptor. There are integral membrane proteins which serve as the docking sites for the receptors and their cargos, and
also as the passageways by which the proteins enter the matrix. There are proteins which regulate the numbers of peroxisomes within a cell, and still others which regulate the distribution of peroxisomes at the time of cell division.
      Collectively, these proteins - the ones involved in peroxisome biogenesis, as distinct from the matrix enzyme proteins involved in peroxisomal function - are known as peroxins. These proteins, and the genes which code for them, are known by the acronym PEX and they are numbered PEX1, PEX2, &c. in the order of their original published descriptions. For instance, PEX5 is the gene which codes for the PTS1 receptor, and PEX7 is the gene which codes for the PTS2 receptor. By no means is the nuts and bolts operation of the targeting signals and the peroxins completely understood or agreed upon. Much of it is downright mysterious. But aside from a number of technical questions (as, for example, whether the receptors uncouple from their proteins at the peroxisome's surface or if this happens in the peroxisome's interior) which are under specialized and on-going investigation, the basic model of peroxisome assembly is pretty much accepted. Much of this knowledge has been gained by the study of certain yeasts. There is an almost complete genetic and chemical identity between peroxisome assembly in these yeasts and in humans, so that understanding the gene mutations in the yeast peroxins is directly applicable to understanding the human peroxisome biogenesis disorders.

PEROXISOMAL DISORDERS
Depending on who's doing the counting, there are about 16 or 17 peroxisomal disorders currently known, with a few more suspected or under investigation. They are typically thought of as falling into one of three groups; peroxisome biogenesis disorders (PBDs), peroxisomal multi-enzyme disorders, and peroxisomal single-enzyme disorders. This is a biochemical classification; a patient's cells are cultured and observed for particular enzymatic activity, a patient's blood is analyzed for the presence or lack of particular biochemicals associated with known peroxisomal functions, and compared against a norm, these types of measurements help to indicate specific defects of peroxisomal function. Diagnosis is aided (but not fully determined) by this identification of specific biochemical defects.
The biochemical classification has been customary since the early 1980s, when the peroxisomal disorders were first being recognized and described. It is the basis of most subsequent diagnosis and casework. It does have its limitations, mainly in that the existence of a particular biochemical abnormality doesn't always correlate neatly with a particular patient or that patients with entirely different biochemical abnormalities may be clinically similar. As identification of the gene mutations which cause the peroxisomal disorders proceeds, it becomes possible that eventually they will all be classified genetically, rather than chemically.

Peroxisome Biogenesis Disorders (PBDs)
These are also variously referred to as the peroxisome assembly disorders, the generalized peroxisomal disorders, or the peroxisomal polydystrophy syndromes.

Cerebro-hepatic-renal (Zellweger) syndrome (ZS) (ZWS1)
     ZWS1 [MIM No. 214100]
     ZWS2 [MIM No. 170995]
     ZWS3 [MIM No. 170993]
Neonatal adrenoleukodystrophy (NALD) [MIM No. 202370]
Infantile Refsum disease (IRD) [MIM No.266510]

    The peroxisome biogenesis disorders (PBDs) are diseases in which the entire process of peroxisomal assembly has malfunctioned, and nearly all normal peroxisomal functions are either absent or deficient. Sometimes, this means that the peroxisomes themselves fail to form, or fail to form in sufficient numbers; other times "ghost peroxisomes" form, having somewhat the appearance of the real thing, but lacking the matrix enzymes necessary to function.
    ZS, NALD, and IRD have so many features in common - biochemically, genetically, and clinically - that they are typically considered a single continuum of disease, with ZS being the most severe and IRD the least. However, there are also some distinct differences between them. Each has characteristics which set it apart from the others, and the names are not used interchangably.
    Because they all involve the same generalized failure, the PBDs share a common set of biochemical abnormalities: the entire range of peroxisomal functions. Of these, some half dozen or so seem to commonly come up as being particularly relevant to the disease states:
> impaired synthesis of ether-phospholipids (which are molecules that go into making up membranes, especially in the central nervous system, and in the formation of myelin);
> impaired synthesis of docosahexaenoic acid (DHA, a long chain fatty acid which is a component of certain more complex lipids, especially in the membranes of the central nervous system)
> impaired decomposition (oxidation) of very long chain fatty acids (VLCFAs),
    A fatty acid with more than 22 carbon atoms in its chain is called a VLCFA. The peroxisome is involved, along with the mitochondria, in the process of shortening these molecules to a length that either the body can use or is able to rid itself of. When they can't be broken down, they accumulate, especially in the central nervous system. While not toxic in the sense of being poisonous, the accumulation of VLCFAs is disruptive to the structure and stability of the affected cells, for reasons which are not completely understood.
> impaired oxidation of phytanic acid (an unusual fatty acid which also accumulates detrimentally when it isn't broken down)
    There are dozens of others, and the chemistry here is beyond the purpose of this page. For example, the peroxisomes are also involved in the metabolism of alcohol. It is really the complex of abnormalities that define the PBDs, and no single one should be thought of as isolated from the others. And to a large degree, there is uncertainty as to how exactly these abnormalities, or what combination of them, cause the pathology and disability of the PBDs.

   A child with Zellweger syndrome (ZS) has dysmorphic facial features (with high forehead and flat nose bridge, wide-set eyes and low-set ears), and deformed limbs and joints, with calcium deposits in the cartilage. The liver and kidneys are usually diseased or abnormal. There is a fundamental malformation of the brain in the developing fetus (abnormal neuronal migration), and myelination does not proceed completely (hypomyelination). There is usually retinal or other eye disease, and almost always sensorineural (cochlear) hearing loss. The child is hypotonic and prone to epileptic seizures. There is a profound lack of any normal psychomotor development. ZS is fatal early, usually within the first year of life.
   There are known to be at least three different gene defects which can cause ZS: ZWS1, ZWS2, and ZWS3 are the names given to these forms. Only the specific genetic causes are different; outwardly these are all essentially the same.
   Neonatal adrenoleukodystrophy (NALD) has many characteristics in common with ZS, and some distinct differences. The dysmorphic facial features and skeletal abnormalities are less pronounced. There is no calcification of cartilage. There is liver disease, but not the kidney cysts associated with ZS. The adrenal glands are diseased. The neuronal migration defect in the developing brain is not as extensive as in ZS, but there are severe abnormalities of myelination. There is retinal or other eye disease and also sensorineural hearing loss. These children are hypotonic and prone to seizures. Psychomotor development is profoundly affected. NALD is fatal, usually within the first ten years.
   Unlike ZS and IRD, NALD is characterized by a process of active demyelination (deterioration of the existing myelin sheath) and by disease of the adrenal glands. When it was first described, in 1978, it took its name from these two similarities with X-linked adrenoleukodystrophy, being considered a "neonatal" form of it. This was at a time before there was even a concept, let alone systematic classification and study, of the peroxisomal disorders. The actual relation between NALD and ALD was unknown, and the similarity of NALD to ZS was not appreciated.
    Infantile Refsum disease (IRD) has characteristics in common with both ZS and NALD, but relative to them the pathology and abnormalities of IRD are not as devastating. This shouldn't be overstated. A child with IRD is still very sick and has severe physical, sensory, and developmental disabilities. However, with time and patience, IRD children usually attain to some degree of motor, cognitive, and communication skills.
    A child with IRD has dysmorphic facial features, often of great subtlety and not recognized unless pointed out. He is apt to be small for his age, but body and limbs are correctly proportioned. The liver is typically enlarged, and there may be some amount of dysfunction. The adrenal glands are possibly affected. The neuronal migration defect, similar to that of NALD, is not as extensive as in ZS. Myelination is abnormal, but there is no active demyelination. There is almost always retinal or other eye disease, and generally sensorineural hearing loss. In IRD, the child is usually born hearing and the loss occurs sometime between six months and a year of age. A child with IRD is probably going to be hypotonic, though not always severely. IRD is sometimes associated with seizure disorders, but not typically. Psychomotor development is severely affected, but is by no means arrested. IRD is also fatal, but survival into the teens and twenties and even beyond is known.
    In some cases, infants with IRD will undergo spontaneous bleeding episodes, in particular intercranial hemorrhage. This may be due to a liver dysfunction that interferes with the synthesis of vitamin K. If the child survives this, the resulting brain injury is an unknown and complicating factor in his development. Its effects, if any, can hardly be distinguished against the backdrop of the IRD. The brain injury may possibly result in a seizure disorder which otherwise would have been absent.
   IRD was originally called infantile phytanic acid storage disease, the first described cases (1982) noting this specific biochemical abnormality. Since the one disease at that time known to be associated with abnormal levels of phytanic acid was Refsum disease, these cases were considered to be an "infantile" form of it. The similarities of the two were noted (especially in the eye disease), but the number of differences between them were striking, and IRD and Refsum disease were always understood to be two separate entities. As with NALD, this was at a time when there was no study or classification of peroxisomal disorders. Within a couple of years the true position of IRD in relation to ZS and NALD, and in relation to Refsum disease, was pretty much established. But as with NALD, the name stuck.
   NALD and IRD are names that sometimes can lead to confusion, historical curiousities that don't reflect their true identities. On the other hand, there are sufficient distinctions between ZS, NALD and IRD to warrant having three names, and these are as good as any. Probably they're with us for a while.
   Accepting these distinctions, there is still a great deal of overlap between ZS, NALD, and IRD. An abnormality typical to one may show up in another, or itself be absent. It is a continuous and dynamic spectrum, from the most profoundly involved child with ZS to a teenager with IRD who bowls in Special Olympics. Since the common defect of the PBDs is known, it seems logical to speculate that the spectrum of disease is reflective of a corresponding spectrum of peroxisome biogenesis failure, that in the most severe cases of ZS the failure is nearly complete and that in IRD some manage to form and carry on (thought to possibly be what's going on with the ghost peroxisomes), or in some other way peroxisomal functions are partially carried out. There is some evidence for this being the case, and it does seem a natural way of understanding it. Beyond this there is as yet no resolved picture. The actual steps from defective genes to defective peroxisomes, from abnormal biochemistry to the disease states, are not fully understood.
    Hyperpipecolic acidemia [MIM No. 239400] was another disease described before there was a study of peroxisomal disorders, and was named for the observed high levels of pipecolic acid in the patients. This was a name that didn't stick. The described cases are thought to be indistinguishable from either NALD or IRD, and the term hyperpipecolic acidemia was eventually considered unnecessary.
     There is at least one described case referred to as pseudo-IRD. This was considered to be a PBD, as catalase-containing peroxisomes did not exist. There were, however, peroxisome-like structures which did contain some peroxisomal matrix proteins, and in which some processes did continue almost normally.

The peroxisome biogenesis disorders are autosomal recessive. They occur in all countries and among all races and ethnic groups. They are diseases of extreme rarity, but any discussion of just how rare immediately falters. Estimates of birth frequencies vary from 1:30,000 to 1:150,000, but the level of conjecture is high. Consistent and reliable census data is itself the rarity.
There is no cure. In general, what therapies do exist are dietary: for example, attempting to limit the intake of VLCFAs and/or phytanic acid, or supplementing the diet with DHA or anti-oxidant vitamins. The theory here is that the pathology and disabilities of these diseases are caused by the biochemical abnormalities (even without always understanding just how) and that therefore they can possibly be alleviated by artificially correcting those abnormalities. This is a reasonable line of thought, and dietary therapies of various kinds are widely practiced. On the other hand, some doctors hold that since the peroxisome dysfunction is global and involves so many different abnormalities (in relations that aren't even fully known) the overall complex is beyond this sort of correction. Consistent, controlled, long-term studies of the effects of dietary limitation and/or supplementation are non-existent. Nor would there be any medical consensus on what that diet should be anyway. Commonly, seizure disorders are treated with anti-convulsants, and IRD children with the bleeding disorder take vitamin K to control it.

Peroxisomal Multi-Enzyme Disorders

These are diseases in which several of the proteins necessary to peroxisomal function are lacking, but there is not a global loss of function as in the PBDs. Because it contains catalase, the peroxisome itself is considered intact, and not the result of a general assembly failure.
However, this classification is not universally used and sometimes these diseases are counted among the PBDs (i.e., resulting from mutation of peroxin genes). Considered this way, the peroxisome biogenesis disorders fall into four groups (and include RCDP):
- failure or deficiency in import of PTS1 only (ZS, NALD)
- failure or deficiency in import of PTS2 only (RCDP)
- failure or deficiency in import of both PTS1 and PTS2 (ZS, NALD, IRD)
- failure or deficiency in the peroxins necessary to biogenesis of the peroxisomal membrane, also in the import of both PTS1
and PTS2 (ZS, NALD, IRD)

Rhizomelic chondrodysplasia punctata (RCDP) [MIM No. 215100]
Zellweger-like syndrome

    RCDP involves defects of three or four specific enzymes in otherwise apparently intact and functioning peroxisomes. These dysfunctions result in the impaired synthesis of ether-phospholipids, the malformation of an enzyme necessary to liver function, and the impaired oxidation with subsequent accumulation of phytanic acid. RCDP is recognized by this particular set of abnormalities. Chondrodysplasia punctata is a broader term, including other disorders which are not peroxisomal, or not definitely determined to be (e.g. Conradi-Hunnermann syndrome). RCDP is the most severe of these; the term is reserved for the peroxisomal disorder.
    RCDP is characterized by certain skeletal abnormalities from which it derives its name, a dwarfism marked by a disproportionate shortening of the upper limbs (rhizomelia), and abnormalities in the formation of cartilage (chondrodysplasia punctata, specifically an abnormal calcification of cartilage). The child's head and face are dysmorphic, cataracts are typical but not other eye disease. Her psychomotor development is severely affected. Unlike the PBDs, RCDP is not associated with neuronal migration defects or with abnormalities of myelination. At its most severe, RCDP is fatal within the first year; however survival into the teens is known.
    To somewhat complicate the nomenclature there are also several described cases in which RCDP is not associated with rhizomelia. This non-rhizomelic (yet peroxisomal) CDP is genetically and biochemically identical to RCDP, and is understood to be a less severe form of it, not a separate disorder.
    Zellweger-like syndrome is known by only one (possibly two) described case(s), both fatal in infancy. As is evident from the name, it was similar in appearance to ZS, but was determined to be a defect of three particular enzymes and not a general loss of peroxisome function.

Peroxisomal Single-Enzyme Disorders

    These are disorders in which the peroxisome is intact and functioning, except that there is a defect in just one enzymatic process, resulting in just one primary biochemical abnormality. It doesn't necessarily follow that these diseases are any less severe than the PBDs; the loss of even a single peroxisome function is sufficient to cause disease that can closely mimic the PBDs and is every bit as severe.
    The identification of the single-enzyme disorders is ongoing. There are differences of opinion between researchers regarding the inclusion of some and/or the true nature of the defects.
    With the exception of X-ALD, all of these disorders are autosomal recessive.

X-linked adrenoleukodystrophy (X-ALD); adrenomyeloneuropathy (AMN)
[MIM No. 300100]
Peroxisomal thiolase deficiency (pseudo-Zellweger syndrome)
[MIM No. 261510]
Acyl-CoA oxidase deficiency (pseudo-NALD) [MIM No. 264470]
Bifunctional protein deficiency (sometimes this is also called
pseudo-NALD, but it is definitely distinguished from the previous)
[MIM No.261515]
DHAP-AT deficiency (pseudo-RCDP) [MIM No. 222765]
Alkyl DHAP synthase deficiency (pseudo-RCDP)
Glutaryl CoA oxidase deficiency
Mevalonate kinase deficiency
Hyperoxaluria type I (PH1) [MIM No. 259900]
Acatalasemia [MIM No. 115500]
Refsum disease (also called adult-onset or classical Refsum disease)
[MIM No.266500]

    X-ALD involves a deficiency in one of the enzymes necessary to the oxidation of the VLCFAs, which subsequently accumulate, especially in myelin and the adrenal glands. X-ALD is characterized by demyelination of the central nervous system and by disease of the adrenal glands. There are six forms (phenotypes) generally recognized, distinguished by age of onset and differences in symptoms and course: childhood cerebral, adolescent cerebral, adult cerebral, adrenomyeloneuropathy, Addison only (which affects only the adrenal glands and not the myelin, although the reason for this isn't known), and asymptomatic (or presymptomatic).
    X-ALD, by far the most common of the peroxisomal disorders, was known and studied for years before it was understood to be a peroxisomal disorder. There is extensive documentation of this disease and the various forms that it takes. It is a study in itself and there's nothing to be added here.
    Pseudo-ZS and the two forms of pseudo-NALD each involve single deficiencies of three other enzymes necessary to the oxidation of VLCFAs. In each of them the accumulation of VLCFAs is the only (or primary) biochemical abnormality, although (as is evident from the names) they are clinically similar to the PBDs. It isn't known why this single abnormality is capable of causing such similarity. Nor is it known why X-ALD is clinically so entirely different from them, even though it also is a single-enzyme deficiency of VLCFA oxidation. It might be noted that pseudo-ZS (peroxisomal thiolase deficiency) is described from one known case.
    The two forms of pseudo-RCDP each involve single deficiencies of two enzymes necessary to the synthesis of ether-phospholipids. In each of them this impairment is the only biochemical abnormality, although clinically the diseases resemble RCDP. There is one described case each, both fatal in infancy. The DHAP-AT deficiency is also reported in cases in which there is no rhizomelia, but are otherwise indistingushable from this form of pseudo-RCDP.
    Glutaryl CoA oxidase is a peroxisome enzyme necessary to the oxidation of glutaric acid. Deficiency of the enzyme leads to accumulation of this acid, a condition known as glutaric aciduria. Type 1 and type 2 are mitochondrial disorders caused by similar deficiencies. The peroxisome enzyme deficiency represents a third type; its description is based on one known case.
    A kinase is an enzyme that converts a protein into an enzyme. Mevalonate kinase in the peroxisome is involved in one of the initial steps in the synthesis of isoprenoids (cholesterol, steroids, and related substances). Mevalonate kinase deficiency results in the impairment of this synthesis. Clinically, it has characteristics resembling other peroxisomal disorders: facial dysmorphia, enlargement of liver and spleen, cataracts, hypotonia, and profound developmental delay. It is also associated with disease of the lymph nodes, anemia, and malabsorption of fats. At its most severe it is fatal in infancy, although all patients are not affected the same by this deficiency and it does take somewhat milder forms.
    Hyperoxaluria type I (PH1) results from a deficiency in a peroxisome enzyme involved in the metabolism of glyoxylate, the end result of the dysfunction being the abnormal accumulation of calcium oxalate crystals in various organs and tissue. PH1 is associated with kidney disease, kidney and urinary tract stones, hydrocephaly, some types of eye disease, malformation of bones, and abnormal skin pigmentation. (PH2 is a similar disorder of glyoxylate metabolism, although less severe. It is not a peroxisomal disorder, being a deficiency in an enzyme normally at work in the cytosol.)
    Acatalasemia is a deficiency in the enzyme catalase, by which hydrogen peroxide (itself a product of the peroxisomal oxidation of fatty acids) is decomposed to oxygen and water. An accumulation of hydrogen peroxide would rapidly kill the cell and this decomposition is essential to its viability. The term specifically applies to the absence of the enzyme in the peroxisome, which is its proper location. The disorder itself is generally quite benign, which points to the fact that even though the enzyme is absent from the peroxisome, the process itself is taking place somewhere else in the cell. This is also the case with the PBDs.
    Refsum disease is a progressive disease of the central nervous system. It is almost always associated with retinal or other eye disease (especially retinitis pigmentosa) and various neurologic abnormalities, and often with sensorineural hearing loss, heart arrhythmia due to the nerve dysfunction, and abnormalities of bone, cartilage, and skin. The first signs of Refsum disease, typically the progressive eye disease and ataxia (irregular and imprecise motor control), are usually not apparent until the teens or twenties. Its full progression may take another twenty or thirty years.
    Refsum disease is characterized by an impairment in the oxidation of phytanic acid and its subsequent accumulation in organs and the nervous system. The oxidation of phytanic acid is a process in which both the peroxisomes and the mitochondria take part. The classification of Refsum disease is a technical question of localizing the defective step to one or the other, and there is apparently not universal agreement that it is a peroxisomal disorder.
    As with most of the biochemical abnormalities present in the peroxisomal disorders, it is not understood precisely why the accumulation of phytanic acid leads to the pathologies of Refsum disease. In Refsum disease the limitation of phytanic acid (or its precursor, phytol) is a widely practiced dietary therapy, and pretty well documented as being effective in controlling some of the disease's progression. There is no particular evidence that such limitation has the same beneficial effect in cases of IRD or the other PBDs.

A note on the leukodystrophies -

Some peroxisomal disorders are leukodystrophies;
some leukodystrophies are peroxisomal disorders.

The generally accepted, and more inclusive, definition of the leukodystrophies is that they are disorders in which there exists some defect in the formation or maintenance of myelin. Sometimes one encounters a narrower definition where only disorders involving active demyelination are considered leukodystrophies.

A note on deafblindness -
The medical literature relating to the peroxisomal disorders does not use the term or concept of deafblindness to describe cases in which there are combined vision and hearing impairments. It is (understandably) not a medical concept, but without it the nature of the disability cannot be understood.

A note on form -
The genetics and chemistry of the peroxisome is incredibly complex, and the subject obviously does not lend itself well to a "general and non-technical" discussion. This paper is intended only as an overview, and took the course of sidestepping the complexities. It needs to be emphasized that these diseases cannot be understood in a vague and oversimplified manner.
In general, I've tried to avoid going out on any limbs, and where the information is sketchy, it is hopefully free of outright error. On this point especially, I would ask anyone reading this who finds error to not hesitate to bring it to my attention, so that appropriate correction can be made.

Acknowledgements -
    Dr Robert Steiner of Oregon Health Sciences University read the manuscript and offered his valuable opinions for change or rewording of some sections. I'm grateful to him for editing this. I'm also especially mindful to state, EXPRESSLY, that Dr Steiner bears no responsibility for any portion of this paper, or any statement made, or any errors of fact. The content of this paper is entirely the responsibility of the author.
    My thanks to Dr Will Pitkin, a professor of English and linguistics at Utah State University (Logan), for reading and editing this manuscript. It was important to get feedback from someone who didn't already know what a peroxisome was, and his suggestions with an aim to clarity have been very helpful. Thanks, Will.
    I'd like to thank Dr Gerald Raymond at Johns Hopkins for the time he has taken, in conversation and correspondence, to play 20 questions. I'd also like to thank Dr Richard Weleber, Casey Eye Institute OHSU, for providing me with a pre-publication draft of his own paper on the peroxisomal disorders and so much helpful explanation over the years.
    And fondest love for Mary, for the interpretation of dreams.

John Harris
jmharr@aracnet.com
26 June, 1998

revised: 08-04-98; 08-27-98; 10-13-98; 02-09-99; 09-27-99; 03-05-00
(Please note: these revision dates refer to revisons in the above text; the date of the most current addition to the following reference materials is reflected by the "Latest Update" at the end of this page.)

Sources and references -

The references and artciles listed here have been placed into broad, general categories as (hopefully) an aid to study and understanding. However, it should be borne in mind that the genetics, assembly, and structure; and the multiple metabolic functions of the peroxisome are in reality an integrated whole, and that the assignment of a reference to one category or another is sometimes entirely arbitrary.

The articles themselves are included for their apparent value as general reference or tutorial. Articles dealing, for instance, with the technical specifics of laboratory methodology, blot analysis, etc. are not typically included; it being felt that such discussions are on a level of detail not important to the general reader. For the most part, the articles were chosen as they relate to human peroxisomes and peroxisome function, as peroxisome function in other animals is not always identical to the human, and it may be potentially misleading to extrapolate from one to the other. However, in many cases animal models provide perfectly good information and such literature has by no means been disregarded. Along the same line, a great deal of understanding has been gained from the study of plant peroxisomes (and the related organelles glyoxysomes) and several articles relating to them have also been included.

By and large, the articles within each category are arranged in descending chronological order, and such arrangement should not be taken to imply the relative importance or validity of the works themselves. It may at times be true that a more recent article will represent an improved understanding on an older one; however this is not always necessarily the case, and some of the older articles on basic peroxisome function (for example, the beta-oxidation of fatty acids) are as valid today as they ever were.

X-linked ALD (including AMN) is a peroxisomal disorder of which there has been considerable study and documentation for many years. Only a very few references regarding it have been included: hopefully just enough to tie into the bigger picture.
The general texts listed at the end are included simply as being representitive. There are of course any number of books on cell biology and biochemistry which may be usefully consulted.

INDEX

PEROXISOMAL DISORDERS
- General
- Neuropathy and Epilepsy
- Neuronal Migration Defects

PEROXISOME FUNCTION AND BIOCHEMISTRY
- General
- Ether-Phospholipid (Plasmalogen) Synthesis
- Cholesterol and Dolichol Synthesis
- Adrenal Steroid Synthesis
- Peroxisomal beta-Oxidation
- beta-Oxidation of Cholesterol (Bile Acid Synthesis)
- Phytanic Acid alpha-Oxidation
- Pipecolic Acid Oxidation (Lysine Metabolism)
- Eicosanoid (Prostanoid and Leukotriene) Oxidation
- Other Peroxisomal Oxidation Processes:
   - General
   - Polyamines (Spermine and Spermidine)
   - D-Amino Acids
   - Purines
- Degradation of Hydrogen Peroxide and Oxygen Free Radicals
- Cell Signalling and Regulation

PEROXISOME STRUCTURE AND ASSEMBLY

GENETICS
- General
- PEX Genes and Peroxins:

PEX1       PEX7
PEX2       PEX8
PEX3       PEX9
PEX4       PEX10
PEX5       PEX11
PEX6       PEX12

PEX13      PEX20
PEX14      PEX21
PEX15      PEX22
PEX16      PEX23
PEX18
PEX19

PEROXISOME BIOGENESIS DISORDERS

- Zellweger syndrome (Cerebro-hepato-renal syndrome) (ZS)
- Neonatal adrenoleukodystrophy (NALD)
- Infantile Refsum disease (IRD)
- Rhizomelic chondrodysplasia punctata (RCDP type1)

- Pipecolic acidemia
- Others, not readily classified

PEROXISOME SINGLE-ENZYME DISORDERS

- Fatty acid beta-oxidation:
- X-linked adrenoleukodystrophy (X-ALD); Adrenomyeloneuropathy (AMN)
- Pseudo-Zellweger syndrome (thiolase deficiency)
- Pseudo-NALD (acyl-CoA oxidase deficiency)
- Pseudo-NALD (bifunctional enzyme deficiency)
- Others
- Ether-phospholipid (and plasmalogen) synthesis:
- RCDP type 2 (DHAP-AT deficiency)
- RCDP type 3 (Alkyl-DHAP synthase deficiency)
- Other single-enzyme disorders:
- Glutaric aciduria type 3 (Glutaryl-CoA oxidase deficiency)
- Mevalonic aciduria (Mevalonate kinase deficiency)
- Primary hyperoxaluria type 1 (PH1)
- Acatalasemia
- Refsum disease

N-3 and N-6 FATTY ACIDS
- General
- Docosahexaenoic acid (DHA)
- Arachidonic acid and the Eicosanoids

OTOLOGY

OPHTHALMOLOGY

DIET AND NUTRITION

MISCELLANEOUS
- Peroxisome proliferators
- Vitamin K

GENERAL TEXTS

- - -
- - -
PEROXISOMAL DISORDERS - GENERAL

The Peroxisome Biogenesis Disorders (pp. 3181-3218, in)
The Metabolic and Molecular Basis of Inherited Disease
(Scriver et al., editors), McGraw-Hill, 2001
Gould, Raymond, Valle

Advances in Human Genetics, Volume 21, Harris and Hirschorn, eds
Plenum Press, New York, 1993
Chapter 1, Peroxisomal Disorders
Hugo Moser

Genetic Diseases of the Eye, Traboulsi, editor
Oxford University Press, 1998
Chapter 33, Peroxisomal Disorders
Richard Weleber

Peroxisomal Disorders: Genotype, Phenotype,
Major Pathological Lesions, and Pathogenesis
Powers and Moser
Brain Pathology, Vol. 8, No. 1, 101-120, January 1998

Handbook of Clinical Neurology, Volume 22 (66) :
Neurodystrophies and Neurolipidoses, Moser, editor,
Elsevier Science, 1996
Chapter 23, Generalized peroxisomal disorders and
disorders of peroxisomal fatty acid oxidation
Wanders, Heymans, Schutgens, Barth

Peroxisomal Disorders: Post- and Prenatal Diagnosis Based on a New
Classification with Flowcharts
Wanders et al.
International Pediatrics, Vol. 11, No. 4, 208-214, 1996

Peroxisomal disorders: a review
Wanders et al.
Journal of Neuropathologic Experimental Neurology
54:726-739, 1995

Disorders of Peroxisome Biogenesis
Braverman et al.
Human Molecular Genetics
Vol. 4, Review, 1791-1798, 1995

Peroxisomal disorders: a review
Fournier et al.
Journal of Inherited Metabolic Disease
17:470-486, 1994

Peroxisomal Disorders: Neurodevelopmental and Biochemical Aspects
Brown et al.
American Journal of the Diseases of Childhood, 147:617-626, 1993

Peroxisomal disorders
Moser et al.
Biochemical Cell Biology, 69:463-474, 1991

Peroxisomal disorders: A newly recognized group of genetic diseases
Schutgens et al.
European Journal of Pediatrics, 144: 430-440, 1986

Peroxisomal Disorders: A Review of a Recently Recognized
Group of Clinical Entities
Talwar and Swaiman
Clinical Pediatrics
Vol. 26, No. 10, 497-504, October 1987

New Approaches in Peroxisomal Disorders
Moser
Dev. Neurosci. 9:1-18, 1987

Peroxisomal disorders: A newly recognized group of genetic diseases
Schutgens et al.
European Journal of Pediatrics, 144: 430-440, 1986

[Return to Index]

- - -
Neuropathy and Epilespy

Normal and Defective Neuronal Membranes:
Structure and Function; Neuronal Lesions in
Peroxisomal Disorders
James Powers
Journal of Molecular Neuroscience, 16:285-287, 2001

Epilepsy in Peroxisomal Diseases
Takahashi et al.
Epilepsia, Vol. 38, No. 2, 182-188, 1997

Globoid Cells, Glial Nodules, and Peculiar Fibrillary Changes
in the Cerebro-Hepato-Renal Syndrome of Zellweger
de Leon et al.
Annals of Neurology, Vol.2, No. 6, 473-484, December 1977

Advances in Neurology, volume 44, edited by Delgado-Escueta et al.
Basic Mechanisms of the Epilepsies: Molecular and Cellular Approaches
Delgado-Escueta et al.
Raven Press, New York, 1986