Background

Peroxisomal disorders are a group of genetically heterogeneous metabolic diseases that share dysfunction of peroxisomes. Peroxisomes are cellular organelles that are an integral part of the metabolic pathway. They measure about 0.5 µm in diameter and can differ in size between different species. They participate in important peroxisome-specific chemical reactions, such as beta-oxidation of very-long-chain fatty acids (VLCFAs) and detoxification of hydrogen peroxide. Peroxisomes are also involved in the production of cholesterol, bile acids, and plasmalogens, which contribute to a big part of the phospholipid content of the brain white matter.

Zellweger described the first case of a peroxisomal disorder in the 1940s. The initial description of the peroxisome (originally termed the microbody) appeared in 1954 in a doctoral thesis about mouse kidneys, almost 10 years after the first case description of peroxisomal disease was published. A study in 1979 of initiating reactions in complex lipid syntheses in rat liver peroxisomes was conducted. Its results helped investigators to understand the role of these organelles in human disease.

Pathophysiology

Peroxisomes are ubiquitous components of the cytoplasm found in nearly all mammalian cells. Their function is indispensable in human metabolism and includes beta-oxidation of fatty acids, biosynthesis of ether phospholipids (including plasmalogen and platelet activating factor [PAF]), biosynthesis of cholesterol and other isoprenoids, detoxification of glycolate to glycine (the accumulation of glycolate leads to precipitation of calcium oxalate in various tissues, with subsequent deleterious effects), oxidation of L-pipecolic acid (the function of which is incompletely understood), and detoxification of hydrogen peroxide by removing hydrogen and forming water and oxygen.

Beta-oxidation of fatty acids

Whereas the mitochondria are responsible for the oxidation of the bulk of dietary fatty acids (palmitate, oleate and linolate), peroxisomes are responsible fully for the beta oxidation of VLCFAs (C24:0 and C26:0) in addition to pristanic acid (from dietary phytanic acid) and dihydroxycholestanoic acid (DHCA) or trihydroxycholestanoic acid (THCA). These last 2 compounds lead to the formation of bile acids, cholic acid, and chenodeoxycholic acid from cholesterol in the liver. Another major function of the peroxisomal beta-oxidation system is related to the biosynthesis of polyunsaturated fatty acid (C22:6w3). Peroxisomes also work in conjunction with mitochondria to shorten fatty acid chains, which are in turn degraded to completion in the mitochondria. The end result is the formation of acetylcoenzyme A (acetyl-CoA) units, which are degraded in the Krebs cycle to produce energy (adenosine triphosphate [ATP]).^[1]

In peroxisomal biogenesis disorders, abnormal accumulation of VLCFAs (C24, C26) is the hallmark of peroxisomal disorders. VLCFAs have deleterious effects on membrane structure and function, increasing microviscosity of RBC membranes and impairing the capacity of cultured adrenal cells to respond to adrenocorticotropic hormone (ACTH).

In the CNS, VLCFA accumulation may cause demyelination associated with an intense inflammatory response in the white matter, with increased levels of leukotrienes due to beta-oxidation deficiency. Accompanying this response is a perivascular infiltration by T cells, B cells, and macrophages in a pattern suggestive of an autoimmune response. Levels of tumor necrosis factor and alpha immunoreactivity in astrocytes and macrophages at the outermost edge of the demyelinating lesion are increased, suggesting a cytokine-mediated mechanism. Furthermore, VLCFAs are postulated to be components of gangliosides and cell-adhesion molecules in growing axons and radial glia, and hence contribute to migrational defects in the CNS.

Biosynthesis of ether phospholipids (including plasmalogen and PAF)

Plasmalogen is essential in maintaining the integrity of cell membranes, especially those in the CNS. PAF deficiency impairs glutaminergic signaling and has been implicated in human lissencephaly and neuronal migration disorders.

One of the most challenging aspects in pathogenesis of these disorders is the mechanism responsible for neuronal migration defects. Migrational abnormalities are the most likely causes of the severe seizures and psychomotor retardation associated with many types of peroxisomal disorders. The severity of migrational defects is correlated with the elevation of VLCFAs, with depressed levels of ether-linked phospholipids, and with elevated levels of bile-acid intermediates.^[2]

Fatty acid alpha-oxidation

Fatty acid alpha-oxidation is a strictly peroxisomal process. It results in the conversion of phytanic acid into pristanic acid (removal of a 3-methyl group), which then undergoes beta-oxidation in peroxisomes. The product is shuttled to the mitochondria by means of carnitine ester for further degradation.

Frequency

The combined incidence of peroxisomal disorders is in excess of 1 in 20,000 individuals. Patients hemizygous or heterozygous for adrenoleukodystrophy (ALD) that is X-linked (X-ALD) are by far the largest subset. Zellweger syndrome (ZWS) is the most common peroxisomal disorder to manifest itself in early infancy. Its incidence has been estimated to be 1 in 50,000–100,000. Baumgartner et al reported that peroxisomal disorders accounted for 2.7% of the 1000 patients with inborn errors of metabolism examined at the Hospital Necker-Enfants Malades between 1982 and publication of their report in 1998.^[3]

The incidence of ALD in Japan is estimated to be 1:30,000–1:50,000 boys.

Mortality/Morbidity

ZWS is the most severe type of peroxisomal disorder. This disorder is apparent at birth and results in death within the first year of life.

The childhood cerebral form of ALD leads to total disability during the first decade and death soon thereafter.

Survival in other patients may extend into the second and third decade.

Adrenomyeloneuropathy (AMN) is compatible with survival to the eighth decade.

Sex

X-ALD affects only boys. Female carriers can manifest with some degree of disability.

Clinical Presentation

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Media Gallery

MRI of a patient with adrenoleukodystrophy showing the typical pattern of posterior white-matter involvement.

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Peroxisomal Disorders

Background