Peroxisomal Disorders

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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.

Epidemiology

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.

History

Four-group classification by clinical criteria

Peroxisomal disorders also can be classified into 4 groups based on clinical criteria.

Group 1 includes disorders of peroxisome biogenesis (PBD) that share the ZWS phenotype, such as ZWS, a subgroup sharing with ZWS a general loss of all peroxisomal enzymes (ie, NALD, infantile Refsum disease [IRD], hyperpipecolic academia [HPA]); disorders displaying the ZWS phenotype in which peroxisomes are present; those with a deficiency of only 1 enzyme of peroxisomal beta-oxidation (eg, pseudo–NALD, pseudo-ZWS, bifunctional protein insufficiency); and disorders displaying the ZWS phenotype characterized by the loss of several enzymes and a normal amount of peroxisomes. In ZWS-like syndrome, enzymes for peroxisomal beta-oxidation are still unidentified.

Group 2 contains the RCDPs and related bone dysplasias. RCDP types II and III are due to plasmalogen deficiency.

Group 3 includes the X-ALD and phenotypic variants.

Group 4 comprises hyperoxaluria, acatalasemia, Refsum's disease, mevalonate kinase deficiency, glutaryl-CoA oxidase deficiency, and dihydroxy or trihydroxy cholestanoic acidemia (enzyme unknown).

Two-group classification based on organelle structure and deficiencies

Although different classifications have been proposed, the growing consensus supports a classification in which 2 groups of disorders are distinguished: (1) disorders of peroxisomal biogenesis (PBD) in which the organelle is abnormally formed and missing several functions and (2) single-enzyme deficiencies with intact peroxisomal structure.

The second group includes at least 10 disorders in which the defect involves a single peroxisomal protein but the structure of the peroxisome is intact. This category includes ALD (ie, VLCFA synthesis deficiency), AMN, pseudo–neonatal ALD (ie, NALD, or acyl-CoA oxidase deficiency), metabolic kinase deficiency, hyperoxaluria type I (ie, alanine glyoxylate aminotransferase deficiency), bifunctional enzyme deficiency, pseudo-ZWS (ie, peroxisome thiolase deficiency), acatalasemia (ie, catalase deficiency), dihydroxy acetone phosphate (DHAP) acyltransferase (AT) deficiency (ie, DHAP-AT deficiency, or type II rhizomelic chondrodysplasia punctata [RCPD]), alkyl-DHAP synthase deficiency (ie, type III RCDP), glutaric aciduria type III, and classic Refsum disease (ie, phytanoyl-CoA hydroxylase deficiency).

Laboratory Studies

See the list below:

Imaging Studies

See the list below:

Other Tests

See the list below:

Histologic Findings

Neuropathologic lesions in the peroxisomal disorders can be divided into 3 major classes: (1) abnormalities in neuronal migration or differentiation, (2) abnormalities in myelination (defects in the formation or maintenance of myelin in the central white matter and/or in the peripheral nerves), and (3) postdevelopmental neuronal degeneration.

Abnormalities in neuronal migration and differentiation

These abnormalities are most prominent in ZWS and ZWS-like disorders, which are characterized by a unique combination of centrosylvian pachygyria-polymicrogyria. Migration of all neuronal classes, particularly those destined for the outer layers of the cortex, appears to be affected. Less severe cerebral-migration abnormalities, usually in the form of polymicrogyria, are seen in NALD as diffuse, focal, or multifocal lesions that may be associated with subcortical heterotopias; they also are seen in thiolase deficiency and in bifunctional enzyme deficiency.

Cerebral neuronal migration problems have not been identified in IRD, classical adult Refsum disease (ARD), hyperpipecolic acidemia, acyl-CoA oxidase deficiency (pseudo-NALD), ALD, or AMN. In rare reports, RCPD was associated with abnormalities of cerebral neuronal migration. Other subtle neuronal migration problems, apparently asymptomatic, are found in the form of heterotopic Purkinje cells. Defects in neuronal differentiation or terminal migration are common and usually involve the principal nuclei of the inferior medullary olives and, infrequently, the dentate nuclei and claustra. The malformations of these structures consist of dysplasia and simplification. Apparent neuronal loss has also been reported.

Abnormalities in myelination

Lesions of the peripheral nerve can be seen in all peroxisomal disorders with neurologic involvement. Involvement of the peripheral nerves has not been studied sufficiently, except in ARD, which typically results in hypertrophic (ie, onion-bulb) demyelinating neuropathy. Central demyelination and dysmyelination are typically noted in these disorders.

Postdevelopmental neural degeneration

Degenerative changes in the CNS white matter can be classified as 1 of 3 types of lesions: inflammatory demyelination, noninflammatory demyelination, and nonspecific reduction in myelin volume or myelin staining with or without reactive astrocytes.

Inflammatory demyelination, for which ALD is the prototype, is characterized by confluent and bilaterally symmetric loss of myelin in the cerebral and cerebellar white matter. The cerebral lesions usually begin in the parieto-occipital regions and progress asymmetrically toward the frontal or temporal lobes. Arcuate fibers generally are spared, except in chronic cases. The loss of myelin exceeds that of axons, but axonal loss may be considerable. On occasion, lesions involve the brainstem, particularly the pons.

The spinal cord is usually not involved except for bilateral degeneration of the corticospinal tract. Characteristic lamellar and lamellar-lipid inclusions typical of ALD are found in the cytoplasm of Schwann cells or in endoneural macrophages when the peripheral nerves are damaged. Inclusions also may be seen in CNS macrophages but not in oligodendrocytes. Spicular or trilaminar inclusions may be found in the CNS.

The sequence of demyelination in ALD is as follows: enlargement of the extraneural space; vacuolization and myelin swelling with reactive astrocytes and macrophage infiltration; perivascular lymphocytic infiltration and increased permeability of the blood-brain barrier. There is loss of myelin with lipophage formation, loss of oligodendroglia and axons, and dystrophic mineralization.

Inflammatory demyelinating lesions may also be seen in AMN, NALD, thiolase deficiency, and some cases of bifunctional enzyme deficiency. Areas of myelin pallor or oligodendroglial loss with or without reactive astrocytes have been seen in ZWS, NALD, IRD, and probably oxidase deficiency.

Noninflammatory dysmyelination is seen mostly in AMN. Myelin pallor is noted with scant interstitial periodic acid-Schiff (PAS)–positive macrophages but no lymphocytes or reactive astrocytes. Dysmyelination has been found in the early stages of the disease; in advanced stages, inflammatory lesions may supervene.

In nonspecific reduction in myelin volume or myelin staining with or without reactive astrocytes, specific neuron or myelinated fiber tracts show major postdevelopmental noninflammatory abnormalities. The first of these is associated with a progressive loss of hearing that has been classified as sensorineural. It can be seen in ZWS, NALD, IRD, ARD, RCDP, and acyl-CoA oxidase deficiency. The second lesion is retinal pigmentary degeneration, which has been reported in ZWS, NALD, IRD, and ARD. In both lesions, the pathologic changes appear to reside in specialized sensory neurons. The third site of pathogenic change is another restricted one in which the neurons of the dorsal nuclei of Clarke and the lateral cuneate nuclei accumulate lamellar lipids containing VLCFA; this has been seen only in ZWS.

Major neuronal and/or axonopathic degeneration is seen in AMN. Patients with AMN have degeneration of the ascending and descending tracts of the spinal cord, especially the fasciculus gracilis and the lateral corticospinal tracts; the pattern is that of wallerian degeneration. The final lesion is cerebellar atrophy, which has been noted in a few patients with RCDP. It is due to loss of Purkinje and granule cells with focal depletion of basket cells. Cerebellar atrophy has been noted in IRD.

Medical Care

Management and treatment are based on the disorder, the age of onset, and the rate of progression as well the risks and benefits associated with the available therapies. Other considerations include parent expectations and the quality of life. 

Cholic acid

In March 2015, cholic acid (Cholbam) was approved by the FDA for adjunctive treatment of peroxisomal disorders, including Zellweger spectrum disorders in patients who exhibit manifestations of liver disease, steatorrhea, or complications from decreased fat-soluble vitamin absorption. Bile acids facilitate fat digestion and absorption by forming mixed micelles, and they facilitate absorption of fat-soluble vitamins in the intestine. The mechanism of action of cholic acid has not been fully established; however, it is known that cholic acid and its conjugates are endogenous ligands of the nuclear receptor, farnesoid X receptor (FXR).

Efficacy of cholic acid for peroxisomal disorders was assessed in a single arm, treatment trial involving 29 patients treated over an 18-year period. An extension trial followed 10 of these patients and enrolled an additional 2 patients with interim efficacy data available for 21 additional months. The majority of patients were younger than 2 years at the start of cholic acid treatment (range 3 weeks to 10 years). Response to treatment was evaluated by improvements in baseline liver function tests and weight. Responses were noted in 46% of patients with evaluable data. Forty-two percent of patients survived >3 years.[9, 10]

The treatment can be specific to the disorder, such as in the case of Refsum disease, which includes elimination of the toxic substance.

In patients with hyperoxaluria type I, combined liver-kidney transplantation has shown the greatest promise.

Elivaldogene autotemcel 

Elivaldogene autotemcel is a one-time gene therapy designed to add functional copies of the ABCD1 gene into a patient’s own hematopoietic stem cells, resulting in the production of the adrenoleukodystrophy protein (ALDP). It is indicated to slow the progression of neurologic dysfunction in boys aged 4–17 years with early, active cerebral adrenoleukodystrophy (CALD), a rare, X-linked metabolic disorder that affects production of ALDP. 

Accelerated approval from the FDA in September 2022 was supported by interim results from the phase 2/3 STARBEAM study that concluded elivaldogene autotemcel may be an effective alternative to allogeneic stem-cell transplantation in boys with early-stage CALD.[12]   

An earlier study by a French team reported success of autologous hematopoietic stem cell (HCT) gene therapy with a lentiviral vector (ie, elivaldogene autotemcel) in 2 patients with X-ALD. Progression of cerebral demyelination in the 2 patients began to stop 14–16 months after infusion of the genetically corrected cells, a clinical outcome comparable to that achieved by allogeneic HCT.[13]  

ALD investigational therapies

In patients with X-ALD, oral administration of a mixture of glyceryl trioleate and trierucate oils (also referred to as Lorenzo oil) normalizes levels of saturated VLCFA in plasma within 4 weeks. However, consider the following:

Other therapies

Postnatal therapy of patients with disorders of peroxisome assembly is limited by the many abnormalities present at birth.

Cholic acid (Cholbam)

Clinical Context:  Endogenous bile acids, including cholic acid, enhance bile flow and provide the physiologic feedback inhibition of bile acid synthesis. Cholic acid is indicated for adjunctive treatment of peroxisomal disorders (PDs), including Zellweger spectrum disorders in patients who exhibit manifestations of liver disease, steatorrhea, or complications from decreased fat-soluble vitamin absorption.

Class Summary

Deficiency of primary bile acids leads to unregulated accumulation of intermediate bile acids and cholestasis. Primary bile acid replacement therapy has been shown to improve liver function and weight gain.[9, 10]

Elivaldogene autotemcel (Skysona)

Clinical Context:  Indicated to slow the progression of neurologic dysfunction in boys aged 4-17 years with early, active CALD. Administered as a one-time gene therapy designed to add functional copies of the ABCD1 gene into a patient’s own hematopoietic stem cells, resulting in the production of ALDP. 

Class Summary

Cerebral adrenoleukodystrophy (CALD) is a rare, X-linked metabolic disorder caused by mutations in the ABCD1 gene, which affects production of adrenoleukodystrophy protein (ALDP).

Author

Hoda Z Abdel-Hamid, MD, Associate Professor, Department of Pediatrics, University of Pittsburgh School of Medicine; Director of EMG Laboratory and Neuromuscular Program, Director of Pediatric MDA Clinic, Division of Child Neurology, Children’s Hospital of Pittsburgh, University of Pittsburgh Medical Center

Disclosure: Nothing to disclose.

Specialty Editors

Francisco Talavera, PharmD, PhD, Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Received salary from Medscape for employment. for: Medscape.

Chief Editor

Stephen L Nelson, Jr, MD, PhD, FAACPDM, FAAN, FAAP, FANA, Professor of Pediatrics, Neurology, Neurosurgery, and Psychiatry, Medical Director, Tulane Center for Autism and Related Disorders, Tulane University School of Medicine; Pediatric Neurologist and Epileptologist, Ochsner Hospital for Children; Professor of Neurology, Louisiana State University School of Medicine

Disclosure: Nothing to disclose.

Additional Contributors

David A Griesemer, MD, Professor, Departments of Neuroscience and Pediatrics, Medical University of South Carolina

Disclosure: Nothing to disclose.

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

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