Peroxisomal Disorders 

Updated: Apr 01, 2015
Author: Hoda Z Abdel-Hamid, MD; Chief Editor: Amy Kao, MD 

Overview

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 metabolic pathways, such as beta-oxidation of very-long-chain fatty acids (VLCFA) 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. Over the next 3 years, a number of case reports followed. 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), and oxidation of L-pipecolic acid (the function of which is incompletely understood).

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

United States

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]

International

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

Mortality/Morbidity

See the list below:

  • 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.

 

Presentation

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).

  • PDBs are due to mutation or mutations in the PEX genes that normally encode for peroxin proteins and whose proper expression is required for peroxisome biogenesis. Fourteen distinct PEX genes have been described.

    • Zellweger syndrome

      • ZWS is considered to be the prototype of the PBD group, which includes NALD, IRD, and HPA. Bowen et al first described ZWS in 1964.[4] Passarge and McAdams introduced the name cerebrohepatorenal syndrome.

      • ZWS causes multiple congenital anomalies dominated by a typical craniofacial dysmorphism, including a high forehead, a large anterior fontanelle, hypoplastic supraorbital ridges, broad nasal bridge, micrognathia, deformed ear lobes, and redundant nuchal skin folds.

      • The neurologic picture comprises severe psychomotor retardation, profound hypotonia with depressed deep tendon reflexes (DTRs), neonatal seizures, and impaired hearing. Brain anomalies include cortical dysplasia with pachygyria and neuronal heterotopia; regressive changes related to storage with subsequent cell death may be seen. Dysmyelination rather than demyelination is observed.

      • Ocular findings include congenital cataract, glaucoma and retinal degeneration with an absent electroretinogram (ERG).

      • Other abnormalities are calcific stippling of the epiphyses, small renal cysts, and liver cirrhosis.

      • Patients with ZWS have a decreased number of hepatic peroxisomes, impaired plasmalogen synthesis (especially in RBCs) and increased levels of VLCFA, bile acids, pipecolic, and phytanic acids. These findings suggest the involvement of different peroxisomal pathways.

      • Patients with NALD and IRD have less severe disease and longer survival rates than those of patients with ZWS. Sensorineural hearing loss and pigmentary retinal degeneration is invariably present. Leukodystrophy may develop in the mild phenotypes; however, migration defects are not common, and seizures are usually absent in IRD but not in NALD, which involves exclusive atrophy of the adrenal cortex. Likewise, renal cysts and chondrodysplasia punctata are not typically present. However, short stature and delayed eruption of teeth are noted.

      • HPA is considered to belong to the PBD group; however, isolated HPA is rare and not well understood.

  • Rhizomelic chondrodysplasia punctata 1

    • RCDP type 1 is a heterogenous group of disorders that is clinically distinct from the ZWS.

    • Various forms of inheritance with autosomal or X-linked, dominant, or recessive patterns have been described.

    • Peroxisomal abnormalities are found in only the rhizomelic autosomal recessive variant. Patients with these abnormalities have short stature, with spasticity and contractures, dysmorphic facies, and severe mental retardation. Shortening mainly involves the proximal parts of the limbs. Patients suffer mostly from severe scoliosis and chronic chest infection. Skeletal radiography typically reveals bone dysplasia with epiphyseal stippling. Death occurs in the first decade of life. Plasmalogen deficiency is a consistent feature and highly reliable for diagnosis.

  • Single-enzyme deficiencies with intact peroxisomal structure include disorders of peroxisomal beta-oxidation (POD), disorders of ether-phospholipid biosynthesis, and disorders of fatty acid alpha-oxidation.

    • Disorders of peroxisomal beta-oxidation - X-ALD

      • These disorders, seen only in males, are due to mutations in the ABCD1 gene.[5] This gene encodes for ABC, a transporter molecule involved in the uptake of VLCFA across peroxisomal membranes. This mutation results in the accumulation of VLCFA due to lack of peroxisomal oxidation. Clinical presentations are diverse, ranging from the lethal cerebral childhood form to an isolated Addison-like disease with no neurologic involvement. Phenotypes in the same pedigree are markedly heterogeneous, a phenomenon attributed to the action of a possible modifier gene.

      • Semmler et al have suggested that polymorphisms of genes involved in methionine metabolism modify phenotype in X-ALD, and have found evidence that the Tc2 genotype contributes to X-ALD phenotype generation.[6]

      • Approximately 20% of women who are heterozygous for the ALD locus develop neurologic disability that is milder and later in onset than that observed in affected men. Deficits vary from mild hyperreflexia and vibratory sense impairment to paraparesis causing patients to use a wheelchair. Signs of dementia are rare. The implicated gene is subject to X-inactivation.

      • In the cerebral form of X-ALD, early development is entirely normal, and the first neurologic manifestations most commonly occur at 4-8 years of age. Asymptomatic boys may have a normal full-scale IQ but a low performance IQ.[7] Early manifestations are often mistaken for attention-deficit/hyperactivity disorder. Characteristic neurologic manifestations, such as impaired auditory discrimination, visual disturbances, spatial disorientation, poor coordination, and seizures supervene later in the disease, which may then progress rapidly. Progression leads to a vegetative state in 2 years and death at some point thereafter. Relatively uncommon adolescent and adult cerebral forms can occur. An inflammatory response is seen in the cerebral form.

      • AMN, another variant of X-ALD, causes slowly progressive paraparesis and sphincter disturbances and is often misdiagnosed as multiple sclerosis. Symptoms typically start at 28 ± 9 years. Forms include pure AMN and AMN-cerebral. Patients with pure AMN present with only spinal cord and peripheral nerve involvement and sparing of higher cognitive functions. However, neuropsychological testing may show subtle deficits in psychomotor speed and visual memory. This variant has a better prognosis than that of other forms. AMN-cerebral is used to describe increased impairment of neuropsychological function. Patients have various degrees of brain MRI abnormalities.

      • Progressive cerebellar disorder resembling olivopontocerebellar degeneration is described.

      • The Addison-like phenotype is distinguished from Addison disease by high levels of serum VLCFA.

      • Patients with acyl-CoA oxidase deficiency, or pseudo-NALD, have a ZWS phenotype but no dysmorphic features. Symptoms consist of hypotonia, psychomotor regression, seizures, deafness and retinopathy with hypodensity of the cerebral white matter in addition to adrenocortical insufficiency. However, all peroxisomal metabolites, for the exception of VLCFA, are normal.

      • D-Bifunctional protein deficiency results in a phenotype similar to that of ZWS, with dysmorphic facies and cerebral migrational defects. levels of both VLCFA and bile-acid intermediates are abnormally elevated. However, peroxisomes appear normal on liver biopsy.

      • Peroxisomal thiolase deficiency, or pseudo-ZWS, is believed to be a subgroup of D-bifunctional protein deficiency.

      • Peroxisomal 2-methylacyl-CoA racemase deficiency (AMACR) is characterized by a defect in beta-oxidation of branched-chain fatty acids. Clinical manifestations consist of adult-onset sensory-motor neuropathy, a symptom also reported in Refsum disease and in the ALD variant. However, phytanic acid and VLCFA levels are normal, though levels of 2-methyl branched-chain fatty acid, pristanic acid, and DHCA and/or THCA are abnormally elevated. Symptoms may vary, and patients may have isolated liver disease without neurologic involvement.

    • Disorders of ether-phospholipid biosynthesis

      • In most patients with RCDP type I, the primary defect involves the PEX-7 gene, which encodes for the peroxisomal targeting sequence (PTS-2) receptor. This receptor helps to target cytosolic proteins to the peroxisome. As a result, multiple peroxisomal enzymes that depend on PTS-2 signaling are affected (eg, peroxisomal thiolase, alkyl DHAP synthase, phytanoyl-CoA hydroxylase, DHAP-AT).

      • RCDP types II and III are characterized by variable severity of clinical manifestations and by disproportionately short stature that primarily affects the proximal parts of the extremities, a typical facial appearance, congenital contractures, cataracts, and mental retardation similar to that of RCDP type I. However, bone stippling is not present. In RCDP types II and III, the PEX-7 protein is normal, and a mutation occurs in the structural gene encoding for their specific enzymes, PHAP-AT and alkyl DHAP synthase, respectively. Plasmalogen is deficient but, unlike RCDP type I, phytanic acid and other peroxisomal metabolites are normal.

      • Mevalonate kinase is implicated in the biosynthesis of isoprenoids. Its deficiency leads to elevated levels of mevalonic acid in the urine. Clinical manifestations include developmental delay, cataracts, hepatosplenomegaly, and lymphadenopathy with early death. Similar symptoms have been observed in patients with hypergammaglobulinemia type D and periodic fever syndrome in addition to skin rash and arthralgias.

      • Acatalasemia is a rare disease variably associated with catalase deficiency and ulcerating oral lesions. It has been described in Japan and in Switzerland.

      • Mulibrey nanism, also known as muscle-liver-brain-eye syndrome, has been described in Finnish people and consists of muscle weakness, constrictive pericarditis, hepatomegaly, and J -shaped sella turcica with enlarged cerebral ventricles. Yellowish dots are noted on funduscopic examination. Patients have severe growth retardation but normal psychomotor development. Plasma VLCFA and liver peroxisomes are normal. The protein involved is strongly suspected but not yet confirmed to be a peroxisomal factor.

      • Patients with hyperoxaluria type I due to deficiency of the liver peroxisomal enzyme alanine:glyoxylate-aminotransferase (AGT), which catalyzes the conversion of glyoxylate to glycine. Calcium oxalate urolithiasis and nephrocalcinosis is present that leads to progressive renal failure at various ages. In addition, they may develop myocarditis, neuropathy, osteosclerosis, and retinopathy as a result of oxalate deposits in various organs. Urine excretion of glyoxylic and glycolic acid is increased. The enzyme is present only in the liver, and liver biopsy is usually needed for diagnosis.

    • Disorders of fatty acid alpha-oxidation: Refsum disease is the only known type in this group. It is characterized by retinitis pigmentosa, sensory-motor polyneuropathy, cerebellar ataxia, and elevated cerebrospinal fluid protein levels without pleocytosis. Other features include sensory-neural hearing loss, anosmia, ichthyosis, skeletal malformation and cardiac abnormalities. Accumulation of phytanic acid in brain, blood, and other tissues is toxic.

 

DDx

 

Workup

Laboratory Studies

See the list below:

  • No single test is sufficient to diagnose all peroxisomal disorders. The selection of laboratory studies is based on the clinical presentation.

  • Four diagnostic groups have been described.

    • PBD and POD: These include ZWS, NALD, IRD as part of PBD, and pseudo-NALD and D-bifunctional protein deficiency as part of POD.

    • All 3 types of RCDP

    • All types of X-ALD

    • Refsum, AMACR, hyperoxaluria type I, glutaric aciduria type III, mevalonate kinase deficiency, acatalasemia, and mulibrey nanism

  • In group 1, VLCFA is abnormal in all patients, and normal VLCFA can rule out group 1 disorders. Elevation of C26:0 and C26:1 and the ratios C24/C22 and C26/C22 are consistent with a defect in peroxisomal fatty acid metabolism.

  • To further differentiate the disorders in this group, additional studies, including tests of erythrocyte plasmalogen, plasma bile-acid intermediates, pristanic acid, and phytanic acid, are recommended. If plasmalogen is deficient, the patient is likely to have PBD.

    • A normal plasmalogen confirms POD. However, plasmalogen may be normal in mild forms of PBD (eg, IRD).

    • Biochemical abnormalities detected in blood and/or urine should be confirmed in cultured fibroblasts.

  • In group 2, analysis of peroxisomal metabolites in plasma should not be used in the diagnostic work-up for RCDP. Instead, the first study should be an analysis of the plasmalogen level in erythrocytes, which is deficient in all cases of RCDP.

    • After RCDP is confirmed, phytanic acid levels should be checked. If these are abnormally elevated, RCDP I is the likely diagnosis because the level is normal in types II and III.

    • However, because phytanic acid is derived from dietary source, a normal level does not necessarily exclude type I and therefore does not distinguish the 3 types. In this case, enzymatic assay and DNA analysis are recommended to differentiate types II and III.

  • In group 3, elevated plasma VLCFA level is highly reliable in the diagnosis of ALD. Molecular studies are essential in determining a carrier state and especially in prenatal diagnosis, which can be performed in all peroxisomal disorders.

    • Hubbard et al have reported on the validation of combined liquid chromatography–tandem mass spectrometric method for detecting X-ALD in newborns.[8]

  • Group 4 is clinically heterogeneous. In Refsum disease, an elevated serum level of phytanic acid is reliable in diagnosis. However, enzymatic and molecular analyses are essential for confirmation.

    • In hyperoxaluria type I, liver biopsy is required for enzymatic assay. Urinary excretion of glyoxylic and glycolic acids is increased.

    • In glutaric aciduria type III, there is persistent elevation of glutaric acid excretion.

    • Mevalonate kinase deficiency results in increased urinary excretion of mevalonic acid. However, enzymatic and molecular results may be normal in patients with hyperimmunoglobulin D (IgD).

    • AMACR increases levels of pristanic acid, as detected on urine gas chromatography mass spectrometry, or levels of bile acid intermediates, as per tandem mass spectrometry. Further confirmation is obtained with enzymatic and molecular assays.

Imaging Studies

See the list below:

  • MRI findings in ALD have been well correlated with the characteristic gross neuropathologic features of bilaterally symmetric demyelination in the parieto-occipital region with involvement of the splenium of the corpus callosum. The demyelination then spreads anteriorly and laterally.

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

    See the list below:

    • MRI shows accumulation of contrast material at the advancing margins. This finding is a predictor of disease progression and is consistent with the inflammatory response.

    • Other patterns less characteristic than these occur. Examples are early frontal involvement, which is observed in approximately 15% of patients, and an asymmetric mass lesion.

    • Milder ALD phenotypes and AMN commonly affect the brainstem corticospinal tracts and the cerebellar white matter.

    • In the literature, 54% of 112 patients with AMN, brain MRIs were normal, and demonstrable neurologic involvement was confirmed in the spinal cord and peripheral nerves.

  • Magnetic resonance spectroscopy shows a diminution in N -acetyl aspartate due to axonal loss, an increase in choline peaks due to active demyelination, and a mild elevation in lactate peak due to inflammation. Spectroscopic changes precede those demonstrable on MRI.

  • MRI findings in ZWS include neocortical dysplasia (pachypolymicrogyria), germinolytic cysts, and delayed myelination. These finding are attributable to the disordered cytoarchitecture of the cerebral cortex due to neuronal migration defects.

    • Colpocephaly (ie, enlargement of the occipital horns of the lateral ventricles) and hypointensity of white matter have been detected. These findings suggest delayed myelinogenesis.

    • In late stages, cortical atrophy gradually appears.

  • In the remaining peroxisomal disorders, no characteristic findings on neuroimaging have been described.

Other Tests

See the list below:

  • In patients with peroxisomal disorders, such as ZWS, EEG usually shows multifocal spikes in the early stages of disease.

  • In late stages, diffuse irregular high-voltage slow waves, correlated with atrophy, are common features.

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.

 

Treatment

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.

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.

  • Because phytanic acid is exclusively of dietary origin (butter, cheese, beef, lamb, and some fish), its restriction can reduce its blood and tissue levels in 1-2 years, and the neurotoxic events can be significantly limited.

  • Long-term follow-up has shown that dietary restriction improves peripheral-nerve and cardiac function and stabilizes the retinal abnormalities and hearing deficit.

  • In sick patients, phytanic acid levels can be rapidly lowered with plasma exchange; this may reverse some symptoms. Alternative means to decrease phytanic acid levels is w-oxidation by means of the cytochrome P-450 enzyme; however, this line of therapy remains experimental.

  • Extracorporeal apheresis is another therapeutic approach that may result in in long-term improvement or stabilization in patients with progressive Refsum disease.[11]

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

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:

  • Clinical rexults in patients who already had neurologic involvement have been disappointing.

  • The therapy also does not appear to alter the rate of progression of endocrine abnormalities. However, it may diminish the frequency and severity of subsequent neurologic involvement, and it has been recommended in asymptomatic boys with X-ALD after the age of 1 year.

  • Bone marrow transplantation reversed neurologic, cognitive, and neuroradiological abnormalities in 1 patient who was treated when nervous-system involvement was still mild. Results in patients with advanced disease have been disappointing.

  • A French team has reported on autologous hematopoietic stem cell (HCT) gene therapy with a lentiviral vector 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.[12]

  • Several laboratories are attempting to develop a genetic model of ADL in knock-out mice, with the aim of evaluating the efficacy of gene therapy.

  • Currently, HSCT is not indicated for AMN and Zellweger syndrome.[13]

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

  • Recent data have demonstrated that patients with ZWS, NALD, and IRD have decreased blood tissue levels of docosahexanoic acid (DHA) and have suggested an important role of this substance in retina and brain. On this basis, Martinez et al initiated a therapeutic trial of this substance in patients with NALD. Improved visual and neurologic function was observed in 1 patient.[14]

  • Noguer and Martinez subsequently reported improved visual function with DHA ethyl ester treatment in 23 patients with peroxisomal disorders, 2 with classic Zellweger syndrome and 1 with D-bifunctional protein deficiency.[15]

  • The development of compounds aimed at limiting the accumulation of VLCFA in fibroblasts is under investigation.[16]

Surgical Care

See Medical Care.

Diet

See Medical Care.

 

Medication

Gastrointestinal Agents, Other

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]

Cholic acid (Cholbam)

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.