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Peroxisomal disorders

Peroxisomal disorders
Ronald JA Wanders, PhD
Section Editors:
Marc C Patterson, MD, FRACP
Helen V Firth, DM, FRCP, FMedSci
Deputy Editor:
Carrie Armsby, MD, MPH
Literature review current through: Mar 2023. | This topic last updated: Jan 18, 2023.

INTRODUCTION — Peroxisomes are subcellular organelles with a variable diameter ranging from 0.05 to 0.5 micron in diameter and are present in all cells except erythrocytes. The highest concentration of peroxisomes is in the liver and kidney [1]. Although they are not present in mature erythrocytes, they are present during the early stages of erythrocyte development when membranes are formed.

Peroxisomes catalyze numerous catabolic and anabolic functions in cellular metabolism [2,3]. Catalytic functions include beta-oxidation of very long-chain fatty acids (VLCFA); oxidation of pipecolic, phytanic, pristanic, and many dicarboxylic acids; and degradation of hydrogen peroxide by catalase [2-4]. Anabolic functions include synthesis of bile acids and plasmalogens, which are important components of cell membranes and myelin.

Peroxisomal disorders are a heterogeneous group of inborn errors of metabolism that result in impairment of peroxisome function. In most cases, this results in neurologic dysfunction of varying extent. The major peroxisomal disorders will be reviewed here. The pathophysiology, clinical manifestations, and management of adrenoleukodystrophy are discussed separately. (See "X-linked adrenoleukodystrophy and adrenomyeloneuropathy".)

CLASSIFICATION — Peroxisomal disorders are divided into two major categories [2,5-8]:

Disorders of peroxisome biogenesis – This group includes:

Zellweger syndrome (ZWS) (see 'Zellweger syndrome' below)

Neonatal adrenoleukodystrophy (NALD) (see 'Neonatal adrenoleukodystrophy' below)

Infantile Refsum disease (IRD) (see 'Infantile Refsum disease' below)

Rhizomelic chondrodysplasia punctata type 1 (RCDP1) (see 'Rhizomelic chondrodysplasia punctata type 1' below)

The first three disorders are thought to represent a clinical continuum, referred to as Zellweger spectrum disorders (ZSD), with ZWS the most severe, IRD the mildest, and NALD intermediate in severity. In ZSD patients, there is a generalized loss of peroxisomal functions, caused by molecular defects in genes coding for peroxins (Pex), proteins required for peroxisome biogenesis [9]. These defects interfere with import of proteins into the peroxisome.

In RCDP1, peroxisomes are present, but they lack a specific group of proteins due to mutations in the PEX7 gene. Two peroxisomal functions are impaired, including the synthesis of etherphospholipids and the alpha-oxidation of phytanic acid.

Deficiency of a single peroxisomal enzyme – The following disorders are characterized by deficiency of a single peroxisomal enzyme; peroxisome structure is intact:

X-linked adrenoleukodystrophy (X-ALD), including adrenomyeloneuropathy (AMN) due to deficiency of adrenoleukodystrophy protein (ALDP), a peroxisomal membrane protein (see "X-linked adrenoleukodystrophy and adrenomyeloneuropathy")

Refsum disease (phytanoyl CoA hydroxylase deficiency) (see 'Refsum disease' below)

Acyl-CoA oxidase deficiency (pseudo-NALD) (see 'Acyl-CoA oxidase deficiency' below)

D-bifunctional protein deficiency (DBP deficiency) (see 'D-bifunctional protein deficiency' below)

Rhizomelic chondrodysplasia punctata type 2 (RCDP2; dihydroxy-acetone phosphate acyltransferase deficiency) (see 'RCDP types 2 and 3' below)

Rhizomelic chondrodysplasia punctata type 3 (RCDP3; alkyldihydroxyacetone phosphate synthase deficiency) (see 'RCDP types 2 and 3' below)

Alpha-methylacyl-CoA racemase (AMACR) deficiency (see 'Alpha-methylacyl-CoA racemase (AMACR) deficiency' below)

Peroxisomal sterol carrier protein-X deficiency (SCPx deficiency)

Acatalasemia (catalase deficiency)

Hyperoxaluria type 1 (alanine glyoxylate aminotransferase deficiency) (see "Primary hyperoxaluria")

EPIDEMIOLOGY — Peroxisomal disorders are thought to occur in at least 1 in 5 to 10,000 live births [5]. In one study, among 1000 patients with inborn errors of metabolism seen between 1982 and 1997 at the hospital Necker–Enfants Malades in Paris, peroxisomal disorders accounted for 2.7 percent [10].

X-linked adrenoleukodystrophy (X-ALD) is the most common peroxisomal disorder and is discussed separately. (See "X-linked adrenoleukodystrophy and adrenomyeloneuropathy", section on 'Epidemiology'.)

Zellweger syndrome is the most common peroxisomal disorder to present in early infancy. The incidence is 1 in 50,000 to 100,000 live births [11].

PATHOPHYSIOLOGY — Peroxisomes catalyze numerous catabolic and anabolic functions in cellular metabolism. Catalytic functions include beta-oxidation of very long-chain fatty acids (VLCFA); oxidation of pipecolic, phytanic, pristanic, and many dicarboxylic acids; and degradation of hydrogen peroxide by catalase [2,4]. Anabolic functions include synthesis of bile acids and plasmalogens, which are important components of cell membranes and myelin.

One of the hallmarks of most peroxisomal disorders is the abnormal elevation of VLCFA, especially those with 26 carbon atoms, and an increased ratio of C26 to C22 fatty acids in the plasma, as well as fibroblasts and amniocytes [12]. Accumulation of VLCFA in the membranes of neuronal cells contributes to neurologic injury [13]. VLCFA accumulation impairs erythrocyte membrane structure and function and the capacity of cultured adrenal cells to respond to adrenocorticotropic hormone (ACTH) [14] and impairs the stability of model membranes [15].

Of note, VLCFA levels are normal in some of the peroxisomal disorders. This applies to rhizomelic chondrodysplasia punctata (where deficiency of plasmalogens is the principal biochemical abnormality) and to Refsum disease (where accumulation of phytanic acid contributes to pathogenesis).

NEUROPATHOLOGY — The mechanism of disease in these conditions is thought to be accumulation of very long-chain fatty acids (VLCFA) in neuronal membranes, resulting in abnormal function, atrophy, and death of vulnerable cells [13]. Studies in an animal model of Zellweger syndrome (ZWS) provide evidence that the neuronal migration defect is due to N-methyl-D-aspartate receptor dysfunction [16].

The neuropathology of peroxisomal disorders is characterized by one or more of the following processes:

Migration and differentiation defects – Disorders of neuronal migration and differentiation vary in severity among the different disorders [17]. Migration of all neuronal classes appears to be affected, especially those destined for the outer layers of cortex.

The abnormalities are most prominent in ZWS and ZWS-like disorders, including D-bifunctional protein (DBP) deficiency, which are characterized by a unique combination of centrosylvian pachygyria-polymicrogyria likely responsible for the seizure disorder and global developmental delay [18]. Less severe defects in cerebral migration, usually polymicrogyria, occur in neonatal adrenoleukodystrophy (NALD) as diffuse, focal or multifocal lesions that may be associated with subcortical heterotopias [19]. These also occur in DBP deficiency [20,21]. More subtle neuronal migration defects appear as heterotopic Purkinje cells [22,23]. These are usually asymptomatic.

Neuronal migration abnormalities do not occur in all peroxisomal disorders. None have been identified in IRD, classic Refsum disease, acyl-CoA oxidase deficiency (pseudo-NALD), X-linked adrenoleukodystrophy (X-ALD), or adrenomyeloneuropathy (AMN). They occur rarely in rhizomelic chondrodysplasia punctate (RCDP) [24].

Defects in neuronal differentiation or terminal migration are common and result in dysplasia and simplification of the affected structures in ZWS. In the brainstem, they usually involve the principal nuclei of the inferior medullary olives. Less frequently, the dentate nuclei and claustra are affected. Neuronal loss may be seen in NALD [25]. The type of neuronal degeneration varies among the disorders.

Myelination abnormalities – Abnormalities in the formation or maintenance of central white matter and/or peripheral nerve myelin are frequently found in patients affected by peroxisomal disorders with neurologic involvement. Peripheral nerve involvement is less well studied than central lesions. An exception is Refsum disease, which typically has a hypertrophic (onion bulb) demyelinating neuropathy.

Degenerative central white matter lesions consist of myelin abnormalities that can be inflammatory [26,27] or noninflammatory, and nonspecific decreases in myelin volume or staining [13]. The latter can occur with or without reactive astrocytosis. The type of neuronal degeneration varies among the disorders:

Inflammatory demyelination – Inflammatory demyelination typically occurs in ALD, resulting in confluent and bilaterally symmetric loss of myelin in the cerebral and cerebellar white matter [28]. The parieto-occipital regions are usually affected first, with asymmetric progression of the lesions toward the frontal or temporal lobes. In general, arcuate fibers are spared, except in chronic cases. Axonal loss may be considerable, but myelin loss is usually greater. Lesions may sometimes involve the brainstem, especially the pons. The spinal cord is usually spared, except for bilateral corticospinal tract degeneration. In mice engineered to be deficient in peroxisomal function, axonal degeneration, progressive demyelination, and an inflammatory response with both B and T cells was noted, suggesting a critical role for peroxisomes in neuroprotection [29].

When peripheral nerves are affected in X-ALD, characteristic lamellar and lamellar-lipid inclusions are seen in Schwann cell cytoplasm or within endoneurial macrophages. The neuropathology of X-ALD is discussed in greater detail separately. (See "X-linked adrenoleukodystrophy and adrenomyeloneuropathy".)

Other conditions in which inflammatory demyelination lesions occur include AMN [28], NALD [19], and some cases of DBP deficiency.

Noninflammatory dysmyelination – Noninflammatory dysmyelination is seen in the early stages of AMN. The myelin appears pale, with scant interstitial macrophages that stain positive with periodic acid Schiff (PAS). No lymphocytes or reactive astrocytes are seen.

Other changes in myelin – Other changes in myelin include nonspecific reductions in volume or staining, with or without reactive astrocytes.

Major post-developmental noninflammatory abnormalities may occur in specific neurons or myelinated fiber tracts. These may affect specialized sensory neurons, resulting in sensorineural hearing loss (in ZWS, NALD, infantile Refsum disease [IRD], alpha-methylacyl-CoA racemase [AMACR] deficiency, RCDP, and acyl CoA oxidase deficiency) or retinal pigmentary degeneration (in ZWS, NALD, IRD, and AMACR deficiency). In another lesion of this type, neurons of the dorsal nuclei of Clarke and the lateral cuneate nuclei accumulate lamellar lipids that contain VLCFA. This lesion occurs only in ZWS.

In AMN, a degenerative axonopathy involves the ascending and descending tracts of the spinal cord, especially in fasciculus gracilis and the lateral corticospinal tracts. The histologic pattern is Wallerian degeneration [30]. Mitochondrial pathology [31] and oxidative stress [32] also contribute to pathogenesis.

Cerebellar atrophy occurs in RCDP and probably IRD. This appears to result from loss of Purkinje and granule cells, with focal depletion of basket cells.

CLINICAL PRESENTATION — The features that should prompt consideration of a peroxisomal disorder in the differential diagnosis are discussed in this section. The clinical features of individual peroxisomal disorders are discussed in greater detail below.

The clinical presentation of peroxisomal disorders varies with age [10,33]. In one review of 27 children with peroxisomal disorders, the following clinical features suggested the diagnosis at various ages [10]:

Neonates – Hypotonia, decreased activity, encephalopathy, seizures, craniofacial dysmorphism, skeletal abnormalities (calcific stippling, shortened proximal limbs).

Children <6 months of age – Craniofacial dysmorphism, failure to thrive, hepatomegaly, prolonged jaundice, neurologic dysfunction, visual abnormalities (retinopathy, cataract, optic nerve dysplasia, abnormal electroretinography [ERG] or visual evoked potential), liver failure, hypocholesterolemia, osteoporosis.

Children six months to four years – Psychomotor retardation, neurologic dysfunction, hearing loss, abnormal brain auditory evoked potential, visual abnormalities (visual impairment, retinopathy, cataract, abnormal ERG), osteoporosis.

Children more than four years – Behavioral changes, intellectual deterioration, visual abnormalities, hearing impairment, peripheral neuropathy, gait abnormalities, white matter demyelination.

In another review of 40 patients, the combination of certain clinical features suggested the diagnosis (≥3 features present in more than 75 percent of patients and at least one feature present in 50 to 75 percent of patients) [33]:

Features present in more than 75 percent of patients – Psychomotor retardation, hypotonia, impaired hearing, low/broad nasal bridge, abnormal ERG, hepatomegaly in the first year.

Features present in 50 to 75 percent of patients – Large fontanelle, shallow orbital ridges, epicanthus, anteverted nostrils, retinitis pigmentosa.


Symptomatic patients — Before addressing the individual disorders, considering a common approach to diagnosis is useful. If a peroxisomal disorder is suspected, plasma concentration of very long-chain fatty acids (VLCFA) should be measured. VLCFA levels are elevated in nearly all peroxisomal disorders [12].

Disorders of peroxisome biogenesis can be distinguished from peroxisomal beta-oxidation defects by additional measurements [34]. The tests are available in specialized laboratories, including the Peroxisomal Disease Laboratory at the Kennedy Krieger Institute (707 North Broadway, Baltimore, MD 21205) and the Genetic Metabolic Diseases Laboratory at the Academic Medical Center of the University of Amsterdam.

The following plasma concentrations should be measured:

Dihydroxy and trihydroxy cholestanoic acid (increased in most disorders of peroxisome biogenesis, as well as D-bifunctional protein (DBP) deficiency, alpha-methylacyl-CoA racemase (AMACR) deficiency, and sterol carrier protein X (SCPx) deficiency).

Phytanic acid (increased in many disorders of peroxisome biogenesis and in Refsum disease).

Pristanic acid (increased in many disorders of peroxisome biogenesis, and in DBP, AMACR deficiency, and SCPx deficiency).

Pipecolic acid (increased in many disorders of peroxisome biogenesis).

Docosahexaenoic acid (moderately diminished in many disorders of peroxisome biogenesis).

Plasmalogens (decreased in many disorders of peroxisome biogenesis and in the three genetic forms of RCDP).

Of note, these tests are not always abnormal early in the course of disorders of peroxisome biogenesis (eg, Zellweger spectrum disorders [ZSD]). One report described six patients with clinical features and magnetic resonance imaging (MRI) findings suggestive of relatively mild infantile peroxisomal defects, in whom plasma VLCFAs and other tests of peroxisomal dysfunction were normal or only mildly elevated [35]. The initial MRI abnormalities were in the hilus of the dentate nucleus, and gradually progressed to demyelination of the cerebral hemispheric white matter. A peroxisomal disorder was ultimately diagnosed through tests of catalase immunofluorescence in cultured skin fibroblasts, which are described in the paragraph below.

Assays of the following processes in cultured skin fibroblasts may be necessary to confirm the diagnosis:

De novo plasmalogen biosynthesis

Fatty acid beta-oxidation

Phytanic acid alpha-oxidation


DNA analysis is available for all peroxisomal diseases including X-linked adrenoleukodystrophy (X-ALD) [36] and is the preferred method for the identification of women who are heterozygous for X-ALD because it avoids the false-negative results that may occur with the VLCFA assay in heterozygotes. DNA is required for the definition of the molecular defect in the disorders of peroxisome biogenesis [37,38], and D-bifunctional protein (DBP) deficiency [39].

Prenatal diagnosis — Prenatal testing for all of the peroxisomal disorders is available for subsequent pregnancies of women with affected children or other positive family history. Prenatal diagnostic methods have generally shifted from biochemical to DNA-based methods. Using assisted reproductive technology, preimplantation diagnosis can be achieved in embryos using multiple displacement amplification [40]. Issues related to preimplantation genetic diagnosis are discussed in greater detail separately. (See "Preimplantation genetic testing".)

Antenatal diagnosis is sometimes made by ultrasonography. In one report, increased nuchal translucency and decreased fetal movements suggested the diagnosis of Zellweger syndrome (ZWS) in a fetus at risk [41]. The diagnosis was confirmed by metabolic studies on cells obtained by chorionic villus sampling. In another report, rhizomelic chondrodysplasia punctate (RCDP) was identified in a fetus with no family history based on the findings of severe limb shortening, premature ossification, and stippling of multiple epiphyses [42].

Newborn screening — Newborn screening for X-ALD is discussed in a separate topic review. (See "X-linked adrenoleukodystrophy and adrenomyeloneuropathy", section on 'Newborn screening'.)

The screening approach used for X-ALD may also detect other peroxisomal disorders, including ZSD.


Zellweger syndrome — Zellweger syndrome (ZWS) (MIM #214100), also known as cerebrohepatorenal syndrome, is the prototype of peroxisome biosynthesis disorders [43]. It is characterized by craniofacial dysmorphism and profound neurologic abnormalities.

Epidemiology — ZWS is the most common peroxisomal disorder to present in early infancy. The incidence is 1 in 50,000 to 100,000 live births [11].

Genetics — The peroxisome biogenesis disorders, including ZWS, neonatal adrenoleukodystrophy (NALD), and infantile Refsum disease (IRD), are inherited in an autosomal recessive manner. They are caused by mutations in at least 12 different genes [44]. The majority of infants with these conditions have mutations in either the PEX1 or PEX6 genes that encode ATPases needed to import protein from the cytosol into peroxisomes [45]. In one report, ZWS resulted from uniparental disomy, the result of maternal isodisomy for chromosome 1 [46].

Clinical features — Affected individuals present at birth with a typical craniofacial dysmorphism. The appearance is characterized by the following features (picture 1) [2,47]:

High forehead

Large anterior fontanelle

Markedly separated cranial sutures

Hypoplastic supraorbital ridges

Upward slant of the eyes

Epicanthal folds

Low and broad nasal bridge

High arched palate

Deformed ear lobes

Infants typically have hepatomegaly, which is associated with cirrhosis and biliary dysgenesis. Calcific stippling of the patellae, hips, and other epiphyses (chondrodysplasia punctata) is present in 50 to 70 percent [2]. Other features are glomerulocystic kidney disease, cataracts, and pigmentary retinopathy [48]. These abnormalities are already present at birth. (See "Cataract in children".)

Neurologic abnormalities include profound hypotonia and weakness with absent reflexes, severe impairment of hearing and vision, and neonatal seizures [47]. Developmental delay is profound. Infants rarely survive beyond six months of age [2].

Neuroimaging — Findings on cranial magnetic resonance imaging (MRI) include cortical and white matter abnormalities. In a study of six infants with ZWS, all had impaired myelination and diffusely abnormal cortical gyral patterns, consisting of microgyria and pachygyria [49]. All had germinolytic cysts in the caudothalamic groove.

Biochemical findings — The biochemical findings in the disorders of peroxisomal biogenesis are due to deficient very long-chain fatty acids (VLCFA) beta-oxidation, phytanic acid oxidation, and plasmalogen synthesis. This results in the following abnormalities:

Increased plasma VLCFA concentration

Increased concentrations of phytanic acid, pristanic acid, and pipecolic acid in plasma and fibroblasts

Reduced erythrocyte concentration of plasmalogen

Diagnosis — The diagnosis of ZWS is established through molecular testing. The "Pex Gene Screen" provides an algorithm that permits the identification of the molecular defect in the Zellweger spectrum peroxisomal disorders (ZSD) [38]. The Pex Gene Screen is available at the Peroxisomal Disease Laboratory at the Kennedy Krieger Institute and at the Laboratory of Genetic Metabolic Diseases at the University of Amsterdam Medical Center.

Treatment — No effective treatment is available for ZWS. Appropriate counseling and support should be provided for the family.

One approach under investigation is to normalize the concentration of docosahexaenoic acid (DHA). DHA concentration is low in brain, retina, and other tissues in this disorder, and may contribute to abnormalities in neurologic function. In one report, 20 individuals with Zellweger spectrum peroxisome biogenesis disorders were treated with DHA ethyl ester [50]. Beneficial effects included normalization of DHA levels and liver function, improved vision in approximately one-half of those treated, and increased muscle tone. Myelination improved on MRI in nine patients. Clinical improvement was greatest in those who started treatment before age six months. Nevertheless, whether DHA treatment is really beneficial or not is still very much in debate [51].

Another potential approach is pharmacologic induction of peroxisome proliferation. In one study, treatment of cultured fibroblasts from individuals with peroxisome biogenesis disorders with sodium 4-phenylbutyrate increased peroxisome number and increased transcription of ALD-related gene and the peroxin gene, PEX11a [52]. Treatment decreased VLCFA concentration and increased VLCFA beta-oxidation and plasmalogen concentrations in NALD and IRD fibroblasts, but not in ZWS.

Neonatal adrenoleukodystrophy — Neonatal adrenoleukodystrophy (NALD) (MIM #601539) is a disorder of peroxisomal biogenesis and is distinct from X-linked adrenoleukodystrophy (X-ALD). Some features are similar to ZWS, but NALD is less severe.

Genetics — NALD is inherited in an autosomal recessive manner. The majority of patients have mutations in either the PEX1 or PEX6 genes that encode ATPases needed to import proteins into peroxisomes [45].

Clinical features — Presentation of NALD is at birth. The craniofacial appearance is dysmorphic, but less marked than ZWS, and consists primarily of mid-face hypoplasia [2]. Patients typically have hepatomegaly but do not have renal microcysts or chondrodysplasia punctata.

Affected children rarely have clinically significant adrenal insufficiency, although they typically have adrenal cortical atrophy. The response to adrenocorticotropic hormone (ACTH) stimulation is reduced. (See "Causes of primary adrenal insufficiency in children" and "Clinical manifestations and diagnosis of adrenal insufficiency in children".)

Neurologic features include weakness and hypotonia, optic atrophy, and seizures. Tremor, hyperreflexia, ataxia, sensory deficits, and progressive visual and auditory dysfunction develop during infancy [2,53]. Some individuals walk, but cognitive function is poor.

Neurologic regression typically occurs in early childhood. Most children die before three to five years of age.

Neuroimaging — Cranial MRI shows severe white matter deficiency. Cerebral cortical heterotopias and polymicrogyria are seen.

Laboratory studies — The biochemical findings in the disorders of peroxisomal biogenesis are due to deficient VLCFA beta-oxidation, phytanic acid oxidation, and plasmalogen synthesis. In NALD, this results in the same biochemical abnormalities seen in ZWS.

Infantile Refsum disease — Infantile Refsum disease (IRD) (MIM #266510) is the third disorder of peroxisomal biogenesis in which multiple peroxisomal functions are lost. It is less severe than ZWS or NALD.

Genetics — IRD is inherited in an autosomal recessive manner. The majority of patients have mutations in either the PEX1 or PEX6 genes that encode ATPases needed to import proteins into peroxisomes [45,54].

Clinical features — IRD typically presents at one to six months of age with severe developmental delay [2]. Because dysmorphic features are mild or absent, the diagnosis is often delayed. Dysmorphic features, when present, are mild to moderate and include a flat nasal bridge, epicanthal folds, and low-set ears. Affected infants typically have hypotonia, abnormalities of the optic nerve and disc, retinitis pigmentosa, and sensorineural hearing loss.

Some infants present with gastrointestinal abnormalities, including vomiting, diarrhea, and malabsorption [55]. Most have hepatomegaly with cirrhosis.

Neurologic deterioration is slower than in ZWS or NALD. Most affected individuals can walk, although they have ataxia. Many survive into adolescence.

Laboratory studies — The biochemical findings in the disorders of peroxisomal biogenesis are due to deficient VLCFA beta-oxidation, phytanic acid oxidation, and plasmalogen synthesis. In IRD, this results in biochemical abnormalities similar to ZWS and NALD, although less pronounced.

Less severe phenotypes — Some individuals with peroxisome biogenesis disorders survive to adulthood, in one instance to the fifth decade [56]. In one series of 31 individuals with prolonged survival, diagnosis was often delayed because dysmorphic features were mild or absent. Clinical features included: retinopathy, sensorineural hearing impairment, moderate to severe psychomotor retardation, and postnatal growth failure. Mutations in the PEX1 gene, particularly the G843D mutation was the most common cause.

RHIZOMELIC CHONDRODYSPLASIA PUNCTATA TYPE 1 — Rhizomelic chondrodysplasia punctata type 1 (RCDP1) (MIM #215100) is a rare disorder of peroxisome biogenesis. Unlike Zellweger syndrome (ZWS), neonatal adrenoleukodystrophy (NALD), and infantile Refsum disease (IRD), fewer peroxisomal enzymes are affected. In the majority of affected children, fibroblasts are deficient in dihydroxyacetonephosphate acyltransferase (DHAP-AT) and alkyldihydroxyacetonephosphate synthase (alkyl-DHAP synthase), the two enzymes needed for plasmalogen synthesis. The third enzyme deficient in RCDP1 is phytanoyl-CoA hydroxylase, a key enzyme involved in phytanic acid alpha-oxidation [57]. They are also unable to import peroxisomal thiolase.

Genetics — RCDP1 is caused by mutations in the PEX7 gene, mapped to chromosome 6p22-q24 [37,57-61]. This gene encodes the peroxisomal type 2 targeting signal receptor that helps target cytosolic proteins to the peroxisome. Some of those with Refsum disease also have mutations in this gene [62].

Clinical features — RCDP presents in early childhood with profound global developmental delay and dysmorphic facies. The unique feature is severe short stature that primarily affects the proximal long bones. Congenital cataracts and ichthyosis affect approximately 72 and 27 percent of patients, respectively. Joint contractures are common. The natural history is uncertain. (See "Cataract in children".)

Radiographic studies — The characteristic radiographic finding is chondrodysplasia punctata, the stippled calcification present in long bones and vertebrae. Ossification of the humerus and femur is also abnormal. Lateral films of the spine demonstrate an unusual coronal cleft of the vertebral bodies, which is thought to represent an embryonic arrest of bony development.

MR imaging and hydrogen-1 magnetic resonance (MR) spectroscopy of the brain was reported in one child [63]. Areas of abnormal signal intensity were seen in the subcortical white matter. Metabolic abnormalities consistent with the deficiency in plasmalogen biosynthesis were detected by spectroscopy in normal-appearing white matter. These included increased levels of mobile lipids and myo-inositol, decreased choline, and the presence of acetate. In a neonate, MR imaging revealed pachygyria-polymicrogyria, brainstem and spinal cord compression due to spinal stenosis, and tethering of the spinal cord [64].

In another report, MR imaging was performed and correlated with clinical and biochemical profiles in 10 individuals (age 0.4 to 20.7 years) with RCDP type 1, and 1 with RCDP type 3 [65]. MR imaging abnormalities (including ventricular enlargement, increased subarachnoid spaces, supratentorial myelin abnormalities, and progressive cerebellar atrophy) were present in those with severe RCDP (defined by inability to sit and deficient verbal and nonverbal communication), but not in those with mild RCDP (defined by ability to sit and possession of verbal communication skills). The severity of the clinical and MR imaging abnormalities correlated with the plasmalogen levels but was not related to the phytanic acid level.

Laboratory studies — The diagnosis of RCDP can be made by demonstrating deficiency in plasmalogen synthesis and phytanic acid oxidation in fibroblasts [2]. Genetic tests are available and can be used to confirm the diagnosis and assess genotype-phenotype correlations [37,61]. Plasma VLCFA concentration is not elevated in this disorder. Erythrocyte levels of plasmalogen are decreased. Plasma concentrations of phytanic acid are increased, and pristanic acid levels are normal.

ADRENOLEUKODYSTROPHY — Adrenoleukodystrophy (ALD) (MIM #300100) is a peroxisomal disorder of beta-oxidation that results in accumulation of very long-chain fatty acids (VLCFA) in all tissues. Abnormalities in ALD primarily affect the central nervous system, adrenal cortex, and Leydig cells in the testis. Affected males have one of three main phenotypes (childhood cerebral forms, adrenomyeloneuropathy [AMN], and Addison disease) (table 1) [66]. These conditions are known as the ALD/AMN complex. The clinical course is milder in females carriers and the onset is later (after age 35 years) than in affected males, though most female carriers develop symptoms of AMN by age 60 [67]. The disorder is discussed in detail separately. (See "X-linked adrenoleukodystrophy and adrenomyeloneuropathy".)

REFSUM DISEASE — Refsum disease (MIM #266500) is also known as hereditary motor and sensory neuropathy IV, and heredopathia atactica polyneuritiformis. (See "Neuropathies associated with hereditary disorders".) A major difference from other peroxisomal disorders is that this disorder responds to dietary treatment.

Genetics — Refsum disease is an autosomal recessive disorder. In most instances, Refsum disease is caused by mutations in the gene (PHYH) encoding the enzyme phytanoyl-CoA hydroxylase (PAHX), located on chromosome 10pter-p11.2 [68-70].

Some individuals with Refsum disease without mutations in the PAHX gene have mutations in the PEX7 gene, mapped to chromosome 6p22-q24 [62]. This gene encodes the peroxisomal type 2 targeting signal receptor, which helps to direct certain peroxisomal proteins from the cytosol into peroxisomes. Mutations in PEX7 usually cause RCDP1 but occasionally cause Refsum disease.

Pathophysiology — Phytanic acid, a branched-chain fatty acid derived from the chlorophyll constituent phytol, is present in the typical human diet. Normally it is metabolized by activation to its CoA ester, phytanoyl-CoA, and then alpha-oxidation to pristanic acid. Patients with Refsum disease are unable to degrade phytanic acid because of deficient activity of PAHX, a peroxisomal enzyme that catalyzes the first step of phytanic acid alpha-oxidation. The mechanism of phytanic acid toxicity to neuronal and other tissues is uncertain.

Clinical features — Affected individuals typically present in adolescence, although onset may be later. Initial clinical features include deteriorating vision due to retinitis pigmentosa and anosmia [2,71]. Sensorineural hearing loss, ataxia, peripheral polyneuropathy, ichthyosis, and cardiac conduction defects typically occur after 10 to 15 years in some [72]. Cognitive function is normal.

Laboratory features include elevated cerebrospinal fluid protein concentration (100 to 600 mg/dL) without an increase in cells [68]. Nerve conduction studies typically show slowed conduction velocity. Peripheral nerve biopsy reveals hypertrophic changes with onion bulb formation and paracrystalline inclusions on electron microscopy [73].

The clinical course is variable. Exacerbations may occur with acute illness, fasting, rapid weight loss, surgery, or pregnancy [2].

Laboratory studies — The diagnosis is usually made clinically and confirmed by elevated plasma concentration of phytanic acid and mutation analysis [74]. Values are typically >200 micromol/L, while normal values are usually <15 micromol/L [71,75]. PAHX activity is reduced in fibroblasts.

Treatment — Treatment consists of dietary restriction to eliminate phytol-containing foods, such as meat or fats from ruminating animals, baked goods containing animal fats, and dairy products [2,71]. Management goals are to reduce dietary intake of phytanic acid to less than 10 mg daily and avoidance of rapid weight loss or fasting, conditions which stimulate lipolysis [76]. The range of foods allowed has gradually broadened to include many green vegetables because the free phytol content is low [77].

Strict reduction in dietary phytanic acid intake may be associated with a significant improvement in both the peripheral neuropathy and ataxia [78]. In a series of 13 adult patients with Refsum disease treated with dietary therapy for 10 years or more, phytanic acid levels declined by almost 90 percent [76]. Phytanic acid levels were normalized (<30 micromol/L) in 30 percent of the participants, partially normalized (30 to 300 micromol/L) in 50 percent, and remained elevated (>300 micromol/L) in 15 percent, to some extent reflecting compliance with dietary restriction. None of the participants required plasmapheresis or admission for acute symptoms of Refsum disease.

Phytanic acid concentration can also be reduced by plasmapheresis, which is used when rapid reduction is required, and can be performed serially if necessary [78,79]. Plasmapheresis efficiently removes phytanic acid associated with lipoproteins but does not efficiently deplete phytanic acid in adipose and neural tissue. This approach halts progression of the disease, but does not completely reverse neurologic abnormalities. Ichthyosis, sensory neuropathy, and ataxia resolve in approximately that order, and ECG abnormalities may improve. However, treatment may not affect retinitis pigmentosa, hearing impairment, or anosmia.

OTHER DISORDERS — Other disorders in which only one peroxisomal enzyme is deficient have each been described in a few children. These are phenotypically similar to the peroxisomal biogenesis disorders. All have autosomal recessive inheritance [6].

Acyl-CoA oxidase deficiency — Acyl-CoA oxidase deficiency (MIM #264470), also known as pseudo-NALD, is caused by mutations in the gene encoding the peroxisomal enzyme acyl-CoA oxidase (ACOX), which catalyzes the first step in the peroxisomal beta-oxidation of very long-chain fatty acids (VLCFAs) [80]. Importantly, a different ACOX catalyzes the first step in the oxidation of pristanic acid and di- and tri-hydroxycholestanoic acid. The gene is localized on chromosome 17q25.

Patients with acyl-CoA oxidase deficiency show a variety of clinical symptoms including neonatal hypotonia (92 percent), seizures (91 percent), failure to thrive (38 percent), visual system failure (78 percent), impaired hearing (77 percent), loss of motor achievements (83 percent), hepatomegaly (50 percent), and external dysmorphism (50 percent) [81]. White matter abnormalities are present in all patients. All patients had psychomotor retardation but acquired limited skills, such as sitting and standing unsupported for a few seconds, voluntary control of hand function, and the use of a few words with comprehension of their meaning. The mean age of death is five years, with the oldest patients surviving until 10 years of age.

Deficiency of ACOX results in increased plasma concentration of VLCFAs and normal levels for pristanic acid and the bile acid intermediates. Methods for the enzymatic and molecular diagnosis of ACOX deficiency are available [81].

D-bifunctional protein deficiency — D-bifunctional protein (DBP) deficiency (MIM #261515) is caused by mutations in the gene encoding the peroxisomal enzyme DBP, which catalyzes the second and third steps in the beta-oxidation of VLCFAs, as well as pristanic acid and di- and tri-hydroxy cholestanoic acid [82]. The gene is located on chromosome 5q2. The range of phenotypic expression varies widely. Some individuals resemble those with Zellweger syndrome (ZWS), while others are more mildly affected [39,83]. Survival is reportedly less than with ACOX deficiency.

Deficiency of this enzyme results in increased plasma concentrations of VLCFA, pristanic acid, and the bile acid intermediates, di- and tri-hydroxycholestanoic acid.

Methods for the molecular diagnosis and assessment of genotype-phenotype correlations of D-bifunctional enzyme deficiency are available [39].

RCDP types 2 and 3 — RCDP types 2 (MIM #222765) and 3 (MIM #600121) have clinical features similar to type 1 (image 1). Survival may be significantly limited. However, the biochemical defect is a deficiency of plasmalogen synthesis alone, rather than deficiency of both plasmalogen synthesis and phytanic acid oxidation, as occurs with type 1.

The more common disorder is RCDP2, which is caused by mutations in the GNPAT gene encoding dihydroxyacetone phosphate acyltransferase (DHAP-AT), located on chromosome 1 [84]. RCDP3 is characterized by a deficiency of alkyldihydroxyacetone phosphate synthase (alkyl-DHAP synthase) [85] resulting from mutations in the ADHAPS gene that is located on chromosome 2q31 [86]. In both disorders, erythrocyte plasmalogen concentration is decreased and plasma phytanic acid concentration is normal.

Alpha-methylacyl-CoA racemase (AMACR) deficiency — AMACR is also known as 2-methylacyl-CoA racemase deficiency. Although only four patients have been described so far, it is already clear that the clinical signs and symptoms of AMACR deficiency may differ markedly. Indeed, the first two patients were characterized by an adult-onset sensorimotor neuropathy, whereas another patient presented very early in life with fulminant liver failure. At this time, it is too early to tell what the dominant phenotype of AMACR deficiency will be [3].

Pseudo-Zellweger syndrome — The clinical presentation of pseudo-Zellweger syndrome (ZWS) is similar to ZWS. The only reported case was originally thought to be due to a deficiency of the peroxisomal enzyme 3-oxoacyl-coenzyme A thiolase [87] but was later shown to be due to a deficiency of D-bifunctional enzyme [88].

Pseudo-infantile Refsum disease — Pseudo-infantile Refsum disease (IRD) has the clinical features of IRD. In one report, oxidation of phytanic and pipecolic acids was severely reduced, while oxidation of VLCFA and plasmalogen synthesis were only partially reduced [89]. Plasma concentrations of phytanic and pipecolic acids were increased.


Peroxisomes are subcellular organelles that are present in all cells except erythrocytes. They host numerous catabolic and anabolic pathways that are essential to normal cellular metabolism. Peroxisomal disorders are a heterogeneous group of inborn errors of metabolism that result in impairment of peroxisome function. In most cases, this results in neurologic dysfunction of varying extent. (See 'Introduction' above.)

Classification – Disorders of peroxisome biogenesis include (see 'Classification' above):

Zellweger spectrum disorders – In these disorders, multiple peroxisomal functions are deficient and peroxisomes are reduced in number. They include:

-Zellweger syndrome (ZWS) (see 'Zellweger syndrome' above)

-Neonatal adrenoleukodystrophy (see 'Neonatal adrenoleukodystrophy' above)

-Infantile Refsum disease (IRD) (see 'Infantile Refsum disease' above)

ZWS is the most common peroxisomal disorder presenting in early infancy. It is characterized by craniofacial dysmorphism (picture 1), profound neurologic abnormalities, hepatomegaly, glomerulocystic kidney disease, cataracts, and pigmentary retinopathy. (See 'Zellweger syndrome' above.)

Rhizomelic chondrodysplasia punctata type 1 – In this disease, peroxisomes are normal and only two peroxisomal functions are lost. (See 'Rhizomelic chondrodysplasia punctata type 1' above.)

Refsum disease – Refsum disease (phytanoyl-CoA hydroxylase deficiency) is the sole peroxisomal disorder that responds to therapy, which includes dietary restriction of phytol-containing foods and avoidance of fasting or rapid weight loss. Plasmapheresis may be utilized when rapid reduction of phytols is required. (See 'Refsum disease' above.)

X-linked adrenoleukodystrophy (X-ALD) – X-ALD is discussed in detail separately. (See "X-linked adrenoleukodystrophy and adrenomyeloneuropathy".)

Other – Other peroxisomal disorders includes (see 'Other disorders' above):

-Acyl-CoA oxidase deficiency (pseudo-neonatal adrenoleukodystrophy) (see 'Acyl-CoA oxidase deficiency' above)

-D-bifunctional protein deficiency (see 'D-bifunctional protein deficiency' above)

-Others rare disorders (see 'Other disorders' above)

Clinical presentation – Peroxisomal disorders can present in infancy or later in childhood:

In neonates and infants, peroxisomal disorders typically present with hypotonia, decreased activity, encephalopathy, seizures, craniofacial dysmorphism, skeletal abnormalities, failure to thrive, hepatomegaly, prolonged jaundice, neurologic dysfunction, visual abnormalities, and hypocholesterolemia. (See 'Clinical presentation' above.)

In older children, peroxisomal disorders may present with behavioral changes, psychomotor retardation, intellectual deterioration, neurologic dysfunction, hearing loss, or visual abnormalities. (See 'Clinical presentation' above.)

Approach to diagnosis – Plasma levels of very long-chain fatty acids (VLCFAs) are elevated in nearly all peroxisomal disorders and are the first step in establishing the diagnosis. Disorders of peroxisome biogenesis can be distinguished from peroxisomal beta-oxidation defects by additional measurements. In most cases, the diagnosis is confirmed with genetic testing. (See 'Approach to diagnosis' above.)

ACKNOWLEDGMENT — The editorial staff at UpToDate would like to acknowledge Alan K Percy, MD, and Raphael Schiffman, MD, MHSc, FAAN, who contributed to earlier versions of this topic review.

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