Peroxisomal disorders

INTRODUCTION — Peroxisomal disorders are a heterogeneous group of inborn errors of metabolism caused by impairment in the biogenesis of peroxisomes or one of their metabolic functions. In most cases, this results in neurologic dysfunction of varying extent.

The major peroxisomal disorders will be reviewed here. The most common peroxisomal disorder, X-linked adrenoleukodystrophy, is discussed in detail separately. (See "Clinical features, evaluation, and diagnosis of X-linked adrenoleukodystrophy".)

CLASSIFICATION — Various classification schemas have been proposed for peroxisomal disorders. In general, they can be classified according to the pathologic mechanism or the clinical characteristics.

Classification by mechanism — Peroxisomal disorders are divided into two major categories depending upon whether the defect is in the biogenesis of peroxisomes or a single peroxisomal enzyme deficiency (table 1) [1,2]. More recently, a third category has been described (disorders of peroxisome division); however, disorders in this category are exceedingly rare [3].

●Peroxisome biogenesis disorders (PBD) – The PBD group is subdivided into two distinct subgroups including:

•Zellweger spectrum disorders (ZSD) – In ZSD, there is a generalized loss of peroxisomal functions [4]. (See 'Zellweger spectrum disorders' below.)

•Rhizomelic chondrodysplasia punctata (RCDP) types 1 and 5 – In these disorders, peroxisomes are present, but they lack a specific group of proteins. (See 'RCDP spectrum disorders' below.)

●Single peroxisomal enzyme deficiencies – The following disorders are characterized by deficiency of a single peroxisomal enzyme; peroxisome biogenesis is intact in these disorders:

•ACBD5 (acyl-CoA-binding domain type 5) deficiency (MIM #618863)

•ACOX1 (acyl CoA oxidase-1) deficiency (see 'ACOX1 and DBP deficiencies' below)

•ACOX2 deficiency (MIM #617308)

•AMACR (alpha-methylacyl-CoA racemase) deficiency (see 'Other disorders' below)

•BAAT (bile acid-CoA: amino acid N-acyltransferase) deficiency (see 'Other disorders' below)

•DBP (D-bifunctional protein) deficiency (see 'ACOX1 and DBP deficiencies' below)

•Glycolate oxidase deficiency

•PMP70 (peroxisomal membrane protein 70) deficiency (MIM #616278)

•Primary hyperoxaluria type 1 (alanine glyoxylate aminotransferase deficiency) (see "Primary hyperoxaluria", section on 'Primary hyperoxaluria type 1')

•RCDP types 2, 3, and 4 (see 'RCDP spectrum disorders' below)

•Refsum disease (phytanoyl CoA hydroxylase deficiency)

•SCPX (sterol carrier protein X) deficiency (MIM #613724)

•X-linked adrenoleukodystrophy (X-ALD) (see "Clinical features, evaluation, and diagnosis of X-linked adrenoleukodystrophy")

●Disorders of peroxisome division – These are rare disorders caused by mutations in genes encoding proteins involved in peroxisome division (eg, PEX11 beta, DLP1/DNML1, MFF, GDAP1) [3].

Clinical classification — Clinically, the peroxisomal disorders can be subdivided into six main groups, including (table 2):

●Cerebrohepatorenal syndromes – This category includes disorders that are characterized by variable degrees of liver and kidney involvement in conjunction with neurologic abnormalities, vision and hearing impairment, and craniofacial dysmorphisms. These include:

•Zellweger spectrum disorders (see 'Zellweger spectrum disorders' below)

•ACOX1 deficiency (see 'ACOX1 and DBP deficiencies' below)

•DBP deficiency (see 'ACOX1 and DBP deficiencies' below)

●Rhizomelic chondrodysplasias – This category includes RCDP types 1 to 5. The unique feature that distinguishes RDCPs from other peroxisomal disorders is pronounced short stature that primarily affects the proximal long bones (rhizomelia). Other clinical features include developmental delay, dysmorphic facies, congenital cataracts, ichthyosis, and joint contractures. (See 'RCDP spectrum disorders' below.)

●Refsum disease – Refsum disease is characterized by progressive vision loss and peripheral neuropathy. Unlike many other peroxisomal disorders, which often present in infancy or early childhood, Refsum disease typically presents in adolescence or early adulthood. (See 'Refsum disease' below.)

●X-ALD – The clinical spectrum of X-ALD is variable, as summarized in the table (table 3) and discussed in detail separately. (See "Clinical features, evaluation, and diagnosis of X-linked adrenoleukodystrophy", section on 'Clinical features'.)

●Primary hyperoxaluria type 1 (PH1) – PH1 is characterized by recurrent kidney stones and chronic kidney disease. It is discussed in detail separately. (See "Primary hyperoxaluria", section on 'Primary hyperoxaluria type 1'.)

●Other rare disorders – The fifth category consists of a group of rare disorders with variable features. Some of these disorders are newly recognized and the full spectrum of disease is still emerging. These include (see 'Other disorders' below):

•ACBD5 deficiency

•ACOX2 deficiency

•AMACR deficiency

•BAAT deficiency

•SCPX deficiency

•PMP70 deficiency

•Glycolate oxidase deficiency

•Disorders of peroxisome division

EPIDEMIOLOGY — Peroxisomal disorders occur in approximately 1 to 5 per 10,000 live births [2]. In one study, among 1000 patients with inborn errors of metabolism referred to a tertiary center between 1982 and 1997, peroxisomal disorders accounted for 3 percent [5].

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

Zellweger syndrome is the most common peroxisomal disorder presenting in early infancy, with an estimated incidence of 1 to 4 per 100,000 live births [6].

PATHOPHYSIOLOGY — 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 [7]. Although long regarded as organelles of little physiologic significance, peroxisomes are now known to catalyze a number of different functions in cellular metabolism, which include the following [8-10]:

●Catalytic functions:

•Beta-oxidation of very long chain fatty acids (VLCFA), pristanic acid, and long-chain dicarboxylic acids

•Alpha-oxidation of phytanic acid

•Oxidation of pipecolic acid

•Detoxification of glyoxylate

•Degradation of hydrogen peroxide by catalase

●Anabolic functions:

•Synthesis of bile acids

•Synthesis of plasmalogens, which are important components of cell membranes and myelin

•Synthesis of certain polyunsaturated fatty acids (PUFAs), notably docosahexaenoic acid (C22:6).

The pathophysiology of the different peroxisomal disorders is complex:

●Zellweger spectrum disorder (ZSD) – In ZSD, there is a generalized loss of peroxisomal functions, caused by molecular defects in different genes coding for peroxins, which are proteins required for the proper biogenesis and maintenance of peroxisomes [4]. These defects interfere with the formation of pre-peroxisomal vesicles at the site of the endoplasmic reticulum, subsequent import of peroxisomal proteins into vesicles, and/or maintenance of peroxisomes [4]. (See 'Zellweger spectrum disorders' below.)

In patients with ZSD who have isolated defects in the peroxisomal beta-oxidation system, the neuropathology appears to be related to cellular injury from metabolites that accumulate as a result of the deficiency.

●Rhizomelic chondrodysplasia punctata (RCDP) type 1 – In type 1 RCDP, peroxisomes are present, but they lack a specific group of proteins due to mutations in one of the peroxisome biogenesis (PEX) genes (most commonly PEX7) [11]. This affects one of the two major import pathways for peroxisomal proteins into peroxisomes (ie, the PTS2-import pathway). As a consequence, several peroxisomal proteins targeted to peroxisomes via the PTS2-pathway are deficient. The result is impaired synthesis of ether phospholipids and the alpha-oxidation of phytanic acid. (See 'RCDP spectrum disorders' below.)

●Refsum disease – Accumulation of phytanic acid is the sole biochemical abnormality responsible for the physiologic consequences of Refsum disease. Phytanic acid is a branched-chain fatty acid derived from the chlorophyll constituent phytol that is present in the typical human diet. Normally, phytanic acid is metabolized by activation to its CoA ester, phytanoyl-CoA, and then metabolized via 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 by which phytanic acid is toxic to neuronal and other tissues is uncertain. (See 'Refsum disease' below.)

●ACOX2 and AMACR deficiencies – In Acyl-CoA oxidase 2 (ACOX2) and alpha-methylacyl-CoA racemase (AMACR) deficiencies, bile acid synthesis is impaired. The resulting accumulation of bile acids intermediates cause early-onset liver disease as the dominant feature. Patients with AMACR deficiency may also develop late-onset progressive neurologic disease. (See 'Other disorders' below.)

NEUROPATHOLOGY — Mounting evidence implicates mitochondrial dysfunction as a potential trigger of both neurodevelopmental defects and neurodegeneration [12]. Accumulation of alpha-synuclein oligomers, cell signaling abnormalities and inflammation have been suggested as additional disease mechanism [12].

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

●Migration and differentiation defects – Abnormal neuronal migration and differentiation vary in severity among the different disorders [13]. Migration of all neuronal classes appears to be affected, especially those destined for the outer layers of cortex.

The abnormalities are most prominent in Zellweger spectrum disorder (ZWS) and ZWS-like disorders, including D-bifunctional protein (DBP) deficiency. ZWS and DBP are characterized by a unique combination of centrosylvian pachygyria-polymicrogyria likely responsible for seizures and global developmental delay seen in these patients [14]. In patients with neonatal adrenoleukodystrophy (NALD), which is now classified as part of the ZWS spectrum, less severe defects in cerebral migration, usually polymicrogyria, occur as diffuse, focal, or multifocal lesions that may be associated with subcortical heterotopias [15]. These also occur in DBP deficiency [16,17]. More subtle neuronal migration defects appear as heterotopic Purkinje cells [18,19]. These are usually asymptomatic.

Neuronal migration abnormalities do not occur in all peroxisomal disorders. None have been identified in classic Refsum disease, acyl-CoA oxidase deficiency (pseudo-NALD), or X-linked adrenoleukodystrophy (X-ALD). They occur rarely in rhizomelic chondrodysplasia punctate (RCDP) [20].

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 [21]. 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 [22,23] or noninflammatory, and nonspecific decreases in myelin volume or staining [24]. 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 X-ALD. This is discussed in detail separately. (See "Clinical features, evaluation, and diagnosis of X-linked adrenoleukodystrophy", section on 'Neuropathology'.)

Other conditions in which inflammatory demyelination lesions occur include NALD [15], and some cases of DBP deficiency.

•Noninflammatory dysmyelination – Noninflammatory dysmyelination is seen in the early stages of adrenomyeloneuropathy (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, alpha-methylacyl-CoA racemase [AMACR] deficiency, RCDP, and acyl CoA oxidase deficiency) or retinal pigmentary degeneration (in ZWS 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 [25]. Mitochondrial pathology [26] and oxidative stress [27] also contribute to pathogenesis.

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

CLINICAL SUSPICION OF PEROXISOMAL DISORDERS

Common clinical features — The clinical spectrum of peroxisomal disorders is broad, ranging from severe neurologic disability presenting in the neonatal period to minor symptoms manifesting in adulthood. Despite these phenotypic variabilities, there are recognizable patterns in clinical presentation suggestive of a peroxisomal disorder.

Common clinical features that should prompt consideration of a peroxisomal disorder include [5,28-30]:

●Central and peripheral nervous system findings – Patients can present with variable degrees of developmental delay or cognitive impairment. Neurological examination may reveal signs of ataxia, myelopathy, and/or peripheral neuropathy.

●Vision problems, retinopathy, cataracts, and other eye problems.

●Sensorineural hearing loss.

●Liver disease.

●Adrenal insufficiency.

●Skeletal abnormalities, such as short stature and calcific stippling on bone radiographs (chondrodysplasia punctata).

Patients identified through next-generation sequencing — Increasingly, patients with peroxisomal disorders are identified through next-generation sequencing methods, including whole genome or whole exome sequencing (WGS or WES). (See "Inborn errors of metabolism: Identifying the specific disorder", section on 'Molecular genetic testing'.)

In most cases when a peroxisomal disorder is identified through WGS or WES, it is appropriate to perform confirmatory biochemical testing for the specific disorder, as discussed in the following sections.

SPECIFIC DISORDERS

Zellweger spectrum disorders — Zellweger syndrome (ZS; MIM #214100), also known as cerebrohepatorenal syndrome, is the prototype of the group of peroxisome biosynthesis disorders. It is characterized by craniofacial dysmorphisms and profound neurologic abnormalities. It is now recognized that ZS represents the most severe presentation within a larger spectrum known as the Zellweger spectrum disorders (ZSDs).

There is considerable variability within the literature regarding the classification of milder variants within the ZSD category. Some conditions included in this category were previously considered separate disorders (eg, neonatal adrenoleukodystrophy [NALD] and infantile Refsum disease [IRD]). However, since NALD and IRD are caused by the same genetic variants as ZSD (PEX1 and PEX6) with a similar constellation of clinical and laboratory findings, they are now considered part of the Zellweger spectrum. As discussed below, D-bifunctional protein (DBP) deficiency and Acyl CoA oxidase-1 (ACOX1) deficiency are clinically indistinguishable from the ZSDs. (See 'ACOX1 and DBP deficiencies' below.)

Genetics

●Genetic variants – ZSDs are caused by mutations in at least 14 different PEX genes which are inherited in an autosomal recessive pattern [31]. Variants in either the PEX1 or PEX6 genes account for approximately 75 percent of cases. PEX1 or PEX6 encode for ATPases that are required to import proteins from the cytosol into peroxisomes [32]. A minority of cases are caused by variants in other PEX genes [33-35].

●Genotype-phenotype relationship – The genotype-phenotype relationship has best been established for variants in PEX1 [36]. Patients with frame shift mutations in PEX1 (referred to as Maxwell variants) have fully inactive protein [37]. These patients are severely affected and do not survive beyond infancy. By contrast, patients homozygous for the G843D variant in PEX1 have some residual protein function and are usually less severely affected. These patients present with features including developmental delay, cerebellar ataxia, peripheral neuropathy, and vision and hearing problems, but they lack craniofacial features and are not at risk for early mortality.

Clinical features — There are three general categories of ZSDs based upon the age at presentation:

●Classical infantile ZS – Infants with classical ZS present in the newborn period with a severe phenotype characterized by a combination of characteristic findings, including [30,38,39]:

•Craniofacial dysmorphisms, which may include (picture 1):

-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

•Hepatomegaly with associated with cholestasis, cirrhosis, biliary dysgenesis, and coagulopathy

•Neurologic abnormalities, including:

-Profound hypotonia and weakness with absent reflexes

-Severe hearing and vision impairment

-Neonatal seizures

-Profound global developmental delay

•Calcific stippling of the patellae, hips, and other epiphyses (chondrodysplasia punctata), which is present in 50 to 70 percent of affected infants [40]

•Cystic kidney disease

•Pigmentary retinopathy and cataracts [41] (see "Cataract in children")

Infants with classical ZS typically do not reach any developmental milestones and survival beyond the age of 6 to 12 months is rare [40].

●Childhood presentation – The usual onset for this category is between the first and second year of life. The disease spectrum of the childhood form is more variable compared with infantile (classical) ZS, though there is some overlap:

•Developmental delay – Children may first come to clinical attention because of delayed developmental milestones and/or hypotonia.

•Vision and hearing impairment – Progressive bilateral visual impairment and sensorineural hearing loss are consistent features. Ocular abnormalities include pigmentary retinopathy, cataract, optic nerve atrophy, glaucoma, and Bushfield spots.

•Liver disease – Liver dysfunction with hepatomegaly, portal hypertension, prolonged jaundice, and cholestasis are frequent findings.

•Facial dysmorphism are usually more subtle compared with classical ZS.

The prognosis is variable, depending on the constellation of findings; most patients do not survive to adulthood [42].

●Adolescent/adult presentation – The phenotypic spectrum of ZSD presenting in adolescence and adulthood is much broader, including patients with isolated hearing loss and vision problems or isolated cerebellar ataxia [43,44]. Sensorineural hearing loss and ocular abnormalities are important clues to the diagnosis of ZDS in these patients [6]. Craniofacial dysmorphisms tend to be subtle or completely absent. Cognitive function can range from normal to severe intellectual disability. Adrenal insufficiency is common although it is asymptomatic in >50 percent of affected patients [45].

Neuroimaging findings — Findings on brain magnetic resonance imaging (MRI) include cortical and white matter abnormalities [46]. In a study of six infants with ZWS, all had impaired myelination and diffusely abnormal cortical gyral patterns, consisting of microgyria and pachygyria [47]. All had germinolytic cysts in the caudothalamic groove. In mildly affected patients, MRI abnormalities may be subtle or absent [48-50].

Diagnosis

●Initial testing – When ZSD is clinically suspected, we suggest initial testing with a plasma C26:0-lysophosphatidylcholine (C26:0-LPC) level. C26:0-LPC is a more sensitive marker compared with the standard very long-chain fatty acid (VLCFA) parameters (which include C26:0 level, ratio of C26:0 to docosanoic acid [C26:0/C22:0], and ratio of C26:0 to tetracosanoic acid [C26:0/C24:0]) [51]. However, C26:0-LPC analysis is not available in all settings and standard VLCFA analysis is acceptable for initial testing if C26:0-LPC is not available.

Elevated plasma VLCFA levels, particularly C26:0-LPC, are suggestive of ZSD, DBP deficiency, or ACOX1 deficiency [52-56]. These levels are also elevated in patients with X-ALD, as discussed separately. (See "Clinical features, evaluation, and diagnosis of X-linked adrenoleukodystrophy", section on 'Very long-chain fatty acid levels'.)

VLCFA levels can occasionally be normal in patients with ZSD, particularly those who are older and/or mildly affected. In addition, abnormal VLCFA can be seen in patients without peroxisomal disorders who are on ketogenic diets and occasionally in those who have consumed large amounts of peanuts [57,58].

●Further biochemical testing – If plasma C26:0-LPC or VLCFA analysis is abnormal, additional testing is performed in the same blood sample, including:

•Analysis of peroxisomal biomarkers in plasma (bile acid intermediates, phytanic acid, pristanic acid, pipecolic acid)

•Peroxisomal biomarkers in erythrocytes (plasmalogens)

●Distinguishing between ZSD and DBP or ACOX1 deficiency – Analysis of this set of peroxisomal biomarkers usually allows discrimination between ZSDs and DBP or ACOX1 deficiency. In patients with ZSD, all peroxisomal biomarkers (including erythrocyte plasmalogen levels) are abnormal whereas in patients with DBP or ACOX1 deficiency, erythrocyte plasmalogen levels are normal. ACOX1 deficiency can easily be distinguished from DBP deficiency because in ACOX1 deficiency, there is only accumulation of VLCFAs. By contrast, in DBP deficiency, there is accumulation of VLCFAs, bile acid intermediates, and pristanic and phytanic acid. A pitfall is that mildly affected patients may show a less uniform biochemical phenotype which may make it challenging to interpret the initial laboratory findings.

●Confirming the diagnosis (genetic testing) – The combination of characteristic clinical features, abnormal VLCFA levels, and pattern of peroxisomal biomarkers in plasma and erythrocytes is sufficient to establish a preliminary diagnosis of ZSD. The diagnosis is confirmed with genetic testing. Genetic testing ensures certainty of the diagnosis and facilitates genetic counseling. Testing consists of sequencing analysis of the PEX genes. Gene panels are available that simultaneously test for multiple genetic variants that cause ZSD and other peroxisomal disorders (eg, PEX screen and others). Additional information on genetic testing, including a list of accepted laboratories providing this testing, is available through the genetic testing registry.

In some cases, additional functional studies in fibroblasts are needed to confirm the diagnosis [59]. This most commonly occurs when genetic testing identifies new mutations or variants of uncertain significance (VUS). Functional assays are performed in this setting to evaluate the biochemical significance of the variant.

Treatment — Treatment for patients with ZSD, DBP deficiency, or ACOX1 deficiency is supportive. There are no treatments that effectively correct the underlying metabolic pathophysiology or prevent or arrest neurologic and other consequences of the disease. Appropriate counseling and support should be provided for the family/caregivers.

Treatments that have been investigated include:

●Docosahexaenoic acid (DHA) supplementation – Limited observational data suggest that DHA supplementation may improve some biochemical markers in patients with ZSD [60]; however, in a small randomized trial, DHA supplementation did not meaningfully improve clinical outcomes [61].

●Cholic acid supplementation – A small uncontrolled study demonstrated that cholic acid supplementation reduced levels of toxic bile acid intermediates compared with pretreatment baseline levels in patients with ZSD [62]; however, after 21 months of treatment, there were no apparent improvements in any clinically relevant outcomes (eg, liver function, growth, survival) [63]. Nevertheless, cholic acid has been approved by the United States Food and Drug Administration for this indication [64]. It was also approved by the European Medicines Agency (EMA), but it was subsequently withdrawn from the European market [65].

ACOX1 and DBP deficiencies — The clinical signs and symptoms in patients with ACOX1 deficiency or DBP deficiency are indistinguishable from those of patients with ZSD [66,67]. Indeed, the first reported cases of DBP deficiency were described as pseudo-Zellweger syndrome. (See 'Zellweger spectrum disorders' above.)

The similarities extend to neuroimaging findings, which include both developmental abnormalities (such as cortical dysplasia, peri-Sylvian polymicrogyria, delayed myelination, and germinolytic cysts) as well as late onset progressive lesions (decreasing white matter volume and bilateral ventricular dilatation and white matter lesions) [29]. (See 'Neuroimaging findings' above.)

The approach to diagnostic testing is the same as for ZSD (ie, plasma C26:0-LPC or VLCFA analysis is the initial test). Ultimately, these disorders are distinguished from ZSD on the basis of the pattern of peroxisomal biomarkers in plasma and erythrocytes and by molecular genetic testing, as discussed above. (See 'Diagnosis' above.)

RCDP spectrum disorders — Rhizomelic chondrodysplasia punctata (RCDP) type 1 (MIM #215100) is the prototype of this group of peroxisomal chondrodysplasias which now includes five distinct genetic forms.

Genetics — Five different genotypic variants of RCDP have been identified, all of which have an autosomal recessive inheritance pattern:

●RCDP type 1 – RCDP type 1 is caused by variants in the PEX7 gene. This is the most common form of RCDP, accounting for 80 to 90 percent of cases [68-74]. PEX7 encodes the peroxisomal type 2 targeting signal receptor that helps target cytosolic proteins to the peroxisome. PEX7 variants can also cause Refsum disease [75]. (See 'Refsum disease' below.)

●RCDP type 2 – RCDP type 2 is caused by variants in the gene that encodes glycerone-3-phosphate:acyltransferase (GNPAT).

●RCDP type 3 – RCDP type 3 is caused by variants in the gene that encodes alkylglycerone-3-phosphate synthase (AGPS).

●RCDP type 4 – RCDP type 4 is caused by variants in the gene that encodes fatty acyl-CoA reductase 1 (FAR1) [76].

●RCDP type 5 – RCDP type 5 is caused by variants in PEX5 [77].

RCDP type 1 and 5 are classified as peroxisome biogenesis disorders since PEX7 and PEX5 genes encode proteins involved in the proper targeting of peroxisomal proteins to peroxisomes. RCDP types 2, 3, and 4, are single peroxisomal enzyme deficiencies. In all five types of RCDP, synthesis of ether phospholipid is defective, which leads to a deficiency of plasmalogens (the dominant ether phospholipid species in mammals) in all cell types, including erythrocytes.

Clinical features — Despite the variety in the molecular defects, RCDP types 1, 2, 3, and 5 are clinically indistinguishable. The clinical features of RCDP type 4 are somewhat distinct though there are few reported cases [76].

RCDPs present in early childhood with characteristic findings that include:

●Short stature with rhizomelia – The unique feature that distinguishes RDCPs from other peroxisomal disorders is pronounced short stature that primarily affects the proximal long bones (rhizomelia).

●Global developmental delay, which can be profound.

●Dysmorphic facies.

●Congenital cataracts (present in approximately 70 percent of patients).

●Ichthyosis (present in approximately 25 percent of patients).

●Joint contractures.

●Seizures.

Patients with severe forms of RCDP are generally recognized shortly after birth with typical symmetrical shortening of the proximal extremities (rhizomelia) and facial dysmorphisms. In patients with milder phenotypes, there may be only minor shortening of the proximal extremities with normal or near normal stature. Developmental delay can also be less severe. In these mildly affected patients, the diagnosis is more difficult.

Radiographic findings — The characteristic radiographic finding is chondrodysplasia punctata, the stippled calcification present in long bones and vertebrae (image 1). Ossification of the humerus and femur is also abnormal. Spine radiographs demonstrate an unusual coronal cleft of the vertebral bodies, which is thought to represent an embryonic arrest of bony development.

Neuroimaging findings — Reported findings on brain MRI in patients with RDCPs include [78-80]:

●White matter changes

●Pachygyria and polymicrogyria

●Ventriculomegaly

●Increased subarachnoid spaces

●Cerebellar atrophy

Children with more severe clinical disease are more likely to have abnormal MRI findings [80].

Even in the absence of white matter lesions on routine MRI, hydrogen-1 MR spectroscopy may demonstrate metabolic abnormalities consistent with the deficient plasmalogen biosynthesis [78].

Diagnosis — When rhizomelic chondrodysplasia is suspected clinically, we suggest initial testing with erythrocyte plasmalogen analysis. Plasma VLCFA analysis does not play a role in the diagnosis of RCDPs since VLCFA levels are not elevated in these disorders.

RCDPs of all types and severities are associated with low levels of plasmalogens, although the deficiency may be less pronounced in mildly affected patients [81]. In RCDP types 2, 3, and 4 the deficiency of plasmalogens is the only biochemical abnormality. Patients with RCDP types 1 and 5 typically also have elevated plasma phytanic acid levels, though these levels can be in the normal range, depending on dietary intake of phytanic acid.

The combination of characteristic clinical features and low levels of erythrocyte plasmalogens is sufficient to establish a preliminary diagnosis of RCDP. The diagnosis is confirmed with genetic testing. Genetic testing ensures certainty of the diagnosis and facilitates genetic counseling. Gene panels are available that simultaneously test for multiple genetic variants that cause RDCPs and other peroxisomal disorders [68,73]. Additional information on genetic testing, including a list of accepted laboratories providing this testing, is available through the genetic testing registry.

Treatment — Treatment for patients with RCDP is supportive and may include:

●Antiseizure medication for patients with seizures (see "Seizures and epilepsy in children: Initial treatment and monitoring")

●Treatment of cataracts (see "Cataract in children")

●Physical therapy to prevent contractures (see "Cerebral palsy: Treatment of spasticity, dystonia, and associated orthopedic issues", section on 'Physical and occupational therapy')

All patients should have routine evaluations to identify cardiac and ocular abnormalities. Orthopedic issues should be managed in collaboration with a pediatric orthopedic specialist. Regular assessment of nutritional status should also be performed.

The available evidence suggests that restriction of phytanic acid intake does not alter the disease course in RCCP [74]. This is in contrast to Refsum disease, which responds to dietary intervention. (See 'Treatment' below.)

Prognosis — The prognosis for patients with RCDP, particularly type 1 RCDP, is generally poor. In a report of 66 patients with RCDP (90 percent had type 1), median survival was 3.9 years [74]. The risk of early death correlated with plasmalogen levels (ie, patients with very low plasmalogen levels had shorter survival compared with those whose plasmalogen levels were only modestly decreased).

Refsum disease — Refsum disease (MIM #266500) is characterized by progressive vision loss and peripheral neuropathy. 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 variants in the gene PHYH, which encodes the enzyme phytanoyl-CoA hydroxylase (PAHX) [82-84]. A minority of individuals with Refsum disease have variants in the PEX7 gene [75].

Clinical features — Patients with adult Refsum disease usually present in adolescence or early adulthood. Clinical features include [40,85]:

●Progressive vision loss – Impaired night vision is often the first symptom, followed by progressive loss of visual acuity due to retinitis pigmentosa (see "Retinitis pigmentosa: Clinical presentation and diagnosis")

●Anosmia

●Sensorineural hearing loss

●Peripheral neuropathy

●Ataxia

●Ichthyosis

●Cardiac arrhythmias (typically with onset 10 to 15 years after initial presentation)

The constellation of symptoms is variable; few patients have all of these findings [85,86]. Cognitive function is typically normal.

The clinical course is variable. Exacerbations of neurologic symptoms may occur with acute illness, fasting, rapid weight loss, surgery, or pregnancy [40].

Brain MRI abnormalities in patients with Refsum disease have been described but no clear pattern can be distinguished [87,88].

Diagnosis — When Refsum disease is suspected clinically, we suggest initial testing with plasma phytanic acid level. Values in individuals with Refsum disease are typically >200 micromol/L, whereas normal values are usually <15 micromol/L [85,89].

The combination of characteristic clinical features and elevated plasma phytanic acid level is sufficient to establish a preliminary diagnosis of Refsum disease. The diagnosis is confirmed with genetic testing [90]. Genetic testing ensures certainty of the diagnosis and facilitates genetic counseling.

Additional confirmatory testing may include a functional assay of PAHX activity in fibroblasts [90]. This is most helpful when genetic testing identifies a VUS. Functional assays are performed in this setting to evaluate the biochemical significance of the variant.

Treatment — The mainstay of treatment is dietary restriction to eliminate phytol-containing foods. Patients with acute severe neurologic symptoms due to elevated phytanic acid levels may require plasmapheresis.

●Dietary restriction of phytanic acid intake – Foods to avoid include [40,85]:

•Meat or fats from cows and other ruminating animals

•Baked goods containing animal fats

•Dairy products

Most green vegetables are allowed since they contain low levels of free phytol [91].

The goal of dietary management is to reduce intake of phytanic acid to <10 mg daily. Care should be taken to avoid rapid weight loss or fasting, since this can trigger exacerbations of neurologic symptoms [92].

Limited data suggest that strict reduction in dietary phytanic acid intake may improve peripheral neuropathy and ataxia [93]. In a series of 13 adult patients with Refsum disease treated with dietary therapy for ≥10 years, phytanic acid levels declined by almost 90 percent [92]. None of the participants required admission for acute symptoms of Refsum disease and/or treatment with plasmapheresis.

●Plasmapheresis – For patients with severe acute neurologic symptoms, plasmapheresis can be used to rapidly lower the phytanic acid level [93,94]. Serial treatments may be necessary in some cases. Plasmapheresis efficiently removes phytanic acid associated with lipoproteins but does not efficiently deplete phytanic acid in adipose and neural tissue. Thus, it does not completely reverse neurologic abnormalities.

X-linked adrenoleukodystrophy — The features of X-linked adrenoleukodystrophy are summarized in the table (table 3) and discussed in detail separately. (See "Clinical features, evaluation, and diagnosis of X-linked adrenoleukodystrophy", section on 'Clinical features'.)

Primary hyperoxaluria type 1 — The primary hyperoxalurias (PH) are a group of rare inborn errors of glyoxylate metabolism resulting in enhanced production of oxalate. Type 1 PH is the most severe form. Affected patients present in infancy or early childhood with symptoms related to nephrocalcinosis, kidney stones, and chronic kidney disease. Type 1 PH is discussed in detail separately. (See "Primary hyperoxaluria", section on 'Primary hyperoxaluria type 1'.)

Other disorders

●ACOX2 deficiency – ACOX2 deficiency is a newly identified defect that is restricted to the involvement of peroxisomes in bile acid synthesis. It has been described in only three patients, all of whom had elevated plasma levels of bile acid intermediates with otherwise normal peroxisomal parameters [95,96]. All three patients had elevated transaminases. Two patients were asymptomatic; the third patient had ataxia, cognitive impairment, and cirrhosis.

●AMACR deficiency – There are few reported cases of AMACR (2-methylacyl-CoA racemase) deficiency in literature. In the available reports, affected patients presented with adult-onset peripheral neuropathy, retinitis pigmentosa, epilepsy, and intermittent encephalopathy [97-103]. There is one case report of an affected patient presenting in the neonatal period with fulminant liver disease presumably due to bile acid abnormalities [104].

●BAAT deficiency – BAAT (bile acid-CoA: amino acid N-acyltransferase) deficiency has been reported in two case series [105,106]. Clinical features of affected patients included fat malabsorption, growth failure, neonatal cholestasis and liver disease (including fulminant liver failure in one patient).

●Other rare disorders – Other rare disorders that have been described in single case reports include:

•ACBD5 (acyl-CoA-binding domain type 5) deficiency [107]

•Glycolate oxidase deficiency [108,109]

•PMP70 (peroxisomal membrane protein 70) deficiency caused by a mutation in the ABCD3 gene [110]

•SCPX (sterol carrier protein X) deficiency [111]

•Rare disorders of peroxisome division (caused by mutations in genes encoding proteins involved in peroxisome division [eg, PEX11 beta, DLP1/DNML1, MFF, GDAP1]) [3]

DIAGNOSISTIC APPROACH

Initial testing — In general, testing for peroxisomal disorders begins with measurement of specific biochemical markers. However, there is no singular approach to the diagnosis of peroxisomal disorders since the choice of initial laboratory test(s) depends upon the constellation of clinical findings. Indeed, the long-held practice of measuring plasma very long-chain fatty acid (VLCFA) levels as an initial screening test to assess for peroxisomal disorders is not advised since VLCFAs are abnormal in only a subset of peroxisomal disorders (specifically, Zellweger spectrum disorders [ZSD], D-bifunctional protein [DBP] deficiency, acyl-CoA oxidase-1 [ACOX1] deficiency, and X-linked adrenoleukodystrophy [X-ALD]). While these represent the most common disorders, there are numerous other peroxisomal disorders that are now recognized that are not associated with elevated plasma VLCFAs.

Testing should be tailored to the specific disorder(s) suspected based upon the constellation of clinical findings (table 2):

●Suspected ZSD (or ACOX1 or DBP deficiency, which are clinically indistinguishable) – Initial testing consists of measuring plasma C26:0-lysophosphatidylcholine (C26:0-LPC), if available. If C26:0-LPC is not available, standard VLCFA analysis is acceptable. (See 'Diagnosis' above.)

●Suspected rhizomelic chondrodysplasia punctata (RCDP) disorders – Initial testing consists of erythrocyte plasmalogen analysis. (See 'Diagnosis' above.)

●Suspected Refsum disease – Initial testing consists of plasma phytanic acid levels. (See 'Diagnosis' above.)

●Suspected X-ALD – Initial testing consists of measuring plasma C26:0-LPC or VLCFA levels (table 3). Laboratory testing for X-ALD is discussed in detail separately. (See "Clinical features, evaluation, and diagnosis of X-linked adrenoleukodystrophy", section on 'Laboratory testing'.)

●Primary hyperoxaluria type 1 (PH1) – Initial testing consists of measuring urinary oxalate. Laboratory testing for PH1 is discussed in detail separately. (See "Primary hyperoxaluria", section on 'Metabolic testing'.)

If results of initial biochemical tests are abnormal, confirmatory genetic testing is generally required. Gene panels are available that simultaneously test for multiple genetic variants that cause peroxisomal disorders. Information on genetic testing, including a list of accepted laboratories providing this testing, is available through the genetic testing registry. Additional confirmatory testing with functional assays using fibroblasts can sometimes be useful in the diagnostic evaluation (eg, if genetic testing identifies a variant of uncertain significance) [59].

Prenatal diagnosis — Prenatal testing for peroxisomal disorders is available for subsequent pregnancies of individuals with affected children or other positive family history. Prenatal diagnostic methods have generally shifted from biochemical to molecular-based methods. Using assisted reproductive technology, preimplantation diagnosis can be achieved in embryos using multiple displacement amplification [112]. Issues related to preimplantation genetic testing 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 in a fetus at risk [113]. The diagnosis was confirmed by metabolic studies on cells obtained by chorionic villus sampling. In another report, 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 [114].

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

The screening approach used for X-ALD, which involves measurement of VLCFAs, may also detect other peroxisomal disorders, including ZSD.

SUMMARY AND RECOMMENDATIONS

●Physiology – 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 'Pathophysiology' above and 'Neuropathology' above.)

Peroxisomal disorders can be caused by defects in the biogenesis of peroxisomes or by deficiencies of individual peroxisomal enzymes (table 1). A rare third category is disorders of peroxisome division. (See 'Classification by mechanism' above.)

●Clinical classification – Clinically, the peroxisomal disorders can be subdivided into six main groups, including (table 2) (see 'Clinical classification' above):

•Cerebrohepatorenal syndromes – This category includes disorders that are characterized by variable degrees of liver and kidney involvement in conjunction with neurologic abnormalities, vision and hearing impairment, and craniofacial dysmorphisms. These include:

-Zellweger spectrum disorders (see 'Zellweger spectrum disorders' above)

-Acyl CoA oxidase-1 (ACOX1) deficiency (see 'ACOX1 and DBP deficiencies' above)

-D-bifunctional protein (DBP) deficiency (see 'ACOX1 and DBP deficiencies' above)

•Rhizomelic chondrodysplasias – This category includes rhizomelic chondrodysplasia punctata (RCDP) types 1 to 5. The unique feature that distinguishes RDCPs from other peroxisomal disorders is pronounced short stature that primarily affects the proximal long bones (rhizomelia). Other clinical features include developmental delay, dysmorphic facies, congenital cataracts, ichthyosis, and joint contractures. (See 'RCDP spectrum disorders' above.)

•Refsum disease – Refsum disease is characterized by progressive vision loss and peripheral neuropathy. Unlike many other peroxisomal disorders, which often present in infancy or early childhood, Refsum disease typically presents in adolescence or early adulthood. Another distinction is that Refsum disease responds to dietary treatment. (See 'Refsum disease' above.)

•X-linked adrenoleukodystrophy (ALD) – The clinical spectrum of X-ALD is variable, as summarized in the table (table 3) and discussed in detail separately. (See "Clinical features, evaluation, and diagnosis of X-linked adrenoleukodystrophy", section on 'Clinical features'.)

•Primary hyperoxaluria type 1 (PH1) – PH1 is characterized by recurrent kidney stones and chronic kidney disease. It is discussed in detail separately. (See "Primary hyperoxaluria", section on 'Primary hyperoxaluria type 1'.)

•Other rare disorders – The fifth category consists of a group of rare disorders with variable features. (See 'Other disorders' above.)

●Clinical features – The clinical spectrum of peroxisomal disorders is broad, ranging from severe neurologic disability presenting in the neonatal period to minor symptoms manifesting in adulthood. Common clinical features that should prompt consideration of a peroxisomal disorder include (see 'Common clinical features' above):

•Central and peripheral nervous system findings

•Vision problems, retinopathy, cataracts, and other eye problems

•Sensorineural hearing loss

•Liver disease

•Adrenal insufficiency

•Skeletal abnormalities, such as short stature and calcific stippling on bone radiographs (chondrodysplasia punctata)

●Diagnostic approach – In general, testing for peroxisomal disorders begins with measurement of biochemical markers. Testing is tailored to the specific disorder(s) suspected based upon the constellation of clinical findings (table 2) (see 'Diagnosistic approach' above):

•Suspected ZSD (or ACOX1 or DBP deficiency, which are clinically indistinguishable) – Initial testing consists of measuring plasma C26:0-lysophosphatidylcholine (C26:0-LPC), where available, or standard very long-chain fatty acid (VLCFA) analysis if C26:0-LPC testing is not available. (See 'Diagnosis' above.)

•Suspected RCDP disorders – Initial testing consists of erythrocyte plasmalogen analysis. (See 'Diagnosis' above.)

•Suspected Refsum disease – Initial testing consists of plasma phytanic acid levels. (See 'Diagnosis' above.)

•Suspected X-ALD – Initial testing consists of measuring plasma C26:0-LYSOPC, where available, or standard VLCFA analysis if C26:0-LYSOPC testing is not available (table 3). (See "Clinical features, evaluation, and diagnosis of X-linked adrenoleukodystrophy", section on 'Laboratory testing'.)

•Primary hyperoxaluria type 1 (PH1) – Initial testing consists of measuring urinary oxalate. (See "Primary hyperoxaluria", section on 'Metabolic testing'.)

If the initial biochemical test is abnormal, confirmatory genetic testing is generally required. Additional confirmatory testing with functional assays using fibroblasts can sometimes be useful in the diagnostic evaluation (eg, if genetic testing identifies a variant of uncertain significance).

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