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Peroxisomal Disorders

By Lee M. Sanders, MD, MPH, Associate Professor of Pediatrics, Stanford University

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Peroxisomes are intracellular organelles that contain enzymes for β-oxidation. These enzymes overlap in function with those in mitochondria, with the exception that mitochondria lack enzymes to metabolize very long-chain fatty acids (VLCFA), those 20 to 26 carbons in length. Therefore, peroxisomal disorders generally manifest with elevated VLCFA levels (except rhizomelic chondrodysplasia). Although VLCFA levels may help screen for these disorders, other assays are also required (eg, plasma levels of phytanic, pristanic, and pipecolic acids; RBC plasmalogen levels). For information on other disorders affecting fatty acid metabolism, see Overview of Fatty acid and Glycerol Metabolism Disorders. Also see Approach to the Patient With a Suspected Inherited Disorder of Metabolism and testing for suspected inherited disorders of metabolism.

There are 2 types of peroxisomal disorders:

  • Those with defective peroxisome formation

  • Those with defects in single peroxisomal enzymes

X-linked adrenoleukodystrophy is the most common peroxisomal disorder (incidence 1/17,000 births); all others are autosomal recessive, with a combined incidence of about 1/50,000 births.

For more information, see Table.

Peroxisome Biogenesis and Very Long-Chain Fatty Acid Metabolism Disorders

Disease (OMIM Number)

Defective Proteins or Enzymes

Defective Gene or Genes (Chromosomal Location)


Cerebrohepatorenal syndrome (Zellweger syndrome; 214100)


PEX1 (7q21-q22)*

Biochemical profile: Decreased dihydroxyacetone phosphate acyltransferase and plasmalogen; elevated very long-chain fatty acids, phytanic acid, pipecolate, iron, and total iron-binding capacity

Clinical features: Growth failure, large fontanelles, macrocephaly, turribrachycephaly, dysmorphic facies, cataracts, nystagmus, congenital heart disease, hepatomegaly, biliary dysgenesis, hypospadias, renal cysts, hypotonia, brain malformation

Treatment: No effective treatment

Ether lipids, low phytanic acid diet, and docosahexanoic acid possibly helpful


PEX2 (8q21.1)*


PEX3 (6q23-q24)*


PEX5 (12p13.3)*


PEX6 (6p21.1)*


PEX12 (17)*


PEX14 (1p36.2)*


PEX26 (22q11.21)*


PEX1 (7q21-q22)*

Biochemical profile: Elevated very long-chain fatty acids

Clinical features:Dolichocephaly, dysmorphic facies, cataracts, hyperpigmentation, seizures, developmental delay, adrenal insufficiency

Treatment: Similar to that for Zellweger syndrome


PEX5 (12p13.3)*


PEX10 (1)*


PEX13 (2p15)*


PEX26 (22q11.21)*


PEX1 (7q21-q22)*

Biochemical profile: Elevated plasma phytanic acid, cholesterol, very long-chain fatty acids, dihydroxycholestanoic acid, trihydroxycholestanoic acid, and pipecolic acid

Clinical features: Growth and developmental delay, peripheral neuropathy, hypotonia, deafness, facial dysmorphism, retinopathy, osteoporosis, steatorrhea, episodic bleeding, hepatomegaly

Treatment: Similar to that for Zellweger syndrome


PEX2 (8q21.1)*


PEX26 (22q11.21)*

Biochemical profile: In type 1, plasmalogen deficiency, elevated plasma phytanic acid and unprocessed 3-oxoacyl CoA thiolase, acyl-CoA dihydroxyacetonephosphate acyltransferase deficiency

In type 2, normal plasmalogen, phytanic acid, alkyl dihydroxyacetonephosphate synthase, and peroxisomal thiolase; dihydroacetonephosphate acyltransferase deficiency

In type 3, abnormal peroxisomes, alkyl dihydroxyacetonephosphate synthase deficiency

Clinical features: Dwarfism with rhizomelic limb shortening, punctuate epiphyseal calcification, and metaphyseal splaying; severe growth and developmental delay; microcephaly; midface hypoplasia; micrognathia; sensorineural deafness; cataracts; cleft palate; ichthyosis; respiratory difficulties; kyphoscoliosis; vertebral clefts; spasticity; cortical atrophy; seizures; death before 2 yr

Treatment: Similar to that for Zellweger syndrome

Type 1 (215100)


PEX7 (6q22-q24)*

Type 2 (222765)

Dihydroxyacetonephosphate acyltransferase

GNPAT (1)*

Type 3 (600121)

Alkyldihydroxyacetonephosphate synthase

AGPS (2q31)*

Hyperpipecolicacidemia (239400)

Pipecolate oxidase

Biochemical profile: Elevated plasma pipecolate, mild generalized aminoaciduria

Clinical features:Hepatomegaly, demyelination, CNS degeneration, severe intellectual disability and developmental delay, retinopathy

Treatment: Reduced intake of very long-chain fatty acids

ATP-binding cassette transporter 1

ABCD1 (Xq28)*

Biochemical profile: Elevated plasma very long-chain fatty acids, peroxisomal lignoceroyl-CoA ligase deficiency

Clinical features:Hyperpigmentation, blindness, cognitive hearing loss, spastic paraplegia, impotence, sphincter disturbance, ataxia, dysarthria, adrenal insufficiency, hypogonadism, pontine and cerebellar atrophy

Treatment: Adrenal hormone replacement, bone marrow transplantation

4:1 mixture of glyceryl trioleate and glycerol trierucate (Lorenzo’s oil) apparently of no clinical benefit

Acyl-CoA oxidase 1 deficiency (pseudoneonatal adrenoleukodystrophy; 264470)

Straight-chain peroxisomal acyl-CoA oxidase

ACOX (17q25)*

Biochemical profile: Elevated plasma very long-chain fatty acids; normal peroxisomal phytanate, pipecolate, dihydroxycholestanoic acid, and trihydroxycholestanoic acid

Clinical features: Neonatal hypotonia, developmental delay, sensorineural deafness, retinopathy, no dysmorphic features, leukodystrophy at age 2 to 3 yr

Treatment: Not established

D-Bifunctional protein deficiency (261515)

D-bifunctional enzyme

HSD17B4 (5q2)*

Biochemical profile: Elevated serum very long-chain fatty acids and pipecolate, elevated trihydroxycholestanoic acid in duodenal aspirate, peroxisomal 3-oxoacyl-CoA thiolase defect

Clinical features: Hypotonia, exaggerated startle reflex, facial diplegia, seizures, high-pitched and weak cry, developmental delay, myopathic facies, high-arched palate, abducted limbs, ventricular heart disease

Treatment: Not established

2-Methylacyl-CoA racemase deficiency

2-Methylacyl-CoA racemase

AMACR (5p13.2-q11.1)*

Biochemical profile: Elevated plasma pristanic acid

Clinical features: Adult-onset sensorimotor neuropathy, retinopathy

Treatment: Not established

Primary oxaluria

Biochemical profile: Elevated urinary oxalate excretion, glycolic aciduria

Clinical features: Ca oxalate urolithiasis, nephrocalcinosis, renal failure, heart block, peripheral vascular insufficiency, arterial occlusion, intermittent claudication, optic neuropathy, fractures, death during childhood or early adulthood

Type 2 milder than type 1

Treatment: Hepatorenal transplantation

Hyperoxaluria type 1 (259900)

Peroxisomal alanine-glyoxylate aminotransferase

AGXT (2q36-q37)*

Hyperoxaluria type 2 (260000)

D-Glycerate dehydrogenase glyoxylate reductase

GRHPR (9cen)*

Refsum disease (266500)

Phytanoyl-CoA hydroxylase

PAHX (10pter-p11.2)*

Biochemical profile: Elevated plasma and tissue phytanic acid

Clinical features: Retinitis pigmentosa, ataxia, ptosis, miosis, peripheral neuropathy, anosmia, heart failure, deafness, ichthyosis, short 4th metacarpal

Treatment: Low phytanic acid diet, plasmapheresis


PEX7 (6q22-q24)*

Glutaric aciduria type 3 (231690)

Peroxisomal glutaryl CoA oxidase

Biochemical profile: Glutaric aciduria exacerbated by lysine loading

Clinical features: Failure to thrive, postprandial vomiting

Treatment: Not established

Mevalonic aciduria

Acatalasemia (115500)


CAT (11p13)*

Biochemical profile: Failure of tissue to cause hydrogen peroxide frothing

Clinical features: Ulcerating oral lesions in Japanese patients but not in Swiss patients

Treatment: Symptomatic

*Gene has been identified, and molecular basis has been elucidated.

OMIM = online mendelian inheritance in man (see the OMIM database).

Zellweger syndrome (ZS), neonatal adrenoleukodystrophy, and infantile Refsum disease (IRD)

These disorders are 3 expressions of a disease continuum, from most (ZS) to least (IRD) severe. The responsible genetic defect occurs in 1 of at least 11 genes involved in peroxisomal formation or protein import (the PEX gene family).

Manifestations include facial dysmorphism, CNS malformations, demyelination, neonatal seizures, hypotonia, hepatomegaly, cystic kidneys, short limbs with stippled epiphyses (chondrodysplasia punctata), cataracts, retinopathy, hearing deficit, psychomotor delay, and peripheral neuropathy.

Diagnosis is by detecting elevated blood levels of VLCFA, phytanic acid, bile acid intermediates, and pipecolic acid.

Experimental treatment with docosahexaenoic acid (DHA—levels of which are reduced in patients with disorders of peroxisome formation) has shown some promise.

Rhizomelic chondrodysplasia punctata

This defect of peroxisomal biogenesis is caused by PEX7 gene mutations and characterized by skeletal changes that include midface hypoplasia, strikingly short proximal limbs, frontal bossing, small nares, cataracts, ichthyosis, and profound psychomotor retardation. Vertebral clefts are also common.

Diagnosis of rhizomelic chondrodysplasia punctata is by x-ray findings, serum elevation of phytanic acid, and low RBC plasmalogen levels; VLCFA levels are normal.

There is no effective treatment for rhizomelic chondrodysplasia punctata.

X-linked adrenoleukodystrophy

This disorder is caused by deficiency of the peroxisomal membrane transporter ALDP, which is coded for by the gene ABCD1.

The cerebral form affects 40% of patients. Onset occurs between age 4 yr and 8 yr, and symptoms of attention deficit progress over time to severe behavioral problems, dementia, and vision, hearing, and motor deficits, causing total disability and death 2 to 3 yr after diagnosis. Milder adolescent and adult forms have also been described.

About 45% of patients have a milder form called adrenomyeloneuropathy (AMN); onset occurs in the 20s or 30s, with progressive paraparesis, and sphincter and sexual disturbance. About one third of these patients also develop cerebral symptoms.

Patients with any form may also develop adrenal insufficiency; about 15% have isolated Addison disease without neurologic involvement.

Diagnosis of X-linked adrenoleukodystrophy is confirmed by isolated elevation of VLCFA.

Bone marrow or stem cell transplantation may help stabilize symptoms in some cases. Adrenal steroid replacement is needed for patients with adrenal insufficiency. Dietary supplement with a 4:1 mixture of glyceryl trioleate and glyceryl trierucate (Lorenzo’s oil) can normalize plasma VLCFA levels and may be beneficial in some cases but is under study.

Classic Refsum disease

Genetic deficiency of a single peroxisomal enzyme, phytanoyl-CoA hydroxylase, which catalyzes metabolism of phytanic acid (a common dietary plant component), causes phytanic acid accumulation.

Clinical manifestations include progressive peripheral neuropathy, impaired vision caused by retinitis pigmentosa, hearing deficit, anosmia, cardiomyopathy and conduction defects, and ichthyosis. Onset is usually in the 20s.

Diagnosis of Refsum disease is confirmed by elevation of serum phytanic acid and decreased levels of pristanic acid (phytanic acid elevation is accompanied by pristanic acid elevation in several other peroxisomal disorders).

Treatment of Refsum disease is dietary restriction of phytanic acid (< 10 mg/day), which can be effective in preventing or delaying symptoms when started before symptom onset.

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