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Peroxisomal Disorders


Matt Demczko

, MD, Sidney Kimmel Medical College of Thomas Jefferson University

Last full review/revision Apr 2020| Content last modified Apr 2020
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Peroxisomes are intracellular organelles that contain enzymes for beta-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 and Refsum disease). Although VLCFA levels may help screen for these disorders, other assays are also required (eg, plasma levels of phytanic, pristanic, and pipecolic acids; red blood cell plasmalogen levels). For information on other disorders affecting fatty acid metabolism, see Overview of Fatty acid and Glycerol Metabolism Disorders Overview of Fatty Acid and Glycerol Metabolism Disorders Fatty acids are the preferred energy source for the heart and an important energy source for skeletal muscle during prolonged exertion. Also, during fasting, the bulk of the body’s energy needs... read more . See also Approach to the Patient With a Suspected Inherited Disorder of Metabolism Approach to the Patient With a Suspected Inherited Disorder of Metabolism Most inherited disorders of metabolism (inborn errors of metabolism) are rare, and therefore their diagnosis requires a high index of suspicion. Timely diagnosis leads to early treatment and... read more and testing for suspected inherited disorders of metabolism Initial testing Most inherited disorders of metabolism (inborn errors of metabolism) are rare, and therefore their diagnosis requires a high index of suspicion. Timely diagnosis leads to early treatment and... read more .

There are 2 types of peroxisomal disorders:

  • Those with defective peroxisome formation

  • Those with defects in single peroxisomal enzymes


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, central nervous system 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.

There is currently no specific treatment for these disorders. Management is mainly symptomatic.

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 suspected by x-ray findings, elevation of serum phytanic acid, and low red blood cell plasmalogen levels; VLCFA levels are normal. Confirmation is by genetic testing.

There is no specific 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. This is an X-linked gene and thus the disorder manifests primarily in males. Currently, > 800 mutations have been identified (see ALD Info).

The cerebral form affects 40% of patients. Onset occurs between age 4 years and 8 years, and symptoms of attention deficit Symptoms and Signs Attention-deficit/hyperactivity disorder (ADHD) is a syndrome of inattention, hyperactivity, and impulsivity. The 3 types of ADHD are predominantly inattentive, predominantly hyperactive/impulsive... read more progress over time to severe behavioral problems, dementia, and vision, hearing, and motor deficits, causing total disability and death 2 to 3 years 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.

Diagnosis of X-linked adrenoleukodystrophy is suspected by isolated elevation of VLCFA and confirmed by gene sequencing.

Bone marrow or stem cell transplantation Hematopoietic Stem Cell Transplantation Hematopoietic stem cell (HSC) transplantation is a rapidly evolving technique that offers a potential cure for hematologic cancers (leukemias, lymphomas, myeloma) and other hematologic disorders... read more 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 but does not appear to stop neurologic degeneration in symptomatic patients. However, if given to boys before symptom onset, it may slow disease progression; the exact benefit has not been determined. Gene therapy trials are currently underway and have shown some preliminary success.

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 Retinitis Pigmentosa Retinitis pigmentosa is a slowly progressive, bilateral degeneration of the retina and retinal pigment epithelium caused by various genetic mutations. Symptoms include night blindness and loss... read more 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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