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. See also 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) (1); all others are autosomal recessive, with a combined incidence of about 1/50,000 births (2).
For more information, see the table.
References
1. Bezman L, Moser AB, Raymond GV, et al. Adrenoleukodystrophy: incidence, new mutation rate, and results of extended family screening. Ann Neurol. 2001;49(4):512-517.
2. Global Foundation for Peroxisomal Disorders: Peroxisomal Disorders. Accessed February 20, 2024.
Classic Refsum Disease
Phytanic acid accumulation is caused by a genetic deficiency of a single peroxisomal enzyme, phytanoyl-CoA hydroxylase. This enzyme catalyzes metabolism of phytanic acid, which is a common dietary plant component.
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. Plasmapheresis also may be helpful for patients with severe neurologic symptoms (1).
Refsum disease reference
1. Harari D, Gibberd FB, Dick JP, Sidey MC. Plasma exchange in the treatment of Refsum's disease (heredopathia atactica polyneuritiformis). J Neurol Neurosurg Psychiatry. 1991;54(7):614-617. doi:10.1136/jnnp.54.7.614
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 radiographic 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 (ALD)
This disorder is caused by deficiency of the peroxisomal membrane transporter ALDP, which is coded for by the gene ABCD1. Because this is an X-linked gene, the disorder manifests primarily in males. Currently, > 1380 variants have been identified (see ALD Info) (1).
The cerebral form affects 40% of patients. Onset occurs between age 4 years and 8 years, 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 years after diagnosis. Milder adolescent and adult forms have also been described.
A significant percentage 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 suspected by isolated elevation of VLCFA and confirmed by gene sequencing.
Bone marrow or stem cell transplantation may help stabilize symptoms in some cases. Adrenal steroid replacement is needed for patients with adrenal insufficiency. Dietary supplementation 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 (2).
X-linked ALD references
1. ALD info: The ABCD1 Variant Database. Accessed February 13, 2024.
2. Gupta AO, Raymond G, Pierpont EI, et al. Treatment of cerebral adrenoleukodystrophy: allogeneic transplantation and lentiviral gene therapy. Expert Opin Biol Ther. 2022;22(9):1151-1162. doi:10.1080/14712598.2022.2124857
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 12 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 suspected when elevated blood levels of VLCFA, phytanic acid, bile acid intermediates, and pipecolic acid are detected and is confirmed by genetic testing.
There is currently no specific treatment for these disorders. Management is mainly symptomatic.
More Information
The following English-language resources may be useful. Please note that THE MANUAL is not responsible for the content of these resources.
ALD Info (adrenoleukodystrophy): A resource providing information about treatment, diagnosis, and other aspects of adrenoleukodystrophy
Online Mendelian Inheritance in Man (OMIM) database: Complete gene, molecular, and chromosomal location information
