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Peroxisomal Disorders

By

Matt Demczko

, MD, Mitochondrial Medicine, Children's Hospital of Philadelphia

Reviewed/Revised Mar 2024
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Topic Resources

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).

There are 2 types of peroxisomal disorders:

  • Those with defective peroxisome formation

  • Those with defects in single peroxisomal enzymes

For more information, see the .

Table

References

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 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. Plasmapheresis also may be helpful for patients with severe neurologic symptoms (1 Refsum disease reference 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... read more ).

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 X-linked ALD references 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... read more ).

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.

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.

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 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 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... read more ).

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.

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