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Peroxisomal Disorders

Amy Goldstein, M.D.

Amy Goldstein, MD is a Child Neurologist at the Children’s Hospital of Pittsburgh, where she is the Director of Neurogenetics and co-Director of the Neurofibromatosis Clinic. She is an Assistant Professor of Pediatrics at the University of Pittsburgh School of Medicine, where she attended medical school.  Dr. Goldstein has had a special interest in neurogenetic and neurometabolic disorders since her Pediatric intern year. She has been a member of the Board of Trustees of the United Mitochondrial Disease Foundation, and on the medical advisory board for MitoAction. She is the current President of the Mitochondrial Medicine Society and a member of the Society for Inherited Metabolic Disorders and the Child Neurology Society, where she helps plan the Neurogenetics Special Interest Group meetings. She has received several awards for patient satisfaction, including Best Doctors in Pittsburgh Magazine. She has contributed to recent literature on the diagnosis, management, and consensus criteria for mitochondrial disease. She was also involved in the completion of the Common Data Elements for Mitochondrial Disease through the National Institutes of Neurological Disorders and Stroke. She has reviewed articles for journals including Pediatric Neurology and Journal of Child Neurology.  Her current interests are in conducting clinical trials for patients with genetically confirmed mitochondrial disorders.


Peroxisomal disorders are a large group of genetic disorders (some can also be considered “inborn errors of metabolism”). These conditions vary in symptoms and age of onset. However, they share a problem with the functioning of the peroxisome. Peroxisome is a small organelle within the cell. Some of the issues are break-down (beta-oxidation) of very long chain fatty acids in the peroxisome, hydrogen peroxide detoxification, and the synthesis (production) of cholesterol, bile acids, and plasmalogens. The myelin (or “white matter”) of the brain is composed of phospholipids made from cholesterol. Because myelin production can be disrupted in some of these disorders, they are also classified as white matter disorders. White matter disorders are called leukodystrophies. The hallmark of peroxisomal disorders is an accumulation of the very long chain fatty acids 24 and 26 carbons long (C24, C26) as well as accumulation of bile-acids.

There are four main groups of peroxisomal disorders based on clinical symptoms:

  1. Peroxisome Biogenesis Disorders (PBD)/Zellweger Syndrome Spectrum (ZSS), referred to together as PBD-ZSS.
  2. Syndromes of bone dysplasias called rhizomelic chondrodysplasia punctata
  3. X-linked Adrenoleukodystrophy (X-ALD)
  4. Adult Refsum’s disease, also called Classic Refsum Disease

In addition, the peroxisomal disorders can be separated into two groups based on the underlying problem in the peroxisome:

  1. Peroxisome Biogenesis Disorders (PBD) where the peroxisome is not shaped normally and has loss of key functions leading to disease
  2. The peroxisome is normally shaped but there is an enzyme deficiency causing the disease

The first category includes Peroxisome Biogenesis Disorders (PBD) and Zellweger Syndrome Spectrum (ZSS), or together PBD-ZSS. Three different diseases are included in this group of PBD-ZSS:

  1. Zellweger syndrome (ZS)
  2. Neonatal Adrenleukodystrophy (NALD
  3. Infantile Refsum Disease (IRD)

These are rare, progressive genetic disorders that currently have no cure. When babies and young children have global developmental delays and/or low muscle tone (hypotonia), the evaluation may include a blood test called “very long chain fatty acids” (VLCFA) which detects a defect in fatty acid metabolism in a small part of the cell ( an organelle called the peroxisome). Different genes have been discovered to play a role in peroxisomal fatty acid metabolism; mutations in these genes cause PBD-ZSS. Zellweger syndrome is the most severe of the three disorders and babies with ZS have trouble feeding, have a distinctive facial appearance, may develop seizures/epilepsy, and have liver and bone involvement. Older children may have visual and hearing impairment.

The second category involves mainly bone dysplasias called rhizomelic chondrodysplasia punctata (RCDP) and will not be discussed here.

The third category is X-linked adrenoleukodystrophy (X-ALD). X-linked disorders affect males more than females; females are asymptomatic carriers with some few exceptions. X-ALD affects the white matter of the brain and the adrenal glands (which are near the kidney).  The childhood form of X-ALD begins between 4-8 years old with attention deficit hyperactivity disorder (ADHD), followed by cognitive decline, behavior issues, loss of vision and hearing, and motor decline. The progression to disability is rapid, often within 2 years. The devastating course of X-ALD was portrayed in the movie “Lorenzo’s Oil” (1992). X-ALD can also present later in life (20’s) as Adrenomyeloneuropathy (AMN) or as ‘Addison disease only’ usually by age 8 years.

The fourth category is Adult Refsum disease. Onset of symptoms can be in the first year of life to late adulthood. Symptoms include blindness (due to retinitis pigmentosa), deafness, balance issues (ataxia), and a skin condition called ichthyosis. Symptoms progress to include heart issues including cardiomyopathy (an enlarged heart).


PBS-ZSS disorders affect children by causing developmental delays and hearing and visual impairments.

X-ALD affects older children by causing attention and behavior issues, followed by major and rapid regression in cognitive and motor abilities, and then by loss of vision and hearing. The child becomes spastic and unable to control their movements within a few years of symptom onset.

Symptom severity in PBD-ZSS ranges from children who gain very few milestones (severe) and never learn head control or how to roll or sit. At the mild end of the severity spectrum, children may learn to walk, talk and gain early education skills. It is possible for children with PBS-ZSS to undergo a regression and lose skills previously gained.

Symptom severity in X-ALD ranges from devastating course in childhood, to a milder form presenting later in life, or symptoms limited to the adrenal gland.

Unfortunately, children with severe PBS-ZSS will die early in life from this condition. There is currently no cure for these disorders, and care is palliative. X-ALD is also an incurable disease.


For PBD-ZSS, diagnosis is made based on a child’s symptoms, in combination with abnormal biochemical testing (VLCFA) and genetic testing for mutations in causative genes.

For X-ALD, the diagnosis is based on the typical clinical symptoms in boys. MRI is abnormal and characteristic for X-ALD with white matter disease that starts in the back of the brain near the occipital lobes. Testing of VLCFA reveals an increase. Genetic testing can be performed on the ABCD1 gene for the associated mutation.

Adult Refsum disease is diagnosed based on symptoms and elevated phytanic acid levels. Genetic testing can confirm mutations in the gene PHYH or less commonly PEX7.

Common symptoms of PBD-ZSS include global developmental delays (delays in gross motor, fine motor, language), hypotonia, hearing and visual impairments.  Symptoms may be present in the newborn period, older childhood, and even adulthood.

In the newborn period, symptoms include:

  • Hypotonia (low muscle tone) with poor feeding
  • Seizures
  • Liver dysfunction (may cause neonatal jaundice and increased liver enzymes testing in blood)
  • Facial features (which may be seen early in life, such as a large open fontanelle, broad nose, and a high forehead with a flattened face)
  • Bones (x-ray may show bone stippling, called chondrodysplasia punctata)
  • Brain imaging may reveal cortical dysplasia, also called migrational abnormalities, due to abnormal formation of brain architecture referred to as pachygyria-polymicrogyria. The brain malformations correlate with the severity of seizures and developmental delay as well as the elevation in very long chain fatty acids and bile-acids.

Older children have milder symptoms at presentation, and may include:

  • Hearing loss (which may be the first sign)
  • Developmental delay
  • Low muscle tone
  • Liver dysfunction (which may lead to abnormal bleed and be the first sign of the disorder)
  • Retinal dystrophy (abnormal retina of the eye).

The combination of hearing and visual problems warrants an evaluation for PBS-ZSS. Presenting as an adult would be very rare for these disorders, but it has been reported in the medical literature. Usually those individuals have had only nerve involvement causing numbness and tingling and have had PEX6 deficiency.

Adult Refsum disease presents later in life, with symptoms such as:

  • Balance issues (ataxia)
  • Retinitis pigmentosa (abnormal pigmentation of the retina of the eye)
  • Hearing loss
  • Peripheral nerve disease

Physical Abnormalities

A child with PBS-ZSS and X-ALD, among other conditions, may have epilepsy, developmental delay, cerebral palsy, visual impairment and deafness.

Laboratory Investigations

Neuroimaging of the brain may reveal an abnormality of myelin, sometimes referred to as “white matter disease” or “leukodystrophy”. Other findings include abnormal brain architecture (cortical dysplasia) and cysts in the germinal matrix. White matter abnormalities might be seen on certain sequences (diffusion-weighted imaging and diffusion tensor imaging: DWI, DTI) and no other standard sequences. Imaging of X-linked adrenoleukodystrophy shows white matter disease in the posterior brain (occipital lobes) but can start in the front of the brain. The white matter abnormalities will spread to involve the remainder of the brain over time.

Biochemical testing includes very long chain fatty acids (VLCFA), phytanic acid, pristanic acid and plasmalogens. VLCFA entails measuring long carbon chain fatty acids and examining their ratios to each other. An elevation of C26:0 and C26:1 and the ratios of C24:C22 and C26:C22, is consistent with a peroxisomal disorder. Genetic testing can be done to confirm a mutation in one of the peroxisomal genes (PEX1, PEX6, PEX26, PEX10, PEX12, PXMP3 (PEX2), PEX3, PEX5, PEX13, PEX14, PEX16, PEX19).

Phytanic acid is present in our diet in dairy products, meat and fish. It is also a fatty acid which undergoes metabolism in the peroxisome by first being converted to pristanic acid. Pristanic acid is then converted to medium chain fats that are further metabolized by the mitochondria. Elevations of phytanic and pristanic acid are seen in dysfunctional peroxisomes and can be an indication of adult Refsum disease. Plasmalogens are synthesized (made) in the peroxisome. Testing for plasmalogens may reveal a deficiency in X-ALD and Zellweger syndrome due to impaired plasmalogen biosynthesis.

Other testing may involve an electroencephalogram (EEG) to detect seizures. In the PBD-ZSS disorders, the EEG shows multifocal spikes initially, which evolves into generalized slowing of the brain as the disease progresses.

The biochemical testing is usually covered by insurance. Genetic testing for confirmation of mutations in involved genes may vary based on insurance companies. Even if initially denied, your doctor may be able to write a letter of appeal stating the importance of confirming the diagnosis so that proper treatment and prognosis may be offered to you.

The biochemical tests do not need to be repeated. However, evaluation of hearing, vision, and development will need to be repeated and followed throughout your child’s lifetime. EEG testing and MRI testing may be repeated as needed to follow your child’s symptoms and disease course.

Therapeutic Intervention

PBD-ZSS disorders are complex and children with these disorders require multiple pediatric specialists. Based on your child’s symptoms, a child may require ongoing evaluation and treatment by:

  • Audiology (for hearing evaluations)
  • Developmental Pediatrics
  • Endocrinology
  • Gastroenterology/Hepatology
  • Hematology
  • Medical Genetics
  • Neurology
  • Ophthalmology
  • Orthopedics
  • Otolaryngology (Ear-Nose-Throat, ENT)
  • Physical Medicine & Rehabilitation (PMR)
  • Pulmonology

Developmental delays are treated by Early Intervention/Infant Stimulation programs, graduating into a school-based program after age three. Interventions may include:

  • Physical Therapy
  • Occupational Therapy
  • Speech Therapy
  • Feeding Therapy
  • Nutrition
  • Vision Therapy
  • Hearing Impairment Therapy


Currently, there is no cure for PBD-ZSS and treatment is based on symptoms and palliative care. Standards of care for PBD-ZSS include:

  • A daily multivitamin including the fat-soluble vitamins A, D, E, and K. Vitamin K is especially important in children with liver involvement and bleeding dysfunction (coagulopathy) and further treatment may be recommended by a Hematologist or Hepatologist. Some children also take a DHA supplement.
  • For children with adrenal insufficiency, a daily steroid may be required as well as “stress dosing” with extra steroids during times of illness, as prescribed by an Endocrinologist.
  • Anti-seizure medication may be required to manage epilepsy (recurrent seizures).
  • Children with osteopenia/osteoporosis may experience fractures and need to be followed by both Endocrinology and Orthopedic specialists. Cholic acid (Cholbam) is an FDA-approved medication for replacement of bile acids in peroxisomal disorders to help with liver disease, weight gain, and vitamin absorption.

Treatment of Refsum disease may include:

  • Restriction of dietary phytanic acid, such as dairy products and meat. This restriction may help with the skin condition (ichthyosis), the nerve disease (neuropathy), and balance disturbance (ataxia).
  • Plasmapheresis (which rapidly removes phytanic acid from the blood)
  • Treating hypertension can help delay the onset of cardiomyopathy and cardiac arrhythmias.
  • Enzyme replacement therapy and gene therapy are under investigation.

In patients with X-ALD, treatment may include:

  • Lorenzo’s oil. It appears to be most effective for boys who are pre-symptomatic (usually identified after an affected sibling has been diagnosed).
  • Bone marrow transplantation
  • Steroid replacement therapy (due to adrenal insufficiency).

DHA (docosahexanoic acid) is a nutritional supplement which is low in patients with PBD-ZSS disorders and is being investigated as a treatment.


The PBD-ZSS disorders are severe disorders. Symptoms are present at birth and the disease causes death early in childhood. The X-ALD form presenting in childhood leads to complete disability and death by the teenage years. The milder forms of disease may not become fatal until early to mid-adulthood.

If survival is possible into adulthood, the likelihood that a child will be able to function in an independent capacity as an adult is very low due to the severity of symptoms seen with these disorders.

It is not possible to outgrow a peroxisomal disorder. Children with these disorders will require full care and multiple therapies. The child will not be able to perform independent activities of daily living (hygiene, dressing, eating).  

The ability to learn and grow will be very limited by these disorders.

The child’s life will be majorly impacted by these disorders. The child may not survive beyond a few years after diagnosis. The child may not achieve typical milestones or may lose milestones already achieved. These are life-threatening disorders, unfortunately, with a very poor prognosis.  

Due to the disability’s effect on the child’s learning ability, an Individualized Education Plan (IEP) or a Medical Service Agreement is accessible by law.  Service accommodations for hearing impairment and/or low vision may be included in the IEP.

How will this disorder change the family? 

Peroxisomal disorders can be devastating for a family. As these disorder are genetic, more than one child in a family could be affected. The family can seek additional support from their medical system including a Palliative Care Team and/or Hospice services to help with choosing care to improve the child’s quality of life and help with end-of-life decision making.

What will need to be done on a daily basis? 

Children will eventually need full supportive care. Feeding can be continued with use of a gastrostomy tube (G tube). Secretions need to be managed to prevent aspiration and can be done with medications that help dry the saliva or with Botox injections to the salivary glands by an experienced doctor. Additional interventions for prevention of chronic lung disease include pulmonary management. Therapies include physical therapy to help preserve range of motion and prevent contractures. Scoliosis may develop and can be aided by braces and frequent repositioning.

In some disorders, dietary changes can be helpful. Adult Refsum disease is treated with dietary restriction of phytanic acid.


Prenatal counseling is available to families who have one affected child or are known carriers of these genetic disorders.

Caretaker Augmentation

Clinicaltrials.gov is an on online resource for clinical trials.

The Global Foundation for Peroxisomal Disorders


Adrenoleukodystrophy Foundation


ALD Connect


Australian Leukodystrophy Support Group, Inc.


National Institute of Neurological Disorders and Stroke (NINDS)

X-ALD Information: http://www.ninds.nih.gov/disorders/adrenoleukodystrophy/adrenoleukodystrophy.htm

Refsum Information: http://www.ninds.nih.gov/disorders/refsum/refsum.htm

Zellweger Information: http://www.ninds.nih.gov/disorders/zellweger/zellweger.htm

NCBI Genes and Disease

Zellweger: http://www.ncbi.nlm.nih.gov/books/NBK22240/

Refsum: http://www.ncbi.nlm.nih.gov/books/NBK22208/

X-ALD: http://www.ncbi.nlm.nih.gov/books/NBK22230/

Myelin Project


United Leukodystrophy Foundation (ULF)


Myelin Disorders Bioregistry Project


Global Foundation for Peroxisomal Disorders


Foundation for Ichthyosis and Related Skin Types, Inc. (FIRST)


Retinitis Pigmentosa International


Families can consult with their state Educational Law Center as well as meet with the Special Education Department at their school district to learn more about Individualized Education Plans (IEPs) and Medical Service Agreements for children with disabilities.


  • Dysplasia: Abnormal growth; can refer to bone, brain, or any organ/body part.
  • Leukodystrophy: “Leuko”, meaning white and “dystrophy”, meaning disease; refers to disorders of white matter of the central nervous system; includes under production of myelin (hypomyelinating) and destruction of myelin (demyelination); the loss of white matter disrupts normal brain function by poor conduction of the nerve impulses.
  • Organelles: Previous
  • Next Section: Pathophysiology
  • Small structures within the cell that are enclosed by a membrane and have a distinct biochemical composition, recognizable shape, and known function.
  • Peroxisomal disorders: A group of inherited metabolic disorders marked by absent or dysfunctional peroxisomes. Most peroxisomal disorders include neurologic symptoms.
  • Peroxisome: Small cellular organelle present in animal and plant cells and some fungi and protozoa; they contain enzymes including peroxidase, catalase, and other important enzymes.
  • Plasmalogens: A large molecule composed of Glycerol which are part of the glycerolphospholipid family.


See comment in PubMed Commons below Braverman NE, D’Agostino MD, Maclean GE. Peroxisome biogenesis disorders: Biological, clinical and pathophysiological perspectives. Dev Disabil Res Rev. 2013;17(3):187-96. doi: 10.1002/ddrr.1113.

Braverman NE, Raymond GV, Rizzo WB, Moser AB, Wilkinson ME, Stone EM, Steinberg SJ, Wangler MF, Rush ET, Hacia JG, Bose M. Peroxisome biogenesis disorders in the Zellweger spectrum: An overview of current diagnosis, clinical manifestations, and treatment guidelines.

Mol Genet Metab. 2016 Mar;117(3):313-21. doi: 10.1016/j.ymgme.2015.12.009. Epub 2015 Dec 23. Review.

Steinberg SJ, Moser AB, Raymond GV. X-Linked Adrenoleukodystrophy. 1999 Mar 26 [Updated 2015 Apr 9]. In: Pagon RA, Adam MP, Ardinger HH, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2016. Available from: http://www.ncbi.nlm.nih.gov/books/NBK1315/

Steinberg SJ, Raymond GV, Braverman NE, et al. Peroxisome Biogenesis Disorders, Zellweger Syndrome Spectrum. 2003 Dec 12 [Updated 2012 May 10]. In: Pagon RA, Adam MP, Ardinger HH, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2016. Available from: http://www.ncbi.nlm.nih.gov/books/NBK1448/

Wanders RJA, Waterham HR, Leroy BP. Refsum Disease. 2006 Mar 20 [Updated 2015 Jun 11]. In: Pagon RA, Adam MP, Ardinger HH, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2016. Available from: http://www.ncbi.nlm.nih.gov/books/NBK1353/

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