Zellweger spectrum disorders (ZSDs) represent the major subgroup within the peroxisomal biogenesis disorders (PBD) caused by defects in PEX genes. The Zellweger spectrum is a clinical and biochemical continuum which can roughly be divided into three clinical phenotypes. Although they were once thought to be 3 separate diseases; from least to most severe; Infantile Refsum Disease, Neonatal Adrenoleukodystrophy and Zellweger Syndrome. It is now understood that these disorders form a spectrum or continuum of disease that can range from mild to moderate to severe and the more formal classifications are less often used.  Patients are often now often classified to the severity of Zellweger Spectrum Disorder (mild, moderate or severe).


As a spectrum, the disorders will affect each patient differently and with much overlap in symptoms. Age of onset and severity can determine where a patient may fall in the classification as well as clinical and laboratory tests that physicians may run including but not limited to, very long chain fatty acids (VLCFAs).

These disorders occur due to a defect or deficiency in a specific part of the cell called the peroxisome. Peroxisomes are important parts of your cells that are responsible for breaking down fats and other chemicals responsible for metabolic processes.  The defective genes are known as PEX genes and can be detected through genetic testing.

At this time, there are no known cures for the disease which impacts multiple organs. Available treatments are largely supportive for individual organs.

Symptoms- ZSD

Because peroxisomes are involved in multiple biochemical functions, ZSDs can cause an

array of effects throughout the body. ZSD’s present and progress with a wide variation in severity, age at when symptoms appear, and organs that are affected

  • Hypotonia
  • Failure to thrive
  • Hepatic dysfunction (jaundice)
  • Feeding problems
  • Hearing and vision loss
  • Seizures
  • Craniofacial abnormalities (such as a high forehead, hypoplastic supraorbital ridges, epicanthal folds, midface hypoplasia, and a large fontanel)
  • Coagulopathy
  • Sensorineural hearing loss
  • Ocular abnormalities
  • Enamel abnormalities
  • Peripheral neuropathy
  • Cerebellar ataxia
  • Leukodystrophy
  • Skeletal abnormalities
  • Development delay
  • Adrenal insufficiency
  • Hepatomegaly (enlarged liver)
  • Chondrodysplasia punctata (punctate calcification of the cartilage in specific regions of the body)

Liver injury is almost universal in people with ZSD. It is important to know that the liver will most likely become affected at some point in your child’s or loved one’s life.

Causes – ZSD

Peroxisome biogenesis disorders in the Zellweger spectrum (PBD-ZSD) is an autosomal recessive disorder caused by mutations in genes that encode peroxins, proteins required for the normal assembly of peroxisomes. Most commonly, patients have mutations in the PEX1, PEX2, PEX3, PEX5, PEX6, PEX10, PEX12, PEX13, PEX14, PEX16, PEX19, or PEX26 genes. In almost all cases, patients have mutations that inactivate or greatly reduce the activity of both the maternal and paternal copies of one these PEX genes.


As a result of impaired peroxisome function, an individual’s tissues and cells can accumulate very long chain fatty acids (VLCFA) and branched chain fatty acids (BCFA) that are normally degraded in peroxisomes. The accumulation of these lipids can impair the normal function of multiple organ systems.

Prevention – ZSD

Since ZSD’s are caused by genetic defect, there is no known prevention. It is important to understand some of the problems that can develop cannot be reversed, such as abnormal brain development and neurological symptoms, but medical issues that arise and affect other organs can often be managed with therapeutic intervention.

Diagnosis – ZSD

Additional studies demonstrating defects in multiple peroxisome enzyme pathways are necessary to diagnose PBD-ZSD, such as measurement of the methyl-branched fatty acids phytanic and pristanic acids, erythrocyte plasmalogens, pipecolic acid in plasma and/or urine, and the bile acid intermediates dihydroxycholestanoic acid (DHCA) and trihydroxycholestanoic acid (THCA) in plasma and/or urine. Testing for multiple biochemical functions in patients or obtaining biochemical studies on patient-derived fibroblasts and genetic testing may be necessary for proper diagnosis. Genetic diagnostics tests involving the sequencing of PEX genes and biochemical tests have also proven highly effective for the diagnosis of ZSD and other peroxisomal disorders.

Prognosis – ZSD

Patients with ZSDs can present a complex range of clinical characteristics that often results in shortened life spans.

Treatment – ZSD

Unfortunately, there is no way to stop ZSDs from progressing. Therapies available are largely supportive treatments for managing the many organs affected by ZSDs. Although current treatments can only help with symptoms and do not cure the disease, they may help improve comfort and quality of life for people with ZSDs.

Feeding and nutrition

Many children have feeding difficulties. Supplying adequate calorie intake for affected children may entail the placement of a G-tube inserted through the abdomen to deliver nutrients to the stomach. With many children having some degree of malabsorption due to bile acid deficiency, vitamins A, D, E, and K amino acid-based formulas may be better tolerated.


To help support liver function, daily supplementation of vitamin K is recommended. Bile acid metabolism is altered and primary bile acid therapy (cholic acid and chenodeoxycholic acid) may improve liver function by reducing the buildup of abnormal bile acids, such as DHCA and THCA. Recently, cholic acid has been approved by the United States Food and Drug Administration as a supportive therapy to treat liver dysfunction in Zellweger Spectrum Disorders.


Many patients have some degree of hearing loss and should be evaluated annually. Hearing aids should be used in children found to have substantive hearing loss. Cochlear implants (device placed in ear) have been effectively placed in children when hearing loss is severe and cannot be compensated by hearing aids.


Vision deterioration or loss is commonly seen due to retinal dystrophy and optic nerve abnormalities. Therefore, ophthalmologic exams are encouraged and cataract removal or corrective lenses may be recommended by your ophthalmologist.

Neurological function

Seizures affect nearly all severe ZSD patients and have been reported to occur in less severe cases of ZSDs. Electroencephalogram (EEG) test can determine the frequency and duration of seizures and should be performed whenever changes in seizure activity are suspected. Therapy to control seizures include a range of anti-epileptic drugs.

Evaluation for early physical, occupational and speech therapy is recommended for all children.


Regarding treatment of bone disease, a recent study has reported successful treatment with bisphosphonate medications in a patient. Bisphosphonate therapy should be carefully considered in consultation with an experienced metabolic bone specialist. Additionally, weight bearing physical activity has shown to slow bone loss in children and therefore prevent fractures.


Dental examination should be performed every 6 months. Many children have enamel abnormalities of permanent teeth and should receive appropriate dental care.


Children affected by ZSD, particularly older children (≥4–6 years), should be monitored for kidney injury or abnormalities, which can lead to kidney stone formation and renal failure. Treatments may include increased fluid intake or urine alkalization injections

Resources – PBD-ZSD

See Research Publications

  • Peroxisome biogenesis disorders in the Zellweger spectrum: An overview of current diagnosis, clinical manifestations, and treatment guidelines- E Braverman et al. Molecular Genetics and Metabolism 117 (2016) 313-321
  • Case Report: Diagnosis of a mild peroxisomal phenotype with next-generation sequencing- J. Ventura et al./ Molecular Genetics and Metabolism Reports 9 (2016) 75-78



Advocacy Groups and Nonprofit Organizations
Global Foundation for Peroxisomal Disorders
The mission of the Global Foundation for Peroxisomal Disorders is to fund and promote Peroxisomal Disorder research and to assist families and professionals through educational programs and support services related to Zellweger Spectrum Disorders.

United Leukodystrophy Foundation

Australian Leukodystrophy Support Group

European Leukodystrophy Foundation

Axel Foundation

ALD Life

National Consortium on Deaf-Blindness

Rare Disease Organizations
A non-governmental patient-driven alliance of patient organizations representing 724 rare disease patient organizations in 64 countries.

National Organization for Rare Disorders
Provides a unified voice for the 30 million people who wake up every day to fight the battle with a rare disease, including parents and caregivers.

Rare Disease Legislative Advocates
A program of the EveryLife Foundation for Rare Diseases designed to support the advocacy of all rare disease patients and organizations.

Genetic Alliance
A nonprofit health advocacy organization that engages individuals, families, and communities to transform health. They create ways to make it easier to find or build solutions in health services and research.

Global Genes
A rare disease patient advocacy organization that aims to build awareness, educate the global community and provide critical connections and resources that equip advocates to become activists for their disease.

Patient Registries
Clinical Trials
The leading online database of publicly and privately supported clinical studies conducted around the world. ClinicalTrials.gov currently lists thousands of studies with locations throughout the world.
Genetic Testing
Genetics Home Reference
An online resource from the National Institutes of Health. The website provides easy-to-understand information about genetic conditions and a range of topics. You’ll find basic explanations of how genes work and how mutations cause disorders. It also includes current information about genetic testing, gene therapy, and the Human Genome Project.

National Society of Genetic Counselors
Provides a helpful, easy-to-use online directory to help connect physicians, patients, and other genetic counselors. Search by state, city, counselor’s name, institution, work setting, type of specialty, or zip code.

Resources for Families and Caregivers
Rare Share
A unique social hub building communities for patients, families, and healthcare professionals affected by rare disorders.

Caregiver Action Network (CAN)
The nation’s leading family caregiver organization working to improve the quality of life for the more than 90 million Americans who care for loved ones with chronic conditions, disabilities, disease, or the frailties of old age. CAN (formerly the National Family Caregivers Association) is a nonprofit organization providing education, peer support, and resources to family caregivers across the United States free of charge.

Center for Parent Information & Resources
A central resource of information and products to the community of Parent Training Information Centers and the Community Parent Resource Centers so they can focus their efforts on serving families of children with disabilities.

Cyberbullying Research Center
Dedicated to providing up-to-date information about the nature, extent, causes, and consequences of cyberbullying, it is intended to be a resource for parents, educators, law enforcement officers, counselors, and others who work with youth. You will find facts, figures, and detailed stories from those who have been directly affected by online aggression. In addition, the site includes numerous resources to help you prevent and respond to cyberbullying incidents.

Family Caregiver Alliance (FCA)
A community-based nonprofit organization that that aims to illuminate the caregivers’ daily challenges to better the lives of caregivers nationally, provide them the assistance they need, and champion their cause through education, services, research and advocacy. FCA offers programs at national, state, and local levels to support and sustain caregivers.

Family Voices
Family Voices aims to achieve family-centered care for all children and youth with special health care needs and/or disabilities. Throughout their national grassroots network, they provide families resources and support to make informed decisions, advocate for improved public and private policies, build partnerships among families and professionals, and serve as a trusted resource on health care.

An email list of family of parents, caregivers and others who are working with children with physical and/or mental disabilities and delays.

Parent to Parent USA
Programs offering parent-to-parent support as a core resource for families with children who have a special health care need, disability, or mental health issue. Through a one-to-one “match,” experienced support parents provide emotional support to families and assist them in finding information and resources.

Sibling Support Project
A national program dedicated to the lifelong and ever-changing concerns of the millions of brothers and sisters of people with special health, developmental and mental health concerns.

A website providing information from various government agencies on what bullying is, what cyberbullying is, who is at risk, and how you can prevent and respond to bullying.

The Bully Project
Inspired by the award-winning film BULLY, this social action campaign includes tools for educators to spark meaningful conversations about bullying.

The Parent Advocacy Center for Educational Rights (PACER Center)
PACER Center is a parent training and information center for families of children and youth with all disabilities from birth to young adults. Parents can find publications, workshops, and other resources to help make decisions about education, vocational training, employment, and other services for their children with disabilities. PACER’s National Bullying Prevention Center provides resources designed to benefit all students, including those with disabilities.

General Health Resources
Agency for Healthcare & Research Quality (AHRQ)
Aims to provide evidence to make health care safer, higher quality, more accessible, equitable and affordable, and to work with the US Department of Health and Human Services and with other partners to ensure that the evidence is used and understood.

Health Hotlines (National Library of Medicine)
A community service to help the public locate health-related information.

Social Security Administration Compassionate Allowances Program
Provides a way of quickly identifying diseases and other medical conditions that may qualify for financial assistance.

Center on Technology & Disability
Designed to increase the capacity of families and providers to advocate for, acquire, and implement effective assistive and instructional technology practices, devices, and services for those who suffer from disabilities.

National Human Genome Research Institute
Developed with the goal of mapping the human genome, the group provides a list of resources for financial assistance with genetic testing.

National Library of Medicine
Provides guidance on how to find reliable information online regarding human genetics.

Patient Advocate Foundation
Provides professional case management services to individuals facing barriers to healthcare access for chronic and disabling disease, medical debt crisis, and employment-related issues at no cost.