What Is Zellweger Syndrome?

The human body is made up of millions and trillions of cells that perform the basic functions required to sustain life. Cells are made of various functional organelles - amongst which is the cell peroxisome. Previously considered insignificant since its physiological function was not known, the peroxisome’s now known function involves metabolism of fatty acids and synthesis of bile acid and other lipids (fats). Moreover, they help to get rid of free radicals that are formed as a byproduct of metabolism. Peroxisomes are also important for helping to form the myelin sheath (a protective cap around nerve fibres).

Zellweger syndrome (ZS) is a rare inherited disorder discovered by Hans Zellweger. ZS is also termed ‘cerebro-hepato-renal syndrome’ due to the clinical manifestations seen in ZS patients. The cause of ZS is mutations in any of the pex genes that code for a protein called peroxin, which is required for the development and functioning of peroxisomes. 

Because peroxisomes are important for functioning of brain, eyes, liver, kidney and bones, the affected ZS patients show multiple signs and symptoms.


Zellweger syndrome (ZS) is part of a group of rare genetic diseases called peroxisomal biogenesis disorder (PBD) caused by defective formation and functioning of cell peroxisomes.

PBD disorders are categorised into two types:

  • Zellweger spectrum disorders (ZSD)
  • Rhizomelic chondrodysplasia punctata

Zellweger spectrum disorder (ZSD) is comprised of several sub-syndromes depending on severity, including:

  • Zellweger syndrome (severe form)
  • Neonatal adrenoleukodystrophy (less severe form)
  • Infantile Refsum disease and Heimler syndrome (mild forms)1

ZSD is used as a broad term to refer to any of these diseases involving pex gene mutations based on the severity level. These syndromes usually come to attention during early infancy, however, the milder forms may go unnoticed until childhood or later. 

In more severe forms, newborn babies are found to be hypotonic (limp with no muscle tone/strength), irritable and unable to feed. Neonatal seizures are common due to associated underlying neurological disorders. 

Babies will also have distinct facial/bone features including: 

  • A flat face
  • The bones of the skull (not fully fused at birth) will appear far apart/widely split  due to the pressure within the skull  
  • A broadened nasal bridge 
  • Large anterior fontanelle (soft spot)
  • Chondrodysplasia punctata (abnormal bone development of arm, knee and leg bones) 

If an infant displays respiratory distress or organ failure due to ZSD, the mortality rate is high and they will usually die within a year of life. 

As a child with ZSD ages, abnormalities involving various organs such as the liver, kidneys, adrenal glands, brain and skeleton may be present. 

Causes of zellweger syndrome

Peroxisome biogenesis disorder (PBD) is caused due to the mutations in a gene called pex. Pex genes encode the protein peroxin necessary for the normal functioning and development of peroxisomes.

The lipid metabolism that normally occurs in the peroxisome gets halted, causing the accumulation of various acidic lipids and other toxic cell metabolites within the liver, resulting in liver failure. If these toxic substances cross the blood brain barrier, they can negatively affect the central nervous system (CNS). 

These symptoms arise due to mutations in pex genes - there are nearly 14 pex genes identified as a risk factor, of which 13 genes were found be mutated in Zellweger syndrome (ZS).

In 70% of individuals with ZS, a mutation in the pex1 gene is known to be the causative factor. The severity of the Zellweger spectrum disorder (ZSD) is assessed based on the extent of peroxisomal damage:

  • Severe forms - complete loss of essential cellular structures and developmental delays 
  • Mild forms - loss of vision/hearing loss, fingernail and tooth enamel abnormalities and other neurological abnormalities2

Signs and symptoms of zellweger syndrome

Zellweger syndrome (ZS) and the other related syndromes have several clinical manifestations, including:

  • Hypotonia (poor muscle strength in babies leading to weak muscle movement and difficulty sucking and swallowing milk)
  • Cognitive defects
  • Enlarged liver
  • Neonatal seizures
  • Facial dysmorphisms
  • Impaired growth
  • Sensory and neurological abnormalities 
  • Adrenal insufficiency
  • Kidney stones
  • Skeletal abnormalities 
  • Developmental delay3

Management and treatment for zellweger syndrome

The severity of the disease decreases with age - usually adolescents and adults experience a slow disease progression (i.e. less risk of organ failure and damage to myelin sheaths surrounding nerves). 

Adults with Zellweger syndrome (ZS) are commonly affected by hearing loss and poor vision, while no signs facial dysmorphism are seen.4

There are no definite/curative treatments for ZS, however, there are several ways to manage its symptoms and the impact of organ dysfunction.

ZSD patients are treated through managing their symptoms. These include methods such as:

  • Gastrostomy - to make up for inadequate calorie intake 
  • Glasses and hearing aids - to correct vision and hearing loss 
  • Supplements - mainly supplementation of cholic acid, fat-soluble vitamins and vitamin D due to being susceptible to these deficiencies 
  • Adrenal replacement therapy - for adrenal insufficiency
  • Biphosphonates - to treat weakening bones
  • Kidney stone removal - through hydration (to flush them out), use of ultrasound shock waves/lithotripsy (to break them down) or through surgical removal
  • Anti-seizure medicines
  • Disability/developmental delay support 

ZSD patients will often need lifelong surveillance through methods including:

  • Continuous evaluation of proper nutrition and growth
  • Annual ear/eye examinations
  • Monitoring any changes in the structure/function of the liver through ultrasound or fibroscan
  • Brain assessment via MRI scan (can identify cognitive/motor disabilities and monitor any improvements/deteriorations)
  • Annual blood tests to monitor ACTH and cortisol levels  
  • Annual urine test to monitor the oxalate to creatinine ratio 
  • Kidney and liver imaging7


How is zellweger syndrome diagnosed?

To be diagnosed with Zellweger syndrome (ZS), you and/or your doctor may have a clinical suspicion of the disease. All syndromes under the umbrella of peroxisome biogenesis disorder (PBD) are diagnosed through biochemical testing of plasma (liquid component of blood). 

Doctors will look for an excess accumaltion of biological products such as:

  • Very-long-chain fatty acids (VLCFA) 
  • Bile acid intermediates (THCA and DHCA) 
  • Docosahexaenoic acid (DHA)

Mild forms of ZSD cannot always be detected via this method as these products are usually found to be within the normal level. Yet due to misdiagnosis of peroxisomal disorder, the search for newer biomarkers is underway.5 

Genetic testing of ZSD patients is used as a confirmatory test to detect the and mutated pex1 gene (the most frequent genetic mutation associated with ZSD, though other variants exist).6

The other tests done include:

  • Transaminases to detect the extent of liver injury or hepatic function
  • Examining the visual impairment and hearing loss 
  • Cerebral MRI to identify the damage towards myelin sheath
  • Newborn screening tests

How can I prevent zellweger syndrome?

Zellweger syndrome cannot be prevented but prenatal diagnosis can identify the disease early. Pregnant individuals should be offered genetic counselling to cope with/act on the diagnosis of ZS.

Who is at risk of zellweger syndrome?

As it is an inherited autosomal recessive genetic disorder, both the parents must be carrying one copy of the altered pex gene to pass it onto the child. 

How common is zellweger syndrome?

Zellweger syndrome is regarded as a rare disorder, occurring 1 in 50,000 individuals.

When should I see a doctor?

Always consult your doctor if you have concerns about your unborn child, whether it is regarding their genetic health or otherwise. They will be able to provide you with the appropriate measures and advice. If you or your child are diagnosed with Zellweger syndrome or any of its variants, you should keep uptodate with regular medical appointments to monitor the condition.


Peroxisomal biogenesis disorder (PBD) is a group of rare diseases, caused by a mutation in the pex1 gene. Zellweger spectrum disorder (ZSD) is one branch of peroxisomal disorders encompassing Zellweger syndrome (ZS), infantile refsum disease and neonatal adreno leukodystrophy. While these vary in severity, ZSD generally causes whole-body dysfunction including neurological, muscle and various organ abnormalities. Loss of vision and hearing is also common. 

Diagnosis is done through biochemical testing of acids and toxins and genetic testing of pex gene. There are no specific treatments available but managing symptoms could improve the condition and quality of life of ZSD patients.


  1. Jiang C, Okazaki T. Control of mitochondrial dynamics and apoptotic pathways by peroxisomes. Front Cell Dev Biol [Internet]. 2022 Sep 9 [cited 2023 Feb 16];10:938177. Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9500405/ 
  2. Judy RM, Sheedy CJ, Gardner BM. Insights into the structure and function of the pex1/pex6 aaa-atpase in peroxisome homeostasis. Cells [Internet]. 2022 Jun 29 [cited 2023 Feb 16];11(13):2067. Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9265785/
  3. Fransen M, Revenco I, Li H, Costa CF, Lismont C, Van Veldhoven PP. Peroxisomal dysfunction and oxidative stress in neurodegenerative disease: a bidirectional crosstalk. Adv Exp Med Biol. 2020;1299:19–30.
  4. Enns GM, Ammous Z, Himes RW, Nogueira J, Palle S, Sullivan M, et al. Diagnostic challenges and disease management in patients with a mild Zellweger spectrum disorder phenotype. Molecular Genetics and Metabolism [Internet]. 2021 Nov 1 [cited 2023 Feb 16];134(3):217–22. Available from: https://www.sciencedirect.com/science/article/pii/S1096719221007824
  5. Wanders RJA. Peroxisomal disorders: Improved laboratory diagnosis, new defects and the complicated route to treatment. Molecular and Cellular Probes [Internet]. 2018 Aug 1 [cited 2023 Feb 16];40:60–9. Available from: https://www.sciencedirect.com/science/article/pii/S0890850818300331
  6. Bose M, Yergeau C, D’Souza Y, Cuthbertson DD, Lopez MJ, Smolen AK, et al. Characterization of severity in zellweger spectrum disorder by clinical findings: a scoping review, meta-analysis and medical chart review. Cells [Internet]. 2022 Jun 10 [cited 2023 Feb 16];11(12):1891. Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9221082/
  7. Steinberg SJ, Raymond GV, Braverman NE, Moser AB. Zellweger spectrum disorder. In: Adam MP, Everman DB, Mirzaa GM, Pagon RA, Wallace SE, Bean LJ, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993 [cited 2023 Feb 16]. Available from: http://www.ncbi.nlm.nih.gov/books/NBK1448/ 
This content is purely informational and isn’t medical guidance. It shouldn’t replace professional medical counsel. Always consult your physician regarding treatment risks and benefits. See our editorial standards for more details.

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Asra Runissa

Master of Science - MS, medical biochemistry Kasturba Medical College, Mangalore

I am Asrarunissa from India. I hold a bachelor's degree in Biomedical science from Nitte university and M.Sc. in Medical Biochemistry from Manipal university. I was been working as a biochemistry lecturer for Physiotherapy students. I love to build my knowledge and also impart it to those who require it, which is what exactly I m doing right now being a medical writer at Klarity. Dedicating ample amount of time, to researching and developing an article that ultimately benefits society at large.

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