Peroxisomal Diseases and their Ocular Manifestations

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 by Vaidehi S. Dedania, MD on June 2, 2023.

Disease Entity


Zellweger syndrome, also known as cerebro-hepato-renal syndrome, is a rare, autosomal recessive condition related to dysfunction of peroxisomes. Zellweger syndrome was first described in 1964 by Bowen et al with prominent ocular and extraocular manifestations.[1] Zellweger syndrome may be distinguished from other peroxisomal diseases such as Refusm’s disease and adrenoleukodystrophy through clinical features and genetic testing.


Zellweger disease is a rare condition with an incidence of only 1 in 50,000 in the United States. Zellweger syndrome is less common than other peroxisomal disorders such as adrenoleukodystrophy and Refsum’s disease.[2] The incidence of Zellweger is also regionally dependent with the highest incidence noted in Quebec (1 in 12,000) and the lowest in Japan (1 in 500,000).[3]


The pathophysiology of Zellweger's disease is related to mutations in the PXE gene causing dysfunction of peroxisomes.[4] Peroxisomes are organelles found in most cells, including in the eye, with the highest distribution in the liver, kidney, and oligodendrocytes. Peroxisomes are critical for the breakdown of a variety of substances such as hydrogen peroxide, uric acid, amino acids, and fatty acids through oxidation reactions.[5] Peroxisomes are also involved in biosynthesis of several important cellular components including synthesis of bile acids and cholesterol. Zellweger disease is considered part of the peroxisomal biogenesis disorder (PBD) spectrum which are most commonly due to mutations in one of 14 PEX genes coding for peroxisomes. Specifically, 70% of zellweger's cases are due to mutations in PEX1.[6]

When compared to other peroxisomal disorders, patients with Zellweger disease are noted to have high levels of very-long-chain fatty acids,and the lowest level of plasmalogens, which are important for synthesis of myelin.[2] Patients are also noted to have elevations in pipecolic acid, phytanic acid, and bile acid intermediate accumulation.


Clinical Presentation

Zellweger syndrome may present in the neonatal period, childhood, or early adolescents with the highest disease severity occurring in the neonatal manifestation.[3] Patients with Zellweger syndrome most commonly present early in infancy with hypotonia, seizures, and multiple organ system dysfunction. Patients may have involvement of the brain, heart, biliary system, liver, kidneys, in addition to ocular manifestations. Hepatomegaly and renal cysts are commonly observed in Zellweger cases (80% and 70% respectively).[7]

Ophthalmologic manifestations of Zellweger syndrome arise in both the anterior and posterior segment. Anterior segment manifestations include corneal clouding, cataracts, and glaucoma.[8] The cataracts can appear in varying densities due to vaculaizations of the cortical lens fibers. Posterior segment findings may include pigmentary retinopathy due to deposition of macrophages containing pigment. The posterior vitreous may also appear hazy due to deposition macrophages. A breakdown of clinical manifestations contrasting Zellweger syndrome, neonatal adrenoleukodystrophy, and Refsum’s disease by Folz et al. can be seen in table 1.

Table 1. Clinical manifestations of Zellweger syndrome contrasted to other peroxisomal disorders.[8]
Zellweger Syndrome Neonatal Adrenoleukodystrophy Infantile Refsum’s Disease
Ophthalmologic Findings
  • Pigmentary retinopathy and retinal arteriolar attenuation
  • Pigment epithelial clumping
  • Optic atrophy
  • Extinguished electroretinogram
  • Pigmentary retinopathy and retinal arteriolar attenuation
  • Optic atrophy
  • Extinguished electroretinogram
Other Clinical Findings
  • Craniofacial dysmorphism
  • Seizures
  • Hypotonia
  • Psychomotor retardation
  • Renal cysts
  • Adrenal cortical atrophy
  • Seizures
  • Hypotonia
  • Psychomotor retardation
  • Deafness
  • Psychomotor retardation

Clinical diagnosis

The first step in diagnostic testing for Zellweger syndrome involves screening for elevated very long chain fatty acids in the blood. Patients can also show elevated levels of other substances as a result of peroxisomal dysfunction such as phytanic acid, pristanic acid, pipecolic acid, bile acid intermediates, and reduced plasminogen. A definitive diagnosis is made by testing for PEX gene mutations.[2]

Differential diagnosis

The clinical manifestations of Zellweger syndrome are not unique. A broad differential including genetic, autoimmune, infectious, or other congenital abnormalities should be considered depending on clinical presentation.[1]


  • Chromosomal abnormalities
  • Other peroxisomal disorders (adrenoleukodystrophy or Refsum’s disease)
  • Non-peroxisomal metabolic disorders
  • Congenital muscular dystrophies
  • Alport syndrome
  • Mitochondrial disorders
  • Cockayne syndrome


  • Autoimmune adrenalitis


  • TORCH infections
  • Toxoplasmosis
  • Rubella
  • CMV
  • Herpes simplex
  • Other congenital abnormalities
  • Hypoxic ischemic encephalopathy
  • Cerebral malformations


There is no curative therapy for Zellweger disease and patients will often die within months. However, several treatments may be offered as supportive care. Steinberg et al. suggested the following interventions to address the common features of Zellweger disease.[9]

Table: Interventions to address the common features of Zellweger disease.[9]


Feeding &


  • Feeding therapy; gastrostomy tube placement may be required for persistent feeding issues.

No specific metabolic diet recommended 1

Hearing Hearing aids in children found to have hearing impairment


  • Cataract removal to preserve vision
  • Glasses to correct refractive errors


  • Supplementation of vitamin K & other fat-soluble vitamins

CholbamTM (cholic acid) supplementation 2

  • Varices can be treated w/sclerosing therapies.
Seizures Standard treatment w/ASM by experienced neurologist
DD/ID Provide early-intervention services.


Adrenal replacement therapy
  • Vitamin D supplementation
  • Consider bisphosphonate.


Treatment per dentist
Renal oxalate


Supportive treatment has included hydration, lithotripsy, surgical intervention.
Vaccination Annual influenza & respiratory syncytial virus vaccines as well as usual vaccination schedule

ASM = anti-seizure medication; DD = developmental delay; ID = intellectual disability

1. A diet low in phytanic acid has been proposed, based mainly on the weak analogy with adult Refsum disease, in which accumulation of phytanic acid is pathogenic and treatment involves restricted dietary intake of phytanic acid (including avoidance of full-fat cow's milk products and high-fat meat products from ruminants). Its effectiveness in ZSD has never been proven. All standard infant formulas are already low in phytanic acid.

2. By providing the final C24 bile acid product, the bile acid pathway undergoes feedback inhibition, thus reducing the levels of elevated C27 bile acid intermediates that are thought to be toxic to the liver. Cholic acid therapy does in fact decrease C27 bile acid intermediates (which should be measured), but its clinical effect in ZSD is not yet known.


  2. 2.0 2.1 2.2 Alsaleem M, Saadeh L. Adrenoleukodystrophy. In: StatPearls. Treasure Island (FL): StatPearls Publishing; November 25, 2021.
  3. 3.0 3.1 Klouwer FC, Berendse K, Ferdinandusse S, Wanders RJ, Engelen M, Poll-The BT. Zellweger spectrum disorders: clinical overview and management approach. Orphanet J Rare Dis. 2015;10:151. Published 2015 Dec 1. doi:10.1186/s13023-015-0368-9
  4. Cooper GM. The Cell: A Molecular Approach. 2nd edition. Sunderland (MA): Sinauer Associates; 2000. Peroxisomes. Available from:
  5. Brodsky MC. Pediatric Neuro-Ophtalmology. New York: Springer; 2016.
  6. Braverman NE, Raymond GV, Rizzo WB, et al. Peroxisome biogenesis disorders in the Zellweger spectrum: An overview of current diagnosis, clinical manifestations, and treatment guidelines. Mol Genet Metab. 2016;117(3):313-321. doi:10.1016/j.ymgme.2015.12.009
  7. Kheir AE. Zellweger syndrome: A cause of neonatal hypotonia and seizures. Sudan J Paediatr. 2011;11(2):54-58.
  8. 8.0 8.1 Folz SJ, Trobe JD. The peroxisome and the eye. Surv Ophthalmol. 1991;35(5):353-368. doi:10.1016/0039-6257(91)90185-i
  9. 9.0 9.1 Steinberg SJ, Raymond GV, Braverman NE, et al. Zellweger Spectrum Disorder. 2003 Dec 12 [Updated 2020 Oct 29]. In: Adam MP, Mirzaa GM, Pagon RA, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2022. Available from:
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