Zellweger Syndrome

Zellweger syndrome (ZWS), also called cerebrohepatorenal syndrome, is a rare congenital peroxisome biosynthesis disorder and is considered an inborn error of metabolism. Zellweger syndrome is the most severe form of a spectrum of conditions called Zellweger spectrum disorder (ZSD), and is characterized by the reduction or absence of functional peroxisomes. Symptoms are present from the time of birth and include hypotonia, poor feeding, seizures, and certain distinctive physical features, notably facial characteristics and skeletal malformations. There is no cure for ZWS. The average survival rate is less than 1 year.

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Epidemiology and Genetics

Epidemiology

  • Incidence: 1:50,000–100,000
  • Most common peroxisome biosynthesis disorder is seen in infancy.
  • Most infants born with Zellweger syndrome (ZWS) do not live past 6 months.

Genetics

  • Inheritance: autosomal recessive
  • Due to a mutation in 1 of 13 PEX genes, which encode peroxins → proteins required for the normal assembly of peroxisomes:
    • Peroxisomes are membrane-bound organelles present in all cells, except mature erythrocytes:
      • Contain enzymes necessary for multiple catabolic and anabolic metabolic functions 
      • Catalyze beta-oxidation of very long chain fatty acids (VLCFAs)
      • Catalyze oxidation of phytanic, pipecolic, pristanic, and other dicarboxylic acids
      • Involved in synthesis of bile acids and plasmalogen
    • PEX gene mutations result in a loss of peroxisomal function → preventing catabolism of VLCFAs → ↑ accumulation of VLCFAs in membranes of neuronal cells → abnormal function, atrophy, and death of cells → impaired neuronal migration and differentiation → abnormal brain development → neurologic dysfunction and injury to variable extents 
  • Most commonly a mutation in the PEX1 gene

Clinical Presentation

Clinical manifestations of ZWS are present at birth.

Craniofacial dysmorphism

  • Separated cranial sutures
  • Large anterior fontanelle
  • High forehead
  • Flattened face
  • Low and broad nasal bridge
  • Upslanting palpebral fissures 
  • Epicanthal folds (skin fold from the upper eyelid to the inner corner of the eye)
  • Protruding tongue
  • Deformed ear lobes
  • High arched palate

Craniofacial dysmorphic features in patients with Zellweger spectrum disorder (ZSD)
A 6-month-old girl (A) with typical craniofacial dysmorphia, epicanthal folds, high forehead, broad nasal bridge, hypoplastic supraorbital ridges, and large anterior fontanel (drawn). Images (B) and (C) show a girl with ZSD at the age of 9 months (B) and 14 months (C). Facial dysmorphism in this girl is less pronounced.

Image: “Zellweger spectrum disorders: clinical overview and management approach” by Klouwer FC, Berendse K, Ferdinandusse S, Wanders RJ, Engelen M, Poll-The BT. License: CC BY 4.0, edited by Lecturio.

Neurologic abnormalities

  • Severe hypotonia and muscle weakness
  • Epileptic seizures
  • Hearing loss
  • Absent reflexes
  • Developmental delay

Ocular abnormalities

  • Vision impairment 
  • Cataracts
  • Pigmentary retinopathy
  • Glaucoma

Hepatic abnormalities

  • Hepatomegaly
  • Jaundice
  • Cirrhosis
  • Coagulopathy
  • Biliary dysgenesis (affects the normal movement of bile)

Renal abnormalities

  • Glomerulocystic kidney disease
  • Renal dysfunction

Associated conditions

  • Chondrodysplasia punctata present in 50%–70% of cases:
    • Encompasses a group of skeletal anomalies characterized by calcific deposits in cartilage (calcific stippling), particularly in the patella and long bones
    • Associated with shortened limbs, joint contractures, and spinal abnormalities
  • Feeding difficulties due to profound hypotonia

Diagnosis and Management

Diagnosis

  • History and clinical examination
  • Laboratory studies:
    • Blood:
      • ↑ Plasma VLCFA concentration
      • ↑ Bile acid intermediaries di- and trihydroxycholestanoic acid (DHCA, THCA)
      • ↑ Phytanic, pristanic, and pipecolic acid concentrations
    • Erythrocytes: ↓ plasmalogen concentration
    • Urine:
      • ↑ Bile acids
      • ↑ Pipecolic acid concentration
  • Imaging:
    • Brain magnetic resonance imaging (MRI): may show various abnormalities including neocortical dysplasia, impaired myelination, abnormal cortical gyral patterns, decreased volume of white matter, bilateral ventricular dilatation, and germinolytic cysts 
    • Abdominal ultrasound: shows hepatomegaly and/or renal cysts
  • Assays of peroxisomal-related processes in cultured skin fibroblasts help confirm the diagnosis.
  • Genetic testing: identifies the specific molecular defect to confirm the diagnosis 
  • In utero diagnosis by chorionic villus sampling may be done if there is a suspicion of the disorder or a family history.

Management

There is no cure and no effective treatment for ZWS. Treatment is supportive at best. 

  • Feeding issues may be treated with a nasogastric tube.
  • Therapeutic and genetic counseling should be offered to the family.

Prognosis

Death typically occurs within 1 year of birth (usually < 6 months), typically due to respiratory failure. 

Clinical Relevance

Related conditions

Zellweger syndrome is part of a clinical continuum of peroxisome biogenesis disorders known as Zellweger spectrum disorder (ZSD). All of the following conditions also have autosomal recessive inheritance, and are diagnosed and managed similar to ZWS: 

  • Neonatal adrenoleukodystrophy (NALD): considered a less-severe form of ZSD than ZWS. Craniofacial dysmorphism is present, but less severe, with mid-face hypoplasia usually the most pronounced. Individuals with NALD also have hepatic dysfunction and may have adrenal insufficiency, but cystic renal disease and chondroplasia punctata are absent. Neurologic dysfunction with progressive leukodystrophy (degeneration of brain white matter) begins in the early years of life. Most children do not survive past 5 years of age. 
  • Infantile Refsum disease (IRD): the clinical presentation is less severe than ZWS and NALD. Facial dysmorphic features are mild or may be absent. Hepatic dysfunction and neurologic features such as hypotonia and vision and hearing impairments occur. Severe developmental delay is noted within the 1st 6 months of life. Gastrointestinal symptoms also occur. Neurologic deterioration is slower and children with IRD may survive into adolescence. 
  • Heimler syndrome: an extremely rare peroxisomal biogenesis disorder that is considered the mildest form of ZSD. Heimler syndrome is characterized by acquired sensorineural hearing loss, retinal dystrophy or pigmentosa, nail abnormalities, and enamel hypoplasia of permanent teeth. The remainder of development and cognition appear to be normal. The lifespan is unaffected. 

Differential diagnosis

The differential diagnosis for ZWS is vast. Clinical features, biochemical testing, imaging, and ultimately genetic testing help to differentiate and provide a diagnosis. The following are disorders that should be considered in any neonate that presents with profound hypotonia:

  • Chromosomal abnormalities:
    • Down’s syndrome (Trisomy 21)
    • Prader-Willi syndrome 
  • Single enzyme peroxisomal disorders: 
    • Acyl-CoA oxidase deficiency (also known as pseudo-NALD) 
    • D-bifunctional protein deficiency
  • Other metabolic disorders: 
    • Acid maltase deficiency (AMD)
    • Carnitine deficiency
    • Cytochrome C oxidase deficiency
  • Neuromuscular disorders:
    • Spinal muscular atrophy
    • Congenital muscular dystrophies
    • Congenital myopathies
  • Infections:
    • Cytomegalovirus (CMV)
    • Rubella virus
    • Toxoplasmosis
    • Herpes simplex virus (HSV)

References

  1. Wanders, R. J. & Schiffman, R. (2020). Peroxisomal disorders. UpToDate. Retrieved December 14, 2020, from https://www.uptodate.com/contents/peroxisomal-disorders
  2. Klouwer, F.C.C., Berendse, K., Ferdinandusse, S. et al. (2015). Zellweger spectrum disorders: Clinical overview and management approach. Orphanet J Rare Dis. 10(151) https://doi.org/10.1186/s13023-015-0368-9
  3. Steinberg SJ, Raymond G V, Braverman NE, & Moser AB. (2020). Peroxisome Biogenesis Disorders, Zellweger Syndrome Spectrum. Gene Reviews. http://www.ncbi.nlm.nih.gov/books/NBK1448/
  4. Gao, FJ., Hu, FY., Xu, P., et al. (2019). Expanding the clinical and genetic spectrum of Heimler syndrome. Orphanet J Rare Dis. 14, 290. https://doi.org/10.1186/s13023-019-1243-x
  5. Böhm, M., Pronicka, E., et al. (2006). Retrospective, multicentric study of 180 children with cytochrome C oxidase deficiency. Pediatric research, 59(1), 21–26. https://doi.org/10.1203/01.pdr.0000190572.68191.13

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