Diagnostic challenges and disease management in patients with a mild Zellweger spectrum disorder phenotype

Gregory M Enns; Zineb Ammous; Ryan W Himes; Janaina Nogueira; Sirish Palle; Meghan Sullivan; Charina Ramirez

doi:10.1016/j.ymgme.2021.09.007

Diagnostic challenges and disease management in patients with a mild Zellweger spectrum disorder phenotype

Mol Genet Metab. 2021 Nov;134(3):217-222. doi: 10.1016/j.ymgme.2021.09.007. Epub 2021 Sep 27.

Authors

Gregory M Enns¹, Zineb Ammous², Ryan W Himes³, Janaina Nogueira⁴, Sirish Palle⁵, Meghan Sullivan⁶, Charina Ramirez⁷

Affiliations

¹ Stanford University, Palo Alto, CA, USA. Electronic address: genns@stanford.edu.
² The Community Health Clinic, Topeka, IN, USA.
³ Ochsner Health, New Orleans, LA, USA.
⁴ The University of Alabama at Birmingham, Children's of Alabama, Birmingham, AL, USA.
⁵ Oklahoma University Medicine, Oklahoma City, OK, USA.
⁶ MedVal Scientific Information Services, LLC, Princeton, NJ, USA.
⁷ University of Texas, Southwestern Medical Center, Children's Medical Center Dallas, Dallas, TX, USA.

PMID: 34625341
DOI: 10.1016/j.ymgme.2021.09.007

Abstract

Peroxisome Biogenesis Disorders-Zellweger spectrum disorder (PBD-ZSD) is a rare, autosomal recessive peroxisome biogenesis disorder that presents with variable symptoms. In patients with PBD-ZSD, pathogenic variants in the PEX family of genes disrupt normal peroxisomal function, impairing α- and β-oxidation of very-long-chain fatty acids and synthesis of bile acids, resulting in increased levels of toxic bile acid intermediates and multisystem organ damage. The spectrum of severity in PBD-ZSD is variable, with some patients dying in the first year of life, while others live into adulthood. Symptoms of mild PBD-ZSD include various combinations of developmental delay, craniofacial dysmorphic features, visual impairment, sensorineural hearing loss, liver disease, and adrenal insufficiency. Disease progression in mild PBD-ZSD is generally slow, and may include extended periods of stability in some cases. The presence and extent to which symptoms occur in mild PBD-ZSD represents a diagnostic challenge that can cause delays in diagnosis with potential significant implications related to disease monitoring and treatment. There is some support for the pharmacologic therapies of Lorenzo's oil, docosohexanoic acid, and batyl alcohol in altering symptoms; however, systematic long-term studies are lacking. Cholic acid (CA) therapy has demonstrated treatment efficacy in patients with PBD-ZSD, including decreased toxic bile acid intermediates, transaminase levels, and liver inflammation, with improvement in growth parameters. However, these responses are most apparent in patients diagnosed and treated at a young age. Advanced liver disease may limit the efficacy of CA, underscoring the need to diagnose and treat these patients before significant liver damage and other related complications occur. Here we discuss the signs and symptoms of PBD-ZSD in patients with mild disease, standard diagnostic tools, factors affecting disease management, and available pharmacological interventions.

Keywords: Cholic acid; Peroxisomal disorder; Zellweger spectrum disorder.

Publication types

Research Support, Non-U.S. Gov't
Review

MeSH terms

Adult
Clinical Trials as Topic
Disease Management*
Humans
Longitudinal Studies
Phenotype*
Zellweger Syndrome / classification
Zellweger Syndrome / diagnosis*
Zellweger Syndrome / drug therapy
Zellweger Syndrome / physiopathology