Zellweger syndrome
Zellweger syndrome spectrum (ZSS) refers to a group of rare genetic disorders caused by deficiencies in peroxisome biogenesis, leading to multisystem organ dysfunction and often resulting in early mortality, typically in infancy or childhood. These disorders are inherited in an autosomal recessive manner, with mutations in one of twelve PEX genes responsible for the condition. Symptoms of ZSS can include severe hypotonia, failure to thrive, seizures, liver dysfunction, and distinctive facial features. Affected individuals may also experience hearing loss, retinal dystrophy, and developmental delays, with severity varying widely among cases. Diagnostic approaches include measuring specific fatty acid levels and genetic testing to confirm the presence of PEX gene mutations. Treatment is primarily supportive, focusing on symptom management, nutritional support, and addressing specific complications. Unfortunately, most severely affected individuals do not survive past the first year of life, while those with milder forms may live into early childhood or longer, but with ongoing health challenges. Genetic counseling is recommended for families with a history of ZSS, as there is currently no prevention for these disorders.
Zellweger syndrome
ALSO KNOWN AS: Zellweger syndrome spectrum (including infantile Refsum disease and neonatal adrenoleukodystrophy); cerebrohepatorenal syndrome; peroxisome biogenesis disorder
DEFINITION The Zellweger syndrome spectrum (ZSS) includes a group of disorders caused by a deficiency in peroxisome biogenesis. Insufficient peroxisomal function results in multisystem organ dysfunction and subsequent death, typically in infancy or childhood.
Risk Factors
The ZSS disorders are inherited in an autosomal recessive manner. Individuals with mutations in both copies of any one of the twelve different PEX genes known to be associated with ZSS disorders are affected. Full siblings of these individuals have a 25 percent risk of being affected, a 50 percent risk of being an asymptomatic carrier, and a 25 percent chance of being unaffected and not a carrier. Male and female infants are affected with equal frequency. Cases of ZSS disorders have been observed worldwide; no particular ethnic preponderance has been noted.
Etiology and Genetics
Peroxisomes are small, membrane-bound organelles found in cells throughout the body. They are involved in a variety of metabolic processes, including the breakdown of toxic substances, such as hydrogen peroxide, and the production of bile acids, necessary for digestion of dietary fats. Peroxisomes are also involved in degradation of very long chain fatty acids (VLCFAs) in a process known as beta-oxidation, essential for energy production. Peroxisomes play a role in the synthesis of certain types of lipids, such as plasmalogens, which are important components of cell membranes in certain tissues (such as the brain).
Proteins necessary for peroxisome function and membrane formation are made within the cell, then transported into existing peroxisomes. Importing these essential proteins prompts growth and division, resulting in the formation of new peroxisomes. In the ZSS disorders, these proteins are unable to be transported into peroxisomes, resulting in decreased biogenesis and function.
ZSS disorders are caused by mutations in the PEX genes, which encode these essential proteins, known as peroxins. Though approximately twenty-nine PEX genes have been identified, ZSS disorders have been associated with mutations in only twelve (located at the following chromosomal positions): PEX1 (7q21q22) PEX2 or PXMP3 (8q21.1), PEX3(6q23q24), PEX5(12p13.3), PEX6(6p21.1), PEX10(1p36.32), PEX12 (17q12), PEX13(2p15), PEX14(1p36.2), PEX16(11p12p11.2), PEX19 (1q22), and PEX26 (22q11.2). In some cases, the particular gene involved and the type of mutations present are predictive of the ultimate effect on biogenesis and can be associated with clinical severity. Mutations in PEX1 is the most common cause of ZSS, affecting nearly 70 percent of individuals with the disease.
Symptoms
Though once considered separate entities, it is now known that Zellweger syndrome (ZS), neonatal adrenoleukodystrophy (NALD), and infantile Refsum disease (IRD) share a common etiology and represent differing degrees of severity along the Zellweger syndrome spectrum. There is little distinction between these conditions, although historically, severely affected infants were characterized as having ZS and those surviving more than one year and making some type of developmental progress were thought to have NALD or IRD.
The ZSS disorder typically appears during childhood; though extremely rare, presentation in adulthood has been reported. Affected neonates often present with severe hypotonia, failure to thrive, seizures, and liver dysfunction. Some are noted to have distinctive facial features and neuronal migration defects. Bony stippling may also be seen on radiographs. Older children may have additional issues such as hearing loss and/or retinal dystrophy. Affected individuals are noted to have decreased levels of docosahexaenoic acid (DHA), thought to be important in brain development, as well as decreased bile acids, important in normal digestion. Liver dysfunction can result in coagulation problems, and renal failure, thought to be due to renal cysts, can also occur. Severely affected individuals usually make no developmental progress; individuals with milder disease have a wide range of intellectual abilities, with most exhibiting developmental delays. Loss of previously acquired skills occurs in some due to progressive leukodystrophy.
Screening and Diagnosis
Analysis of levels of VLCFAs in the plasma is a useful initial screening test. Affected individuals typically have elevated concentrations of C26:0 and C26:1 and elevated C24/C22 and C26/C22 ratios. Measurements of plasmalogens, phytanic and pristanic acids, pipecolic acid, and plasma bile acids are also helpful in diagnosing ZSS and distinguishing this from other peroxisomal disorders. Confirmation of abnormalities noted on blood samples should be performed on cultured fibroblasts. Documentation of causative mutations in one of the PEX genes associated with ZSS can also further confirm the diagnosis.
Treatment and Therapy
Treatment for ZSS disorders remains largely symptomatic. Supplying an adequate caloric intake may require the placement of a gastrostomy tube. Supplementation of vitamin K and other fat-soluble vitamins is recommended. Hearing aids are used to address hearing loss. Antiepileptic drugs may be used to control seizures. Supplementation with bile acids, deficient in ZSS, is currently under investigation. Supplemental DHA has been proposed as a treatment for ZSS, but its clinical effects have not been proven. Liver transplantation has been attempted in a few cases, though long-term clinical outcomes are currently unavailable.
Prevention and Outcomes
Most severely affected individuals die before one year of age. Evidence suggests that of those who survive beyond this point with an apparently stable course, most will survive through early childhood, and survival into young adulthood has been documented. Death in older individuals is typically the result of respiratory complications and/or renal failure.
There is no effective means of prevention for the ZSS disorders. Prenatal testing is typically available for those in which the causative mutations in the index case have been identified, or the biochemical abnormalities have been demonstrated on cultured fibroblasts. Individuals with a family history of these disorders should be offered genetic counseling.
Bibliography
Bose, Mousumi, and Steven J. Steinberg. "Zellweger Spectrum Disorders." National Organization for Rare Disorders, 2021, rarediseases.org/rare-diseases/zellweger-spectrum-disorders/. Accessed 4 Sept. 2024.
Fazi, C. "Case Report: Zellweger Syndrome and Humoral Immunodeficiency: The Relevance of Newborn Screening for Primary Immunodeficiency." Frontiers in Pediatrics, vol. 10, 24 Mar. 2022, doi.org/10.3389/fped.2022.852943. Accessed 4 Sept. 2024.
Poll-The, B., et al. “Peroxisome Biogenesis Disorders with Prolonged Survival: Phenotypic Expression in a Cohort of 31 Patients.” American Journal of Medical Genetics126A.4 (2004): 333–38. Print.
Rahim, R. S., A. C. B. Meedeniya, and D. I. Crane. "Central Serotonergic Neuron Deficiency in a Mouse Model of Zellweger Syndrome." Neuroscience 274 (2014): 229–41. Print.
Steinberg, S., et al. “Peroxisome Biogenesis Disorders.” Biochimica et Biophysica Acta 1763 (2006): 1733–1748. Print.
Steinberg, Steven J., et al. "Peroxisome Biogenesis Disorders, Zellweger Syndrome Spectrum." GeneReviews. University of Washington, 10 May 2012. Web. 4 Aug. 2014.
Tran, Christel, et al. "Late-Onset Zellweger Spectrum Disorder Caused by PEX6 Mutations Mimicking X-Linked Adrenoleukodystrophy." Pediatric Neurology 51.2 (2014): 262–65. Print.
Wanders, R., et al. “Peroxisomal Disorders I: Biochemistry and Genetics of Peroxisome Biogenesis Disorders.” Clinical Genetics 67.2 (2005): 107–33. Print.