November 2020 Case Competition: Winning Abstract #1

Zellweger Spectrum Disorder (ZSD) is an autosomal recessive condition caused by the mutation of one of twelve genes involved in the formation and function of peroxisomes (1). Peroxisomes play a role in waste management and the production and breakdown of fatty acids. Several gene mutations are associated with peroxisome dysfunction in ZSD, however, roughly 70% of individuals with ZSD have a mutation in the PEX1 gene (1). Mutations in the genes responsible for ZSD cause dysfunction of the nervous system, digestive system and brain (2). Symptoms typically appear in early childhood, usually in the first few days after birth (2). Distinctive facial characteristics include a flat face, high forehead, broad nasal bridge, and upslanting eyes (1, 2). Symptoms can vary depending on the age of the child at symptom onset. In newborns, common symptoms include low muscle tone, poor feeding, distinctive facies, brain malformations, seizures, renal cysts, bone calcification, liver abnormalities, such as liver cysts, obstruction of bile flow, and enlargement of the liver (1). Older infants and younger children experience hearing, vision, and teeth impairment and adrenal dysfunction (1). They also suffer from developmental delays and low muscle tone, but intellect may not be impacted. Many children suffer from neurological conditions, such as deterioration of the white matter of the brain and the nerves, and lack of muscle coordination. All children suffer from liver dysfunction and can develop life-threatening health issues in other organs and tissues (2). ZSD is prevalent in 50,000 newborns in the US and is presumed to occur worldwide but incidence may differ between regions. For example, the estimated incidence of ZSD in Quebec, Canada is 1 in 12,191 live births, whereas in Japan, it is 1 in 500,000 births (3, 4). Diagnosis of ZSD can be established through biochemical testing, fibroblast analysis (i.e. evaluating cells used to make the extracellular matrix and collagen) and mutation analysis. Biochemical testing can be conducted through examining blood plasma, erythrocytes and urine, assessing levels of components such as very-long-chain fatty acids, pipecolic acid, plasmalogen levels and bile acids (3, 5). While this method of testing may be effective, it is possible that some patients may have near normal results in these tests (3). As a result, fibroblast testing can help provide some more clarity (3, 5). Mutation analysis is another diagnostic test that is employed in ZSD and with its increasing availability, it is likely to be used more often (3). This type of testing also has an added advantage of identifying heterozygous carriers (those who may be carrying genes for ZSD but do not have the disease) (5). Although there are no curative treatment options available for ZSD, research has shown several advances in ways to address the metabolic defects of the disease, such as supplementing metabolic end products (i.e. docosahexaenoic acid and cholic acid) (6, 7). However, research of these treatment modalities is minimal due to limited efficacy. Some symptom management options include restricting foods rich in phytanic acid such as cow’s milk by-products (8). Overall, symptoms of ZSD can vary greatly and further research is needed to better treat individuals with this disease.

Tiffany Chen, Angela Lin, Dixon Pinto, Heba Shahaed

---

References

1. Steinberg SJ, Raymond GV, Braverman NE, Moser AB. Zellweger Spectrum Disorder. In: Adam MP, Ardinger HH, Pagon RA, Wallace SE, Bean LJ, Stephens K, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993 [cited 2020 Nov 13]. Available from: http://www.ncbi.nlm.nih.gov/books/NBK1448/
2. Zellweger syndrome | Genetic and Rare Diseases Information Center (GARD) – an NCATS Program [Internet]. [cited 2020 Nov 13]. Available from: https://rarediseases.info.nih.gov/diseases/7917/zellweger-syndrome
3. Klouwer FCC, Berendse K, Ferdinandusse S, Wanders RJA, Engelen M, Poll-The BT. Zellweger spectrum disorders: clinical overview and management approach. Orphanet J Rare Dis. 2015 Dec 1;10(1):151.
4. Levesque S, Morin C, Guay S-P, Villeneuve J, Marquis P, Yik WY, et al. A founder mutation in the PEX6 gene is responsible for increased incidence of Zellweger syndrome in a French Canadian population. BMC Med Genet. 2012 Aug 15;13:72.
5. Braverman NE, Raymond GV, Rizzo WB, Moser AB, Wilkinson ME, Stone EM, et al. Peroxisome biogenesis disorders in the Zellweger spectrum: An overview of current diagnosis, clinical manifestations, and treatment guidelines. Mol Genet Metab. 2016 Mar;117(3):313–21.
6. Paker AM, Sunness JS, Brereton NH, Speedie LJ, Albanna L, Dharmaraj S, Moser AB, Jones RO, Raymond GV. Docosahexaenoic acid therapy in peroxisomal diseases: results of a double-blind, randomized trial. Neurology. 2010 Aug 31;75(9):826-30.
7. Keane MH, Overmars H, Wikander TM, Ferdinandusse S, Duran M, Wanders RJ, Faust PL. Bile acid treatment alters hepatic disease and bile acid transport in peroxisome-deficient PEX2 Zellweger mice. Hepatology. 2007 Apr;45(4):982-97.
8. Hellgren LI. Phytanic acid—an overlooked bioactive fatty acid in dairy fat?. Annals of the New York Academy of Sciences. 2010 Mar;1190(1):42-9.
   
   

Cite This Article:

Chen T., Lin A., Pinto D., Shahaed H., Carmona A., Zada D. November 2020 Case Competition: Winning Abstract #1. Illustrated by C. Qian. Rare Disease Review. January 2021. DOI: 10.13140/RG.2.2.29922.76487