Characterization of Severity in Zellweger Spectrum Disorder by Clinical Findings: A Scoping Review, Meta-Analysis and Medical Chart Review

Abstract

Zellweger spectrum disorder (ZSD) is a rare, debilitating genetic disorder of peroxisome biogenesis that affects multiple organ systems and presents with broad clinical heterogeneity. Although severe, intermediate, and mild forms of ZSD have been described, these designations are often arbitrary, presenting difficulty in understanding individual prognosis and treatment effectiveness. The purpose of this study is to conduct a scoping review and meta-analysis of existing literature and a medical chart review to determine if characterization of clinical findings can predict severity in ZSD. Our PubMed search for articles describing severity, clinical findings, and survival in ZSD resulted in 107 studies (representing 307 patients) that were included in the review and meta-analysis. We also collected and analyzed these same parameters from medical records of 136 ZSD individuals from our natural history study. Common clinical findings that were significantly different across severity categories included seizures, hypotonia, reduced mobility, feeding difficulties, renal cysts, adrenal insufficiency, hearing and vision loss, and a shortened lifespan. Our primary data analysis also revealed significant differences across severity categories in failure to thrive, gastroesophageal reflux, bone fractures, global developmental delay, verbal communication difficulties, and cardiac abnormalities. Univariable multinomial logistic modeling analysis of clinical findings and very long chain fatty acid (VLCFA) hexacosanoic acid (C26:0) levels showed that the number of clinical findings present among seizures, abnormal EEG, renal cysts, and cardiac abnormalities, as well as plasma C26:0 fatty acid levels could differentiate severity categories. We report the largest characterization of clinical findings in relation to overall disease severity in ZSD. This information will be useful in determining appropriate outcomes for specific subjects in clinical trials for ZSD.

Keywords: PEX genes; Zellweger spectrum disorder; disease severity; feeding difficulties; hexacosanoic acid; medical chart review; peroxisome biogenesis disorder; renal cysts; scoping review; seizure disorder; signs and symptoms; survival.

Figure 1

Flowchart showing overview of the literature search and study selection process for the scoping review.

Figure 2

Kaplan–Meier analyses of survival according to severe, mild, and intermediate severity categories in individuals with ZSD. (A) Survival for 46 severe (red), 21 intermediate (blue), and 36 mild (green) (total 103) subjects from the case studies is shown; (B) survival for 72 severe, 52 intermediate, and 71 mild (total 195) subjects from the cohort studies is shown; (C) survival for 23 severe, 64 intermediate, and 49 mild (total 136) subjects from the natural history study is shown. The corresponding log-rank p value is shown for each cohort. The numbers at risk (number of surviving patients) are indicated below each curve.

Figure 2

Kaplan–Meier analyses of survival according to severe, mild, and intermediate severity categories in individuals with ZSD. (A) Survival for 46 severe (red), 21 intermediate (blue), and 36 mild (green) (total 103) subjects from the case studies is shown; (B) survival for 72 severe, 52 intermediate, and 71 mild (total 195) subjects from the cohort studies is shown; (C) survival for 23 severe, 64 intermediate, and 49 mild (total 136) subjects from the natural history study is shown. The corresponding log-rank p value is shown for each cohort. The numbers at risk (number of surviving patients) are indicated below each curve.

Figure 3

Predicted probabilities of each severity category by number of clinical findings at any age among seizure disorder, abnormal EEG, bilateral renal cortical microcysts, and cardiac abnormalities. Univariable multinomial logistic model was used to predict the probabilities of having severe (red), intermediate (blue), or mild (green) overall disease severity from the number of any of these 4 clinical findings. The 95% confidence intervals are shown as the error bars.

Figure 4

Predicted probabilities of each severity category by plasma C26:0 fatty acid levels at any age. Univariable multinomial logistic model was used to predict the probabilities of having severe (red), intermediate (blue), or mild (green) overall disease severity from plasma C26:0 fatty acid levels measured in 8 severe, 44 intermediate, and 36 mild ZSD individuals (total 88 patients) from our natural history study. The 95% confidence intervals are shown as the dotted lines.