Clinical Guidance

A general relationship appears to exist among the genotype, cellular phenotype (i.e., import of peroxisomal matrix proteins), and clinical phenotype . PEX gene defects are associated with loss-of-function variants; hence, variants that abolish activity (e.g., large deletions, nonsense, frameshift variants) are most severe. In contrast, missense variants that retain some residual function have a less severe effect on peroxisome assembly; however, it should be noted that not all missense variants have residual activity. Due to the overall rarity of ZSD the opportunities to rigorously assess genotype and phenotype are limited.

Source: GeneReviews — "Zellweger Spectrum Disorder"

Diagnostic Criteria

Suggestive Findings Zellweger spectrum disorder (ZSD) should be suspected in children with the following and findings. Clinical Findings In newborns: • Hypotonia • Poor feeding • Distinctive facies • Brain malformations • Seizures • Renal cysts • Hepatomegaly, cholestasis, and hepatic dysfunction • Bony stippling (chondrodysplasia punctata) of the patella(e) and other long bones In older infants and children: • Developmental delays with or without hypotonia (Note: Intellect can be normal.) • Failure to thrive • Hearing loss • Vision impairment • Liver dysfunction • Adrenal dysfunction • Leukodystrophy • Peripheral neuropathy and ataxia Laboratory Findings The screening assays for ZSD are summarized in . Note that because some individuals with ZSD do not have abnormalities of these screening assays in body fluids or cultured cells, molecular genetic testing is necessary to establish the diagnosis . Functional testing in fibroblasts remains an ancillary tool to confirm equivocal molecular and/or biochemical results. Table 1. Screening Assays for Zellweger Spectrum Disorder

Source: GeneReviews — "Zellweger Spectrum Disorder"

Differential Diagnosis

The differential diagnosis of Zellweger spectrum disorder (ZSD) varies with age at presentation and most prominent feature of the presentation. ZSD in newborns is most often confused with other conditions that result in profound hypotonia including Down syndrome, other chromosome abnormalities, and the disorders summarized in . Table 3. Differential Diagnosis of ZSD in a Newborn with Profound Hypotonia

Management Guidelines

(full text) and (full text) have published management and treatment guidelines for Zellweger spectrum disorder (ZSD). Evaluations Following Initial Diagnosis To establish the extent of disease and needs in an individual diagnosed with ZSD, the evaluations summarized (if not performed as part of the evaluation that led to the diagnosis) are recommended. Table 5. Recommended Evaluations Following Initial Diagnosis in Individuals with Zellweger Spectrum Disorder

Source: GeneReviews — "Zellweger Spectrum Disorder"

Therapies Under Investigation

Search ClinicalTrials.gov in the US and EU Clinical Trials Register in Europe for access to information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.

Source: GeneReviews — "Zellweger Spectrum Disorder"

Surveillance Guidelines

Table 7. Recommended Surveillance for Individuals with Zellweger Spectrum Disorder

Source: GeneReviews — "Zellweger Spectrum Disorder"