Mild Zellweger syndrome due to functionally confirmed novel PEX1 variants

Abstract

Zellweger spectrum disorders (ZSD) constitute a group of rare autosomal recessive disorders characterized by a defect in peroxisome biogenesis due to mutations in one of 13 PEX genes. The broad clinical heterogeneity especially in late-onset presenting patients and a mild phenotype complicates and delays the diagnostic process. Here, we report a case of mild ZSD, due to novel PEX1 variants. The patient presented with an early hearing loss, bilateral cataracts, and leukodystrophy on magnetic resonance (MR) images. Normal results of serum very-long-chain fatty acids (VLCFA) and phytanic acid were found. Molecular diagnostics were performed to uncover the etiology of the clinical phenotype. Using whole exome sequencing, there have been found two variants in the PEX1 gene-c.3450T>A (p.Cys1150*) and c.1769T>C (p.Leu590Pro). VLCFA measurement in skin fibroblasts and C26:0-lysoPC in dried blood spot therefore was performed. Both results were in line with the diagnosis of ZSD. To conclude, normal results of routine serum VLCFA and branched-chain fatty acid measurement do not exclude mild forms of ZSD. The investigation of C26:0-lysoPC should be included in the diagnostic work-up in patients with cataract, hearing loss, and leukodystrophy on MR images suspected to suffer from ZSD.

Genotype–phenotype correlations and disease mechanisms in PEX13-related Zellweger spectrum disorders

“…In all the affected individuals from this cohort who underwent detailed metabolic work-up, VLCFA levels resulted within normal limits. This finding is consistent with previous studies of ZSDs due to genetic defects in different peroxins that were found with normal serum VLCFA [ 30 – 33 ]. Our study further highlights the importance of genetic screening targeting peroxisomal disorders, even though plasma peroxisomal metabolites are unremarkable, in case of moderate clinical presentations of ZSDs (e.g., visual and hearing impairment, progressive psychomotor regression, white matter abnormalities on brain MRI).…”

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

“…There were 10 cohort studies [ 8 , 16 , 29 , 42 , 51 , 99 , 117 , 118 , 119 , 120 ] and 31 case studies [ 6 , 11 , 15 , 26 , 32 , 121 , 122 , 123 , 124 , 125 , 126 , 127 , 128 , 129 , 130 , 131 , 132 , 133 , 134 , 135 , 136 , 137 , 138 , 139 , 140 , 141 , 142 , 143 , 144 , 145 , 146 ] that described 124 patients with mild ZSD (80 from cohort studies, 36 from case studies). In the cohort studies, a seizure disorder was reported in 15.9% of patients (out of 63 total), hypotonia was present in 50.0% of patients (out of 42 patients total), reduced mobility was reported in 35.7% of patients (out of 70 patients total), feeding difficulties were reported in 14.8% of patients (out of 54 patients total), abnormal liver function or structure was reported in 54.3% of patients (out of 70 patients total), adrenal insufficiency was reported in 11.8% of patients (out of 34 patients total), and hearing loss was present in 52.0% of patients (out of 75% patients total) ( Table 1 ).…”

Serum very long-chain fatty acids (VLCFA) levels as predictive biomarkers of diseases severity and probability of survival in peroxisomal disorders

“…A mutation with a milder phenotype described earlier has been identified in Patient 2 [ 15 ]. In turn, mutations found in P.1 and P. 3 are the ones that are newly described, and due to the presented clinical picture and length of life (P.1 –died at 6 y), (P.3—currently 23 y) should be thought to cause PD with milder course than classical ZS [ 11 , 16 ]. The data presented indicates that milder clinical symptoms correspond to lower VLCFA levels and longer survival.…”