Figure 1. Clinical characteristics of study subjects with mild or moderate peroxisome biogenesis disorders–Zellweger spectrum disorders (PBD-ZSD).

(a) A $3\frac{1}{2}$-year-old female. (b) A 3-year-old male subject. (c) A $2\frac{1}{2}$-year-old male subject. (d) Spectrum of hearing loss in the subjects; number of subjects is shown on the y-axis. (e) Presence of seizures in the subjects; number of subjects is shown on the y-axis. Three subjects had experienced one seizure only at the time of the study. (f) Schematic model of the process of peroxisomal biogenesis showing the role for PEX1 protein; 18 of 19 subjects had mutations in PEX1. (g) Summary of biochemical pathways implicated by peroxisomal functions (see also Supplementary Figure S1 online). (h) Pipecolic acid levels measured by electron capture negative ion mass fragmentography of the pentafluorobenzyl ester of pipecolic acid, shown in μmol/L. Normal controls shown in light blue, a group of subjects with severe PBD-ZSD (not included in our study and more severe subjects²⁰) shown in dark blue, and our study cohort of mild or moderate PBD-ZSD shown in royal blue. ****P < 0.0001, ns indicates not significant. Pipecolic acid was elevated, although variable in the cohort (mean ± SD 54.6 ± 60.7 μmol/L in our cohort versus 1.7 ± 1.1 μmol/L in clinical controls over 5 years). (i) C26:0 levels measured by capillary gas chromatography/mass spectroscopy of pentafluorobenzyl bromide fatty acid esters; μg/ml quantity is shown on y-axis. Normal controls shown in light blue, a group of subjects with severe PBD-ZSD (not included in our study and more severe subjects²⁰) shown in dark blue, and our study cohort of mild–intermediate PBD-ZSD shown in royal blue. ****P < 0.0001. C26:0 levels are elevated in the cohort (1.65 ± 0.88 μg/ml versus 0.23 ± 0.09 μg/ml in controls). (j) C26:1 levels measured by capillary gas chromatography/mass spectroscopy of pentafluorobenzyl bromide fatty acid esters, μg/ml quantity is shown on y-axis. Normal controls shown in light blue, a group of individuals with severe PBD-ZSD (not included in our study and more severe subjects²⁰) shown in dark blue, and our study cohort of mild or moderate PBD-ZSD shown in royal blue. ****P < 0.0001. C26:1 levels are elevated in the cohort (0.78 ± 0.46 μg/ml versus 0.18 ± 0.09 in controls). (k) C24/C22 fatty acid ratios. Normal controls shown in light blue, a group of individuals with severe PBD-ZSD (not included in our study and more severe subjects) shown in dark blue, and our study cohort of mild or moderate PBD-ZSD shown in royal blue. ****P < 0.0001. C24/C22 (1.46 ± 0.32 versus 0.84 ± 0.10, (l)) fatty acids were also elevated, although not to the degree of severe PBD-ZSD (C26/C22: 0.50 ± 0.16). (l) C26/C22 fatty acid ratios. Normal controls shown in light blue, a group of individuals with severe PBD-ZSD (not included in our study and more severe subjects) shown in dark blue, and our study cohort of mild or moderate PBD-ZSD shown in royal blue. ****P < 0.0001. (m) Pristanic acid levels in μg/ml in the subjects exhibited elevated pristanic acid levels (0.73 ± 0.44 μg/ml). The dashed line (ULN) marks the upper limit of normal. (n) Phytanic acid levels in μg/ml in the subjects who exhibited elevated phytanic acid levels (3.8 ± 2.8). The dashed line (ULN) marks the upper limit of normal.