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Clinical, genetic, neuroimaging, and severity spectrum of peroxisomal disorders in Iran: a multicenter cohort study
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DOI：10.1186/s13023-026-04549-2.png)
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Abstract
En 中文
Peroxisomal disorders comprise a heterogeneous group of inherited metabolic diseases including peroxisome biogenesis disorders (PBDs), single-enzyme defects, and peroxisomal dynamics disorders. Data from Middle Eastern populations remain limited despite high regional consanguinity rates. We aimed to characterize the clinical, genetic, and neuroimaging spectrum of peroxisomal disorders in a multicenter Iranian cohort. We performed a retrospective multicenter study of genetically confirmed pediatric peroxisomal disorders diagnosed between 2016 and 2023 across five referral centers. Clinical, neuroimaging, and molecular data were systematically reviewed. Patients were classified as PBDs or non-PBD peroxisomal disorders, while non-classical peroxisome-associated phenotypes were analyzed separately. A pragmatic retrospective severity index was applied to assess disease burden. Forty-two patients from 42 families with peroxisomal gene-associated disorders were identified, including 40 patients in the primary analysis cohort. PBDs accounted for 33 patients and non-PBD peroxisomal disorders for seven. PEX1 was the most frequently affected gene. Novel variants accounted for 67% of disease-associated alleles, and parental consanguinity was present in 79% of families. Developmental delay or regression was universal, while visual impairment (62%), gait abnormalities (59%), hearing impairment (54%), pyramidal signs (46%), and seizures (41%) were common. Brain MRI data were available for 20 patients, including serial studies in five, demonstrating recurrent involvement of the parieto-occipital white matter, cerebellum, brainstem, and corpus callosum, with progressive neuroimaging abnormalities observed across genetically distinct disorders. Several recurrent variants raised the possibility of regional founder effects. Non-PBD peroxisomal disorders demonstrated higher median severity indices than PBDs, although the difference did not reach statistical significance. This study expands the clinical, genetic, and neuroimaging spectrum of peroxisomal disorders in the Middle East and highlights extensive allelic heterogeneity, a high burden of novel variants, many occurring in the homozygous state, and substantial genotype-phenotype variability. These findings support broad genomic testing and integrated neuroimaging assessment in highly consanguineous populations.
Keywords:
Zellweger spectrum disorder
Peroxisome biogenesis disorders
Neuroimaging
Genotype–phenotype correlation
Whole-exome sequencing
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