A founder mutation in PEX12 among Egyptian patients in peroxisomal biogenesis disorder
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ORIGINAL ARTICLE
A founder mutation in PEX12 among Egyptian patients in peroxisomal biogenesis disorder Maha S. Zaki 1 & Mahmoud Y. Issa 1 & Manal M. Thomas 1 & Hasnaa M. Elbendary 1 & Karima Rafat 1 & Nihal M. Al Menabawy 2 & Laila A. Selim 2 & Samira Ismail 1 & Ghada M. Abdel-Salam 1 & Joseph G. Gleeson 3 Received: 8 June 2020 / Accepted: 17 October 2020 # Fondazione Società Italiana di Neurologia 2020
Abstract At least 14 distinctive PEX genes function in the biogenesis of peroxisomes. Biallelic alterations in the peroxisomal biogenesis factor 12 (PEX12) gene lead to Zellweger syndrome spectrum (ZSS) with variable clinical expressivity ranging from early lethality to mildly affected with long-term survival. Herein, we define 20 patients derived from 14 unrelated Egyptian families, 19 of which show a homozygous PEX12 in-frame (c.1047_1049del p.(Gln349del)) deletion. This founder mutation, reported rarely outside of Egypt, was associated with a uniformly severe phenotype. Patients showed developmental delay in early life followed by motor and mental regression, progressive hypotonia, unsteadiness, and lack of speech. Seventeen patients had sparse hair or partial alopecia, a striking feature that was not noted previously in PEX12. Neonatal cholestasis was manifested in 2 siblings. Neurodiagnostics showed consistent cerebellar atrophy and variable white matter demyelination, axonal neuropathy in about half, and cardiomyopathy in 10% of patients. A single patient with a compound heterozygous PEX12 mutation exhibited milder features with late childhood onset with gait disturbance and learning disability. Thus, the PEX12 relatively common founder mutation accounts for the majority of PEX12-related disease in Egypt and delineates a uniform clinical and radiographic phenotype. Keywords PEX12 . Cerebellar atrophy . Neuropathy . Regression of milestones . Founder mutation . Peroxisomal disorders
Introduction Peroxisomes are single-membrane-bounded ubiquitous organelles that are fundamental in many metabolic pathways, like β-oxidation of very long-chain fatty acids, biosynthesis Supplementary Information The online version contains supplementary material available at https://doi.org/10.1007/s10072-020-04843-2. * Maha S. Zaki [email protected] 1
Clinical Genetics Department, Human Genetics and Genome Research Division, National Research Centre, El-Tahrir Street, Dokki, Cairo 12311, Egypt
2
Neurology and Metabolic Division, Cairo University Children Hospital, Cairo, Egypt
3
Department of Neurosciences, University of California and Rady Children’s Institute for Genomic Medicine, Rady Children’s Hospital San Diego, La Jolla, CA 92093, USA
of ether phospholipids, and bile–acid metabolism [1]. Peroxisomal disorders are classified into two main groups: peroxisome biogenesis disorders (PBDs) caused by impaired formation of functional peroxisomes and single enzyme/ transporter deficiencies (PEDs) in which there is lack of individual enzymatic activities performed by peroxisomes [2]. PBDs are a group of inherited autosom
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