TY - JOUR
T1 - Clinical, neuroradiological, and molecular characterization of patients with atypical Zellweger spectrum disorder caused by PEX16 mutations
T2 - a case series
AU - Cheung, Anthony
AU - Argyriou, Catherine
AU - Yergeau, Christine
AU - D’Souza, Yasmin
AU - Riou, Émilie
AU - Lévesque, Sébastien
AU - Raymond, Gerald
AU - Daba, Mebratu
AU - Rtskhiladze, Irakli
AU - Tkemaladze, Tinatin
AU - Adang, Laura
AU - La Piana, Roberta
AU - Bernard, Geneviève
AU - Braverman, Nancy
N1 - Funding Information:
We acknowledge the Global Foundation for Peroxisomal Disorders and all families involved in this study for their collaboration and support for research to improve patient care.
Funding Information:
Medical Class of 1961 Research Bursary and Harold and Rhea Pugash Research Bursary (AC); Canadian Institutes of Health Research (CIHR), Grant Number: 144213 (NB); Fonds de Recherche du Quebec – Santé (2012–2016, Research Scholar Junior 1 award) and Canadian Institutes of Health Research (2017–2022, the New Investigator Salary Award) (GB). This study was supported by the Canadian Institutes of Health Research (CIHR) to NB. CY and YD were supported by an academic fund from Travere Therapeutics, Inc.
Publisher Copyright:
© 2022, The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.
PY - 2022/4
Y1 - 2022/4
N2 - Peroxisome biogenesis disorders—Zellweger spectrum disorders (PBD-ZSD)—are primarily autosomal recessive disorders caused by mutations in any of 13 PEX genes involved in peroxisome assembly. Compared to other PEX-related disorders, some PEX16 defects are associated with an atypical phenotype consisting of spasticity, cerebellar dysfunction, preserved cognition, and prolonged survival. In this case series, medical records and brain MRIs from 7 patients with this PEX16 presentation were reviewed to further characterize this phenotype. Classic PBD features such as sensory deficits and amelogenesis imperfecta were absent in all 7 patients, while all patients had hypertonia. Five patients were noted to have dystonia and received a treatment trial of levodopa/carbidopa. Four treated patients had partial but significant improvements in their dystonia and tremors, and 1 patient had only minimal response. Brain MRI studies commonly showed T2/FLAIR hyperintensities in the brainstem, superior and middle cerebellar peduncles, corticospinal tracts, and splenium of the corpus callosum. Genetic analysis revealed novel biallelic variants in 3 probands (c.683C > T/372delG; c.692A > G homozygous; c.865C > G/451C > T) and 1 novel variant (c.956_958delCGC) in another proband. We demonstrated residual PEX16 protein amounts by immunoblotting in fibroblasts available from 5 patients with this atypical PEX16 disease (3 from this series, 2 previously reported), in contrast to the absence of PEX16 protein in fibroblasts from a patient with the severe ZSD presentation. This study further characterizes the phenotype of PEX16 defects by highlighting novel and distinctive clinical, neuroradiological, and molecular features of the disease and proposes a potential treatment for the dystonia. ClinicalTrials.gov Identifier: NCT01668186. Date of registration: January 2012.
AB - Peroxisome biogenesis disorders—Zellweger spectrum disorders (PBD-ZSD)—are primarily autosomal recessive disorders caused by mutations in any of 13 PEX genes involved in peroxisome assembly. Compared to other PEX-related disorders, some PEX16 defects are associated with an atypical phenotype consisting of spasticity, cerebellar dysfunction, preserved cognition, and prolonged survival. In this case series, medical records and brain MRIs from 7 patients with this PEX16 presentation were reviewed to further characterize this phenotype. Classic PBD features such as sensory deficits and amelogenesis imperfecta were absent in all 7 patients, while all patients had hypertonia. Five patients were noted to have dystonia and received a treatment trial of levodopa/carbidopa. Four treated patients had partial but significant improvements in their dystonia and tremors, and 1 patient had only minimal response. Brain MRI studies commonly showed T2/FLAIR hyperintensities in the brainstem, superior and middle cerebellar peduncles, corticospinal tracts, and splenium of the corpus callosum. Genetic analysis revealed novel biallelic variants in 3 probands (c.683C > T/372delG; c.692A > G homozygous; c.865C > G/451C > T) and 1 novel variant (c.956_958delCGC) in another proband. We demonstrated residual PEX16 protein amounts by immunoblotting in fibroblasts available from 5 patients with this atypical PEX16 disease (3 from this series, 2 previously reported), in contrast to the absence of PEX16 protein in fibroblasts from a patient with the severe ZSD presentation. This study further characterizes the phenotype of PEX16 defects by highlighting novel and distinctive clinical, neuroradiological, and molecular features of the disease and proposes a potential treatment for the dystonia. ClinicalTrials.gov Identifier: NCT01668186. Date of registration: January 2012.
KW - Dopa-responsive dystonia
KW - Dystonia
KW - Leukodystrophy
KW - PEX16
KW - Peroxisome biogenesis disorder
KW - Zellweger spectrum disorder
UR - http://www.scopus.com/inward/record.url?scp=85124044399&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85124044399&partnerID=8YFLogxK
U2 - 10.1007/s10048-022-00684-7
DO - 10.1007/s10048-022-00684-7
M3 - Article
C2 - 35106698
AN - SCOPUS:85124044399
SN - 1364-6745
VL - 23
SP - 115
EP - 127
JO - Neurogenetics
JF - Neurogenetics
IS - 2
ER -