HUMAN STUDIES
Retrospective Natural History Study
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Peroxisomal disorders are a group of inherited disorders due to defects in peroxisome functions and/or assembly causing complex developmental and metabolic sequelae. In spite of advancements in peroxisome biology, the pathophysiology remains unknown, the spectrum of phenotypes poorly characterized and the natural history not yet systematically reported.
In order to further define this population clinically, biochemically and genetically, we are conducting a longitudinal retrospective natural history study on patients with peroxisomal disorders. We recruit participants internationally and collect data from medical evaluations, blood, urine and imaging studies that would be performed on a clinical care basis. Clinical data from medical records can be banked in our Peroxisomal Disorder Research Databank and Biobank. We hope that the results of our study will help healthcare professionals and care takers provide optimal care to their patients with peroxisome conditions.
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Natural History Study: Current projects
We collect data from the participant's medical records and input it in a custom-made database. We then extract relevant data that will help address a specific research question. Here are some projects we are currently working on:
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(1) Neurological and neuroradiological spectrum in patients with PBD-ZSD. We collected information about different clinical features, brain MRI features and biochemical profiles for 66 PBD-ZSD patients and we found that generally the severity of the symptoms correlate with how severely their gene changes affect their PEX protein function. Jiaru Liu, Medical student, in collaboration with Dr Geneviève Bernard, Dr Roberta La Piana and Dr Nagwa Wilson. Manuscript in preparation.
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(2) Natural history study of vision loss in PBD-ZSD. We compiled and analyzed ophthalmic findings and retinal imaging results for 67 PBD-ZSD individuals and complemented our findings with the existing literature. Christine Yergeau in collaboration with Dr Razek Coussa, Fares Antaki and Dr Robert Koenekoop. Manuscript in preparation.
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(3) Growth curves for PBD-ZSD. We collected growth data from 102 individuals with PBD-ZSD, including participants in our natural history study and the patient cohort from our Dutch colleagues. We have generated ZSD-specific growth curves for clinicians and families to use instead of the standard growth curves. Christine Yergeau in collaboration with Dr Tim Niiler. Manuscript in preparation.
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(4) Natural history study of hearing loss in PBD-ZSD. We compiled and analyzed audiological data for 45 individuals with PBD-ZSD. We found relatively slow rates of longitudinal changes in hearing sensitivity. Improvements were observed with use of hearing aid amplification. We found that there may be an increased occurrence of mixed and/or conductive hearing losses in PBD-ZSD populations that must be accurately documented. Published in Lee, J., Yergeau, C., Kawai, K., Braverman, N., Géléoc, G. (2021) Retrospective Study of Hearing Loss in Patients Diagnosed with Peroxisome Biogenesis Disorders in the Zellweger Spectrum, Ear and Hearing: September 15, 2021 - doi: 10.1097/AUD.0000000000001126.
(5) Clinical, biochemical and molecular profiles of individuals with mild (nonclassic) RCDP. Only a few mild RCDP patients with limited information about their clinical features and disease progression were previously reported. In order to understand the natural course of mild (nonclassic) disease, we established specific criteria to distinguish mild RCDP and systematically described the clinical, biochemical and molecular profiles of 16 individuals with mild (nonclassic) RCDP. We have also identified several common and 4 novel PEX7 or GNPAT hypomorphic alleles associated with this mild RCDP phenotype. Published in Fallatah, W., et al (2020). Journal of Inherited Metabolic Disease. https://doi: 10.1002/jimd.12349
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(6) Ongoing studies of genotype-phenotype correlations in PBD patients. Identification of novel mutations in PEX genes, effects on protein functions and further delineation of phenotypes.
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Human tissue studies
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By collecting and studying biological tissue samples from patients with PBD-ZSD, we hope to gain more knowledge on the pathophysiology of peroxisomal dysfunction on different organ systems.
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(1) Analysis of liver samples from PBD-ZSD patients. We are studying liver biopsy material and post-mortem liver samples provided by the NIH Neurobiobank in order to better understand the pathophysiology of the liver dysfunction in PBD-ZSD individuals. We aim to correlate the pathogenicity of the PEX mutations and the age of the patients with the severity of the liver tissue features we will observe by immunohistochemistry. Lingxiao Chen. Work in progess.
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(2) Analysis of brain samples from RCDP patients. We obtained post-mortem brain samples for one patient with RCDP1 and two age-matched controls from the NIH Neurobiobank to evaluate the neuropathological consequences of RCDP1. We found normal morphology and content of myelin basic protein (MBP) in cerebellum by histochemistry. Furthermore, we measured the levels of brain neurotransmitters: dopamine, norepinephrine and serotonin by HPLC analysis and showed global deficiency in all neurotransmitters in several brain regions of Patient 1 compared to controls. This demonstrates the interrelation between RCDP1 and brain neurotransmitters deficiencies, which might play a crucial role in the underlying disease mechanism.
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Prospective vision study
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We are preparing to conduct a prospective study on vision loss characterization in individuals with mild/intermediate PBD-ZSD. We will collaborate with several eye centers in the US and in Canada to perform the same set of opthhalmological exams in the same cohort of patients over five years. This study will allow to identify and measure reliable clinical endpoints which will be crucial for any future therapy trials to treat vision loss in individuals with PBD-ZSD.
