Clinical trial NCT03056794: Natural History and Advanced Genetic Study of Pyruvate Dehydrogenase Complex Deficiencies
Official title: Natural History and Advanced Genetic Study of Pyruvate Dehydrogenase Complex Deficiencies (North American Mitochondrial Disease Consortium, Rare Diseases Clinical Research Network, Project 7413)
Study type: OBSERVATIONAL
Overall status: RECRUITING
Conditions: Pyruvate Dehydrogenase Complex Deficiency Disease
Keywords: pyruvate
pyruvate dehydrogenase
PDC
PDCD
Lead sponsor: University of Pittsburgh
Sponsor class: OTHER
Collaborators: name: Rare Diseases Clinical Research Network
name: National Institute of Neurological Disorders and Stroke (NINDS)
First posted: 2017-02-17
Enrollment: 150
Sex: ALL
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Observational model: COHORT
Time perspective: OTHER
Sampling method: NON_PROBABILITY_SAMPLE
Study population: Children and adults with pyruvate dehydrogenase complex deficiency

Brief summary: Children and adults with pyruvate dehydrogenase complex deficiency (PDCD) are participating in a research study seeking to better understand the genetic causes, symptoms, usefulness of current treatments, and outcomes for these disorders. The research project involves completing a questionnaire about the individual or family's medical history and experiences with PDCD, review of medical records by the researchers, and in some cases, advanced genetic testing.

Detailed description: Pyruvate dehydrogenase complex deficiencies (PDCDs) are a major class of mitochondrial diseases, limiting oxidation of carbohydrate for energy production, which is especially important in the brain. So far, there is not a definitive treatment for these disorders. This study, "Advanced Genetic Study and Pilot Newborn Screening for Disorders of Pyruvate Metabolism," will continue with the created database with information that is collected over a long period of time about patients with PDCDs. This database is part of the existing North American Mitochondrial Disease Consortium (NAMDC) Patient Data Registry and Biorepository database. The study will collect data specific to PDC deficiencies, including data that is derived from patients/families. Approximately 75 subjects with confirmed PDCD will be enrolled over 5 years. The genetic basis and pathophysiology will be explored in up to a third of confirmed PDC deficient patients, who currently have not been found to have an identified mutation in DLD or any of the five "primary" PDC-specific genes (PDHA1, PDHB, DLAT, PDHX, and PDP1), and who might benefit from different treatments.

The specific aims of the study are:

1. Continue to add to the Pyruvate Dehydrogenase Complex Deficiencies (PDCDs) specific database within the NAMDC Patient Data Registry
2. Use advanced genetic analysis technologies to find mutations in those people in whom none has been found

About this Study:

This study will collect comprehensive longitudinal natural history clinical data for proven Pyruvate Dehydrogenase Complex deficiencies (PDCDs), including data about diagnoses, symptoms, and outcomes. The study will include data from patients/parents as well as medical data. The investigators will use medical records and a short questionnaire targeted to collect information about critical outcomes. This questionnaire will collect information from the subject and parent about the importance of different outcomes and allow families to discuss other outcomes that they may consider important at home. Additional details of treatment will be sought to maximize our knowledge about their effects and serve to inform future clinical trials.

Data Dictionary: On file at Data Monitoring Core Council in Cincinnati Children's Hospital Medical Center and has been provided to investigators at University Hospitals Cleveland Medical Center.

Eligibility criteria: Inclusion Criteria:

1. Low PDC activity in skin fibroblasts, blood lymphocytes or a muscle biopsy, below the reference range, and with valid internal controls to establish sample and assay integrity, and have had PDHA1 testing, and/or
2. A known pathogenic mutation of a gene associated with PDC deficiency.

Relative Subjects Inclusion Criteria:

1. First or second degree relative of a primary subject for whom genetic testing indicates the presence of variants of unknown significance (VUS).

Exclusion Criteria:

1. Another chronic neurological disease (mitochondrial or non-mitochondrial) which is not considered likely to be related to PDC deficiency.
2. Inadequacy of needed blood or tissue sample and unwillingness or inability to submit such a sample.
3. Unwillingness to participate in the NAMDC Patient Data Registry and Biorepository protocol.

Relative Subjects Exclusion Criteria:

1. Inadequacy of needed blood sample and unwillingness or inability to submit such a sample.

Primary outcomes:
measure: Survival outcomes in pyruvate dehydrogenase deficiency disease
timeFrame: Data will be collected about duration of survival from birth until the last date known to be living at the time of data analysis.
Secondary outcomes:
measure: Neurological outcomes in pyruvate dehydrogenase deficiency disease
timeFrame: Through a participant questionnaire and retrospective review of medical records, neurological outcomes will be assessed for the entire lifetime of the participant up to the time of data collection.
Other outcomes:
Locations:
city: Pittsburgh
country: United States
facility: University of Pittsburgh
state: Pennsylvania
Study officials:
affiliation: University of Pittsburgh
name: Jirair K. Bedoyan, MD, PhD
role: PRINCIPAL_INVESTIGATOR
References:
citation: DeBrosse SD, Okajima K, Zhang S, Nakouzi G, Schmotzer CL, Lusk-Kopp M, Frohnapfel MB, Grahame G, Kerr DS. Spectrum of neurological and survival outcomes in pyruvate dehydrogenase complex (PDC) deficiency: lack of correlation with genotype. Mol Genet Metab. 2012 Nov;107(3):394-402. doi: 10.1016/j.ymgme.2012.09.001. Epub 2012 Sep 7.
citation: Huang X, Bedoyan JK, Demirbas D, Harris DJ, Miron A, Edelheit S, Grahame G, DeBrosse SD, Wong LJ, Hoppel CL, Kerr DS, Anselm I, Berry GT. Succinyl-CoA synthetase (SUCLA2) deficiency in two siblings with impaired activity of other mitochondrial oxidative enzymes in skeletal muscle without mitochondrial DNA depletion. Mol Genet Metab. 2017 Mar;120(3):213-222. doi: 10.1016/j.ymgme.2016.11.005. Epub 2016 Nov 12.
citation: Bedoyan JK, Yang SP, Ferdinandusse S, Jack RM, Miron A, Grahame G, DeBrosse SD, Hoppel CL, Kerr DS, Wanders RJA. Lethal neonatal case and review of primary short-chain enoyl-CoA hydratase (SCEH) deficiency associated with secondary lymphocyte pyruvate dehydrogenase complex (PDC) deficiency. Mol Genet Metab. 2017 Apr;120(4):342-349. doi: 10.1016/j.ymgme.2017.02.002. Epub 2017 Feb 2.
citation: Ferdinandusse S, Friederich MW, Burlina A, Ruiter JP, Coughlin CR 2nd, Dishop MK, Gallagher RC, Bedoyan JK, Vaz FM, Waterham HR, Gowan K, Chatfield K, Bloom K, Bennett MJ, Elpeleg O, Van Hove JL, Wanders RJ. Clinical and biochemical characterization of four patients with mutations in ECHS1. Orphanet J Rare Dis. 2015 Jun 18;10:79. doi: 10.1186/s13023-015-0290-1.
citation: Deeb KK, Bedoyan JK, Wang R, Sremba L, Schroeder MC, Grahame GJ, Boyer M, McCandless SE, Kerr DS, Zhang S. Somatic mosaicism for a novel PDHA1 mutation in a male with severe pyruvate dehydrogenase complex deficiency. Mol Genet Metab Rep. 2014 Aug 28;1:362-367. doi: 10.1016/j.ymgmr.2014.08.001. eCollection 2014.
citation: Shin HK, Grahame G, McCandless SE, Kerr DS, Bedoyan JK. Enzymatic testing sensitivity, variability and practical diagnostic algorithm for pyruvate dehydrogenase complex (PDC) deficiency. Mol Genet Metab. 2017 Nov;122(3):61-66. doi: 10.1016/j.ymgme.2017.09.001. Epub 2017 Sep 8.
citation: Bedoyan JK, Hecht L, Zhang S, Tarrant S, Bergin A, Demirbas D, Yang E, Shin HK, Grahame GJ, DeBrosse SD, Hoppel CL, Kerr DS, Berry GT. A novel null mutation in the pyruvate dehydrogenase phosphatase catalytic subunit gene (PDP1) causing pyruvate dehydrogenase complex deficiency. JIMD Rep. 2019 Jun 17;48(1):26-35. doi: 10.1002/jmd2.12054. eCollection 2019 Jul.