Natural History and Advanced Genetic Study of Pyruvate Dehydrogenase Complex Deficiencies

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.

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.