7413: Natural History and Advanced Genetic Study of Pyruvate Dehydrogenase Complex Deficiencies

Status: Recruiting




Pyruvate dehydrogenase complex (PDC) deficiencies 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 treatment for these disorders. This study, "Natural History and Advanced Genetic Study of Pyruvate Dehydrogenase Complex Deficiencies," will create a database with information that is collected over a long period of time about patients with PDC deficiencies.  This database will be a 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 150-200 subjects with confirmed PDC deficiencies will be enrolled over 4 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 and any of the five "primary" PDC-specific genes (PDHA1, PDHB, DLAT, PDHX, and PDP1), and who might benefit from different treatments.

The specific aims are:

  1. Create a Pyruvate Dehydrogenase Complex (PDC) Deficiencies 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
  3. Identify connections between these clinical and genetic findings to see if there are different types of PDC deficiencies that may respond to different treatments, and to identify outcomes and forms of treatment that could be tested in ongoing and future studies.

About this Study

This study will collect comprehensive (complete) longitudinal natural history clinical data (data collected over a long period of time), for proven Pyruvate Dehydrogenase Complex (PDC) deficiencies, including data about diagnoses, symptoms, and outcomes. The study will include data from patients/parents as well as medical data. We will use medical records and a detailed questionnaire targeted to collect in-depth 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.

The target is to recruit a total of 150-200 participants in this study over 4 years.

Primary Subjects (those who have PDC deficiencies) that agree to be in the study will be asked to participate in the following:

  1. Collection of selected Medical Records
  2. Blood sample (at 6 or 12 month intervals)
  3. Skin Biopsy (if not available and considered necessary)
  4. Advanced Genetic Testing (if the subject does not already have a genetic diagnosis)
  5. Questionnaire (detailed, written and by phone)

Selected family subjects will provide a blood sample and participate in genetic testing procedures only to see if advanced genetic testing is helpful.


Targeted Enrollment

Inclusion/Exclusion Criteria Primary Subjects

Inclusion Criteria:
Proven PDC deficiency based on:

  • Low PDC activity in skin fibroblasts, blood lymphocytes or a muscle biopsy, below the reference range, with valid internal controls to establish sample and assay integrity, and PDHA1 testing,


  • A known pathogenic mutation of a gene associated with PDC deficiency.

Exclusion Criteria:

  • Another chronic neurological disease which is not considered likely to be related to PDC deficiency.
  • Do not have needed blood or tissue sample and unwillingness or inability to submit such a sample.
  • Unwillingness to participate in the NAMDC Patient Data Registry.

Inclusion/Exclusion Criteria Relative Subjects

Inclusion Criteria:

  • Direct family or extended family relative of a primary subject for whom genetic testing indicates the presence of genetic variants of unknown significance (VUS).

Exclusion Criteria:

  • No blood sample and not willing or unable to submit such a sample.

How to participate:

In order to participate, you may contact the study coordinator:

Genya Kisin, Clinical Research Specialist 1
University Hospitals Cleveland  Medical Center, Cleveland, OH
Phone: 216-286-9202

We greatly appreciate your interest in this study and in advancing the understanding of Pyruvate Dehydrogenase Complex Deficiencies.