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7413: Advanced Genetic Study and Pilot Newborn Screening for Disorders of Pyruvate Metabolism



Pyruvate dehydrogenase complex (PDC) deficiencies are a major class of mitochondrial diseases, limiting the 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 PDC deficiencies (PDCDs). This database is 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 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 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. 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 known and novel genetic etiologies for PDCD.
  3. To pilot a newborn screening protocol using biomarkers and specific molecular tests for early diagnosis of newborns/infants with PDCD due to “primary” PDC-specific gene mutations and early intervention with ketogenic diet and/or other treatment.

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.

The target is to recruit a total of 75 participants in this study over 5 years.

Primary Subjects (those who have PDCDs) 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 for Primary Subjects

Inclusion Criteria:
  • 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 PDHA1 testing,


  • A known pathogenic mutation of a gene associated with PDCD.
Exclusion Criteria:
  • Another chronic neurological disease (mitochondrial or non-mitochondrial) which is not considered likely to be related to PDCD.
  • Inadequacy of needed blood or tissue sample and unwillingness or inability to submit such a sample.
  • Unwillingness to participate in the NAMDC Patient Data Registry and Biorepository protocol.

Inclusion/Exclusion Criteria for Relative Subjects

Inclusion Criteria:
  • First or second degree relative of a primary subject for whom genetic testing indicates the presence of gene variants of uncertain (or unknown) significance (VUS).
Exclusion Criteria:
  • Inadequacy of needed blood sample and unwillingness or inability to submit such a sample.

How to participate:

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

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

This study is registered on under identifier (NCT number): NCT03056794 Visit our page for more information.