Natural History and Advanced Genetic Study of Pyruvate Dehydrogenase Complex Deficiencies

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 definitive 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 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 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
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. The investigators 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. These data will
be updated cyclically on an annual basis (every 6 months in infants) from medical and
laboratory records and family questionnaires/interviews.

Additional details of treatment will be sought to maximize our knowledge about their effects.
The investigators will obtain from enrolled subjects, on an annual basis, deproteinized whole
EDTA-blood samples for analysis of lactate, beta-hydroxybutyrate (βOHB), thiamine and
thiamine pyrophosphate (TPP), as markers of disease status and treatment efficacy.

Data analysis will focus on the spectrum of neurological manifestations of PDC deficiency,
clinically relevant outcome measures, and responses to therapeutic interventions. Such
analyses will serve to inform future clinical trials.

Data Dictionary: On file at Columbia University Medical Center and has been provided to
investigators at University Hospitals Cleveland Medical Center.

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.