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Table 2. NAMDC-funded pilot projects
RDCRN protocol number Pilot project title Project principal investigator/site
NAMDC7407 Prototype development of an exome variant analysis pipeline Marni Falk, MD, Children’s Hospital of Philadelphia
and public interface for the community-wide Mitochondrial
Disease Sequence Data Resource (MSeqDR) [2-4]
NAMDC7408 Natural history of pearson syndrome Sumit Parikh, MD, Cleveland Clinic
NAMDC7416 Citrulline supplementation for treatment of nitric oxide Fernando Scaglia, MD, Baylor College of Medicine
deficiency in MELAS: a Phase I dose-finding and safety study
NAMDC7415 The clinical utility and a clinician’s guide to new mitochondrial Johan L. K. Van Hove, MD, PhD
functional tests [1]
NAMDC7417 Activators of AMPK for Treatment of Mitochondrial Disorders Tina M. Cowan, PhD, Stanford University
NAMDC7418 Genomic testing for molecularly undefined NAMDC Registry Amel Karaa, MD, Massachusetts General Hospital
cases
NAMDC7420 The use of amino acids to enhance the activity of enzymes Marisa Friederich, PhD, University of Colorado
involved in mitochondrial translation defects: a possible
therapeutic approach
NAMDC7421 Development of Minimally Invasive Nanosensor Technology to Zarazuela Zolkipli Cunningham, MBChB MRCP,
Quantify Mitochondrial Function in Human Muscle Children’s Hospital of Philadelphia
NAMDC: North American Mitochondrial Disease Consortium; RDCRN: Rare Diseases Clinical Research Network; AMPK: adenosine
monophosphate–activated protein kinase; MELAS: mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes

NAMDC survey studies
In addition to the pilot studies, five patient surveys have been assessed through the NAMDC Registry: (1)
attitudes of women carrying mitochondrial DNA mutations and healthy egg donors regarding oocyte nuclear
transfer to prevent transmission of mtDNA disease; (2) nutritional supplement use in mitochondrial disease;
(3) cardiovascular events in patients with metabolic diseases on chronic carnitine supplementation; (4)
motivations and barriers for participation in clinical trials by individuals with mitochondrial diseases; and
(5) the diagnostic odyssey of mitochondrial disease patients. Results of four of the five completed surveys
[5-8]
have been published . In addition, a survey of NAMDC investigators regarding the NAMDC Research
Diagnostic Criteria has been completed and the results have contributed to the refinement of the NAMDC
Diagnostic Criteria.

DISCUSSION
Mitochondrial diseases are challenging because they may be the most diverse human disorders at every level:
clinical, biochemical, and genetic. Some are confined to the nervous system but most are multi-systemic,
often affecting the brain, heart, liver, skeletal muscle, kidney, endocrine, and respiratory systems. Although
severity varies, largely these are progressive and often crippling disorders. They frequently cause weakness,
exercise intolerance, fatigue, seizures, mental retardation, dementia, hearing loss, blindness, and premature
death.

The challenge lies in the extraordinary clinical spectrum of mitochondrial diseases, which all too often leads
practitioners to either underdiagnose (“what is this complex disorder?”) or to overdiagnose (“this disorder is
so complex that it must be mitochondrial!”). The diagnostic difficulty is reflected in the diagnostic odyssey
encountered by patients; in our survey study utilizing the RDCRN Contact Registry, subjects reported seeing,
[4]
on average, more than eight clinicians before being given the diagnosis of mitochondrial disease . Given
this heterogeneity of mitochondrial disorders, it is essential to apply common, agreed-upon standards to the
diagnosis and classification of patients. Further, given the variety of clinical and biochemical phenotypes,
effective research on any given subset depends on aggregating relatively large numbers of patients.

These exigencies make clear that two prerequisites are necessary before effective clinical research can
take place: (1) a clinical patient registry/longitudinal study to evaluate and expedite subsequent research
with available patients; and (2) uniform diagnostic criteria for mitochondrial diseases. NAMDC was
established with the goal of addressing these essential elements. After 8 years of continuous support of a
U54 RDCRN cooperative agreement, NAMDC has built a basic infrastructure, established a robust clinical