Neurometabolic disorders stem from errors in metabolic processes yielding a neurological
phenotype. A subset of those disorders encompasses mitochondrial abnormalities partially
due to mitochondrial DNA (mtDNA) depletion. mtDNA depletion can be attributed to inheritance,
spontaneous mutations or acquired from drug-related toxicities. In the armamentarium
of diagnostic procedures, mtDNA quantification is a standard for disease classification.
However, alterations in mtDNA obtained from peripheral tissues such as skin fibroblasts
and blood cells do not often reflect the severity of the affected organ, in this case,
the brain. The purpose of this review is to highlight the pitfalls of quantitating
mtDNA from peripheral -and not limited to-tissues for diagnosing patients suffering
from a variety of mtDNA depletion syndromes exhibiting neurologic abnormalities. In
lieu, a qualitative test of mitochondrial substrate-level phosphorylation -even from
peripheral tissues-reflecting the ability of mitochondria to rely on glutaminolysis
in the presence of respiratory chain defects is proposed as a novel diagnostic assessment
of mitochondrial functionality.
