The predominantly gastrointestinal form of MDDS, mitochondrial neurogastrointestinal encephalomyopathy (MNGIE), is caused by a thymidine phosphorylase deficiency due to TYMP mutations and primarily affects smooth muscle and the brain (13).
We also analyzed 165 samples from patients with molecularly proven MDDS (i.e., 2 deleterious mutations): 122 blood, 21 muscle, 15 liver, and 7 skin fibroblast samples from patients with 2 proven mutations in 1 of 8 nuclear genes (POLG, DGUOK, TK2, TYMP, MPV17, SUCLA2, SUCLG1, and RRM2B) known to cause mtDNA depletion.
Ninety-seven samples from symptomatic individuals suspected of having a mitochondrial disorder but with sequence analyses revealing only 1 mutation or an unclassified novel variant were also evaluated for mtDNA depletion (POLG, 59 blood and 6 muscle samples; DGUOK, 16 blood samples; TK2, 1 muscle and 5 blood samples; MPV17, 6 blood samples; TYMP, 4 blood samples) (see Table S4A in the Data Supplement that accompanies the online version of this article at http://www.clinchem.org/content/vol56/issue7).
The mean mtDNA content in blood samples was reduced to 78% of the control value in samples from individuals with POLG mutations, 52% in those with DGUOK or MPV17 mutations, 79% in those with TK2 mutations, 70% in those with TYMP mutations, and 39% in those with RRM2B mutations (see Table 2A in the online Data Supplement).
The mtDNA content was not reduced in blood samples from 97 symptomatic individuals with a single mutation or unclassified variant in POLG, DGUOK, TK2, or TYMP (mean mtDNA content 105%, 98%, 118%, and 141% of the age-matched pooled control value, respectively) (Fig.
A sequencing analysis of the POLG, TYMP, TK2, RRM2B, DGUOK, and SUCLA2 genes from a blood sample revealed no deleterious mutations.