Hemodialysis in MNGIE transiently reduces serum and urine levels of thymidine and deoxyuridine, but not CSF levels and neurological function

Mitochondrial neurogastrointestinal encephalomyopathy (MNGIE) is a rare, autosomal-recessive mitochondrial disorder caused by mutations in TYMP encoding for the thymidine phosphorylase [1, 2]. Clinically, MNGIE comprises a multisystemic syndrome of progressive leukoencephalopathy, ophthalmoparesis, demyelinating peripheral neuropathy, cachexia and gastrointestinal dysmotility [1, 2]. Biallelic carriers of TYMP mutations show reduced thymidine phosphorylase enzyme activity resulting in elevation of thymidine and deoxyuridine. Accumulation of these toxic metabolites leads to unbalanced intramitochondrial deoxynucleotide pools, which in turn cause site-specific mitochondrial DNA (mtDNA) depletion, multiple deletions and point mutations [1, 3, 4]. Several recent studies have demonstrated that it is indeed this nucleoside accumulation, rather than the deficiency of thymidine phosphorylase per se, that accounts for the molecular and phenotypic alterations in MNGIE [4].

Based on this pathophysiologic rationale, nucleoside reduction by dialysis has been proposed as a promising therapy in MNGIE patients [5, 6]. However, all studies so far did not measure these metabolites in cerebrospinal fluid (CSF), which is, however, the crucial compartment for CNS damage in MNGIE. Nor has any treatment study been conducted prospectively or with predefined quantitative outcome measures so far.

We here report a prospective, longitudinal case study with serial testing of predefined clinical and nucleoside outcome parameters (including serial CSF assessments) of a male MNGIE patient undergoing 1 year of extensive hemodialysis (HMD).

We present the first prospective investigation on the effectiveness of HMD in MNGIE, capturing multiple predefined outcome measures. Our results demonstrate that HMD only transiently reduces increased serum and urine levels of thymidine and deoxyuridine and is ineffective to influence clinical disease progression.

At the same time, these results provide some preliminary insights into the HMD-associated kinetics of these two metabolites in three different body fluid compartments: urine, serum and CSF. HMD was able to transiently decrease both metabolites in urine by about 50% directly after dialysis at each of the four assessment time points, showing a reproducible relative share of urinary metabolite clearance even after repeated dialysis over 12 months. However, neither the basal levels nor the maximum levels reduced over time. This urinary clearance was paralleled by a reduction of serum levels by 20–50% directly after dialysis at each of the four assessment time points (see Fig. 1d). This suggests that the kinetics of the metabolites in both compartments runs largely in parallel. Our 6-months follow-up long-term data do not provide any clear evidence for a (e.g. compensatory) increase in synthesis of metabolites in any of the two compartments (see Fig. 1d, e). Importantly, we show for the first time that HMD fails to achieve a sustained reduction of these metabolites also in the CSF compartment, which might explain the missing neurological benefit.

Our findings thus question the alleged efficacy of dialysis, which has been based so far only on retrospective case studies of peritoneal dialysis, lacking predetermined quantitative outcome measures and long-term measurement of metabolites [5, 6]. Also alternative therapeutic options in MNGIE, including liver [7] and stem cell transplantation [3], need to be critically tested by prospective studies with predefined outcome measures.

Our report has thus direct important implications for clinical practice: it prevents a burdensome, long-term invasive, but finally probably ineffective procedure in MNGIE patients.