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

Abstract

Mitochondrial neurogastrointestinal encephalomyopathy (MNGIE) is a rare, autosomal-recessive mitochondrial disorder caused by TYMP mutations presenting with a multisystemic, often lethal syndrome of progressive leukoencephalopathy, ophthalmoparesis, demyelinating neuropathy, cachexia and gastrointestinal dysmotility. Hemodialysis (HMD) has been suggested as a treatment to reduce accumulation of thymidine and deoxyuridine. However, all studies so far have failed to measure the toxic metabolites in cerebrospinal fluid (CSF), which is the crucial compartment for CNS damage.Our study is the first prospective, longitudinal investigation, exploiting detailed serial testing of predefined clinical and molecular outcome parameters (including serial CSF assessments) in a 29-year-old MNGIE patient undergoing 1 year of extensive HMD. We demonstrate that HMD only transiently restores increased serum and urine levels of thymidine and deoxyuridine, but fails to reduce CSF levels of the toxic metabolites and is ineffective to influence neurological function. These findings have direct important implications for clinical practice: They prevent a burdensome, long-term invasive, but ultimately probably ineffective procedure in future MNGIE patients.Electronic supplementary materialThe online version of this article (doi:10.1186/s13023-017-0687-0) contains supplementary material, which is available to authorized users.

Mitochondrial Neurogastrointestinal Encephalomyopathy Imitating Crohn’s Disease: A Rare Cause of Malnutrition

“…Liver transplantation has also been proposed as a treatment for MNGIE due to the high hepatic thymidine phosphorylase expression that could normalize thymidine levels and decrease serum levels of toxic nucleotides [10]. Other published studies utilized hemodialysis or peritoneal dialysis [11,12]. Current gene therapy research employs a generated vector containing the coding sequence of the human TYMP gene under the control of a liver-specific thyroxine-binding globulin promoter [13].…”

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“…The third patient demonstrated transient reductions in plasma and urine metabolite concentrations, with the metabolites returning to baseline within 24 h of stopping the procedure. Disease progression was also reported in this patient, as demonstrated by worsening of the score for the Ataxia Assessment scale, and declines in the Montreal Cognitive Assessment score and nerve conduction measures [ 86 ] . For all three cases, 3-4 haemodialysis procedures per week were required to maintain a sustained reduction in deoxyribonucleosides.…”

“…However, by 19 h post-dialysis, the metabolite levels returned to pre-treatment concentration. The procedure was subsequently used to treat three further patients between 2 and 19 months [ 63 , 86 , 74 ] . In one patient, there were longterm reductions in the urinary excretion of thymidine and in a second patient there was a reported a reduction in the frequency of vomiting to once every 2-3 days, as opposed to after every meal [ 63 , 74 ] .…”

Characterization of a Novel Pathogenic Mutation Causing Mitochondrial Neurogastrointestinal Encephalopathy

“…Hemodialysis and peritoneal dialysis have also been proposed as treatment modalities in these patients intending to remove the nucleosides from the peripheral circulation. A prospective study evaluating a 29-year-old patient with MNGIE who underwent extensive hemodialysis for one year also revealed that it has only a transient effect on the serum and urine levels of nucleosides with no long-term effects; there were no changes in the level of the toxic metabolites in the CSF in both short-term (within 24 hours) and long-term (at months 6 and 12) [30]. Our patient in this report underwent hemodialysis with only mild improvements in the gastrointestinal symptoms.…”