Pearls &amp; Oy-sters: Mitochondrial neurogastrointestinal encephalomyopathy

Sivadasan, Ajith; Muthusamy, Karthik; Patil, Anil Kumar; Mathew, Vivek; Alexander, Mathew

doi:10.1212/wnl.0000000000002536

Cited by 5 publications

(8 citation statements)

References 10 publications

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“…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.…”

Section: Discussionmentioning

confidence: 88%

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

Röeben

Marquetand

Bender

et al. 2017

Orphanet J Rare Dis

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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.

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Section: Discussionmentioning

confidence: 88%

“…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.…”

Section: Introductionmentioning

confidence: 99%

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

Röeben

Marquetand

Bender

et al. 2017

Orphanet J Rare Dis

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“…Clinical improvements were reported in all four patients and included reductions in vomiting, nausea and epigastric pain; no longer requiring parenteral nutrition; improvements in appetite; increases in body weight (ranging between 3.5 and 13 kg); slight improvement in sensorimotor polyneuropathy and sensory ataxia; and a resolution of the numbness in peripheries. Regained abilities to perform normal daily activities were also reported, for example climb stairs, ambulant without support and improved walking distances [74,87,88] . Of interest, many of the clinical improvements reported were gastrointestinal in nature, and CAPD may therefore offer an important approach to targeting the gastrointestinal symptoms of MNGIE.…”

Section: Capdmentioning

confidence: 99%

“…CAPD involves the filling of the peritoneal cavity with a dialysis solution to encourage the diffusion of thymidine and 2'-deoxyuridine from the blood passing through the capillary network within the peritoneal membrane, and then after several hours of exchange, draining the dialysate containing the metabolites from the peritoneal cavity to waste [ Figure 2]. This approach has been reported for the treatment of four single cases, with patients receiving exchanges every 4-8 h, over periods of 22-36 months [74,[87][88][89] . Although CAPD had no reported effects on the plasma biochemical imbalances, in one study, it was shown to remove approximately 100 µmol per day of thymidine and 2'-deoxyuridine from the peritoneal cavity [74,87] .…”

Section: Capdmentioning

confidence: 99%

“…Of interest, many of the clinical improvements reported were gastrointestinal in nature, and CAPD may therefore offer an important approach to targeting the gastrointestinal symptoms of MNGIE. In two cases, the gastrointestinal manifestations reappeared if CAPD was missed or discontinued [74,88] . A standardised approach should be implicated in recording body weight gain as the reported increases could be a consequence of fluid retention.…”

Section: Capdmentioning

confidence: 99%

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Mitochondrial neurogastrointestinal encephalomyopathy: approaches to diagnosis and treatment

Bax¹

2019

JTGG

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Mitochondrial neurogastrointestinal encephalomyopathy (MNGIE) is an ultra-rare disease caused by mutations in TYMP, the gene encoding for the enzyme thymidine phosphorylase. The resulting enzyme deficiency leads to a systemic accumulation of thymidine and 2'-deoxyuridine and ultimately mitochondrial failure due to a progressive acquisition of secondary mitochondrial DNA (mtDNA) mutations and mtDNA depletion. MNGIE is characterised by gastrointestinal dysmotility, cachexia, peripheral neuropathy, ophthalmoplegia, ptosis and leukoencephalopathy. The disease is progressively degenerative and leads to death at an average age of 37.6 years. Patients invariably encounter misdiagnoses, diagnostic delays, and non-specific clinical management. Despite its rarity, MNGIE has invoked much interest in the development of therapeutic strategies, mainly because it is one of the few mitochondrial disorders where the molecular abnormality is metabolically and physically accessible to manipulation. This review provides a résumé of the current diagnosis and treatment approaches and aims to increase the clinical awareness of MNGIE and thereby facilitate early diagnosis and timely access to treatments, before the development of untreatable and irreversible organ damage.

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Mitochondrial neurogastrointestinal encephalomyopathy (MNGIE): Position paper on diagnosis, prognosis, and treatment by theMNGIEInternational Network

Hirano

Carelli

Giorgio

et al. 2020

J of Inher Metab Disea

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Mitochondrial neurogastrointestinal encephalomyopathy (MNGIE) is a rare autosomal recessive disease caused by TYMP mutations and thymidine phosphorylase (TP) deficiency. Thymidine and deoxyuridine accumulate impairing the mitochondrial DNA maintenance and integrity. Clinically, patients show severe and progressive gastrointestinal and neurological manifestations. The onset typically occurs in the second decade of life and mean age at death is 37 years. Signs and symptoms of MNGIE are heterogeneous and confirmatory

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Pearls & Oy-sters: Mitochondrial neurogastrointestinal encephalomyopathy

Cited by 5 publications

References 10 publications

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

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

Mitochondrial neurogastrointestinal encephalomyopathy: approaches to diagnosis and treatment

Mitochondrial neurogastrointestinal encephalomyopathy (MNGIE): Position paper on diagnosis, prognosis, and treatment by theMNGIEInternational Network

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