Late-onset MNGIE without peripheral neuropathy due to incomplete loss of thymidine phosphorylase activity

Massa, Roberto; Tessa, Alessandra; Margollicci, Maria; Micheli, Vanna; Romigi, Andrea; Tozzi, Giulia; Terracciano, Chiara; Piemonte, Fiorella; Bernardi, Giorgio; Santorelli, Filippo M.

doi:10.1016/j.nmd.2009.08.013

Cited by 35 publications

(40 citation statements)

References 14 publications

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“…To date, around 60 different TYMP mutations have been associated with MNGIE (Giordano, et al, 2008;Massa, et al, 2009;Poulton, et al, 2009). More than 50% are missense mutations, followed by splice site mutations (~20%), and frameshifts generating nonstop mRNA (~10%).…”

Section: Introductionmentioning

confidence: 99%

A novel nonstop mutation in TYMP does not induce nonstop mRNA decay in a MNGIE patient with severe neuropathy

et al. 2011

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ABSTRACT:The cellular quality control systems enable surveillance and selective degradation of nonsense, nonstop, and no-go mRNAs. In the case of nonstop mRNA, different mechanisms of nonstop-mediated decay (NSD) have been described for bacteria, yeast and mammals, but the molecular consequences of nonstop mutations have been examined in only few cases of human disease. We describe a novel homozygous nonstop mRNA mutation (c.1416delC) in the TYMP gene encoding thymidine phosphorylase, in a patient with mitochondrial neurogastrointestinal encephalomyopathy (MNGIE). In contrast to previous reports showing selective decay of pathogenic nonstop mRNAs, quantitative real-time PCR and 3'-RACE-RFLP analysis revealed unreduced nonstop mRNA levels in our patient and 2 heterozygous carriers of the mutation. The absence of thymidine phosphorylase protein in the homozygous patient, together with the partial decrease in levels of this protein in 2 carriers suggest that the main control system in this case resides at the translational or post-translational levels rather than through NSD. This is the first report showing an absence of NSD in a human disease, revealing that this surveillance mechanism has exceptions in vivo.

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Section: Introductionmentioning

confidence: 99%

A novel nonstop mutation in TYMP does not induce nonstop mRNA decay in a MNGIE patient with severe neuropathy

et al. 2011

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“…Although heterozygous carriers are clinically asymptomatic, TP activity is decreased to 26-35% of the normal level (15). Patients with compound heterozygous mutations have been reported to have mild symptoms with a later onset than that found in typical homozygous patients (15,16). In an Italian family, compound heterozygous mutations in TYMP exhibited different clinical presentations between two affected siblings (17).…”

Section: Discussionmentioning

confidence: 99%

“…To date, several homozygous and compound heterozygous TYMP mutations have been reported to be causative of autosomal recessive MNGIE (5,(12)(13)(14)(15)(16)(17). Homozygous mutations in TYMP usually result in an almost complete abolition of TP activity, with <5% remaining (5,13,14); however, compound heterozygous mutations exhibit a partial loss of activity with 10-20% normal TP activity (15,16).…”

Section: Discussionmentioning

confidence: 99%

“…Homozygous mutations in TYMP usually result in an almost complete abolition of TP activity, with <5% remaining (5,13,14); however, compound heterozygous mutations exhibit a partial loss of activity with 10-20% normal TP activity (15,16). Although heterozygous carriers are clinically asymptomatic, TP activity is decreased to 26-35% of the normal level (15).…”

Section: Discussionmentioning

confidence: 99%

“…Several homozygous or compound heterozygous mutations in TYMP have been reported to be the underlying causes of MNGIE (5,(10)(11)(12)(13)(14)(15)(16)(17). Thymidine phosphorylase (TP) encoded by TYMP catalyzes the phosphorylation of thymidine or deoxyuridine to thymine or uracil in mtDNA synthesis (4).…”

Section: Introductionmentioning

confidence: 99%

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Compound heterozygous mutations of TYMP as underlying causes of mitochondrial neurogastrointestinal encephalomyopathy (MNGIE)

Suh

Jeong

Yoon

et al. 2013

Molecular Medicine Reports

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Abstract. Mitochondrial neurogastrointestinal encephalomyopathy (MNGIE), an autosomal recessive multiorgan disease, frequently associated with mutations in the thymidine phosphorylase (TYMP) gene. TYMP encodes thymidine phosphorylase (TP), which has an essential role in the nucleotide salvage pathway for mitochondrial DNA (mtDNA) replication. This study reports an MNGIE patient with novel compound heterozygous missense mutations (Thr151Pro and Leu270Pro) in TYMP. Each mutation was inherited from one parent. Neither mutation was found in the controls and the mutation sites were well conserved between different species. Neither large deletion nor causative point mutations were found in the mtDNA. The patient presented with MNGIE symptoms, including gastrointestinal discomfort, external ophthalmoplegia, pigmentary retinopathy and demyelinating type diffuse sensory motor polyneuropathy. The patient demonstrated an early-onset but mild phenotype, with 9.6% TP activity; therefore, patients with these compound heterozygous mutations may exhibit a mild phenotype with a variable onset age according to TP activity level.

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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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Late-onset MNGIE without peripheral neuropathy due to incomplete loss of thymidine phosphorylase activity

Cited by 35 publications

References 14 publications

A novel nonstop mutation in TYMP does not induce nonstop mRNA decay in a MNGIE patient with severe neuropathy

A novel nonstop mutation in TYMP does not induce nonstop mRNA decay in a MNGIE patient with severe neuropathy

Compound heterozygous mutations of TYMP as underlying causes of mitochondrial neurogastrointestinal encephalomyopathy (MNGIE)

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

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