Mitochondrial neurogastrointestinal encephalomyopathy: An autosomal recessive disorder due to thymidine phosphorylase mutations

Abstract

Mitochondrial neurogastrointestinal encephalomyopathy (MNGIE) is an autosomal recessive disorder defined clinically by severe gastrointestinal dysmotility; cachexia; ptosis, ophthalmoparesis, or both; peripheral neuropathy; leukoencephalopathy; and mitochondrial abnormalities. The disease is caused by mutations in the thymidine phosphorylase (TP) gene. TP protein catalyzes phosphorolysis of thymidine to thymine and deoxyribose 1‐phosphate. We identified 21 probands (35 patients) who fulfilled our clinical criteria for MNGIE. MNGIE has clinically homogeneous features but varies in age at onset and rate of progression. Gastrointestinal dysmotility is the most prominent manifestation, with recurrent diarrhea, borborygmi, and intestinal pseudo‐obstruction. Patients usually die in early adulthood (mean, 37.6 years; range, 26–58 years). Cerebral leukodystrophy is characteristic. Mitochondrial DNA (mtDNA) has depletion, multiple deletions, or both. We have identified 16 TP mutations. Homozygous or compound heterozygous mutations were present in all patients tested. Leukocyte TP activity was reduced drastically in all patients tested, 0.009 ± 0.021 μmol/hr/mg (mean ± SD; n = 16), compared with controls, 0.67 ± 0.21 μmol/hr/mg (n = 19). MNGIE is a recognizable clinical syndrome caused by mutations in thymidine phosphorylase. Severe reduction of TP activity in leukocytes is diagnostic. Altered mitochondrial nucleoside and nucleotide pools may impair mtDNA replication, repair, or both. Ann Neurol 2000;47:792–800

Mitochondrial neurogastrointestinal encephalomyopathy in three siblings

“…The clinical manifestations of the few known MNGIE patients have been reviewed in detail [8,20,43]. Frequent findings in MNGIE ( > 70% of all cases in the series of Hirano et al [43]) that we observed in one or more of our patients were: cachexia, intestinal pseudo-obstruction, borborygmi, abdominal pain, diarrhoea, early satiety, abdominal cramps, nausea, vomiting, ptosis, ophthalmoparesis, polyneuropathy, and areflexia.…”

Altered Thymidine Metabolism Due to Defects of Thymidine Phosphorylase

“…The clinical diagnosis of MNGIE required the presence of six features as follows: 1) severe gastrointestinal dysmotility; 2) cachexia; 3) ptosis, ophthalmoparesis, or both; 4) peripheral neuropathy; 5) leukodystrophy on brain magnetic resonance imaging scan; and 6) laboratory evidence of mitochondrial dysfunction. As reported previously, we identified homozygous or compound heterozygous mutations in the TP gene in all 27 probands and heterozygous mutations in 22 relatives (7,9). Samples from three patients with diagnosis of autosomal dominant progressive external ophthalmoplegia, another disorder associated with multiple deletions of mtDNA, were also studied.…”

“…Clinically, MNGIE presents between the 1st and the 5th decades with ptosis, ophthalmoparesis, or both; skeletal myopathy; peripheral neuropathy; gastrointestinal dysmotility, manifesting as diarrhea and pseudo-obstruction; and cachexia (7). Clinical diagnostic tests typically reveal leukodystrophy on brain magnetic resonance imaging scans, lactic acidosis, and peripheral neuropathy with demyelination, axonal degeneration, or both.…”

Peripheral neuropathies in mitochondrial disorders

“…Additional manifestations include progressive external ophthalmoplegia, retinopathy, myopathy and diffuse leukoencephalopathy (present in all patients). All patients develop a sensorimotor demyelinating PNP but with varying degrees of severity, resulting in distal weakness and atrophy of the lower limb muscles [12]. Nerve biopsies performed in MNGIE patients disclosed demyelinating features, reduction of myelinated fiber density, and clusters of regenerating fibers.…”