More than three decades after the initial description by
Okamura et al. (1976), MNGIE is a well-characterized disorder. Clinically, MNGIE is a multisystemic autosomic recessive disorder characterized by: onset typically in the first three decades of life, but as late as the fifth decade; ptosis; progressive external ophthalmoplegia; gastrointestinal dysmotility; cachexia; peripheral neuropathy; and diffuse leucoencephalopathy (
Hirano et al., 2004). MNGIE is caused by the
TYMP gene mutations that cause severe biochemical defects of thymine phosphorylase activity, which, in turn, cause marked increases in thymidine and deoxyuridine nucleoside levels in blood, urine and tissues (
Nishino et al., 1999;
Spinazzola et al., 2002;
Martí et al., 2003;
Valentino et al., 2007). The increased nucleosides, in turn, cause mitochondrial DNA instability and respiratory chain dysfunction (
Hirano et al., 1994;
Nishino et al., 1999;
Spinazzola et al., 2002;
Martí et al., 2003;
Nishigaki et al., 2003,
2004;
Pontarin et al., 2006;
López et al., 2009).
There have been reports of patients with MNGIE-like clinical manifestations of gastrointestinal dysmotility, progressive external ophthalmoplegia, ptosis, cachexia and peripheral neuropathy due to the mitochondrial myopathy, encephalopathy, lactic acidosis and stroke, m.32443A>G,
POLG or
RRM2B mutations; however, all patients had patchy or absent white matter lesions in contrast to the diffuse leucoencephalopathy that is characteristic of MNGIE (
van Goethem et al., 2003;
Chang et al., 2004;
Shaibani et al., 2009).
In the 12 years since our identification of
TYMP gene mutations in MNGIE (
Nishino et al., 1999), we have collected a cohort of 102 patients, showing a high incidence of MNGIE relative to other autosomal recessive mitochondrial disorders. The patient distribution suggests a relatively high prevalence in Europeans. The mutation distribution suggests founder effects for some mutations such as c.866A>G in Europe and c.518T>G in the Dominican Republic; this information can guide genetic screening in each area.
Although there is considerable variation in the age-at-onset and sequence of organ involvement in MNGIE, half of the patients initially reported gastrointestinal symptoms. As previously reported, peripheral neuropathy or extraocular muscle weakness were often the initial manifestations (
Nishino et al., 2000;
Hirano et al., 2004).
In the early stages of MNGIE, the neuropathy may resemble demyelinating forms of Charcot–Marie–Tooth disease or chronic inflammatory demyelinating polyneuropathy, while the gastrointestinal manifestations may be misdiagnosed as a psychiatric eating disorder, coeliac disease, inflammatory bowel disease, Whipple disease or other gastrointestinal disorder.
Diagnosis of an eating disorder requires an aberrant pattern of eating behaviour and weight regulation as well as disturbances in attitude to weight and perception of body shape, which patients with MNGIE do not manifest (
American Psychiatric Association, 2000). When these criteria for eating disorders are absent, we recommend screening thymine phosphorylase activity for MNGIE. In a case of neuropathy or malabsorption syndrome, associated symptoms including ophthalmoparesis and leucoencephalopathy should be indicators for clinicians to screen thymine phosphorylase activity.
Demyelinating neuropathy has been reported in almost all patients of our cohort from electrophysiological studies and supported by nerve biopsy studies.
Said et al. (2005) reported reductions of nerve fibre density and segmental abnormalities of myelin including demyelination, remyelination and clusters of regenerating fibres and tomacula-like irregularity in nerve biopsies of four patients.
Petcharunpaisan and Castillo (2010) postulated that demyelinating neuropathy may contribute to progressive external ophthalmoplegia in MNGIE, based on the observation of post-contrast enhancement of cisternal portions of the oculomotor and trigeminal nerves on T
2-weighted images, in addition to multiple symmetric white matter changes on T
2 fluid-attenuated inversion recovery signals.
Although the leucoencephalopathy in MNGIE had been considered asymptomatic (
Nishino et al., 2000), an increasing number of patients have been noted to have mild neurological symptoms such as cognitive impairment, dementia, seizure, headache or other psychiatric symptoms. Longitudinal neuropsychological studies should be performed to confirm a decline of cognitive functions during the course of the disease and to characterize the psychiatric disorders.
Absence of correlation between the clinical features and
TYMP mutation and intra- and inter-familiar phenotype variability suggests a role for unknown nuclear modifier or mitochondrial genes (
Nishino et al., 2001). Nuclear gene modifiers have been hypothesized to contribute to the phenotypic expression of homoplasmic mitochondrial mutations causing Leber hereditary optic neuropathy, mitochondrial cardiomyopathy or sensorineural hearing loss (
Davidson et al., 2009).
MNGIE can be diagnosed by demonstrating severely reduced thymine phosphorylase activity in the buffy coat, marked elevations of thymidine, deoxyuridine or both in plasma or urine, or by detecting
TYMP gene mutations (
Marti et al., 2004;
Schüpbach et al., 2007). Muscle biopsies typically reveal mitochondrial alterations such as ragged-red fibres, cytochrome
c oxidase-deficient fibres or decreased activities of mitochondrial respiratory chain enzymes; however, as previously reported (
Szigeti et al., 2004) and confirmed in our series (
Supplementary Table 3), skeletal muscle may not show mitochondrial abnormalities in patients with MNGIE. Thus, absence of mitochondrial pathology in a skeletal muscle biopsy does not exclude the diagnosis of MNGIE.
The reduction of circulating nucleosides, as achieved transiently by haemodialysis and platelet infusion, and long-term by successful allogeneic stem cell transplantation, should be therapeutic in MNGIE (
Spinazzola et al., 2002;
Hirano et al., 2006;
Lara et al., 2006). Preliminary data for enzyme replacement by allogeneic haematopoetic stem cell transplantation showed a biochemical improvement with a rapid restoration of enzyme activity and reduction or disappearance of plasma thymidine and deoxyuridine (
Hirano et al., 2006;
Schüpbach et al., 2009;
Halter et al., 2011). Although follow-up is too short to evaluate clinical benefit, in all nine patients engrafted, ‘considerable clinical improvement up to 3.5 years post-transplantation’ has been reported (
Schüpbach et al., 2009;
Halter et al., 2011). However, most patients are not eligible for allogeneic haematopoetic stem cell transplantation because of their poor medical conditions at the time of diagnosis. Therefore, to maximize the benefits of treatment, diagnosis in children should be achieved to prevent organ damage and to reduce the risk of complications associated with transplantation (
Halter et al., 2011).
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