A new thymidine phosphorylase mutation causing elongation of the protein underlies mitochondrial neurogastrointestinal encephalomyopathy

Abstract

Mitochondrial neurogastrointestinal encephalomyopathy (MNGIE; OMIM: #603041) is an uncommon, autosomal recessive multisystem disorder, caused by loss-of-function mutations in the nuclear TYMP gene (OMIM: *131222) encoding thymidine phosphorylase (TP). MNGIE should be suspected in young patients presenting with gastrointestinal tract symptoms (abdominal pain, diarrhoea and repeated episodes of pseudo-occlusion) leading to relevant weight loss, and associated with neurological involvement including muscle weakness, ptosis, peripheral neuropathy and leukoencephalopathy. Parental consanguinity has been reported in nearly half of all cases [1, 2]. Clinical diagnosis is confirmed by determination of TP activity in buffy coat samples, which in MNGIE patients is \10% of the mean activity in controls. The lack of TP activity leads to a general increase in its substrates, deoxythymidine (dThd) and deoxyuridine (dUrd), in urine and serum [3]. Different mutations in the TYMP gene have been identified but no predominant mutation has yet been reported. While most are missense mutations, splice-site mutations, deletions, insertions and nonsense mutations have also been reported (http://www.hgmd.org, http://www.genetests.org/). In this study, we report the clinical and genetic findings of a 21-year-old patient with a mild MNGIE phenotype carrying a novel homozygous 1-bp insertion mutation in the TYMP gene. A 21-year-old Italian female, born of healthy consanguineous parents, came to our attention for cervicobrachialgia and paresthesia presenting after a road accident. The patient’s clinical history disclosed repeated episodes of abdominal pain, recurrent vomiting and diarrhoea since the age of 15 years, previously thought to be Campylobacter jejuni infection. Physical examination revealed short stature (150 cm) and thinness (weight 37 kg), with a body mass index (BMI) of 16.4 kg/m. Neurological examination showed mild limb weakness, absent deep tendon reflexes and mild palpebral ptosis. Routine blood chemistry was normal. Serum lactate was significantly increased (2.3 mmol/l; normal value: 0.3–1.3 mmol/l). Peripheral nerve conduction velocity analysis were consistent with a demyelinating sensory motor neuropathy. A diagnosis of MNGIE was suspected. TP activity was absent in the buffy coat (normal range 75–850 nmol/h/mg) and deoxythymidine and deoxyuridine plasma levels were elevated, at 9.0 and 16.0 lmol/L, respectively (normally not detected). Brain magnetic resonance imaging (MRI), showed bilateral periventricular white matter hyperintensities in T2-W and FLAIR images (Fig. 1a). Having obtained informed consent, genomic DNA was extracted from blood samples of the proband, her parents E. Cardaioli F. Sicurelli M. A. Carluccio G. N. Gallus P. Da Pozzo A. Federico M. T. Dotti (&) Department of Neurological, Neurosurgical and Behavioural Sciences, University of Siena, Siena, Italy e-mail: dotti@unisi.it