Clinical and biochemical improvement following HSCT in a patient with MNGIE: 1-year follow-up

Abstract

Mitochondrial neurogastrointestinal encephalomyopathy (MNGIE) is an inherited and almost invariably fatal disorder due to thymidine phosphorylase (TP) deficiency leading to a general increase in its substrates, deoxythymidine (dThd) and deoxyuridine (dUrd), in urine and serum. Typically, MNGIE phenotype is characterized by severe gastrointestinal dysmotility, ophthalmoplegia, peripheral neuropathy, and leukoencephalopathy [1–3]. Allogeneic hematopoietic stem cell transplantation (HSCT) seems to halt its clinical course by restoring biochemical abnormalities, but clinical evidence is still very limited [4]. Here we report the successful treatment with allogeneic HSCT in a 23-year-old MNGIE woman with mild clinical phenotype carrying a novel homozygous c.1249dupC mutation of TYMP gene, already described in detail by Cardaioli et al. [5] in this journal. In brief, the patient complained of frequent diarrhea, abdominal pain, recurrent episodes of vomiting, and fatigability. Neurological signs included mild palpebral ptosis, limb weakness, and absent deep-tendon reflexes. Sensitivity was normal. Following the decision to perform HSCT, the healthy, 30-year-old, HLA-A, -B, -C, -DR, and -DP matched brother without TYMP gene mutations was identified as the donor. The patient was infused with bone marrow from her brother (4.14 9 10 mononucleated cells) after a myeloablative conditioning regimen with busulfan 12.8 mg/kg and fludarabine 150 mg/m, chosen for their reduced mitochondrial toxicity. Graft versus host disease prophylaxis consisted of cyclosporin (1 mg/kg/day in continuous infusion from day -6 to -1; 2 mg/kg/day from day 0 to ?2; 3 mg/kg/day from day ?3 to ?20 and subsequently 3 mg/kg/day orally) and methotrexate (10 mg/m/day ?1, and 8 mg/m days ?3 and ?6). Engraftment was prompt with an absolute neutrophil count of [500/ll on day ?17 and a platelet count [20,000/ll on day ?14. Chimerism studies using polymorphic STR genes on day 30 showed 100 % marrow cells of donor origin. One month after transplant, the patient reported complete normalization of all aforementioned gastrointestinal symptoms and, 3 months later, she referred reduced susceptibility to fatigue. Clinical assessment 1 year after HSCT revealed mild increase in body weight (37.7 vs. 37 kg before transplant) and significant improvement in muscle strength measured by the Medical Research Council (MRC) score (Fig. 1a). Palpebral ptosis and areflexia were unchanged. Sensitivity examination was still normal. Electromyography at baseline showed sensorymotor demyelinating neuropathy. One year after transplant, proximal motor conduction velocities improved, especially in the upper limbs. Sensory conduction velocities and F. Sicurelli and M. A. Carluccio contributed equally to this manuscript.