J Neurol (2012) 259:1985–1987 DOI 10.1007/s00415-012-6500-z
LETTER TO THE EDITORS
Clinical and biochemical improvement following HSCT in a patient with MNGIE: 1-year follow-up F. Sicurelli • M. A. Carluccio • F. Toraldo • M. Tozzi • A. Bucalossi • M. Lenoci • G. Jacomelli • V. Micheli • E. Cardaioli • M. Mondelli • A. Federico • G. Marotta • M. T. Dotti
Received: 30 November 2011 / Accepted: 27 March 2012 / Published online: 25 April 2012 Ó Springer-Verlag 2012
Dear Sirs, 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
F. Sicurelli and M. A. Carluccio contributed equally to this manuscript. F. Sicurelli M. A. Carluccio E. Cardaioli A. Federico M. T. Dotti (&) Department of Neurological, Neurosurgical and Behavioral Sciences, University of Siena, Viale Bracci 1, 53100 Siena, Italy e-mail:
[email protected] F. Toraldo M. Tozzi A. Bucalossi M. Lenoci G. Marotta Stem Cell Transplant and Cellular Therapy Unit, University of Siena, Siena, Italy G. Jacomelli V. Micheli Department of Biotechnology, University of Siena, Siena, Italy M. Mondelli EMG Service, Asl 7, Siena, Italy
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 9 108 mononucleated cells) after a myeloablative conditioning regimen with busulfan 12.8 mg/kg and fludarabine 150 mg/m2, 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/m2/day ?1, and 8 mg/m2 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
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J Neurol (2012) 259:1985–1987
Fig. 1 a MRC before and after HSCT in different muscles. One year after treatment, the full MRC score significantly improved (p = 0.0001 at nonparametric sign test for paired data). b Buffy coat
thymidine phosphorylase (TP) activity (nmol/h/mg protein) and c plasma concentrations of deoxythymidine (dThd) and deoxyuridine (dUrd) (lM)
sensory action potential amplitudes were further reduced (Table 1). The leukoencephalopathy originally observed on brain magnetic resonance imaging was unchanged. Blood lactate sharply decreased (from 2.3 to 1.5 mmol/l). Normal TP activity was restored from the first month and progressive normalization of deoxyuridine and deoxythymidine plasma concentration was observed (Fig. 1b and c). Hirano et al. [4] first reported a correction of biochemical abnormalities after HSCT in two MNGIE patients. However, the more severely affected patient died of unsuccessful engraftment [6]. More recently, in a paper reporting the proposal for a common approach to HSCT in MNGIE [7], seven more patients treated by this procedure are mentioned but clinical details are lacking. In our MNGIE patient, HSCT restored normal TP activity, reduced plasma concentrations of deoxyuridine and thymidine, and eliminated all gastrointestinal tract manifestations. Improvement in motor neurography was observed. This finding could, at least in part, account for the significant improvement in muscle strength. The worsening of sensory neurography, not mirrored by clinical signs, was probably due to a toxic effect of chemotherapy.
In spite of gastrointestinal motility normalization, no sensible variation in body weight was recorded. Although an observation period of 1 year is too short to draw definite conclusions on long-term efficacy of HSCT, we consider this case noteworthy for the following reasons. First, HSCT seems to be the most effective treatment for MNGIE [7], though the rarity of transplanted patients makes it difficult to evaluate clinical benefits. The present case report contributes to the scanty literature on clinical outcome of HSCT in MNGIE [6]. Second, allogeneic HSCT is still associated with significant transplant-related complications and mortality. The choice of a conditioning regimen with reduced mitochondrial toxicity may be crucial for safety in this disorder. Finally, in the present case, early diagnosis and the patient’s fitness may have been determinant for the positive outcome. The experience with other neurometabolic disorders suggests that disease stage and transplant characteristics are equally important for the clinical outcome both in terms of transplant-related risks and reversibility of clinical (neurological and systemic) symptoms. In this regard, our mildly affected patient with a sibling donor, seemed to be an ideal candidate for transplantation. However, guidelines
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J Neurol (2012) 259:1985–1987
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Table 1 Motor (MCV) and sensory conduction velocities (SCV), amplitude of the sensory action (SAP), compound muscle action potentials (CMAP), and distal motor latency (DML) Peripheral nerve
Time 0
12 months after HSCT
Lower/ upper limits
Right median
are warranted in order to help the clinicians to address the ethical dilemma of exposing a mildly affected patient to a potentially life-threatening procedure. Acknowledgments The authors thank Dr. Michio Hirano and Dr. Carlo Casali for their support on clinical decisions. Conflicts of interest
None.
MCV (m/s) Elbow–wrist
28.1
34.3
49.6
Axilla–elbow
33.6
32.1
52.3
43.6
39.9
27.4
4.7
4.2
4.0
Wrist
10.7
13.7
7.7
Elbow
10.2
13.2
7.4
Axilla SCV (m/s) third finger–wrist
10.1 37
12 34.7
7.2 45.6
SAP (lV)
10
9.7
11.5
Below elbow–wrist
30
30.1
51.4
Above–below elbow
30.6
33.3
Axilla–above elbow
35
33.8
40.7
41.3
4.0
4.0
10.6
10.1
9.4
7.7
9.0
8.9
F wave latency (ms) DML (ms) CMAP (mV)
Right ulnar MCV (m/s)
F wave latency (ms) DML (ms)
26.3 3.75
CMAP (mV) Wrist Below elbow Above elbow
5.1
8.4
8.1
Axilla
5.1
7.8
8
42.3 7.5
34.0 2.1
43.6 8.5
Capitulum fibulae–flexor retinaculum
27.7
31.3
40.7
Lateral popliteal fovea–capitulum fibulae
26.1
21.2
39.4
79.8
SCV (m/s) fifth digit–wrist SAP (lV) Right deep peroneal MCV (m/s)
F wave latency (ms)
70.9
48.9
5.32
6.2
5.3
Flexor retinaculum
8.9
7.2
1.7
Cap. fibulae
7.9
6.9
1.5
Popliteal fovea
6.6
6.9
1.4
38.2
32.2
41.5
6.2
1.6
10.3
DML (ms) CMAP (mV)
References 1. Hirano M, Silvestri G, Blake DM et al (1994) Mitochondrial neurogastrointestinal encephalomyopathy (MNGIE): clinical, biochemical, and genetic features of an autosomal recessive mitochondrial disorder. Neurology 44:721–727 2. Nishino I, Spinazzola A, Hirano M (1999) Thymidine phosphorylase gene mutations in MNGIE, a human mitochondrial disorder. Science 283:689–692 3. Nishino I, Spinazzola A, Papadimitriou A et al (2000) Mitochondrial neurogastrointestinal encephalomyopathy: an autosomal recessive disorder due to thymidine phosphorylase mutations. Ann Neurol 47:792–800 4. Hirano M, Martı´ R, Casali C et al (2006) Allogeneic stem cell transplantation corrects biochemical derangements in MNGIE. Neurology 67:1458–1460 5. Cardaioli E, Sicurelli F, Carluccio MA et al (2012) A new thymidine phosphorylase mutation causing elongation of the protein underlies mitochondrial neurogastrointestinal encephalomyopathy. J Neurol 259:172–174 6. Hirano M, Casali C, Tadesse S et al (2008) Sustained biochemical and clinical improvements two years postallogeneic stem cell transplantation in a patient with MNGIE. In: AAN annual meeting. Available via http://www.abstracts2view.com/aan2008chicago/. Accessed 13 April 2010 7. Halter J, Schu¨pbach WMM, Casali C et al (2011) Allogeneic hematopoietic SCT as treatment option for patients with mitochondrial neurogastrointestinal encephalomyopathy (MNGIE): a consensus conference proposal for a standardized approach. Bone Marrow Transplant 46:330–337
Right sural SCV (m/s) sura-lateral malleolus SAP (lV)
F values refers to the shortest latency out of eight consecutive responses. Upper/lower limits are ± 2SD of the mean of the values of a control group of 30 health subjects (mean age 15–40 years). Upper limits of the shortest latency are referred to subjects’ height
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