Allogeneic haematopoietic stem cell transplantation for mitochondrial neurogastrointestinal encephalomyopathy

Abstract

Haematopoietic stem cell transplantation has been proposed as treatment for mitochondrial neurogastrointestinal encephalomyopathy, a rare fatal autosomal recessive disease due to TYMP mutations that result in thymidine phosphorylase deficiency. We conducted a retrospective analysis of all known patients suffering from mitochondrial neurogastrointestinal encephalomyopathy who underwent allogeneic haematopoietic stem cell transplantation between 2005 and 2011. Twenty-four patients, 11 males and 13 females, median age 25 years (range 10-41 years) treated with haematopoietic stem cell transplantation from related (n = 9) or unrelated donors (n = 15) in 15 institutions worldwide were analysed for outcome and its associated factors. Overall, 9 of 24 patients (37.5%) were alive at last follow-up with a median follow-up of these surviving patients of 1430 days. Deaths were attributed to transplant in nine (including two after a second transplant due to graft failure), and to mitochondrial neurogastrointestinal encephalomyopathy in six patients. Thymidine phosphorylase activity rose from undetectable to normal levels (median 697 nmol/h/mg protein, range 262-1285) in all survivors. Seven patients (29%) who were engrafted and living more than 2 years after transplantation, showed improvement of body mass index, gastrointestinal manifestations, and peripheral neuropathy. Univariate statistical analysis demonstrated that survival was associated with two defined pre-transplant characteristics: human leukocyte antigen match (10/10 versus <10/10) and disease characteristics (liver disease, history of gastrointestinal pseudo-obstruction or both). Allogeneic haematopoietic stem cell transplantation can restore thymidine phosphorylase enzyme function in patients with mitochondrial neurogastrointestinal encephalomyopathy and improve clinical manifestations of mitochondrial neurogastrointestinal encephalomyopathy in the long term. Allogeneic haematopoietic stem cell transplantation should be considered for selected patients with an optimal donor.

Keywords: allogeneic haematopoietic stem cell transplantation; mitochondrial neurogastrointestinal encephalomyopathy (MNGIE); outcome; risk factors; thymidine phosphorylase.

Mitochondrial neurogastrointestinal encephalopathy (MNGIE) is a rare fatal autorecessive disease. Halter et al. report outcomes from all known haematopoietic stem cell transplantations worldwide from sibling or unrelated donors for MNGIE between 2005 and 2011. In some of the recipients, correction of the underlying metabolic defect results in gradual clinical improvement.

Figure 1

Number of patients treated and outcome.

Figure 2

Overall survival. (A) Overall survival of the whole cohort with a median overall survival of 453 days. (B–E) Univariate analysis for factors associated with overall survival: HLA-match (B), history of gastrointestinal pseudo-obstruction and/or liver disease (C), intensity of conditioning regimen (D) and overall survival depending on intensity of conditioning regimen if outcome after second HSCT is included into survival analysis (E). RIC = reduced-intensity conditioning; IC = intensive, myeloablative conditioning.

Figure 3

Metabolic and clinical MNGIE manifestations pre- and post-transplant. (A) TP activity in buffy coat before and after HSCT (paired t-test, two tailed: P < 0.0001). (B) Thymidine levels in plasma before and after HSCT (P < 0.0001). (C–F) Results of patients with follow-up >2 years. Shapes of symbols identify individual patients. Due to small patient numbers no statistical analysis was performed but a trend towards improvements of body mass index (BMI) and nerve conduction studies can be observed in long-term follow-up as exemplified by: (C) change of body mass index 2, 3, and 4 years after transplantation; (D) F-wave latency of ulnar nerve; (E) distal motor conduction velocity of ulnar nerve; and (F) ulnar compound muscle potential (mV).