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CHICAGO—Noteworthy clinical gains have resulted from an allogeneic stem cell transplantation in a patient with mitochondrial neurogastrointestinal encephalomyopathy, or MNGIE, a Columbia University neurologist reported at the AAN annual meeting here in April.

While the same team reported two years ago that transplantation had corrected the biochemical abnormalities in the serum of two patients, the new report offered the first evidence of clinical gains; one of the patients reached the 30-month post-transplant mark in starkly improved health.

MNGIE is an autosomal recessive disorder of intergenomic communication. Mutations in the thymidine phosphorylase gene of the patient's nuclear DNA causes a buildup of thymidine and deoxyuridine, explained Michio Hirano, MD, associate professor of neurology at Columbia University Medical Center, who was the lead author of the new report.

“There's a cellular problem,” Dr. Hirano said. “The cells can't metabolize food substrates sufficiently…using anaerobic glycolysis, to convert sugars and fats into lactic acid rather than into carbon dioxide and water. We think the buildup of thymidine and deoxyuridine is toxic to mitochondria.”

Dr. Hirano said he hopes the case will alert neurologists to be more vigilant in considering the possibility of MNGIE when faced with a patient with the syndrome of ophthalmoplegia, severe GI dysmotility, extreme cachexia, peripheral neuropathy, and leukoencephalopathy.

“I cannot think of any other disease that has this combination of symptoms, but the condition remains under-recognized and under-diagnosed,” he said. “Most neurologists are unfamiliar with MNGIE. Frequently these patients go to gastroenterologists or psychiatrists and are misdiagnosed with anorexia nervosa, celiac disease, or inflammatory bowel disease. Every patient we've seen had been misdiagnosed with one of these conditions.”


The patient, a 30-year-old Italian pharmacologist who weighed just 55 pounds on her 5'2” frame at the time of the procedure in October 2005, had reached 61 pounds by the AAN meeting and was gaining about a pound each month, Dr. Hirano reported. Her bowel movements became normal, foot dysesthesias had disappeared, and total parenteral nutrition had been replaced by a normal diet of 3,000 calories daily. Previously absent tendon reflexes returned at the biceps and triceps, and nerve conduction studies showed improvement in distal latencies and conduction velocities.

“We are greatly encouraged,” Dr. Hirano told Neurology Today in an interview before his presentation. “It's now two and a half years [since the transplant], and she's continuing to show improvements.”

The other patient who had the transplant, however, died three months after the procedure, his condition having already reached a more severe stage before the transplant.

Dr. Hirano said the successful results need to be replicated in some of the other transplants that have been performed around the world — including one in Australia, two in Spain, and one in Switzerland — before the procedure can be more widely adopted.

“Unfortunately at least three of those transplants failed,” Dr. Hirano said. “Those patients may be re-transplanted. I'm anxiously awaiting word about the outcome in those cases. If they have results similar to ours, it would certainly confirm our findings and encourage us to do more.”


A British neuroscientist who specializes in mitochondrial disorders said the case report is proof of principle that offers hope for the future.

“Dr. Hirano is appropriately conservative about the clinical benefits, which have yet to be formally established,” said Patrick Chinnery, MD, PhD, the Wellcome senior fellow in clinical science and professor of neurogenetics at the University of Newcastle upon Tyne. “Dr. Hirano's results are most encouraging, but a few more cases need to be studied with objective clinical measures pre-and post-transplant over a few years before we can conclude this treatment is definitely the right thing to do.”

An alternative approach to treating MNGIE was reported last March in Neurology by Turkish researchers, who gave a patient peritoneal dialysis for three years. The female patient no longer vomited, had reduced abdominal pain, had gained 5 kg in weight, and had resumed menstruating, even though dialysis did not affect plasma nucleoside levels.

While dialysis seeks to eliminate the noxious metabolites, Dr. Hirano's team had shown in a 2006 Neurology paper that another effective approach is to give the patients platelets, which are naturally rich in the thymidine phosphorylase that patients lacks.

As a permanent solution, they performed a reduced-intensity allogeneic stem cell transplantation in the Italian woman, using peripheral blood progenitor cells obtained from her healthy HLA 6/6-matched 32-year-old brother.

Prior to transplantation, the patient had undetectable buffy coat thymidine phosphorylase activity and elevated plasma thymidine. Two weeks post-transplant, circulating donor chimerism was 36 percent with significant buffy coat thymidine phosphorylase activity and reductions in plasma thymidine and deoxyuridine (2.5 M).

Three months after the transplant, decreased donor chimerism prompted discontinuation of immunosuppression. About one year post-transplant, donor chimerism rose to 100 percent. Since then, buffy coat thymidine phosphorylase activity has been in the low-normal range (280–440 nmol/h/mg-prot) with markedly reduced thymidine (≤0.1M) and deoxyuridine (≤0.05 M) demonstrating sustained biochemical improvements, which preceded the clinical benefits.


•Hirano M, Casali C, Tadesse S, et al. Sustained biochemical and clinical improvements two years post-allogeneic stem cell transplantation in a patient with MNGIE. AAN Annual Meeting Abstract S48.002. April 2008.
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