Long‐term survival after liver transplantation in children with metabolic disorders

Kayler, Liise K.; Merion, Robert M.; Lee, Samuel; Sung, Randall S.; Punch, Jeffrey D.; Rudich, Steven M.; Turcotte, Jeremiah G.; Campbell, Darrell A.; Holmes, Richard D.; Magee, John C.

doi:10.1034/j.1399-3046.2002.02009.x

Cited by 121 publications

(88 citation statements)

References 22 publications

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“…After the first attempt in 1997, 5 liver and kidney transplants have been anecdotally performed in MMA, with questionable results. [6][7][8][9][10] Because of the lack of consensus and guidelines on transplantation in MMA, reports on additional experience may help challenge earlier conclusions and instigate debate on newer clinical options.…”

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confidence: 99%

Early Liver Transplantation for Neonatal-Onset Methylmalonic Acidemia

Spada¹,

Calvo²,

Brunati³

et al. 2015

Pediatrics

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With conventional dietary treatment, the clinical course of methylmalonic acidemia due to cobalamin-unresponsive methylmalonyl-CoA mutase (MCM) deficiency is characterized by the persistent risk of recurrent life-threatening decompensation episodes with metabolic acidosis, hyperammonemia, and coma. Liver transplant has been proposed as an alternative treatment and anecdotally attempted in the last 2 decades with inconsistent results. Most criticisms of this approach have been directed at the continuing risk of neurologic and renal damage after transplant. Here, we report the perioperative and postoperative clinical and biochemical outcomes of 2 patients with severe MCM deficiency who underwent early liver transplant. In both cases, liver transplant allowed prevention of decompensation episodes, normalization of dietary protein intake, and a marked improvement of quality of life. No serious complications have been observed at 12 years' and 2 years' follow-up, respectively, except for mild kidney function impairment in the older patient. On the basis of our experience, we strongly suggest that liver transplant should be offered as a therapeutic option for children with cobalamin-unresponsive MCM deficiency at an early stage of the disease.

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confidence: 99%

Early Liver Transplantation for Neonatal-Onset Methylmalonic Acidemia

Spada¹,

Calvo²,

Brunati³

et al. 2015

Pediatrics

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“…Elective liver (Kayler et al, 2002;Nyhan et al, 2002;Hsui et al, 2003;Kaplan et al, 2006b;Kasahara et al, 2006) and/or combined liver-kidney transplantation (van 't Hoff et al, 1998;Nagarajan et al, 2005) has been used to treat a subset of mut 0 patients. Although solid organ recipients do not experience peripheral metabolic correction after transplantation (van 't Hoff et al, 1998;Nagarajan et al, 2005;Kaplan et al, 2006b), they have improved growth and protection from intermittent metabolic crises.…”

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confidence: 99%

Liver-Directed Recombinant Adeno-Associated Viral Gene Delivery Rescues a Lethal Mouse Model of Methylmalonic Acidemia and Provides Long-Term Phenotypic Correction

et al. 2010

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Methylmalonic acidemia is a severe metabolic disorder caused by a deficiency of the ubiquitously expressed mitochondrial enzyme, methylmalonyl-CoA mutase (MUT). Liver transplantation has been used to treat a small number of patients with variable success, and whether liver-directed gene therapy might be employed in such a pleiotropic metabolic disorder is uncertain. In this study, we examined the therapeutic effects of hepatocytedirected delivery of the Mut gene to mice with a severe form of methylmalonic acidemia. We show that a single intrahepatic injection of recombinant adeno-associated virus serotype 8 expressing the Mut gene under the control of the liver-specific thyroxine-binding globulin (TBG) promoter is sufficient to rescue Mut -/-mice from neonatal lethality and provide long-term phenotypic correction. Treated Mut -/-mice lived beyond 1 year of age, had improved growth, lower plasma methylmalonic acid levels, and an increased capacity to oxidize [1-13 C]propionate in vivo. The older treated mice showed increased Mut transcription, presumably mediated by upregulation of the TBG promoter during senescence. The results indicate that the stable transduction of a small number of hepatocytes with the Mut gene can be efficacious in the phenotypic correction of an inborn error of organic acid metabolism and support the rapid translation of liver-directed gene therapy vectors already optimized for human subjects to patients with methylmalonic acidemia.

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“…In that respect, transplantation has been largely successful, and most patients have not had ketoacidosis following transplantation. Positive outcomes and improved quality of life have been reported (Kayler et al 2002;Nagarajan et al 2005), but limited impact on clinical outcome or progressive neurologic disorder has been reported in some cases, so the role of liver transplantation in MMA is debated (Kaplan et al 1996(Kaplan et al , 2006Chakrapani et al 2002;Nyhan et al 2002;Kasahara et al 2006;Chen et al 2010). Our previous experience with domino liver transplantation for MSUD led us to speculate that transplanting a methylmalonic acid domino graft would not cause symptomatic methylmalonic acidemia in the recipient, but this transplant sequence had never been performed previously or documented in the peer review literature.…”

Section: Discussionmentioning

confidence: 98%

“…Liver transplantation (LTx) in MMA has been found to eliminate life-threatening recurrent ketoacidosis in some, but not all, cases (Leonard et al 2001;Kayler et al 2002;Nagarajan et al 2005;Morioka et al 2007;Chen et al 2010). The mutase remains deficient in extrahepatic tissues, so, not surprisingly, disease manifestations may persist.…”

Section: Introductionmentioning

confidence: 99%

Successful Domino Liver Transplantation from a Patient with Methylmalonic Acidemia

et al. 2015

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Liver transplantation has been reported in patients with methylmalonic acidemia (MMA), but longterm outcome is controversial. Many patients with other approved indications for liver transplantation die before donor grafts are available. A 28-year-old man with MMA underwent cadaveric liver transplantation. His liver was used as a domino graft for a 61-year-old man with primary sclerosing cholangitis, who had low priority on the transplant waiting list. Surgical outcome was successful, and after transplantation both patients have excellent graft function. The patient with MMA showed substantial decrease in methylmalonate in urine (from 5,277 AE 1,968 preoperatively to 1,068 AE 384 mmol/mol creatinine) and plasma (from 445.9 AE 257.0 to 333.3 AE 117.7 mmol/l) over >1-year follow-up, while dietary protein intake increased from 0.6 to 1.36 AE 0.33 g/kg/day. The domino recipient maintained near-normal levels of plasma amino acids but did develop elevated methylmalonate in blood and urine while receiving an unrestricted diet (peak plasma methylmalonate 119 mmol/l and urine methylmalonate 84-209 mmol/mol creatinine, with 1.0-1.9 g/kg/day protein). Neither patient demonstrated any apparent symptoms of MMA or metabolic decompensation during the postoperative period or following discharge.Conclusion: Liver transplantation substantially corrects methylmalonate metabolism in MMA and greatly attenuates the disease. In this single patient experience, a liver from a patient with MMA functioned well as domino graft although it did result in subclinical methylmalonic acidemia and aciduria in the recipient. Patients with MMA can be considered as domino liver donors for patients who might otherwise spend long times waiting for liver transplantation.

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Long‐term survival after liver transplantation in children with metabolic disorders

Abstract: Pediatric liver transplantation for metabolic disorders results in excellent clinical and biochemical outcome with long survival and excellent quality of life for most recipients.

Cited by 121 publications

References 22 publications

Early Liver Transplantation for Neonatal-Onset Methylmalonic Acidemia

Early Liver Transplantation for Neonatal-Onset Methylmalonic Acidemia

Liver-Directed Recombinant Adeno-Associated Viral Gene Delivery Rescues a Lethal Mouse Model of Methylmalonic Acidemia and Provides Long-Term Phenotypic Correction

Successful Domino Liver Transplantation from a Patient with Methylmalonic Acidemia

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