Long-Term Outcomes of Living Donor Liver Transplantation for Methylmalonic Acidemia.

BACKGROUND: Despite early diagnosis and medical interventions, patients with methylmalonic acidemia (MMA) suffer from multi-organ damage and recurrent metabolic decompensations. METHODS: We conducted the largest retrospective multi-center cohort study so far, involving five transplant centers (NCCHD, KUH, KUHP, ATAK, and EMC), and identified all MMA patients (n = 38) undergoing LDLT in the past two decades. Our primary outcome was patient survival, and secondary outcomes included death-censored graft survival and posttransplant complications. RESULTS: The overall 10-year patient survival and death-censored graft survival rates were 92% and 97%, respectively. Patients who underwent LDLT within 2 years of MMA onset showed significantly higher 10-year patient survival compared to those with an interval more than 2 years (100% vs. 81%, p = 0.038), although the death-censored graft survival were not statistically different (100% vs. 93%, p = 0.22). Over the long-term follow-up, 14 patients (37%) experienced intellectual disability, while two patients developed neurological complications, three patients experienced renal dysfunction, and one patient had biliary anastomotic stricture. The MMA level significantly decreased from 2218.5 mmol/L preoperative to 307.5 mmol/L postoperative (p = 0.038). CONCLUSIONS: LDLT achieves favorable long-term patient and graft survival outcomes for MMA patients. While not resulting in complete cure, our findings support the consideration of early LDLT within 2 years of disease onset. This approach holds the potential to mitigate recurrent metabolic decompensations, and preserve the long-term renal function.

Safety and long-term outcomes of early liver transplantation for pediatric methylmalonic acidemia patients.

BACKGROUND: LT is a treatment option for MMA patients, but renal function impairment is one of the long-term concerns. The aim of this study was to evaluate the outcomes of early LT in these patients. METHODS: A total of 11 MMA mut-type patients (including 10 mut0 cases and 1 mut-case) who received LT in our institute were reviewed. Their metabolic profiles were compared between the pre/post-transplant periods. Their immunosuppressant and renal function changes after transplantation were assessed. RESULTS: After a mean follow-up of 97.5 ± 38.4 months, there were two deaths, and the actual survival rate was 81.8%. Their metabolic profiles had improved (mean blood ammonia level 366.8 ± 105.5 vs. 53.1 ± 17.4 µg/dl, p < .001; C3/C2 ratio 2.68 ± 0.87 vs. 0.73 ± 0.22, p = .003; mean urine MMA level 920.5 ± 376.6 vs. 196.2 ± 85.4, p = .067), and hospital stays were decreased (78.8 ± 74.5 vs. 7.4 ± 7.0 days/year, p = .009) after transplantation. The mean age at transplant was 1.81 ± 2.02 years old, and nine of these patients received LT before the age of 1.5 years old (early LT). Under prospective immunosuppressant dose reduction, three of these early LT patients discontinued the drug and were sustained for more than 5 years. Most of the patients had a preserved renal function, and no patient is currently on dialysis. CONCLUSIONS: In addition to the improvement in the metabolic parameters, early LT in MMA patients may allow for a dose reduction of the immunosuppressant, and the patient's renal function could be preserved in the long term.

Long-term outcome of methylmalonic aciduria after kidney, liver, or combined liver-kidney transplantation: The French experience.

Organ transplantation is discussed in methylmalonic aciduria (MMA) for renal failure, and poor quality of life and neurological outcome. We retrospectively evaluated 23 French MMA patients after kidney (KT), liver-kidney (LKT), and liver transplantation (LT). Two patients died, one after LKT, one of hepatoblastoma after KT. One graft was lost early after KT. Of 18 evaluable patients, 12 previously on dialysis, 8 underwent KT (mean 12.5 years), 8 LKT (mean 7 years), and 2 LT (7 and 2.5 years). At a median follow-up of 7.3 (KT), 2.3 (LKT), and 1.0 years (LT), no metabolic decompensation occurred except in 1 KT. Plasma and urine MMA levels dramatically decreased, more after LKT. Protein intake was increased more significantly after LKT than KT. Enteral nutrition was stopped in 7/8 LKT, 1/8 KT. Early complications were frequent after LKT. Neurological disorders occurred in four LKT, reversible in one. Five years after KT, four patients had renal failure. The metabolic outcomes were much better after LKT than KT. LKT in MMA is difficult but improves the quality of life. KT will be rarely indicated. We need more long-term data to indicate early LT, in the hope to delay renal failure and prevent neurodevelopmental complications.

Differential Intraoperative Effect of Liver Transplant in Different Inborn Errors of Metabolism.

Liver transplant (LT) is a therapeutic option for a growing number of inborn errors of metabolism (IEM), including some disorders not confined to the liver. Clinical advantages of LT in maple syrup urine disease (MSUD), methylmalonic acidemia (MMA), and argininosuccinic aciduria (ASA) have been reported. However, no information on the early metabolic effect of LT after portal reperfusion is available in these disorders. Here we describe the intraoperative differential metabolic outcome of LT in MSUD, MMA, and ASA. In these IEM, LT promptly cleared toxic metabolites to safe concentrations. In MSUD, leucine concentration reached physiological concentration within 12 hours after portal reperfusion. In MMA and ASA, LT allowed faster clearance of methylmalonate and argininosuccinate, respectively, both dropping by ∼90% within the first hour after portal reperfusion. The early biochemical benefits of LT in MSUD, MMA, and ASA demonstrate its immediate effectiveness in protecting patients from intercurrent metabolic decompensations.

Successful liver transplantation using a whole liver graft with gallbladder agenesis: First report in pediatric liver transplantation.

INTRODUCTION: Gallbladder agenesis (GA) is a rare congenital condition, occurring in approximately 40/100.000. It is likely due to an embryologic mishap in the development of the gallbladder bud and can be associated with other congenital variations in biliary anatomy. However, the liver likely suffers no functional impairment and can be safely used for transplantation. To the best of our knowledge, this is the first case report describing a pediatric liver transplantation (PLT) using a graft with GA. CASE REPORT: A 10-year-old boy with methylmalonic aciduria underwent isolated liver transplant with a deceased graft from a donor with no relevant medical or surgical history and normal laboratory tests. During the back-table liver preparation procedure, no evidence of gallbladder was found, raising the possibility of a GA, confirmed by intraoperative cholangiography. The liver transplantation procedure was uneventful despite the particularly rare combination of biliary tree anatomic distribution found in the cholangiography. At 1 year of follow-up, there were no clinical, laboratory, or imagological signs of bile leaks or anastomotic site stricture. DISCUSSION: The present report highlights the importance of the accurate knowledge of the vasculobiliary anatomic variation, particularly in extremely rare cases, such as GA, and in complex hepatobiliary procedures, such as PLT. In our opinion, grafts with GA should not be discarded for transplantation.

Kidney disease and organ transplantation in methylmalonic acidaemia.

OBJECTIVES: MMA is associated with chronic tubulointerstitial nephritis and a progressive decline in GFR. Optimal management of these children is uncertain. Our objectives were to document the pre-, peri-, and post-transplant course of all children with MMA who underwent liver or combined liver-kidney transplant in our centers. DESIGN AND METHODS: Retrospective chart review of all cases of MMA who underwent organ transplantation over the last 10 years. RESULTS: Five children with MMA underwent liver transplant (4/5) and combined liver-kidney transplant (1/5). Three were Mut0 and two had a cobalamin B disorder. Four of five were transplanted between ages 3 and 5 years. Renal dysfunction prior to transplant was seen in 2/5 patients. Post-transplant (one liver transplant and one combined transplant) renal function improved slightly when using creatinine-based GFR formula. We noticed in 2 patients a big discrepancy between creatinine- and cystatin C-based GFR calculations. One patient with no renal disease developed renal failure post-liver transplantation. Serum MMA levels have decreased in all to <300 µmol/L. Four patients remain on low protein diet, carnitine, coenzyme Q, and vitamin E post-transplant. CONCLUSIONS: MMA is a complex metabolic disorder. Renal disease can continue to progress post-liver transplant and close follow-up is warranted. More research is needed to clarify best screening GFR method in patients with MMA. Whether liver transplant alone, continued protein restriction, or the addition of antioxidants post-transplant can halt the progression of renal disease remains unclear.

Liver Transplantation for Propionic Acidemia and Methylmalonic Acidemia: Perioperative Management and Clinical Outcomes.

Propionic acidemia (PA) and methylmalonic acidemia (MMA) comprise the most common organic acidemias and account for profound morbidity in affected individuals. Although liver transplantation (LT) has emerged as a bulk enzyme-replacement strategy to stabilize metabolically fragile patients, it is not a metabolic cure because patients remain at risk for disease-related complications. We retrospectively studied LT and/or liver-kidney transplant in 9 patients with PA or MMA with additional focus on the optimization of metabolic control and management in the perioperative period. Metabolic crises were common before transplant. By implementing a strategy of carbohydrate minimization with gradual but early lipid and protein introduction, lactate levels significantly improved over the perioperative period (P < 0.001). Posttransplant metabolic improvement is demonstrated by improvements in serum glycine levels (for PA; P < 0.001 × 10-14 ), methylmalonic acid levels (for MMA; P < 0.001), and ammonia levels (for PA and MMA; P < 0.001). Dietary restriction remained after transplant. However, no further metabolic crises have occurred. Other disease-specific comorbidities such as renal dysfunction and cardiomyopathy stabilized and improved. In conclusion, transplant can provide a strategy for altering the natural history of PA and MMA providing stability to a rare but metabolically brittle population. Nutritional management is critical to optimize patient outcomes.

Shunt surgery for early-onset severe hydrocephalus in methylmalonic acidemia: report on two cases and review of the literature.

OBJECT: Methylmalonic acidemia (MMA) with early-onset severe hydrocephalus is rare. In this paper, we described two cases of MMA with hydrocephalus and review the literature to elucidate the clinical features of the disease, treatment options, and follow-up results. METHODS: The PubMed and Embase databases were searched for clinical reports on MMA with severe hydrocephalus, and two unreported cases were presented to illustrate the clinical spectrum. RESULTS: Six cases of MMA with severe hydrocephalus were observed in the previous literature. Our two patients with severe hydrocephalus but not bulging fontanelle received a ventriculo-peritoneal shunt, and intracranial hypertension was confirmed in both cases during the operation. These patients' clinical symptoms significantly improved after the operation. CONCLUSIONS: Intracranial hypertension can exist in early-onset severe hydrocephalus in MMA, even if the bulging anterior fontanelle is not apparent. These patients could benefit from a ventriculo-peritoneal shunt.

Recent advances in liver transplantation for metabolic disease.

The indications and outcomes of liver transplantation for metabolic disease have been reviewed recently and this short review concentrates on recent developments and advances. Recently recognized metabolic causes of acute liver failure are reviewed and their implications for transplantation discussed. Newly described indications for liver transplantation in systemic metabolic diseases are described and an update is given on the role of auxiliary and domino liver transplantation.

Severe Acute Subdural Hemorrhages in a Patient with Glutaric Acidemia Type 1 under Recommended Treatment.

Glutaric acidemia type 1 is a rare autosomal recessive disease caused by a deficiency of glutaryl-CoA dehydrogenase. Previous studies have reported subdural hemorrhage in untreated patients with glutaric acidemia type 1. However, there is only one report of severe acute subdural hemorrhage after minor head trauma in a patient with glutaric acidemia type 1 under guideline-recommended treatment. We report a second case of life-threatening severe acute subdural hemorrhage after a minor head trauma in a patient with glutaric acidemia type 1. This patient was previously diagnosed by newborn screening, and treatment began at 25 days of age. Early diagnosis and guideline-recommended treatment produce better outcomes for patients with glutaric acidemia type 1, although the risk of subdural hemorrhage remains.

Methylmalonic and propionic acidemias: clinical management update.

PURPOSE OF REVIEW: Recent clinical studies and management guidelines for the treatment of the organic acidopathies methylmalonic acidemia (MMA) and propionic acidemia address the scope of interventions to maximize health and quality of life. Unfortunately, these disorders continue to cause significant morbidity and mortality due to acute and chronic systemic and end-organ injury. RECENT FINDINGS: Dietary management with medical foods has been a mainstay of therapy for decades, yet well controlled patients can manifest growth, development, cardiac, ophthalmological, renal, and neurological complications. Patients with organic acidopathies suffer metabolic brain injury that targets specific regions of the basal ganglia in a distinctive pattern, and these injuries may occur even with optimal management during metabolic stress. Liver transplantation has improved quality of life and metabolic stability, yet transplantation in this population does not entirely prevent brain injury or the development of optic neuropathy and cardiac disease. SUMMARY: Management guidelines should identify necessary screening for patients with methylmalonic acidemia and propionic acidemia, and improve anticipatory management of progressive end-organ disease. Liver transplantation improves overall metabolic control, but injury to nonregenerative tissues may not be mitigated. Continued use of medical foods in these patients requires prospective studies to demonstrate evidence of benefit in a controlled manner.

Posterior reversible encephalopathy syndrome after kidney transplantation in pediatric recipients: Two cases.

PRES is a neuro-clinical and radiological syndrome that can result as a consequence of several different conditions including hypertension, fluid overload, and immunosuppressive treatment. Herein, we report two children who received kidney and combined liver-kidney transplantation as treatment for renal hypodysplasia associated with bilateral vesico-ureteral reflux and methylmalonic acidemia, respectively. Early after surgery (seven and 10 days), both patients presented with hypertension and seizures. The patients' immunosuppressive regimen included steroid and calcineurin inhibitors (tacrolimus and cyclosporine, respectively) and basiliximab and one with anti-IL2 receptor. In both cases, the imaging strongly supported the diagnosis of PRES. In details, the CT scan showed hypodensities in the posterior areas of the brain, and brain MRI demonstrated parieto-occipital alterations indicative of vasogenic edema. Treatment with calcineurin inhibitors was temporally discontinued and restarted at lower dosage; arterial hypertension was treated with Ca-channel blockers. Both children fully recovered without any neurological sequels. In conclusion, in children undergoing solid organ transplantation, who develop neurological symptoms PRES, should be carefully considered in the differential diagnosis and once the diagnosis is ruled in, we recommend strict arterial blood pressure control and adjustment or withholding of calcineurin inhibitor therapy should be considered based upon blood levels.

Perioperative management of living-donor liver transplantation for methylmalonic acidemia.

Methymalonic acidemia (MMA) is a hereditary metabolic disorder characterized by a defect of the methylmalonyl-CoA mutase that breaks down propionate. The efficacy of liver transplantation for MMA was recently reported. However, the anesthetic management of liver transplant for MMA is not clear. The aim of this article is to describe an anesthetic management algorithm of liver transplant for MMA by reviewing our cases of liver transplant for MMA. Fourteen patients received a liver transplant; three cases showed metabolic decompensation during the transplant and two of the patients died. In the two patients who expired, propofol was used for maintenance anesthesia and preoperative continuous hemodiafiltration was used to reduce plasma methylmalonic acid level in one case, and to control severe metabolic decompensation before transplant for the other case. Their renal function was also worse than others and they were already experiencing metabolic decompensation before induction of anesthesia. Based on our experience of these 14 cases, we have established an anesthetic algorithm for patients with MMA undergoing liver transplant or other procedures. There are three important points in our experience: propofol should be avoided, dextrose infusion therapy should be continued to prevent metabolic decompensation, and liver transplant or other procedures should be avoided during metabolic decompensation.

Liver transplantation for treatment of severe S-adenosylhomocysteine hydrolase deficiency.

A child with severe S-adenosylhomocysteine hydrolase (AHCY) deficiency (AHCY c.428A>G, p.Tyr143Cys; c.982T>G, p.Tyr328Asp) presented at 8 months of age with growth failure, microcephaly, global developmental delay, myopathy, hepatopathy, and factor VII deficiency. Plasma methionine, S-adenosylmethionine (AdoMet), and S-adenosylhomocysteine (AdoHcy) were markedly elevated and the molar concentration ratio of AdoMet:AdoHcy, believed to regulate a myriad of methyltransferase reactions, was 15% of the control mean. Dietary therapy failed to normalize biochemical markers or alter the AdoMet to AdoHcy molar concentration ratio. At 40 months of age, the proband received a liver segment from a healthy, unrelated living donor. Mean AdoHcy decreased 96% and the AdoMet:AdoHcy concentration ratio improved from 0.52±0.19 to 1.48±0.79 mol:mol (control 4.10±2.11 mol:mol). Blood methionine and AdoMet were normal and stable during 6 months of follow-up on an unrestricted diet. Average calculated tissue methyltransferase activity increased from 43±26% to 60±22%, accompanied by signs of increased transmethylation in vivo. Factor VII activity increased from 12% to 100%. During 6 postoperative months, head growth accelerated 4-fold and the patient made promising gains in gross motor, language, and social skills.

Treatment of methylmalonic acidemia by liver or combined liver-kidney transplantation.

OBJECTIVE: To assess biochemical, surgical, and long-term outcomes of liver (LT) or liver-kidney transplantation (LKT) for severe, early-onset methylmalonic acidemia/acid (MMA). STUDY DESIGN: A retrospective chart review (December 1997 to May 2012) of patients with MMA who underwent LT or LKT at Lucile Packard Children's Hospital at Stanford. RESULTS: Fourteen patients underwent LT (n = 6) or LKT (n = 8) at mean age 8.2 years (range 0.8-20.7). Eleven (79%) were diagnosed during the neonatal period, including 6 by newborn screening. All underwent deceased donor transplantation; 12 (86%) received a whole liver graft. Postoperative survival was 100%. At a mean follow-up of 3.25 ± 4.2 years, patient survival was 100%, liver allograft survival 93%, and kidney allograft survival 100%. One patient underwent liver re-transplantation because of hepatic artery thrombosis. After transplantation, there were no episodes of hyperammonemia, acidosis, or metabolic decompensation. The mean serum MMA at the time of transplantation was 1648 ± 1492 µmol/L (normal <0.3, range 99-4420). By 3 days, post-transplantation levels fell on average by 87% (mean 210 ± 154 µmol/L), and at 4 months, they were 83% below pre-transplantation levels (mean 305 ± 108 µmol/L). Developmental delay was present in 12 patients (86%) before transplantation. All patients maintained neurodevelopmental abilities or exhibited improvements in motor skills, learning abilities, and social functioning. CONCLUSIONS: LT or LKT for MMA eradicates episodes of hyperammonemia, results in excellent long-term survival, and suggests stabilization of neurocognitive development. Long-term follow-up is underway to evaluate whether patients who undergo early LT need kidney transplantation later in life.

Anesthesia and organic aciduria: is the use of lactated Ringer's solution absolutely contraindicated?

BACKGROUND: Organic acidurias (OAs) are rare inborn errors of metabolism that can present with various neurologic manifestations, propensity for acute metabolic decompensation with anion-gap metabolic acidosis, developmental delay, poor feeding, and failure to thrive. OBJECTIVE: In this case series, we outline the anesthetic management and perioperative outcomes of OA patients. METHODS: We reviewed demographic characteristics, comorbidities, and perioperative course of patients with four different OAs who underwent anesthetic care at our institution between January 1, 2000, and December 31, 2013. RESULTS: Eleven patients with OA underwent 19 anesthetic procedures, of which 13 were <2 h in duration and seven were outpatient procedures. One patient with methylmalonic acidemia developed metabolic acidosis during a 10-h procedure with substantial blood loss but lacked evidence that this acidosis could be attributed to his underlying metabolic disease. The patients who received hydration with lactated Ringer's solution and/or nitrous oxide anesthetic had a perioperative course free of metabolic complication. Two patients died within 30 days of surgery from causes likely to be unrelated to anesthetic exposure. CONCLUSIONS: Our patients with various forms of metabolically compensated OAs tolerated anesthetics for surgical procedures without metabolic decompensation, even when lactated Ringer's solution was used for hydration. Measures to prevent protein catabolism and intraoperative events that may precipitate metabolic acidosis, in addition to close monitoring of acid-base status during more extensive procedures, must be part of perioperative treatment of these patients.

Fetal progenitor cell transplantation treats methylmalonic aciduria in a mouse model.

Methylmalonic aciduria is a rare disorder caused by an inborn error of organic acid metabolism. Current treatment options are limited and generally focus on disease management. We aimed to investigate the use of fetal progenitor cells to treat this disorder using a mouse model with an intermediate form of methylmalonic aciduria. Fetal liver cells were isolated from healthy fetuses at embryonic day 15-17 and intravenously transplanted into sub-lethally irradiated mice. Liver donor cell engraftment was determined by PCR. Disease correction was monitored by urine and blood methylmalonic acid concentration and weight change. Initial studies indicated that pre-transplantation sub-lethal irradiation followed by transplantation with 5 million cells were suitable. We found that a double dose of 5 million cells (1 week apart) provided a more effective treatment. Donor cell liver engraftment of up to 5% was measured. Disease correction, as defined by a decrease in blood methylmalonic acid concentration, was effected in methylmalonic acid mice transplanted with a double dose of cells and who showed donor cell liver engraftment. Mean plasma methylmalonic acid concentration decreased from 810 ± 156 (sham transplanted) to 338 ± 157 µmol/L (double dose of 5 million cells) while mean blood C3 carnitine concentration decreased from 20.5 ± 4 (sham transplanted) to 5.3 ± 1.9 µmol/L (double dose of 5 million cells). In conclusion, higher levels of engraftment may be required for greater disease correction; however these studies show promising results for cell transplantation biochemical correction of a metabolic disorder.