Safety, efficacy, and timing of transplantation(s) in propionic and methylmalonic aciduria

Abstract

Propionic (PA) and methylmalonic aciduria (MMA) share many clinical similarities, which include the risk of acute metabolic encephalopathies, and some long-term complications, such as optic neuropathy, pancreatic involvement, developmental disability, and similar management approaches, but they also represent distinct clinical and biochemical entities. In the severe forms of PA and MMA, most long-term complications cannot be prevented with conventional clinical management. Organ transplantation represents a form of partial enzyme replacement to improve the long-term outlook for these disorders. There is evidence that early liver transplant in both disorders greatly improves metabolic stability and reduces the risk of long-term complications. For MMA, early liver transplant reduces methylmalonic acid levels which in turns reduces its effects on kidneys, and therefore slows progression of chronic kidney disease. However, established organ damage cannot be reversed. For patients with MMA who present with chronic kidney disease, consideration should be given for combined liver and kidney transplants. Transplantation in PA and MMA carries a high risk of complications and requires highly specialised pre-operative and peri-operative management. Involvement of a multidisciplinary team is essential and should include metabolic team, nephrologist, hepatologist, hepatobiliary and renal transplant surgeons, anaesthesiologists, cardiologists, intensive care team, dieticians and specialist nurses. These patients require life-long multidisciplinary follow-up. There is increasing evidence in the literature on excellent short to medium-term patient and allograft survival following transplantation when patients are managed by a multidisciplinary team in a specialist centre. Improved early diagnosis and reductions in transplant-related mortality and morbidity have allowed early transplantation to be used electively to further improve the outcome.

Collaborative evaluation study on 18 candidate diseases for newborn screening in 1.77 million samples

“…Organ affections, most notably cardiomyopathy and chronic kidney disease are frequent. However, organ transplantation, particularly liver transplantation, is increasingly being considered not only in patients with poor metabolic control or to treat the long‐term complications of the diseases, but also as a pre‐emptive measure in early‐diagnosed patients 55–57 …”

Current status and future directions of liver transplantation for metabolic liver disease in children

“…Well-designed fasting and procedural protocols should be adopted in the pre-and perioperative liver transplantation period to prevent intra-procedural decompensation, and use of renal sparing immunosuppression protocols. 16,93 Perioperative vascular and long-term graft complications may be more common in this group. 11,17,89 However, long-term survival is generally favorable at over 80%.…”

“…Surgical team experience is known to be an important prognostic factor in children undergoing liver transplantation 14,15 . Care of children with inborn errors of metabolism undergoing OLT is further optimized with multidisciplinary design of a patient's individualized peri and postoperative protocol, with input from metabolic and specialists relevant to a child's extra‐hepatic comorbidities 16,17 . Transplantation is ideally avoided in children during active metabolic crises.…”

“…Decision to proceed with liver transplantation is highly individualized based on the child's dynamic risk-benefit profile, their family unit, and their treating multidisciplinary team. 16,19 Also to be considered is the chance of future treatments, such as gene therapies, emerging in the medium term.…”

Organic acidurias: Ingredients for precision medicine

“…Next, Head et al 7 outline how precise knowledge about pathophysiology in methylmalonic aciduria has enabled the development of targeted therapy. Since conservative therapy does not prevent disease progression and the manifestation of irreversible organ dysfunction in individuals with methylmalonic and propionic aciduria, two articles presented by Martinelli et al 8 and Chakrapani et al 9 focus on safety, efficacy and timing of solid organ transplantation as well as neurological outcome following transplantation. In the final articles, the themed issue explores the importance of evidence-based guidelines for individuals with rare disorders such as OADs.…”