Combined liver-kidney transplantation in methylmalonic acidemia

doi:10.1016/S0022-3476(98)70407-X

The Journal of Pediatrics

Volume 132, Issue 6, June 1998, Pages 1043-1044

https://doi.org/10.1016/S0022-3476(98)70407-X Get rights and content

Abstract

A 13-year-old boy with non-B12-responsive methylmalonic acidemia (MMA) had chronic renal failure. Hemodialysis led to symptomatic and biochemical improvement. He subsequently received a combined liver-kidney transplant. After 16 months of follow-up he has a normal lifestyle and a marked reduction in plasma and urine methylmalonate. (J Pediatr 1998;132:1043-4.)

Section snippets

Case History

A male infant was born by cesarean section at 39 weeks gestation because of intrauterine growth retardation. The birth weight was 2.72 kg (3rd percentile). He failed to thrive and had several hospital admissions because of vomiting and impaired consciousness. The diagnosis of MMA was made after urine organic acid analysis was performed at 9 months of age; methylmalonyl Coenzyme A mutase activity was absent in cultured fibroblasts. There was no response to vitamin B12 supplements.

Over the next

Discussion

Chronic renal failure is a common long-term complication in non-B12-responsive MMA, affecting between 20% and 60% of adolescents with the disorder.3, 5 There are no reports of the management of end-stage renal failure in MMA. In this case hemodialysis led to a marked symptomatic improvement. We speculated that (1) a kidney transplant alone might have a reduced survival because of continued damage from toxic metabolites, (2) a liver transplant would provide a new source of methylmalonyl Coenzyme

References (6)

D Marsden et al.
Anabolic effect of human growth hormone: management of inherited disorders of catabolic pathways
Biochem Med Metab Biol
(1994)
WA Fenton et al.
Disorders of propionate and methylmalonate metabolism
CT D’Angio et al.
Renal tubular dysfunction in methylmalonic acidaemia
Eur J Pediatr
(1991)

There are more references available in the full text version of this article.

Cited by (82)

Solid organ transplantation in methylmalonic acidemia and propionic acidemia: A points to consider statement of the American College of Medical Genetics and Genomics (ACMG)
2023, Genetics in Medicine
Systemic gene therapy for methylmalonic acidemia using the novel adeno-associated viral vector 44.9
2022, Molecular Therapy Methods and Clinical Development
Methylmalonic acidemia (MMA) is a severe and potentially lethal autosomal recessive inborn error of metabolism most frequently caused by mutations in the methylmalonyl-CoA mutase (MMUT) gene. Proof-of-concept adeno-associated virus (AAV) gene therapy studies using mouse models of MMA have demonstrated promise for this therapeutic approach but translation to the clinic could be limited by preexisting capsid immunity and vector potency. Here we explore the efficacy of a novel clade E capsid, 44.9, as a serotype for systemic AAV gene therapy for MMA. An anti-AAV44.9 neutralizing antibody (NAb) survey in adult volunteers (n = 19) and a large cohort of MMA patients (n = 48) revealed a seroprevalence rate of ∼26% and 13%, respectively. The efficacy of AAV44.9 gene delivery was examined in two murine models of MMA, representing neonatal lethal and juvenile phenotypes of MMA. Systemic delivery of the AAV44.9-Mmut vector prevented lethality and lowered disease-related metabolites in MMA mice. Tissue biodistribution and transgene expression studies in treated MMA mice showed that AAV44.9 was efficient at transducing the liver and heart. In summary, we establish that AAV44.9 exhibits a low prevalence of preexisting NAb in humans, is highly efficacious in the treatment of clinically severe MMA mouse models and is therefore a promising vector for clinical translation.
In vivo genome editing at the albumin locus to treat methylmalonic acidemia
2021, Molecular Therapy Methods and Clinical Development
Citation Excerpt :
However, even with vigilant monitoring, MMA is associated with increased morbidity and mortality due to acute and chronic multi-systemic disease manifestations. The guarded prognosis of MMA has led to the use of elective liver transplantation increasingly at younger ages, to improve survival and delay long-term disease complications.5–8 Successful liver transplant eliminates the propensity toward metabolic instability characteristic of MMA and related organic acidemias, but carries the need for lifelong immune suppression and the risk of developing transplant-related complications, including post-transplant lymphoproliferative disorder.9
Methylmalonic acidemia (MMA) is a metabolic disorder most commonly caused by mutations in the methylmalonyl-CoA mutase (MMUT) gene. Although adeno-associated viral (AAV) gene therapy has been effective at correcting the disease phenotype in MMA mouse models, clinical translation may be impaired by loss of episomal transgene expression and magnified by the need to treat patients early in life. To achieve permanent correction, we developed a dual AAV strategy to express a codon-optimized MMUT transgene from Alb and tested various CRISPR-Cas9 genome-editing vectors in newly developed knockin mouse models of MMA. For one target site in intron 1 of Alb, we designed rescue cassettes expressing MMUT behind a 2A-peptide or an internal ribosomal entry site sequence. A second guide RNA targeted the initiator codon, and the donor cassette encompassed the proximal albumin promoter in the 5′ homology arm. Although all editing approaches were therapeutic, targeting the start codon of albumin allowed the use of a donor cassette that also functioned as an episome and after homologous recombination, even without the expression of Cas9, as an integrant. Targeting the albumin locus using these strategies would be effective for other metabolic disorders where early treatment and permanent long-term correction are needed.
Safety and efficacy of liver transplantation for methylmalonic acidemia: A systematic review and meta-analysis
2021, Transplantation Reviews
Citation Excerpt :
After removal of duplicates and initial screening, 47 papers were assessed for eligibility in full text and 2 were further excluded for full text not found, 6 for having insufficient data, 1 with another intervention, and 6 for having duplicate study populations (Fig. 2). Ultimately, 32 studies [15, 21–51] met all the inclusion criteria and were included in the systematic review. The main characteristics of the studies are summarized in Table 2.
Background-objectives: Liver transplantation (LT) and combined liver and kidney transplantation (CLKT) have been proposed as enzyme replacement therapies for methylmalonic aciduria (MMA). We aimed to synthesize the available evidence on their safety and efficacy.
Methods: Medline, Embase and Cochrane library were searched to identify studies that reported post-LT/CLKT clinical outcomes of MMA from their inception to February 1, 2020. The pooled rate was calculated using random-effects model with Freeman–Tukey double arcsine transformation method.
Results: Thirty-two studies involving 109 patients were included. The pooled estimate rates were 99.9% (95% CI 95.3–100.0) for patient survival, 98.5% (95% CI 91.5–100.0) for graft survival after LT/CLKT. The combined incidence of biliary, vascular complications and rejection were 0.2% (95% CI 0.0–6.6), 7.7% (95% CI 0.1–22.1) and 18.4% (95% CI 4.6–36.3), respectively. The pooled estimate rates were 100.0% (95% CI 99.4–100.0) for metabolic eradication, 61.5% (95% CI: 33.4–87.0) for normalization of kidney function. Chronic kidney disease (CKD) remission is more promising after CLKT (70.3% VS 37.6% in LT group). The pooled estimate rates for neurodevelopmental status improvement and protein intake liberalization were 52.0% (95% CI 2.8–98.8) and 36.3% (95% CI 6.3–71.7), respectively.
Conclusions: This first quantitative systematic review confirms favorable survival outcomes and partially improved disease-related complications in transplanted MMA patients, although some results should be interpreted with caution. Future studies with detailed description of long-term outcomes and consensus on neurodevelopmental evaluation method can help provide a more accurate picture.
Systemic Messenger RNA Therapy as a Treatment for Methylmalonic Acidemia
2017, Cell Reports
Isolated methylmalonic acidemia/aciduria (MMA) is a devastating metabolic disorder with poor outcomes despite current medical treatments. Like other mitochondrial enzymopathies, enzyme replacement therapy (ERT) is not available, and although promising, AAV gene therapy can be limited by pre-existing immunity and has been associated with genotoxicity in mice. To develop a new class of therapy for MMA, we generated a 5-methoxyU-modified codon-optimized mRNA encoding human methylmalonyl-CoA mutase (hMUT), the enzyme most frequently mutated in MMA, and encapsulated it into biodegradable lipid nanoparticles (LNPs). Intravenous (i.v.) administration of hMUT mRNA in two different mouse models of MMA resulted in a 75%–85% reduction in plasma methylmalonic acid and was associated with increased hMUT protein expression and activity in liver. Repeat dosing of hMUT mRNA reduced circulating metabolites and dramatically improved survival and weight gain. Additionally, repeat i.v. dosing did not increase markers of liver toxicity or inflammation in heterozygote MMA mice.
Liver or combined liver-kidney transplantation for patients with isolated methylmalonic acidemia: Who and when?
2015, Journal of Pediatrics

View all citing articles on Scopus

^☆: From the Renal Unit, Great Ormond Street Hospital for Children, London; the Department of Dietetics, Great Ormond Street Hospital for Children, London; Liver Transplantation and Hepatobiliary Medicine, Royal Free Hospital, London; the Department of Surgery, Royal Free Hospital, London; and the Metabolic Unit, Institute of Child Health, London.

^☆☆: Reprint requests: William G. van't Hoff, BSc, MD, MRCP, Consultant Paediatric Nephrologist, Great Ormond Street Hospital for Children, Great Ormond St., London, WC1N 3JH, U.K.

^★: 9/22/87263

View full text

Combined liver-kidney transplantation in methylmalonic acidemia☆,☆☆,★

Abstract

Section snippets

Case History

Discussion

Biochem Med Metab Biol

Disorders of propionate and methylmalonate metabolism

Renal tubular dysfunction in methylmalonic acidaemia

Eur J Pediatr