Progressive neurologic disability in methylmalonic acidemia despite transplantation of the liver

Nyhan, William L.; Gargus, J. Jay; Boyle, Karen; Selby, Rick; Koch, Richard

doi:10.1007/s00431-002-0970-4

Cited by 94 publications

(89 citation statements)

References 18 publications

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“…The risk of infection with encapsulated organisms was thought to contraindicate splenectomy. Although, CKLT in our patient was not curative and had a post-operative clinical course similar to that described in previous reports [19,23,32,37], we conclude that the patient has benefited from an improved quality of life based on the dramatic decrease in time spent in hospital or in chronic care facilities during recovery from decompensations. Besides the single episode of iatrogenic decompensation, he has not been hospitalized for metabolic acidosis since the transplantation, reflecting the beneficial effect of the CKLT.…”

Section: Discussionsupporting

confidence: 78%

“…Of the four patients with neurologic disability (Table 2), two were confirmed mut0, while the remaining two cases were undefined [19,23,32,37]. In our case, the initial neurologic presentation of tremors, seizures, altered mental status and fever was consistent with tacrolimus toxicity.…”

Section: Discussionmentioning

confidence: 56%

“…Neurologic deterioration post-transplant in methylmalonic aciduria is well documented [17,19,23,32,37]. Of the four patients with neurologic disability (Table 2), two were confirmed mut0, while the remaining two cases were undefined [19,23,32,37].…”

Section: Discussionmentioning

confidence: 99%

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Combined liver–kidney transplant for the management of methylmalonic aciduria: A case report and review of the literature

Guire

Lim-Melia

Diaz

et al. 2008

Molecular Genetics and Metabolism

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Over 27 cases of liver transplant, kidney transplant and combined liver-kidney transplant have been reported for the treatment of methylmalonic aciduria. We describe a case of a 5-year-old boy who underwent combined liver-kidney transplant (CLKT) for phenotypic mut0 disease. His history was notable for more than 30 hospitalizations for severe acidosis, metabolic strokes, liver disease, pancreatic disease, chronic renal insufficiency with interstitial nephritis, and decreased quality of life. Post-CLKT, there was a marked reduction in serum (80%) and urine MMA levels (90%) as well as a cessation of metabolic decompensations. Neurologic deterioration continued post-CKLT manifested as a cerebellar stroke. The clinical details and therapeutic implications of solid organ transplant for methylmalonic aciduria are discussed.

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Section: Discussionsupporting

confidence: 78%

Section: Discussionmentioning

confidence: 56%

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Combined liver–kidney transplant for the management of methylmalonic aciduria: A case report and review of the literature

Guire

Lim-Melia

Diaz

et al. 2008

Molecular Genetics and Metabolism

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“…Patients with MMA who have been treated by orthotopic liver transplantation display metabolic stability yet develop extrahepatic disease, including ESRD, and, therefore, provide a clinical paradigm for the development of animal models to study the renal pathophysiology of MMA (8). In the present work, we have used transgenesis to create Mut −/− mice that express Mut in hepatocytes under the control of the mouse albumin promoter (Mut −/− ;Tg INS-Alb-Mut ).…”

mentioning

confidence: 99%

Targeting proximal tubule mitochondrial dysfunction attenuates the renal disease of methylmalonic acidemia

Manoli

Sysol

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

144

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Isolated methylmalonic acidemia (MMA), caused by deficiency of the mitochondrial enzyme methylmalonyl-CoA mutase (MUT), is often complicated by end stage renal disease that is resistant to conventional therapies, including liver transplantation. To establish a viable model of MMA renal disease, Mut was expressed in the liver of Mut −/− mice as a stable transgene under the control of an albumin (INS-Alb- Mut ) promoter. Mut −/− ;Tg INS-Alb- Mut mice, although completely rescued from neonatal lethality that was displayed by Mut −/− mice, manifested a decreased glomerular filtration rate (GFR), chronic tubulointerstitial nephritis and ultrastructural changes in the proximal tubule mitochondria associated with aberrant tubular function, as demonstrated by single-nephron GFR studies. Microarray analysis of Mut −/− ;Tg INS-Alb- Mut kidneys identified numerous biomarkers, including lipocalin-2, which was then used to monitor the response of the GFR to antioxidant therapy in the mouse model. Renal biopsies and biomarker analysis from a large and diverse patient cohort ( ClinicalTrials.gov identifier: NCT00078078) precisely replicated the findings in the animals, establishing Mut −/− ;Tg INS-Alb- Mut mice as a unique model of MMA renal disease. Our studies suggest proximal tubular mitochondrial dysfunction is a key pathogenic mechanism of MMA-associated kidney disease, identify lipocalin-2 as a biomarker of increased oxidative stress in the renal tubule, and demonstrate that antioxidants can attenuate the renal disease of MMA.

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“…Liver and combined liver/kidney transplantation can completely eliminate the inherent tendency toward ketoacidotic crises but the patients are not cured of the biochemical phenotype and can still exhibit progression of the disease after transplant. For example, one patient who received a liver transplant subsequently developed renal failure requiring transplantation [59] and another had a metabolic stroke 5 years after transplantation [60]. Transplant patients may enable the study of organ specific contributions to whole body MMA metabolism.…”

Section: Humanmentioning

confidence: 99%

Genetic and genomic systems to study methylmalonic acidemia

Chandler

Venditti

2005

Molecular Genetics and Metabolism

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Methylmalonic acidemia (MMAemia) is the biochemical hallmark of a group of genetic metabolic disorders that share a common defect in the ability to convert methylmalonyl-CoA into succinylCoA. This disorder is due to either a mutant methylmalonyl-CoA mutase apoenzyme or impaired synthesis of adenosylcobalamin, the cofactor for this enzyme. In this article, we will provide an overview of the pathways disrupted in these disorders, discuss the known metabolic blocks with a particular focus on molecular genetics, and review the use of selected model organisms to study features of methylmalonic acidemia.

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Progressive neurologic disability in methylmalonic acidemia despite transplantation of the liver

Abstract: experience with a 24-year-old patient treated with hepatic transplantation indicates that this procedure does not prevent progressive renal failure and neurologic dysfunction.

Cited by 94 publications

References 18 publications

Combined liver–kidney transplant for the management of methylmalonic aciduria: A case report and review of the literature

Combined liver–kidney transplant for the management of methylmalonic aciduria: A case report and review of the literature

Targeting proximal tubule mitochondrial dysfunction attenuates the renal disease of methylmalonic acidemia

Genetic and genomic systems to study methylmalonic acidemia

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