Positive Clinical, Neuropsychological, and Metabolic Impact of Liver Transplantation in Patients With Argininosuccinate Lyase Deficiency

Overview

Journal J Inherit Metab Dis

Publisher Wiley

Date 2025 Jan 8

PMID 39776112

Authors

Barbara Siri

Benedetta Greco

Diego Martinelli

Sara Cairoli

Alessia Guarnera

Daniela Longo

Antonio Napolitano

Chiara Parrillo

Lucilla Rava

Raffaele Simeoli

Gionata Spagnoletti

Roberta Taurisano

Silvio Veraldi

Andrea Pietrobattista

Marco Spada

Carlo Dionisi-Vici

Affiliations

Soon will be listed here.

Abstract

Liver transplantation (LTx) is increasingly used in Urea Cycle Defects (UCDs) to prevent recurrent hyperammonemia and related neurological irreversible injury. Among UCDs, argininosuccinate lyase deficiency (ASLD) has a more complex phenotype than other UCDs, with long-term neurocognitive deficits. Therefore, the role of LTx in ASLD is still debated. The impact of LTx on nine patients with early-onset ASLD was assessed through pre- and post-LTx clinical, neuropsychological, MRI and biochemical evaluations. After LTx, no episodes of metabolic decompensations were reported. Neuropsychological evaluations documented significant improvement in cognitive/developmental functioning especially in patients transplanted in early childhood. Improvements were also highlighted in daily living skills and emotional-behavioral problems, with a reduction in attention disturbances and somatic complaints. Movement disorders resolved after LTx in patient transplanted in early childhood. Any patients developed epilepsy with stability of EEG alterations after LTx. A positive effect of LTx on other disease-related outcomes such as growth, diet, medications, hospitalizations, and long-term ASLD-related complications was highlighted. The primary biomarker argininosuccinic acid dramatically reduced in plasma after transplantation with a decreasing trend in CSF at long-term follow-up. Moreover, health-related quality of life improved after LTx, especially when assessed through MetabQoL, a tool designed for intoxication diseases such as ASLD. In conclusion, our study showed a global beneficial impact of LTx in early-onset ASLD patients to avoid episodes of hyperammonemia, and improve neurocognitive outcome, adaptive and behavioral deficits when performed in early childhood with a dramatic benefit in terms of quality of life.

References

Greco B, Caviglia S, Martinelli D, Grimaldi Capitello T, Liccardo D, De Nictolis F . The impact of liver transplantation on health-related quality of life in (acute) intoxication-type inborn errors of metabolism. J Inherit Metab Dis. 2023; 46(5):906-915. DOI: 10.1002/jimd.12648. View

Spada M, Angelico R, Trapani S, Masiero L, Puoti F, Colledan M . Tailoring allocation policies and improving access to paediatric liver transplantation over a 16-year period. J Hepatol. 2023; 80(3):505-514. DOI: 10.1016/j.jhep.2023.11.031. View

Waisbren S, Gropman A, Batshaw M . Improving long term outcomes in urea cycle disorders-report from the Urea Cycle Disorders Consortium. J Inherit Metab Dis. 2016; 39(4):573-84. PMC: 4921309. DOI: 10.1007/s10545-016-9942-0. View

Morris Jr S . Arginine: beyond protein. Am J Clin Nutr. 2006; 83(2):508S-512S. DOI: 10.1093/ajcn/83.2.508S. View

Baruteau J, Diez-Fernandez C, Lerner S, Ranucci G, Gissen P, Dionisi-Vici C . Argininosuccinic aciduria: Recent pathophysiological insights and therapeutic prospects. J Inherit Metab Dis. 2019; 42(6):1147-1161. DOI: 10.1002/jimd.12047. View

Altassan R, Bubshait D, Imtiaz F, Rahbeeni Z . A retrospective biochemical, molecular, and neurocognitive review of Saudi patients with argininosuccinic aciduria. Eur J Med Genet. 2018; 61(6):307-311. DOI: 10.1016/j.ejmg.2018.01.007. View

Tuchman M, Lee B, Lichter-Konecki U, Summar M, Yudkoff M, Cederbaum S . Cross-sectional multicenter study of patients with urea cycle disorders in the United States. Mol Genet Metab. 2008; 94(4):397-402. PMC: 2640937. DOI: 10.1016/j.ymgme.2008.05.004. View

Newnham T, Hardikar W, Allen K, Wellard R, Hamilton C, Angus P . Liver transplantation for argininosuccinic aciduria: clinical, biochemical, and metabolic outcome. Liver Transpl. 2007; 14(1):41-5. DOI: 10.1002/lt.21297. View

Patterson C, Gold A, So S, Kahnami L, Dworsky-Fried M, Mamak E . Long-term neurodevelopmental outcomes following liver transplantation for metabolic disease-a single centre experience. J Inherit Metab Dis. 2024; 48(1):e12785. PMC: 11670442. DOI: 10.1002/jimd.12785. View

10.

Levin B, MacKay H, Oberholzer V . Argininosuccinic aciduria, an inborn error of amino acid metabolism. Arch Dis Child. 1961; 36:622-32. PMC: 2012826. DOI: 10.1136/adc.36.190.622. View

11.

Moser H, Efron M, Brown H, Diamond R, Neumann C . Argininosuccinic aciduria. Report of two new cases and demonstration of intermittent elevation of blood ammonia. Am J Med. 1967; 42(1):9-26. DOI: 10.1016/0002-9343(67)90003-4. View

12.

Martinelli D, Catesini G, Greco B, Guarnera A, Parrillo C, Maines E . Neurologic outcome following liver transplantation for methylmalonic aciduria. J Inherit Metab Dis. 2023; 46(3):450-465. DOI: 10.1002/jimd.12599. View

13.

Kolker S, Garcia-Cazorla A, Cazorla A, Valayannopoulos V, Lund A, Burlina A . The phenotypic spectrum of organic acidurias and urea cycle disorders. Part 1: the initial presentation. J Inherit Metab Dis. 2015; 38(6):1041-57. DOI: 10.1007/s10545-015-9839-3. View

14.

Gurung S, Karamched S, Perocheau D, Seunarine K, Baldwin T, Alrashidi H . The incidence of movement disorder increases with age and contrasts with subtle and limited neuroimaging abnormalities in argininosuccinic aciduria. J Inherit Metab Dis. 2023; 47(6):1213-1227. PMC: 11586606. DOI: 10.1002/jimd.12691. View

15.

Kido J, Matsumoto S, Ito T, Hirose S, Fukui K, Kojima-Ishii K . Physical, cognitive, and social status of patients with urea cycle disorders in Japan. Mol Genet Metab Rep. 2021; 27:100724. PMC: 7876628. DOI: 10.1016/j.ymgmr.2021.100724. View

16.

Eldredge J, Hardikar W . Current status and future directions of liver transplantation for metabolic liver disease in children. Pediatr Transplant. 2023; 28(1):e14625. DOI: 10.1111/petr.14625. View

17.

KEMP J, Woodbury D . Synthesis of urea-cycle intermediates from citrulline in brain. Biochim Biophys Acta. 1965; 111(1):23-31. DOI: 10.1016/0304-4165(65)90469-1. View

18.

Molema F, Martinelli D, Horster F, Kolker S, Tangeraas T, De Koning B . Liver and/or kidney transplantation in amino and organic acid-related inborn errors of metabolism: An overview on European data. J Inherit Metab Dis. 2020; 44(3):593-605. PMC: 8247334. DOI: 10.1002/jimd.12318. View

19.

Baruteau J, Perocheau D, Hanley J, Lorvellec M, Rocha-Ferreira E, Karda R . Argininosuccinic aciduria fosters neuronal nitrosative stress reversed by Asl gene transfer. Nat Commun. 2018; 9(1):3505. PMC: 6115417. DOI: 10.1038/s41467-018-05972-1. View

20.

Ozcay F, Baris Z, Moray G, Haberal N, Torgay A, Haberal M . Report of 3 Patients With Urea Cycle Defects Treated With Related Living-Donor Liver Transplant. Exp Clin Transplant. 2015; 13 Suppl 3:126-30. DOI: 10.6002/ect.tdtd2015.P69. View