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

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.

Keywords: Argininosuccinate lyase deficiency; argininosuccinic acid; developmental/intellectual quotient; liver transplantation; quality of life.

FIGURE 1

Timeline of hyperammonemic episodes (), liver transplantation and long‐term follow‐up in nine ASLD patients. Neonatal hyperammonemia () management required neonatal intensive care unit and 4/9 patients also required dialytic treatment (CVVH *).

FIGURE 2

Neuropsychological outcome in 9 ASLD patients pre‐ and post‐transplantation. (A) Neurodevelopmental and cognitive outcome; (B) Adaptive behaviour assessment; (C–D) Emotional‐behavioral outcome; (E–F) Health‐related quality of life though MetabQoL and relative subscales. Child Behavioural Checklist and MetabQoL values of each patient are expressed as the median and IQR.

FIGURE 3

(A–F): T2W brain MRI of Patient 2 pre‐LTx (A, B) and after 1 year from LTx (C, D) and at last follow‐up (E, F) at centrum semiovale (A, C, E) basal ganglia (B, D, F). The DWM/periventricular hyperintensities in the pre‐transplantation MRI (B) disappeared in the post‐transplantation MRI (D, F). T2 score improved from 1 to 0.

FIGURE 4

Effect of transplantation on Neurite orientation dispersion density imaging studies (NODDI). Patient 1 and Patient 5 were studied before and after transplantation. Bar plots show the difference in cortical thickness (CT, mm), neurite density index (NDI, Arbitrary unit—AU) and orientation dispersion index (ODI, AU) pre‐ and post‐LTx versus 10 age matched controls.

FIGURE 5

(A–C): Plasma ammonia (A) and ASLD‐related biomarkers in plasma (B) and CSF (C) before and after liver transplantation in nine ASLD patients. Arginine values before transplantation were under arginine supplementation. Values of analytes for each patient are expressed as the median and IQR of all values pre‐ versus post‐LTx.

FIGURE 6

Multiple linear regression analysis identified ammonia levels at (neonatal) disease onset (p = 0.0333) and age at transplantation p = 0.0359) as significant predictors of DQ/IQ outcome.