Orphanet Journal of Rare Diseases | Retrospective Analysis of Liver Transplantation for HHH Syndrome

Recommend:

This article presents a retrospective analysis of clinical data from six patients with HHH syndrome who underwent liver transplantation. The results show that liver transplantation can effectively correct metabolic abnormalities and improve neurological symptoms, especially when performed at an early stage. The study provides detailed clinical data, mutant gene information, and changes in postoperative neurological function scores, offering important clinical evidence for the treatment strategy of HHH syndrome.

 

Literature Overview
This article, titled 'Retrospective Analysis of Liver Transplantation for HHH Syndrome,' was published in the Orphanet Journal of Rare Diseases. It reviews and summarizes the clinical data of six HHH syndrome patients who underwent liver transplantation between 2016 and 2022 at Beijing Friendship Hospital.

Background Knowledge
Hyperornithinemia-Hyperammonemia-Homocitrullinuria (HHH) syndrome is a rare urea cycle disorder caused by mutations in the SLC25A15 gene. It is characterized by hyperornithinemia, hyperammonemia, and homocitrullinuria. The disease can lead to metabolic disturbances and neurological damage, such as spastic paraplegia, motor dysfunction, and intellectual disabilities. Current treatments mainly rely on low-protein diets and supplementation with arginine and citrulline, along with ammonia-lowering agents. However, while conservative management can control acute hyperammonemia, neurological symptoms continue to progress, indicating the need for more effective interventions. Liver transplantation (LT) has been proposed as a potentially curative treatment, as it can restore urea cycle function and reduce ammonia toxicity. Although a few case reports have shown the potential of LT in treating HHH syndrome, its efficacy and safety still lack support from larger sample sizes. This study is the largest single-center retrospective analysis of LT for HHH syndrome to date and systematically evaluates metabolic and neurological changes before and after transplantation, providing clinical evidence for its application.

 

Used for comparing gene sequence differences between species or populations, suitable for evolutionary analysis.

Learn More

 

Study Methods and Experiments
This study adopted a retrospective design, including six patients with HHH syndrome who underwent liver transplantation at Beijing Friendship Hospital between 2016 and 2022. All patients had their SLC25A15 mutation types confirmed via genetic testing. Pre- and post-transplant outcomes were analyzed using blood biochemistry, neurological function assessments, and quality-of-life scores. The Kasahara transplant scoring system was used to assess surgical indications, and the neurological scoring followed the classification criteria proposed by Morioka et al.

Key Findings and Perspectives

• Liver transplantation successfully restored urea cycle function, significantly reducing blood ammonia and plasma ornithine levels, allowing patients to resume a normal diet.
• Five out of six patients (83.3%) showed improvement in post-transplant neurological scores, including reduced lower-limb spasticity and improved gait. Two patients achieved nearly normal gait, and one patient recovered normal motor function within 3 months post-surgery.
• Quality-of-life scores improved significantly in two patients, while the rest primarily showed improvements in motor function.
• The overall survival rate was 83.3%. One patient died due to non-surgical causes, and no severe long-term complications were observed in the remaining patients.
• Postoperative complications included cytomegalovirus infection and bile leakage, but these were manageable and no Clavien-Dindo grade I or higher adverse events occurred.
• The study suggests that early liver transplantation (before irreversible neurological damage) can effectively prevent neurodegeneration and improve outcomes, particularly for patients with ineffective conservative treatment or recurrent metabolic decompensation.

Research Significance and Future Directions
This study is the largest single-center clinical experience report on liver transplantation for HHH syndrome to date, providing evidence of postoperative metabolic stability and neurological improvement. Future studies should include larger cohorts to systematically assess pre-transplant metabolic markers, imaging findings, and their relationship with prognosis. Further exploration of the comprehensive impact of liver transplantation on extrahepatic metabolism and neurological function is also needed to optimize treatment timing and strategies.

 

Quickly obtain reference sequences, transcripts, and exons of a gene for functional studies.

Learn More

 

Conclusion
HHH syndrome is a rare urea cycle disorder typically presenting with hyperammonemia, hyperornithinemia, and homocitrullinuria, along with progressive neurological impairment. This retrospective study analyzed six HHH syndrome patients who underwent liver transplantation. The results showed normalization of postoperative metabolic markers and improvement in neurological function in most patients, particularly those who received early transplantation. No severe complications were observed within five years post-surgery, and quality-of-life scores improved in some patients, indicating that liver transplantation is both safe and effective for treating HHH syndrome. Although the sample size is small and long-term follow-up data are limited, the findings provide new clinical insights into HHH syndrome treatment and highlight the importance of early transplantation in preventing neurological deterioration. Future research should further investigate the effects of liver transplantation on extrahepatic metabolism and long-term neurological improvement to optimize treatment strategies.

 

Hongfei Ju, Jun Wang, Xinyue Wang, Lin Wei, and Zhi-Jun Zhu. Liver transplantation can prevent the progression of neurological damage in hyperornithinemia-hyperammonemia-homocitrullinuria syndrome and maintain long-term metabolic stability — The largest single-center experience. Orphanet Journal of Rare Diseases.