A Case of ECTH1 Deficiency with Elective Liver Transplantation

Tomohiro Ebihara ¹ Taro Nagatomo ² Tomoko Tsuruoka ¹ Yohei Sugiyama ³ Masaru Shimura ⁴ Keiko Ichimoto ⁴ Takuya Fushimi ⁴ Yukiko Yatsuka ⁵ Yoshihito Kishita ^5,6 Mureo Kasahara ⁷ Akira Ohtake ^8,9 Yasushi Okazaki ^5,10 Kei Murayama ⁴

¹Center for Medical Genetics, Department of Neonatology, Chiba Children’s Hospital, Japan
²Department of Neonatology, Japanese Red Cross Fukuoka Hospital, Japan
³Department of Pediatrics, Juntendo University Hospital, Japan
⁴Center for Medical Genetics, Department of Metabolism, Chiba Children’s Hospital, Japan
⁵Diagnostics and Therapeutics of Intractable Diseases, Intractable Disease Research Center, Juntendo University, Graduate School of Medicine, Japan
⁶Department of Life Science, Faculty of Science and Engineering, Kindai University, Japan
⁷Center for Organ Transplantation, National Center for Child Health and Development, Japan
⁸Department of Pediatrics and Clinical Genomics, Saitama Medical University, Japan
⁹Center for Intractable Diseases, Saitama Medical University Hospital, Japan
¹⁰Laboratory for Comprehensive Genomic Analysis, RIKEN Center for Integrative Medical Sciences, Japan

BACKGROUND: The pathogenesis of enoyl-CoA hydratase deficiency (ECTH1D) has been partly interpreted as secondary to the accumulation of valine metabolites. We report a female patient with compound heterozygous ECHS1 mutations in whom elective liver transplantation was proposed to reduce organ damage and improve life support and quality of life by maintaining branched-chain amino acid (BCAA) homeostasis.

CASE REPORT: This case is the fourth child of healthy non-consanguineous parents. The first and second children died early after birth of ECTH1D. Prenatal diagnosis using chorionic villus samples confirmed a compound heterozygosity of c.[176AG], [476AG], p.[Asn59Ser] and [Gln159Arg] variant. She was born at 38 weeks without neonatal asphyxia. After birth, she was started on a mitochondrial vitamin cocktail, a BCAA-restricted diet, and N-acetylcysteine. Brain MRI revealed total volume loss 29 days after birth. At 38 days old, living-related donor liver transplantation was performed. The short- and long-term efficacy of liver transplantation for ECHS1D was completely unknown, so the future benefits, risks, and ethics were fully discussed.

RESULTS: The explanted liver showed no significant findings in histopathological examination and normal respiratory chain enzyme activity in biochemical analysis. She had a good postoperative course and was able to maintain nutrition on a BCAA-restricted diet. Hypertrophic cardiomyopathy (HCM) was observed from 5 months of age, and brain atrophy progressed even after liver transplantation to decrease the level of consciousness to coma. At just over 1 year of age, she suddenly developed severe circulatory collapse and died the same day from an acute exacerbation of heart failure. The autopsy revealed myocardial hypertrophy, with no specific abnormalities in the liver, lungs, or other organs. Mitochondrial complex activity assays of the cardiac muscle elucidated severe defects in complex I and II (complex I/CS ratio=5.2%, complex II/CS ratio=22.7%)

CONCLUSION: In this case, disease progression and new symptoms were observed after liver transplantation. A better understanding of the correlation between ECHS1D genotype and phenotype is needed to debate the pros and cons of elective liver transplantation for ECTH1D.