Early continuous blood purification and timely liver transplantation in a neonatal-onset ornithine transcarbamylase deficiency: a case report

Introduction

Urea cycle disorders (UCD) are a group of rare inherited metabolic diseases. They are characterized by a deficiency of enzymes or transporters involved in the urea cycle, leading to the accumulation of ammonia in the blood (1). Hyperammonemia can cause rapid and irreversible brain injury, making it a leading cause of death in UCD patients (2). Ornithine transcarbamylase deficiency (OTCD) is one of the most prevalent UCDs, representing 50–66% of cases (3,4). OTCD is caused by disease-causing variants in the OTC gene, located on chromosome Xp21.1, and predominantly affects male infants. OTCD patients are classified into two types based on the age of onset: neonatal-onset (onset age ≤30 days) and late-onset (onset age >30 days) (5). The neonatal-onset OTCD has a particularly high mortality rate, approximately 45% (6). Early recognition and timely intervention can dramatically reduce the severity of hyperammonemia and its associated complications, thereby improving the long-term prognosis of OTCD infants (7).

We present a case of a 9-day-old male infant with neonatal-onset OTCD, who was successfully managed with continuous blood purification (CBP) followed by liver transplantation. At 1 year of age, the patient achieved favorable neurological and developmental outcomes, highlighting the importance of early diagnosis and timely intervention on neonatal-onset OTCD. We present this article in accordance with the CARE reporting checklist (available at https://tp.amegroups.com/article/view/10.21037/tp-2025-436/rc).

Case presentation

All procedures performed in this study were in accordance with the Declaration of Helsinki and its subsequent amendments. This study was approved by the Ethics Committee of Children’s Hospital, Zhejiang University School of Medicine (No. 2025-IRB-0270-P-01). Written informed consent was waived by the Ethics Committee due to the retrospective and anonymized nature of this case report.

A 9-day-old male neonate was admitted to Children’s Hospital, Zhejiang University School of Medicine in May 2024. He was born at 38⁺⁵ weeks of gestation via spontaneous vaginal delivery at a local facility, with a birth weight of 3,000 g. At birth, he exhibited slow and shallow respiration, partial flexion of the limbs and facial grimace to stimulation, resulting in an Apgar score of 7 at 1 minute. Following airway clearance, thermal support, drying, tactile stimulation, and positive pressure ventilation, he responded promptly and achieved a score of 9 at 5 minutes. The infant was then placed in rooming-in care and discharged on the 4th day of life. At 7 days of life, he developed somnolence, hypothermia (35.7 ℃), reduced oral intake and intermittent vomiting. A septic work-up was promptly initiated and piperacillin-tazobactam was administered. On day 8 of life, his clinical condition worsened, and initial measurement of plasma ammonia revealed a markedly elevated level of 428 µmol/L. He underwent endotracheal intubation and was placed on synchronized intermittent mandatory ventilation with concurrent intravenous arginine therapy. At 9 days of life, he was transferred to our institution for further management. Upon admission, the vital signs were recorded as follows: temperature 36.2 ℃, heart rate 110 beats per minute, respiratory rate 48 breaths per minute (on ventilator support), and blood pressure 112/79 mmHg. Physical examination revealed a flat anterior fontanelle, sluggish pupillary light reflexes, generalized cutis marmorata, mild respiratory effort, hypotonia, hepatomegaly (liver palpable 2 cm below the right costal margin, soft and sharp-edged), abdominal distension, and reduced spontaneous limb movement. Initial laboratory results showed a further increase in plasma ammonia to 459 µmol/L, with prolonged prothrombin time (15.9 s), elevated activated partial thromboplastin time (47.9 s) and increased serum lactate (4.0 mmol/L). Other biochemical parameters, including alanine aminotransferase (ALT), lipid profile, serum ferritin, ceruloplasmin, and anion gap, remained within normal limits. Given the suspicion of an inborn error of metabolism, protein and lipid intake were discontinued, and arginine infusion continued. Tandem mass spectrometry and genetic testing were initiated.

Despite ongoing supportive care, plasma ammonia levels rose sharply to 1,150 µmol/L within 20 hours of admission. CBP was promptly initiated using an 8F double-lumen catheter placed in the right internal jugular vein. Anticoagulation therapy with unfractionated heparin was maintained throughout the procedure. An initial blood flow was 10 mL/h, the dialysate was 80 mL/h, and replacement fluid was 70 mL/h. Due to borderline hypotension, albumin infusion and dopamine (10 µg/kg/min) were administered prior to initiating CBP. After hemodynamically stable, blood flow was increased to 30 mL/h, and the dialysate flow rate was adjusted to 500 mL/h. Plasma ammonia levels decreased to 145 µmol/L after 24 hours of CBP, and the therapy was subsequently discontinued (Figure 1).

Figure 1 Ammonium level during treatment. The graph shows the fluctuation in ammonium levels (µmol/L) during the patient’s treatment course, measured across postnatal days 7 to 13. The ammonium level initially increased following admission (day 9), peaking before the start of CBP on day 10. CBP was initiated at this point, and the ammonium level dropped significantly after treatment began. CBP ended on day 12, with the ammonium level stabilizing as the patient was discharged on day 13. CBP, continuous blood purification.

At 11 days of age, tandem mass spectrometry and urinary organic acid analysis revealed reduced plasma citrulline levels (3.67 µmol/L), elevated urinary orotic acid (918.4; reference ≤0.62) and increased uracil concentrations (30.02; reference ≤8.5). As shown in Figure 2, brain magnetic resonance imaging (MRI) with diffusion-weighted imaging (DWI) demonstrated patchy hyperintense signals in the bilateral basal ganglia, thalami, cerebral peduncles, frontal and parietal lobes, and insular cortices. The basal ganglia were swollen with ill-defined margins, and the hyperintense T1 signal in the posterior limbs of the internal capsules appeared indistinct. Patchy short-T1 areas were present in the periventricular white matter adjacent to the lateral ventricles. The cerebral hemispheric white matter exhibited bilaterally reduced T1 and increased T2 signal intensities. Based on the infant's urinary and blood findings, UCD was strongly suspected. After stabilization, he was extubated at 11 days of age and discharged on a formula based on essential amino acids, supplemented with oral citrulline and arginine (850 mg/day). Subsequently, genetic testing confirmed the presence of a maternally inherited hemizygous variant in the OTC gene (NM_000531.6:c.542A>G, p.E181G), which confirmed the diagnosis of OTCD (Figure 3). At 2 months of age, outpatient metabolic evaluation revealed carnitine deficiency, prompting the addition of oral levocarnitine (2.5 mL every 12 hours) to the infant’s regimen. Follow-up assessments demonstrated stable blood ammonia levels and normal liver enzyme activity.

Figure 2 Brain MRI of a 9-day-old neonate with neonatal-onset ornithine transcarbamylase deficiency. (A) DWI showing symmetrical abnormal signal intensity in the basal ganglia. (B) DWI showing symmetrical hyperintensities in the insular cortex. (C) DWI showing symmetrical abnormal signal intensity involving the cingulate gyrus, frontal, and parietal cortices, as indicated by the red arrows. DWI, diffusion-weighted imaging; MRI, magnetic resonance imaging.

Figure 3 Genetic sequencing of OTC gene (c.542A>G) variant. Visualization of the OTC disease-causing variant using BAM format files in IGV. The disease-causing variant found in this study is marked in red rectangles. BAM, binary alignment/map; IGV, integrative genomics viewer; OTC, ornithine transcarbamylase.

At 7 months of age, the infant was readmitted for episodes of inconsolable crying. Blood ammonia levels remained within normal limits, however, serum ALT rose to 302 U/L and later declined to 149 U/L following treatment with compound glycyrrhizin injection. At 8 months, the patient underwent a successful orthotopic liver transplantation using a graft from a donation after circulatory death. The native liver was excised, and the graft was implanted using a piggyback technique with hepatic vein-to-inferior vena cava anastomosis. Abdominal computed tomography angiography (CTA) performed at 11 months of age revealed excellent graft perfusion, with only mild narrowing observed at the hepatic and portal vein anastomoses (Figure 4). No evidence of thrombosis or occlusion was noted. During the 6-month postoperative period, the patient received regular follow-up evaluations. After liver transplantation, he transitioned from a protein-restricted formula to a standard infant formula, with no recurrence of hyperammonemia or other metabolic complications. Liver function remained stable, and plasma ammonia levels consistently stayed within the normal range.

Figure 4 Abdominal CTA images showing the hepatic vascular anastomosis. (A) Two days post-liver transplantation. (B) Three months post-liver transplantation. CTA, computed tomography angiography.

Follow-up was conducted every 1–2 months during the first year of life at either the local hospital or our institution. Most visits included growth assessments (weight, length, and head circumference), all of which remained within age-appropriate ranges (Figure 5). Developmental surveillance, covering adaptive behavior, gross motor, fine motor, language, and personal-social domains, indicated that all milestones were achieved within expected timeframes. After 12 months of age, follow-up visits have been scheduled at 3–6-month intervals. Given his consistent progress in both physical and developmental areas, brain MRI has not yet been performed.

Figure 5 Curves of weight (A) and height (B) percentiles according to WHO standards. WHO, World Health Organization.

Discussion

This report contributes to the limited neonatal OTCD literature by illustrating that a strictly sequential strategy—CBP followed by early orthotopic liver transplantation—can effectively reverse fulminant hyperammonemia and lead to favorable outcomes.

Diagnosing OTCD in neonates is challenging. Early symptoms—such as lethargy, poor feeding, and hypothermia—are nonspecific and often mimic neonatal sepsis (8). Given their lack of specificity, early recognition relies heavily on laboratory findings. In neonates showing unexplained neurological symptoms or metabolic abnormalities, blood ammonia measurement should be prioritized, as it provides an important clue for diagnosing OTCD. In our case, prompt plasma ammonia testing revealed severe hyperammonemia, leading to rapid intervention and ultimately preventing severe neurological damage.

Ammonia levels and the duration of hyperammonemic coma are strongly associated with poor neurological outcomes (9,10). When plasma ammonia exceeds 200 µmol/L, the risk of death increases (8). Infants with ammonia levels over 1,000 µmol/L, hyperammonemic coma lasting more than 3 days, or elevated intracranial pressure typically have a worse prognosis (8,11). Therefore, early and aggressive treatment to lower ammonia is essential. Immediate intravenous access should be established, and intubation with ventilation should be considered when necessary. Rehydration, cessation of protein intake, and intravenous supplementation with arginine and citrulline should be initiated without delay (12). Notably, CBP is a key intervention for controlling hyperammonemia, especially in infants with congenital metabolic disorders or acute liver failure. The primary indication for CBP is the rapid deterioration of neurological symptoms, without a fixed ammonia threshold (12). Various CBP techniques, including continuous veno-venous hemofiltration (CVVH), continuous veno-venous hemodialysis (CVVHD), and continuous veno-venous hemodiafiltration (CVVHDF), have been employed. Although these approaches are all safe and effective (13), hemodialysis provides faster ammonia clearance than hemofiltration (12). Hemodiafiltration, which combines the convective clearance of hemofiltration with the diffusive clearance of hemodialysis, offers a more balanced and efficient removal of a broader range of solutes, including ammonia (14). Considering these advantages and our department’s clinical practice, CVVHDF was selected. And a high-dose CBP regimen was implemented with a blood flow rate of 30 mL/min, as well as a dialysate flow rate of 500 mL/h. The high-dose CBP reduced ammonia from 1,150 to 145 µmol/L within 24 hours, without complications observed. This rapid reduction likely minimized further neuronal damage, despite initial cerebral involvement as evidenced by MRI.

In recent years, liver transplantation has emerged as a potentially curative treatment for OTCD (11,15-18). A multicenter cohort study showed sustained metabolic stability without hyperammonemia recurrence after transplantation (19). However, neurological impairment already present prior to transplantation is often difficult to reverse (20). Consequently, the neurological status at the time of transplantation is considered an important determinant of prognosis (15,21). In addition, transplantation performed before 1 year of age may be associated with more favorable outcomes (20,22). Our case is consistent with these findings. The patient underwent liver transplantation at 8 months of age, after which metabolic control remained stable, and neurodevelopment progressed appropriately for age throughout follow-up. Similarly, Arcos-Minguela reported comparable findings in a cohort of 13 OTCD patients who underwent liver transplantation, with 7 transplanted before 12 months (19). All survived with excellent graft function, and 5 of the 6 transplanted before neurological decline had near-normal neurodevelopment (19). Likewise, McBride also observed favorable outcomes in OTCD infants transplanted before 1 year (15).

Liver transplantation is an effective definitive treatment, however, its application is restricted by the scarcity of suitable donor organs. Moreover, recipients must take lifelong immuno-suppressive therapy to prevent graft rejection, which may increase the risk of postoperative infections (23). Gene therapy is emerging as a long-term alternative treatment for UCD, with various approaches under investigation, including AAV gene addition and mRNA therapy (24). But for now, live transplantation remains the gold standard for metabolic cure in severe neonatal-onset OTCD.

This report still has some limitations. Although early neurodevelopment was normal in this patient, intellectual disabilities or subtle cognitive impairment may manifest later in childhood, underscoring the need for ongoing developmental surveillance. Additionally, as the patient’s mother is an asymptomatic carrier, her health will be monitored as part of the family’s follow-up plan. Nevertheless, the positive outcome suggests that prompt ammonia detoxification and timely liver transplantation can lead to survival with minimal neurodevelopmental impairment.

Conclusions

Early recognition, prompt CBP and timely liver transplantation are essential to rescue neonates with OTCD and preserve neurodevelopment.

Acknowledgments

We would like to express our gratitude to the patient and his parents, as well as for the help of all the physicians in the course of the medical care.

Footnote

Reporting Checklist: The authors have completed the CARE reporting checklist. Available at https://tp.amegroups.com/article/view/10.21037/tp-2025-436/rc

Peer Review File: Available at https://tp.amegroups.com/article/view/10.21037/tp-2025-436/prf

Funding: This work was supported by grants from the National Natural Science Foundation of China (No. 82201890) and Wu Jieping Medical Foundation (No. 320.6750.2025-9-25).

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://tp.amegroups.com/article/view/10.21037/tp-2025-436/coif). All authors report that this work was supported by grants from the National Natural Science Foundation of China (No. 82201890) and Wu Jieping Medical Foundation (No. 320.6750.2025-9-25). The authors have no other conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. All procedures performed in this study were in accordance with the Declaration of Helsinki and its subsequent amendments. This study was approved by the Ethics Committee of Children’s Hospital, Zhejiang University School of Medicine (No. 2025-IRB-0270-P-01). Written informed consent was waived by the Ethics Committee due to the retrospective and anonymized nature of this case report.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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