Liver transplantation for late-onset ornithine transcarbamylase deficiency: A ca

lNTRODUCTlON

Ornithine transcarbamylase deficiency (OTCD) is the most common urea cycle disorder, with an incidence of approximately 1/56500 to 1/80000 reported in the literature[1-4]. The 2019 Urea Cycle Disorders Diagnosis and Management guidelines recommend liver transplantation (LT) for patients with severe urea cycle disorders who do not have severe neurological impairment and have stable metabolic status[5]. Opinions regarding LT for children with pre-existing severe brain damage differ as LT does not restore pre-existing neurological damage and due to the high risk of LT in children with acute encephalopathy; there is no experience regarding the extent to which neurological damage can be restored after surgery[5]. We report a patient with late-onset OTCD with good neurological recovery after LT.

CASE PRESENTATlON

Chief complaints

An 11.7-year-old boy was admitted to our hospital due to headache, vomiting and altered mental status.

History of present illness

Two days before admission, the patient complained of a headache without obvious inducement,accompanied by vomiting 25 times. The headache did not improve with cold medication. He became unconscious 12 h before admission, and relevant tests were completed at a referring hospital. His blood ammonia was ＞ 500 μmol/L. He was referred to our hospital for further treatment.

术前预康复是指在术前针对有可能影响术后康复的状态进行调理，以减少术后并发症的发生，加速术后患者的康复速度。术前1个月的戒酒有利于减少出血、伤口愈合不良、心肺并发症等。术前戒烟有利于降低肺部及切口并发症的风险，术前戒烟1个月以上获益更多。通过改善营养，纠正术前低蛋白、贫血情况可有效改善预后，针对术前存在中度以上通气功能障碍的患者，术前呼吸功能锻炼(如指导患者进行有效咳嗽，体位引流及胸背部拍击等)有利于提高患者肺功能及对手术的耐受性，显著降低术后肺部并发症发生率，缩短住院时间。

History of past illness

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Personal and family history

The patient had no significant family history. No patients in the family had OTCD or symptoms associated with the disease.

Physical examination

On physical examination, he was in a moderate comatose state [Glasgow coma score (GSC) 6] and was unresponsive to sound. His eyes could not be closed, the pupils were equally large and round, about 3 mm in diameter, and light reflex was delayed. There were no significant abnormalities on cardiopulmonary or abdominal examinations. Muscle strength in the limbs could not be tested, muscle tone was normal, and all pathological signs were negative.

Laboratory examinations

Hu YH, Liao JX, Chen L, Hu ZQ and Wen JL were responsible for the treatment and management of the patient; Fu XH and Chen SL collected the patient’s clinical data and wrote the paper; all authors were involved in writing the manuscript and read and approved the final manuscript.

Whole exome gene testing revealed the

gene exon2 hemizygote variant c.119G ＞ A (p.R40H),inherited from his mother. The missense mutation was located in the well-studied exon functional domain without benign variation [Pathogenic moderate (PM) 1]. The frequencies of all normal population databases (dsSNP, 1000 genomes) were less than 0.0005 (PM2). This is a variant with different amino acid changes at the same locus reported in the literature as pathogenic variants (PM5).Pathogenic missense mutations of this gene are common, and benign missense mutations are rare[Pathogenic supporting (PP) 2]. The literature reported that variant to caused impaired gene function as show by

functional assays [Pathogenic strong (PS) 3]. In summary, according to American College of Medical Genetics (ACMG)guidelines, this variant is likely pathogenic (PM1 + PM2 + PM5 +PP2 + PS3).

Imaging examinations

Brain magnetic resonance imaging (MRI) revealed that large patches of symmetrical high signal shadows on T2 weighted imaging (T2WI) and fluid attenuated inversion recovery in the cerebral hemispheres, and diffusion WI (DWI) revealed a significant high signal, more pronounced in the bilateral dorsal thalamus, caudate nucleus, lenticular nucleus, insula, cingulate gyrus and frontal lobe into the cortex at the falx.

The patient was the product of a first pregnancy and first birth (G1P1) mother, and delivered by cesarean section at term with a birth weight of 3.0 kg. His perinatal condition was unremarkable, with no history of asphyxia. He was generally healthy and developed normally for a child of the same age.Prior to this episode, the family was not aware that the patient had OTCD.

FlNAL DlAGNOSlS

Outcomes in urea cycle disorders are related to blood ammonia levels and the duration of the coma.According to a European questionnaire, patients with blood ammonia levels ＞ 300 μmol/L or peak blood ammonia levels ＞ 480 μmol/L during the first episode suffered neurological dysfunction[8].Although patients with late-onset OTCD generally have better outcomes than those with neonatal onset,there is a higher incidence of residual neurological damage, and the mortality rate for late-onset OTCD with coma on the first episode is high. In a follow-up study that included 90 OTCD cases, 18 patients had coma as their first presentation and 6 of them died[9]. Among 16 genetically confirmed cases of lateonset OTCD reported in the Chinese literature[10], nine died shortly after hospital admission,suggesting the disease’s aggressive nature at acute onset. In our case, the patient was physically fit and had normal development before the presentation. Headache and vomiting were the primary manifestations; these symptoms were not taken seriously until the onset of unconsciousness, which delayed the treatment. Although blood ammonia levels reduced to the normal range after aggressive treatment,neurological damage did not improve with the normalization of blood ammonia. The patient was in a moderate coma before LT.

TREATMENT

After admission, the patient underwent continuous hemodiafiltration (Disposable hemodialysate filter and supporting pipeline, Prismaflex M100 set, Gambro Industries, Meyzieu, France; blood flow velocity 150-300 mL/min, replacement velocity 1000-2500 mL/h, dialysis velocity 1500-5000 mL/h) to lower the blood ammonia level. The impairment of consciousness worsened, and the repeat blood ammonia level was 511.72 μmol/L. Within a few hours, he fell into a severe coma (GSC 3) and developed central respiratory failure. We immediately provided ventilation, reduced intracranial pressure (mannitol and hypertonic sodium), nitrogen scavenger agents including sodium benzoate and arginine, antibiotics to inhibit ammonia production by intestinal bacteria, along with multiple nutritional support treatments.

On day 31, modified piggyback orthotopic LT (anastomosis of the donor inferior vena cava to the recipient inferior vena cava) was performed, the donor was deceased. Postoperatively, the patient was treated with tacrolimus, sodium mescaline, and methylprednisolone. On day 35 (day 4 after surgery),the patient was conscious (opened eyes autonomously, obeyed commands, verbal response was “T”). A repeat brain MRI more than 2 mo after transplantation showed that the previous subcortical lesions had largely disappeared; however, hydrocephalus was worse (Figure 2). He was discharged after 3 mo and underwent abdominal ventricular drainage at another hospital.

地震活动频率上云南省MS6.5级以上地震的泊松分布参数为0.2154，每年发生MS6.5级以上大震概率为19.3%，约每5年发生一次，其中发生1次的概率为17.4%，2次以上的概率为1.9%。MS7.0级以上地震的泊松分布参数为0.1061，每年发生7级以上大震概率为9.5%，具有每10年发生1次的特点，其中发生1次MS7.0级地震的概率为17.3%，2次以上的概率为2%。

On day 3, blood ammonia decreased to normal and was maintained in the normal range for the remainder of the hospital stay. The continuous hemodiafiltration parameters (blood flow velocity 120 mL /min, replacement velocity 500 mL/h, dialysis velocity 2500 mL/h) were gradually adjusted downwards. On day 6, the patient discontinued hemodiafiltration. On day 7, the patient’s consciousness changed from deep coma to moderate coma. On day 12, the patient was weaned from the ventilator;however, he remained in a moderate coma.

OUTCOME AND FOLLOW-UP

At follow-up, 6 mo after surgery, he could sit, squat, and walk smoothly on his own. He could say simple superlatives, and his command execution rate was approximately 30%. He showed poor emotional control and a greater temper to his parents; however, he was gentler to strangers and his brother.

the Sanming Project of Medicine in Shenzhen, No. SZSM201812005.

DlSCUSSlON

OTCD can develop at any age. Depending on the time of onset, OTCD can be divided into the neonatalonset type and the late-onset type (age of onset ＞ 28 d)[6]. Patients with neonatal onset usually present in the first few hours and days after birth with severe disease and high mortality. The clinical presentation of late-onset disease varies widely, with no specific clinical manifestations before initial onset. Acute onset of late-onset OTCD can be induced by infection, prolonged fasting, or fatigue. The outcome for conservative treatment is poor in patients with hyperammonemia crisis, and 5-year survival is approximately 45%[7].

Hyperammonemic encephalopathy and ornithine transcarbamylase deficiency.

OTCD is treated with a low-protein diet and long-term oral ammonia-lowering medications. LT is the radical treatment for OTCD. After LT, patients no longer need to restrict their diet or take nitrogen scavenging agents[5]. Statistics on LT in patients with urea circulation disorders show that the 5-year survival rate of patients after LT can exceed 90%[11,12]. There is no consensus regarding the indications or timing of LT. It is now believed that LT should be performed in all patients with neonatal onset to prevent neurological damage[13]. The indications and timing of LT for late-onset OTCD must be determined by the clinical symptoms, including poor drug efficacy, recurrent episodes of hyperammonemia, growth retardation, and inability to strictly control the diet[14]. Although post-transplant patients require long-term immunosuppressive drugs, there is evidence that OTCD patients who underwent LT have a better quality of life than those who did not and no longer risked death due to sudden-onset hyperammonemia[11,15].

The present patient had an acute onset, a long duration of hyperammonemia, severe brain damage,and was in a moderate coma before LT. Therefore, the optimal time window for LT was missed, and the choice of LT and the extent to which the patient would recover from neurological damage after transplantation were a concern for his physicians and parents. Most LTs for OTCD patients are carried out in the context of stable metabolism, and there are few reports of LT in patients with severe neurological injury. Nevertheless, given the patient’s inability to regain consciousness, we performed LT, and he was conscious 4 d later. After LT, he did not take nitrogen scavenging agents, and blood ammonia, liver, and kidney function biochemistry were maintained in the normal range at regular follow-up. Kawagishi

[16] reported a patient who underwent LT for recurrent hyperammonemia due to late-onset OTCD, and blood ammonia was maintained in the normal range without further nitrogen scavenging agents after surgery. Nevertheless, at 16 mo after surgery showed no change in subcortical lesions. Brain MRI in our patient was repeated about 2 mo after surgery, and suggested a significant reduction in abnormal cranial signals compared with the previous MRI, indicating that LT was effective in the treatment of this patient, However, brain MRI showed that hydrocephalus had progressed and brain atrophy was present, suggesting that some neurological damage may not be reversed after LT.

Several studies have shown that LT could be used as a radical treatment which significantly improves the quality of life[11,17]. However, it is not clear whether LT is beneficial for OTCD patients who already have severe neurological damage. This case report suggests that LT can be attempted in children with late-onset OTCD, even if severe neurological impairment is already present. Neurological recovery after LT in this patient was unexpected; the recovery of higher functions such as emotional control and spatial thinking require long-term rehabilitation training and psychotherapy, and its effects need to be observed during follow-up.

CONCLUSlON

In summary, patients with late-onset OTCD and acute hyperammonemic encephalopathy are at high risk, and LT can significantly improve the neurological damage caused by this disease. As a radical cure for OTCD, LT should be considered more aggressively.

FOOTNOTES

Laboratory tests showed a significantly elevated blood ammonia level (Table 1). Liver function and coagulation times were abnormal. Blood tandem mass spectrometry showed moderately elevated glutamine. Citrulline and arginine were in the normal range. Urine organic acid gas phase mass spectrometry showed that uracil and orotic acid levels were elevated. Blood ammonia levels during the first week of admission are shown in Figure 1. During the remainder rest of his hospital stay, levels were in the normal range.

毋庸置疑，宾利全新欧陆GT敞篷版是这个细分领域里最为核心的一款产品，也是宾利品牌旗下最具魅力的车型之一。从发布会现场来宾对它的兴趣盎然就可以看出，这款随时可以享受真正“全景天空”的宾利汽车，肯定会有一个相当乐观而美好的前途。

缺钾发生原因：首先与土壤及气候因素有关，砂质土、红壤和冲积土等土壤钾的含量较低，砂质土壤或有机质含量低的土壤钾易于流失。其次，含钙、镁量高的土壤，由于钙和镁的颉颃作用，使钾的有效性降低。此外干旱也会导致土壤中钾的有效性降低。最后，柑橘园长期不施钾肥或钾肥用量不足，也会导致土壤中钾的缺乏。

本研究结果显示，HBO联合DDP处理后，食管鳞癌裸鼠的肿瘤细胞凋亡明显增加，肿瘤组织Fas/FasL mRNA和蛋白表达水平显著升高，应用前景提示HBO联合DDP治疗食管鳞癌具有应用前景。

Informed written consent was obtained from the patient for the publication of this report and any accompanying images.

The authors declare that they have no conflict of interest.

The authors have read the CARE Checklist (2016), and the manuscript was prepared and revised according to the CARE Checklist (2016).

逐渐形成县、乡、村、农户四级科技推广服务网络体系，成立乡（镇)林果站、农民技术协会、研究会、果农协会等，为花椒产前、产中和产后提供多层次、全方位优质服务、技术指导和技术人员培训，并建立较为完善的科技服务体系。

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China

Xiao-Hui Fu 0000-0002-9000-224X; Yu-Hui Hu 0000-0002-6989-2460; Jian-Xiang Liao 0000-0001-9769-3365; Li Chen 0000-0002-9029-9581; Zhan-Qi Hu 0000-0001-5926-3962; Jia-Lun Wen 0000-0002-1399-5890; Shu-Li Chen 0000-0001-9989-6414.

全国政协常委、副秘书长、新教育发起人朱永新在主旨演讲中指出，公私合作、民办学校的分类管理及小微学校的合法化是当前体制改革的热点；国家教育发展研究中心教育体制改革研究室主任王烽对当前深化办学体制改革的几个关键问题进行了解读；北京师范大学教授曾晓东和台湾振铎学会理事长丁志仁分别就美国的“择校”现象及台湾实验教育的立法与实践等话题与参会者进行了深入探讨。

Guo XR

Webster JR

Guo XR

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