Clinical characteristics and molecular genetic analysis of ten cases of ornithine carbamoyltransferase deficiency in southeastern China

doi:10.21203/rs.3.rs-3557771/v1

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Research Article

Clinical characteristics and molecular genetic analysis of ten cases of ornithine carbamoyltransferase deficiency in southeastern China

https://doi.org/10.21203/rs.3.rs-3557771/v1

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published 11 Sep, 2024

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BackgroundThis study aimed to investigate the clinical and molecular genetic characteristics of ten children with ornithine carbamoyltransferase deficiency (OTCD) in southeastern China, as well as the correlation between the genotype and phenotype of OTCD.

MethodsThe clinical manifestations, laboratory testing, and genetic test findings of ten children with OTCD admitted between August 2015 and October 2021 were analyzed retrospectively.

ResultsFive boys presented with early-onset symptoms, including poor appetite, drowsiness, groaning, seizures, and liver failure. Five patients (one boy and four girls) had late-onset gastrointestinal symptoms as the primary clinical manifestation, all with hepatic impairment, and four with hepatic failure. Coagulopathy occurred in eight patients. Urinary orotic acid levels were elevated in all patients except in one who received blood purification therapy. Only six patients showed decreased serum citrulline levels. Nine distinct variants of the OTC gene were identified, including two novel mutations: c.1033del(p.Y345Tfs*50) and c.167T>A(p.M56K). Despite active treatment, seven patients died, of whom five had early-onset disease. Three patients survived, and two underwent liver transplantation.

ConclusionsThe clinical manifestations of OTCD lack specificity. Elevated blood ammonia is a diagnostic clue for OTCD, elevated urinary orotate is specific for its diagnosis, and genetic testing can help confirm the diagnosis. These two novel variants expand the mutational spectra of OTC, which may contribute to a better understanding of the clinical and genetic characteristics of patients with OTCD.

Ornithine transcarbamylase deficiency

Hyperammonemia

Gene mutation

Urea cycle disorders

Acute liver failure

Ornithine transcarbamylase deficiency (OTCD; MIM 311250) is an X-linked inborn error of the urea cycle. It is caused by mutations in the OTC located on chromosome Xp11.4. Consequently, nearly all hemizygous male individuals develop this condition. Hemizygous male patients have a spectrum of severity, ranging from complete OTCD, which presents at the neonatal stage with acute hyperammonemia, to partial OTCD, which presents with mild symptoms at late onset ¹. The clinical presentation of carrier female individuals also differs greatly, owing to the degree of X-inactivation in hepatocytes ². Therefore, it can be easily misdiagnosed.

In the urea cycle, ornithine transcarbamylase (OTC) is required for the production of citrulline and inorganic phosphates from carbamyl phosphate and ornithine. OTC variants result in decreased or absent OTC enzyme activity and block citrulline synthesis, thus interrupting the urea cycle and causing hyperammonemia and accumulation of orotic acid ³. Acute or chronic hyperammonemia may present as altered level of consciousness (from lethargy and somnolence to coma), acute encephalopathy, vomiting and progressive poor appetite, elevated levels of liver enzymes, liver failure, coagulopathy, psychiatric symptoms, epilepsy, protein aversion, self-selected low-protein diet, (recurrent) abdominal pain, and failure to thrive ⁴. The clinical manifestations of hyperammonemia are nonspecific and often lead to a delay in the diagnosis of OTCD. Metabolic screening and genetic detection are helpful to make a correct diagnosis.

Depending on the onset period, OTCD can typically be divided into two groups: early onset (onset age, ≤ 30 days) and late onset (onset age, > 30 days). Because the onset of OTCD symptoms is extremely variable and molecular genetic testing is useful for diagnosis, it is essential to accumulate information on genetic analysis and clinical phenotypes to determine the genotype/phenotype. This study reports the clinical and biochemical features and molecular characteristics of ten Chinese patients with OTCD. We also reviewed the relevant literature and analyzed the relationship between the phenotypes and genotypes.

Study subjects

Ten patients diagnosed with OTCD were recruited between August 2015 and October 2021. Diagnosis of OTCD was based on clinical features, specific biochemical criteria, and molecular analyses. A retrospective review of clinical manifestations and laboratory tests, including blood ammonia, coagulation, liver function tests, liver color ultrasound, tandem mass spectrometry (MS/MS), and urine organic acids, was conducted. This study was approved by the Ethics Committee of the Quanzhou Maternity and Children’s Hospital. The patients’ parents provided written informed consent for participation in the study.

Genetic analysis

After obtaining informed consent, 2 mL of peripheral blood was collected from patients and their parents. Whole-exome sequencing (WES) was performed on samples from the ten patients. Raw reads were processed by fastp, followed by paired-end sequencing of reads aligned to the human GRCh37/hg19 genome using the Burrows-Wheeler Aligner (BWA) software package. GATK software (https://software.Broadinstitute.org/gatk/) was used for SNPs and indel calling. Mutations were described according to the HGVS recommendations (http://wwwhgvs.org/mutnomen/recsprot.htm1). PolyPhen-2, PROVEAN, Mutation Taster, and Sorting Intolerant From Tolerant (SIFT) were used to analyze the potential pathogenicity of the missense mutations. Amino acid conservation was predicted using phyloP and phastCons, and homologous amino acid sequences were compared using DNAMAN software. The pathogenicity of all variants was evaluated according to the American Academy of Medical Genetics and Genomics (ACMG) clinical practice guidelines ⁵. These variants were considered novel if they were not found in the Human Gene Mutation, ClinVarMiner, or Exome Aggregation databases. The results were verified using Sanger sequencing.

Clinical features of patients with OTCD

Table 1 presents the demographic and clinical findings of ten patients with OTCD from nine unrelated families. All patients appeared normal at birth. Five patients (one boy and four girls) had late-onset disease, with normal growth and development before onset. No adverse reactions were observed after vaccination, as planned. The median age of onset was 3.2 years (ranging 1.5 years to 6.3 years). Only Patient 2 had respiratory infections before onset. The other patients had no apparent triggers. The most prevalent symptoms observed in these five patients were gastrointestinal distress, such as vomiting and feeding refusal, followed by liver dysfunction and psychiatric symptoms. Treatment was initiated with a low-protein diet, intravenous fluid and energy replenishment, arginine supplementation to reduce blood ammonia, and blood purification. Among the late-onset patients, one died and four exhibited clinical remission, two of whom were transferred for liver transplantation; normal growth and development were observed post-surgery. However, two other patients (P4 and P7) experienced multiple hospitalizations due to hepatic dysfunction and hyperammonemia. P4 died of hyperammonemia after 1 year. P7 also experienced mild intellectual disability. The disease presented with early onset in five male patients, within 1–7 days of birth, and manifested as poor appetite, drowsiness, groaning, and seizures. Initially misdiagnosed as neonatal infection or neonatal encephalopathy, the condition progresses to seizures or coma within 1–2 days of age in hospitals, leading to patient death within days.

Table 1

Clinical features and laboratory findings at presentation in 10 patients with OTCDM male; F, female; d, days; y, years; EO, early onset; LO, late onset; CIT, blood citrulline; AMON, blood ammonia; ND, not detected.
ptient No	Sex	Onset age	Type	Presenting features	AMON(10–47µmol/L)	Peak AMON (µmol/L)	ALT(0-40U/L)	AST(0-40U/L)	PT(9-13s)	APTT(20-40s)	INR (0.7–1.5)	CIT(5–35 umol/L)	Uracil(0-7mmol/molCr)	Urine orotic acid( 0-2.5 mmol/molCr)	Color doppler ultrasound of liver	Family history
1	F	2.7y	LO	Repeated vomiting, poor appetite, liver dysfunction	468	483	647	126	23.8	59.8	2.07	15.1	8.1	0	Enhanced echo of liver arenchyma	NO
2	F	3.5y	LO	Psychiatric symptoms, Vomiting, lethargy	450	753	276	73	22	30.4	1.91	12.74	142.04	1407.81	Enhanced echo of liver arenchyma	NO
3	M	6.3y	LO	Abdominal pain, Vomiting, lethargy	101	135	129	154	15.9	28.5	1.38	3.39	75.5	321.8	normal	NO
4	F	1.5y	LO	Vomiting, liver dysfunction	248	428	267	184	21.9	42.4	1.9	19.46	95.33	35.54	normal	Yes, an older brother died of unknown cause 3 days after birth
5	M	1d	EO	drowsiness, poor appetite	280	725	32	50	15.1	63.8	1.31	2.55	ND	ND	ND	Yes, Is the younger brother of P4
6	M	2d	EO	drowsiness, groan	1011	1020	48	42	14.3	29.1	1.24	4.95	0	34.65	ND	NO
7	F	1.8y	LO	Abdominal distention, Vomiting, poor appetite,	150	222	4670	2135	42.6	65.2	3.7	2.9	65.3	39.7	Enhanced echo of liver arenchyma	NO
8	M	1d	EO	drowsiness, groan, poor appetite	360	630	17	68	21.4	56.1	1.86	3.85	12.87	470.66	ND	Yes, His maternal grandmother gave birth to 8 children, 4 daughters were alive and 4 sons died 2–3 days after birth.
9	M	2d	EO	drowsiness, poor appetite, tachypnea, Seizures	400	400	19	78	48	112.7	14.24	2.66	4.68	132.92	ND	NO
10	M	7d	EO	jaundice, poor appetite, Seizures	3620	3620	578	416	27.1	53.2	2.36	5.88	5.11	99.56	ND	NO

2.2 Biochemical results at OTCD diagnosis

Table 1 summarizes the results of the biochemical analyses for each patient. Notably, elevated blood ammonia levels were observed in all patients tested. Peak ammonia levels were significantly higher in the early-onset group than in the late-onset group, indicating a potential association with disease severity. In the late-onset group, all patients exhibited elevated transaminase levels, with four individuals (P1, P2, P4, and P7) experiencing liver failure, whereas only one patient in the early-onset group experienced liver failure. Coagulopathy was present in eight patients. Urinary orotic acid levels increased in all patients tested except for one, for whom specimens were retained after blood purification therapy. Furthermore, only six patients demonstrated decreased serum levels of citrulline.

2.3 Mutation analysis of the OTC

We detected nine distinct mutations in the OTC in ten patients, consisting of six missense mutations, two frameshift mutations, and one gross deletion (Table 2). Two of these mutations were previously unreported (NM_000531.6): c.1033del and c.167T > A. According to the ACMG guidelines, the variant c.1033del (p.Y345Tfs*50) was evaluated as pathogenic (PVS1 + PS2_Moderate + PM2) with clinical concordance and c.167T > A (p.M56K) as likely pathogenic (PM1 + PM2 + PM5 + PP3). Multiple sequence alignment using Clustal X. The methionine residue at position 56 and tyrosine residue at position 345 (highlighted by a red box) are highly conserved among different species (Fig. 1). The remaining seven variants (c.140del, c.1028C > G, c.116G > T, c.674C > T, exon5 del, c.77G > A, and c.725C > T) have been documented in HGMD, ClinVar, and the literature. Both variants identified in P1 and P2 were spontaneous and were not detected in the peripheral blood of the mother, and the mutations in the remaining eight patients were inherited from their healthy mothers.

Table 2

Molecular detective results and clinical outcomes identified in 10 patients with OTCD
Patient No	Chromosome position	Exon	Nucleotide change	Amino acid change	Variation type	Nature of mutation	Clinical type	Outcome
1	ChrX:38280302	E10	c.1033del	p.Y345Tfs*50	frameshift variation	De novo	LO	Liver Transplantation, Alive
2	chrX:38226606	E2	c.140del	p.N47Tfs*17	frameshift variation	De novo	LO	Deceased
3	chrX:38280298	E10	c.1028C > G	p.T343R	missense variation	Inherited	LO	Liver Transplantation, Alive
4	chrX:38226582	E2	c.116G > T	p.G39V	missense variation	Inherited	LO	Deceased
5	chrX:38226582	E2	c.116G > T	p.G39V	missense variation	Inherited	EO	Deceased
6	chrX:38226633	E2	c.167T > A	p.M56K	missense variation	Inherited	EO	Deceased
7	chrX38268005	E7	c.674C > T	p.P225L	missense mutations	Inherited	LO	low-protein diet, Drug
8	chrX:38401275–38401428	E5	exon5 del NM_000531.6	ND	CNV	Inherited	EO	Deceased
9	chrX:38212026	E1	c.77G > A	p.R26Q	missense variation	Inherited	EO	Deceased
10	chrX:38268136	E1	c.725C > T	p.T242I	missense variation	Inherited	EO	Deceased

The onset time of OTCD is correlated with the degree of enzyme activity deficiency, and the clinical symptoms are not specific. During the acute phase, the primary indications are neuropsychiatric symptoms caused by hyperammonemia, including sudden disturbances of consciousness, seizures, and ataxia. Digestive system symptoms, such as loss of appetite, vomiting, liver damage, and even acute liver failure (ALF), may accompany these symptoms ^6,7. Unfortunately, OTCD is often misdiagnosed as gastrointestinal disease, liver disease, food or drug poisoning, or intracranial infection, leading to delayed diagnosis and treatment and a high mortality rate^6–8.Hyperammonemia is a critical diagnostic indicator. In this study, we discovered that five male patients presented with early-onset symptoms, including feeding difficulties, drowsiness, groaning, and seizures, which appeared within 1–7 days of birth and were nonspecific. The main symptoms in the five late-onset cases were poor appetite, vomiting, lethargy, and abnormal liver function. Given the strong family histories of P5 and P8, the possibility of hereditary metabolic diseases was immediately considered upon hospital admission.In other cases, a uric acid circulation disorder was suspected due to a noticeable increase in blood ammonia levels. Therefore, blood ammonia levels should be promptly tested in patients with unexplained gastrointestinal symptoms, abnormal liver function, or encephalopathy. In patients with high levels of blood ammonia, blood amino acids and urinary organic acids should be immediately tested.Although early-onset patients exhibited significantly increased ammonia levels,late-onset patients exhibited greater variability. Despite receiving active treatment with blood purification,five patients with early-onset OTCD died due to brain injury caused by severe hyperammonemia. Among the five late-onset cases, two patients with significantly increased blood ammonia levels died despite active treatment, while two children who underwent liver transplantation survived. One patient (P7) with moderately increased blood ammonia levels improved after treatment but later presented with recurrent hyperammonemia and mild intellectual disability.These cases underscore the high mortality rate associated with OTCD and highlight the crucial role of blood ammonia levels in determining the disease severity and prognosis.

Most patients with OTCD are typically males with hemizygous OTC mutations, and a minority of female carriers with OTC mutations, accounting for approximately 20%, are symptomatic ². The onset of symptoms in heterozygous female individuals can occur at any age, and the clinical presentations can exhibit a broad spectrum of diversity. Hyperammonemia may be triggered by a variety of factors, such as high protein intake, acute illness, trauma, pregnancy, delivery, or corticosteroid intake ^{4, 7}, ^{9, 10}. Moreover, the clinical manifestations of OTCD in affected women within the same family may differ ⁹, ¹¹. Due to the coexistence of multiple underlying medical conditions, symptoms related to hyperammonemia are often overlooked in adult patients ⁹. Making the diagnosis of female OTCD exceedingly difficult. A 64-year-old woman with congestive heart failure, type 2 diabetes mellitus, impaired renal function, and obesity presented with lifelong aversion to proteins. She experienced vomiting, abdominal pain,drowsiness,and unexplained confusion 4–6 times annually. Unfortunately, these symptoms were not accurately diagnosed at the time. Following two visits to the emergency room for transient confusion, high blood ammonia levels were detected, and the patient was ultimately diagnosed with OTCD ¹². Marquetand et al. reported a 68-year-old heterozygous woman who developed hyperammonemia after consuming a large amount of protein ¹³. The four female heterozygotes in this study were all late-onset, showing mental disorders or abnormal liver function accompanied by serious clinical phenotypes, although they had developed and grown normally. A systematic review revealed reduced maternal and neonatal morbidity and mortality when OTCD was diagnosed before pregnancy compared to when it was diagnosed during pregnancy ¹⁴. Therefore, heterozygous women have a high risk of OTCD and require appropriate medical monitoring and management.

Urea cycle disorder (UCD) is the most common congenital metabolic defect of the liver. In fact, UCDs have been linked to both acute and chronic liver diseases, as reported in multiple studies ^15–18. Among UCDs, OTCD is the most common and is increasingly recognized for its association with liver complications, occurring in more than 50% of symptomatic patients with OTCD^15–17,19. Most commonly, these complications manifest as acute liver diseases(ALF) accompanied by coagulopathy^15,17–19.In some instances, ALF may be the first sign of OTCD ^{16, 19}. Furthermore, patients with acute hyperammonemia may experience recurrent episodes of ALF ^{17, 20}. Gallagher et al. showed that liver failure occurred in 58% of men with early-onset OTCD¹⁶. In a study by Lemler et al., ALF occurred in six of nine male patients with early-onset OTCD and in three of nine patients with late-onset OTCD, while six of 15 symptomatic female patients developed ALF ¹⁷. In summary, the literature suggests that ALF is the most common complication in male newborns with severe OTCD. In contrast, all four girls with late-onset OTCD in this study had ALF, whereas only one of five boys with early-onset OTCD experienced ALF. Although the association between hyperammonemia and ALF is clear, the exact pathophysiological sequence may be more complicated. Interestingly, among the five male early-onset OTCD patients with significantly increased blood ammonia levels, only one had ALF. Moreover, a late-onset patient with a peak blood ammonia level of 222 mol/L developed severe ALF, indicating that the blood ammonia level is not always the direct cause of liver failure. Studies have proposed that the inhibition of liver protein synthesis rather than nonspecific cell death due to hyperammonemia is a potential mechanism in hyperammonemia-induced ALF ¹⁷. One study showed that patients had a high rate of liver hyperechogenicity, which was present in 53% of female patients and 42% of male patients ¹⁵. In our study, four female patients underwent color Doppler ultrasound examination of the liver, of which three showed a hyperechoic liver and one did not. The specific significance of liver hyperechogenicity is unclear, and with improved diagnostic and therapeutic measures for OTCD, patient survival has improved. Further research is needed to investigate the underlying mechanisms of liver disease in OTCD to provide better treatment strategies for this complication.

The diagnosis of OTCD depends largely on mutations in the OTC, and there are 650 known pathogenic mutations (HGMD) with high genetic heterogeneity ^{1, 6}. In this study, nine OTC variants were detected in ten patients, seven of which were previously reported. The remaining two variants, c.1033del and c.167T > A, are novel. The heterozygous deletion of c.1033del resulted in a frameshift mutation, leading to the formation of a truncated protein (p.Y345Tfs*50) and a loss-of-function variant. ACMG has been identified as a pathogenic variant (PVS1 + PS2_Moderate + PM2). The c.167T > A missense variant is located in a highly conserved region of OTC enzymes at the junction of three crucial helices (helices 1, 5, and 11) that bridge the two domains of the protein ²¹. Therefore, this variant may affect interdomain alignment, thus affecting enzyme activity, as well as a mutation in the pathogenic amino acid residue p.M56T at this locus, which has been reported to be related to late-onset OTCD ^21–23. In addition, it may be show up as deleterious in prediction servers (Provean, Sift, MutationTaster, M-CAP, and REVEL). According to the pathogenicity classification of ACMG, this is likely to be a pathogenic mutation (PM1 + PM2 + PM5 + PP3).

Disease severity depends on OTC activity, which is influenced by the type and site of mutations ^{22, 24} and environmental factors, including daily protein intake ^{7, 8}. The complete loss of OTC function caused by large deletions, frameshifts, or nonsense mutations often leads to a severe neonatal onset^22,23. This study found that P8, with missing OTC exon 5, exhibited early-onset OTCD, and two patients (P1 and P2) with frameshift mutations showed severe late-onset OTCD. P2 experienced a severe hyperammonemia attack at the age of 3.5 years, ultimately succumbing to a hyperammonemic coma 4 days later. The c.140del variant of P2 has also been reported in a Chinese female patient who died after drug treatment ⁶. Some missense mutations can cause a complete loss of OTC function, leading to severe neonatal-onset diseases in hemizygous males and most symptomatic heterozygous females. Missense mutations that retain some OTC activity can cause late-onset diseases in hemizygous males ^22,23. This study identified six missense variants, with three causing severe early-onset, two causing late-onset, and one causing both early- and late-onset disease. Because our sample size was very small, we reviewed the literature and detected the missense mutation c.1028C > G in P3, which has a relatively mild late-onset clinical presentation. This mutation was previously found in a male late-onset patient without neurological damage ²⁵, suggesting that it may partially preserve OTC activity.

P4 and P5, who were siblings, were found to carry a heterozygous c.116G > T variant of the OTC gene. This mutation is located in a highly conserved region of the protein sequence, and 3D-modeling analysis demonstrated that the c.116G > T (p. Gly39Val) mutation induced an extension of the amino acid side chain and might distort the structure of the OTC protein. The c.116G > T (p.Gly39Val) variant is considered deleterious ²⁶. Notably, P4 and P5 had brothers who died a few days after birth due to unknown causes, presumably related to OTCD. This mutation was also detected in a Chinese male patient with early-onset disease²⁷. It is speculated that c.116G > T may result in early onset in male patients, whereas female individuals may experience late-onset disease with severe clinical symptoms.

P225L is a relatively common mutation in the Chinese OTCD population ⁶. It has been identified in several male patients with early onset, all of whom experienced severe hyperammonemia and died during the neonatal period ^{11, 27–30}. Two female individuals from the same family with late-onset disease were diagnosed at 20 months and 28 years of age, with varying degrees of symptoms ¹¹. In our study, patient P7 was found to carry the P225L variant and had an initial onset at the age of 1 year and 7 months, accompanied by liver failure and hyperammonemia. She was treated with a low-protein diet, medications, and blood purification. After her condition stabilized, she continued treatment with a low-protein diet and medications. She was hospitalized several times for hyperammonemia and abnormal liver function; however, she survived until the age of 7 years. Thus, P225L is characterized by severe early onset in males and milder late onset in females, but it can still lead to acute hyperammonemia.

The c.77G > A mutation was first reported in a 5-year-old Spanish boy who developed hyperammonemic coma at the age of 2 weeks. Despite appropriate diet and drug treatment, the patient exhibited mild intellectual disability ³¹. Two of his brothers also experienced unexplained coma and died on the 2nd and 3rd day after birth, respectively, presumably related to OTCD, but this was not confirmed. In addition, two Korean boys and one Chinese boy carrying the variant exhibited early-onset disease^{1, 28}. Kim reported a girl diagnosed with salt-wasting congenital adrenal hyperplasia after birth. Her condition was stabilized by steroid replacement therapy, but she developed hyperammonemia and hepatitis after consuming a high-protein diet for 2.2 years. OTC genetic testing revealed a c.77G > A missense mutation inherited from her healthy mother. Interestingly, her family also reported sudden neonatal death of a maternal aunt and uncle ³². In our study, P9 had an onset of symptoms only at 2 days of age. Thus, we speculated that the c.77G > A missense mutation is associated with early-onset OTCD in males and that a high-protein diet may induce acute hyperammonemia in females.

The c.725C > T mutation was found in a male patient with early-onset OTCD, who died 44 days after a low-protein diet and drug treatment ⁶. In our study, P10 also exhibited serious early onset. A case of late-onset disease with this mutation has been reported, but patient sex was not specified ²³. In summary, missense mutations that lead to early-onset disease in male patients and late-onset disease in female heterozygotes are often symptomatic. Among the ten patients with parental validation, eight had mutations in healthy mothers, which can partially be attributed to random X chromosome inactivation or mosaicism ^{2, 33}, reflecting the diversity of clinical manifestations of late-onset OTCD and the multi-factor influence of the OTC, while increasing the difficulty of prenatal diagnosis of female heterozygotes.

Overall,we analyzed the clinical and genetic characteristics of ten patients with OTCD and identified two novel pathogenic variants. The clinical symptoms of patients with OTCD are nonspecific, especially late-onset OTCD, and the biochemical phenotype may be a good predictor of OTCD. Hyperammonemia is an important diagnostic clue, whereas elevated urine orotic acid levels are highly specific. The prognosis of OTCD is closely related to liver complications. Further studies are needed to explore the potential mechanisms underlying OTCD liver disease. Further studies using animal models are required for the analysis of the detailed effects of the mutations in OTCD. Our sample size is small, and more samples are needed to deeply explore the correlation between genotype and phenotype.

OTCD ornithine carbamoyltransferase deficiency

OTC ornithine transcarbamylase

MS/MS tandem mass spectrometry

WES Whole-exome sequencing

ACMG American Academy of Medical Genetics and Genomics

UCD Urea cycle disorder

ALF acute liver diseases

ACKNOWLEDGMENT The authors wish to thank the patients and their families for their participation in this study.

AUTHORs’ CONTRIBUTIONS

GY and ZL conceived the study and wrote the first draft of the manuscript. WZ and DC helped critically revise the manuscript for important intellectual content and were the mentors who designed and guided the research study. XZ, ZC, and JW oversaw patient care and collected the clinical data. All authors contributed to manuscript revision, read, and approved the final submitted version of the manuscript.

FUNDING

This work was funded by Science and Technology Plan Project of Quanzhou Science and Technology Bureau (Grant No. 2022C002).

Data Availability

The datasets used and analyzed in the current study are available from the corresponding author upon reasonable request.

Ethics approval and consent to participate

This study was approved by the Medical Ethics Committee of Quanzhou Women’s and Children’s Hospital.All procedures in this study involving human participants were carried out in line with the principles of Helsinki Declaration.And informed consent from the patient's parents prior to conducting the exome sequencing had been obtained, including the patient's clinical details in the manuscript for the purpose of publication.

Consent for publication

The written informed consent was waived because of the retrospective and

anonymous nature of the data.

Competing interests

The authors declare no competing interests.

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published 11 Sep, 2024

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Editorial decision: Major revision
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Clinical characteristics and molecular genetic analysis of ten cases of ornithine carbamoyltransferase deficiency in southeastern China

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Abstract

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Introduction

Materials and Methods

Results

2.2 Biochemical results at OTCD diagnosis

Discussion

Conclusion

Abbreviations

Declarations

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References

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