Art. 1.9973

European Review for Medical and Pharmacological Sciences

2020; 24: 10051-10053

Long-term survival of a patient with acuteneonatal-onset metabolic encephalopathy withcarbamoyl phosphate synthetase 1 deficiency
G. IMATAKA1, J. ISHII1, Y. ANDO1, S. YOSHIHARA1, Y. TAKAGI1, A. NITTA1,2,O. ARISAKA1,3, S. YOSHIHARA1
Department of Pediatrics, Dokkyo Medical University, Tochigi, Japan
Department of Pediatrics, Saitama Medical Center, Dokkyo Medical University, Saitama, Japan3
Department of Pediatrics, Nasu Red Cross Hospital, Tochigi, Japan1
2Abstract. – OBJECTIVE: Long-term sur-vival of patients with neonatal-onset carbamoyl-phosphate synthetase 1 deficiency (CPS1D),
an autosomal recessive disorder characterized
by repeated, life-threatening hyperammonemia,is rare. We describe the diagnosis and clinicalmanagement of a teenager with neonatal-onset CPS1D who did not undergo therapeutic liver transplantation.
CASE REPORT: Following emergent neonatal
therapy, the patient was diagnosed with CPS1D
based on clinical, radiological, biochemical andgenetic analyses. Her clinical course, neurobehavioral development and therapeutic interventions are presented and discussed.
RESULTS: Born from nonconsanguineousparents, the proband underwent phototherapy
for neonatal jaundice, associated with acuteencephalopathy, apnea and cerebral edema.
Based on blood and urinary biochemical abnormalities, neonatal-onset CPS1D was diagnosed.
Her hyperammonemia was corrected by hemodialysis, followed by sodium benzoate, L-arginine, levocarnitine and protein-free diet therapy. Because of a relapse and persistent neurobehavioral regression by age 1, a planned liver transplantation was cancelled. At age 10, sodium phenylbutyrate was substituted as ammonia scavenger. Genetic testing revealed compound heterozygote c.2359C>T (R787X) andc.236+6T>C variants of CPS1, confirming her diagnosis. Despite severe neurological sequelae,
the patient is 16 and in stable condition.
CONCLUSIONS: Our case suggests that early hemodialysis and pharmacologic interventions for acute neonatal hyperammonemia can
improve the prognosis of patients with neonatal-onset CPS1D.
Key Words:
Carbamoyl phosphate synthase 1 deficiency, Neonatal, Hemodialysis.

Introduction
Carbamoyl phosphate synthase is an important
enzyme involved in the synthesis of carbamoyl
phosphate from ammonia in the urea cycle. Carbamoyl phosphate synthase 1 deficiency (CPS1D)
is a rare autosomal recessive disorder with aninborn error of metabolism1. The onset of CPS1D
includes the early neonatal type (develops during
the first few days after birth) and late type (occurs in adulthood)2. The initial symptoms of
neonatal-onset CPS1D include respiratory andconsciousness disorders and convulsions within a few days after birth3. CPS1D commonly
progresses with acute metabolic encephalopathy
associated with acute severe hyperammonemia
resulting in early postnatal death1,4. In this letter,
we report on the long-term survival of a patient
despite neonatal-onset CPS1D and severe neurological sequelae.
Case Report
The patient was born spontaneously during
the 38th week of pregnancy from nonconsanguineous parents and has a healthy brother. She
had been drinking milk since she was born.
On the third to the fourth day after birth, thepatient ran a fever of 38 degrees. On the fifthday, the patient underwent phototherapy for neonatal jaundice, after which she was referred toour neonatal intensive care unit (NICU) due torepeated vomiting and consciousness disorder.
After admission to the NICU, the patient experienced frequent apnea and partial seizures. Braincomputed tomography showed occipital-dominant mild cerebral edema and subarachnoid andsubdural hemorrhages. Therefore, we adminis-Corresponding Author: George Imataka MD. PhD, BPhil, LLB, PGDBA; e-mail: geo@dokkyomed.ac.jp 10051

G. Imataka, J. Ishii, Y. Ando, S. Yoshihara, Y. Takagi, A. Nitta, O. Arisaka, S. Yoshihara

tered the patient artificial respiration. The bloodgas tests revealed a pH, bicarbonate levels, Base
Excess and anion gap of 7.277, 16.6 mmol/L,−9.7 mmol/L, and 24.7 mEq/L, respectively.
Moreover, blood tests revealed that aspartate
aminotransferase, alanine aminotransferase, andlactate dehydrogenase levels had increased to99 U/L, 22 U/L, and 906 U/L, respectively. The
blood glucose level was normal, and the urinary
ketone test was negative. The blood ammonia
level was abnormally high at 3197 μg/dL, andblood amino acid analysis showed a decreasein citrulline to 6.3 μmmol/L. Urinary organicacid analysis showed no excretion of orotic acid.
Therefore, the patient was biochemically diagnosed with neonatal-onset CPS1D.
On day six, the patient was transferred toanother medical center and treated with hemodialysis for hyperammonemia due to acutemetabolic encephalopathy. After 30 h of dialysis, her blood ammonia levels improved to 131
μg/dL. The patient was started on sodium benzoate (320 mg/kg/day), arginine (400 mg/kg/day), and levocarnitine (40 mg/kg/day), and herammonia levels were controlled. At one month,
the patient was diagnosed through ultrasonography with encephalomalacia and ventricularenlargement. After the diagnosis, the patient’s
blood ammonia levels frequently increased;
therefore, she started on a special protein-freemilk. At the age of ten months, she began
to sit with support. The patient frequentlylaughed, and her motor developed as expected.
We, therefore, planned for a living-donor livertransplantation from her parents. After thetransplantation had been planned, the patient
relapsed into hyperammonemia due to a viral
infection and was treated in the ICU. By theage of one year, her movement abilities and in-telligence had regressed, she was unable to eat
orally and had to be tube fed, and she showedpersistent neurological sequelae. Therefore, wecanceled her liver transplantation surgery andcontinued physical therapy rehabilitation. The
patient’s hepatic enzyme activity was not measured.
During her childhood, the patient experienced repeated vomiting and was diagnosed
with gastroesophageal reflux disease. She required duodenal tube feeding and treatmentwith intravenous hyperalimentation. At the ageof nine years, she underwent gastric fistula
surgery for the gastroesophageal reflex. Cephalic computed tomography revealed dilationof both lateral ventricles and cerebral atrophy(Figure 1). At the age of ten years, the patientbegan therapy with 450 mg/kg/day of sodium
phenylbutyrate, resulting in more stable bloodammonia levels. At the age of 12 years, sheexperienced repeated aspiration pneumonia. At
the age of 13 years, she underwent tracheotomy and laryngotracheal isolation surgery. For
her chronic respiratory failure, the patient employed a small home mechanical ventilator. At
approximately 14 years of age, the patient experienced her menarche. Numerous complications such as partial epilepsy, hypothyroidism,
diabetes mellitus, ulcerative colitis, proximal
tubular acidosis, osteoporosis, bone fractures,and urinary tract infections because of rectal
vaginal fistula were observed during this time.
Once the patient reached 16 years of age, weobtained informed consent from her parents
and analyzed the amino acid changes at theCPS1 gene on chromosome 2 through genetic testing. We analyzed the CPS1 gene using
targeted next-generation sequencing employing the hybrid capture method on one of theFigure 1. At 9 years of age, the patient’s brain CT revealed severe cerebellar cortex atrophy compared with the preserved
cerebellum. Leukoencephalopathy and ventricular enlargement can also be observed

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Long-term survival of a patient with acute neonatal-onset metabolic encephalopathy with CPS1D

patient’s blood samples, resulting in the confirmation of 2 mutations: c.236 + 6T > C andc.2359C > T, exon 19, p.Arg787X. Despite her
severe intellectual motor development disorder,
the patient’s physical condition was stable, andshe is currently recovering at home with herfamily.

Discussion
CPS1D is a rare congenital inborn error of metabolism, and its incidence rate has been reported
to range from 1 in 300,000 to 800,0005,6. Manycases of CPS1D develop within a few days after
birth as neonatal onset and tend to result in death
due to acute hyperammonemia and metabolic
encephalopathy. There are numerous reports ofgenes involved in patients with CPS1D; however,there have been few reported cases of long-term
survival. Kurokawa et al2 reported 24 Japanesecases of CPS1D, including 19 neonatal patients.
Thirteen of whom died within 60 days and nineof whom died within 2 weeks after birth. Only
one patient underwent liver transplantation, andmental retardation was not noted. Considering
the prognosis of neonatal CPS1D is usually fatal,
our detailed clinical report of long-term survival
without liver transplantation is invaluable.

Conclusions
Our case suggests that hemodialysis and theappropriate administration of sodium phenylbutyrate, sodium benzoate, arginine, and levocarnitine for acute neonatal hyperammonemia canimprove the prognosis of patients with neonatal-onset CPS1D.

Conflict of Interest
The Authors declare that they have no conflict of interests.

Authors’ Contribution

J.I, Y.A, Shinya Yoshihara and Y.T treated and collected data of the patient in general ward. G.I, A.N and O.A were thetreated patient in intensive care unit. G.I and Y.T analyzed
patient’s genetic samples. O.A and Shigemi Yoshihara supervised the findings of this work. G.I wrote this paper andall authors approved the final manuscript.

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