Expanding Clinical Spectrums in Carbamoyl Phosphate Synthetase I deficiency: A Case Series of four patients - a tertiary institution's experience.
Biochemical/Metabolic and Therapeutics
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Introduction
CPS I deficiency is an autosomal recessive proximal urea cycle defect caused by a deficiency of the mitochondrial enzyme CPS I. This enzyme is the rate limiting step of the urea cycle and responsible for catalyzing the condensation of ammonia and bicarbonate into carbamoyl phosphate in the mitochondrial matrix. The symptoms of CPS1 deficiency can vary widely, manifesting at any age. Patients present with life-threatening hyperammonemia, and outcomes are poor with high morbidity and mortality. Typically, phenotypes are categorized into neonatal-onset and late-onset forms based on the age of onset.
Case Presentation
We present a case series of four patients with CPS1 deficiency who were evaluated and managed at our institution over an eighteen-month period. All four patients had biallelic variants in carbamoyl phosphate synthetase 1 (CPS1, MIM *608307).
Patient one was born term and presented on day of life (DOL) 3 with emesis, seizures, and an ammonia of >1000 µmol/L. Initial plasma amino acids revealed significantly elevated glutamine (1,415.4 µmol/L) and low citrulline (<2.0 µmol/L).
Patient two was born at 35 weeks gestation with pregnancy and delivery complicated by fetal growth restriction and placenta accreta requiring positive pressure ventilation and dextrose fluids at delivery. Physical exam was concerning for apnea, decreased arousal, hypertonia, and clonus. The ammonia level was >600 µmol/L and peaked at >1000 µmol/L. Initial plasma amino acids revealed an undetectable citrulline level and a glutamine of 2,276.4 µmol/L. The urine orotic acid was normal.
Patient three was born at term with irritability, emesis, and temperature instability at DOL1. Initial ammonia was 220 µmol/L which peaked at 635 µmol/L. Initial plasma amino acids had a citrulline level of < 2.0 umol/L and a glutamine of 1,250.7 µmol/L. The urine orotic acid was normal.
Patient four presented in the neonatal period and was managed for respiratory failure and seizures with hyperammonemia levels that required hemodialysis and ECMO. Patient was diagnosed at an outside hospital and initial glutamine, citrulline, and orotic acid levels were unavailable for review.
Diagnostic Workup
All patients were evaluated with biochemical and molecular testing. Patient one was found to be compound heterozygous for two pathogenic variants, c.3125A>C, p.(Asp1042Ala) and a pathogenic gene deletion including exon 13-14 in CPS1 respectively. Patient two was compound heterozygous for likely pathogenic variants, c.1003C>T, p.(Gln335*) and c.2140G>T, p. (Glu714*) in CPS1. Patient three was compound heterozygous for a pathogenic missense variant c.2339G>A, p.(Arg780His) and a variant of uncertain significance c.3092A>G, p.(Tyr1031Cys) in CPS1. Patient four was found to have homozygous likely pathogenic variants c.3945G>, p.(Gly982Asp) in CPS1.
Treatment and Management
Patients one, two, and three underwent emergency treatment with hemofiltration and high-dose intravenous Dextrose fluids. Treatment in all three have aimed at a combination of protein restriction, citrulline supplementation, and nitrogen scavengers.
Outcome and Follow-Up
Patient one is currently eighteen months old and received a liver transplant at one year of age after several admissions for hyperammonemic crises. Patient two is three months old and remains admitted with stable ammonia levels and awaiting liver transplant. Patient three is two months old and has had a complicated hospital course including iatrogenic occlusion of the superior vena cava with persistent chylous effusions secondary to central line placement. Patient four is currently six years old and received a liver transplant at 1 year of age. She remains globally delayed with Gastro-Jejunostomy tube dependence, epilepsy and severe hypertonia.
Discussion
We present a case series of four patients with clinically and molecularly distinct CPS1 deficiency as a means of understanding the variability in clinical course and present the novel Y1031C variant associated with the condition.
CPS I deficiency is an autosomal recessive proximal urea cycle defect caused by a deficiency of the mitochondrial enzyme CPS I. This enzyme is the rate limiting step of the urea cycle and responsible for catalyzing the condensation of ammonia and bicarbonate into carbamoyl phosphate in the mitochondrial matrix. The symptoms of CPS1 deficiency can vary widely, manifesting at any age. Patients present with life-threatening hyperammonemia, and outcomes are poor with high morbidity and mortality. Typically, phenotypes are categorized into neonatal-onset and late-onset forms based on the age of onset.
Case Presentation
We present a case series of four patients with CPS1 deficiency who were evaluated and managed at our institution over an eighteen-month period. All four patients had biallelic variants in carbamoyl phosphate synthetase 1 (CPS1, MIM *608307).
Patient one was born term and presented on day of life (DOL) 3 with emesis, seizures, and an ammonia of >1000 µmol/L. Initial plasma amino acids revealed significantly elevated glutamine (1,415.4 µmol/L) and low citrulline (<2.0 µmol/L).
Patient two was born at 35 weeks gestation with pregnancy and delivery complicated by fetal growth restriction and placenta accreta requiring positive pressure ventilation and dextrose fluids at delivery. Physical exam was concerning for apnea, decreased arousal, hypertonia, and clonus. The ammonia level was >600 µmol/L and peaked at >1000 µmol/L. Initial plasma amino acids revealed an undetectable citrulline level and a glutamine of 2,276.4 µmol/L. The urine orotic acid was normal.
Patient three was born at term with irritability, emesis, and temperature instability at DOL1. Initial ammonia was 220 µmol/L which peaked at 635 µmol/L. Initial plasma amino acids had a citrulline level of < 2.0 umol/L and a glutamine of 1,250.7 µmol/L. The urine orotic acid was normal.
Patient four presented in the neonatal period and was managed for respiratory failure and seizures with hyperammonemia levels that required hemodialysis and ECMO. Patient was diagnosed at an outside hospital and initial glutamine, citrulline, and orotic acid levels were unavailable for review.
Diagnostic Workup
All patients were evaluated with biochemical and molecular testing. Patient one was found to be compound heterozygous for two pathogenic variants, c.3125A>C, p.(Asp1042Ala) and a pathogenic gene deletion including exon 13-14 in CPS1 respectively. Patient two was compound heterozygous for likely pathogenic variants, c.1003C>T, p.(Gln335*) and c.2140G>T, p. (Glu714*) in CPS1. Patient three was compound heterozygous for a pathogenic missense variant c.2339G>A, p.(Arg780His) and a variant of uncertain significance c.3092A>G, p.(Tyr1031Cys) in CPS1. Patient four was found to have homozygous likely pathogenic variants c.3945G>, p.(Gly982Asp) in CPS1.
Treatment and Management
Patients one, two, and three underwent emergency treatment with hemofiltration and high-dose intravenous Dextrose fluids. Treatment in all three have aimed at a combination of protein restriction, citrulline supplementation, and nitrogen scavengers.
Outcome and Follow-Up
Patient one is currently eighteen months old and received a liver transplant at one year of age after several admissions for hyperammonemic crises. Patient two is three months old and remains admitted with stable ammonia levels and awaiting liver transplant. Patient three is two months old and has had a complicated hospital course including iatrogenic occlusion of the superior vena cava with persistent chylous effusions secondary to central line placement. Patient four is currently six years old and received a liver transplant at 1 year of age. She remains globally delayed with Gastro-Jejunostomy tube dependence, epilepsy and severe hypertonia.
Discussion
We present a case series of four patients with clinically and molecularly distinct CPS1 deficiency as a means of understanding the variability in clinical course and present the novel Y1031C variant associated with the condition.