Carbamoylphosphate synthetase 1 (CPS1) deficiency

Actionability Pediatric Summary Report

Secondary Findings in Pediatric Subjects. Non-diagnostic, excludes newborn screening & prenatal testing/screening.

• Gene: CPS1 (HGNC:2323)
• Mode(s) of Inheritance: Autosomal Recessive
• Literature Search: 03/16/2022
• Curation Status: Released (1.0.2)

Assertions and Scores

Actionability Assertions

Gene	Condition (MONDO ID)	OMIM ID	Final Assertion
CPS1	carbamoyl phosphate synthetase I deficiency disease (0009376)	237300	Strong Actionability

Actionability Assertion Rationale

• Despite the rubric calculating a preliminary actionability assertion as moderate, there were multiple components of the actionability scores (severity, effectiveness, and nature of the intervention) that scored in the moderate range but were considered by scorers to be on the higher end of moderate actionability. The intervention will clearly improve outcomes though may not normalize them. Given this rationale, all scorers agreed on a consensus assertion of strong actionability.

Actionability Scores

Outcome / Intervention Pair	Severity	Likelihood	Effectiveness	Nature of Intervention	Total Score
Morbidity and mortality due to hyperammonemic crises / Referral to a specialist for evaluation to guide dietary management, arginine/citrulline, nitrogen scavengers, and emergency management to mitigate hyperammonemic crises	2	3A	2B	2	9AB

Severity of Outcome

Prevalence of the Genetic Condition

Carbamoylphosphate synthetase I deficiency (CPS1 deficiency) has incidence estimates that range from 1/200,000 to 1/1,300,000.

Clinical Features (Signs / symptoms)

CPS1 deficiency is often considered the most severe of the urea cycle disorders (UCDs). It is characterized by the rapid accumulation of ammonia which can lead to encephalopathy and development of related symptoms. Clinical features are heterogenous depending on the age of the patient and on severity of the deficiency. Individuals with complete enzyme deficiency are typically normal at birth but rapidly develop symptoms of hyperammonemia, which are nonspecific and include failure to feed, loss of thermoregulation with a low core temperature, hyper- or hypoventilation, hypotonia, vomiting, seizures, neurologic posturing, and somnolence. Symptoms can progress from somnolence to lethargy and coma and potentially death. Individuals with partial deficiencies typically have a less severe presentation and symptoms are more subtle, with a hyperammonemic episode marked by loss of appetite, vomiting, lethargy, seizures, hypotonia, and behavioral abnormalities. Irritability, confusion, sleep disorders, delusions, hallucinations, and psychosis may occur. If untreated, hyperammonemia and its metabolites are neurotoxic and can cause irreversible brain damage in both the developing and mature brain.

Natural History (Important subgroups & survival / recovery)

Individuals with complete enzyme deficiency normally present in the newborn period. Historically, the outcome of newborns with hyperammonemia was considered poor, but with the rapid identification and current treatment strategies, survival has improved dramatically in the last few decades. In partial deficiency, the first recognized clinical episode may be delayed for months or years. In all individuals with CPS1 deficiency, ammonia accumulation may be triggered at almost any time of life by illness (e.g., febrile illness, infection, vomiting, diarrhea) or stress (e.g., surgery, prolonged fasting, protein loading, holidays, intense exercise, constipation, the peripartum period). Postpartum coma has been reported as a first manifestation in females. Prognosis depends on disease severity and time to diagnosis; with early diagnosis and optimal treatment started without delay, prognosis improves. However, children who are successfully rescued from crisis are chronically at risk for repeated bouts of hyperammonemia. Episodes of hyperammonemic coma of long duration are associated with a poor neurological outlook.

Likelihood of Outcome

Mode of Inheritance

Autosomal Recessive

Prevalence of Genetic Variants

< 1-2 in 100000

CPS1 deficiency has an incidence estimate that ranges from 1/200,000 to 1/1,300,000.

Tier 3

Penetrance (Includes any high-risk racial or ethnic subgroups)

>= 40 %

A meta-analysis of observational studies of individuals with CPS1 deficiency reported neonatal mortality and outcomes at the end of the first year of life:

• Among a total of 148 individuals, 75% (n=107) had early onset CPS1 deficiency (e.g., neonatal hyperammonemic crises)

• Among 107 individuals with early onset CPS1 deficiency, 64% survived their first year of life

• Among 23 individuals surviving their first year of life and had the relevant outcome data, 47% had developmental delay and 20% had normal outcomes.

Tier 1

Expressivity

Manifestations of partial CPS1 deficiency can vary among individuals in the same family having the same pathogenic variant genotype.

Tier 3

Intervention Effectiveness

Patient Management

The American College of Medical Genetics and Genomics (ACMG) has developed an ACT sheet to help clinical decision-making in the transition to adult health care for people with CPS1 deficiency: https://www.acmg.net/PDFLibrary/CPS-I-Deficiency-Transition.pdf.

The mainstay of long-term management is individualized treatment by a specialist metabolic dietitian. Management aims to maintain stable metabolic control, to reduce or eliminate chronic complications, and to achieve as close to normal development and growth as possible. Treatment includes medications to promote waste nitrogen excretion (nitrogen scavengers such as sodium benzoate, sodium phenylacetate, sodium phenylbutyrate, and glycerol phenylbutyrate); low-protein diet; and supplementation with arginine or citrulline, essential nutrients, and essential amino acids. A study of 88 individuals with UCDs (including 8 with CPS1 deficiency) reported that long-term management with protein restriction combined with more extensive management (L-arginine/L-citrulline, essential amino acid supplements, and nitrogen scavengers) was associated with increased survival in all UCDs compared to protein restriction alone (63.6% vs. 38.6%, respectively), though this difference was limited to cases that presented neonatally.

Tier 2

A study described outcomes in 3 patients with CPS1 deficiency identified prenatally and treated prospectively at birth with dietary modifications and sodium benzoate, sodium phenylacetate, and arginine. Two patients survived (follow-up of 49 and 125 months, respectively) and one patient only survived to 46 months. Though the surviving patients had some developmental delay, the authors concluded based on their experience that the outcomes were more favorable compared to patients rescued from hyperammonemic coma.

Tier 5

Given the risk of acute metabolic decompensation during surgery and general anesthesia, elective surgery should only be carried out in centers able and prepared to deal with hyperammonemic decompensations. The patient should be well, with normal preoperative ammonia and amino acid concentrations and without even minor intercurrent illness. Postsurgical close monitoring of the clinical status and ammonia is required.

Tier 2

High index and early clinical suspicion as well as prompt diagnosis of hyperammonemia are vital for a good outcome. The family should be taught to recognize the symptoms and signs to initiate treatment at earliest possible stage. An emergency regimen for treatment of intercurrent illness is recommended. A management plan should be provided to parents, caregivers, nursery, and school. The treatment of hyperammonemia is based on clinical status, with particular attention to any degree of encephalopathy, and should be started without delay. If the patient is not well or at risk of illness, emergency treatment could be initiated at home followed by hospital admission, if needed. Treatment aims to reduce the production of ammonia and includes cessation of protein intake, initiation of intravenous (IV) dextrose/glucose, intralipid infusions, anti-emetics, ammonia scavengers IV sodium benzoate/sodium phenylacetate mixture with IV L-arginine, oral sodium phenylbutyrate as IV nitrogen scavengers are stopped, , hydration therapy, and renal hemo(dia)filtration if needed. Any infection or constipation, which increase ammonia absorption from the gut, should be treated. Regular monitoring should include blood pH and gases, ammonia, urea and electrolytes, and glucose. If there is any hint of encephalopathy, neurological observations should be done at least hourly. The individual should be transferred to a specialist center without delay.

Tier 2

A 25-year open-label, uncontrolled clinical trial of IV sodium phenylacetate and sodium benzoate as an emergency treatment of acute hyperammonemia, including 41 patients with CPS1 deficiency, reported that individuals with CPS1 deficiency experienced a total of 203 episodes of hyperammonemia and that 83% survived all known hyperammonemic episodes over the 25-year period.

Tier 5

Successful pregnancies in UCD patients require addressing the special nutritional needs of pregnancy and lactation, avoiding undernutrition of protein. Continuation of treatment with nitrogen scavengers is generally necessary in pregnant individuals with UCDs. Based on biochemical mechanisms, the use of nitrogen scavengers is suggested. There is insufficient evidence to comment on fetal outcomes after nitrogen scavenger therapy in pregnancy. Close monitoring during and early after delivery is essential to recognize hyperammonemia within the first 5 days after delivery.

Tier 2

Liver transplant is the only “curative” treatment and allows for a normal diet without nitrogen scavengers. It is recommended for consideration in individuals with severe UCDs without sufficient response to standard treatment, with poor quality of life, without severe neurological damage, and while in stable metabolic condition. It is recommended to be undertaken between 3 and 12 months of age when the body weight exceeds 5kg to maximize outcomes. However, liver transplant will not reverse preexisting neurological damage. Though no evidence is available for CPS1 deficiency, the same overall posttransplant survival has been found in ornithine transcarbamylase deficiency (OTCD) and in non-UCD individuals. Survival rates in large pediatric programs attain now ~95% at 1 year and ~90% at 5 years, with self-reported “good” or “excellent” quality of life posttransplant. In a study of 186 children with UCDs, the 5-year patient survival rate was 88% for children younger than 2 years old at transplant and 99% for children 2 years or older at transplant.

Tier 2

Surveillance

Individuals with UCDs require lifelong monitoring by a multidisciplinary team. Clinical and biochemical monitoring depends on age and metabolic status. Young and severely affected individuals should be seen at least every 3 months while older or less severely affected individuals may only need annual appointments.

• Record growth and head circumference; inspect for thin, sparce hair or hair loss, skin rashes, or other signs of protein/vitamin deficiency

• Brain MRI, even in the absence of neurological and/or cognitive impairment, with timing based on the individual

• Neurological and neurocognitive assessments should be performed at regular intervals even in individuals with milder presentation

• Liver size and structure should be assessed by ultrasound scan

• Regular dietary assessment is essential, including review of supplementations

• Monitor plasma ammonia and amino acid profile as well as vitamin, mineral, trace elements, carnitine, ferritin, cholesterol, triglyceride, alpha-fetoprotein, and essential fatty acid levels

• Psychological monitoring and counseling to address health-related quality of life, anxiety, stress, and psychosocial factors.

Tier 2

Circumstances to Avoid

Steroids should be avoided as they increase the amount of protein turnover and hence increase the nitrogen load.

Tier 2

Valproic acid should be avoided in any patient who has known risk for hyperammonemia. It is known to decrease urea cycle function by inhibition of N-acetylglutamate synthase.

Tier 2

Nature of Intervention

Nature of Intervention

Long-term treatment of UCDs is challenging for patients and families because of the poor palatability of the diet, the volume and frequency of diet and drug administrations; all these are serious barriers to adherence. Hyperammonemia treatment includes cessation of protein intake and interventions (medications, dialysis) for ammonia removal. Nitrogen scavengers may be administered orally as a powder, capsule, tablet, or liquid. During a hyperammonemic crisis, nitrogen scavengers may be oral or intravenous depending on severity of the clinical status. Adverse reactions associated with ammonia scavengers include hypotension, injection site reaction, hyperglycemia, hypokalemia, hypernatremia, vomiting, diarrhea, altered mental status, seizure, cerebral edema, and fever. Sodium phenylbutyrate causes amenorrhea or menstrual dysfunction in 25% of females, decreased appetite, taste disturbances, body odor, and can deplete branch chain amino acids which increases the risk of endogenous protein catabolism. Sodium benzoate and sodium phenylbutyrate can cause mucositis or gastritis in the granule, tablet, or undiluted liquid preparations. Metabolic acidosis has been observed with high doses of nitrogen scavengers. Adverse reactions associated with IV L-arginine include hyperchloremic metabolic alkalosis, hypokalemia, elevated BUN and creatinine levels, hypotension, flushing, nausea, vomiting, abdominal cramps, bloating, numbness, and headache.

Context: Adult Pediatric

Chance to Escape Clinical Detection

CPS1 deficiency is screened for in newborns in several states. However, the sensitivity and specificity of screening varies by state, and current newborn metabolic screenning cannot reliably identify all cases. Additionally, even for UCDs detectable by newborn screening, neonates are often symptomatic prior to availability of the screening results; thus a high level of clinical suspicion on the part of health care providers is necessary.

Context: Adult Pediatric

Tier 4

UCDs may present with acute, chronic, or intermittent symptoms at any age and in many cases a precipitating factor cannot be identified. Clinical signs and symptoms may be subtle and nonspecific and commonly neurological, gastrointestinal, or psychiatric.

Context: Adult Pediatric

Tier 4

Under-recognition and delayed diagnosis of UCDs is widespread.

Context: Adult Pediatric

Tier 4

Gene Condition Association

Gene			Condition Associations
			OMIM Identifier	Primary MONDO Identifier	Additional MONDO Identifiers
			CPS1			237300	0009376

References List

ACMG. American College of Medical Genetics ACT Sheet. Transition to Adult Health Care ACT Sheet: Carbamoyl Phosphate Synthetase I (CPS I) Deficiency [Urea Cycle Disorder]. (2012) Accessed: 2022-07-20. URL: https://www.acmg.net/PDFLibrary/CPS-I-Deficiency-Transition.pdf

Adult Emergency Management: Oral Emergency Regimen. British Inherited Metabolic Disease Group (BIMDG) (2017) URL: https://www.bimdg.org.uk/tempdoc/09062022_164342_BIMDG_ADULT-OralERGeneral_2017_holding_898483_05042017.pdf

Adult Emergency Management: Urea Cycle Defects. British Inherited Metabolic Disease Group (BIMDG) (2014) URL: https://bimdg.org.uk/store/guidelines/ADULT_UCD-rev_2015_422170_09012016.pdf

Alfadhel M, Mutairi FA, Makhseed N, Jasmi FA, Al-Thihli K, Al-Jishi E, AlSayed M, Al-Hassnan ZN, Al-Murshedi F, Häberle J, Ben-Omran T. (2016) Guidelines for acute management of hyperammonemia in the Middle East region. Therapeutics and clinical risk management. 12(1176-6336):479-87.

Burgard P, Kölker S, Haege G, Lindner M, Hoffmann GF. (2016) Neonatal mortality and outcome at the end of the first year of life in early onset urea cycle disorders--review and meta-analysis of observational studies published over more than 35 years. Journal of inherited metabolic disease. 39(1573-2665):219-29.

CARBAMOYL PHOSPHATE SYNTHETASE I DEFICIENCY, HYPERAMMONEMIA DUE TO 1986 (updated 2021). OMIM (2021) URL: https://www.omim.org/entry/237300

Carbamoyl-phosphate synthetase 1 deficiency. Orphanet encyclopedia, http://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=en&Expert=147

Enns GM, Berry SA, Berry GT, Rhead WJ, Brusilow SW, Hamosh A. (2007) Survival after treatment with phenylacetate and benzoate for urea-cycle disorders. The New England journal of medicine. 356(1533-4406):2282-92.

General dietary information for emergency regimens. British Inherited Metabolic Disease Group (BIMDG) (2017) URL: https://www.bimdg.org.uk/store/guidelines/General_dietary_information_for_ER_2016_441245_09092016.pdf

Häberle J, Burlina A, Chakrapani A, Dixon M, Karall D, Lindner M, Mandel H, Martinelli D, Pintos-Morell G, Santer R, Skouma A, Servais A, Tal G, Rubio V, Huemer M, Dionisi-Vici C. (2019) Suggested guidelines for the diagnosis and management of urea cycle disorders: First revision. Journal of inherited metabolic disease. 42(1573-2665):1192-1230.

Hyperammonemia: Urea Cycle Disorders OTC And CPS Deficiencies. British Inherited Metabolic Disease Group (BIMDG) (2017) URL: https://bimdg.org.uk/store/guidelines/ER-UCD1-v4_256112_09092016.pdf

Maestri NE, Hauser ER, Bartholomew D, Brusilow SW. (1991) Prospective treatment of urea cycle disorders. The Journal of pediatrics. 119(0022-3476):923-8.

N Ah Mew, BC Lanpher, A Gropman, KA Chapman, KL Simpson, , ML Summar. Urea Cycle Disorders Overview. (2003) [Updated Apr 09 2015]. In: RA Pagon, MP Adam, HH Ardinger, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2026. Available from: https://www.ncbi.nlm.nih.gov/books/NBK1217/

Raina R, Bedoyan JK, Lichter-Konecki U, Jouvet P, Picca S, Mew NA, Machado MC, Chakraborty R, Vemuganti M, Grewal MK, Bunchman T, Sethi SK, Krishnappa V, McCulloch M, Alhasan K, Bagga A, Basu RK, Schaefer F, Filler G, Warady BA. (2020) Consensus guidelines for management of hyperammonaemia in paediatric patients receiving continuous kidney replacement therapy. Nature reviews. Nephrology. 16(1759-507X):471-482.