Continuing Education Activity

This educational activity addresses urea cycle disorders, a group of inherited metabolic conditions that impair the conversion of ammonia to urea and can rapidly cause severe neurologic injury, liver dysfunction, and death if not recognized early. A major practice gap exists in the timely identification and treatment of hyperammonemia, particularly in newborns and other patients with nonspecific symptoms such as poor feeding, vomiting, lethargy, tachypnea, encephalopathy, or psychiatric changes. This activity is designed to narrow the practice gap by strengthening clinicians’ ability to recognize high-risk presentations, interpret diagnostic studies, differentiate urea cycle disorders from other causes of encephalopathy, and initiate urgent evidence-based treatment. Participants are expected to gain improved diagnostic accuracy, more effective acute and long-term treatment strategies, better risk assessment for neurologic complications, and stronger interprofessional coordination to improve patient-centered outcomes across the continuum of care.

Objectives:

• Identify clinical presentations and risk factors that should raise suspicion for urea cycle disorders in newborns, children, and adults with encephalopathy, liver dysfunction, or hyperammonemia.
• Differentiate urea cycle disorders from neonatal sepsis, congenital infection, transient hyperammonemia of the newborn, liver failure, medication reactions, and other inborn errors of metabolism.
• Assess the risk of neurologic injury, developmental impairment, and other complications associated with delayed diagnosis or prolonged hyperammonemia in patients with urea cycle disorders.
• Coordinate care with neonatology, genetics, nephrology, neurology, hepatology, nutrition, and developmental specialists to improve diagnostic efficiency, treatment timing, and longitudinal patient outcomes.

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Introduction

Urea cycle disorders (UCDs) are a type of inborn error of metabolism (IEM) resulting from genetic defects in any one of the 6 enzymes or 2 transporters involved in the hepatic conversion of ammonia to urea, which is then excreted by the kidneys.[1] As the name suggests, IEMs are a heterogeneous group of disorders caused by errors in the cellular pathways involved in the metabolism of carbohydrates, fats, and proteins. A block at any level of the pathway can cause metabolites to accumulate in the body, leading to toxicity if not removed. 

Protein metabolism releases amino acids, and their deamination generates ammonia. Ammonia presents as ammonium at physiological pH. Ammonia is extremely toxic, particularly to the central nervous system.[1] Newborns with defects in the proximal enzymes of the urea cycle (see Image. The Urea Cycle) can become catastrophically ill within 24 to 48 hours after birth despite normal physical examination findings at birth. Hyperammonemia is the key to diagnosing UCDs, and treatment should be prompt while a final diagnosis is still being evaluated.

Etiology

The urea cycle is a complex pathway because multiple proteins in 2 subcellular compartments (the mitochondrial matrix and the cytoplasm) are involved.[2] The first 2 enzymatic steps in the urea cycle take place in the mitochondrial matrix, and all other remaining steps occur in the cytoplasm. In total, 8 types of UCDs are due to a defect in the urea cycle pathway (see Image. The Urea Cycle).[2][3][4][5]

• Carbamoyl phosphate synthetase 1 deficiency: Carbamoyl phosphate synthetase I (CPS1) is an enzyme that ligates ammonia with bicarbonate to form carbamoyl phosphate, which then enters the urea cycle (see Image. The Urea Cycle). CPS1 is a significant enzyme and is considered a rate-limiting step in the urea cycle. Stressors such as sepsis can easily initiate defects in CPS1, resulting in the severe form of UCDs and hyperammonemia presenting in the neonatal period. CPS1D is inherited in an autosomal recessive manner (gene location in 2q34-35).
• N-acetylglutamate synthase deficiency: The conversion to carbamoyl phosphate also requires N-acetylglutamate, which is an allosteric activator of CPS1. N-acetylglutamate is formed from glutamate and acetyl-Coenzyme A in a reaction catalyzed by N-acetylglutamate synthase (NAGS), a mitochondrial enzyme. Although rare, defects in NAGS mimic CPS1D. NAGSD is also autosomal recessive (gene located on 17q21.3).
• Ornithine transcarbamylase deficiency: Ornithine transcarbamylase (OTC) catalyzes the reaction between carbamoyl phosphate and ornithine to form citrulline. The gene encoding OTC is located on the X chromosome (Xp21.1, in the Online Mendelian Inheritance in Man database, MIM 311250: Xp11.4), and OTC defects are inherited in an X-linked manner. Defect in OTC is the most common cause of UCDs. In boys, the condition presents with a severe phenotype in the neonatal period. In girls, presentation is variable, ranging from asymptomatic to severe, depending on the random nature of X chromosome inactivation, and clinical symptoms may present late in the course of the disease.
• Mitochondrial ornithine transporter 1 deficiency: Ornithine transporter 1 (ORNT1) protein is a mitochondrial transporter protein involved in 2 pathways in the urea cycle. ORNT1 facilitates the transport of ornithine from the cytosol to the mitochondrial matrix (thus supporting the formation of citrulline) and the subsequent reverse transport of citrulline from the mitochondria into the cytosol. The deficiency is also called hyperornithinemia, hyperammonemia, and homocitrullinuria syndrome (HHH syndrome). Patients present with symptoms of hyperammonemia, which could be intermittent, along with abnormalities in coagulation. ORNT1 is encoded by the SLC25A15 gene (located on 13q14).
• Argininosuccinate synthetase deficiency: Argininosuccinate synthase 1 (ASS1) catalyzes the formation of argininosuccinate from citrulline and aspartate. Defects in ASS1 result in both citrullinemia and hyperammonemia. This step also involves citrin, which transports both aspartate and glutamate. ASSD, also denoted as citrullinemia type 1, can manifest as a variable clinical spectrum, ranging from mild to severe clinical symptoms at any age. ASSD is also autosomal recessive (the gene is located on 9q34).
• Citrin deficiency: Citrin is a carrier that contributes to the cytoplasmic pool of aspartate by transporting it from mitochondria into the cytoplasm, where it is needed for the urea cycle. Citrin also transports glutamate from the cytoplasm back into the mitochondria. Citrin deficiency can cause citrullinemia type 2, which presents with mild symptoms, often causing cholestasis in neonates, and can also present in older age. Citrin is encoded by the SLC25A13 gene (7q21.3).
• Argininosuccinate lyase deficiency: Argininosuccinate lyase (ASL) converts argininosuccinate into arginine and fumarate. Defects in ASL can cause a severe UCD in neonates as well as clinical symptoms of liver dysfunction. In the adult-onset form, it affects cognition as well as other organ systems. In addition to ammonia, elevated plasma levels of argininosuccinate and citrulline are characteristic of ASL deficiency. This defect is also autosomal recessive and is caused by a mutation in the ASL gene (located on 7q11.2).
• Arginase deficiency: Arginase 1 (ARG 1) is the enzyme involved in the last step of the urea cycle (see Image. The Urea Cycle), and helps in the cleavage of arginine into urea and ornithine. Defects in ARG1 can result in both argininemia and hyperammonemia. The symptoms of arginase deficiency usually appear later in childhood, as developmental delays and limb spasticity, without a rapid onset of hyperammonemia. ARGD is also inherited as an autosomal recessive pattern (gene located on 6q23).

Epidemiology

The combined incidence of UCDs is estimated to be 1 in 35,000 live births. The incidence of ornithine transcarbamylase deficiency is 1 in 56,500, followed by argininosuccinate lyase deficiency as 1 in 218,750, and argininosuccinate synthase deficiency as 1 in 250,000 live births. OTC deficiency accounts for approximately two-thirds of all UCDs, followed by argininosuccinate synthase 1 deficiency (approximately 20%) and argininosuccinate lyase deficiency (approximately 10%). N-acetylglutamate synthase deficiency is the rarest form, occurring in fewer than 1 in 2 million births.[6]

Pathophysiology

The understanding of the pathophysiology of UCDs has advanced significantly recently, which may ultimately lead to improved medical interventions.[4] Hyperammonemia is a key etiological factor in UCDs and plays a vital role in central nervous system toxicity. The toxic effects of ammonia are more catastrophic to the developing brain than to the adult brain.

The reversibility of ammonia's toxic effects depends on the duration of exposure, the severity of ammonia elevation, and the stage of neurological development at the time of exposure. In the newborn brain, hyperammonemia leads to cerebral edema due to astrocyte swelling. Acute hyperammonemia activates N-methyl-D-aspartate receptors, leading to excitotoxic cell death, mitochondrial dysfunction, and disruption of the glutamate-glutamine cycle.[7]

The subsequent frequency and extent of cerebral swelling further determine the severity of neurological manifestations such as seizures, coma, and cognitive/motor deficits.[1] All the UCDs (CPS1D, NAGSD, ASSD, ORNT1D, citrin deficiency, ASLD, ARGD) follow an autosomal recessive pattern, except ornithine transcarbamylase deficiency, which is inherited in an X-linked manner.[3][4] Unexplained neonatal death in the family can indicate possible inherited UCDs, and hence a detailed family history is important.[5] 

History and Physical

The urea cycle disorders can present early in the neonatal period (especially OTCD, CPS1D, and NAGSD) or have a delayed onset (infancy through adulthood), depending on the UCD subtype, with varied presentations involving the central nervous system, liver, and other systems. Several factors, such as illness, fever, and stress, can increase protein catabolism, leading to hyperammonemia and thereby triggering symptoms.[3][8] The neonatal presentation in severe UCDs is often a newborn with initially normal physical examination findings who develops decreased feeding, vomiting, irritability, lethargy, tachypnea, followed by rapid signs of encephalopathy like posturing, seizures, coma, and even death.[1][9] 

Hyperammonemia can affect the developing brain, with symptoms such as cognitive impairment, seizures, and cerebral palsy, which may manifest later in life.[1][10] For UCDs that present later in life and in adulthood, the symptoms can be suggested by the effects of hyperammonemia in the brain and liver. Patients can have frequent headaches, developmental delays, limb spasticity, seizures, psychiatric symptoms, protein aversion, or symptoms of liver dysfunction.[11]

Evaluation

Infants presenting with clinical symptoms initially should also be evaluated for neonatal sepsis. The laboratory examination findings in UCDs typically demonstrate respiratory alkalosis (secondary to hyperventilation), which is usually significant. The key biomarker is an elevated ammonia level.[9][12] Hyperammonemia is considered when levels are greater than 100 μmol/L in neonates or greater than 50 μmol/L in term infants, children, and adolescents.[13] 

In newborns presenting with urea cycle disorders, ammonia concentration can exceed 500 μmol/L. Other metabolic tests include lactic acid, plasma amino acids, urinary organic acids, and plasma acylcarnitines. Urine orotic acid should also be evaluated in the presence of hyperammonemia. The type of urea cycle defect can be identified based on plasma/urine analytical parameters.[5] The block at different levels of the urea cycle leads to increased levels (elevated plasma glutamate, alanine, or variable arginine level).[14] Activity assays of urea cycle enzymes can aid diagnosis, although molecular genetic testing can confirm the final diagnosis of urea cycle defects.[3][5]

Treatment / Management

Patients with urea cycle disorders should be treated intensively. Newborns should be treated in a neonatal intensive care unit by a neonatologist, with consultation with an appropriate genetics and metabolic expert. The immediate treatment goal is to rapidly lower ammonia, limit dietary protein intake, and address ongoing stress. Infants should be started on intravenous fluids (including 10% dextrose or higher for calories) and intravenous lipids to provide nutrition.

Arginine hydrochloride, sodium phenylacetate, and sodium benzoate help lower ammonia levels and should be started intravenously under the supervision of a metabolic specialist. Severe cases with very high ammonia levels may require immediate hemodialysis.[8][15] Hence, the nephrology team should also be consulted immediately.

Peritoneal dialysis is usually not recommended because it is inefficient at removing ammonia; it may be considered if hemodialysis cannot be performed.[16] After an initial protein-free period of 24 to 48 hrs, supplementation with branched-chain amino acids should be considered, as their levels are reportedly low.[3][5][14] After the acute phase, when the patient exhibits clinical and laboratory improvement (eg, ammonia levels), protein-free enteral feeds should be initiated cautiously, with a gradual addition of protein under strict supervision. The long-term management of UCDs comprises a low-protein diet, the addition of certain amino acids, nutrients, and medications (for nitrogen excretion) to support optimal growth, and diet supervision by a metabolic team and dietitian.[5]

For long-term treatment, glycerol phenylbutyrate has been introduced as a better-tolerated alternative to sodium phenylbutyrate, with evidence of improved ammonia control and executive function in pediatric patients.[5][17] N-carbamylglutamate (carglumic acid) is an analog of N-acetylglutamate and could be considered in oral or enteral treatment of N-acetylglutamate synthase deficiency and carbamoyl phosphate synthetase 1 deficiency.[18] Patients with severe disease who are not medically treated would eventually require a liver transplant. Liver transplant corrects the metabolic defect, with 5- and 10-year survival rates exceeding 90%.[19] Emerging gene therapy approaches, including adeno-associated virus-based gene addition and in vivo gene editing for ornithine transcarbamylase deficiency, are currently under clinical investigation and may provide curative options without the need for lifelong immunosuppression.[5][20][21][22]

Differential Diagnosis

UCDs should be considered at any age if there are signs of encephalopathy, liver involvement, or hyperammonemia.[5][16] The most common conditions in the differential diagnosis include:

• Neonatal sepsis
• Inborn error of metabolism (eg, fatty acid oxidation defects, organic acidemia)
• Congenital infection
• Transient hyperammonemia of the newborn
• Liver failure
• Exogenous toxins
• Medication reaction
• Reye syndrome

Prognosis

UCDs manifest in most (50%) of cases as neonatal hyperammonemia, and have an increased mortality (25%-50%). Survivors can often have severe neurological sequelae.[5] Prolonged hyperammonemia or ammonia levels between 200 and 500 μM in the initial years of life can lead to irreversible brain damage.[1] Additionally, patients who present at a later age can have adverse outcomes.[5]

Complications

Urea cycle disorders can result in extremely elevated serum ammonia levels, leading to severe effects on the brain, liver, and other organs. Patients require treatment to remove the ammonia, and may eventually need hemodialysis, which can add further complications. 

Consultations

If evaluating a patient with a history of previous neonatal loss due to a confirmed case of UCD, appropriate prenatal genetic counseling and evaluation are required due to the genetic inheritance pattern of UCDs.[5] Patients with urea cycle defects are treated in intensive care during acute decompensation. If the presentation occurs in the neonatal period, they require admission to a neonatal intensive care unit and care under a neonatologist. After intensive care, patients need lifelong management and care. The interdisciplinary team often comprises:

• Neonatologist and intensivist
• Genetics and metabolic expert
• Pediatric nephrologist
• Metabolic dietician
• Neurologist
• Pediatrician
• Developmental behavioral specialist
• Hepatologist (liver involvement, liver transplant in a few cases)

Deterrence and Patient Education

The newborn screening test, collected between 24 and 48 hrs of life (in the United States and many other countries), can detect some urea cycle enzyme defects; however, it usually takes 5 to 7 days for the results to be reported. Additionally, there is variability across the United States' states for the panel results, and not all UCDs are tested by newborn screening.[23] Clinical symptoms can manifest before newborn screening results are available and may be very nonspecific initially, with rapid clinical deterioration; hence, parents should seek medical attention immediately if they have suggestive symptoms. After initial management of urea cycle disorders, a lifelong low-protein diet is necessary, along with treatment by a metabolic dietitian and other specialists.

Enhancing Healthcare Team Outcomes

The diagnosis and management of urea cycle disorders are complex and best done with an interprofessional team that includes a neonatologist, geneticist, pediatrician, nephrologist, internist, and dialysis team. The team should obtain blood ammonia levels, along with other tests, when a newborn presents with signs of encephalopathy. Labs suggesting respiratory alkalosis and elevated ammonia levels should alert the team to the possibility of urea cycle disorders.

Treatment for UCDs should be prompt, with the immediate goal of rapidly lowering ammonia and reducing dietary protein intake. Treatment requires medications such as arginine hydrochloride, sodium phenylacetate, and sodium benzoate; in severe cases, hemodialysis may be required. Patients with UCDs, after stabilization, require lifelong monitoring by the entire interdisciplinary team, especially the metabolic team and dietitians.[3][5]

In urea cycle defects eg, OTCD, patients can also have a late onset of the disease, with a wide range of mild to severe cognitive and neurological presentation. Importantly, the treating team needs to be aware that certain UCD can manifest later in life, and investigate accordingly.[24] As discussed, the prognosis for most of these infants depends on the subtype of urea cycle disorders and can be highly variable.

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References

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Disclosure: Supriya Bisht declares no relevant financial relationships with ineligible companies.

Disclosure: Andres Corado declares no relevant financial relationships with ineligible companies.

Disclosure: Gayatri Jaishankar declares no relevant financial relationships with ineligible companies.