The Signs of UCDs

Recognize the Signs of Urea Cycle Disorders and Hyperammonemia

Stages of Onset

THE NEONATAL PERIOD: Children with severe urea cycle disorders typically show symptoms after the first 24 hours of life. The baby may be irritable at first, or refuse feedings, followed by vomiting and increasing lethargy. Soon after, seizures, hypotonia (poor muscle tone, floppiness), respiratory distress (respiratory alkalosis), and coma may occur. These symptoms are caused by rising ammonia levels in the blood. Sepsis and Reye’s syndrome are common misdiagnoses. If untreated, these severely affected infants will die. Severe neonatal symptoms are more commonly seen in both boys and girls with OTC and CPS deficiency, but can also occur with citrullinemia or argininosuccinate lyase deficiency (ASA lyase).

CHILDHOOD: Children with mild or moderate urea cycle enzyme deficiencies may not show recognizable symptoms until early childhood. Earliest symptoms may include failure to thrive, inconsolable crying, agitation or hyperactive behavior, sometimes accompanied by screaming, self-injurious behavior, and refusal to eat meat or other high-protein foods. Later symptoms may include frequent episodes of vomiting, especially following high-protein meals, lethargy and delirium, and finally, if the condition is undiagnosed and untreated, hyperammonemic coma or death may occur. Undiagnosed children may be referred to child psychologists because of their behavior, developmental delays and eating problems. Childhood episodes of hyperammonemia (high ammonia levels in the blood) may be brought on by viral illnesses including chicken pox, colds or flu, teething, growth spurts, high-protein meals, or even exhaustion. Common misdiagnoses include Reye’s syndrome. Childhood onset can be seen in both boys and girls affected by any of the urea cycle disorders. 

Early clinical manifestations (symptoms) of arginase deficiency (similar to those of the other disorders), may be seen as early as one year of age, but some children with AG remain asymptomatic at four years of age. AG symptoms are usually progressive and include growth failure, spastic tetraplegia (lower limbs more severely affected than upper limbs), seizures, psychomotor retardation and hyperactivity. 

Major characteristics of NAGS deficiency, considered the rarest urea cycle disorder, include severe hyperammonemia (elevated blood ammonia), deep encephalopathy despite only mild hyperammonemia, recurrent diarrhea and acidosis, movement disorder, hypoglycemia and hyperornithinemia.1

ADULTHOOD: Recently, the number of adults being diagnosed with urea cycle disorders has dramatically increased. These individuals have survived undiagnosed to adulthood due to mild enzyme deficiencies. Many adults are being identified due to improved diagnostics and increased awareness among medical professionals. Symptoms include episodes of disorientation, confusion, slurred speech, unusual and extreme combativeness or agitation, stroke-like symptoms, lethargy and delirium. Many may be seen by neurologists or psychiatrists because of psychiatric symptoms, including schizophrenia and bipolar disorder. Without proper diagnosis and treatment, these individuals are at risk for permanent brain damage, coma, and death. Symptoms in undiagnosed adults have been observed following viral illnesses, childbirth, excessive dieting including high-protein diets, excessive exercising, gastric bypass surgery, use of valproic acid (an anti-epileptic drug which causes excess ammonia), and chemotherapy. 

OTC CARRIERS: Approximately 85% of adult female carriers (heterozygotes) for OTC deficiency are asymptomatic (exhibit no symptoms). The remainder show symptoms including protein intolerance, headache, episodes of confusion or trouble concentrating, behavioral or neurological abnormalities, vomiting and episodes of mild hyperammonemia. Studies have shown carriers to be of normal to above-normal intelligence, but some have been shown to demonstrate subtle deficits in fine motor, visual-spatial and non-verbal functions. Concerns are beginning to emerge about carriers with regard to common health issues (diabetes, cholesterolemia, cancer, liver disease) and potential negative effects that drugs used to treat these common conditions may have on urea cycle function.

1. S. Brusilow, A. Horwich, “Urea Cycle Enzymes,” The Metabolic and Molecular Bases of Inherited Disease, Vol II p.1810-1962: McGraw Hill
2. A. Gropman, M. Batshaw: Cognitive outcome in urea cycle disorders. Molecular Genetics and Metabolism Vol 81, Sup 1, Apr 2004, p. 58-62