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The specific symptoms of disorders related to the urea cycle vary among the different types of these disorders. Typically, with complete deficiency of urea cycle enzymes, symptoms present within the first 24 hours after birth and hence urea cycle disorders are mostly diagnosed during infancy. However, some children start showing symptoms only during early childhood.
In partial enzyme deficiency, symptoms are usually shown in response to triggers such as infection or stress. General symptoms of a urea cycle disorder are a result of hyperammonemia and include encephalopathy characterized by brain edema or neurotransmitter disturbance.
Babies born with severe urea cycle defects usually show symptoms in the first few days of life. Such babies seem normal right after birth and nurse well, but over time the following symptoms emerge:
Other symptoms such as hypotonia or poor muscle tone, seizures, ataxia, respiratory problems and coma may follow.
These symptoms develop gradually in line with increasing levels of ammonia in the infant’s blood. Infants with ornithine transcarbamylase (OTC) and carbamoylphosphate synthetase deficiency usually show severe neonatal symptoms, though deficiency of argininosuccinate lyase or citrullinemia can also cause severe symptoms. Urea cycle disorders in infants are commonly misdiagnosed as sepsis or Reye’s syndrome. Infants with severe symptoms will die if not treated in time.
Children with partial deficiencies of urea cycle enzymes may show symptoms only in early childhood. Clinical manifestations usually start with:
Gradually, other symptoms such as frequent vomiting following protein-rich meals, lethargy and delirium develop. If not treated, hyperammonemic coma follows and leads to death. Undiagnosed children with behavioral problems and developmental delays unfortunately often end up at child psychology clinics.
Hyperammonemia in childhood can be triggered by viral infections such as cold, flu or chicken pox, growth spurts, teething and foods rich in protein. Some children with arginase deficiency don’t show symptoms till about four years of age. Arginase deficiency symptoms are progressive growth failure with severely affected lower limbs, seizures, and psychomotor retardation.
The rarest of urea cycle disorders, NAGS deficiency, usually presents with severe hyperammonemia, encephalopathy, hypoglycemia, movement disorders and recurring acidosis and diarrhea.
Of late, there is a marked increase in the diagnosis of urea cycle defects in adulthood, thanks to increased awareness among health care professionals and advancement in diagnostics. Most of them have only mild deficiencies of urea cycle enzymes.
Common symptoms seen in adulthood are:
Since these symptoms are common in psychiatric problems such as schizophrenia and bipolar disorder, many of these adults see neurologists or psychiatrists before diagnosis of a urea cycle defect. Lack of or delayed diagnosis and treatment in these individuals can even cause permanent brain damage, leading to coma and death.
In undiagnosed adults, symptoms are usually triggered by viral illnesses, protein-rich diets, childbirth, over exercising, anti-epileptic drugs that cause excess ammonia production, gastric bypass surgery and chemotherapy.
About 85% of adult female carriers of the defective OTC gene show no symptoms. The rest of the carriers present with symptoms such as headache, protein intolerance, vomiting, confusion, behavioral issues, lack of concentration and mild hyperammonemia. Intelligence levels in carriers are found to be mostly normal, though some carriers show subtle deficits in motor skills and non-verbal functions.
Studies have raised concerns about common conditions such as liver disease, diabetes and cancer in carriers and how the drugs used to treat these conditions will affect the function of the urea cycle.