Urea Cycle Disorder

Urea Cycle Disorder (UCD) is a rare group of inherited metabolic conditions where the body is unable to effectively eliminate ammonia, a waste product formed when protein is broken down. The urea cycle, which takes place primarily in the liver, is responsible for converting ammonia into urea that can be excreted in the urine. In individuals with UCD, enzyme deficiencies disrupt this process, leading to the accumulation of ammonia in the blood—a condition known as hyperammonemia—which can cause serious health problems, particularly in the brain.

UCD is caused by mutations in genes that encode the enzymes or transporters required for the urea cycle. These mutations lead to partial or complete loss of enzyme function, which prevents the body from properly eliminating nitrogen in the form of urea. Most UCDs are inherited in an autosomal recessive manner, except for OTC deficiency, which is inherited in an X-linked manner.

There are eight recognized types of UCD, each associated with a deficiency in a different enzyme or transporter involved in the urea cycle:

• Cabamoyl phosphate synthetase I deficiency (CPS1 gene, autosomal recessive)
• Ornithine transcarbamylase deficiency (OTC gene, X-linked)
• Argininosuccinate synthetase deficiency (ASS1 gene, autosomal recessive)
• Argininosuccinate lyase deficiency (ASL gene, autosoaml recessive)
• Arginase deficiency (ARG1 gene, autosomal recessive)
• N-acetylglutamate synthase (NAGS gene, autosomal recessive)
• Citrin deficiency (Citrullinemia type II, SLC25A13 gene, autosomal recessive)
• Mitochondrial ornithine transporter problem (HHH syndrome, SLC25A15 gene, autosomal recessive)

Among these, OTC deficiency is the most common, followed by ASL and ASS1 deficiencies.

Symptoms of UCD vary widely depending on the age at onset and the severity of the enzyme deficiency. In newborns, symptoms can appear within the first few days of life and may include poor feeding, vomiting, lethargy, seizures, hypothermia, hyperventilation, breathing difficulties, and coma. These signs are often nonspecific and may closely resemble other acute conditions such as sepsis, making early diagnosis particularly challenging. Because of this, UCD should be considered in any newborn presenting with unexplained encephalopathy or metabolic crisis.

If not recognized and treated promptly, the elevated ammonia levels can cause irreversible brain damage or death.

In late-onset forms, which may manifest in childhood, adolescence, or even adulthood, symptoms are often intermittent and triggered by stressors such as illness, fasting, or high protein intake. These may include behavioral changes, recurrent vomiting, headaches, confusion, ataxia, and lethargy, particularly after protein-rich meals or infections. In some cases, psychiatric symptoms may dominate, delaying appropriate metabolic evaluation.

Early identification and management of symptoms, especially in neonates, are crucial for preventing serious neurological outcomes.