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Urea Cycle Disorder

A urea cycle disorder (UCD) is a group of genetic diseases that are caused by malfunctions in one or more parts of the urea cycle.  The urea cycle is the body’s way of neutralizing highly toxic ammonia, produced from protein breakdown, into the less toxic urea, which can be removed by the urine.  Individuals with UCD are deficient in or missing key parts of the urea cycle, including transporters, which move essential materials to the cycle, or enzymes, which complete sequential steps in the cycle to remove waste from the body. Defects in one or more of these enzymes or transporters leads to high levels of ammonia in the blood (hyperammonemia), which can cause serious complications, including permanent neurological damage, coma, or death.

Common urea cycle disorders

            Transporter malfunctions:

  • Citrin
  • Ornithin Translocase

Enzyme deficiencies:

  • N-Acetylglutamate Synthetase (NAGS)
  • Carbamoyl Phosphate Synthetase (CPS-1)
  • Argininosuccinate Synthetase (ASS)
  • Argininosuccinate Lyase (ASL)
  • Arginase (ARG1)
  • Ornithine Transcarbamylase (OTC)

The number of individuals with a urea cycle disorder is estimated to be 1 in every 30,000 births in the US.  Infants born with severe UCD deficiencies may present with complications within hours to days after birth.  However, individuals with only partial enzyme or transporter deficiency may not be diagnosed until much later - usually when surgery, infection, or other medical complications further impair their ability to break down protein or the if patient’s dietary intake of protein increases.  The rarity of these disorders and high early mortalilty of UCDs make diagnosis difficult, and early diagnosis and treatment are crucial to improving survival and preventing brain damage.  Disease onset in the first 30 days of life carries a 50% mortality rate. Recent advances in treatment have reduced the mortality in children and adults.

In patients with suspected urea cycle disorders, family history, blood chemistries, enzyme activity from liver biopsy and genetic testing can identify which components of the urea cycle are defective.  In individuals with family history of known or suspected urea cycle disorders, genetic counseling and pregnancy planning is strongly recommended.

Symptoms related to high levels of ammonia in the blood (hyperammonemia) include, but are not limited to:

Newborn Children – initial symptoms

  • Failure to feed
  • Inability to maintain normal body temperature (low core body temperature)
  • Abnormal drowsiness
  • Loss of appetite
  • Breathing too fast or too slow
  • Seizures
  • Abnormal body posturing (indicator of brain toxicity)

Any Age (Mild or partial UCD)

  • Loss of appetite
  • Vomiting
  • Abnormal behaviors
  • Abnormal behaviors associated with sleep:
    • Difficulty falling or staying asleep
    • Falling asleep at inappropriate times
    • Excessive total sleep time or drowsiness
    • Delusions
    • Hallucinations

For long-term management of urea cycle disorders, patients must maintain a low protein diet.   Different enzyme and transporter deficiencies require different drug therapies and dietary supplements to support urea cycle function. 

Current drug therapy for urea cycle disorders at Accredo includes:

  • Ravicti – For the treatment of patients with UCD (NOT for patients with UCD due to NAGS deficiency)
  • Carbaglu – For the treatment of patients with UCD due to NAGS deficiency
 

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