Citrullinemia, Type I, Metabolic Disorder, Amino acid disorder Screening -Infant

Citrullinemia, Type I, Metabolic Disorder, Amino acid disorder Screening -Infant

Citrullinemia, Type I, Metabolic Disorder, Amino acid disorder Screening

Summary of Recommendation and Evidence

Population

Recommendation

Grade
(What's This?)

Screening of both genders

The genetic screening for Citrullinemia, Type I is recommended.

B

Citrullinemia type I (CTLN1) is a rare autosomal recessive genetic disorder that includes a neonatal acute (classic) form, a milder late-onset form, a form that begins during or after pregnancy, and an asymptomatic form.

OVERVIEW

Citrulinemia results from a deficiency of argininosuccinate synthetase (ASS). Mutations in the ASS1 gene provide instructions to make ASS which is needed for the third step in the urea cycle. Timing of clinical manifestations ranges from acute, early onset to asymptomatic to onset during pregnancy, depending on the residual enzyme activity left by the specific mutations. Milder forms of the disease are triggered by catabolic state or excess dietary proteins and can present with acute hyperammonemia, psychotic changes or acute liver failure . There is a second form of citrullinemia, called Type 2 or Citrin deficiency. Type 2 ,is caused by a mutation in SLC25A13 and is more common in people of Japanese descent. This is caused by a defect in a mitochondrial transporter unrelated to ASS and can result in nenonatal cholestasis or in adult-onset disease. It is extremely important to distinguish the two forms since treatment is completely different.

SCREENING

Finding

Elevated citrulline.

Tested By

Tandem mass spectrometry (MS/MS); sensitivity=100%; specificity=100% 

PREVALENCE

Approximately 1 in 250,000 live births.

INHERITANCE

CTLN1 is inherited in an autosomal recessive manner. It affects both boys and girls equally.

PRENATAL TESTING

For both types of citrullinemia, DNA testing is possible by amniocentesis if both disease causing mutations of an affected family member have been identified.

OTHER TESTING

For both types of citrullinemia, genetic testing is possible for at-risk family members if both disease causing mutations of an affected family member have been identified.

CLINICAL CHARACTERISTICS

With treatment preventing serious hyperammonemic episodes, normal IQ and development are possible. Without treatment, classical citrullinemia type I generally presents in the first week of life. Less acute forms may present later in life (childhood, pregnancy) with severe symptoms during prolonged fasting, periods of increased energy demands (fever, stress, lack of sleep), and after meals high in protein. There are even milder forms with only mildly increased citrulline that might remain asymptomatic for life (periodic monitoring without therapy is recommended in these forms). Citrullinemia type 2 (citrin deficiency) can cause intrahepatic cholestasis in the neonatal period that usually improves over time. Adults with this condition can have acute liver failure and hyperammonemia. 

Initial symptoms may include:

  • poor appetite
  • vomiting
  • lethargy
  • increased intracranial pressure
  • apnea
  • seizures
  • coma, possibly leading to death and
  • Lab findings:
  1. hyperammonemia
  2. elevated citrulline and glutamine
  3. absent argininosuccinic acid 

 

Symptoms of the milder form in children may include:

  • poor growth
  • poor appetite
  • vomiting
  • headaches
  • learning disabilities
  • behavior problems
  • hyperactivity
  • balance and coordination problems
  • spasticity

EARLY SIGNS

There are two main forms of citrullinemia, type I (CIT): the “classic” form seen in babies and a “mild” form that is first seen later in childhood or adulthood. Some signs of the mild form are different from the classic form seen in babies.

Babies usually start to show signs within the first few days of life. Signs of classic CIT include:

  • Sleeping longer or more often
  • Tiredness
  • Poor appetite
  • Vomiting
  • Seizures (Epilepsy)
  • Irritability
  • Delayed growth

Mild CIT may share some of the signs of classic CIT.

Many of these signs may occur when your baby eats foods that his or her body cannot break down. They can be triggered by long periods of time without eating, illnesses, and infections.

CAUSES

When we eat food, enzymes help break it down. Some enzymes help break down proteins into their building blocks, called amino acids. Other enzymes help break down these amino acids. When we break down proteins and their amino acids, our bodies need even more enzymes to get rid of waste products, like ammonia.

In citrullinemia, type I (CIT) babies do not make enough of the enzyme arginosuccinate synthetase (ASS1). When ASS1 is not working correctly, the body cannot remove ammonia through the urine. This causes a dangerous build-up of ammonia in the blood.

CIT is an autosomal recessive genetic condition. This means that a child must inherit two copies of the non-working gene for CIT, one from each parent, in order to have the condition. The parents of a child with an autosomal recessive condition each carry one copy of the non-working gene, but they typically do not show signs and symptoms of the condition. While having a child with CIT is rare, when both parents are carriers, they can have more than one child with the condition. 

TREATMENT

Dietary Treatment

Your baby may need to follow a restricted diet in order to avoid foods that your baby cannot break down. A dietician or nutritionist can help you plan the right diet for your child.

Your baby’s doctor might also recommend special formulas and foods for babies with citrullinemia, type I (CIT). These formulas will likely need to be continued through adulthood.

Supplements and Medications
Your baby’s doctor may prescribe medications to help lower ammonia levels in your baby’s blood. Everyone has some ammonia is his or her blood, but high levels can be toxic.

Arginine supplements may also be helpful for babies with CIT. Arginine is a natural substance that can help prevent the build-up of ammonia in individuals with CIT. Your baby’s doctor can write a prescription for these supplements.

EXPECTED OUTCOMES

Babies who receive early treatment for citrullinemia, type I (CIT) can have healthy growth and development. This is why newborn screening for CIT is so important.

Some children can still have high ammonia levels, even with treatment. These children may need to seek treatment in a hospital to remove ammonia from their blood.

It is important to treat CIT early because babies who do not receive treatment are at risk for coma, brain damage, or death.