Citrullinemia type I (CTLN1) is a rare and severe autosomal, recessive inherited urea cycle disorder that causes high blood levels of citrulline and neurotoxic ammonia.
CTLN1 is caused by mutations in the argininosuccinate synthase (ASS1) gene (note that citrullinemia type II is a different disorder caused by mutations in the SLC25A13 gene coding for the citrin transporter).
In patients affected by CTLN1, inactive ASS1 cannot condense citrulline with aspartate to form argininosuccinic acid, resulting in high blood levels of citrulline and neurotoxic ammonia.
CTLN1 is inherited in an autosomal recessive manner, which means that each patient has received one copy of the mutated gene from each parent.
CTLN1 has an estimated birth prevalence of 1:250,000 live births (Summar et al. 2013), and an estimated prevalence of 500 patients in EU and 300 patients in the US.
CTLN1 usually becomes evident in the first few days of life. Affected infants typically experience progressive lack of energy (lethargy), poor feeding, vomiting, seizures, and loss of consciousness due to acute episodes of hyperammonemia, called hyperammonemia crises. These crises can lead to hyperammonemic encephalopathy within a few hours or days of life, resulting in severe and irreversible brain damage. If left untreated, death may occur within days.
Later onset (childhood or adulthood) form represent 10-20% cases, and manifest as recurrent lethargy and somnolence, intellectual disability, chronic less severe or recurrent hyperammonemia.
The most critical period is infancy but all patients remain at risk of hyperammonemic crises for life upon triggering factors such as low-protein diet interruption or flu.
CTLN1 diagnosis is confirmed by genotyping after suspicion from clinical and laboratory findings (hyperammonemia, citrullinemia).
There is currently no cure for CTLN1. Current standard of care involves acute and chronic management:
Acute management of hyperammonemia crises aiming at:
- rapidly lowering plasma ammonia concentrations using intravenous nitrogen scavenger therapy (sodium phenylacetate and sodium benzoate); hemodialysis may also be needed in case intravenous scavenger therapy is not sufficiently effective during hyperammonemic coma.
-reversing of catabolism: IV glucose, intralipids or protein-free enteral nutrition, if tolerated
- controlling intracranial pressure
Chronic management for life with the objective to prevent excessive ammonia from being formed with two complementary approaches:
- Low-protein diet
- Oral nitrogen scavenger therapy to assist in the removal of ammonia from the body (sodium benzoate, glycerol phenylbutyrate, sodium phenylbutyrate) to be taken every day (3 to 6 times per day)
UNMET MEDICAL NEEDS:
Changes of CTLN1 management during the past two decades has improved survival, but deaths in the neonatal period still account for approximately 20% patients in developed countries, and access to optimal care remain challenging in other countries. The constraints of strict life-long low-protein diet and medical treatment, and the permanent risk of life-threatening encephalopathy remain major issues.
There is currently no cure for CTLN1 and unmet medical needs are high.
POTENTIAL BENEFITS OF AAV GENE THERAPY, AS A NOVEL APPROACH TO MANAGE CTLN1:
Correction by gene therapy of the defective ASS1 gene may ultimately bring a cure to CTLN1 patients.
The goal of gene therapy for CTLN1 is to overcome the main limitations of standard of care. It carries the potential to provide long-lasting benefits by restoring a normal urea cycle, thereby durably reducing neurotoxic ammonia levels without the need for very strict and constraining low-protein diet and lifelong medical therapy while outweighing its related significant costs.