ASS1 gene
Also known as: Classic citrullinemia; Argininosuccinate synthase deficiency; Argininosuccinic acid synthetase deficiency; ASS deficiency; CTLN1
OMIM#215700 https://omim.org/entry/215700
1. The disease:
Citrullinemia type I (CTLN1) presents as a clinical spectrum that includes an acute neonatal form (the “classic” form), a milder late-onset form (the “non-classic” form), a form without symptoms or hyperammonemia, and a form in which women have onset of severe symptoms during pregnancy or post partum. Distinction between the clinical forms is based on clinical findings and it is not perfect. Lack of early signs or symptoms does not exclude the diagnosis.
2. The Symptoms:
- Infants with the acute neonatal form appear normal at birth. Shortly thereafter, they develop hyperammonemia and become progressively lethargic, feed poorly, frequent vomiting, and may develop signs of increased intracranial pressure (ICP). Without emergency treatment, hyperammonemia and the accumulation of other toxic metabolites (e.g., glutamine) result in increased ICP, increased neuromuscular tone, spasticity, ankle clonus, seizures, loss of consciousness and death.
- Children with the severe form who are treated promptly may survive for an indeterminate period of time, but usually with significant neurologic sequelae.
- The late-onset form may be milder than that seen in the acute neonatal form, for unknown reasons. The episodes of hyperammonemia are similar to those seen in the acute neonatal form, but the initial neurologic findings may be subtler because of the older age of the affected individuals.
3. Actions to take in case of early diagnosis:
- Infants with a positive genetic test (having 2 pathogenic variants or 2 copies of a single pathogenic variant in the gene ASS1) should continue breastfeeding and avoid baby formulas. Early treatment is essential in preventing chronic symptoms.
- Biochemical correlation is essential for confirming diagnosis with plasma quantitative amino acids, ammonia levels and urinary organic acids. Biochemical NBS with tandem mass spectrometry can also help.
- CTLN1 is a lifelong disease that requires lifetime management and regular follow-up with a metabolic physician and dietician, a part from a multidisciplinary approach to care.
- Nitrogen scavenging therapy (with sodium benzoate and/or sodium phenylacetate/phenylbutyrate and arginine) or hemodialysis in the emergency should decrease ammonia levels.
- Liver transplantation, the only known cure for CTLN1, is best performed between age three months (and/or attainment of 5 kg body weight) and one year to decrease complications and improve survival; liver transplantation does not reverse any neurologic sequelae present at the time of transplant.
- Genetic counseling is highly recommended for family planning and evaluation of at-risk family members such as siblings.
4. For more information
Orphanet: https://www.orpha.net/consor/cgi-bin/Disease_Search_Simple.php?lng=EN
Biblio: https://www.ncbi.nlm.nih.gov/books/NBK1458/