Adenylosuccinate lyase deficiency
Rare metabolic disorder causing neurological symptoms from purine biosynthesis defect.
Adenylosuccinate lyase deficiency is a rare autosomal recessive metabolic disorder characterized by the appearance of succinylaminoimidazolecarboxamide riboside (SAICA riboside) and succinyladenosine (S-Ado) in cerebrospinal fluid and urine. These succinylpurines are dephosphorylated derivatives of the two substrates of adenylosuccinate lyase (ADSL), an enzyme that catalyzes two distinct reactions in the de novo pathway of purine biosynthesis. The disorder presents with a spectrum of neurological symptoms, including seizures, psychomotor retardation, and autistic features, and is classified into three categories based on severity: fatal neonatal form, type I, and type II.
- field
- Metabolic genetic disorder
- known_for
- Accumulation of succinylpurines due to ADSL deficiency, causing neurological symptoms
- types
- Fatal neonatal form, type I, type II
Lore & Background
Adenylosuccinate lyase deficiency results from mutations in the ADSL gene, with more than 50 different mutations discovered. The enzyme normally catalyzes the β-elimination of fumarate to produce aminoimidazole carboxamide ribotide (AICAR) from SAICAR or adenosine monophosphate (AMP) from S-AMP. In affected individuals, the substrates accumulate and are dephosphorylated to SAICA riboside and S-Ado, which are detected in body fluids.
Reader's Guide
The significance of adenylosuccinate lyase deficiency lies in its role as a model for understanding purine metabolism disorders and the neurotoxic effects of accumulating metabolites. Two main theories explain its symptoms: decreased purine nucleotide concentrations (though not consistently found) and neurotoxic effects of succinylpurines. In severely affected individuals, SAICA riboside and S-Ado concentrations are comparable, while in milder forms, the S-Ado ratio is more than double that of severe cases. Diagnosis relies on demonstrating succinylpurines in plasma, cerebrospinal fluid, or urine via high-pressure liquid chromatography, with or without mass spectroscopy, and genetic testing. Treatment options include D-ribose and uridine administration, ketogenic diet, and S-adenosyl-l-methionine, though none has been proven effective. The neonatal form is almost always fatal, while other forms may have a stable outcome in childhood, though some experience shortened lifespan.
Did You Know?
- The disorder is caused by mutations in the ADSL gene, with more than 50 different mutations discovered.
- Two common theories for symptoms are decreased purine nucleotide concentrations and neurotoxic effects of accumulating succinylpurines.
- In milder forms of the disease, the ratio of S-Ado is more than double that of severely affected individuals, while SAICA riboside levels remain comparable.
- The neonatal form is almost always fatal, with death occurring within the first few weeks of life.
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