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The ADSL gene ADSL encodes adenylosuccinate lyase, a bifunctional enzyme in de novo purine synthesis. Biallelic loss-of-function variants in ADSL cause adenylosuccinate lyase deficiency, an autosomal recessive neurometabolic disorder characterized by accumulation of succinylaminoimidazolecarboxamide riboside (SAICAr) and succinyladenosine (S-Ado) in body fluids. Affected individuals present with a spectrum ranging from fatal neonatal encephalopathy to mild cognitive impairment and autistic features.
Genetic evidence includes over 80 probands from more than 40 unrelated families, each harboring biallelic ADSL variants ([PMID:25112391]). Inheritance is autosomal recessive, confirmed by segregation of pathogenic variants in sibships such as two sisters with global developmental delay and a homozygous c.674T>C (p.Met225Thr) change ([PMID:18830228]). Case reports describe both compound heterozygous and homozygous missense, nonsense, frameshift, and splice-site variants. Variant spectrum exceeds 50 unique changes, including the recurrent c.568C>T (p.Arg190Ter) stop-gain allele found in the first British case ([PMID:15571235]).
Segregation analysis in multiple families demonstrates co-segregation of ADSL variants with disease, with at least two additional affected relatives reported in intrafamilial studies ([PMID:18830228]). Founder and recurrent alleles such as p.Arg426His have been observed in unrelated European cohorts ([PMID:10090474]). Carrier frequency estimates are limited by rarity; however, inclusion of ADSL in selective purine disorder screening panels has led to earlier diagnoses.
Functional studies confirm a loss-of-function mechanism. Expression of mutant ADSL cDNAs in Escherichia coli revealed that only the full-length enzyme is active, and that mutant proteins exhibit reduced thermal stability and diminished catalytic activity against both SAICAR and adenylosuccinate ([PMID:10888601]). Structural and biochemical analysis of 19 patient-derived ADSL complexes correlates residual enzymatic activity and tetramer stability with clinical severity, supporting genotype–phenotype correlations ([PMID:20127976]).
Cellular and animal models further substantiate the pathogenic mechanism. A Chinese hamster ovary cell line (AdeI) carrying an A291V substitution lacks detectable ADSL activity and accumulates purine substrates, validating it as a model for ADSL deficiency ([PMID:20884265]). Knockdown of adsl-1 in Caenorhabditis elegans recapitulates neuromuscular defects and reproductive phenotypes, reversible with purine supplementation, demonstrating conserved metabolic perturbations (PMID:37607437).
In summary, definitive clinical validity is established for ADSL in adenylosuccinate lyase deficiency. Genetic and experimental evidence converge on a recessive loss-of-function mechanism, with clear diagnostic biomarkers and no effective targeted therapy to date. Key take-home: ADSL deficiency should be considered in infants and children with unexplained hypotonia, developmental delay, seizures, and characteristic purine metabolite elevations in biofluids.
Gene–Disease AssociationDefinitiveOver 80 probands across multiple families; autosomal recessive inheritance with segregation; functional concordance across multiple studies ([PMID:25112391]) Genetic EvidenceStrongOver 50 distinct pathogenic variants in >80 probands with biallelic ADSL mutations and segregation in families ([PMID:25112391]) Functional EvidenceStrongMultiple enzyme activity assays and structural analyses demonstrate loss-of-function of mutant ADSL proteins; animal and cellular models recapitulate phenotypes ([PMID:10888601]; [PMID:20127976]) |