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Adenylosuccinate Lyase Deficiency

MONDO:0007068 Curated 2026-07-04T00:00:00Z 10 harmonized findings
falcon · 32 citations openscientist · 25 citations
Concordant asserts the finding Partial supports a weaker/qualified form Contradictory conflicts with it Silent does not address it

Harmonized findings

Adenylosuccinate lyase (ADSL) is a bifunctional enzyme that acts twice at two non-sequential steps of de novo purine biosynthesis and the purine nucleotide cycle; biallelic loss-of-function ADSL variants cause this autosomal recessive inborn error of purine metabolism.

UNANIMOUS INTEGRATED
gene_functionpathophysiologygenetic_factor
ProviderStanceScoreEvidence
falcon CONCORDANT 90% Adenylosuccinate lyase is required for de novo purine biosynthesis, acting twice in the pathway at non-sequential steps.
Falcon quotes the PLOS Genetics abstract stating the enzyme acts twice at non-sequential steps of de novo purine biosynthesis.
DOI:10.1371/journal.pgen.1010974
openscientist CONCORDANT 95% ADSL encodes a bifunctional homotetrameric enzyme that catalyzes two non-sequential steps in de novo purine synthesis and the purine nucleotide recycling pathway
OpenScientist adds the homotetramer detail and names both catalyzed conversions (SAICAR to AICAR; S-AMP to AMP).

The biochemical hallmark is accumulation of the dephosphorylated succinylpurines SAICAr and succinyladenosine (S-Ado) in body fluids (urine, plasma, CSF), which serve as the primary diagnostic biomarkers.

UNANIMOUS INTEGRATED
pathophysiologydiagnosis
ProviderStanceScoreEvidence
falcon CONCORDANT 90% Diagnosis is facilitated by demonstration of SAICAr and S-Ado in extracellular fluids such as plasma, cerebrospinal fluid
Falcon quotes the Jurecka review establishing succinylpurine detection in extracellular fluids as the diagnostic hallmark.
DOI:10.1007/s10545-014-9755-y
openscientist CONCORDANT 95% Loss of ADSL function results in accumulation of dephosphorylated substrates -- succinylaminoimidazole carboxamide riboside (SAICAr) and succinyladenosine (S-Ado) -- in body fluids, which serve as diagnostic biomarkers and correlate with disease severity.
OpenScientist explicitly ties the accumulated succinylpurines to diagnostic biomarker use and severity correlation.

SAICAr is the more neurotoxic of the two accumulated succinylpurines, and substrate toxicity (not only purine shortage) is a primary driver of the neurological phenotype.

UNANIMOUS INTEGRATED
pathophysiology
ProviderStanceScoreEvidence
falcon CONCORDANT 85% The C. elegans neurobehavioral work explicitly argues that altered behavior likely arises from accumulated substrate toxicity rather than only purine shortage
Falcon frames substrate toxicity (over purine depletion) as the dominant driver, sourced from the C. elegans model.
DOI:10.1371/journal.pgen.1010974
openscientist CONCORDANT 85% SAICAr, the more toxic of the two accumulated succinylpurines, appears to promote neuroinflammation directly.
OpenScientist agrees SAICAr is the more toxic species and links it to a neuroinflammatory mechanism.

The disorder is predominantly neurological, with epilepsy present in ~81.8% of patients (often polymorphic and intractable) and disease onset within the first year of life in the large majority of cases.

UNANIMOUS INTEGRATED
phenotype
ProviderStanceScoreEvidence
falcon CONCORDANT 90% Epilepsy is present in 81.8% of the patients, with polymorphic and often intractable seizures.
Falcon quotes the 2024 Cutillo appraisal for the 81.8% epilepsy frequency.
DOI:10.1002/epi4.12837
openscientist CONCORDANT 95% In the majority (89.2%), disease onset was within the first year of life. Epilepsy is present in 81.8% of the patients, with polymorphic and often intractable seizures
OpenScientist reports the identical 81.8% epilepsy figure and adds the 89.2% first-year-onset statistic.
PMID:37842880

ADSL deficiency spans a phenotypic continuum classified into three categories -- a fatal neonatal form, type I (severe infantile), and type II (mild/moderate).

UNANIMOUS INTEGRATED
phenotypeprognosis
ProviderStanceScoreEvidence
falcon CONCORDANT 80% A 2024 long-term cohort + literature appraisal provides a quantitative view of the spectrum (n=88 total, including 7 new and 81 literature cases):
Falcon presents the three-way spectrum quantitatively (Type I 58%, Type II 28%, Neonatal 14%) from the 88-patient appraisal.
DOI:10.1002/epi4.12837
openscientist CONCORDANT 90% classified into three phenotypic categories: a fatal neonatal form, type I (severe infantile), and type II (moderate/mild).
OpenScientist names the same three categories with matching approximate proportions.

ADSL deficiency is genetically heterogeneous with the recurrent missense variants p.R426H (homozygous, ~19 patients), p.Y114H (compound heterozygous, ~13 patients), and p.D430N (homozygous, ~6 patients) being the most frequently reported.

UNANIMOUS INTEGRATED
genetic_factor
ProviderStanceScoreEvidence
falcon CONCORDANT 80% Over 50 ADSL mutations have been identified
Falcon establishes the heterogeneity (>50 variants) and separately lists the same three most frequent variants from the 2024 appraisal.
DOI:10.1007/s10545-014-9755-y
openscientist CONCORDANT 90% Most frequent pathogenic variants: p.R426H (homozygous in 19 patients), p.Y114H (compound heterozygous in 13 patients), p.D430N (homozygous in 6 patients)
OpenScientist lists the identical three recurrent variants with the same patient counts (and reports >70 distinct variants overall).
PMID:37842880

Phenotypic severity tracks residual ADSL enzyme activity and the structural stability of the mutant enzyme complex rather than substrate-specific catalytic differences.

MAJORITY INTEGRATED
genetic_factorprognosis
ProviderStanceScoreEvidence
falcon PARTIAL 55% severity is suggested to track residual enzyme activity and certain variants are enriched in severe neonatal/type I phenotypes
Falcon supports the residual-activity/severity link but frames it tentatively and does not add the protein-stability mechanism or exclude substrate-specific catalysis.
DOI:10.1002/epi4.12837
openscientist CONCORDANT 95% Phenotypic severity in ADSL deficiency is correlated with residual enzymatic activity and structural stability of the corresponding mutant ADSL complexes and does not seem to result from genotype-specific disproportional catalytic activities toward one of the enzyme substrates
OpenScientist quotes the primary source asserting both residual activity and complex stability as determinants, explicitly excluding substrate-specific catalytic differences.
PMID:20127976

There is no curative or specific disease-modifying therapy; management is primarily supportive, but repurposed allopurinol has shown clinical and biochemical improvement, most notably in younger, less cognitively impaired patients.

MAJORITY INTEGRATED
treatmentprognosis
ProviderStanceScoreEvidence
falcon PARTIAL 60% was validated in 3 minor patients with biological and clinical improvement
Falcon confirms no specific therapy and describes the allopurinol Phase II trial (NCT03776656) rationale, but cautions the efficacy publication was not retrievable and results are provisional -- so it stops short of asserting the trial outcome.
clinicaltrials:NCT03776656
openscientist CONCORDANT 90% Results showed clinical improvements in younger, less cognitively impaired patients, indicated by better Vineland Adaptive Behavior Scale (VABS II) scores and reduced hyperactivity on the Aberrant Behavior Checklist (ABC) and Conners Rating Scale-Revised (CRSR).
OpenScientist reports the published Phase II allopurinol results with the demographic responder pattern and the specific behavioral outcome measures.
PMID:41053929

Emerging mechanistic work reframes ADSL deficiency as a secondary mitochondrial disease (fragmentation, impaired respiration, reduced ATP, ERK2/AKT suppression) with alternative-complement-pathway-driven neuroinflammation.

SINGLE LEAD
pathophysiology
ProviderStanceScoreEvidence
falcon SILENT —
Falcon does not discuss mitochondrial dysfunction, ERK2/AKT signaling, or the complement-mediated neuroinflammation hypothesis; its mechanistic advances focus on the C. elegans tyramine pathway instead.
openscientist CONCORDANT 90% ADSLd is associated with mitochondrial dysfunction, including increased fragmentation, impaired respiration, and reduced ATP production. The severity of mitochondrial impairment correlates with ADSLd pathology, especially in mitochondria-dependent tissues
OpenScientist introduces the recent secondary-mitochondrial-disease and complement-neuroinflammation framing as newer mechanistic leads.
PMID:40914938, PMID:40896413

A C. elegans (adsl-1) model shows that substrate accumulation perturbs tyrosine metabolism and tyramine signaling, with behavioral phenotypes rescued by tyramine supplementation via TYRA-2 receptor signaling -- implicating disrupted neurotransmitter pathways beyond purine synthesis itself.

SINGLE LEAD
pathophysiology
ProviderStanceScoreEvidence
falcon CONCORDANT 90% substrate accumulation due to adsl-1 deficiency perturbs tyrosine metabolism and tyramine signaling; behavioral phenotypes are rescued by tyramine supplementation and involve TYRA-2 receptor signaling
Falcon foregrounds the 2023 C. elegans tyramine-signaling mechanism as its principal mechanistic advance.
DOI:10.1371/journal.pgen.1010974
openscientist SILENT —
OpenScientist's model-organism coverage lists yeast and human cell models but not the C. elegans tyramine-signaling work, so it does not address this neurotransmitter mechanism.

Narrative

Overview

Both providers frame adenylosuccinate lyase deficiency as an ultra-rare autosomal recessive inborn error of purine metabolism caused by biallelic ADSL variants, in which loss of a bifunctional enzyme acting at two non-sequential steps of de novo purine synthesis and the purine nucleotide cycle leads to accumulation of the succinylpurines SAICAr and S-Ado and a predominantly neurological, early-onset phenotype (developmental delay, epilepsy, hypotonia, autistic features).

Agreement

The reports strongly converge on the core biology: the bifunctional enzyme mechanism, SAICAr/S-Ado accumulation as the diagnostic biochemical hallmark, SAICAr as the more neurotoxic species, the three-tier phenotypic spectrum (fatal neonatal, type I, type II), and the recurrent variants p.R426H, p.Y114H and p.D430N with the same patient counts. Both independently report the 81.8% epilepsy frequency from the 2024/2023 cohort appraisal, agree that severity tracks residual enzyme activity, and agree there is no curative therapy.

Divergence

Divergence is one of coverage and recency rather than contradiction. OpenScientist is broader and more current, contributing the emerging secondary-mitochondrial-disease framing (fragmentation, impaired respiration, ERK2/AKT suppression) and the alternative-complement-pathway neuroinflammation hypothesis, plus the published Phase II allopurinol outcomes and the residual-activity-plus-protein-stability genotype-phenotype rule. Falcon, pathophysiology-focused, instead foregrounds the 2023 C. elegans adsl-1 tyramine-signaling mechanism (silent in OpenScientist) and treats the allopurinol efficacy publication as provisional/unretrievable.

Integration

Promote the shared, well-supported concepts into the disorder YAML: the bifunctional ADSL mechanism and dual purine synthesis / nucleotide-cycle role, SAICAr/S-Ado accumulation and diagnostic biomarker use, SAICAr neurotoxicity, the neurological phenotype with 81.8% epilepsy and first-year onset, the three-tier spectrum, the recurrent ADSL variants, the residual-activity severity correlation, and supportive management with allopurinol as a repurposing lead.

Not integrated (leads)

Retain as research leads pending primary-literature verification: the secondary mitochondrial dysfunction / ERK2-AKT axis, the alternative-complement neuroinflammation hypothesis, and the C. elegans tyramine-signaling mechanism. These are single-provider, recent, and model-based, and should be confirmed against their cited abstracts before promotion to curated disease mechanisms.

Cross-provider synthesis comparing falcon (Edison Scientific Literature, pathophysiology-focused) and openscientist (autonomous, comprehensive 15-domain) reports. No direct contradictions were found; divergence is coverage/recency plus each provider's distinct single-source mechanistic advance (falcon: C. elegans tyramine signaling; openscientist: mitochondrial dysfunction and complement neuroinflammation). MONDO:0007068 follows the dismech disorder entry (kb/disorders/Adenylosuccinate_Lyase_Deficiency.yaml); OpenScientist's report cited MONDO:0010041, a discrepancy not adjudicated here. best_matching_text values are verbatim excerpts from the cited report files; per-provider citations are recorded but literature evidence snippets are intentionally left for the main curation pipeline to verify.