Adenylosuccinate lyase deficiency

Summary

Adenylosuccinate lyase deficiency (MONDO:0007068) is a disease caused by ADSL (GenCC Definitive), with 3 cohort genes and 1 clinical trial. Top therapeutic interventions include allopurinol.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: ADSL (GenCC Definitive)
• Cohort genes: 3
• ClinVar variants: 838
• Phenotypes (HPO): 17
• Clinical trials: 1

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		56	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Signs & symptoms

Clinical features (HPO)

17 HPO clinical features (Orphanet curated; top 17 by frequency):

HPO ID	Term	Frequency
HP:0000219	Thin upper lip vermilion	Very frequent (80-99%)
HP:0000248	Brachycephaly	Very frequent (80-99%)
HP:0000252	Microcephaly	Very frequent (80-99%)
HP:0000319	Smooth philtrum	Very frequent (80-99%)
HP:0000343	Long philtrum	Very frequent (80-99%)
HP:0000369	Low-set ears	Very frequent (80-99%)
HP:0000463	Anteverted nares	Very frequent (80-99%)
HP:0001249	Intellectual disability	Very frequent (80-99%)
HP:0001250	Seizure	Very frequent (80-99%)
HP:0001290	Generalized hypotonia	Very frequent (80-99%)
HP:0001344	Absent speech	Very frequent (80-99%)
HP:0001999	Abnormal facial shape	Very frequent (80-99%)
HP:0003196	Short nose	Very frequent (80-99%)
HP:0005469	Flat occiput	Very frequent (80-99%)
HP:0005487	Prominent metopic ridge	Very frequent (80-99%)
HP:0007103	Hypointensity of cerebral white matter on MRI	Very frequent (80-99%)
HP:0011344	Severe global developmental delay	Very frequent (80-99%)

Identifiers

Disease identifiers

Field	Value
Canonical name	adenylosuccinate lyase deficiency
Mondo ID	MONDO:0007068
MeSH	C538235
OMIM	103050
Orphanet	46
DOID	DOID:0050762
ICD-11	1725611919
SNOMED CT	15285008
UMLS	C0268126
MedGen	78641
GARD	0000550
Is cancer (heuristic)	no

Also known as: adenylosuccinase deficiency · adenylosuccinate lyase deficiency · ADSL deficiency · ADSLD · inborn (S)-2-(5-amino-1-(5-phospho-D-ribosyl)imidazole-4-carboxamido)succinate AMP-lyase (fumarate-forming) activity disorder · inborn error of (S)-2-(5-amino-1-(5-phospho-D-ribosyl)imidazole-4-carboxamido)succinate AMP-lyase (fumarate-forming) activity · rare inborn error of (S)-2-(5-amino-1-(5-phospho-D-ribosyl)imidazole-4-carboxamido)succinate AMP-lyase (fumarate-forming) activity

Data availability: 838 ClinVar variants · 4 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by etiologic mechanism › disease of genetic or genomic mechanism › hereditary disease › inborn errors of metabolism › inborn disorder of amino acid and other organic acid metabolism › inborn disorder of amino acid metabolism › adenylosuccinate lyase deficiency

Related subtypes (32): disorder of methionine catabolism, inborn serine deficiency, cerebral creatine deficiency syndrome, inborn organic aciduria, gamma-amino butyric acid metabolism disorder, homocystinuria, urea cycle disorder, systemic primary carnitine deficiency disease, cystathioninuria, hyperlysinemia, Brunner syndrome, glycine encephalopathy, aminoacylase 1 deficiency, adenine phosphoribosyltransferase deficiency, hyperphenylalaninemia due to tetrahydrobiopterin deficiency, inborn disorder of tryptophan metabolism, inborn disorder of proline metabolism, inborn disorder of ornithine metabolism, inborn disorder of amino acid transport, inborn disorder of histidine metabolism, inborn disorder of phenylalanine and tyrosine metabolism, inborn disorder of branched-chain amino acid metabolism, arakawa syndrome 2, 2-methylacetoacetyl CoA thiolase deficiency, albinism, hyperphenylalaninemia due to DNAJC12 deficiency, inborn disorder of the metabolism of sulfur-containing amino acids and hydrogen sulfide, inborn disorder of glycine and serine metabolism, inborn disorder of ornithine, proline and hydroxyproline metabolism, inborn disorder of glutamate/glutamine and aspartate/asparagine metabolism, hyperglycinemia, transient neonatal, tetrahydrobiopterin (BH4)-deficient hyperphenylalaninemia

Genetics & variants

GWAS landscape

No GWAS associations recorded — common-variant (GWAS) studies don’t cover this disease (typical for Mendelian / rare diseases). See the curated gene cohort and Mendelian overlap below.

Variant details and genetic-evidence tiers

ClinVar germline variants

600 retrieved; paginated sample, class counts are floors:

380 uncertain significance, 118 likely benign, 25 benign, 24 pathogenic, 23 conflicting classifications of pathogenicity, 16 likely pathogenic, 11 pathogenic/likely pathogenic, 3 benign/likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
1070255	NM_000026.4(ADSL):c.1026del (p.Glu343fs)	ADSL	Pathogenic	criteria provided, single submitter
1070511	NM_000026.4(ADSL):c.802G>A (p.Asp268Asn)	ADSL	Pathogenic	criteria provided, multiple submitters, no conflicts
1070913	NM_000026.4(ADSL):c.666del (p.Asp223fs)	ADSL	Pathogenic	criteria provided, single submitter
1071793	NM_000026.4(ADSL):c.829G>T (p.Glu277Ter)	ADSL	Pathogenic	criteria provided, single submitter
1074151	NM_000026.4(ADSL):c.955del (p.Leu319fs)	ADSL	Pathogenic	criteria provided, single submitter
1420897	NM_000026.4(ADSL):c.187del (p.Gln63fs)	ADSL	Pathogenic	criteria provided, single submitter
1452821	NM_000026.4(ADSL):c.628C>T (p.Gln210Ter)	ADSL	Pathogenic	criteria provided, single submitter
1454363	NC_000022.10:g.(?40749057)(40750351_?)del	ADSL	Pathogenic	criteria provided, single submitter
1454913	NM_000026.4(ADSL):c.733C>T (p.Arg245Ter)	ADSL	Pathogenic	criteria provided, single submitter
1455911	NM_000026.4(ADSL):c.1222C>T (p.Gln408Ter)	ADSL	Pathogenic	criteria provided, multiple submitters, no conflicts
1458015	NM_000026.4(ADSL):c.151C>T (p.Gln51Ter)	ADSL	Pathogenic	criteria provided, single submitter
1691571	NM_000026.4(ADSL):c.1191+5G>C	ADSL	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1942226	NM_000026.4(ADSL):c.807dup (p.Arg270fs)	ADSL	Pathogenic	criteria provided, multiple submitters, no conflicts
1962288	NM_000026.4(ADSL):c.701+1G>T	ADSL	Pathogenic	criteria provided, single submitter
204789	NM_000026.4(ADSL):c.1009C>T (p.Arg337Ter)	ADSL	Pathogenic	criteria provided, multiple submitters, no conflicts
204792	NM_000026.4(ADSL):c.953C>T (p.Pro318Leu)	ADSL	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
204796	NM_000026.4(ADSL):c.1187G>A (p.Arg396His)	ADSL	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
204807	NM_000026.4(ADSL):c.340T>C (p.Tyr114His)	ADSL	Pathogenic	criteria provided, multiple submitters, no conflicts
204813	NM_000026.4(ADSL):c.1337CTT[2] (p.Ser448del)	ADSL	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
204814	NM_000026.4(ADSL):c.568C>T (p.Arg190Ter)	ADSL	Pathogenic	criteria provided, multiple submitters, no conflicts
204815	NM_000026.4(ADSL):c.421C>T (p.Arg141Trp)	ADSL	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
204816	NM_000026.4(ADSL):c.1349C>G (p.Thr450Ser)	ADSL	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2138451	NM_000026.4(ADSL):c.802G>C (p.Asp268His)	ADSL	Pathogenic	criteria provided, single submitter
2154932	NM_000026.4(ADSL):c.445C>T (p.Arg149Ter)	ADSL	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2422149	NC_000022.10:g.(?40741451)(40756516_?)del	ADSL	Pathogenic	criteria provided, single submitter
2461	NM_000026.4(ADSL):c.1312T>C (p.Ser438Pro)	ADSL	Pathogenic	no assertion criteria provided
2462	NM_000026.4(ADSL):c.1277G>A (p.Arg426His)	ADSL	Pathogenic	criteria provided, multiple submitters, no conflicts
2463	NM_000026.4(ADSL):c.298C>G (p.Pro100Ala)	ADSL	Pathogenic	no assertion criteria provided
2464	NM_000026.4(ADSL):c.1264G>T (p.Asp422Tyr)	ADSL	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2465	NM_000026.4(ADSL):c.569G>A (p.Arg190Gln)	ADSL	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 4 · Orphanet: 1 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

GenCC gene–disease validity (cohort genes)

the Disease column is the GenCC-asserted condition — a cohort gene’s strongest validity may be for a related predisposition syndrome.

Gene	Classification	Inheritance	Disease	Records
ADSL	Definitive	Autosomal recessive	adenylosuccinate lyase deficiency	4

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
ADSL	Orphanet:46	Adenylosuccinate lyase deficiency

Cohort genes → proteins

3 cohort genes, 2 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	3

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
ADSL	HGNC:291	ENSG00000239900	P30566	Adenylosuccinate lyase	gencc,clinvar
SNORD43	HGNC:10182	ENSG00000263764		small nucleolar RNA, C/D box 43	clinvar
MCM5	HGNC:6948	ENSG00000100297	P33992	DNA replication licensing factor MCM5	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
ADSL	Adenylosuccinate lyase	Catalyzes two non-sequential steps in de novo AMP synthesis: converts (S)-2-(5-amino-1-(5-phospho-D-ribosyl)imidazole-4-carboxamido)succinate (SAICAR) to fumarate plus 5-amino-1-(5-phospho-D-ribosyl)imidazole-4-carboxamide, and thereby als…
MCM5	DNA replication licensing factor MCM5	Acts as a component of the MCM2-7 complex (MCM complex) which is the replicative helicase essential for ‘once per cell cycle’ DNA replication initiation and elongation in eukaryotic cells.

Protein-family classification

Druggable: 1 · Difficult: 0 · Unknown: 2 · Druggable fraction: 0.33

Family distribution

Cohort families vs a genome-wide background (hypergeometric, BH-FDR; fold = observed/expected). Counts kept; sorted by enrichment, so the catch-all Other/Unknown bucket no longer leads.

Family	Genes	Fold	FDR
Enzyme (other)	1	4.0×	0.460
Other/Unknown	2	1.2×	0.587

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
ADSL	Enzyme (other)	yes	4.3.2.2	Fumarate_lyase_fam, Pur_lyase, L-Aspartase-like
SNORD43	Other/Unknown	no
MCM5	Other/Unknown	no		MCM_dom, MCM5, NA-bd_OB-fold

Expression context

Cohort genes with no expression data: 0.

2 cohort genes are a single-cell marker in ≥1 SCXA experiment.

Breadth distribution (Bgee present_calls)

Bucket	Genes
narrow (1-5 tissues)	0
moderate (6-20)	0
broad (>20)	3
unknown	0

Top tissues across cohort

Tissue	Cohort genes
gastrocnemius	1
hindlimb stylopod muscle	1
skeletal muscle tissue	1
adrenal tissue	1
bone marrow	1
sural nerve	1
embryo	1
ganglionic eminence	1
ventricular zone	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
ADSL	147	ubiquitous	marker	hindlimb stylopod muscle, gastrocnemius, skeletal muscle tissue
SNORD43	101		yes	sural nerve, bone marrow, adrenal tissue
MCM5	246	ubiquitous	marker	ventricular zone, ganglionic eminence, embryo

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
MCM5	4,221
ADSL	3,934
SNORD43	0

Structural data

PDB: 2 · AlphaFold-only: 0 · No structure: 1

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
MCM5	P33992	27
ADSL	P30566	4

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 22. Enrichment computed across 3 evidence-associated genes (2 with Reactome annotation).

Pathways by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 2 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Regulation of MITF-M-dependent genes involved in DNA replication, damage repair and senescence	1	815.7×	0.013	MCM5
DNA strand elongation	1	571.0×	0.013	MCM5
Purine ribonucleoside monophosphate biosynthesis	1	519.1×	0.013	ADSL
Unwinding of DNA	1	439.2×	0.013	MCM5
Activation of the pre-replicative complex	1	163.1×	0.016	MCM5
DNA Replication Pre-Initiation	1	158.6×	0.016	MCM5
Activation of ATR in response to replication stress	1	150.3×	0.016	MCM5
Switching of origins to a post-replicative state	1	150.3×	0.016	MCM5
Synthesis of DNA	1	150.3×	0.016	MCM5
DNA Replication	1	119.0×	0.016	MCM5
G1/S Transition	1	116.5×	0.016	MCM5
Mitotic G1 phase and G1/S transition	1	92.1×	0.016	MCM5
S Phase	1	90.6×	0.016	MCM5
MITF-M-dependent gene expression	1	90.6×	0.016	MCM5
Orc1 removal from chromatin	1	89.2×	0.016	MCM5
Assembly of the pre-replicative complex	1	69.6×	0.019	MCM5
G2/M Checkpoints	1	67.2×	0.019	MCM5
MITF-M-regulated melanocyte development	1	57.1×	0.021	MCM5
Cell Cycle Checkpoints	1	44.3×	0.026	MCM5
Cell Cycle, Mitotic	1	24.1×	0.045	MCM5
Cell Cycle	1	18.0×	0.057	MCM5
Developmental Biology	1	7.2×	0.134	MCM5

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 2 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
AMP biosynthetic process	1	2106.5×	0.003	ADSL
‘de novo’ IMP biosynthetic process	1	1404.3×	0.003	ADSL
AMP salvage	1	1404.3×	0.003	ADSL
‘de novo’ AMP biosynthetic process	1	1053.2×	0.003	ADSL
‘de novo’ XMP biosynthetic process	1	1053.2×	0.003	ADSL
GMP biosynthetic process	1	936.2×	0.003	ADSL
double-strand break repair via break-induced replication	1	648.1×	0.003	MCM5
purine nucleotide biosynthetic process	1	648.1×	0.003	ADSL
regulation of DNA-templated DNA replication initiation	1	526.6×	0.003	MCM5
DNA replication initiation	1	312.1×	0.005	MCM5
response to muscle activity	1	290.6×	0.005	ADSL
response to starvation	1	234.1×	0.006	ADSL
response to nutrient	1	147.8×	0.008	ADSL
aerobic respiration	1	123.9×	0.009	ADSL
DNA replication	1	82.6×	0.013	MCM5
response to hypoxia	1	47.9×	0.021	ADSL

Therapeutics

Drug target analysis

Approved (phase 4): 0 · Phase ≥3: 0 · Phased (≥1): 0 · Undrugged: 3

Druggability breadth: 2 of 3 evidence-associated genes (67%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
ADSL	0	0
SNORD43	0	0
MCM5	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

Cohort genes with ChEMBL bioactivity (full, sorted by assay count)

Symbol	Assays	Type breakdown
MCM5	10	Binding:10
ADSL	1	Binding:1

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
ADSL	4.3.2.2	adenylosuccinate lyase

Pharmacogenomics

Cohort genes with a PharmGKB record: 3; with CPIC/DPWG dosing guidelines: 0.

No cohort gene has a CPIC/DPWG genotype-guided dosing guideline (PharmGKB).

Chemical tractability of cohort targets

0 approved/phased compounds have measured bioactivity against a cohort gene (and aren’t yet in disease-level trials). This is a research / tractability signal, NOT a therapeutic recommendation — a bioactivity row often reflects off-target or screening binding (e.g. promiscuous kinase inhibitors against a cohort kinase), implying no disease mechanism.

Druggability pyramid

Cohort genes binned by druggability tier (high → low):

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	0
B	Phased (≥1) drug, not yet approved	0
C	Druggable family + PDB, no drug	1	ADSL
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	2	SNORD43, MCM5

Undrugged target profiles

3 cohort genes are undrugged. Ranked by ‘starting-point quality’ (assay depth + drugged-partner adjacency).

Symbol	ChEMBL assays	Drugged partners (top 3)
ADSL	1	—
SNORD43	0	—
MCM5	10	—

Clinical trials & evidence

Clinical trials

Clinical trials: 1.

Phase distribution (across all retrieved trials)

Phase	Trials
PHASE2	1

Top trials by phase / activity

NCT	Phase	Status	Title
NCT03776656	PHASE2	COMPLETED	Evaluation of a Treatment With Allopurinol in Adenylosuccinate Lyase Deficiency

Drugs tested across these trials (top 30)

Molecule	Max phase	Trials referencing
ALLOPURINOL	4	1