Hyperlysinemia

Summary

Hyperlysinemia (MONDO:0009388) is a disease caused by AASS (GenCC Strong), with 1 cohort gene.

At a glance

• Prevalence: Unknown (Worldwide)
• Causal gene: AASS (GenCC Strong)
• Cohort genes: 1
• ClinVar variants: 31
• Phenotypes (HPO): 57

Clinical features

Signs & symptoms

Clinical features (HPO)

57 HPO clinical features (Orphanet curated; top 50 by frequency):

HPO ID	Term	Frequency
HP:0000252	Microcephaly	Frequent (30-79%)
HP:0000708	Atypical behavior	Frequent (30-79%)
HP:0000736	Short attention span	Frequent (30-79%)
HP:0000750	Delayed speech and language development	Frequent (30-79%)
HP:0001249	Intellectual disability	Frequent (30-79%)
HP:0001250	Seizure	Frequent (30-79%)
HP:0001263	Global developmental delay	Frequent (30-79%)
HP:0001987	Hyperammonemia	Frequent (30-79%)
HP:0002161	Hyperlysinemia	Frequent (30-79%)
HP:0003131	Cystinuria	Frequent (30-79%)
HP:0003268	Argininuria	Frequent (30-79%)
HP:0003297	Hyperlysinuria	Frequent (30-79%)
HP:0004322	Short stature	Frequent (30-79%)
HP:0008947	Floppy infant	Frequent (30-79%)
HP:0010850	EEG with spike-wave complexes	Frequent (30-79%)
HP:0012379	Abnormal enzyme/coenzyme activity	Frequent (30-79%)
HP:0012403	Decreased urine alpha-ketoglutarate concentration	Frequent (30-79%)
HP:0012758	Neurodevelopmental delay	Frequent (30-79%)
HP:0500163	Hypoornithinemia	Frequent (30-79%)
HP:0500204	Decreased CSF arginine concentration	Frequent (30-79%)
HP:0500208	Increased CSF lysine concentration	Frequent (30-79%)
HP:0500243	Abnormal CSF ornithine concentration	Frequent (30-79%)
HP:0025331	Upgaze palsy	Occasional (5-29%)
HP:0030051	Tip-toe gait	Occasional (5-29%)
HP:0031867	Neck hypertonia	Occasional (5-29%)
HP:0040288	Nasogastric tube feeding	Occasional (5-29%)
HP:0045074	Thin eyebrow	Occasional (5-29%)
HP:0100022	Abnormality of movement	Occasional (5-29%)
HP:0000218	High palate	Occasional (5-29%)
HP:0000319	Smooth philtrum	Occasional (5-29%)
HP:0000457	Depressed nasal ridge	Occasional (5-29%)
HP:0000486	Strabismus	Occasional (5-29%)
HP:0000601	Hypotelorism	Occasional (5-29%)
HP:0000752	Hyperactivity	Occasional (5-29%)
HP:0001264	Spastic diplegia	Occasional (5-29%)
HP:0001285	Spastic tetraparesis	Occasional (5-29%)
HP:0001310	Dysmetria	Occasional (5-29%)
HP:0001337	Tremor	Occasional (5-29%)
HP:0001348	Brisk reflexes	Occasional (5-29%)
HP:0001363	Craniosynostosis	Occasional (5-29%)
HP:0001508	Failure to thrive	Occasional (5-29%)
HP:0001999	Abnormal facial shape	Occasional (5-29%)
HP:0002013	Vomiting	Occasional (5-29%)
HP:0002015	Dysphagia	Occasional (5-29%)
HP:0002020	Gastroesophageal reflux	Occasional (5-29%)
HP:0002033	Poor suck	Occasional (5-29%)
HP:0002179	Opisthotonus	Occasional (5-29%)
HP:0002275	Poor motor coordination	Occasional (5-29%)
HP:0002312	Clumsiness	Occasional (5-29%)
HP:0004971	Pulmonary artery hypoplasia	Occasional (5-29%)

Identifiers

Disease identifiers

Field	Value
Canonical name	hyperlysinemia
Mondo ID	MONDO:0009388
OMIM	238700
Orphanet	2203
DOID	DOID:9274
NCIT	C123433
SNOMED CT	58558003
UMLS	C0268553
MedGen	82816
GARD	0002828
Is cancer (heuristic)	no

Also known as: hyperlysinemia · hyperlysinemia (disease) · hyperlysinemia type I · L-lysine NAD-oxido-reductase deficiency · lysine alpha-ketoglutarate reductase deficiency

Data availability: 31 ClinVar variants · 5 GenCC gene-disease records · 1 HPO phenotype · 1 cell line.

Disease family

An umbrella term covering 1 Mondo subtype.

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 › hyperlysinemia

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, adenylosuccinate lyase deficiency, systemic primary carnitine deficiency disease, cystathioninuria, 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

Subtypes (1): hyperlysinemia due to defect in lysine transport into mitochondria

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

31 retrieved; paginated sample, class counts are floors:

10 pathogenic, 9 likely pathogenic, 8 uncertain significance, 2 pathogenic/likely pathogenic, 1 conflicting classifications of pathogenicity, 1 likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
100642	NM_005763.4(AASS):c.2662+1_2662+5delinsTT	AASS	Pathogenic	no assertion criteria provided
100643	NM_005763.4(AASS):c.874A>G (p.Ile292Val)	AASS	Pathogenic	no assertion criteria provided
100644	NM_005763.4(AASS):c.976_977del (p.Gln326fs)	AASS	Pathogenic	no assertion criteria provided
100645	NM_005763.4(AASS):c.1925C>G (p.Ser642Ter)	AASS	Pathogenic	no assertion criteria provided
100647	NM_005763.4(AASS):c.1256T>G (p.Leu419Arg)	AASS	Pathogenic	no assertion criteria provided
1030964	NM_005763.4(AASS):c.1767-1G>A	AASS	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1322091	NM_005763.4(AASS):c.2100T>G (p.Tyr700Ter)	AASS	Pathogenic	criteria provided, single submitter
2682543	NC_000007.13:g.(121733213_121738503)(121784304?)del	AASS	Pathogenic	criteria provided, single submitter
3063765	NM_005763.4(AASS):c.904dup (p.Tyr302fs)	AASS	Pathogenic	criteria provided, single submitter
3629522	NC_000007.13:g.(121758685_121766428)(121784304?)del	AASS	Pathogenic	criteria provided, single submitter
3899464	NM_005763.4(AASS):c.2076dup (p.Pro693fs)	AASS	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
5209	NM_005763.4(AASS):c.1601_1609del (p.Cys534_Glu537delinsTer)	AASS	Pathogenic	no assertion criteria provided
100646	NM_005763.4(AASS):c.194G>A (p.Arg65Gln)	AASS	Likely pathogenic	criteria provided, single submitter
1048521	NM_005763.4(AASS):c.3G>A (p.Met1Ile)	AASS	Likely pathogenic	criteria provided, single submitter
1048522	NM_005763.4(AASS):c.395G>A (p.Arg132His)	AASS	Likely pathogenic	criteria provided, multiple submitters, no conflicts
1334629	NM_005763.4(AASS):c.2196dup (p.Ala733fs)	AASS	Likely pathogenic	criteria provided, single submitter
1878391	NC_000007.13:g.(121733213_121738503)_(121773796_121784214)del	AASS	Likely pathogenic	criteria provided, single submitter
3065764	NM_005763.4(AASS):c.2397-1G>T	AASS	Likely pathogenic	criteria provided, single submitter
3764618	NM_005763.4(AASS):c.2280G>A (p.Trp760Ter)	AASS	Likely pathogenic	criteria provided, single submitter
4072352	NM_005763.4(AASS):c.2583T>A (p.Tyr861Ter)	AASS	Likely pathogenic	criteria provided, single submitter
4849157	NM_005763.4(AASS):c.1407-1G>A	AASS	Likely pathogenic	criteria provided, single submitter
2957962	NM_005763.4(AASS):c.1345A>C (p.Ile449Leu)	AASS	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1098670	NM_005763.4(AASS):c.1393C>G (p.Leu465Val)	AASS	Uncertain significance	criteria provided, multiple submitters, no conflicts
1220244	NM_005763.4(AASS):c.2339A>C (p.Lys780Thr)	AASS	Uncertain significance	criteria provided, multiple submitters, no conflicts
1516672	NM_005763.4(AASS):c.2317T>A (p.Ser773Thr)	AASS	Uncertain significance	criteria provided, single submitter
2438707	NM_005763.4(AASS):c.1733A>G (p.Tyr578Cys)	AASS	Uncertain significance	criteria provided, multiple submitters, no conflicts
252652	NM_005763.4(AASS):c.2762A>G (p.Gln921Arg)	AASS	Uncertain significance	criteria provided, multiple submitters, no conflicts
3712709	NM_005763.4(AASS):c.394C>T (p.Arg132Cys)	AASS	Uncertain significance	criteria provided, multiple submitters, no conflicts
973452	NM_005763.4(AASS):c.1048G>A (p.Val350Met)	AASS	Uncertain significance	criteria provided, multiple submitters, no conflicts
973464	NM_005763.4(AASS):c.1876A>G (p.Ile626Val)	AASS	Uncertain significance	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 5 · Orphanet: 2 · 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
AASS	Strong	Autosomal recessive	hyperlysinemia	5

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
AASS	Orphanet:2203	Hyperlysinemia
AASS	Orphanet:3124	Saccharopinuria

Cohort genes → proteins

1 cohort genes, 1 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	1

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
AASS	HGNC:17366	ENSG00000008311	Q9UDR5	Alpha-aminoadipic semialdehyde synthase, mitochondrial	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
AASS	Alpha-aminoadipic semialdehyde synthase, mitochondrial	Bifunctional enzyme that catalyzes the first two steps in lysine degradation.

Protein-family classification

Druggable: 0 · Difficult: 0 · Unknown: 1 · Druggable fraction: 0.0

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
Other/Unknown	1	1.8×	0.558

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
AASS	Other/Unknown	no		Sacchrp_dh_NADP-bd, AlaDH/PNT_NAD(H)-bd, AlaDH/PNT_N

Expression context

Cohort genes with no expression data: 0.

1 cohort gene 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)	1
unknown	0

Top tissues across cohort

Tissue	Cohort genes
left ovary	1
mucosa of stomach	1
right ovary	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
AASS	260	ubiquitous	marker	mucosa of stomach, left ovary, right ovary

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
AASS	1,333

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
AASS	Q9UDR5	9

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 3. Enrichment computed across 1 evidence-associated genes (1 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 1 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Lysine catabolism	1	1142.0×	0.003	AASS
Metabolism of amino acids and derivatives	1	67.6×	0.022	AASS
Metabolism	1	11.6×	0.086	AASS

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 1 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
obsolete L-lysine biosynthetic process via aminoadipic acid	1	8426.0×	4e-04	AASS
obsolete L-lysine catabolic process to acetyl-CoA via L-saccharopine	1	5617.3×	4e-04	AASS
obsolete lysine catabolic process	1	2407.4×	6e-04	AASS
negative regulation of transcription by RNA polymerase II	1	17.7×	0.056	AASS

Therapeutics

Drug target analysis

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

Druggability breadth: 0 of 1 evidence-associated genes (0%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
AASS	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

Pharmacogenomics

Cohort genes with a PharmGKB record: 1; 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	0
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	1	AASS

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
AASS	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.