aromatic L-amino acid decarboxylase deficiency

Summary

aromatic L-amino acid decarboxylase deficiency (MONDO:0012084) is a disease caused by DDC (GenCC Definitive), with 2 cohort genes and 9 clinical trials. Top therapeutic interventions include eladocagene exuparvovec.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: DDC (GenCC Definitive)
• Cohort genes: 2
• ClinVar variants: 571
• Phenotypes (HPO): 38
• Clinical trials: 9

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		140	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Signs & symptoms

Clinical features (HPO)

38 HPO clinical features (Orphanet curated; top 38 by frequency):

HPO ID	Term	Frequency
HP:0001263	Global developmental delay	Very frequent (80-99%)
HP:0003785	Decreased CSF homovanillic acid concentration	Very frequent (80-99%)
HP:0025455	Decreased CSF 5-hydroxyindolacetic acid concentration	Very frequent (80-99%)
HP:0000708	Atypical behavior	Frequent (30-79%)
HP:0000737	Irritability	Frequent (30-79%)
HP:0000975	Hyperhidrosis	Frequent (30-79%)
HP:0001249	Intellectual disability	Frequent (30-79%)
HP:0001250	Seizure	Frequent (30-79%)
HP:0001252	Hypotonia	Frequent (30-79%)
HP:0001270	Motor delay	Frequent (30-79%)
HP:0001332	Dystonia	Frequent (30-79%)
HP:0001508	Failure to thrive	Frequent (30-79%)
HP:0002020	Gastroesophageal reflux	Frequent (30-79%)
HP:0002360	Sleep abnormality	Frequent (30-79%)
HP:0002421	Poor head control	Frequent (30-79%)
HP:0010553	Oculogyric crisis	Frequent (30-79%)
HP:0011968	Feeding difficulties	Frequent (30-79%)
HP:0000508	Ptosis	Occasional (5-29%)
HP:0000616	Miosis	Occasional (5-29%)
HP:0000729	Autistic behavior	Occasional (5-29%)
HP:0000870	Increased circulating prolactin concentration	Occasional (5-29%)
HP:0001260	Dysarthria	Occasional (5-29%)
HP:0001315	Reduced tendon reflexes	Occasional (5-29%)
HP:0001742	Nasal congestion	Occasional (5-29%)
HP:0001943	Hypoglycemia	Occasional (5-29%)
HP:0002015	Dysphagia	Occasional (5-29%)
HP:0002019	Constipation	Occasional (5-29%)
HP:0002307	Drooling	Occasional (5-29%)
HP:0002353	EEG abnormality	Occasional (5-29%)
HP:0002375	Hypokinesia	Occasional (5-29%)
HP:0002509	Limb hypertonia	Occasional (5-29%)
HP:0002615	Hypotension	Occasional (5-29%)
HP:0003487	Babinski sign	Occasional (5-29%)
HP:0004322	Short stature	Occasional (5-29%)
HP:0100660	Dyskinesia	Occasional (5-29%)
HP:0001337	Tremor	Very rare (<1-4%)
HP:0002014	Diarrhea	Very rare (<1-4%)
HP:0034392	Joint contracture	Very rare (<1-4%)

Identifiers

Disease identifiers

Field	Value
Canonical name	aromatic L-amino acid decarboxylase deficiency
Mondo ID	MONDO:0012084
MeSH	C537437
OMIM	608643
Orphanet	35708
DOID	DOID:0090123
ICD-10-CM	E70.81
ICD-11	1134258245
NCIT	C142085
SNOMED CT	237922009
UMLS	C1291564
MedGen	220945
GARD	0000770
NORD	2010
Is cancer (heuristic)	no

Also known as: AADC deficiency · aromatic amino acid decarboxylase deficiency · aromatic L-amino acid decarboxylase deficiency · aromatic L-amino-acid decarboxylase deficiency

Data availability: 571 ClinVar variants · 5 GenCC gene-disease records · 3 cell lines.

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 biogenic amine metabolism and transport › inborn disorder of neurotransmitter metabolism and transport › disorder of catecholamine synthesis › aromatic L-amino acid decarboxylase deficiency

Related subtypes (1): orthostatic hypotension 1

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

571 retrieved; paginated sample, class counts are floors:

246 likely benign, 180 uncertain significance, 46 pathogenic, 32 conflicting classifications of pathogenicity, 26 likely pathogenic, 21 pathogenic/likely pathogenic, 12 benign, 8 benign/likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
1034300	NM_001082971.2(DDC):c.19C>T (p.Arg7Ter)	DDC	Pathogenic	criteria provided, multiple submitters, no conflicts
1036808	NM_001082971.2(DDC):c.367G>A (p.Gly123Arg)	DDC	Pathogenic	criteria provided, single submitter
1057684	NM_001082971.2(DDC):c.206C>T (p.Thr69Met)	DDC	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1068763	NM_001082971.2(DDC):c.1297dup (p.Ile433fs)	DDC	Pathogenic	criteria provided, multiple submitters, no conflicts
1068764	NM_001082971.2(DDC):c.1234C>T (p.Arg412Trp)	DDC	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1069673	NC_000007.13:g.(?50563038)(50563125_?)del	DDC	Pathogenic	criteria provided, single submitter
1074024	NM_001082971.2(DDC):c.1055del (p.Pro352fs)	DDC	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1075848	NM_001082971.2(DDC):c.480del (p.Thr161fs)	DDC	Pathogenic	criteria provided, single submitter
1324215	NM_001082971.2(DDC):c.175G>A (p.Asp59Asn)	DDC	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1353224	NM_001082971.2(DDC):c.48_49delinsAG (p.Tyr16_Met17delinsTer)	DDC	Pathogenic	criteria provided, single submitter
1355136	NM_001082971.2(DDC):c.564_568dup (p.Gln190fs)	DDC	Pathogenic	criteria provided, single submitter
1373356	NM_001082971.2(DDC):c.82C>T (p.Gln28Ter)	DDC	Pathogenic	criteria provided, single submitter
1374428	NM_001082971.2(DDC):c.1233del (p.Arg412fs)	DDC	Pathogenic	criteria provided, single submitter
1385192	NM_001082971.2(DDC):c.526C>T (p.Gln176Ter)	DDC	Pathogenic	criteria provided, single submitter
1399541	NM_000790.4(DDC):c.316del	DDC	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1401179	NM_001082971.2(DDC):c.201+5G>C	DDC	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1433147	NM_001082971.2(DDC):c.568C>T (p.Gln190Ter)	DDC	Pathogenic	criteria provided, single submitter
1677200	NM_001082971.2(DDC):c.710T>C (p.Phe237Ser)	DDC	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1677221	NM_001082971.2(DDC):c.242C>T (p.Pro81Leu)	DDC	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1683497	NM_001082971.2(DDC):c.995A>G (p.Tyr332Cys)	DDC	Pathogenic	criteria provided, single submitter
17809	NM_001082971.2(DDC):c.304G>A (p.Gly102Ser)	DDC	Pathogenic	criteria provided, multiple submitters, no conflicts
17810	NM_001082971.2(DDC):c.749C>T (p.Ser250Phe)	DDC	Pathogenic	criteria provided, multiple submitters, no conflicts
17811	NM_001082971.2(DDC):c.925T>C (p.Phe309Leu)	DDC	Pathogenic	no assertion criteria provided
17812	NM_001082971.2(DDC):c.439A>C (p.Ser147Arg)	DDC	Pathogenic	no assertion criteria provided
17813	NM_001082971.2(DDC):c.272C>T (p.Ala91Val)	DDC	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
17814	NM_001082971.2(DDC):c.823G>A (p.Ala275Thr)	DDC	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1805503	NM_001082971.2(DDC):c.1339C>T (p.Arg447Cys)	DDC	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
202181	NM_001082971.2(DDC):c.1040G>A (p.Arg347Gln)	DDC	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2022937	NM_001082971.2(DDC):c.1107T>A (p.Tyr369Ter)	DDC	Pathogenic	criteria provided, single submitter
2030127	NM_001082971.2(DDC):c.1013_1016dup (p.Asp339fs)	DDC	Pathogenic	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 5 · 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
DDC	Definitive	Autosomal recessive	aromatic L-amino acid decarboxylase deficiency	5

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
DDC	Orphanet:35708	Aromatic L-amino acid decarboxylase deficiency

Cohort genes → proteins

2 cohort genes, 1 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	2

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
DDC	HGNC:2719	ENSG00000132437	P20711	Aromatic-L-amino-acid decarboxylase	gencc,clinvar
DDC-AS1	HGNC:40171	ENSG00000226122		DDC antisense RNA 1	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
DDC	Aromatic-L-amino-acid decarboxylase	Catalyzes the decarboxylation of L-3,4-dihydroxyphenylalanine (DOPA) to dopamine and L-5-hydroxytryptophan to serotonin.

Protein-family classification

Druggable: 1 · Difficult: 0 · Unknown: 1 · Druggable fraction: 0.5

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	6.0×	0.320
Other/Unknown	1	0.9×	0.805

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
DDC	Enzyme (other)	yes	4.1.1.28	PyrdxlP-dep_de-COase, Aromatic_deC, PyrdxlP-dep_Trfase_major
DDC-AS1	Other/Unknown	no

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)	1
broad (>20)	1
unknown	0

Top tissues across cohort

Tissue	Cohort genes
adult organism	1
ileal mucosa	1
jejunal mucosa	1
islet of Langerhans	1
right adrenal gland	1
right adrenal gland cortex	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
DDC	177	tissue_specific	marker	jejunal mucosa, ileal mucosa, adult organism
DDC-AS1	17		yes	right adrenal gland cortex, right adrenal gland, islet of Langerhans

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
DDC	2,649
DDC-AS1	0

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
DDC	P20711	8

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 2. Enrichment computed across 2 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
Catecholamine biosynthesis	1	2855.0×	4e-04	DDC
Serotonin and melatonin biosynthesis	1	2284.0×	4e-04	DDC

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
catecholamine metabolic process	1	4213.0×	9e-04	DDC
serotonin biosynthetic process	1	4213.0×	9e-04	DDC
carboxylic acid metabolic process	1	2808.7×	9e-04	DDC
dopamine biosynthetic process	1	1872.4×	0.001	DDC
amino acid metabolic process	1	802.5×	0.002	DDC
response to toxic substance	1	210.7×	0.006	DDC
kidney development	1	140.4×	0.008	DDC
gene expression	1	79.9×	0.013	DDC

Therapeutics

Drug target analysis

Approved (phase 4): 0 · Phase ≥3: 0 · Phased (≥1): 0 · Undrugged: 2

Druggability breadth: 1 of 2 evidence-associated genes (50%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
DDC	0	0
DDC-AS1	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
DDC	8	Functional:6, Binding:2

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
DDC	4.1.1.28	aromatic-L-amino-acid decarboxylase

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	1	DDC
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	1	DDC-AS1

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
DDC	8	—
DDC-AS1	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 9.

Phase distribution (across all retrieved trials)

Phase	Trials
Not specified	3
PHASE2	2
PHASE2/PHASE3	1
PHASE1/PHASE2	1
PHASE1	1
EARLY_PHASE1	1

Top trials by phase / activity

NCT	Phase	Status	Title
NCT06432140	PHASE2/PHASE3	ACTIVE_NOT_RECRUITING	A Trial to Evaluate Safety and Efficacy of a Product Named VGN-R09b in Severe AADC Deficiency
NCT04903288	PHASE2	ACTIVE_NOT_RECRUITING	A Study of SmartFlow Magnetic Resonance (MR) Compatible Ventricular Cannula for Administering Eladocagene Exuparvovec to Pediatric Participants
NCT01395641	PHASE1/PHASE2	COMPLETED	A Phase I/II Clinical Trial for Treatment of Aromatic L-amino Acid Decarboxylase (AADC) Deficiency Using AAV2-hAADC
NCT02926066	PHASE2	COMPLETED	A Clinical Trial for Treatment of Aromatic L-amino Acid Decarboxylase (AADC) Deficiency Using AAV2-hAADC - An Expansion
NCT02852213	PHASE1	RECRUITING	A Single-Stage, Adaptive, Open-label, Dose Escalation Safety and Efficacy Study of AADC Deficiency in Pediatric Patients
NCT05765981	EARLY_PHASE1	RECRUITING	An Early Clinical Trial to Evaluate VGN-R09b for Treatment of Aromatic L-amino Acid Decarboxylase (AADC) Deficiency.
NCT02399761	Not specified	COMPLETED	Newborn Screening for Aromatic L-amino Acid Decarboxylase Deficiency
NCT05211609	Not specified	UNKNOWN	Prevalence of High Plasmatic 3OMethyldopa Level in a Specific Population of Patients With a Symptomatology Compatible With AADC Deficiency
NCT05687474	Not specified	COMPLETED	Baby Detect : Genomic Newborn Screening

Drugs tested across these trials (top 30)

Molecule	Max phase	Trials referencing
ELADOCAGENE EXUPARVOVEC	4	1