porphyria due to ALA dehydratase deficiency

Summary

porphyria due to ALA dehydratase deficiency (MONDO:0013000) is a disease caused by ALAD (GenCC Strong), with 1 cohort gene and 8 clinical trials. Top therapeutic interventions include givosiran.

At a glance

• Prevalence: <1 / 1 000 000 (Europe)
• Causal gene: ALAD (GenCC Strong)
• Cohort genes: 1
• ClinVar variants: 88
• Phenotypes (HPO): 43
• Clinical trials: 8

Clinical features

Epidemiology

Prevalence records

1 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Point prevalence	<1 / 1 000 000		Europe	Not yet validated

Signs & symptoms

Clinical features (HPO)

43 HPO clinical features (Orphanet curated; top 43 by frequency):

HPO ID	Term	Frequency
HP:0012379	Abnormal enzyme/coenzyme activity	Very frequent (80-99%)
HP:0040322	Purple urine	Frequent (30-79%)
HP:0010472	Abnormal circulating porphyrin concentration	Frequent (30-79%)
HP:0000707	Abnormality of the nervous system	Frequent (30-79%)
HP:0009830	Peripheral neuropathy	Frequent (30-79%)
HP:0001324	Muscle weakness	Frequent (30-79%)
HP:0002027	Abdominal pain	Frequent (30-79%)
HP:0012217	Increased urinary porphobilinogen	Frequent (30-79%)
HP:0012187	Increased erythrocyte protoporphyrin concentration	Frequent (30-79%)
HP:0033010	Increased fecal coproporphyrin 3	Frequent (30-79%)
HP:0030272	Abnormal erythrocyte enzyme activity	Frequent (30-79%)
HP:0001288	Gait disturbance	Occasional (5-29%)
HP:0001289	Confusion	Occasional (5-29%)
HP:0000713	Agitation	Occasional (5-29%)
HP:0000739	Anxiety	Occasional (5-29%)
HP:0000711	Restlessness	Occasional (5-29%)
HP:0000738	Hallucinations	Occasional (5-29%)
HP:0031258	Delirium	Occasional (5-29%)
HP:0007159	Fluctuations in consciousness	Occasional (5-29%)
HP:0000741	Apathy	Occasional (5-29%)
HP:0000716	Depression	Occasional (5-29%)
HP:0100852	Abnormal fear/anxiety-related behavior	Occasional (5-29%)
HP:0007178	Motor polyneuropathy	Occasional (5-29%)
HP:0000763	Sensory neuropathy	Occasional (5-29%)
HP:0004302	Functional motor deficit	Occasional (5-29%)
HP:0002018	Nausea	Occasional (5-29%)
HP:0002572	Episodic vomiting	Occasional (5-29%)
HP:0002019	Constipation	Occasional (5-29%)
HP:0003270	Abdominal distention	Occasional (5-29%)
HP:0002014	Diarrhea	Occasional (5-29%)
HP:0001271	Polyneuropathy	Occasional (5-29%)
HP:0002902	Hyponatremia	Occasional (5-29%)
HP:0002086	Abnormality of the respiratory system	Occasional (5-29%)
HP:0005547	Myeloproliferative disorder	Occasional (5-29%)
HP:0003690	Limb muscle weakness	Occasional (5-29%)
HP:0001260	Dysarthria	Occasional (5-29%)
HP:0002093	Respiratory insufficiency	Occasional (5-29%)
HP:0005946	Ventilator dependence with inability to wean	Occasional (5-29%)
HP:0001256	Intellectual disability, mild	Occasional (5-29%)
HP:0000717	Autism	Occasional (5-29%)
HP:0000365	Hearing impairment	Occasional (5-29%)
HP:0006466	Ankle flexion contracture	Occasional (5-29%)
HP:0011121	Abnormal skin morphology	Excluded (0%)

Identifiers

Disease identifiers

Field	Value
Canonical name	porphyria due to ALA dehydratase deficiency
Mondo ID	MONDO:0013000
MeSH	C562618
OMIM	612740
Orphanet	100924
NCIT	C133887
UMLS	C0268328
MedGen	78659
GARD	0016937
NORD	747
Is cancer (heuristic)	no

Also known as: 5-aminolevulinic acid dehydratase deficiency porphyria · acute hepatic porphyria · ALA dehydratase deficiency pophyria · ALAD Porphyria · ALAD porphyria · ALAD-related hepatic porphyria · ALAD-related porphyria · aminolevulinate dehydratase deficiency porphyria · porphyria due to ALAD deficiency · porphyria due to delta-aminolevulinate dehydratase deficiency · porphyria of Doss

Data availability: 88 ClinVar variants · 6 GenCC gene-disease records · 1 cell line.

Disease family

Classification path: disease › human disease › disease by body system or component › digestive system disorder › hepatobiliary disorder › liver disorder › hepatic porphyria › porphyria due to ALA dehydratase deficiency

Related subtypes (6): erythropoietic protoporphyria, hereditary coproporphyria, porphyria cutanea tarda, HMBS-related hepatic porphyria, PPOX-related hepatic porphyria, hepatic cutaneous porphyria

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

88 retrieved; paginated sample, class counts are floors:

52 uncertain significance, 11 benign, 8 conflicting classifications of pathogenicity, 8 likely benign, 4 benign/likely benign, 3 pathogenic, 2 likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
16866	NM_000031.6(ALAD):c.820G>A (p.Ala274Thr)	ALAD	Pathogenic	no assertion criteria provided
16868	NM_000031.6(ALAD):c.165-11C>A	ALAD	Pathogenic	no assertion criteria provided
16869	NM_000031.6(ALAD):c.165-11C>T	ALAD	Pathogenic	no assertion criteria provided
16862	NM_000031.6(ALAD):c.397G>A (p.Gly133Arg)	ALAD	Likely pathogenic	criteria provided, multiple submitters, no conflicts
3067962	NM_000031.6(ALAD):c.165-2A>G	ALAD	Likely pathogenic	criteria provided, single submitter
364641	NM_000031.6(ALAD):c.931+15G>A	ALAD	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
364644	NM_000031.6(ALAD):c.715-14C>A	ALAD	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
364645	NM_000031.6(ALAD):c.678G>T (p.Leu226=)	ALAD	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
364647	NM_000031.6(ALAD):c.501G>A (p.Pro167=)	ALAD	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
364652	NM_000031.6(ALAD):c.264C>T (p.Asp88=)	ALAD	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
364655	NM_000031.6(ALAD):c.16G>A (p.Val6Ile)	ALAD	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
913819	NM_000031.6(ALAD):c.801+14C>T	ALAD	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
914516	NM_000031.6(ALAD):c.*1322G>A	ALAD	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1033602	NM_000031.6(ALAD):c.874G>A (p.Gly292Arg)	ALAD	Uncertain significance	criteria provided, multiple submitters, no conflicts
16863	NM_000031.6(ALAD):c.823G>A (p.Val275Met)	ALAD	Uncertain significance	criteria provided, single submitter
16865	NM_000031.6(ALAD):c.718C>T (p.Arg240Trp)	ALAD	Uncertain significance	criteria provided, single submitter
2431037	NM_000031.6(ALAD):c.446G>A (p.Arg149Gln)	ALAD	Uncertain significance	criteria provided, single submitter
2690871	NM_000031.6(ALAD):c.415G>A (p.Gly139Arg)	ALAD	Uncertain significance	criteria provided, single submitter
364620	NM_000031.6(ALAD):c.*1864A>C	ALAD	Uncertain significance	criteria provided, single submitter
364622	NM_000031.6(ALAD):c.*1741G>A	ALAD	Uncertain significance	criteria provided, single submitter
364623	NM_000031.6(ALAD):c.*1675C>T	ALAD	Uncertain significance	criteria provided, single submitter
364624	NM_000031.6(ALAD):c.*1631G>A	ALAD	Uncertain significance	criteria provided, single submitter
364625	NM_000031.6(ALAD):c.*1511T>C	ALAD	Uncertain significance	criteria provided, single submitter
364626	NM_000031.6(ALAD):c.*1470G>A	ALAD	Uncertain significance	criteria provided, single submitter
364627	NM_000031.6(ALAD):c.*1464A>G	ALAD	Uncertain significance	criteria provided, single submitter
364634	NM_000031.6(ALAD):c.*438G>C	ALAD	Uncertain significance	criteria provided, single submitter
364635	NM_000031.6(ALAD):c.*422G>T	ALAD	Uncertain significance	criteria provided, single submitter
364636	NM_000031.6(ALAD):c.*400G>A	ALAD	Uncertain significance	criteria provided, single submitter
364637	NM_000031.6(ALAD):c.*381G>A	ALAD	Uncertain significance	criteria provided, single submitter
364638	NM_000031.6(ALAD):c.*127C>T	ALAD	Uncertain significance	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 6 · 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
ALAD	Strong	Autosomal recessive	porphyria due to ALA dehydratase deficiency	6

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
ALAD	Orphanet:100924	Porphyria due to ALA dehydratase deficiency

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
ALAD	HGNC:395	ENSG00000148218	P13716	Delta-aminolevulinic acid dehydratase	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
ALAD	Delta-aminolevulinic acid dehydratase	Catalyzes an early step in the biosynthesis of tetrapyrroles.

Protein-family classification

Druggable: 1 · Difficult: 0 · Unknown: 0 · Druggable fraction: 1.0

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
Enzyme (other)	1	12.0×	0.083

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
ALAD	Enzyme (other)	yes	4.2.1.24	ALAD, Aldolase_TIM, ALAD_AS

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 adrenal gland	1
right adrenal gland	1
right adrenal gland cortex	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
ALAD	287	ubiquitous	marker	right adrenal gland, right adrenal gland cortex, left adrenal gland

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
ALAD	2,190

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
ALAD	P13716	4

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 2. 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
Heme biosynthesis	1	761.3×	0.003	ALAD
Neutrophil degranulation	1	23.1×	0.043	ALAD

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
response to aluminum ion	1	5617.3×	0.001	ALAD
response to vitamin B1	1	5617.3×	0.001	ALAD
cellular response to lead ion	1	5617.3×	0.001	ALAD
response to platinum ion	1	4213.0×	0.001	ALAD
response to herbicide	1	3370.4×	0.001	ALAD
response to vitamin E	1	2808.7×	0.001	ALAD
response to cobalt ion	1	2407.4×	0.001	ALAD
response to mercury ion	1	2407.4×	0.001	ALAD
response to methylmercury	1	2407.4×	0.001	ALAD
obsolete protoporphyrinogen IX biosynthetic process	1	1685.2×	0.002	ALAD
heme B biosynthetic process	1	1685.2×	0.002	ALAD
heme A biosynthetic process	1	1532.0×	0.002	ALAD
response to selenium ion	1	1404.3×	0.002	ALAD
negative regulation of proteasomal protein catabolic process	1	1404.3×	0.002	ALAD
response to arsenic-containing substance	1	1203.7×	0.002	ALAD
response to fatty acid	1	1053.2×	0.002	ALAD
response to amino acid	1	991.3×	0.002	ALAD
response to iron ion	1	936.2×	0.002	ALAD
response to cadmium ion	1	732.7×	0.002	ALAD
cellular response to interleukin-4	1	648.1×	0.002	ALAD
response to zinc ion	1	624.1×	0.002	ALAD
heme biosynthetic process	1	601.9×	0.002	ALAD
response to ionizing radiation	1	411.0×	0.003	ALAD
response to activity	1	324.1×	0.004	ALAD
response to glucocorticoid	1	324.1×	0.004	ALAD
response to ethanol	1	146.5×	0.008	ALAD
response to oxidative stress	1	130.6×	0.009	ALAD
response to lipopolysaccharide	1	124.8×	0.009	ALAD
protein homooligomerization	1	122.1×	0.009	ALAD
response to hypoxia	1	95.8×	0.011	ALAD

Therapeutics

Drug target analysis

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

Druggability breadth: 1 of 1 evidence-associated genes (100%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
ALAD	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
ALAD	10	Binding:10

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
ALAD	4.2.1.24	porphobilinogen synthase

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	ALAD
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	0

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)
ALAD	10	—

Clinical trials & evidence

Clinical trials

Clinical trials: 8.

Phase distribution (across all retrieved trials)

Phase	Trials
Not specified	6
PHASE3	1
PHASE1	1

Top trials by phase / activity

NCT	Phase	Status	Title
NCT03338816	PHASE3	COMPLETED	ENVISION: A Study to Evaluate the Efficacy and Safety of Givosiran (ALN-AS1) in Patients With Acute Hepatic Porphyrias (AHP)
NCT03505853	PHASE1	COMPLETED	A Study to Investigate the Interaction Between Givosiran and a 5-probe Drug Cocktail in Patients With Acute Intermittent Porphyria (AIP)
NCT04883905	Not specified	RECRUITING	ELEVATE, a Registry of Patients With Acute Hepatic Porphyria (AHP)
NCT05344599	Not specified	ACTIVE_NOT_RECRUITING	Evaluating the Prevalence of Acute Hepatic Porphyria in Postural Tachycardia Syndrome
NCT02240784	Not specified	COMPLETED	EXPLORE: A Natural History Study of Acute Hepatic Porphyria (AHP)
NCT03547297	Not specified	TERMINATED	INSIGHT-AHP: A Study to Characterize the Prevalence of Acute Hepatic Porphyria (AHP) in Patients With Clinical Presentation and History Consistent With AHP
NCT04056481	Not specified	APPROVED_FOR_MARKETING	Expanded Access Protocol of Givosiran for Patients With Acute Hepatic Porphyria
NCT04923516	Not specified	COMPLETED	Prevalence of Acute Hepatic Porphyria

Drugs tested across these trials (top 30)

Molecule	Max phase	Trials referencing
GIVOSIRAN	3	3
CHEMBL1235151	0	1