Porphyria due to ALA dehydratase deficiency, also called ALAD porphyria or porphyria of Doss, is an ultra-rare autosomal recessive acute hepatic porphyria caused by severe aminolevulinate dehydratase / porphobilinogen synthase deficiency. The block occurs at the second step of heme biosynthesis, so affected patients accumulate 5-aminolevulinic acid (ALA) with little or no porphobilinogen (PBG) overproduction. Clinically, the disorder causes recurrent neurovisceral attacks with abdominal pain, peripheral neuropathy, muscle weakness, and no blistering photosensitivity. Hemin or heme arginate with glucose is the main documented attack treatment; givosiran efficacy remains uncertain in this specific ultra-rare subtype.
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Conditions with similar clinical presentations that must be differentiated from Porphyria due to ALA Dehydratase Deficiency:
name: Porphyria due to ALA Dehydratase Deficiency
category: Mendelian
creation_date: '2026-05-05T09:35:36Z'
updated_date: '2026-05-21T06:40:48Z'
description: >
Porphyria due to ALA dehydratase deficiency, also called ALAD porphyria or
porphyria of Doss, is an ultra-rare autosomal recessive acute hepatic
porphyria caused by severe aminolevulinate dehydratase / porphobilinogen
synthase deficiency. The block occurs at the second step of heme
biosynthesis, so affected patients accumulate 5-aminolevulinic acid (ALA)
with little or no porphobilinogen (PBG) overproduction. Clinically, the
disorder causes recurrent neurovisceral attacks with abdominal pain,
peripheral neuropathy, muscle weakness, and no blistering photosensitivity.
Hemin or heme arginate with glucose is the main documented attack treatment;
givosiran efficacy remains uncertain in this specific ultra-rare subtype.
disease_term:
preferred_term: porphyria due to ALA dehydratase deficiency
term:
id: MONDO:0013000
label: porphyria due to ALA dehydratase deficiency
synonyms:
- ALAD porphyria
- Porphyria due to ALAD deficiency
- Porphyria due to delta-aminolevulinate dehydratase deficiency
- Porphyria of Doss
parents:
- Acute Hepatic Porphyria
- Inborn Error of Heme Biosynthesis
notes: >
ORPHA:100924 includes broad frequent terms for abnormal nervous system and
abnormal enzyme/coenzyme activity; this entry models those with more specific
neuropathy, weakness, and reduced erythrocyte ALAD activity terms. ORPHA also
lists increased urinary porphobilinogen, but PMID:9516683 states that ADP
patients excrete large amounts of ALA "but not PBG"; the biochemical section
therefore models urinary PBG as not increased.
references:
- reference: ORPHA:100924
title: Porphyria due to ALA dehydratase deficiency
findings:
- statement: Orphanet defines ALAD porphyria as an acute hepatic porphyria without skin symptoms.
supporting_text: A rare acute hepatic porphyria characterized by neurovisceral attacks without skin symptoms.
evidence:
- reference: ORPHA:100924
supports: SUPPORT
evidence_source: OTHER
snippet: "A rare acute hepatic porphyria characterized by neurovisceral attacks without skin symptoms."
explanation: Orphanet provides the core disease definition.
- reference: PMID:9516683
title: ALAD porphyria.
findings:
- statement: ALAD porphyria differs biochemically from AIP because ALA, but not PBG, is overproduced.
supporting_text: >
Because of an almost complete lack of ALAD activity, patients excrete a
large amount of ALA, but not PBG, into urine.
evidence:
- reference: PMID:9516683
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >
Because of an almost complete lack of ALAD activity, patients excrete a
large amount of ALA, but not PBG, into urine.
explanation: This review summarizes the distinguishing diagnostic biochemical pattern of ADP.
- reference: PMID:33199206
title: "5-Aminolevulinate dehydratase porphyria: Update on hepatic 5-aminolevulinic acid synthase induction and long-term response to hemin."
findings:
- statement: Hepatic ALAS1 induction and hemin response support a hepatic source of excess ALA in ADP.
supporting_text: >
Elevation in circulating hepatic ALAS1 and response to treatment with
hemin indicate that the liver is an important source of excess ALA in
ADP, although the marrow may also contribute.
evidence:
- reference: PMID:33199206
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >
Elevation in circulating hepatic ALAS1 and response to treatment with
hemin indicate that the liver is an important source of excess ALA in
ADP, although the marrow may also contribute.
explanation: This patient update links hepatic ALAS1 induction, excess ALA production, and hemin responsiveness.
- reference: PMID:33786855
title: Porphyric neuropathy.
findings:
- statement: Acute hepatic porphyria neuropathy can progress to quadriparesis and respiratory weakness.
supporting_text: >
Acute hepatic porphyrias are inherited metabolic disorders that may present
with polyneuropathy, which if not diagnosed early can lead to quadriparesis,
respiratory weakness, and death.
evidence:
- reference: PMID:33786855
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >
Acute hepatic porphyrias are inherited metabolic disorders that may
present with polyneuropathy, which if not diagnosed early can lead to
quadriparesis, respiratory weakness, and death.
explanation: ADP is an acute hepatic porphyria, so this review supports neuropathic weakness and respiratory weakness as severe downstream attack manifestations.
- reference: PMID:6826727
title: Hereditary tyrosinemia and the heme biosynthetic pathway. Profound inhibition of delta-aminolevulinic acid dehydratase activity by succinylacetone.
findings:
- statement: Hereditary tyrosinemia type I can mimic acute porphyria through succinylacetone-mediated ALAD inhibition.
supporting_text: >
Patients with hereditary tyrosinemia can excrete excessive urinary ALA
and develop a syndrome resembling acute intermittent porphyria, while
succinylacetone competitively inhibits ALA dehydratase.
evidence:
- reference: PMID:6826727
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >
It is known that patients with this hereditary disease excrete
excessive amounts of delta-aminolevulinic acid (ALA) in urine and that
certain patients have an accompanying clinical syndrome resembling that
of acute intermittent porphyria (AIP).
explanation: Patient observations support tyrosinemia type I as an acute-porphyria mimic.
- reference: PMID:6826727
supports: SUPPORT
evidence_source: IN_VITRO
snippet: >
Our data indicate that succinylacetone is an extremely potent
competitive inhibitor of ALA dehydratase in human as well as in animal
tissues.
explanation: Biochemical enzyme data support succinylacetone-mediated ALAD inhibition as the mimic mechanism.
- reference: DOI:10.1002/0471142905.hg1720s86
title: "Porphyria Diagnostics-Part 1: A Brief Overview of the Porphyrias"
found_in:
- Porphyria_due_to_ALA_Dehydratase_Deficiency-deep-research-falcon.md
- reference: DOI:10.1023/b:boli.0000037341.21975.9d
title: "The third case of Doss porphyria (delta-aminolevulinic acid dehydratase deficiency) in Germany"
found_in:
- Porphyria_due_to_ALA_Dehydratase_Deficiency-deep-research-falcon.md
- reference: DOI:10.1053/j.gastro.2022.11.034
title: "AGA Clinical Practice Update on Diagnosis and Management of Acute Hepatic Porphyrias: Expert Review"
found_in:
- Porphyria_due_to_ALA_Dehydratase_Deficiency-deep-research-falcon.md
- reference: DOI:10.1055/s-0043-1776760
title: "The Hepatic Porphyrias: Revealing the Complexities of a Rare Disease"
found_in:
- Porphyria_due_to_ALA_Dehydratase_Deficiency-deep-research-falcon.md
- reference: DOI:10.1093/clinchem/44.9.1892
title: "5-Aminolevulinic acid dehydratase deficiency porphyria: a twenty-year clinical and biochemical follow-up"
found_in:
- Porphyria_due_to_ALA_Dehydratase_Deficiency-deep-research-falcon.md
- reference: DOI:10.1136/bmjgast-2024-icpp.75
title: "Functional characterization of new pathogenic and lead-poisoning predisposing variants in ALA Dehydratase Porphyria"
found_in:
- Porphyria_due_to_ALA_Dehydratase_Deficiency-deep-research-falcon.md
- reference: DOI:10.3389/fgene.2022.867856
title: "Case Report: Lack of Response to Givosiran in a Case of ALAD Porphyria"
found_in:
- Porphyria_due_to_ALA_Dehydratase_Deficiency-deep-research-falcon.md
- reference: DOI:10.3390/diagnostics11081343
title: "Laboratory Diagnosis of Porphyria"
found_in:
- Porphyria_due_to_ALA_Dehydratase_Deficiency-deep-research-falcon.md
prevalence:
- population: Europe
percentage: Less than 1 per 1,000,000
notes: >
Orphanet reports European point prevalence below one per million for this
ultra-rare porphyria subtype.
evidence:
- reference: ORPHA:100924
supports: SUPPORT
evidence_source: OTHER
snippet: "<1 / 1 000 000 | Europe | Point prevalence | ORPHANET"
explanation: Orphanet reports a very low European point prevalence.
inheritance:
- name: Autosomal recessive
inheritance_term:
preferred_term: Autosomal recessive inheritance
term:
id: HP:0000007
label: Autosomal recessive inheritance
description: >
ALAD porphyria is an autosomal recessive disorder usually caused by
biallelic ALAD variants that leave very low residual enzyme activity.
evidence:
- reference: PMID:33199206
reference_title: "5-Aminolevulinate dehydratase porphyria: Update on hepatic 5-aminolevulinic acid synthase induction and long-term response to hemin."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >
BACKGROUND: 5-Aminolevulinic acid dehydratase (ALAD) porphyria (ADP) is
an ultrarare autosomal recessive disease, with only eight documented
cases, all of whom were males.
explanation: This ADP clinical update directly states autosomal recessive inheritance.
- reference: ORPHA:100924
supports: SUPPORT
evidence_source: OTHER
snippet: "Autosomal recessive"
explanation: Orphanet records autosomal recessive inheritance.
progression:
- phase: Childhood or adolescent acute neurovisceral attacks
notes: >
Reported genetic ADP cases usually begin in childhood or adolescence with
acute neurovisceral attacks; long-term natural history is poorly understood
because very few patients have been documented.
evidence:
- reference: ORPHA:100924
supports: SUPPORT
evidence_source: OTHER
snippet: "Age of onset: Childhood"
explanation: Orphanet records childhood onset.
- reference: ORPHA:100924
supports: SUPPORT
evidence_source: OTHER
snippet: "Age of onset: Adolescent"
explanation: Orphanet records adolescent onset.
- reference: PMID:33199206
reference_title: "5-Aminolevulinate dehydratase porphyria: Update on hepatic 5-aminolevulinic acid synthase induction and long-term response to hemin."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >
Seven reported ADP cases had compound heterozygous ALAD mutations
resulting in very low residual ALAD activity and symptoms early in life
or adolescence.
explanation: Review of documented cases supports early-life or adolescent presentation.
pathophysiology:
- name: ALAD conformational and biallelic variant defects
description: >
Pathogenic ALAD variants can impair porphobilinogen synthase by destabilizing
the active octameric enzyme, shifting the morpheein equilibrium toward
low-activity hexamers, or producing unstable or low-activity mutant proteins.
The result is profound residual ALAD activity loss in affected patients.
genes:
- preferred_term: ALAD
term:
id: hgnc:395
label: ALAD
modifier: DECREASED
molecular_functions:
- preferred_term: porphobilinogen synthase activity
term:
id: GO:0004655
label: porphobilinogen synthase activity
modifier: DECREASED
evidence:
- reference: PMID:17236137
reference_title: "ALAD porphyria is a conformational disease."
supports: SUPPORT
evidence_source: IN_VITRO
snippet: >
Thus, all porphyria-associated human PBGS variants are found to shift the
morpheein equilibrium for PBGS toward the less active hexamer.
explanation: Biochemical expression work supports a conformational mechanism for multiple ALAD variants.
- reference: PMID:16343966
reference_title: "delta-Aminolevulinate dehydratase (ALAD) porphyria: the first case in North America with two novel ALAD mutations."
supports: SUPPORT
evidence_source: IN_VITRO
snippet: >
These results suggest that the combination of the two aberrant ALADs with
little enzyme activity accounts for the markedly decreased ALAD activity
observed in the proband.
explanation: In vitro expression of patient ALAD variants supports markedly reduced enzyme activity.
- reference: PMID:10706561
reference_title: "Novel molecular defects of the delta-aminolevulinate dehydratase gene in a patient with inherited acute hepatic porphyria."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >
These data thus demonstrate that the proband was associated with 2 novel
molecular defects of the ALAD gene, 1 in each allele, and account for the
extremely low ALAD activity in his erythrocytes ( approximately 1% of
normal).
explanation: A second patient study supports biallelic ALAD defects with near-absent erythrocyte activity.
downstream:
- target: ALAD block in heme biosynthesis
description: Variant-driven loss of ALAD / PBGS function blocks the second step of heme biosynthesis.
causal_link_type: DIRECT
- target: Reduced erythrocyte ALAD activity
description: Biallelic ALAD defects manifest as markedly reduced erythrocyte ALAD enzyme activity.
causal_link_type: DIRECT
evidence:
- reference: PMID:9732973
reference_title: "5-Aminolevulinic acid dehydratase deficiency porphyria: a twenty-year clinical and biochemical follow-up."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "The patients' enzyme activity was <10% from 1977 to 1997."
explanation: Longitudinal patient data directly document severely reduced ALAD enzyme activity.
- reference: PMID:10706561
reference_title: "Novel molecular defects of the delta-aminolevulinate dehydratase gene in a patient with inherited acute hepatic porphyria."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >
These data thus demonstrate that the proband was associated with 2 novel
molecular defects of the ALAD gene, 1 in each allele, and account for the
extremely low ALAD activity in his erythrocytes ( approximately 1% of
normal).
explanation: Patient molecular and enzyme data directly connect biallelic ALAD defects to extremely low erythrocyte activity.
- target: Erythrocyte ALAD activity
description: Molecular ALAD defects account for extremely low erythrocyte ALAD activity.
causal_link_type: DIRECT
evidence:
- reference: PMID:10706561
reference_title: "Novel molecular defects of the delta-aminolevulinate dehydratase gene in a patient with inherited acute hepatic porphyria."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >
These data thus demonstrate that the proband was associated with 2 novel
molecular defects of the ALAD gene, 1 in each allele, and account for the
extremely low ALAD activity in his erythrocytes ( approximately 1% of
normal).
explanation: Patient molecular and enzyme data connect biallelic ALAD defects to the biochemical enzyme-activity readout.
- name: ALAD block in heme biosynthesis
description: >
ALAD, also known as porphobilinogen synthase, normally condenses two ALA
molecules to form PBG in the cytosolic part of the heme biosynthetic pathway.
Profound ALAD deficiency blocks this second heme-biosynthesis step.
genes:
- preferred_term: ALAD
term:
id: hgnc:395
label: ALAD
modifier: DECREASED
biological_processes:
- preferred_term: heme biosynthetic process
term:
id: GO:0006783
label: heme biosynthetic process
modifier: DECREASED
molecular_functions:
- preferred_term: porphobilinogen synthase activity
term:
id: GO:0004655
label: porphobilinogen synthase activity
modifier: DECREASED
cell_types:
- preferred_term: hepatocyte
term:
id: CL:0000182
label: hepatocyte
locations:
- preferred_term: liver
term:
id: UBERON:0002107
label: liver
evidence:
- reference: PMID:35991568
reference_title: "Case Report: Lack of Response to Givosiran in a Case of ALAD Porphyria."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >
Introduction: 5-Aminolevulinic acid dehydratase (ALAD) porphyria (ADP)
is an autosomal recessive disease characterized by a profound deficiency
in ALAD, the second enzyme in the heme biosynthetic pathway, and acute
neurovisceral attacks with abdominal pain and peripheral neuropathy.
explanation: This ADP case report directly places the ALAD defect at the second heme-biosynthesis step.
- reference: PMID:17236137
reference_title: "ALAD porphyria is a conformational disease."
supports: SUPPORT
evidence_source: IN_VITRO
snippet: >
PBGS, also called "delta-aminolevulinate dehydratase," is encoded by the
ALAD gene and catalyzes the second step in the biosynthesis of heme.
explanation: Biochemical evidence confirms the enzyme identity and pathway step.
downstream:
- target: Hepatic and erythroid ALA accumulation without PBG overproduction
description: The enzymatic block prevents efficient conversion of ALA to PBG, causing ALA excess with little PBG overproduction.
causal_link_type: DIRECT
- target: Urinary porphobilinogen
description: Because the ALAD block lies upstream of PBG formation, ADP lacks the urinary PBG overproduction typical of AIP.
causal_link_type: DIRECT
evidence:
- reference: PMID:9516683
reference_title: "ALAD porphyria."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >
Because of an almost complete lack of ALAD activity, patients excrete a
large amount of ALA, but not PBG, into urine.
explanation: ADP review evidence directly supports absent or non-increased urinary PBG despite excess ALA.
- name: Hepatic ALAS1 induction and excess ALA production
description: >
ADP is classified as an acute hepatic porphyria, and patient data show
elevated circulating hepatic ALAS1 mRNA. Hepatic ALAS1 induction increases
upstream pathway flux and supports the liver as an important source of
excess ALA, although erythroid marrow may also contribute.
genes:
- preferred_term: ALAS1
term:
id: hgnc:396
label: ALAS1
modifier: INCREASED
biological_processes:
- preferred_term: heme biosynthetic process
term:
id: GO:0006783
label: heme biosynthetic process
modifier: INCREASED
cell_types:
- preferred_term: hepatocyte
term:
id: CL:0000182
label: hepatocyte
locations:
- preferred_term: liver
term:
id: UBERON:0002107
label: liver
evidence:
- reference: PMID:33199206
reference_title: "5-Aminolevulinate dehydratase porphyria: Update on hepatic 5-aminolevulinic acid synthase induction and long-term response to hemin."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >
RESULTS: Circulating hepatic 5-aminolevulinic acid synthase-1 (ALAS1)
mRNA was elevated in this case, as in other AHPs.
explanation: Direct patient evidence supports hepatic ALAS1 induction in ADP.
- reference: PMID:33199206
reference_title: "5-Aminolevulinate dehydratase porphyria: Update on hepatic 5-aminolevulinic acid synthase induction and long-term response to hemin."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >
Elevation in circulating hepatic ALAS1 and response to treatment with
hemin indicate that the liver is an important source of excess ALA in
ADP, although the marrow may also contribute.
explanation: This supports both hepatic source and possible erythroid contribution to ALA excess.
downstream:
- target: Hepatic and erythroid ALA accumulation without PBG overproduction
description: Increased upstream synthesis feeds into the ALAD block and raises ALA levels.
causal_link_type: DIRECT
- name: Hepatic and erythroid ALA accumulation without PBG overproduction
description: >
Because ALAD lies upstream of PBG, affected patients excrete large amounts
of urinary ALA while lacking the PBG overproduction seen in acute
intermittent porphyria. Total porphyrins, coproporphyrin III, and
protoporphyrin abnormalities can also be present, contributing to abnormal
porphyrin laboratory profiles and dark or purple urine.
biological_processes:
- preferred_term: porphyrin-containing compound metabolic process
term:
id: GO:0006778
label: porphyrin-containing compound metabolic process
modifier: INCREASED
chemical_entities:
- preferred_term: 5-aminolevulinic acid
term:
id: CHEBI:17549
label: 5-aminolevulinic acid
modifier: INCREASED
- preferred_term: porphobilinogen
term:
id: CHEBI:17381
label: porphobilinogen
- preferred_term: coproporphyrin III
term:
id: CHEBI:27609
label: coproporphyrin III
modifier: INCREASED
- preferred_term: protoporphyrin
term:
id: CHEBI:15430
label: protoporphyrin
modifier: INCREASED
evidence:
- reference: PMID:9516683
reference_title: "ALAD porphyria."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >
Because of an almost complete lack of ALAD activity, patients excrete a
large amount of ALA, but not PBG, into urine.
explanation: This is the defining biochemical distinction from AIP.
- reference: PMID:9732973
reference_title: "5-Aminolevulinic acid dehydratase deficiency porphyria: a twenty-year clinical and biochemical follow-up."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >
After this therapy both urinary 5-aminolevulinic acid (ALA) and total
porphyrins were diminished to 65% in patient B.
explanation: Follow-up data show urinary ALA and porphyrins as measurable disease activity markers.
- reference: PMID:10211628
reference_title: "Investigations on the formation of urinary coproporphyrin isomers I-IV in 5-aminolevulinic acid dehydratase deficiency porphyria, acute lead intoxication and after oral 5-aminolevulinic acid loading."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >
The concentration of total coproporphyrins was about 30-fold increased in
patients with ALAD deficiency porphyria and acute lead intoxication as
compared with controls.
explanation: Patient biochemical data support abnormal coproporphyrin excretion in ADP.
- reference: ORPHA:100924
supports: SUPPORT
evidence_source: OTHER
snippet: "HP:0010472 | Abnormal circulating porphyrin concentration | Frequent (79-30%)"
explanation: Orphanet records abnormal porphyrin concentration as a frequent ADP phenotype.
- reference: ORPHA:100924
supports: SUPPORT
evidence_source: OTHER
snippet: "HP:0012187 | Increased erythrocyte protoporphyrin concentration | Frequent (79-30%)"
explanation: Orphanet records increased erythrocyte protoporphyrin as a frequent ADP phenotype.
- reference: ORPHA:100924
supports: SUPPORT
evidence_source: OTHER
snippet: "HP:0033010 | Increased fecal coproporphyrin 3 | Frequent (79-30%)"
explanation: Orphanet records increased fecal coproporphyrin 3 as a frequent ADP phenotype.
downstream:
- target: ALA-mediated neurovisceral attack susceptibility
description: ALA excess is linked to recurrent abdominal pain, neuropathy, and weakness during attacks.
causal_link_type: DIRECT
- target: Urinary 5-aminolevulinic acid
description: ALAD deficiency causes excessive urinary ALA excretion.
causal_link_type: DIRECT
evidence:
- reference: PMID:9516683
reference_title: "ALAD porphyria."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >
Because of an almost complete lack of ALAD activity, patients excrete a
large amount of ALA, but not PBG, into urine.
explanation: ADP review evidence directly links ALAD activity loss to large urinary ALA excretion.
- target: Urinary coproporphyrins
description: ALAD deficiency is associated with markedly increased urinary total coproporphyrins.
causal_link_type: DIRECT
evidence:
- reference: PMID:10211628
reference_title: "Investigations on the formation of urinary coproporphyrin isomers I-IV in 5-aminolevulinic acid dehydratase deficiency porphyria, acute lead intoxication and after oral 5-aminolevulinic acid loading."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >
The concentration of total coproporphyrins was about 30-fold increased in
patients with ALAD deficiency porphyria and acute lead intoxication as
compared with controls.
explanation: Patient biochemical data directly connect ALAD deficiency porphyria to elevated urinary coproporphyrins.
- target: Abnormal circulating porphyrin concentration
description: Porphyrin-pathway intermediate accumulation produces an abnormal porphyrin biochemical profile in ADP.
causal_link_type: DIRECT
evidence:
- reference: ORPHA:100924
supports: SUPPORT
evidence_source: OTHER
snippet: "HP:0010472 | Abnormal circulating porphyrin concentration | Frequent (79-30%)"
explanation: Orphanet records abnormal porphyrin concentration as frequent in ADP.
- target: Purple urine
description: Urinary porphyrin-pathway intermediate accumulation can manifest clinically as purple or dark urine.
causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
intermediate_mechanisms:
- urinary porphyrin-pathway intermediate accumulation and oxidation
evidence:
- reference: ORPHA:100924
supports: SUPPORT
evidence_source: OTHER
snippet: "HP:0040322 | Purple urine | Frequent (79-30%)"
explanation: Orphanet records purple urine as frequent in ADP.
- reference: PMID:9732973
reference_title: "5-Aminolevulinic acid dehydratase deficiency porphyria: a twenty-year clinical and biochemical follow-up."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >
After this therapy both urinary 5-aminolevulinic acid (ALA) and total
porphyrins were diminished to 65% in patient B.
explanation: Longitudinal ADP data document urinary porphyrins as disease-activity markers, supporting the urinary pigment intermediate.
- target: Increased erythrocyte protoporphyrin concentration
description: ADP is associated with erythrocyte protoporphyrin elevation, although the exact intermediate steps are not resolved here.
causal_link_type: UNKNOWN
evidence:
- reference: ORPHA:100924
supports: SUPPORT
evidence_source: OTHER
snippet: "HP:0012187 | Increased erythrocyte protoporphyrin concentration | Frequent (79-30%)"
explanation: Orphanet records increased erythrocyte protoporphyrin concentration as frequent in ADP.
- target: Increased fecal coproporphyrin 3
description: ADP is associated with increased fecal coproporphyrin 3, but the exact causal path from the ALAD block is not specified in cached evidence.
causal_link_type: UNKNOWN
evidence:
- reference: ORPHA:100924
supports: SUPPORT
evidence_source: OTHER
snippet: "HP:0033010 | Increased fecal coproporphyrin 3 | Frequent (79-30%)"
explanation: Orphanet records increased fecal coproporphyrin 3 as frequent in ADP.
- name: ALA-mediated neurovisceral attack susceptibility
description: >
Accumulation of ALA in acute hepatic porphyria causes acute neurovisceral
attacks, including abdominal pain, peripheral neuropathy, muscle weakness,
and sometimes respiratory insufficiency. ALAD porphyria lacks primary skin
symptoms.
evidence:
- reference: PMID:35991568
reference_title: "Case Report: Lack of Response to Givosiran in a Case of ALAD Porphyria."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >
Introduction: 5-Aminolevulinic acid dehydratase (ALAD) porphyria (ADP)
is an autosomal recessive disease characterized by a profound deficiency
in ALAD, the second enzyme in the heme biosynthetic pathway, and acute
neurovisceral attacks with abdominal pain and peripheral neuropathy.
explanation: The clinical pattern in ADP directly links ALAD deficiency to acute neurovisceral attacks.
- reference: ORPHA:100924
supports: SUPPORT
evidence_source: OTHER
snippet: "A rare acute hepatic porphyria characterized by neurovisceral attacks without skin symptoms."
explanation: Orphanet confirms neurovisceral attacks without skin symptoms.
- reference: PMID:33786855
reference_title: "Porphyric neuropathy."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >
Acute hepatic porphyrias are inherited metabolic disorders that may
present with polyneuropathy, which if not diagnosed early can lead to
quadriparesis, respiratory weakness, and death.
explanation: Review evidence supports motor and respiratory weakness as severe downstream manifestations of acute hepatic porphyric neuropathy.
downstream:
- target: Abdominal pain
description: ADP neurovisceral attacks include abdominal pain.
causal_link_type: DIRECT
evidence:
- reference: PMID:35991568
reference_title: "Case Report: Lack of Response to Givosiran in a Case of ALAD Porphyria."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >
Introduction: 5-Aminolevulinic acid dehydratase (ALAD) porphyria (ADP)
is an autosomal recessive disease characterized by a profound deficiency
in ALAD, the second enzyme in the heme biosynthetic pathway, and acute
neurovisceral attacks with abdominal pain and peripheral neuropathy.
explanation: ADP case-report evidence directly identifies abdominal pain as part of neurovisceral attacks.
- target: Peripheral neuropathy
description: ADP neurovisceral attacks include peripheral neuropathy.
causal_link_type: DIRECT
evidence:
- reference: PMID:35991568
reference_title: "Case Report: Lack of Response to Givosiran in a Case of ALAD Porphyria."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >
Introduction: 5-Aminolevulinic acid dehydratase (ALAD) porphyria (ADP)
is an autosomal recessive disease characterized by a profound deficiency
in ALAD, the second enzyme in the heme biosynthetic pathway, and acute
neurovisceral attacks with abdominal pain and peripheral neuropathy.
explanation: ADP case-report evidence directly identifies peripheral neuropathy as part of neurovisceral attacks.
- target: Muscle weakness
description: Motor-predominant porphyric neuropathy during severe attacks can cause generalized weakness.
causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
intermediate_mechanisms:
- motor-predominant porphyric neuropathy
evidence:
- reference: ORPHA:100924
supports: SUPPORT
evidence_source: OTHER
snippet: "HP:0001324 | Muscle weakness | Frequent (79-30%)"
explanation: Orphanet records muscle weakness as frequent in ADP.
- reference: PMID:33786855
reference_title: "Porphyric neuropathy."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >
Acute hepatic porphyrias are inherited metabolic disorders that may
present with polyneuropathy, which if not diagnosed early can lead to
quadriparesis, respiratory weakness, and death.
explanation: Review evidence supports weakness as a consequence of acute hepatic porphyric neuropathy.
- target: Respiratory insufficiency
description: Severe porphyric neuropathy can involve respiratory muscle weakness, producing respiratory insufficiency.
causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
intermediate_mechanisms:
- porphyric neuropathy with respiratory muscle weakness
evidence:
- reference: ORPHA:100924
supports: SUPPORT
evidence_source: OTHER
snippet: "HP:0002093 | Respiratory insufficiency | Occasional (29-5%)"
explanation: Orphanet records respiratory insufficiency as an occasional ADP manifestation.
- reference: PMID:33786855
reference_title: "Porphyric neuropathy."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >
Acute hepatic porphyrias are inherited metabolic disorders that may
present with polyneuropathy, which if not diagnosed early can lead to
quadriparesis, respiratory weakness, and death.
explanation: Review evidence supports respiratory weakness as a severe consequence of acute hepatic porphyric neuropathy.
- target: Nausea
description: ADP neurovisceral attacks can include nausea, but the precise intermediate mechanism is not specified in cached ADP evidence.
causal_link_type: UNKNOWN
evidence:
- reference: ORPHA:100924
supports: SUPPORT
evidence_source: OTHER
snippet: "HP:0002018 | Nausea | Occasional (29-5%)"
explanation: Orphanet records nausea as an occasional ADP manifestation.
- target: Constipation
description: ADP neurovisceral attacks can include constipation, but the precise intermediate mechanism is not specified in cached ADP evidence.
causal_link_type: UNKNOWN
evidence:
- reference: ORPHA:100924
supports: SUPPORT
evidence_source: OTHER
snippet: "HP:0002019 | Constipation | Occasional (29-5%)"
explanation: Orphanet records constipation as an occasional ADP manifestation.
phenotypes:
- name: Abdominal pain
frequency: FREQUENT
description: >
Abdominal pain is a frequent neurovisceral manifestation during acute ADP
attacks.
phenotype_term:
preferred_term: Abdominal pain
term:
id: HP:0002027
label: Abdominal pain
evidence:
- reference: ORPHA:100924
supports: SUPPORT
evidence_source: OTHER
snippet: "HP:0002027 | Abdominal pain | Frequent (79-30%)"
explanation: Orphanet records abdominal pain as frequent in ADP.
- reference: PMID:35991568
reference_title: "Case Report: Lack of Response to Givosiran in a Case of ALAD Porphyria."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >
Introduction: 5-Aminolevulinic acid dehydratase (ALAD) porphyria (ADP)
is an autosomal recessive disease characterized by a profound deficiency
in ALAD, the second enzyme in the heme biosynthetic pathway, and acute
neurovisceral attacks with abdominal pain and peripheral neuropathy.
explanation: Patient-level ADP evidence identifies abdominal pain during neurovisceral attacks.
- name: Peripheral neuropathy
frequency: FREQUENT
description: >
Peripheral neuropathy is a frequent neurologic manifestation of ADP attacks.
phenotype_term:
preferred_term: Peripheral neuropathy
term:
id: HP:0009830
label: Peripheral neuropathy
evidence:
- reference: ORPHA:100924
supports: SUPPORT
evidence_source: OTHER
snippet: "HP:0009830 | Peripheral neuropathy | Frequent (79-30%)"
explanation: Orphanet records peripheral neuropathy as frequent in ADP.
- reference: PMID:35991568
reference_title: "Case Report: Lack of Response to Givosiran in a Case of ALAD Porphyria."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >
Introduction: 5-Aminolevulinic acid dehydratase (ALAD) porphyria (ADP)
is an autosomal recessive disease characterized by a profound deficiency
in ALAD, the second enzyme in the heme biosynthetic pathway, and acute
neurovisceral attacks with abdominal pain and peripheral neuropathy.
explanation: This ADP case report identifies peripheral neuropathy as part of attacks.
- name: Muscle weakness
frequency: FREQUENT
description: >
Muscle weakness is a frequent manifestation of the neurologic attack
phenotype.
phenotype_term:
preferred_term: Muscle weakness
term:
id: HP:0001324
label: Muscle weakness
evidence:
- reference: ORPHA:100924
supports: SUPPORT
evidence_source: OTHER
snippet: "HP:0001324 | Muscle weakness | Frequent (79-30%)"
explanation: Orphanet records muscle weakness as frequent in ADP.
- name: Nausea
frequency: OCCASIONAL
description: >
Nausea can accompany acute neurovisceral attacks.
phenotype_term:
preferred_term: Nausea
term:
id: HP:0002018
label: Nausea
evidence:
- reference: ORPHA:100924
supports: SUPPORT
evidence_source: OTHER
snippet: "HP:0002018 | Nausea | Occasional (29-5%)"
explanation: Orphanet records nausea as occasional in ADP.
- name: Constipation
frequency: OCCASIONAL
description: >
Constipation is one of the gastrointestinal symptoms reported in ADP.
phenotype_term:
preferred_term: Constipation
term:
id: HP:0002019
label: Constipation
evidence:
- reference: ORPHA:100924
supports: SUPPORT
evidence_source: OTHER
snippet: "HP:0002019 | Constipation | Occasional (29-5%)"
explanation: Orphanet records constipation as occasional in ADP.
- name: Respiratory insufficiency
frequency: OCCASIONAL
description: >
Severe attacks can include respiratory insufficiency, likely through
porphyric neuropathy affecting respiratory muscles.
phenotype_term:
preferred_term: Respiratory insufficiency
term:
id: HP:0002093
label: Respiratory insufficiency
evidence:
- reference: ORPHA:100924
supports: SUPPORT
evidence_source: OTHER
snippet: "HP:0002093 | Respiratory insufficiency | Occasional (29-5%)"
explanation: Orphanet records respiratory insufficiency as occasional in ADP.
- name: Purple urine
frequency: FREQUENT
description: >
Purple or dark urine reflects accumulation and oxidation of porphyrin-pathway
intermediates during attacks.
phenotype_term:
preferred_term: Purple urine
term:
id: HP:0040322
label: Purple urine
evidence:
- reference: ORPHA:100924
supports: SUPPORT
evidence_source: OTHER
snippet: "HP:0040322 | Purple urine | Frequent (79-30%)"
explanation: Orphanet records purple urine as frequent in ADP.
- name: Abnormal circulating porphyrin concentration
frequency: FREQUENT
description: >
Abnormal circulating or excreted porphyrin-pathway intermediates are a
frequent biochemical phenotype.
phenotype_term:
preferred_term: Abnormal circulating porphyrin concentration
term:
id: HP:0010472
label: Abnormal circulating porphyrin concentration
evidence:
- reference: ORPHA:100924
supports: SUPPORT
evidence_source: OTHER
snippet: "HP:0010472 | Abnormal circulating porphyrin concentration | Frequent (79-30%)"
explanation: Orphanet records abnormal porphyrin concentration as frequent in ADP.
- name: Increased erythrocyte protoporphyrin concentration
frequency: FREQUENT
description: >
Increased erythrocyte protoporphyrin concentration is one of the porphyrin
pathway laboratory abnormalities recorded for ADP.
phenotype_term:
preferred_term: Increased erythrocyte protoporphyrin concentration
term:
id: HP:0012187
label: Increased erythrocyte protoporphyrin concentration
evidence:
- reference: ORPHA:100924
supports: SUPPORT
evidence_source: OTHER
snippet: "HP:0012187 | Increased erythrocyte protoporphyrin concentration | Frequent (79-30%)"
explanation: Orphanet records increased erythrocyte protoporphyrin concentration as frequent in ADP.
- name: Increased fecal coproporphyrin 3
frequency: FREQUENT
description: >
Fecal coproporphyrin 3 elevation is a porphyrin-profile abnormality
reported for ADP.
phenotype_term:
preferred_term: Increased fecal coproporphyrin 3
term:
id: HP:0033010
label: Increased fecal coproporphyrin 3
evidence:
- reference: ORPHA:100924
supports: SUPPORT
evidence_source: OTHER
snippet: "HP:0033010 | Increased fecal coproporphyrin 3 | Frequent (79-30%)"
explanation: Orphanet records increased fecal coproporphyrin 3 as frequent in ADP.
- name: Reduced erythrocyte ALAD activity
frequency: FREQUENT
description: >
Erythrocyte ALAD enzyme activity is markedly reduced in reported ADP cases.
phenotype_term:
preferred_term: Reduced erythrocyte enzyme activity
term:
id: HP:0030272
label: Abnormal erythrocyte enzyme concentration or activity
evidence:
- reference: ORPHA:100924
supports: SUPPORT
evidence_source: OTHER
snippet: "HP:0030272 | Abnormal erythrocyte enzyme activity | Frequent (79-30%)"
explanation: Orphanet records abnormal erythrocyte enzyme activity as frequent in ADP.
- reference: PMID:9732973
reference_title: "5-Aminolevulinic acid dehydratase deficiency porphyria: a twenty-year clinical and biochemical follow-up."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >
The patients' enzyme activity was <10% from 1977 to 1997.
explanation: Longitudinal patient data directly document severely reduced ALAD activity.
biochemical:
- name: Urinary 5-aminolevulinic acid
presence: INCREASED
context: >
Urinary ALA is markedly increased because the ALAD block prevents efficient
conversion of ALA to PBG.
readouts:
- target: Hepatic and erythroid ALA accumulation without PBG overproduction
relationship: READOUT_OF
direction: POSITIVE
endpoint_context: DIAGNOSTIC
interpretation: Increased urinary ALA reports the ALA-accumulation branch downstream of the ALAD enzymatic block.
evidence:
- reference: PMID:9516683
reference_title: "ALAD porphyria."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >
Because of an almost complete lack of ALAD activity, patients excrete a
large amount of ALA, but not PBG, into urine.
explanation: The ADP review directly supports urinary ALA as the diagnostic readout of ALA accumulation without PBG overproduction.
evidence:
- reference: PMID:9516683
reference_title: "ALAD porphyria."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >
Because of an almost complete lack of ALAD activity, patients excrete a
large amount of ALA, but not PBG, into urine.
explanation: This directly supports increased urinary ALA and distinguishes ADP from AIP.
- name: Urinary porphobilinogen
presence: NOT_INCREASED
context: >
Unlike most other acute hepatic porphyrias, ADP does not cause PBG
overproduction because the enzymatic block is upstream of PBG formation.
readouts:
- target: ALAD block in heme biosynthesis
relationship: READOUT_OF
direction: PRESENT_ABSENT
endpoint_context: DIAGNOSTIC
interpretation: Lack of urinary PBG overproduction reports that the heme-biosynthesis block lies upstream of PBG formation, distinguishing ADP from AIP.
evidence:
- reference: PMID:9516683
reference_title: "ALAD porphyria."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >
The symptoms in this disease are similar to those seen in AIP, but ALAD
porphyria can be differentiated from AIP by its autosomal recessive,
rather than dominant, inheritance, by the lack of PBG overproduction, and
by markedly decreased ALAD activity.
explanation: This review identifies absent PBG overproduction as a diagnostic discriminator of the ALAD block.
evidence:
- reference: PMID:9516683
reference_title: "ALAD porphyria."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >
Because of an almost complete lack of ALAD activity, patients excrete a
large amount of ALA, but not PBG, into urine.
explanation: This supports the lack of PBG overproduction as a distinguishing ADP biomarker.
- name: Erythrocyte ALAD activity
presence: DECREASED
context: >
Erythrocyte ALAD activity is profoundly reduced in documented genetic ADP
cases and can help confirm the diagnosis.
readouts:
- target: ALAD block in heme biosynthesis
relationship: READOUT_OF
direction: NEGATIVE
endpoint_context: DIAGNOSTIC
interpretation: Markedly reduced erythrocyte ALAD activity directly reports the deficient porphobilinogen synthase step in heme biosynthesis.
evidence:
- reference: PMID:10706561
reference_title: "Novel molecular defects of the delta-aminolevulinate dehydratase gene in a patient with inherited acute hepatic porphyria."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >
These data thus demonstrate that the proband was associated with 2 novel
molecular defects of the ALAD gene, 1 in each allele, and account for the
extremely low ALAD activity in his erythrocytes ( approximately 1% of
normal).
explanation: Patient molecular and enzyme data support erythrocyte ALAD activity as a direct readout of the heme-biosynthesis block.
evidence:
- reference: PMID:10706561
reference_title: "Novel molecular defects of the delta-aminolevulinate dehydratase gene in a patient with inherited acute hepatic porphyria."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >
These data thus demonstrate that the proband was associated with 2 novel
molecular defects of the ALAD gene, 1 in each allele, and account for the
extremely low ALAD activity in his erythrocytes ( approximately 1% of
normal).
explanation: Patient molecular and enzyme data directly document very low erythrocyte activity.
- name: Urinary coproporphyrins
presence: INCREASED
context: >
Urinary coproporphyrin isomers are elevated in ADP and can overlap with the
biochemical pattern of acquired ALAD inhibition from lead intoxication.
readouts:
- target: Hepatic and erythroid ALA accumulation without PBG overproduction
relationship: READOUT_OF
direction: POSITIVE
endpoint_context: DIAGNOSTIC
interpretation: Increased urinary coproporphyrins report the abnormal porphyrin-intermediate profile downstream of ALAD deficiency.
evidence:
- reference: PMID:10211628
reference_title: "Investigations on the formation of urinary coproporphyrin isomers I-IV in 5-aminolevulinic acid dehydratase deficiency porphyria, acute lead intoxication and after oral 5-aminolevulinic acid loading."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >
The concentration of total coproporphyrins was about 30-fold increased in
patients with ALAD deficiency porphyria and acute lead intoxication as
compared with controls.
explanation: Patient biochemical data support urinary coproporphyrins as a readout of the abnormal porphyrin profile in ADP.
evidence:
- reference: PMID:10211628
reference_title: "Investigations on the formation of urinary coproporphyrin isomers I-IV in 5-aminolevulinic acid dehydratase deficiency porphyria, acute lead intoxication and after oral 5-aminolevulinic acid loading."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >
The concentration of total coproporphyrins was about 30-fold increased in
patients with ALAD deficiency porphyria and acute lead intoxication as
compared with controls.
explanation: Patient biochemical data document elevated urinary coproporphyrins.
genetic:
- name: ALAD pathogenic variants
gene_term:
preferred_term: ALAD
term:
id: hgnc:395
label: ALAD
association: Causative
inheritance:
- name: Autosomal recessive
description: >
Most reported genetic ADP patients have compound heterozygous or
homozygous ALAD variants with very low residual enzyme activity.
features: >
Pathogenic ALAD variants reduce porphobilinogen synthase activity through
unstable, low-activity, or conformationally shifted proteins. The disorder
is molecularly heterogeneous, and the 2026 update reported the first known
female patient.
evidence:
- reference: PMID:16343966
reference_title: "delta-Aminolevulinate dehydratase (ALAD) porphyria: the first case in North America with two novel ALAD mutations."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >
This case represents the molecular analysis of the ALAD gene defects in
the first case of ADP identified in North America, who is a compound
heterozygote for two novel ALAD gene defects.
explanation: This directly supports compound heterozygous ALAD variants as causative.
- reference: PMID:41268747
reference_title: "New cases of delta-aminolevulinic acid dehydratase deficiency: Functional insights into gene variants using an innovative mouse liver model."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >
These findings underscore the molecular heterogeneity of the ALAD gene
and present the first reported case of ADP in a female patient.
explanation: Recent patient data broaden the molecular and sex representation of reported genetic ADP cases.
- reference: CGGV:assertion_0ac683af-ca8d-46ab-8641-66ab9b537d16-2025-01-14T200000.000Z
reference_title: "ALAD / porphyria due to ALA dehydratase deficiency (Moderate)"
supports: SUPPORT
evidence_source: OTHER
snippet: "ALAD | HGNC:395 | porphyria due to ALA dehydratase deficiency | MONDO:0013000 | AR | Moderate"
explanation: ClinGen classifies the ALAD-porphyria due to ALA dehydratase deficiency gene-disease relationship as moderate with autosomal recessive inheritance.
diagnosis:
- name: Urinary ALA and porphobilinogen measurement
diagnosis_term:
preferred_term: urine chemistry measurement
term:
id: MAXO:0000789
label: urine chemistry measurement
description: >
During symptoms, urine chemistry should measure ALA and PBG together. ADP is
suggested by high ALA without the PBG overproduction typical of AIP.
results: Increased urinary ALA with absent or non-increased urinary PBG supports ADP over AIP.
evidence:
- reference: PMID:9516683
reference_title: "ALAD porphyria."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >
The symptoms in this disease are similar to those seen in AIP, but ALAD
porphyria can be differentiated from AIP by its autosomal recessive,
rather than dominant, inheritance, by the lack of PBG overproduction, and
by markedly decreased ALAD activity.
explanation: This directly supports the diagnostic distinction using PBG and ALAD activity.
- name: Erythrocyte ALAD enzyme activity
diagnosis_term:
preferred_term: diagnostic procedure
term:
id: MAXO:0000003
label: diagnostic procedure
description: >
Measurement of erythrocyte ALAD activity supports confirmation of ADP and
helps distinguish inherited deficiency from other acute porphyrias.
results: Markedly reduced erythrocyte ALAD activity supports ADP.
evidence:
- reference: PMID:9516683
reference_title: "ALAD porphyria."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >
The symptoms in this disease are similar to those seen in AIP, but ALAD
porphyria can be differentiated from AIP by its autosomal recessive,
rather than dominant, inheritance, by the lack of PBG overproduction, and
by markedly decreased ALAD activity.
explanation: This review identifies markedly decreased ALAD activity as a key diagnostic discriminator.
- name: ALAD molecular genetic testing
diagnosis_term:
preferred_term: genetic testing
term:
id: MAXO:0000127
label: genetic testing
description: >
Molecular testing confirms biallelic ALAD pathogenic variants after
biochemical testing suggests ADP.
results: Biallelic pathogenic ALAD variants confirm genetic ADP.
evidence:
- reference: PMID:16343966
reference_title: "delta-Aminolevulinate dehydratase (ALAD) porphyria: the first case in North America with two novel ALAD mutations."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >
Nucleotide sequence analysis of ALAD cDNAs from the proband revealed two
novel mutations, a 265G to A base transition (C1) and a 394C to T base
transition (C2), resulting in amino acid substitutions, Glu89Lys and
Cys132Arg, respectively.
explanation: Patient sequencing established the molecular diagnosis.
treatments:
- name: Intravenous hemin or heme arginate for acute attacks
description: >
Intravenous hemin or heme arginate is the best documented attack-directed
therapy in ADP. Clinical benefit supports hepatic ALAS1 repression and
reduction of ALA production as the main therapeutic mechanism.
treatment_term:
preferred_term: Pharmacotherapy
term:
id: NCIT:C15986
label: Pharmacotherapy
therapeutic_agent:
- preferred_term: hemin
term:
id: CHEBI:50385
label: hemin
target_mechanisms:
- target: Hepatic ALAS1 induction and excess ALA production
treatment_effect: INHIBITS
description: >
Heme therapy represses hepatic ALAS1 and reduces the upstream ALA burden.
evidence:
- reference: PMID:33199206
reference_title: "5-Aminolevulinate dehydratase porphyria: Update on hepatic 5-aminolevulinic acid synthase induction and long-term response to hemin."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >
Elevation in circulating hepatic ALAS1 and response to treatment with
hemin indicate that the liver is an important source of excess ALA in
ADP, although the marrow may also contribute.
explanation: ADP patient data link hemin response to hepatic ALAS1-associated ALA production.
- target: Hepatic and erythroid ALA accumulation without PBG overproduction
treatment_effect: INHIBITS
description: >
Heme arginate plus glucose lowers urinary ALA and total porphyrins in
documented ADP crises.
evidence:
- reference: PMID:9732973
reference_title: "5-Aminolevulinic acid dehydratase deficiency porphyria: a twenty-year clinical and biochemical follow-up."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >
After this therapy both urinary 5-aminolevulinic acid (ALA) and total
porphyrins were diminished to 65% in patient B.
explanation: Longitudinal ADP treatment data show biochemical improvement after heme arginate and glucose.
evidence:
- reference: PMID:33199206
reference_title: "5-Aminolevulinate dehydratase porphyria: Update on hepatic 5-aminolevulinic acid synthase induction and long-term response to hemin."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >
Intravenous hemin was effective in most reported cases for treatment and
prevention of acute attacks of neurological symptoms.
explanation: Review of documented ADP cases supports intravenous hemin for attack treatment and prevention.
- reference: PMID:35991568
reference_title: "Case Report: Lack of Response to Givosiran in a Case of ALAD Porphyria."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >
Hemin infusions are often effective in treating and preventing such
attacks.
explanation: The 2022 ADP case report summarizes hemin as an often-effective attack therapy.
- name: Glucose infusion or carbohydrate loading
description: >
Glucose infusion has been used with heme arginate during acute ADP crises,
but available evidence supports it as adjunctive rather than definitive
therapy.
treatment_term:
preferred_term: dietary intervention
term:
id: MAXO:0000088
label: dietary intervention
therapeutic_agent:
- preferred_term: glucose
term:
id: CHEBI:17234
label: glucose
evidence:
- reference: PMID:9732973
reference_title: "5-Aminolevulinic acid dehydratase deficiency porphyria: a twenty-year clinical and biochemical follow-up."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >
An acute crisis in each patient was successfully treated by infusion of
glucose and heme arginate.
explanation: Long-term ADP follow-up documents glucose used with heme arginate in successful crisis treatment.
- name: Givosiran not established for ADP
description: >
Givosiran is approved for recurrent acute hepatic porphyria attacks, but the
published ADP experience in one patient reported continued attacks and only
transient ALA decreases related to rescue hemin. The treatment remains
uncertain for ADP specifically.
treatment_term:
preferred_term: Pharmacotherapy
term:
id: NCIT:C15986
label: Pharmacotherapy
therapeutic_agent:
- preferred_term: givosiran
term:
id: NCIT:C146805
label: Givosiran
evidence:
- reference: PMID:35991568
reference_title: "Case Report: Lack of Response to Givosiran in a Case of ALAD Porphyria."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >
The patient has continued to have recurrent attacks, with transient
decreases in ALA levels only as related to treatment of his attacks with
hemin.
explanation: This patient-level report cautions against assuming givosiran efficacy in ADP.
- name: Hydroxyurea as experimental erythroid-directed option
description: >
Hydroxyurea has only case-level rationale in ADP. It may be considered
investigational when an erythropoietic contribution is suspected, but there
is no controlled evidence base.
treatment_term:
preferred_term: Pharmacotherapy
term:
id: NCIT:C15986
label: Pharmacotherapy
therapeutic_agent:
- preferred_term: hydroxyurea
term:
id: CHEBI:44423
label: hydroxyurea
evidence:
- reference: PMID:35991568
reference_title: "Case Report: Lack of Response to Givosiran in a Case of ALAD Porphyria."
supports: PARTIAL
evidence_source: HUMAN_CLINICAL
snippet: >
Since ADP may have an erythropoietic component, treatment with
hydroxyurea, which was beneficial in one previous case, is planned.
explanation: This supports hydroxyurea only as a limited case-level/experimental option, not established therapy.
clinical_trials:
- name: NCT03338816
phase: PHASE_III
status: COMPLETED
description: >
ENVISION was the pivotal phase III study of givosiran in acute hepatic
porphyrias. It is relevant background for givosiran exposure in the AHP
class, but published ADP-specific case evidence does not establish efficacy.
evidence:
- reference: clinicaltrials:NCT03338816
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >
The purpose of this study is to evaluate the effect of subcutaneous
givosiran (ALN-AS1), compared to placebo, on the rate of porphyria
attacks in patients with Acute Hepatic Porphyrias (AHP).
explanation: ClinicalTrials.gov documents the general AHP givosiran trial that motivated ADP use, while the treatment entry separately captures ADP-specific uncertainty.
differential_diagnoses:
- name: Acute intermittent porphyria
description: >
AIP causes similar neurovisceral attacks but is autosomal dominant and
characterized by PBG overproduction, while ALAD porphyria is autosomal
recessive with markedly decreased ALAD activity and little or no PBG
overproduction.
disease_term:
preferred_term: acute intermittent porphyria
term:
id: MONDO:0008294
label: acute intermittent porphyria
evidence:
- reference: PMID:9516683
reference_title: "ALAD porphyria."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >
The symptoms in this disease are similar to those seen in AIP, but ALAD
porphyria can be differentiated from AIP by its autosomal recessive,
rather than dominant, inheritance, by the lack of PBG overproduction, and
by markedly decreased ALAD activity.
explanation: This directly supports AIP as the key clinical and biochemical differential.
- name: Acquired ALAD inhibition from lead intoxication
description: >
Lead intoxication can inhibit ALAD and mimic aspects of ADP biochemistry,
including increased ALA and coproporphyrins. Exposure history and genetic
testing help distinguish acquired inhibition from inherited ADP.
disease_term:
preferred_term: lead poisoning
term:
id: MONDO:0018019
label: lead poisoning
evidence:
- reference: PMID:10211628
reference_title: "Investigations on the formation of urinary coproporphyrin isomers I-IV in 5-aminolevulinic acid dehydratase deficiency porphyria, acute lead intoxication and after oral 5-aminolevulinic acid loading."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >
These results demonstrate that oral ALA loading can be used as an in vivo
model to study the metabolism of the four urinary coproporphyrin isomers
I-IV especially in ALAD deficiency porphyria and in acute lead poisoning.
explanation: This supports lead intoxication as a biochemical mimic and comparator for ALAD inhibition.
- name: Tyrosinemia type I
description: >
Tyrosinemia type I can mimic acute porphyria biochemically and clinically
because succinylacetone, an abnormal tyrosine-catabolism metabolite,
inhibits ALAD and causes excessive urinary ALA without inherited ALAD
variants.
disease_term:
preferred_term: tyrosinemia type I
term:
id: MONDO:0010161
label: tyrosinemia type I
evidence:
- reference: PMID:6826727
reference_title: "Hereditary tyrosinemia and the heme biosynthetic pathway. Profound inhibition of delta-aminolevulinic acid dehydratase activity by succinylacetone."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >
It is known that patients with this hereditary disease excrete excessive
amounts of delta-aminolevulinic acid (ALA) in urine and that certain
patients have an accompanying clinical syndrome resembling that of acute
intermittent porphyria (AIP).
explanation: Patient observations support tyrosinemia type I as an acute-porphyria mimic.
- reference: PMID:6826727
reference_title: "Hereditary tyrosinemia and the heme biosynthetic pathway. Profound inhibition of delta-aminolevulinic acid dehydratase activity by succinylacetone."
supports: SUPPORT
evidence_source: IN_VITRO
snippet: >
Our data indicate that succinylacetone is an extremely potent competitive
inhibitor of ALA dehydratase in human as well as in animal tissues.
explanation: Biochemical enzyme data support succinylacetone-mediated ALAD inhibition as the mimic mechanism.
Question: You are an expert researcher providing comprehensive, well-cited information.
Provide detailed information focusing on: 1. Key concepts and definitions with current understanding 2. Recent developments and latest research (prioritize 2023-2024 sources) 3. Current applications and real-world implementations 4. Expert opinions and analysis from authoritative sources 5. Relevant statistics and data from recent studies
Format as a comprehensive research report with proper citations. Include URLs and publication dates where available. Always prioritize recent, authoritative sources and provide specific citations for all major claims.
Please provide a comprehensive research report on Porphyria due to ALA Dehydratase Deficiency covering all of the disease characteristics listed below. This report will be used to populate a disease knowledge base entry. Be thorough and cite primary literature (PMID preferred) for all claims.
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For each mechanism, describe: - The causal chain from initial trigger to clinical manifestation - Which mechanisms are upstream vs downstream - What cell types and biological processes are involved - Suggest GO terms for biological processes and CL terms for cell types
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For each treatment, suggest MAXO (Medical Action Ontology) terms where applicable.
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Structure your response as a comprehensive narrative organized by the sections above. For each section, provide: - Factual content with specific details (numbers, percentages, gene names, variant nomenclature) - Ontology term suggestions (HPO, GO, CL, UBERON, CHEBI, MAXO, MONDO) where applicable - Evidence citations with PMIDs - Direct quotes from abstracts to support key claims - Clear indication when information is not available or not applicable for this disease
This report will be used to populate a disease knowledge base entry with: - Pathophysiology descriptions with causal chains - Gene/protein annotations (HGNC, GO terms) - Phenotype associations (HP terms) with frequencies - Cell type involvement (CL terms) - Anatomical locations (UBERON terms) - Chemical entities (CHEBI terms) - Treatment annotations (MAXO terms) - Evidence items with PMIDs and exact abstract quotes - Epidemiology, prognosis, diagnostic, and prevention information - Animal model descriptions with phenotype recapitulation details
Porphyria due to ALA dehydratase deficiency (ADP) is an ultra-rare, autosomal recessive acute hepatic porphyria caused by biallelic pathogenic variants in ALAD (also called porphobilinogen synthase, PBGS), leading to profound deficiency of ALA dehydratase—the second enzyme in heme biosynthesis. The most characteristic biochemical pattern is markedly elevated δ-aminolevulinic acid (ALA) with porphobilinogen (PBG) normal or only slightly elevated, plus increased urinary coproporphyrins and erythrocyte zinc protoporphyrin. Clinically it presents with acute neurovisceral attacks (severe abdominal pain, autonomic symptoms, and peripheral neuropathy/weakness) without typical cutaneous features. Evidence-based 2023 expert guidance for acute hepatic porphyrias highlights that PBG is elevated in all acute hepatic porphyrias except ALAD porphyria, which has important diagnostic implications. First-line management is shared with other acute hepatic porphyrias (trigger avoidance, carbohydrate loading, and IV hemin), but emerging therapies (e.g., givosiran) may be less effective in ADP based on limited case-level evidence. (wang2023agaclinicalpractice pages 1-3, wang2023agaclinicalpractice pages 3-5, graff2022casereportlack pages 1-2)
ADP is an inborn error of heme biosynthesis classified among acute hepatic porphyrias (AHPs). It results from a severe deficiency of 5-aminolevulinic acid dehydratase (ALAD), causing accumulation of upstream heme precursors—especially ALA—and episodic, potentially severe neurovisceral attacks. (ramanujam2015porphyriadiagnostics—part1 pages 9-11, wang2023agaclinicalpractice pages 1-3)
Most ADP knowledge is derived from: - Aggregated disease-level expert reviews and guidelines (e.g., AGA Clinical Practice Update for AHPs). (wang2023agaclinicalpractice pages 1-3) - A very small number of individual human cases/longitudinal follow-up studies due to extreme rarity. (gross19985aminolevulinicaciddehydratase pages 1-2, doss2004thethirdcase pages 1-4)
Evidence across ADP-focused reviews/cases indicates that ALAD activity can be reduced by genetic deficiency or secondary inhibition, creating an ADP-like biochemical/clinical picture: - Lead exposure: ALAD is zinc-dependent and susceptible to inactivation when lead replaces Zn2+. (balogun2023thehepaticporphyrias pages 3-5, ramanujam2015porphyriadiagnostics—part1 pages 9-11) - Hereditary tyrosinemia type 1: via succinylacetone-mediated ALAD inhibition (noted as a differential/secondary cause in ADP-focused review). (ramanujam2015porphyriadiagnostics—part1 pages 9-11) - Alcohol ingestion: associated with at least one severe attack in long-term follow-up; alcohol can increase hepatic ALAS activity and precipitate crises. (gross19985aminolevulinicaciddehydratase pages 4-5, gross19985aminolevulinicaciddehydratase pages 2-3) - Other conditions listed as potential contributors to reduced ALAD activity / ADP-like biochemical patterns include zinc deficiency, smoking, diabetes, and chronic renal failure. (ramanujam2015porphyriadiagnostics—part1 pages 9-11)
No ADP-specific protective genetic variants or environmental protective factors were identified in the captured evidence set.
A practical, clinically relevant interaction is carrier status + lead exposure: heterozygotes with partial ALAD activity are generally asymptomatic but may have increased susceptibility to lead toxicity. (ramanujam2015porphyriadiagnostics—part1 pages 9-11)
Symptoms/signs (neurovisceral attacks): - Severe abdominal pain (often colicky) during acute crises. (doss2004thethirdcase pages 1-4) - Peripheral neuropathy / weakness, including polyneuropathy and potentially persistent deficits (e.g., paresis; “foot and wrist drop” reported in a chronic course). (graff2022casereportlack pages 1-2, gross19985aminolevulinicaciddehydratase pages 1-2) - Autonomic/cardiovascular involvement reported in long-term follow-up (“cardiovascular symptoms”). (gross19985aminolevulinicaciddehydratase pages 1-2) - Severe crises can include transient respiratory paralysis / respiratory involvement. (gross19985aminolevulinicaciddehydratase pages 1-2)
Onset / course: - Typically childhood to adolescence in reported cases; one longitudinal case began at age 12 and continued into adulthood with recurrent attacks. (graff2022casereportlack pages 1-2, gross19985aminolevulinicaciddehydratase pages 1-2) - The disorder is so rare that phenotype frequency estimates are not robust; older reviews emphasized extremely small case counts (≈6–8 cases worldwide). (ramanujam2015porphyriadiagnostics—part1 pages 9-11, graff2022casereportlack pages 1-2)
Cutaneous findings: - ADP is described as presenting with neurovisceral symptoms similar to other acute porphyrias without cutaneous manifestations in classic descriptions. (ramanujam2015porphyriadiagnostics—part1 pages 9-11)
Direct ADP-specific QoL instruments were not captured in the evidence set; however, the described recurrent attacks and persistent neuropathic deficits imply major functional impairment in some individuals (case-level evidence). (graff2022casereportlack pages 1-2)
From an ADP case report (2022): - c.265G>A (p.Glu89Lys) and c.394T>C (p.Cys132Arg) in ALAD. (graff2022casereportlack pages 1-2)
From a 2004 genetically characterized case: - Compound heterozygous intronic substitutions in intron 3 (IVS3 -11C substitutions), proposed to alter splicing. (doss2004thethirdcase pages 1-4)
From 2024 functional characterization (conference poster): - Newly reported variants in three young patients including c.440_441delinsTT (reported to yield p.Arg147Leu) (homozygous in siblings) and compound heterozygosity for c.839G>A (p.Gly280Glu) and c.724G>A (p.Val242Ile); in vivo hepatocyte expression in C57BL/6 mice showed ~5% wild-type activity for one variant. (castelbon202404163functionalcharacterization pages 1-1)
Protein dysfunction concepts: - A 2023 hepatic porphyria review describes ADP as a “conformational disease,” with mutations causing destabilized tertiary/quaternary structure, misfolding, and reduced half-life; it also reiterates lead’s displacement of Zn2+ leading to inactivation. (balogun2023thehepaticporphyrias pages 3-5)
Across reports: missense, small indels, and intronic/splice-affecting variants are represented. (graff2022casereportlack pages 1-2, doss2004thethirdcase pages 1-4, castelbon202404163functionalcharacterization pages 1-1)
No ADP-specific modifier genes or epigenetic changes were identified in the captured evidence set.
No infectious etiology is implicated.
ALAD is the second enzyme in heme biosynthesis and catalyzes the condensation of two ALA molecules to form PBG. Deficiency leads to ALA accumulation and characteristic downstream porphyrin abnormalities. (balogun2023thehepaticporphyrias pages 3-5, graff2022casereportlack pages 1-2)
1) Biallelic ALAD pathogenic variants → profound enzyme deficiency in relevant tissues (erythrocytes; and likely hepatic/erythroid contributions). (graff2022casereportlack pages 1-2, ramanujam2015porphyriadiagnostics—part1 pages 9-11) 2) Block in ALA→PBG step → marked ALA accumulation (urine/plasma). (doss2004thethirdcase pages 1-4, gross19985aminolevulinicaciddehydratase pages 2-3) 3) Accumulated ALA and altered porphyrin intermediates associate with acute neurovisceral attacks and neuropathy. (gross19985aminolevulinicaciddehydratase pages 1-2, graff2022casereportlack pages 1-2)
No ADP-specific transcriptomic/proteomic/metabolomic multi-omics datasets were identified in the captured evidence set. A 2024 poster used an in vivo hepatocyte expression assay for functional evaluation of variants. (castelbon202404163functionalcharacterization pages 1-1)
Based on neurovisceral attacks and biochemical production/handling of heme intermediates: - Liver (UBERON:0002107): central to AHP biochemistry and therapeutic targeting (e.g., ALAS1 suppression strategies). (wang2023agaclinicalpractice pages 1-3, NCT03338816 chunk 1) - Peripheral nervous system / peripheral nerves: neuropathy/weakness and motor deficits are prominent. (graff2022casereportlack pages 1-2, gross19985aminolevulinicaciddehydratase pages 1-2) - Blood/erythroid compartment: erythrocyte ALAD deficiency and zinc protoporphyrin elevation are diagnostic clues. (gross19985aminolevulinicaciddehydratase pages 1-2, graff2022casereportlack pages 1-2)
Not available from the captured evidence set (e.g., gnomAD/ClinVar frequencies were not retrieved in this run).
Patients can present with recurrent severe abdominal pain and neurologic/autonomic symptoms consistent with acute hepatic porphyria. Because symptoms are nonspecific, expert guidance recommends screening during an attack. (wang2023agaclinicalpractice pages 1-3)
The AGA Clinical Practice Update recommends random urine ALA and PBG corrected to creatinine as screening tests in suspected AHP; importantly, it highlights that PBG is elevated in all AHP except ALAD porphyria, so an ADP pattern may be high ALA with absent/minimal PBG elevation. (wang2023agaclinicalpractice pages 1-3, wang2023agaclinicalpractice pages 3-5)
A diagnostics review describes plasma fluorescence scanning as a rapid qualitative screen; ADP/AIP/HCP may show emission maxima around 618–622 nm in symptomatic patients, supporting porphyria-type discrimination. (pierro2021laboratorydiagnosisof pages 2-4)
Because of extreme rarity and case ascertainment bias, formal survival rates are not available.
The 2023 AGA Clinical Practice Update for AHPs lists cornerstones of management: discontinuation of porphyrinogenic drugs/chemicals, oral/IV dextrose, IV hemin, and symptomatic therapy; for frequent attacks (≥4/year), prophylaxis with IV hemin or subcutaneous givosiran is considered, and liver transplantation is a curative option in refractory cases (general AHP guidance). (wang2023agaclinicalpractice pages 1-3)
Human case data support efficacy: - A 20-year follow-up reported acute crises “successfully treated” with glucose plus heme arginate, with reductions in urinary ALA and porphyrins and sustained symptom-free periods. (gross19985aminolevulinicaciddehydratase pages 1-2) - A 2004 case (17-year-old) improved with haem arginate; weekly haem for one year provided sustained biochemical/clinical benefit and appeared prophylactic. (doss2004thethirdcase pages 1-4)
Adverse effects / implementation issues: - Long-term prophylactic hemin can cause iron overload; in a 2022 case, ferritin reached 659 ng/mL and was managed with phlebotomy. (graff2022casereportlack pages 1-2)
MAXO suggestions: intravenous hemin administration; heme arginate therapy; intravenous glucose administration.
Clinical trial landscape: - The phase 3 ENVISION trial (NCT03338816) lists ALA dehydratase deficient porphyria among included conditions and measures urinary ALA/PBG and attack rates; however, the excerpted record does not provide numeric results in this evidence set. (NCT03338816 chunk 1)
ADP-specific real-world evidence: - A 2022 ADP case report describes a patient treated with givosiran (2.5 mg/kg monthly) for 6 months with no observed liver adverse effects, but continued recurrent attacks and only transient ALA decreases associated with hemin infusions; the authors conclude givosiran “may not be effective” for ADP based on this single case. (graff2022casereportlack pages 1-2, graff2022casereportlack pages 2-4)
Figure-based evidence: The paper’s Figure 1 shows urine ALA decreases after hemin but lack of sustained suppression with givosiran and persistent elevation of related markers during the treatment interval. (graff2022casereportlack media 69c1e72f, graff2022casereportlack media 97eb2153, graff2022casereportlack media 0a38561c)
MAXO suggestions: small interfering RNA therapy; ALAS1 inhibition therapy (mechanism-based).
A 2022 case report notes hydroxyurea was “beneficial in one previous case” and was planned for the reported patient due to a possible erythropoietic component of ADP, but controlled evidence is lacking. (graff2022casereportlack pages 1-2)
MAXO suggestion: hydroxyurea therapy.
Historical evidence suggests limited benefit in at least one child with ADP, and expert reviews reserve transplantation for refractory AHP generally. (ramanujam2015porphyriadiagnostics—part1 pages 9-11, wang2023agaclinicalpractice pages 1-3, gross19985aminolevulinicaciddehydratase pages 4-5)
MAXO suggestion: liver transplantation.
After biochemical diagnosis, confirm by ALAD sequencing and offer cascade testing to relatives for counseling (general AHP approach). (wang2023agaclinicalpractice pages 1-3)
No naturally occurring ADP in other species was identified in the captured evidence set.
A 2024 conference poster reports in vivo functional characterization of newly identified ALAD variants by vector transfer into hepatocytes of C57BL/6 mice using hydrodynamic tail vein injection, with one variant showing ~5% wild-type enzyme activity. This supports use of mouse liver expression systems for variant functional validation in ADP. (castelbon202404163functionalcharacterization pages 1-1)
1) 2023 expert clinical guidance (AGA Clinical Practice Update) clarified a key diagnostic pitfall: urinary PBG is elevated in all AHP except ALAD porphyria, reinforcing the need to measure ALA and PBG together and not rely on PBG alone. Publication date: March 2023. URL: https://doi.org/10.1053/j.gastro.2022.11.034 (wang2023agaclinicalpractice pages 3-5, wang2023agaclinicalpractice pages 1-3)
2) 2023 mechanistic synthesis emphasized ALAD’s Zn2+ dependence and lead susceptibility and framed ADP as a mutation-driven “conformational disease,” connecting structural disruption to enzyme instability/misfolding. Publication date: November 2023. URL: https://doi.org/10.1055/s-0043-1776760 (balogun2023thehepaticporphyrias pages 3-5)
3) 2024 variant discovery + functional validation (conference poster) reported previously unreported ALAD variants in young patients and used a mouse hepatocyte expression approach for functional assessment, illustrating continued discovery of allelic heterogeneity and translation of variant interpretation methods. Publication date: September 2024. URL: https://doi.org/10.1136/bmjgast-2024-icpp.75 (castelbon202404163functionalcharacterization pages 1-1)
| Finding | Details | Key source (year; DOI/URL) |
|---|---|---|
| Disease name / identifiers | 5-Aminolevulinic acid dehydratase deficiency porphyria; ALAD deficiency porphyria; ADP; Doss porphyria. OMIM 612740 reported in recent reviews/case reports. Described as the rarest/ultra-rare acute hepatic porphyria (graff2022casereportlack pages 1-2, ramanujam2015porphyriadiagnostics—part1 pages 9-11). | Graff et al., 2022, Front Genet, https://doi.org/10.3389/fgene.2022.867856 (graff2022casereportlack pages 1-2); Ramanujam & Anderson, 2015, https://doi.org/10.1002/0471142905.hg1720s86 (ramanujam2015porphyriadiagnostics—part1 pages 9-11) |
| Synonyms | ALAD porphyria, ALA dehydratase deficiency porphyria, aminolevulinate dehydratase deficiency porphyria, Doss porphyria (ramanujam2015porphyriadiagnostics—part1 pages 9-11). | Ramanujam & Anderson, 2015, https://doi.org/10.1002/0471142905.hg1720s86 (ramanujam2015porphyriadiagnostics—part1 pages 9-11) |
| Inheritance | Autosomal recessive; affected patients usually have biallelic/compound heterozygous ALAD variants; heterozygotes have ~50% ALAD activity and are usually asymptomatic (ramanujam2015porphyriadiagnostics—part1 pages 9-11, gross19985aminolevulinicaciddehydratase pages 1-2). | Ramanujam & Anderson, 2015, https://doi.org/10.1002/0471142905.hg1720s86 (ramanujam2015porphyriadiagnostics—part1 pages 9-11); Gross et al., 1998, https://doi.org/10.1093/clinchem/44.9.1892 (gross19985aminolevulinicaciddehydratase pages 1-2) |
| Causal gene | ALAD (also PBGS), chromosome 9q34; zinc-dependent enzyme catalyzing condensation of 2 ALA molecules to porphobilinogen (PBG) (ramanujam2015porphyriadiagnostics—part1 pages 9-11, balogun2023thehepaticporphyrias pages 3-5). | Ramanujam & Anderson, 2015, https://doi.org/10.1002/0471142905.hg1720s86 (ramanujam2015porphyriadiagnostics—part1 pages 9-11); Balogun & Nejak-Bowen, 2023, https://doi.org/10.1055/s-0043-1776760 (balogun2023thehepaticporphyrias pages 3-5) |
| Example pathogenic variants | Reported ALAD variants include c.265G>A p.Glu89Lys and c.394T>C p.Cys132Arg; historical/functional examples include K59N, F12L, G133R, R240W, A274T, V275M, delTC; 2024 poster reported c.440_441delinsTT / p.Arg147Leu, c.839G>A / p.Gly280Glu, and c.724G>A / p.Val242Ile (graff2022casereportlack pages 1-2, balogun2023thehepaticporphyrias pages 3-5, castelbon202404163functionalcharacterization pages 1-1). | Graff et al., 2022, https://doi.org/10.3389/fgene.2022.867856 (graff2022casereportlack pages 1-2); Balogun & Nejak-Bowen, 2023, https://doi.org/10.1055/s-0043-1776760 (balogun2023thehepaticporphyrias pages 3-5); Castelbón et al., 2024 poster, https://doi.org/10.1136/bmjgast-2024-icpp.75 (castelbon202404163functionalcharacterization pages 1-1) |
| Key biochemical finding: ALA | Markedly increased urinary/plasma ALA is the hallmark; examples include 32-fold urinary increase in one 17-year-old case, and 44-fold to 80-fold increases in long-term follow-up cases (doss2004thethirdcase pages 1-4, gross19985aminolevulinicaciddehydratase pages 2-3). | Doss et al., 2004, https://doi.org/10.1023/b:boli.0000037341.21975.9d (doss2004thethirdcase pages 1-4); Gross et al., 1998, https://doi.org/10.1093/clinchem/44.9.1892 (gross19985aminolevulinicaciddehydratase pages 2-3) |
| Key biochemical finding: PBG | PBG is normal or only slightly elevated in ADP; this distinguishes ADP from most other acute hepatic porphyrias where PBG is typically elevated (graff2022casereportlack pages 1-2, wang2023agaclinicalpractice pages 3-5, doss2004thethirdcase pages 1-4). | Graff et al., 2022, https://doi.org/10.3389/fgene.2022.867856 (graff2022casereportlack pages 1-2); Wang et al., 2023, https://doi.org/10.1053/j.gastro.2022.11.034 (wang2023agaclinicalpractice pages 3-5); Doss et al., 2004, https://doi.org/10.1023/b:boli.0000037341.21975.9d (doss2004thethirdcase pages 1-4) |
| Key biochemical finding: urinary porphyrins | Urinary coproporphyrin III / coproporphyrin excretion is increased; one case had urinary coproporphyrin increased 76-fold and long-term cases had excessive urinary coproporphyrin excretion (graff2022casereportlack pages 1-2, gross19985aminolevulinicaciddehydratase pages 4-5, doss2004thethirdcase pages 1-4). | Graff et al., 2022, https://doi.org/10.3389/fgene.2022.867856 (graff2022casereportlack pages 1-2); Gross et al., 1998, https://doi.org/10.1093/clinchem/44.9.1892 (gross19985aminolevulinicaciddehydratase pages 4-5); Doss et al., 2004, https://doi.org/10.1023/b:boli.0000037341.21975.9d (doss2004thethirdcase pages 1-4) |
| Key biochemical finding: erythrocyte Zn-protoporphyrin | Erythrocyte zinc protoporphyrin is elevated/markedly increased; one case showed 5.4-fold elevation and case report/review also note increased erythrocyte zinc protoporphyrin (graff2022casereportlack pages 1-2, gross19985aminolevulinicaciddehydratase pages 4-5, doss2004thethirdcase pages 1-4). | Graff et al., 2022, https://doi.org/10.3389/fgene.2022.867856 (graff2022casereportlack pages 1-2); Gross et al., 1998, https://doi.org/10.1093/clinchem/44.9.1892 (gross19985aminolevulinicaciddehydratase pages 4-5); Doss et al., 2004, https://doi.org/10.1023/b:boli.0000037341.21975.9d (doss2004thethirdcase pages 1-4) |
| Key biochemical finding: ALAD activity | Profound ALAD deficiency in erythrocytes/lymphocytes, typically <10% of normal; examples include 10% activity in a 2004 case and <10% activity sustained over 20 years in 2 patients (gross19985aminolevulinicaciddehydratase pages 1-2, doss2004thethirdcase pages 1-4, pierro2021laboratorydiagnosisof pages 12-13). | Gross et al., 1998, https://doi.org/10.1093/clinchem/44.9.1892 (gross19985aminolevulinicaciddehydratase pages 1-2); Doss et al., 2004, https://doi.org/10.1023/b:boli.0000037341.21975.9d (doss2004thethirdcase pages 1-4); Di Pierro et al., 2021, https://doi.org/10.3390/diagnostics11081343 (pierro2021laboratorydiagnosisof pages 12-13) |
| Hallmark clinical features | Acute neurovisceral attacks with severe abdominal pain, peripheral neuropathy/weakness, polyneuropathy, autonomic/cardiovascular symptoms; can progress to paresis, respiratory paralysis/failure. No cutaneous manifestations are typical (graff2022casereportlack pages 1-2, ramanujam2015porphyriadiagnostics—part1 pages 9-11, gross19985aminolevulinicaciddehydratase pages 1-2, doss2004thethirdcase pages 1-4). | Graff et al., 2022, https://doi.org/10.3389/fgene.2022.867856 (graff2022casereportlack pages 1-2); Ramanujam & Anderson, 2015, https://doi.org/10.1002/0471142905.hg1720s86 (ramanujam2015porphyriadiagnostics—part1 pages 9-11); Gross et al., 1998, https://doi.org/10.1093/clinchem/44.9.1892 (gross19985aminolevulinicaciddehydratase pages 1-2); Doss et al., 2004, https://doi.org/10.1023/b:boli.0000037341.21975.9d (doss2004thethirdcase pages 1-4) |
| Typical onset / rarity | Usually childhood to adolescence; reported as extremely rare with ~6 cases in older review and ~8 documented worldwide in 2022 case report; historical reports noted all known cases male (graff2022casereportlack pages 1-2, ramanujam2015porphyriadiagnostics—part1 pages 9-11). | Graff et al., 2022, https://doi.org/10.3389/fgene.2022.867856 (graff2022casereportlack pages 1-2); Ramanujam & Anderson, 2015, https://doi.org/10.1002/0471142905.hg1720s86 (ramanujam2015porphyriadiagnostics—part1 pages 9-11) |
| Recommended first-line diagnostic tests | In suspected acute hepatic porphyria, first-line testing is random urine ALA and PBG corrected to creatinine; in ADP, elevated ALA with absent/minimal PBG rise should raise suspicion. Follow with porphyrin fractionation, erythrocyte ALAD activity assay, and molecular testing of ALAD (wang2023agaclinicalpractice pages 3-5, wang2023agaclinicalpractice pages 1-3, pierro2021laboratorydiagnosisof pages 2-4, pierro2021laboratorydiagnosisof pages 12-13). | Wang et al., 2023, https://doi.org/10.1053/j.gastro.2022.11.034 (wang2023agaclinicalpractice pages 3-5, wang2023agaclinicalpractice pages 1-3); Di Pierro et al., 2021, https://doi.org/10.3390/diagnostics11081343 (pierro2021laboratorydiagnosisof pages 2-4, pierro2021laboratorydiagnosisof pages 12-13) |
| Additional diagnostic clues | Plasma fluorescence scan may show emission peak around 618–622 nm in symptomatic ADP/AIP/HCP; blood lead level should be checked because lead poisoning can mimic ADP by inhibiting ALAD (pierro2021laboratorydiagnosisof pages 2-4, ramanujam2015porphyriadiagnostics—part1 pages 9-11, doss2004thethirdcase pages 1-4). | Di Pierro et al., 2021, https://doi.org/10.3390/diagnostics11081343 (pierro2021laboratorydiagnosisof pages 2-4); Ramanujam & Anderson, 2015, https://doi.org/10.1002/0471142905.hg1720s86 (ramanujam2015porphyriadiagnostics—part1 pages 9-11); Doss et al., 2004, https://doi.org/10.1023/b:boli.0000037341.21975.9d (doss2004thethirdcase pages 1-4) |
| Differential diagnosis / triggers | Important mimics and modifiers include lead poisoning, hereditary tyrosinemia type 1 (succinylacetone inhibits ALAD), zinc deficiency, alcohol, smoking, diabetes, and chronic renal failure. Lead displaces zinc from ALAD and can produce an ADP-like picture (ramanujam2015porphyriadiagnostics—part1 pages 9-11, balogun2023thehepaticporphyrias pages 3-5, gross19985aminolevulinicaciddehydratase pages 4-5). | Ramanujam & Anderson, 2015, https://doi.org/10.1002/0471142905.hg1720s86 (ramanujam2015porphyriadiagnostics—part1 pages 9-11); Balogun & Nejak-Bowen, 2023, https://doi.org/10.1055/s-0043-1776760 (balogun2023thehepaticporphyrias pages 3-5); Gross et al., 1998, https://doi.org/10.1093/clinchem/44.9.1892 (gross19985aminolevulinicaciddehydratase pages 4-5) |
| Key treatment: hemin / heme arginate | Best-supported acute and prophylactic treatment. Effective in several reported ADP patients; reduces urinary ALA and porphyrins and improves symptoms. Weekly haem arginate for 1 year produced sustained benefit in one case; long-term weekly prophylactic hemin reduced attacks in another but caused iron overload (doss2004thethirdcase pages 7-8, gross19985aminolevulinicaciddehydratase pages 1-2, doss2004thethirdcase pages 1-4, graff2022casereportlack pages 1-2). | Doss et al., 2004, https://doi.org/10.1023/b:boli.0000037341.21975.9d (doss2004thethirdcase pages 7-8, doss2004thethirdcase pages 1-4); Gross et al., 1998, https://doi.org/10.1093/clinchem/44.9.1892 (gross19985aminolevulinicaciddehydratase pages 1-2); Graff et al., 2022, https://doi.org/10.3389/fgene.2022.867856 (graff2022casereportlack pages 1-2) |
| Key treatment: glucose / dextrose | Used as part of acute attack management in AHPs; historical ADP cases improved with glucose plus heme arginate, but older review notes glucose loading alone was not effective in some young male ADP cases (wang2023agaclinicalpractice pages 1-3, gross19985aminolevulinicaciddehydratase pages 1-2, ramanujam2015porphyriadiagnostics—part1 pages 9-11). | Wang et al., 2023, https://doi.org/10.1053/j.gastro.2022.11.034 (wang2023agaclinicalpractice pages 1-3); Gross et al., 1998, https://doi.org/10.1093/clinchem/44.9.1892 (gross19985aminolevulinicaciddehydratase pages 1-2); Ramanujam & Anderson, 2015, https://doi.org/10.1002/0471142905.hg1720s86 (ramanujam2015porphyriadiagnostics—part1 pages 9-11) |
| Key treatment: givosiran | Included under broad AHP approvals/trials and ALAD-deficient patients were eligible for ENVISION, but no dedicated ALAD trial identified. Single ADP case report found no durable biochemical or clinical benefit after 6 months; attacks continued, though no liver adverse effects were observed in that patient (NCT03338816 chunk 1, graff2022casereportlack pages 2-4, graff2022casereportlack pages 1-2). | ClinicalTrials.gov NCT03338816, 2017, https://clinicaltrials.gov/study/NCT03338816 (NCT03338816 chunk 1); Graff et al., 2022, https://doi.org/10.3389/fgene.2022.867856 (graff2022casereportlack pages 2-4, graff2022casereportlack pages 1-2) |
| Key treatment: hydroxyurea | Not established, but reported as beneficial in one previous ADP case; considered/planned in 2022 case because ADP may have an erythropoietic component (graff2022casereportlack pages 1-2). | Graff et al., 2022, https://doi.org/10.3389/fgene.2022.867856 (graff2022casereportlack pages 1-2) |
| Key treatment: liver transplantation | Reserved for refractory AHP generally, but evidence in ADP is poor; one child with ADP did not benefit and died after liver transplantation according to historical reports/reviews (wang2023agaclinicalpractice pages 1-3, ramanujam2015porphyriadiagnostics—part1 pages 9-11, gross19985aminolevulinicaciddehydratase pages 4-5). | Wang et al., 2023, https://doi.org/10.1053/j.gastro.2022.11.034 (wang2023agaclinicalpractice pages 1-3); Ramanujam & Anderson, 2015, https://doi.org/10.1002/0471142905.hg1720s86 (ramanujam2015porphyriadiagnostics—part1 pages 9-11); Gross et al., 1998, https://doi.org/10.1093/clinchem/44.9.1892 (gross19985aminolevulinicaciddehydratase pages 4-5) |
Table: This table compiles the most actionable disease-definition, diagnostic, biochemical, and treatment facts for ALAD deficiency porphyria (Doss porphyria) using only gathered evidence. It is useful as a compact source for knowledge-base population and clinical differentiation from other acute hepatic porphyrias and lead toxicity.
References
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(wang2023agaclinicalpractice pages 3-5): Bruce Wang, Herbert L. Bonkovsky, Joseph K. Lim, and Manisha Balwani. Aga clinical practice update on diagnosis and management of acute hepatic porphyrias: expert review. Gastroenterology, 164:484-491, Mar 2023. URL: https://doi.org/10.1053/j.gastro.2022.11.034, doi:10.1053/j.gastro.2022.11.034. This article has 91 citations and is from a highest quality peer-reviewed journal.
(graff2022casereportlack pages 1-2): Erica Graff, Karl E. Anderson, and Cynthia Levy. Case report: lack of response to givosiran in a case of alad porphyria. Frontiers in Genetics, Aug 2022. URL: https://doi.org/10.3389/fgene.2022.867856, doi:10.3389/fgene.2022.867856. This article has 11 citations and is from a peer-reviewed journal.
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(graff2022casereportlack pages 2-4): Erica Graff, Karl E. Anderson, and Cynthia Levy. Case report: lack of response to givosiran in a case of alad porphyria. Frontiers in Genetics, Aug 2022. URL: https://doi.org/10.3389/fgene.2022.867856, doi:10.3389/fgene.2022.867856. This article has 11 citations and is from a peer-reviewed journal.
(graff2022casereportlack media 69c1e72f): Erica Graff, Karl E. Anderson, and Cynthia Levy. Case report: lack of response to givosiran in a case of alad porphyria. Frontiers in Genetics, Aug 2022. URL: https://doi.org/10.3389/fgene.2022.867856, doi:10.3389/fgene.2022.867856. This article has 11 citations and is from a peer-reviewed journal.
(graff2022casereportlack media 97eb2153): Erica Graff, Karl E. Anderson, and Cynthia Levy. Case report: lack of response to givosiran in a case of alad porphyria. Frontiers in Genetics, Aug 2022. URL: https://doi.org/10.3389/fgene.2022.867856, doi:10.3389/fgene.2022.867856. This article has 11 citations and is from a peer-reviewed journal.
(graff2022casereportlack media 0a38561c): Erica Graff, Karl E. Anderson, and Cynthia Levy. Case report: lack of response to givosiran in a case of alad porphyria. Frontiers in Genetics, Aug 2022. URL: https://doi.org/10.3389/fgene.2022.867856, doi:10.3389/fgene.2022.867856. This article has 11 citations and is from a peer-reviewed journal.
(doss2004thethirdcase pages 7-8): M. O. Doss, T. Stauch, U. Gross, M. Renz, R. Akagi, M. Doss‐Frank, H. P. Seelig, and S. Sassa. The third case of doss porphyria (δ-amino-levulinic acid dehydratase deficiency) in germany. Journal of Inherited Metabolic Disease, 27:529-536, Jul 2004. URL: https://doi.org/10.1023/b:boli.0000037341.21975.9d, doi:10.1023/b:boli.0000037341.21975.9d. This article has 68 citations and is from a peer-reviewed journal.