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Mappings

MONDO

MONDO:0060527 maleylacetoacetate isomerase deficiency

MONDO:0060527 (maleylacetoacetate isomerase deficiency) cross-references OMIM:617596, MEDGEN:713903 and UMLS:C1291607, and carries MAAID as a synonym. OMIM:617596 is the GSTZ1 entity, matching IEMbase WP-002 row 1.4.06.01 (GSTZ1-related maleylacetoacetate isomerase deficiency, OMIM 617596). No named-entity confusion against tyrosinemia types I, II or III, alkaptonuria or hawkinsinuria, which are separate MONDO entities on separate genes.

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Inheritance

1

Autosomal recessive HP:0000007

Biallelic GSTZ1 variants are required. Segregation in the German family is the clearest demonstration: the index case was homozygous for a canonical splice-site variant, his mother heterozygous and clinically unremarkable, and his father homozygous and — at 32 years, on an unrestricted diet — also unremarkable.

Autosomal recessive inheritance

Show evidence (2 references)

PMID:27876694 SUPPORT Human Clinical

"Four individuals were homozygous for c.449C>T (p.Ala150Val). One was compound heterozygous for c.259C>T (p.Arg87Ter) and an intronic sequence variant."

Homozygous and compound heterozygous genotypes in the founding case series establish the recessive requirement.

PMID:38535121 SUPPORT Human Clinical

"The mother was found to be heterozygous and the father homozygous for this variant."

Family segregation showing an unaffected heterozygous carrier alongside a homozygous relative.

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Mechanistic Hypotheses

2

A glutathione-dependent non-enzymatic bypass keeps the enzymatic block clinically silent

gsh_bypass_sufficiency CANONICAL

Evidence balance 1 support

The accepted explanation for why loss of the penultimate enzyme of tyrosine catabolism is benign while loss of the final one is lethal. Glutathione binds maleylacetoacetate spontaneously and can isomerise it to fumarylacetoacetate without the enzyme, slowly but fast enough at the millimolar hepatic glutathione concentrations found in vivo. The bypass was shown directly in vitro, and inferred in vivo from Maai/Fah double-mutant mice, which die of a fumarylacetoacetate-driven phenotype that could only have arisen if maleylacetoacetate reached fumarylacetoacetate in the absence of the enzyme.

Pathograph links

Maleylacetoacetate accumulation behind the block -> Glutathione-dependent non-enzymatic isomerisation to fumarylacetoacetate DIRECT Accumulating maleylacetoacetate is bound by glutathione and slowly isomerised without the enzyme, so most of the flux still reaches fumarylacetoacetate.

Show evidence (1 reference)

PMID:12052898 SUPPORT In Vitro

"A glutathione-mediated isomerization of MAA to FAA independent of MAAI enzyme was demonstrated in vitro. This nonenzymatic bypass is likely responsible for the lack of a phenotype in nonstressed MAAI mutant mice."

The in vitro demonstration and the authors' attribution of the absent phenotype to it.

The bypass is saturable, so substrate overload or glutathione depletion should be toxic

bypass_saturation_toxicity EMERGING

Evidence balance 1 support

A conditional-toxicity model derived entirely from the mouse. Because the non-enzymatic reaction is slow, it should fail when maleylacetoacetate production is raised or when glutathione is consumed — and in mice it does, producing hepatic and renal necrosis, leucopenia and death. Curated as EMERGING rather than CANONICAL because no human has been reported in that stressed state: the only long-term human observations are of unrestricted ordinary diets, which the mouse data would not predict to be dangerous either. The model is what motivates the standing advice to avoid protein supplements, dichloroacetate and glutathione-depleting drugs, so it is currently doing clinical work on animal evidence alone.

Pathograph links

Glutathione-dependent non-enzymatic isomerisation to fumarylacetoacetate -> Bypass saturation under substrate overload or glutathione depletion DIRECT Because the reaction is slow and glutathione-dependent, raising maleylacetoacetate production or consuming glutathione exhausts it.

Bypass saturation under substrate overload or glutathione depletion -> Hepatorenal injury and leucopenia in the saturated state DIRECT Once free maleylacetoacetate accumulates, tissue injury follows in the mouse, with the kidney as the predominant target.

Show evidence (1 reference)

PMID:12052898 SUPPORT Model Organism

"A complete redundancy of MAAI could be ruled out because substrate overload of the tyrosine catabolic pathway (administration of homogentisic acid, phenylalanine, or tyrosine) resulted in renal and hepatic damage."

Establishes the saturability of the bypass under substrate load in the mouse.

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Discussions and Knowledge Gaps

3

Gstz1-null mice die of hepatic and renal necrosis on a high-protein diet of beans and lentils, yet a homozygous human adult ate an unrestricted diet including dairy and meat for 32 years without a single episode of hepatic decompensation. Does the murine substrate-overload arm describe a real human vulnerability at all, and if so at what exposure?

HUMAN MODEL MISMATCH OPEN maai_bypass_saturation_no_human_counterpart

Attached to

pathophysiology#Bypass saturation under substrate overload or glutathione depletion pathophysiology#Hepatorenal injury and leucopenia in the saturated state

This is not an absence of evidence but a conflict between evidence in a model and evidence in humans, which is why it is curated as a model mismatch rather than a knowledge gap. The mouse result is robust and internally controlled — the injury is prevented by nitisinone, so it is genuinely flux-driven — and it is the sole mechanistic basis for the standing advice to avoid protein supplements, dichloroacetate and glutathione-depleting drugs. But the murine loading protocols are extreme relative to human intake, mouse chow is unusually low in phenylalanine and tyrosine so the baseline is not the human baseline, and mouse survival on high phenylalanine varied by sex and strain by an order of magnitude, which points to modifiers that have no human counterpart mapped. The strain effect reaches the baseline as well as the challenge: a second, independently derived null on BALB/c has hepatomegaly, renomegaly, splenic atrophy and multifocal hepatitis on ordinary chow, where the line that is healthy for 22 months has none of it. So the murine arm does not speak with one voice about what an unstressed null looks like, and its human extrapolation inherits that. Two readings remain open: either humans sit permanently below the saturation threshold under any realistic diet, or the threshold exists and no ascertained individual has yet crossed it. The nine people with clinical follow-up are far too few to distinguish these.

Proposed experiments

Prospective biochemical monitoring of confirmed cases through glutathione-depleting exposures

exp_maai_glutathione_stress_challenge

Register-based prospective collection of paired succinylacetone, maleic acid, transaminase, creatinine and tubular-function measurements in molecularly confirmed individuals before and during naturally occurring glutathione-depleting exposures — therapeutic acetaminophen courses, febrile intercurrent illness, high-protein dietary periods — rather than any deliberate challenge.

Decision criterion

A reproducible rise in succinylacetone or maleic acid with concurrent tubular or hepatic markers during such exposures would establish that the murine saturation threshold is reachable in humans and would convert the avoidance advice from prediction to evidence. Stable metabolites and normal organ markers across the exposure range would argue that human glutathione turnover keeps the bypass unsaturated and that the advice is precautionary only.

Show evidence (2 references)

PMID:12052898 SUPPORT Model Organism

"Humans, at least in developed countries, are unlikely to experience nutritional stress severe enough to be affected by MAAI deficiency if this gene defect exists in the human population."

The originating authors' own statement of the translational limit, written before any human case was known.

PMID:38535121 REFUTE Human Clinical

"The father was without obvious medical complaints at the age of 32 years and adhered to a regular diet including dairy and meat. He had never experienced episodes of liver disease or clinical decompensation despite having experienced several intercurrent infections."

The longest human observation refutes a dietary-protein vulnerability at ordinary intakes, which is the specific extrapolation the mouse invites.

Succinylacetone has been characterised as an oncometabolite in GSTZ1-deficient hepatocellular carcinoma models. Is decades of mild, intermittent succinylacetone exposure in constitutional maleylacetoacetate isomerase deficiency genuinely inert, and does the surveillance recommendation have any evidential basis?

KNOWLEDGE GAP OPEN maai_lifelong_succinylacetone_exposure_unknown

Attached to

pathophysiology#Escape of succinylacetone and maleic acid into blood and urine treatments#Withholding nitisinone and dietary tyrosine restriction, with structured surveillance

Every human observation to date says the disorder is benign, and every observation to date is short. Only four individuals have longitudinal follow-up, the longest to 32 years, in a condition whose plausible harm — hepatocellular carcinoma — is a late outcome. Meanwhile, somatic GSTZ1-1 loss in hepatocellular carcinoma drives NRF2 activation through succinylacetone-mediated alkylation of KEAP1 and is described as tumour-promoting, and the same review that argues against treating this disorder notes that these cancer observations would argue for lowering succinylacetone. The two literatures have not been reconciled, and the difference between them may simply be somatic loss in a transformed hepatocyte versus lifelong constitutional loss with an intact bypass — but that is a hypothesis, not a finding. Concretely: the imaging surveillance now recommended has no reported yield, and no cohort large or old enough to estimate one exists.

Proposed experiments

International registry of molecularly confirmed cases with standardised long-term outcome capture

exp_maai_international_registry_longitudinal_outcome

Pooling of confirmed GSTZ1 cases across newborn screening programmes with a common minimum dataset — periodic transaminases, alpha-fetoprotein, hepatic imaging and time-integrated succinylacetone — carried into adult life, since no single centre has enough cases to answer the question.

Decision criterion

Any excess of hepatic nodules, alpha-fetoprotein elevation or hepatocellular carcinoma over an age-matched expectation would justify the current surveillance and reopen the case for lowering succinylacetone. Event-free ageing across a registry-scale cohort would support de-escalating surveillance to reassurance.

Show evidence (2 references)

PMID:31267557 SUPPORT In Vitro

"Mechanistically, GSTZ1-1 deficiency led to succinylacetone accumulation, alkylation modification of KEAP1, and NRF2 activation, thus promoting IGF1R transcription by recruiting SP1 to its promoter."

Gives the mechanistic reason succinylacetone cannot simply be assumed inert, and is the basis for the gap.

PMID:38535121 SUPPORT Human Clinical

"While this suggests a benign clinical course of MAAI deficiency without specific treatment, the long-term consequences of human MAAI deficiency are currently unknown"

States the gap directly in the human literature.

A historical patient attributed to maleylacetoacetate isomerase deficiency died of hepatic and renal failure but was never molecularly confirmed. Should that case be counted when describing the phenotypic spectrum, or excluded as a probable misdiagnosis?

CONTROVERSY OPEN maai_unconfirmed_fatal_case

Attached to

clinical_burden#

It matters because it is the only human report inconsistent with a benign course, and because the reasoning is circular in both directions. Excluding it on the grounds that confirmed cases are benign assumes the conclusion; including it risks importing a case that, on today's differential, could equally have been tyrosinemia type 1 or partial fumarylacetoacetate hydrolase deficiency — both of which were unavailable as diagnoses at the time and both of which produce the same succinylacetone elevation. This entry describes the disorder from molecularly confirmed cases only and records the unconfirmed case here rather than in the burden assessment, but that is a curation choice with consequences: it is what licenses the LOW burden level, and a single confirmed severe case would overturn it.

Show evidence (1 reference)

PMID:41009955 SUPPORT Human Clinical

"While Berger et al. described one patient showing fatal hepatic and renal failure, for whom molecular confirmation was not available"

Records the single discordant report and its lack of molecular confirmation.

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Pathophysiology

6

Maleylacetoacetate isomerase deficiency

Biallelic GSTZ1 variants reduce maleylacetoacetate isomerase activity, blocking the glutathione-dependent isomerisation of maleylacetoacetate to fumarylacetoacetate — the step immediately upstream of fumarylacetoacetate hydrolase, whose loss causes tyrosinemia type 1. The pathway operates in hepatocytes and renal proximal tubular cells. Patient missense alleles have been expressed in bacteria and shown to retain only low activity, so the lesion is a genuine enzymatic deficiency rather than a regulatory or transport defect.

GSTZ1 hgnc:4643

L-tyrosine catabolic process GO:0006572 ↓ DECREASED

maleylacetoacetate isomerase activity GO:0016034 ↓ DECREASED

liver UBERON:0002107 kidney UBERON:0002113

Animal models

Gstz1/Maai-null mouse Mouse recapitulates A germline null for the orthologous gene, with complete loss of enzyme protein and activity in liver and kidney.

Downstream

Maleylacetoacetate accumulation behind the block Loss of the isomerase leaves its substrate unconsumed at the blocked step.

Show evidence (2 references)

PMID:41009955 SUPPORT Human Clinical

"Within the tyrosine degradation pathway, the enzyme catalyzes the isomerization of maleylacetoacetate (MAA) to fumarylacetoacetate (FAA), a step immediately upstream of fumarylacetoacetate hydrolase."

Defines the reaction blocked by the lesion and fixes its position relative to the tyrosinemia type 1 step.

PMID:27876694 SUPPORT In Vitro

"Bacterial expression of p.Ala150Val and p.Val99Met revealed low MAAI activity."

Functional expression of patient alleles establishes reduced enzyme activity as the molecular consequence.

Maleylacetoacetate accumulation behind the block

Maleylacetoacetate builds up in hepatocytes and renal tubular cells. This is the node where the disorder diverges from tyrosinemia type 1: at a matched plasma succinylacetone concentration, the predicted intracellular profile here is high maleylacetoacetate with low fumarylacetoacetate, whereas fumarylacetoacetate hydrolase deficiency predicts the reverse. Since fumarylacetoacetate is the strongly electrophilic species held responsible for hepatocyte and tubular injury in tyrosinemia type 1, the swap of which intermediate accumulates is the leading account of why the two disorders share a marker but not a phenotype. Note this is an inference from pathway position, not a measurement: neither intermediate is stable enough to have been quantified in human tyrosinemic liver.

A glutathione-dependent non-enzymatic bypass keeps the enzymatic block clinically silent

liver UBERON:0002107

Downstream

Glutathione-dependent non-enzymatic isomerisation to fumarylacetoacetate Accumulating maleylacetoacetate is bound by glutathione and slowly isomerised without the enzyme, so most of the flux still reaches fumarylacetoacetate.

Escape of succinylacetone and maleic acid into blood and urine A minority fraction of maleylacetoacetate leaves the cell and is converted to the excreted metabolites that make the disorder detectable.

Show evidence (2 references)

PMID:29326876 SUPPORT INDIRECT Human Clinical

"At a similar level of plasma SA, MAAI deficiency is predicted to cause higher MAA in liver than FAH deficiency, but low levels of FAA."

States the predicted intracellular metabolite swap that distinguishes this node from the tyrosinemia type 1 counterpart.

PMID:29326876 SUPPORT INDIRECT Human Clinical

"The first three are reactive and labile, and have not been accurately measured in tyrosinemic liver. The relative toxicities of FAA and MAA are not known"

States that the intracellular intermediates have never been measured and their relative toxicities are unknown, which is why the metabolite-swap account is curated as an inference rather than a direct toxicity claim.

Glutathione-dependent non-enzymatic isomerisation to fumarylacetoacetate

Glutathione binds maleylacetoacetate spontaneously, and the bound adduct can rearrange to fumarylacetoacetate with no enzyme present. The reaction is slow and needs high glutathione — it is undetectable below 1 mM in vitro and approaches its maximum near 5 to 10 mM, against a measured hepatic glutathione concentration of 3 to 7 mM in both wild-type and mutant mice. This node, not any residual enzyme activity, is why the disorder is mild: mutant liver extracts contain no alternative isomerase, so the rescue is chemical rather than enzymatic. The strongest in vivo argument is the Maai/Fah double mutant, which dies of a fumarylacetoacetate-driven phenotype that could not exist unless maleylacetoacetate still reached fumarylacetoacetate without the enzyme.

The bypass is saturable, so substrate overload or glutathione depletion should be toxic

liver UBERON:0002107

Animal models

Gstz1/Maai-null mouse Mouse measures Liver extract from mutant mice, which contains no isomerase, was the assay system in which the glutathione-dependent reaction was titrated, and glutathione-depleting agents were used in vivo to remove it.

Maai/Fah double-mutant mouse Mouse perturbs Removing the downstream hydrolase converts the products of the bypass into a lethal readout, so the double mutant reports on whether the bypass is carrying flux.

Downstream

Bypass saturation under substrate overload or glutathione depletion Because the reaction is slow and glutathione-dependent, raising maleylacetoacetate production or consuming glutathione exhausts it.

Show evidence (2 references)

PMID:12052898 SUPPORT In Vitro

"MAAI enzyme activity was also completely obliterated, indicating that liver cell extracts did not contain an alternate enzyme capable of metabolizing MAA to FAA in the in vitro assay."

Excludes a redundant enzyme, which is what forces the chemical rather than enzymatic interpretation of the bypass.

PMID:12052898 SUPPORT Model Organism

"Mice doubly mutant for MAAI and fumarylacetoacetate hydrolase (FAH) died rapidly on a normal diet, indicating that MAA could be isomerized to FAA in the absence of MAAI."

In vivo genetic evidence that flux still reaches fumarylacetoacetate without the enzyme.

Escape of succinylacetone and maleic acid into blood and urine

The fraction of maleylacetoacetate that neither the enzyme nor the bypass handles leaves the cell and is reduced and decarboxylated to succinylacetone, while maleic acid appears in urine. Both are excreted markers rather than established effectors of injury in this disorder. The quantitative point carries the diagnosis: circulating succinylacetone here is roughly one to two orders of magnitude below untreated tyrosinemia type 1, and is often intermittent, dropping into the reference range on repeat sampling.

Animal models

Gstz1/Maai-null mouse Mouse partially recapitulates Mutants excrete both fumarylacetoacetate and succinylacetone in urine while remaining well, reproducing the central paradox of the human disorder — an abnormal metabolite profile without disease.

Downstream

Mild hypersuccinylacetonaemia The circulating marker on which newborn-screening ascertainment rests.

Elevated urinary succinylacetone Urinary succinylacetone may be only at trace levels, below the laboratory abnormal cut-off yet above what healthy urine contains.

Elevated urinary maleic acid excretion Urinary maleic acid rises well outside the control range and is the discriminating finding against tyrosinemia type 1.

Show evidence (2 references)

PMID:27876694 SUPPORT Human Clinical

"Initial plasma SA levels ranged from 233 to 1282 nmol/L, greater than normal (<24 nmol/L) but less than the initial values of patients with HT1 (16 944-74 377 nmol/L, n=15)."

Quantifies the escaping succinylacetone against both the normal range and tyrosinemia type 1.

PMID:37545091 SUPPORT Human Clinical

"Maleic acid was elevated in uOA of 5/7 false-positive newborns and in the three available samples of confirmed MAAI-D children, but not in TT1 patients."

Establishes maleic acid as the second escaping metabolite and as specific to this block.

Bypass saturation under substrate overload or glutathione depletion

A conditional state, established only in the mouse, in which the chemical rescue fails. It is reached by raising flux into the blocked step (homogentisic acid, phenylalanine or tyrosine loading, or simply a bean-and-lentil high-protein diet) or by consuming the co-substrate (diethylmaleate or phorone, and by extension glutathione-depleting drugs such as acetaminophen). Free maleylacetoacetate then accumulates. No human has been reported in this state, and the ordinary unrestricted human diets under which affected people have remained well are not obviously equivalent to any of the murine loading protocols — so this node is a prediction about humans, not an observation of them.

The bypass is saturable, so substrate overload or glutathione depletion should be toxic

Animal models

Gstz1/Maai-null mouse Mouse perturbs Homogentisic acid, phenylalanine or tyrosine loading, a high-protein bean-and-lentil diet, and glutathione depletion by diethylmaleate or phorone are the interventions that drive the animal into the saturated state; nitisinone rescues it, confirming the injury is flux-dependent.

Downstream

Hepatorenal injury and leucopenia in the saturated state Once free maleylacetoacetate accumulates, tissue injury follows in the mouse, with the kidney as the predominant target.

Show evidence (2 references)

PMID:12052898 SUPPORT INDIRECT Model Organism

"Therefore, MAAI deficiency may manifest itself as hypersensitivity to GSH-depleting drugs, such as acetaminophen."

States the glutathione-depletion arm of the saturating condition and its predicted pharmacological consequence.

PMID:12052898 SUPPORT Model Organism

"To simulate nutritional conditions experienced by mice in the wild, experimental animals were fed a diet consisting of beans and lentils, which are high in protein. Under these conditions, MAAI mutant mice also developed renal and hepatic injury and had reduced survival"

Shows the substrate-load arm is reachable by ordinary dietary protein in the mouse, not only by pharmacological loading.

Hepatorenal injury and leucopenia in the saturated state

The terminal node of the mouse-derived arm: renal epithelial vacuolization, apoptosis and necrosis with rising creatinine, hepatic necrosis and steatosis with rising transaminases, and — on high dietary phenylalanine — a rapid 60 percent fall in circulating white cells attributed to maleylacetoacetate or maleylacetone reaching the circulation. Nitisinone, which blocks the pathway two steps above, prevents it, confirming the injury is driven by flux through tyrosine catabolism rather than by the genotype as such. This node has no reported human counterpart and therefore carries no downstream phenotype in this entry; the prediction that it would present as renal tubular dysfunction or Fanconi syndrome remains untested.

kidney UBERON:0002113 liver UBERON:0002107

Animal models

Gstz1-null BALB/c mouse Mouse partially recapitulates Reproduces the hepatic, renal, splenic and leucocyte injury of the saturated state, and reproduces its phenylalanine dependence, but reaches part of it without any loading at all.

Show evidence (3 references)

PMID:19426674 SUPPORT Model Organism

"Exposure of GSTZ1-1 deficient mice to high dietary phenylalanine causes a rapid loss of circulating white blood cells (WBCs)."

Documents the haematological arm of the saturated-state injury.

PMID:19426674 SUPPORT Model Organism

"The rapid loss of WBCs was attributed to the accumulation of the catabolic intermediates maleylacetoacetate or maleylacetone (MA) in the circulation."

Attributes the leucopenia to the accumulating intermediate rather than to phenylalanine itself.

PMID:12052898 SUPPORT INDIRECT Model Organism

"Therefore, the most likely manifestation of MAAI deficiency in humans would be renal tubular dysfunction or renal Fanconi syndrome."

The authors' extrapolation to a human phenotype, recorded as indirect because it is a prediction from the murine target organ and has not been observed.

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Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.

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Phenotypes

3

Genitourinary 2

Elevated urinary succinylacetone Elevated urinary succinylacetone level HP:6000598

Show evidence (1 reference)

PMID:38535121 SUPPORT Human Clinical

"An analysis of urinary organic acids showed traces of succinylacetone in urine, quantitatively still below the cut-off of the laboratories' abnormal range (N < 1 mmol/mol creatinine)."

Documents the urinary finding and its sub-cut-off magnitude in a confirmed case.

Elevated urinary maleic acid excretion Abnormal urine carboxylic acid level HP:0031980

↑ INCREASED

Show evidence (1 reference)

PMID:37545091 SUPPORT Human Clinical

"Our study shows that MAAI-D is a recognizable cause of false-positive TT1 NBS results. Elevated urine maleic acid excretion seems highly effective in discriminating MAAI-D from TT1."

Establishes both the finding and its discriminating value against tyrosinemia type 1.

Metabolism 1

Mild hypersuccinylacetonaemia Elevated circulating succinylacetone concentration HP:6001410

Severity: MILD

Show evidence (2 references)

PMID:27876694 SUPPORT Human Clinical

"MHSA can be caused by sequence variants in GSTZ1. Such individuals have thus far remained asymptomatic despite receiving no specific treatment."

Names the biochemical phenotype and records that it is unaccompanied by clinical disease.

PMID:37545091 SUPPORT Human Clinical

"Elevated SA may also be due to maleylacetoacetate isomerase deficiency (MAAI-D), which appears to be clinically insignificant."

Independently states that the succinylacetone elevation here carries no evident clinical significance.

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Genetic Associations

1

GSTZ1 deficiency

Gene: GSTZ1 hgnc:4643

Autosomal recessive

Show evidence (2 references)

PMID:41009955 SUPPORT Human Clinical

"The GSTZ1 gene encodes maleylacetoacetate isomerase, a bifunctional enzyme that plays a critical role in both tyrosine catabolism and detoxification of xenobiotic compounds, such as dichloroacetate."

Establishes the gene's second, xenobiotic-metabolising function.

PMID:29641284 SUPPORT Human Clinical

"Variation in the GSTZ1 haplotype is the principal variable influencing DCA kinetics and dynamics in humans."

Quantifies the pharmacogenetic consequence of GSTZ1 variation in humans.

Variants (3)

GSTZ1 missense variants

c.449C>T (p.Ala150Val) was homozygous in four of the six individuals in the founding Québec series and c.295G>A (p.Val99Met) was seen in a further individual; both retained only low activity on bacterial expression. p.Val99Met has since recurred in trans with a splicing allele in an Italian infant and is classified likely pathogenic.

Show evidence (2 references)

PMID:27876694 SUPPORT Human Clinical

"In one, a single heterozygous GSTZ1 sequence variant was identified, c.295G>A (p.Val99Met)."

Documents the p.Val99Met allele in the founding series.

PMID:41009955 SUPPORT Human Clinical

"The genetic analysis highlighted the presence of the variants c.68-12G>A and c.295G>A, p.(Val99Met), in the GSTZ1 gene."

Documents recurrence of the same missense allele in an unrelated case.

GSTZ1 splicing variants

Splicing alleles account for much of the reported molecular spectrum. A homozygous canonical acceptor-site change, c.136-2A>G, was found in a German consanguineous family and predicted to trigger nonsense-mediated decay. The deep-intronic c.68-12G>A, shared by two unrelated Italian infants, creates a cryptic acceptor: RNA from a patient showed retention of 10 bp at the exon 2 to 3 junction, which upgraded the variant from uncertain significance to likely pathogenic and, by trans configuration, upgraded the partner allele with it.

Show evidence (2 references)

PMID:38535121 SUPPORT Human Clinical

"This variant is predicted to lead to a loss of the splice acceptor site in exon 4 and therefore to aberrant splicing and presumably the nonsense-mediated mRNA decay of abnormally spliced protein."

Documents the canonical splice-acceptor allele and its predicted consequence.

PMID:41009955 SUPPORT In Vitro

"To confirm this hypothesis, we carried out patient 1 RNA sequencing, which highlighted retention of 10 bp in the exon 2-3 junction, due to the creation of a cryptic splice site in position c.68-10 (Figure 2)."

RNA-level functional evidence establishing the cryptic-acceptor mechanism of the recurrent intronic allele.

GSTZ1 nonsense variants

c.259C>T (p.Arg87Ter) was found in trans with an intronic variant in one individual of the founding series.

Show evidence (1 reference)

PMID:27876694 SUPPORT Human Clinical

"One was compound heterozygous for c.259C>T (p.Arg87Ter) and an intronic sequence variant."

Documents the reported nonsense allele and its compound heterozygous context.

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Medical Actions

3

Withholding nitisinone and dietary tyrosine restriction, with structured surveillance

Platform: Other

The management decision in this disorder is a decision not to treat. Every reported cohort has been managed without nitisinone or protein restriction, or has had both withdrawn once GSTZ1 variants were found, with no clinical or biochemical deterioration afterwards. What replaces treatment is surveillance — regular clinical, biochemical and imaging review — plus advice to seek evaluation of liver function and clotting during severe intercurrent illness. Note the asymmetry that makes this hard in practice: withholding is correct only once tyrosinemia type 1 has been excluded, and until then the cost of treating unnecessarily is much lower than the cost of not treating tyrosinemia type 1.

Show evidence (2 references)

PMID:41009955 SUPPORT Human Clinical

"we suggest regular clinical, biochemical and imaging surveillance in MAAID."

States the surveillance recommendation that stands in place of disease-directed therapy.

PMID:41009955 SUPPORT Human Clinical

"Our data are in line with previous sparse reports (Table 2), strengthening the observation that subjects with MAAID do not develop symptoms and arguing against the need to start any treatment."

The authors' explicit argument against initiating treatment, which is the claim this entry records as management.

Avoidance of dichloroacetate, glutathione-depleting drugs and protein supplements

Platform: Behavioral / lifestyle

A mechanism-derived precaution rather than a therapy. Because the non-enzymatic rescue consumes glutathione, and because GSTZ1 is itself the enzyme that detoxifies dichloroacetate, exposures that either deplete glutathione or load the blocked step are predicted to be the circumstances under which this disorder could become symptomatic. The advice is standing clinical guidance in the human literature but rests on the mouse for its mechanism; no human adverse event of this kind has been reported.

Mechanism Target:

INHIBITS Bypass saturation under substrate overload or glutathione depletion — Removing glutathione-depleting drugs and pathway substrate load keeps the non-enzymatic isomerisation from being exhausted.

Show evidence (2 references)

PMID:29641284 SUPPORT Human Clinical

"Dichloroacetate (DCA) represents the first targeted therapy for pyruvate dehydrogenase complex deficiency; it is metabolized by glutathione transferase zeta1 (GSTZ1)."

Establishes in humans that dichloroacetate is cleared by the enzyme this disorder disables, which is the pharmacological rationale for avoiding it in this genotype.

PMID:12052898 SUPPORT INDIRECT Other

"It has been shown that DCA, a compound which is in clinical trials for the treatment of lactic acidosis, is detoxified by MAAI"

Background attribution to prior work rather than a result of the mouse study this sentence appears in, so it is graded OTHER rather than MODEL_ORGANISM.

Show evidence (1 reference)

PMID:41009955 SUPPORT Human Clinical

"In confirmed MAAID cases, Yang et al. suggested avoiding protein supplements and some medications, such as acetaminophen, dichloroacetate (DCA) and chloralhydrate"

Records the specific avoidance advice as given in the human clinical literature.

Genetic counselling and cascade testing

Action: genetic counseling Ontology label: Genetic Counseling NCIT:C15240

Platform: Other

Confirming the recessive genotype allows correct counselling and identifies homozygous relatives who would otherwise never be found — in the German family, cascade testing identified a 32-year-old homozygous father whose screening succinylacetone was within the reference range. Because the finding carries no treatment implication, the counselling content is largely reassurance plus the avoidance advice above.

Show evidence (1 reference)

PMID:38535121 SUPPORT Human Clinical

"MAAI has to be considered a rare differential diagnosis in NBS for HT1 in cases with slight elevations of succinylacetone to allow for correct counselling and treatment decisions."

States that recognising the diagnosis is what enables correct counselling and treatment decisions.

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Biochemical Markers

2

Plasma and dried-blood-spot succinylacetone (INCREASED)

Context: The screening analyte. It is sensitive for the block but not specific to it: the same elevation is produced by fumarylacetoacetate hydrolase deficiency, including partial deficiency from the pseudodeficient p.Arg341Trp allele. The magnitude separates them in practice — hundreds of nmol/L here against tens of thousands in untreated tyrosinemia type 1 — but the ranges are a guide rather than a boundary, and nanomolar-range quantitation by GC-MS/MS is what makes the distinction analytically tractable.

Show evidence (2 references)

PMID:27876694 SUPPORT Human Clinical

"Initial plasma SA levels ranged from 233 to 1282 nmol/L, greater than normal (<24 nmol/L) but less than the initial values of patients with HT1 (16 944-74 377 nmol/L, n=15)."

Gives the observed concentration range against the normal range and against tyrosinemia type 1.

PMID:41767123 SUPPORT Other

"This assay facilitates laboratory diagnosis and monitoring of HT1, permits identification and characterization of other hypersuccinylacetonemias including maleylacetoacetate isomerase deficiency"

Establishes that nanomolar-range quantitation is what allows this disorder to be characterised biochemically.

Urinary maleic acid (INCREASED)

Context: Quantitative urinary maleic acid by LC-MS/MS separated confirmed cases from controls cleanly in the only study to measure it: undetectable to 1.16 mmol/mol creatinine in 66 controls against 0.95 to 192.06 in ten screen-positive or confirmed children, and normal in tyrosinemia type 1. Genetic confirmation tracked the analyte in that series — the two normal-maleic-acid newborns were both genetically excluded.

Show evidence (1 reference)

PMID:37545091 SUPPORT Human Clinical

"MAAI-D was genetically confirmed in 4/7 false-positive newborns, all with elevated Q-uMA, and rejected in the two newborns with normal Q-uMA."

Shows the analyte tracking the molecular diagnosis in both directions.

🔬

Diagnosis

4

Newborn screening for dried-blood-spot succinylacetone

Ascertainment is a by-product of screening for tyrosinemia type 1. The finding that brings the infant to attention is an elevated succinylacetone with normal tyrosine; because the elevation is mild and sometimes intermittent, cut-off choice determines whether the disorder is seen at all.

newborn screening NCIT:C81178

Show evidence (1 reference)

PMID:41009955 SUPPORT Human Clinical

"Both cases displayed elevated SA and normal Tyrosine levels at newborn screening."

Defines the screening finding that initiates the diagnostic pathway.

Coagulation and liver function testing to exclude tyrosinemia type 1

Normal coagulation at initial evaluation is the first discriminator, since newborns with tyrosinemia type 1 are clinically asymptomatic but show coagulation abnormalities. It is a negative finding rather than a positive one, and does not by itself distinguish this disorder from partial fumarylacetoacetate hydrolase deficiency.

laboratory procedure NCIT:C25294

Show evidence (1 reference)

PMID:27876694 SUPPORT Human Clinical

"Newborns with HT1 are usually clinically asymptomatic but show liver dysfunction with coagulation abnormalities (prolonged prothrombin time and/or high international normalised ratio)."

Establishes why normal coagulation is informative at referral.

Quantitative urinary maleic acid

LC-MS/MS quantitation of urinary maleic acid, normalised to creatinine, is the positive biochemical test for this disorder and separated confirmed cases from tyrosinemia type 1 and from controls in the study that introduced it. Conventional urine organic acid analysis by GC-MS detects the same abnormality in most but not all cases.

laboratory procedure NCIT:C25294

Show evidence (1 reference)

PMID:37545091 SUPPORT Human Clinical

"This study investigated whether urine organic acid (uOA) and quantitative urine maleic acid (Q-uMA) analyses can distinguish between TT1 and MAAI-D."

Identifies the assay and the diagnostic question it was designed to answer.

GSTZ1 molecular genetic testing

Confirmation requires biallelic GSTZ1 variants. Both a targeted two-gene FAH-plus-GSTZ1 approach and a five-gene hereditary tyrosinemia panel (HPD, FAH, TAT, HGD, GSTZ1) have been used; the panel shortened time to diagnosis from months to weeks in directly compared cases, which matters because the interval is when unnecessary treatment is given.

genetic testing NCIT:C15709

Show evidence (2 references)

PMID:41009955 SUPPORT Human Clinical

"In case 2, the molecular testing was carried out by analysis of a multigene NGS (Next Generation Sequencing) panel, including the five genes associated with hereditary tyrosinemia (i.e., HPD, FAH, TAT, HGD, and GSTZ1)"

Documents the panel-based confirmatory approach.

PMID:41009955 SUPPORT Human Clinical

"In Case 2, the final diagnosis was reached within a few weeks, making use of an NGS multigene panel."

Records the time-to-diagnosis advantage over sequential single-gene sequencing.

📈

Progression

3

Newborn-screening ascertainment

Age: First days of life

Detection is by an elevated dried-blood-spot succinylacetone on newborn screening for tyrosinemia type 1, with normal plasma tyrosine. Coagulation testing and liver enzymes are normal at referral, which is the observation that separates these infants from tyrosinemia type 1 at the bedside before any genetic result is available.

Show evidence (1 reference)

PMID:27876694 SUPPORT Human Clinical

"Six newborns referred for hypersuccinylacetonaemia but who had normal coagulation testing on initial evaluation had sequence variants in the GSTZ1 gene, encoding maleylacetoacetate isomerase (MAAI), the enzyme preceding FAH in tyrosine degradation."

Defines the presenting picture and the normal-coagulation discriminator at referral.

Diagnostic interval

Age: Weeks to months after screening

Until tyrosinemia type 1 is excluded, some infants are started on nitisinone and a tyrosine- and phenylalanine-restricted diet. In the reported Italian case this ran to 21 months before GSTZ1 sequencing allowed withdrawal. Succinylacetone in dried blood spots falls into the reference range on treatment and rises modestly again afterwards, without any accompanying change in tyrosine, transaminases, bilirubin, coagulation or renal parameters — so the treatment moves the marker without evidence of moving anything else.

Show evidence (2 references)

PMID:41009955 SUPPORT Human Clinical

"Case 1 showed intermittent SA elevation; Nitisinone and dietary treatment were started, then discontinued after the identification of two variants in the GSTZ1 gene and the definitive diagnosis of MAAID."

Documents the treat-then-withdraw course of the diagnostic interval.

PMID:41009955 SUPPORT Human Clinical

"The absence of clinical and biochemical deterioration after therapy withdrawal suggests that the intervention did not confer a measurable benefit in MAAID, at least during the follow-up period."

Records the authors' reading of the withdrawal experiment.

Untreated long-term course

Age: Childhood through at least the fourth decade

Longitudinal follow-up exists for only four individuals, spanning 10 to 32 years, and has been unremarkable throughout. The oldest is a homozygous adult ascertained by cascade testing rather than screening, with normal renal function, transaminases, coagulation and alpha-fetoprotein, and undetectable urinary succinylacetone.

Show evidence (1 reference)

PMID:38535121 SUPPORT Human Clinical

"Our observation of natural history over 32 years adds evidence for a benign clinical course of MAAI deficiency without specific treatment."

States the longest untreated natural history reported.

📊

Prevalence

2

Worldwide, published case literature

Cases In Literature <1 in 1,000,000

No population-based rate has been established. As of the 2025 review, fewer than 20 people with MAAI deficiency had been reported, clinical follow-up was available for nine, and biallelic GSTZ1 variants had been confirmed in only eight. The band is recorded as the coarse ultra-rare tier on that published-case basis, not from a measured rate. Ascertainment is almost entirely through succinylacetone-based newborn screening, so the reported count is a lower bound on an unknown true frequency: individuals whose screening succinylacetone falls below the local cut-off — as it did in the 32-year-old homozygous father, whose dried-blood-spot value was within the reference range — are invisible to that route entirely.

Show evidence (1 reference)

PMID:41009955 SUPPORT Human Clinical

"Less than 20 people with MAAID have been reported, with clinical follow-up only available for 9 of them; among these, bi-allelic variants in the GSTZ1 gene were identified in only eight individuals"

Provides the published-case count from which the ultra-rare band is derived.

Heidelberg newborn screening cohort, Germany, August 2016 to December 2020

Birth Prevalence 0.19 per 100,000 live births 1–9 per 1,000,000 (births)

One genetically confirmed case among 516,803 newborns screened for tyrosinemia type 1 gives approximately 0.19 per 100,000 live births. This is an ascertainment-limited detection rate, not a true birth prevalence: only infants exceeding the succinylacetone cut-off entered the diagnostic pathway, a second suspected case in the same cohort was never genetically resolved, and the cut-off was raised mid-study. Read it as a floor.

Show evidence (2 references)

PMID:38535121 SUPPORT Human Clinical

"A total of 516,803 children underwent NBS for HT1 at the NBS center in Heidelberg between August 2016 and December 2020."

Gives the screening denominator behind the detection rate.

PMID:38535121 SUPPORT Human Clinical

"MAAI deficiency was suspected in two cases and genetically confirmed in one who showed traces of succinylacetone in urine."

Gives the numerator, and shows why it is a floor rather than a count.

⚖️

Clinical Burden

Low

No molecularly confirmed individual has developed disease. The Québec series of six went untreated with a normal course to 13 years; a German homozygote reached 32 years on an unrestricted diet including dairy and meat with normal liver and kidney chemistry; two Italian infants were well at 2 and 4 years, one of them after nitisinone and dietary restriction were withdrawn without consequence. The real burden is iatrogenic and informational rather than pathophysiological: a positive newborn screen for a lethal treatable disease, an interval of unnecessary nitisinone and protein restriction while tyrosinemia type 1 is excluded, and a lifelong surveillance recommendation whose necessity is unestablished. Recorded LOW rather than UNKNOWN because the observed burden across every confirmed case is genuinely low; the residual uncertainty about lifelong metabolite exposure is carried by a knowledge-gap discussion instead.

Show evidence (2 references)

PMID:27876694 SUPPORT Human Clinical

"The six individuals with mild hypersuccinylacetonaemia (MHSA) were not treated with diet or nitisinone. Their clinical course has been normal for up to 13 years."

The founding series establishes a normal untreated course over more than a decade.

PMID:38535121 SUPPORT Human Clinical

"The father was without obvious medical complaints at the age of 32 years and adhered to a regular diet including dairy and meat. He had never experienced episodes of liver disease or clinical decompensation despite having experienced several intercurrent infections."

The longest natural history on record, on an unrestricted protein intake.

🔀

Differential Diagnoses

2

Conditions with similar clinical presentations that must be differentiated from Maleylacetoacetate Isomerase Deficiency:

Tyrosinemia type 1 MONDO:0010161

Overlapping Features The disorder this one is mistaken for. Both raise succinylacetone; only tyrosinemia type 1 causes liver failure, and it requires nitisinone within the first month of life. Distinguished by the magnitude of the succinylacetone elevation, by coagulation testing at referral, by normal urinary maleic acid, and definitively by FAH sequencing.

Distinguishing Features

Succinylacetone in the tens of thousands of nmol/L rather than the hundreds
Coagulation abnormality at initial evaluation
Urinary maleic acid not elevated
Biallelic FAH rather than GSTZ1 variants

Show evidence (1 reference)

PMID:37545091 SUPPORT Human Clinical

"Maleic acid was elevated in uOA of 5/7 false-positive newborns and in the three available samples of confirmed MAAI-D children, but not in TT1 patients."

Gives the analyte that separates the two disorders.

Partial fumarylacetoacetate hydrolase deficiency (FAH pseudodeficiency)

Overlapping Features The other cause of mild hypersuccinylacetonaemia, and the one that this entry's discriminators do not fully separate: compound heterozygotes for the prevalent p.Arg341Trp pseudodeficient FAH allele and a severe FAH allele have succinylacetone three- to fivefold above normal, normal coagulation, and have remained well untreated to 9 and 15 years. Only FAH and GSTZ1 sequencing distinguishes them with confidence.

Distinguishing Features

Biallelic FAH variants including the c.1021C>T (p.Arg341Trp) pseudodeficient allele, rather than biallelic GSTZ1 variants
Urinary maleic acid predicted normal, though this has not been directly tested in that genotype

Show evidence (1 reference)

PMID:29326876 SUPPORT Human Clinical

"All newborns identified with mild hypersuccinylacetonemia in Québec have had genetic deficiencies of tyrosine degradation: either deficiency of the enzyme preceding FAH, maleylacetoacetate isomerase, or partial deficiency of FAH itself."

States the two-way differential for mild hypersuccinylacetonaemia.

🐁

Animal Models

3

Gstz1/Maai-null mouse

The defining model of this disorder, and the one that supplied its mechanism before any human case was known. Homozygotes are enzymatically and immunologically null for maleylacetoacetate isomerase, are born at Mendelian ratios, and remain healthy for at least 22 months on standard chow with normal weight, fertility and histology and no tumours — while excreting fumarylacetoacetate and succinylacetone in urine. That combination is the human phenotype in miniature and is what makes the model unusually informative here. Under phenylalanine, tyrosine or homogentisic acid loading, a high-protein bean-and-lentil diet, or pharmacological glutathione depletion, the same animals develop hepatic necrosis and steatosis, renal epithelial vacuolisation, apoptosis and necrosis, and die; nitisinone prevents it.

Species

Mouse

Genotype

Targeted deletion of Maai (Gstz1), homozygous

Background

129SvJ and C57BL/6

Genes

GSTZ1 hgnc:4643

Publication

PMID:12052898

Pathograph links

Maleylacetoacetate isomerase deficiency recapitulates fidelity: high observes: organism A germline null for the orthologous gene, with complete loss of enzyme protein and activity in liver and kidney.

Limitations: The lesion is a targeted whole-gene deletion, whereas the reported human genotypes are missense and splicing alleles with residual activity, so the model represents the severe end of the human allelic spectrum rather than its centre.

Readouts

Hepatic maleylacetoacetate isomerase activity

Enzyme assay of liver extracts from homozygous mutants, used both to confirm the null and to test for a redundant isomerase.

Direction: ABOLISHED

Interpretation: Complete loss of activity with no alternative activity detectable in the extract is what forces the chemical rather than enzymatic reading of the bypass.

Show evidence (1 reference)

PMID:12052898 SUPPORT In Vitro

"MAAI enzyme activity was also completely obliterated, indicating that liver cell extracts did not contain an alternate enzyme capable of metabolizing MAA to FAA in the in vitro assay."

Reports the enzyme measurement and its negative control for a redundant enzyme.

Show evidence (1 reference)

PMID:12052898 SUPPORT Model Organism

"This test showed a complete absence of MAAI (Fig.2C), consistent with deletion of the majority of the gene."

Confirms loss of the protein itself, establishing the model as a null for this node.

Escape of succinylacetone and maleic acid into blood and urine partially recapitulates fidelity: moderate observes: organism Mutants excrete both fumarylacetoacetate and succinylacetone in urine while remaining well, reproducing the central paradox of the human disorder — an abnormal metabolite profile without disease.

Limitations: Urinary maleic acid, which is the discriminating human analyte, was not measured in this study, so the model covers only the succinylacetone half of the node. Metabolite detection was qualitative by GC-MS and the concentrations are not comparable with the human nmol/L ranges on which the clinical distinction from tyrosinemia type 1 rests.

Readouts

Urinary fumarylacetoacetate and succinylacetone

GC-MS analysis of urine from homozygous mutants and wild-type controls.

Direction: INCREASED

Interpretation: Appearance of metabolites absent from control urine, in an animal with no clinical or histological abnormality, is the model's counterpart of mild hypersuccinylacetonaemia.

Show evidence (1 reference)

PMID:12052898 SUPPORT Model Organism

"GC-MS analysis of the urine from mutant mice showed the presence of both FAA and SA (Fig.3), compounds which are not present in normal controls."

Reports the urinary measurement against controls.

Show evidence (1 reference)

PMID:12052898 SUPPORT Model Organism

"MAAI-deficient mice accumulated FAA and succinylacetone in urine but appeared otherwise healthy."

Pairs the metabolite finding with the absence of disease, which is the claim this node makes.

Glutathione-dependent non-enzymatic isomerisation to fumarylacetoacetate measures fidelity: moderate observes: molecular Liver extract from mutant mice, which contains no isomerase, was the assay system in which the glutathione-dependent reaction was titrated, and glutathione-depleting agents were used in vivo to remove it.

Limitations: The in vitro titration used murine liver extract and non-physiological glutathione-depleting agents (diethylmaleate, phorone); human hepatic glutathione concentrations and turnover were not measured, so the margin by which the human bypass operates above its 1 mM floor is unknown. This link is a molecular-scale measurement cited for a molecular-scale node, so it carries no scale extrapolation, but it does carry a species one.

Readouts

In vitro conversion of maleylacetoacetate to fumarylacetoacetate versus glutathione concentration

Titration of the non-enzymatic isomerisation rate against glutathione concentration in isomerase-free mutant liver extract, with dithiothreitol as a chemical comparator.

Direction: INCREASED

Interpretation: A reaction rate that rises with glutathione and is undetectable below 1 mM defines the bypass as a saturable chemical reaction rather than a constitutive rescue.

Show evidence (1 reference)

PMID:12052898 SUPPORT In Vitro

"GSH concentrations lower than 1 mM did not result in the chemical isomerization of MAA to FAA. However, higher concentrations of GSH increased the speed of the reaction until a maximal effect was achieved with 10 mM GSH."

Reports the concentration-response measurement that defines the bypass.

Show evidence (1 reference)

PMID:12052898 SUPPORT In Vitro

"We were able to demonstrate the enzyme-independent bypass of MAAI activity by increasing the GSH concentration in the in vitro reaction using protein extract from MAAI mutant mouse liver"

Establishes that this model is the system in which the bypass was demonstrated.

Bypass saturation under substrate overload or glutathione depletion perturbs fidelity: low observes: organism Homogentisic acid, phenylalanine or tyrosine loading, a high-protein bean-and-lentil diet, and glutathione depletion by diethylmaleate or phorone are the interventions that drive the animal into the saturated state; nitisinone rescues it, confirming the injury is flux-dependent.

Limitations: Fidelity is recorded LOW because the node it perturbs has no observed human counterpart: the loading protocols are far outside human dietary exposure, laboratory chow is unusually low in aromatic amino acids so the murine baseline is not the human one, and survival on high phenylalanine varied several-fold with sex and strain, implying modifiers that are unmapped in humans. The model establishes that the bypass is saturable in mice; it does not establish the human threshold, or that one is reachable.

Readouts

Survival and hepatic and renal injury under phenylalanine loading

Survival, transaminases, creatinine and histopathology in mutants versus controls on phenylalanine-supplemented food or drinking water, with nitisinone as the rescue arm.

Direction: DECREASED

Interpretation: Dose-dependent lethality abolished by blocking the pathway upstream shows the injury is caused by flux into the blocked step rather than by the genotype itself.

Show evidence (2 references)

PMID:12052898 SUPPORT Model Organism

"With the Phe diet, blood amino acid analysis showed no differences between wild-type and mutant mice, but liver function tests indicated hepatocellular damage (elevated transaminases) and renal injury (increased creatinine)"

Reports the hepatic and renal injury measurements under phenylalanine loading, with amino acid levels unchanged.

+ 1 more reference

Circulating white blood cell count under high dietary phenylalanine

Total white cell counts in Gstz1-null mice on high dietary phenylalanine, with splenocyte cytotoxicity assays of mutant serum as the mechanistic follow-up.

Direction: DECREASED

Interpretation: A 60 percent white cell loss within six days, reproduced by direct incubation of normal splenocytes with maleylacetone, identifies a circulating intermediate rather than phenylalanine as the toxic species.

Show evidence (1 reference)

PMID:19426674 SUPPORT Model Organism

"The loss was significant (P<0.05) after 2 days and total WBCs were reduced by 60% after 6 days."

Reports the haematological measurement and its magnitude.

Show evidence (1 reference)

PMID:12052898 SUPPORT Model Organism

"To simulate nutritional conditions experienced by mice in the wild, experimental animals were fed a diet consisting of beans and lentils, which are high in protein. Under these conditions, MAAI mutant mice also developed renal and hepatic injury and had reduced survival"

Establishes that the saturated state is reachable by dietary protein alone in this model, which is what makes the link worth curating despite its low translational fidelity.

Show evidence (1 reference)

PMID:12052898 SUPPORT Model Organism

"Here, we describe the phenotype of mice with a targeted deletion of the MAAI (GSTZ1) gene."

Establishes that the model carries a targeted lesion in the orthologous gene, which is what licenses treating it as informative for this disorder.

Maai/Fah double-mutant mouse

A genetic test of the bypass rather than a model of the disease. If maleylacetoacetate could not reach fumarylacetoacetate without the enzyme, removing fumarylacetoacetate hydrolase as well should have been harmless or protective; instead the double mutants died within about a week of nitisinone withdrawal, with severe liver and kidney injury and a marked creatinine rise and acute renal necrosis not seen in Fah-null animals. That is the strongest in vivo evidence that the non-enzymatic bypass operates, and it simultaneously shows that maleylacetoacetate deficiency generates a toxic species distinct from the fumarylacetoacetate of tyrosinemia type 1.

Species

Mouse

Genotype

Maai (Gstz1) and Fah double homozygous null

Genes

GSTZ1 hgnc:4643

Publication

PMID:12052898

Pathograph links

Glutathione-dependent non-enzymatic isomerisation to fumarylacetoacetate perturbs fidelity: moderate observes: organism Removing the downstream hydrolase converts the products of the bypass into a lethal readout, so the double mutant reports on whether the bypass is carrying flux.

Limitations: The genotype has no human counterpart — no person carries biallelic null alleles at both loci — so this model speaks only to the existence of the bypass and not to any human phenotype. Its severe renal necrosis is evidence about maleylacetoacetate toxicity in a doubly blocked pathway, and must not be read as a prediction for constitutional GSTZ1 deficiency, where the hydrolase is intact.

Readouts

Plasma creatinine and renal histology in double mutants

Blood chemistry and kidney histopathology in Maai/Fah double mutants compared with Fah single mutants after nitisinone withdrawal.

Direction: INCREASED

Interpretation: Renal injury exceeding that of Fah-null animals shows the double mutant accumulates something the single mutant does not, which is the signature of maleylacetoacetate rather than fumarylacetoacetate.

Show evidence (1 reference)

PMID:12052898 SUPPORT Model Organism

"The marked elevation of plasma creatinine indicated severe renal glomerular dysfunction, a phenotype not seen in FAH-deficient animals."

Reports the measurement distinguishing the double mutant from the single mutant.

Show evidence (1 reference)

PMID:12052898 SUPPORT Model Organism

"First, there is a bypass for MAAI activity in hepatocytes and renal tubular cells."

The authors' conclusion from this genotype, which is the claim the link records.

Show evidence (1 reference)

PMID:12052898 SUPPORT Model Organism

"Mice doubly mutant for MAAI and fumarylacetoacetate hydrolase (FAH) died rapidly on a normal diet, indicating that MAA could be isomerized to FAA in the absence of MAAI."

States the genotype and the inference it licenses about the bypass.

Gstz1-null BALB/c mouse

An independently derived germline Gstz1 deletion, on a different genetic background from the model above, and the reason the "unstressed null mouse is well" reading cannot be taken as general. On standard chow these animals have enlarged liver and kidneys, splenic atrophy, multifocal hepatitis and renal ultrastructural change, with constitutive induction of alpha, mu and pi class glutathione transferases and NQO1 — an antioxidant response consistent with chronic accumulation of a toxic metabolite rather than with a silent block. Phenylalanine loading then reproduces the same lethality, hepatic necrosis, steatosis, splenic atrophy and leucopenia seen in the other line, with animals under 28 days old dying. The strain discrepancy at baseline is itself the finding: whether the bypass suffices appears to be modifier-dependent in mice, which is one reason the murine arm is not read as a prediction for humans.

Species

Mouse

Genotype

Gstz1 homozygous null on a BALB/c background

Genes

GSTZ1 hgnc:4643

Publication

PMID:15277241

Pathograph links

Hepatorenal injury and leucopenia in the saturated state partially recapitulates fidelity: low observes: tissue Reproduces the hepatic, renal, splenic and leucocyte injury of the saturated state, and reproduces its phenylalanine dependence, but reaches part of it without any loading at all.

Limitations: Baseline organ pathology on ordinary chow is not what this node describes: the node is defined by bypass saturation under overload, and this strain shows hepatomegaly, renomegaly, splenic atrophy and multifocal hepatitis without it. That makes the finding strain- rather than genotype-determined in the mouse, since the line in the entry above is healthy for 22 months on the same kind of diet. Neither baseline state has a human counterpart — no ascertained person has hepatic, renal or splenic pathology — so this link constrains the murine arm rather than extending it to humans.

Divergences from the human mechanism

population mismatch qualifying

The two published Gstz1-null lines disagree at baseline on ordinary chow, so the murine baseline phenotype tracks genetic background. Which background, if either, corresponds to the human modifier landscape is unknown.

species mismatch qualifying

Mouse chow is unusually low in phenylalanine and tyrosine relative to ordinary human intake, so "standard diet" in this model is not the same exposure as the unrestricted human diets under which affected people have remained well.

Readouts

Liver, kidney and spleen morphology on standard chow

Organ weights plus light and electron microscopy of liver and kidney in unchallenged homozygous nulls fed a standard diet.

Direction: ALTERED

Interpretation: Pathology in the absence of any substrate load is the observation that separates this line from the other, and is why the saturation account is curated as a hypothesis rather than as settled.

Show evidence (1 reference)

PMID:15277241 SUPPORT Model Organism

"When fed a standard diet, the GSTZ1-1-deficient mice showed enlarged liver and kidneys as well as splenic atrophy. Light and electron microscopic examination revealed multifocal hepatitis and ultrastructural changes in the kidney."

Reports the unchallenged organ pathology, which is the measurement this link turns on.

Circulating leukocyte count and hepatic histology under phenylalanine loading

Survival, liver histology and leukocyte counts after 3 percent phenylalanine in the drinking water, in young and older animals.

Direction: DECREASED

Interpretation: Independent replication of the loading phenotype in a second line, with an age dependence the first study did not report.

Show evidence (1 reference)

PMID:15277241 SUPPORT Model Organism

"The addition of 3% (w/v) phenylalanine to the drinking water was lethal for young mice (<28 days old) and caused liver necrosis, macrovesicular steatosis, splenic atrophy, and a significant loss of circulating leukocytes in older surviving mice."

Replicates the substrate-overload injury and its haematological arm in an independent line.

Show evidence (1 reference)

PMID:15277241 SUPPORT Model Organism

"The overall response is consistent with the chronic accumulation of a toxic metabolite(s). We detected the accumulation of succinylacetone in the serum of deficient mice but cannot exclude the possibility that maleylacetoacetate and maleylacetone may also accumulate."

The authors' own reading of the baseline phenotype as metabolite-driven, which is what makes this line informative for the injury node rather than merely an incidental strain difference.

Show evidence (1 reference)

PMID:15277241 SUPPORT Model Organism

"In this study we have deleted the Gstz1 gene in BALB/c mice and characterized their phenotype."

Establishes that this is a second, independently derived germline null in the orthologous gene, which is what makes the strain comparison meaningful.

{ }

Source YAML

click to show

name: Maleylacetoacetate Isomerase Deficiency
category: Mendelian
creation_date: '2026-09-06T00:00:00Z'
synonyms:
- MAAI deficiency
- MAAID
- GSTZ1 deficiency
- Glutathione transferase zeta 1 deficiency
- Mild hypersuccinylacetonaemia
- MHSA
description: >
  Maleylacetoacetate isomerase deficiency is an autosomal recessive inborn error
  of tyrosine catabolism caused by biallelic variants in GSTZ1, which encodes
  maleylacetoacetate isomerase — the glutathione-dependent enzyme that isomerises
  maleylacetoacetate to fumarylacetoacetate, the step immediately upstream of
  fumarylacetoacetate hydrolase. It is curated here because it is the exception
  that the rest of the distal tyrosine pathway does not predict: a block one
  enzyme above the lesion that causes hepatorenal tyrosinemia type 1 produces
  only mild, often intermittent hypersuccinylacetonaemia and, in every
  molecularly confirmed individual followed to date, no disease. The
  mechanistic explanation is a glutathione-mediated non-enzymatic isomerisation
  of maleylacetoacetate that partially substitutes for the missing enzyme,
  demonstrated in vitro and in Gstz1-null mice. That bypass is not unconditional:
  under phenylalanine or tyrosine overload, a high-protein diet, or glutathione
  depletion, mutant mice develop renal and hepatic necrosis and die, and no human
  counterpart of that stressed state has been reported. Clinically the entry
  matters mainly as a differential diagnosis in newborn screening — elevated
  dried-blood-spot succinylacetone is no longer pathognomonic for tyrosinemia
  type 1 — where elevated urinary maleic acid discriminates the two and spares
  the infant unnecessary nitisinone and dietary restriction.
disease_term:
  preferred_term: maleylacetoacetate isomerase deficiency
  term:
    id: MONDO:0060527
    label: maleylacetoacetate isomerase deficiency
parents:
- Disorder of Tyrosine Metabolism
- Inborn Error of Metabolism
mappings:
  mondo_mappings:
  - term:
      id: MONDO:0060527
      label: maleylacetoacetate isomerase deficiency
    mapping_predicate: skos:exactMatch
    mapping_source: OMIM:617596
    mapping_justification: >
      MONDO:0060527 (maleylacetoacetate isomerase deficiency) cross-references
      OMIM:617596, MEDGEN:713903 and UMLS:C1291607, and carries MAAID as a
      synonym. OMIM:617596 is the GSTZ1 entity, matching IEMbase WP-002 row
      1.4.06.01 (GSTZ1-related maleylacetoacetate isomerase deficiency,
      OMIM 617596). No named-entity confusion against tyrosinemia types I, II or
      III, alkaptonuria or hawkinsinuria, which are separate MONDO entities on
      separate genes.
inheritance:
- name: Autosomal recessive
  description: >
    Biallelic GSTZ1 variants are required. Segregation in the German family is
    the clearest demonstration: the index case was homozygous for a canonical
    splice-site variant, his mother heterozygous and clinically unremarkable,
    and his father homozygous and — at 32 years, on an unrestricted diet —
    also unremarkable.
  inheritance_term:
    preferred_term: Autosomal recessive inheritance
    term:
      id: HP:0000007
      label: Autosomal recessive inheritance
  evidence:
  - reference: PMID:27876694
    reference_title: "Hypersuccinylacetonaemia and normal liver function in maleylacetoacetate isomerase deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Four individuals were homozygous for c.449C>T (p.Ala150Val). One was compound heterozygous for c.259C>T (p.Arg87Ter) and an intronic sequence variant."
    explanation: Homozygous and compound heterozygous genotypes in the founding case series establish the recessive requirement.
  - reference: PMID:38535121
    reference_title: "New Cases of Maleylacetoacetate Isomerase Deficiency with Detection by Newborn Screening and Natural History over 32 Years: Experience from a German Newborn Screening Center."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The mother was found to be heterozygous and the father homozygous for this variant."
    explanation: Family segregation showing an unaffected heterozygous carrier alongside a homozygous relative.
prevalence:
- population: Worldwide, published case literature
  measure_type: CASES_IN_LITERATURE
  prevalence_class: BELOW_1_IN_1000000
  notes: >
    No population-based rate has been established. As of the 2025 review, fewer
    than 20 people with MAAI deficiency had been reported, clinical follow-up
    was available for nine, and biallelic GSTZ1 variants had been confirmed in
    only eight. The band is recorded as the coarse ultra-rare tier on that
    published-case basis, not from a measured rate. Ascertainment is almost
    entirely through succinylacetone-based newborn screening, so the reported
    count is a lower bound on an unknown true frequency: individuals whose
    screening succinylacetone falls below the local cut-off — as it did in the
    32-year-old homozygous father, whose dried-blood-spot value was within the
    reference range — are invisible to that route entirely.
  evidence:
  - reference: PMID:41009955
    reference_title: "Variants in GSTZ1 Gene Underlying Maleylacetoacetate Isomerase Deficiency: Characterization of Two New Individuals and Literature Review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Less than 20 people with MAAID have been reported, with clinical follow-up only available for 9 of them; among these, bi-allelic variants in the GSTZ1 gene were identified in only eight individuals"
    explanation: Provides the published-case count from which the ultra-rare band is derived.
- population: Heidelberg newborn screening cohort, Germany, August 2016 to December 2020
  measure_type: BIRTH_PREVALENCE
  prevalence_class: BAND_1_9_PER_1000000
  rate_per_100000: 0.19
  rate_denominator: LIVE_BIRTHS
  notes: >
    One genetically confirmed case among 516,803 newborns screened for
    tyrosinemia type 1 gives approximately 0.19 per 100,000 live births. This is
    an ascertainment-limited detection rate, not a true birth prevalence: only
    infants exceeding the succinylacetone cut-off entered the diagnostic
    pathway, a second suspected case in the same cohort was never genetically
    resolved, and the cut-off was raised mid-study. Read it as a floor.
  evidence:
  - reference: PMID:38535121
    reference_title: "New Cases of Maleylacetoacetate Isomerase Deficiency with Detection by Newborn Screening and Natural History over 32 Years: Experience from a German Newborn Screening Center."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "A total of 516,803 children underwent NBS for HT1 at the NBS center in Heidelberg between August 2016 and December 2020."
    explanation: Gives the screening denominator behind the detection rate.
  - reference: PMID:38535121
    reference_title: "New Cases of Maleylacetoacetate Isomerase Deficiency with Detection by Newborn Screening and Natural History over 32 Years: Experience from a German Newborn Screening Center."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "MAAI deficiency was suspected in two cases and genetically confirmed in one who showed traces of succinylacetone in urine."
    explanation: Gives the numerator, and shows why it is a floor rather than a count.
clinical_burden:
  burden_level: LOW
  rationale: >
    No molecularly confirmed individual has developed disease. The Québec series
    of six went untreated with a normal course to 13 years; a German homozygote
    reached 32 years on an unrestricted diet including dairy and meat with normal
    liver and kidney chemistry; two Italian infants were well at 2 and 4 years,
    one of them after nitisinone and dietary restriction were withdrawn without
    consequence. The real burden is iatrogenic and informational rather than
    pathophysiological: a positive newborn screen for a lethal treatable disease,
    an interval of unnecessary nitisinone and protein restriction while
    tyrosinemia type 1 is excluded, and a lifelong surveillance recommendation
    whose necessity is unestablished. Recorded LOW rather than UNKNOWN because
    the observed burden across every confirmed case is genuinely low; the residual
    uncertainty about lifelong metabolite exposure is carried by a knowledge-gap
    discussion instead.
  evidence:
  - reference: PMID:27876694
    reference_title: "Hypersuccinylacetonaemia and normal liver function in maleylacetoacetate isomerase deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The six individuals with mild hypersuccinylacetonaemia (MHSA) were not treated with diet or nitisinone. Their clinical course has been normal for up to 13 years."
    explanation: The founding series establishes a normal untreated course over more than a decade.
  - reference: PMID:38535121
    reference_title: "New Cases of Maleylacetoacetate Isomerase Deficiency with Detection by Newborn Screening and Natural History over 32 Years: Experience from a German Newborn Screening Center."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The father was without obvious medical complaints at the age of 32 years and adhered to a regular diet including dairy and meat. He had never experienced episodes of liver disease or clinical decompensation despite having experienced several intercurrent infections."
    explanation: The longest natural history on record, on an unrestricted protein intake.
progression:
- phase: Newborn-screening ascertainment
  age_range: First days of life
  notes: >
    Detection is by an elevated dried-blood-spot succinylacetone on newborn
    screening for tyrosinemia type 1, with normal plasma tyrosine. Coagulation
    testing and liver enzymes are normal at referral, which is the observation
    that separates these infants from tyrosinemia type 1 at the bedside before
    any genetic result is available.
  evidence:
  - reference: PMID:27876694
    reference_title: "Hypersuccinylacetonaemia and normal liver function in maleylacetoacetate isomerase deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Six newborns referred for hypersuccinylacetonaemia but who had normal coagulation testing on initial evaluation had sequence variants in the GSTZ1 gene, encoding maleylacetoacetate isomerase (MAAI), the enzyme preceding FAH in tyrosine degradation."
    explanation: Defines the presenting picture and the normal-coagulation discriminator at referral.
- phase: Diagnostic interval
  age_range: Weeks to months after screening
  notes: >
    Until tyrosinemia type 1 is excluded, some infants are started on nitisinone
    and a tyrosine- and phenylalanine-restricted diet. In the reported Italian
    case this ran to 21 months before GSTZ1 sequencing allowed withdrawal.
    Succinylacetone in dried blood spots falls into the reference range on
    treatment and rises modestly again afterwards, without any accompanying
    change in tyrosine, transaminases, bilirubin, coagulation or renal
    parameters — so the treatment moves the marker without evidence of moving
    anything else.
  evidence:
  - reference: PMID:41009955
    reference_title: "Variants in GSTZ1 Gene Underlying Maleylacetoacetate Isomerase Deficiency: Characterization of Two New Individuals and Literature Review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Case 1 showed intermittent SA elevation; Nitisinone and dietary treatment were started, then discontinued after the identification of two variants in the GSTZ1 gene and the definitive diagnosis of MAAID."
    explanation: Documents the treat-then-withdraw course of the diagnostic interval.
  - reference: PMID:41009955
    reference_title: "Variants in GSTZ1 Gene Underlying Maleylacetoacetate Isomerase Deficiency: Characterization of Two New Individuals and Literature Review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The absence of clinical and biochemical deterioration after therapy withdrawal suggests that the intervention did not confer a measurable benefit in MAAID, at least during the follow-up period."
    explanation: Records the authors' reading of the withdrawal experiment.
- phase: Untreated long-term course
  age_range: Childhood through at least the fourth decade
  notes: >
    Longitudinal follow-up exists for only four individuals, spanning 10 to 32
    years, and has been unremarkable throughout. The oldest is a homozygous
    adult ascertained by cascade testing rather than screening, with normal
    renal function, transaminases, coagulation and alpha-fetoprotein, and
    undetectable urinary succinylacetone.
  evidence:
  - reference: PMID:38535121
    reference_title: "New Cases of Maleylacetoacetate Isomerase Deficiency with Detection by Newborn Screening and Natural History over 32 Years: Experience from a German Newborn Screening Center."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Our observation of natural history over 32 years adds evidence for a benign clinical course of MAAI deficiency without specific treatment."
    explanation: States the longest untreated natural history reported.
mechanistic_hypotheses:
- hypothesis_group_id: gsh_bypass_sufficiency
  hypothesis_label: A glutathione-dependent non-enzymatic bypass keeps the enzymatic block clinically silent
  status: CANONICAL
  description: >
    The accepted explanation for why loss of the penultimate enzyme of tyrosine
    catabolism is benign while loss of the final one is lethal. Glutathione
    binds maleylacetoacetate spontaneously and can isomerise it to
    fumarylacetoacetate without the enzyme, slowly but fast enough at the
    millimolar hepatic glutathione concentrations found in vivo. The bypass was
    shown directly in vitro, and inferred in vivo from Maai/Fah double-mutant
    mice, which die of a fumarylacetoacetate-driven phenotype that could only
    have arisen if maleylacetoacetate reached fumarylacetoacetate in the absence
    of the enzyme.
  evidence:
  - reference: PMID:12052898
    reference_title: "Maleylacetoacetate isomerase (MAAI/GSTZ)-deficient mice reveal a glutathione-dependent nonenzymatic bypass in tyrosine catabolism."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "A glutathione-mediated isomerization of MAA to FAA independent of MAAI enzyme was demonstrated in vitro. This nonenzymatic bypass is likely responsible for the lack of a phenotype in nonstressed MAAI mutant mice."
    explanation: The in vitro demonstration and the authors' attribution of the absent phenotype to it.
- hypothesis_group_id: bypass_saturation_toxicity
  hypothesis_label: The bypass is saturable, so substrate overload or glutathione depletion should be toxic
  status: EMERGING
  description: >
    A conditional-toxicity model derived entirely from the mouse. Because the
    non-enzymatic reaction is slow, it should fail when maleylacetoacetate
    production is raised or when glutathione is consumed — and in mice it does,
    producing hepatic and renal necrosis, leucopenia and death. Curated as
    EMERGING rather than CANONICAL because no human has been reported in that
    stressed state: the only long-term human observations are of unrestricted
    ordinary diets, which the mouse data would not predict to be dangerous
    either. The model is what motivates the standing advice to avoid protein
    supplements, dichloroacetate and glutathione-depleting drugs, so it is
    currently doing clinical work on animal evidence alone.
  evidence:
  - reference: PMID:12052898
    reference_title: "Maleylacetoacetate isomerase (MAAI/GSTZ)-deficient mice reveal a glutathione-dependent nonenzymatic bypass in tyrosine catabolism."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "A complete redundancy of MAAI could be ruled out because substrate overload of the tyrosine catabolic pathway (administration of homogentisic acid, phenylalanine, or tyrosine) resulted in renal and hepatic damage."
    explanation: Establishes the saturability of the bypass under substrate load in the mouse.
pathophysiology:
- name: Maleylacetoacetate isomerase deficiency
  role: trigger
  biological_scale: MOLECULAR
  description: >
    Biallelic GSTZ1 variants reduce maleylacetoacetate isomerase activity,
    blocking the glutathione-dependent isomerisation of maleylacetoacetate to
    fumarylacetoacetate — the step immediately upstream of fumarylacetoacetate
    hydrolase, whose loss causes tyrosinemia type 1. The pathway operates in
    hepatocytes and renal proximal tubular cells. Patient missense alleles have
    been expressed in bacteria and shown to retain only low activity, so the
    lesion is a genuine enzymatic deficiency rather than a regulatory or
    transport defect.
  genes:
  - preferred_term: GSTZ1
    term:
      id: hgnc:4643
      label: GSTZ1
  molecular_functions:
  - preferred_term: maleylacetoacetate isomerase activity
    term:
      id: GO:0016034
      label: maleylacetoacetate isomerase activity
    modifier: DECREASED
  biological_processes:
  - preferred_term: L-tyrosine catabolic process
    term:
      id: GO:0006572
      label: L-tyrosine catabolic process
    modifier: DECREASED
  locations:
  - preferred_term: liver
    term:
      id: UBERON:0002107
      label: liver
  - preferred_term: kidney
    term:
      id: UBERON:0002113
      label: kidney
  evidence:
  - reference: PMID:41009955
    reference_title: "Variants in GSTZ1 Gene Underlying Maleylacetoacetate Isomerase Deficiency: Characterization of Two New Individuals and Literature Review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Within the tyrosine degradation pathway, the enzyme catalyzes the isomerization of maleylacetoacetate (MAA) to fumarylacetoacetate (FAA), a step immediately upstream of fumarylacetoacetate hydrolase."
    explanation: Defines the reaction blocked by the lesion and fixes its position relative to the tyrosinemia type 1 step.
  - reference: PMID:27876694
    reference_title: "Hypersuccinylacetonaemia and normal liver function in maleylacetoacetate isomerase deficiency."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Bacterial expression of p.Ala150Val and p.Val99Met revealed low MAAI activity."
    explanation: Functional expression of patient alleles establishes reduced enzyme activity as the molecular consequence.
  downstream:
  - target: Maleylacetoacetate accumulation behind the block
    description: >
      Loss of the isomerase leaves its substrate unconsumed at the blocked step.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:41009955
      reference_title: "Variants in GSTZ1 Gene Underlying Maleylacetoacetate Isomerase Deficiency: Characterization of Two New Individuals and Literature Review."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Deficiency of this enzyme leads to the accumulation of upstream intermediates, including succinylacetone, a toxic metabolite traditionally regarded as pathognomonic for tyrosinemia type I."
      explanation: States that the enzyme block causes accumulation of the intermediates proximal to it.
- name: Maleylacetoacetate accumulation behind the block
  biological_scale: MOLECULAR
  description: >
    Maleylacetoacetate builds up in hepatocytes and renal tubular cells. This is
    the node where the disorder diverges from tyrosinemia type 1: at a matched
    plasma succinylacetone concentration, the predicted intracellular profile
    here is high maleylacetoacetate with low fumarylacetoacetate, whereas
    fumarylacetoacetate hydrolase deficiency predicts the reverse. Since
    fumarylacetoacetate is the strongly electrophilic species held responsible
    for hepatocyte and tubular injury in tyrosinemia type 1, the swap of which
    intermediate accumulates is the leading account of why the two disorders
    share a marker but not a phenotype. Note this is an inference from pathway
    position, not a measurement: neither intermediate is stable enough to have
    been quantified in human tyrosinemic liver.
  chemical_entities:
  - preferred_term: 4-maleylacetoacetate
    term:
      id: CHEBI:17105
      label: 4-maleylacetoacetate
    modifier: INCREASED
  - preferred_term: 4-fumarylacetoacetate
    term:
      id: CHEBI:18034
      label: 4-fumarylacetoacetate(2-)
    modifier: DECREASED
  locations:
  - preferred_term: liver
    term:
      id: UBERON:0002107
      label: liver
  evidence:
  - reference: PMID:29326876
    reference_title: "Mildly elevated succinylacetone and normal liver function in compound heterozygotes with pathogenic and pseudodeficient FAH alleles."
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: "At a similar level of plasma SA, MAAI deficiency is predicted to cause higher MAA in liver than FAH deficiency, but low levels of FAA."
    explanation: States the predicted intracellular metabolite swap that distinguishes this node from the tyrosinemia type 1 counterpart.
  - reference: PMID:29326876
    reference_title: "Mildly elevated succinylacetone and normal liver function in compound heterozygotes with pathogenic and pseudodeficient FAH alleles."
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: "The first three are reactive and labile, and have not been accurately measured in tyrosinemic liver. The relative toxicities of FAA and MAA are not known"
    explanation: States that the intracellular intermediates have never been measured and their relative toxicities are unknown, which is why the metabolite-swap account is curated as an inference rather than a direct toxicity claim.
  downstream:
  - target: Glutathione-dependent non-enzymatic isomerisation to fumarylacetoacetate
    description: >
      Accumulating maleylacetoacetate is bound by glutathione and slowly
      isomerised without the enzyme, so most of the flux still reaches
      fumarylacetoacetate.
    causal_link_type: DIRECT
    hypothesis_groups:
    - gsh_bypass_sufficiency
    evidence:
    - reference: PMID:12052898
      reference_title: "Maleylacetoacetate isomerase (MAAI/GSTZ)-deficient mice reveal a glutathione-dependent nonenzymatic bypass in tyrosine catabolism."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "A glutathione-mediated isomerization of MAA to FAA independent of MAAI enzyme was demonstrated in vitro."
      explanation: Direct in vitro demonstration that the substrate is isomerised without the enzyme.
  - target: Escape of succinylacetone and maleic acid into blood and urine
    description: >
      A minority fraction of maleylacetoacetate leaves the cell and is converted
      to the excreted metabolites that make the disorder detectable.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:12052898
      reference_title: "Maleylacetoacetate isomerase (MAAI/GSTZ)-deficient mice reveal a glutathione-dependent nonenzymatic bypass in tyrosine catabolism."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "MAAI-deficient mice accumulated FAA and succinylacetone in urine but appeared otherwise healthy."
      explanation: Shows the escaping fraction appearing in urine while the animal remains well.
- name: Glutathione-dependent non-enzymatic isomerisation to fumarylacetoacetate
  role: modifier
  biological_scale: MOLECULAR
  description: >
    Glutathione binds maleylacetoacetate spontaneously, and the bound adduct can
    rearrange to fumarylacetoacetate with no enzyme present. The reaction is slow
    and needs high glutathione — it is undetectable below 1 mM in vitro and
    approaches its maximum near 5 to 10 mM, against a measured hepatic
    glutathione concentration of 3 to 7 mM in both wild-type and mutant mice.
    This node, not any residual enzyme activity, is why the disorder is mild:
    mutant liver extracts contain no alternative isomerase, so the rescue is
    chemical rather than enzymatic. The strongest in vivo argument is the
    Maai/Fah double mutant, which dies of a fumarylacetoacetate-driven phenotype
    that could not exist unless maleylacetoacetate still reached
    fumarylacetoacetate without the enzyme.
  chemical_entities:
  - preferred_term: glutathione
    term:
      id: CHEBI:16856
      label: glutathione
  - preferred_term: 4-fumarylacetoacetate
    term:
      id: CHEBI:18034
      label: 4-fumarylacetoacetate(2-)
  locations:
  - preferred_term: liver
    term:
      id: UBERON:0002107
      label: liver
  evidence:
  - reference: PMID:12052898
    reference_title: "Maleylacetoacetate isomerase (MAAI/GSTZ)-deficient mice reveal a glutathione-dependent nonenzymatic bypass in tyrosine catabolism."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "MAAI enzyme activity was also completely obliterated, indicating that liver cell extracts did not contain an alternate enzyme capable of metabolizing MAA to FAA in the in vitro assay."
    explanation: Excludes a redundant enzyme, which is what forces the chemical rather than enzymatic interpretation of the bypass.
  - reference: PMID:12052898
    reference_title: "Maleylacetoacetate isomerase (MAAI/GSTZ)-deficient mice reveal a glutathione-dependent nonenzymatic bypass in tyrosine catabolism."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Mice doubly mutant for MAAI and fumarylacetoacetate hydrolase (FAH) died rapidly on a normal diet, indicating that MAA could be isomerized to FAA in the absence of MAAI."
    explanation: In vivo genetic evidence that flux still reaches fumarylacetoacetate without the enzyme.
  downstream:
  - target: Bypass saturation under substrate overload or glutathione depletion
    description: >
      Because the reaction is slow and glutathione-dependent, raising
      maleylacetoacetate production or consuming glutathione exhausts it.
    causal_link_type: DIRECT
    hypothesis_groups:
    - bypass_saturation_toxicity
    evidence:
    - reference: PMID:12052898
      reference_title: "Maleylacetoacetate isomerase (MAAI/GSTZ)-deficient mice reveal a glutathione-dependent nonenzymatic bypass in tyrosine catabolism."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "Our data showed clearly that hepatic GSH levels are essential for the MAAI bypass reaction."
      explanation: Establishes glutathione dependence as the saturable term.
- name: Escape of succinylacetone and maleic acid into blood and urine
  biological_scale: ORGANISM
  description: >
    The fraction of maleylacetoacetate that neither the enzyme nor the bypass
    handles leaves the cell and is reduced and decarboxylated to succinylacetone,
    while maleic acid appears in urine. Both are excreted markers rather than
    established effectors of injury in this disorder. The quantitative point
    carries the diagnosis: circulating succinylacetone here is roughly one to two
    orders of magnitude below untreated tyrosinemia type 1, and is often
    intermittent, dropping into the reference range on repeat sampling.
  chemical_entities:
  - preferred_term: succinylacetone
    term:
      id: CHEBI:87897
      label: 4,6-dioxoheptanoic acid
    modifier: INCREASED
  - preferred_term: maleic acid
    term:
      id: CHEBI:18300
      label: maleic acid
    modifier: INCREASED
  evidence:
  - reference: PMID:27876694
    reference_title: "Hypersuccinylacetonaemia and normal liver function in maleylacetoacetate isomerase deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Initial plasma SA levels ranged from 233 to 1282 nmol/L, greater than normal (<24 nmol/L) but less than the initial values of patients with HT1 (16 944-74 377 nmol/L, n=15)."
    explanation: Quantifies the escaping succinylacetone against both the normal range and tyrosinemia type 1.
  - reference: PMID:37545091
    reference_title: "Maleic acid is a biomarker for maleylacetoacetate isomerase deficiency; implications for newborn screening of tyrosinemia type 1."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Maleic acid was elevated in uOA of 5/7 false-positive newborns and in the three available samples of confirmed MAAI-D children, but not in TT1 patients."
    explanation: Establishes maleic acid as the second escaping metabolite and as specific to this block.
  downstream:
  - target: Mild hypersuccinylacetonaemia
    description: >
      The circulating marker on which newborn-screening ascertainment rests.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:41009955
      reference_title: "Variants in GSTZ1 Gene Underlying Maleylacetoacetate Isomerase Deficiency: Characterization of Two New Individuals and Literature Review."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "However, SA levels appear to be lower and/or discontinuously elevated in MAAID as compared to HT-1"
      explanation: Describes the magnitude and intermittency of the circulating marker.
  - target: Elevated urinary succinylacetone
    description: >
      Urinary succinylacetone may be only at trace levels, below the laboratory
      abnormal cut-off yet above what healthy urine contains.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:38535121
      reference_title: "New Cases of Maleylacetoacetate Isomerase Deficiency with Detection by Newborn Screening and Natural History over 32 Years: Experience from a German Newborn Screening Center."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "However, traces of succinylacetone as detected in this individual are usually not found in urine samples of healthy individuals analyzed with this method."
      explanation: Records the urinary finding and the sub-cut-off level at which it is still informative.
  - target: Elevated urinary maleic acid excretion
    description: >
      Urinary maleic acid rises well outside the control range and is the
      discriminating finding against tyrosinemia type 1.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:37545091
      reference_title: "Maleic acid is a biomarker for maleylacetoacetate isomerase deficiency; implications for newborn screening of tyrosinemia type 1."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Q-uMA ranged from not detectable to 1.16 mmol/mol creatinine in controls (n = 66) and from 0.95 to 192.06 mmol/mol creatinine in false-positive newborns and MAAI-D children (n = 10)."
      explanation: Quantifies the urinary maleic acid elevation against a control distribution.
- name: Bypass saturation under substrate overload or glutathione depletion
  biological_scale: MOLECULAR
  description: >
    A conditional state, established only in the mouse, in which the chemical
    rescue fails. It is reached by raising flux into the blocked step
    (homogentisic acid, phenylalanine or tyrosine loading, or simply a
    bean-and-lentil high-protein diet) or by consuming the co-substrate
    (diethylmaleate or phorone, and by extension glutathione-depleting drugs such
    as acetaminophen). Free maleylacetoacetate then accumulates. No human has
    been reported in this state, and the ordinary unrestricted human diets under
    which affected people have remained well are not obviously equivalent to any
    of the murine loading protocols — so this node is a prediction about humans,
    not an observation of them.
  chemical_entities:
  - preferred_term: 4-maleylacetoacetate
    term:
      id: CHEBI:17105
      label: 4-maleylacetoacetate
    modifier: INCREASED
  - preferred_term: glutathione
    term:
      id: CHEBI:16856
      label: glutathione
    modifier: DECREASED
  evidence:
  - reference: PMID:12052898
    reference_title: "Maleylacetoacetate isomerase (MAAI/GSTZ)-deficient mice reveal a glutathione-dependent nonenzymatic bypass in tyrosine catabolism."
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: MODEL_ORGANISM
    snippet: "Therefore, MAAI deficiency may manifest itself as hypersensitivity to GSH-depleting drugs, such as acetaminophen."
    explanation: States the glutathione-depletion arm of the saturating condition and its predicted pharmacological consequence.
  - reference: PMID:12052898
    reference_title: "Maleylacetoacetate isomerase (MAAI/GSTZ)-deficient mice reveal a glutathione-dependent nonenzymatic bypass in tyrosine catabolism."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "To simulate nutritional conditions experienced by mice in the wild, experimental animals were fed a diet consisting of beans and lentils, which are high in protein. Under these conditions, MAAI mutant mice also developed renal and hepatic injury and had reduced survival"
    explanation: Shows the substrate-load arm is reachable by ordinary dietary protein in the mouse, not only by pharmacological loading.
  downstream:
  - target: Hepatorenal injury and leucopenia in the saturated state
    description: >
      Once free maleylacetoacetate accumulates, tissue injury follows in the
      mouse, with the kidney as the predominant target.
    causal_link_type: DIRECT
    hypothesis_groups:
    - bypass_saturation_toxicity
    evidence:
    - reference: PMID:12052898
      reference_title: "Maleylacetoacetate isomerase (MAAI/GSTZ)-deficient mice reveal a glutathione-dependent nonenzymatic bypass in tyrosine catabolism."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "Double mutants showed predominant renal injury, indicating that this organ is the primary target for the accumulated compound(s) resulting from MAAI deficiency."
      explanation: Identifies the target organ of the accumulating compound in the saturated state.
- name: Hepatorenal injury and leucopenia in the saturated state
  biological_scale: TISSUE
  description: >
    The terminal node of the mouse-derived arm: renal epithelial vacuolization,
    apoptosis and necrosis with rising creatinine, hepatic necrosis and
    steatosis with rising transaminases, and — on high dietary phenylalanine —
    a rapid 60 percent fall in circulating white cells attributed to
    maleylacetoacetate or maleylacetone reaching the circulation. Nitisinone,
    which blocks the pathway two steps above, prevents it, confirming the
    injury is driven by flux through tyrosine catabolism rather than by the
    genotype as such. This node has no reported human counterpart and therefore
    carries no downstream phenotype in this entry; the prediction that it would
    present as renal tubular dysfunction or Fanconi syndrome remains untested.
  locations:
  - preferred_term: kidney
    term:
      id: UBERON:0002113
      label: kidney
  - preferred_term: liver
    term:
      id: UBERON:0002107
      label: liver
  evidence:
  - reference: PMID:19426674
    reference_title: "Phenylalanine-induced leucopenia in genetic and dichloroacetic acid generated deficiency of glutathione transferase Zeta."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Exposure of GSTZ1-1 deficient mice to high dietary phenylalanine causes a rapid loss of circulating white blood cells (WBCs)."
    explanation: Documents the haematological arm of the saturated-state injury.
  - reference: PMID:19426674
    reference_title: "Phenylalanine-induced leucopenia in genetic and dichloroacetic acid generated deficiency of glutathione transferase Zeta."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "The rapid loss of WBCs was attributed to the accumulation of the catabolic intermediates maleylacetoacetate or maleylacetone (MA) in the circulation."
    explanation: Attributes the leucopenia to the accumulating intermediate rather than to phenylalanine itself.
  - reference: PMID:12052898
    reference_title: "Maleylacetoacetate isomerase (MAAI/GSTZ)-deficient mice reveal a glutathione-dependent nonenzymatic bypass in tyrosine catabolism."
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: MODEL_ORGANISM
    snippet: "Therefore, the most likely manifestation of MAAI deficiency in humans would be renal tubular dysfunction or renal Fanconi syndrome."
    explanation: The authors' extrapolation to a human phenotype, recorded as indirect because it is a prediction from the murine target organ and has not been observed.
phenotypes:
- category: Biochemical
  name: Mild hypersuccinylacetonaemia
  description: >
    Circulating succinylacetone above the reference range but far below
    untreated tyrosinemia type 1, and frequently intermittent — normalising on
    repeat dried-blood-spot sampling in some infants. This is the entire
    consistent human phenotype of the disorder; no clinical abnormality has been
    reported alongside it in any molecularly confirmed individual.
  phenotype_term:
    preferred_term: Mild elevation of circulating succinylacetone
    term:
      id: HP:6001410
      label: Elevated circulating succinylacetone concentration
    severity: MILD
  evidence:
  - reference: PMID:27876694
    reference_title: "Hypersuccinylacetonaemia and normal liver function in maleylacetoacetate isomerase deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "MHSA can be caused by sequence variants in GSTZ1. Such individuals have thus far remained asymptomatic despite receiving no specific treatment."
    explanation: Names the biochemical phenotype and records that it is unaccompanied by clinical disease.
  - reference: PMID:37545091
    reference_title: "Maleic acid is a biomarker for maleylacetoacetate isomerase deficiency; implications for newborn screening of tyrosinemia type 1."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Elevated SA may also be due to maleylacetoacetate isomerase deficiency (MAAI-D), which appears to be clinically insignificant."
    explanation: Independently states that the succinylacetone elevation here carries no evident clinical significance.
- category: Biochemical
  name: Elevated urinary succinylacetone
  description: >
    Urine organic acid analysis shows succinylacetone, sometimes only as traces
    quantitatively below the laboratory's abnormal cut-off. Reported values in
    screened infants have ranged from traces to 2 mmol/mol creatinine against a
    cut-off of 1. In the 32-year-old homozygous adult, urinary succinylacetone
    was undetectable — so a negative urine result does not exclude the genotype.
  phenotype_term:
    preferred_term: Elevated urinary succinylacetone
    term:
      id: HP:6000598
      label: Elevated urinary succinylacetone level
  evidence:
  - reference: PMID:38535121
    reference_title: "New Cases of Maleylacetoacetate Isomerase Deficiency with Detection by Newborn Screening and Natural History over 32 Years: Experience from a German Newborn Screening Center."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "An analysis of urinary organic acids showed traces of succinylacetone in urine, quantitatively still below the cut-off of the laboratories' abnormal range (N < 1 mmol/mol creatinine)."
    explanation: Documents the urinary finding and its sub-cut-off magnitude in a confirmed case.
- category: Biochemical
  name: Elevated urinary maleic acid excretion
  description: >
    Urinary maleic acid is raised in maleylacetoacetate isomerase deficiency and
    not in tyrosinemia type 1, which makes it the discriminating analyte rather
    than merely another marker of the block. Bound to the broader HPO carboxylic
    acid concept because HPO has no term for maleic acid specifically.
  phenotype_term:
    preferred_term: Elevated urinary maleic acid
    term:
      id: HP:0031980
      label: Abnormal urine carboxylic acid level
    modifier: INCREASED
  diagnostic: true
  evidence:
  - reference: PMID:37545091
    reference_title: "Maleic acid is a biomarker for maleylacetoacetate isomerase deficiency; implications for newborn screening of tyrosinemia type 1."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Our study shows that MAAI-D is a recognizable cause of false-positive TT1 NBS results. Elevated urine maleic acid excretion seems highly effective in discriminating MAAI-D from TT1."
    explanation: Establishes both the finding and its discriminating value against tyrosinemia type 1.
biochemical:
- name: Plasma and dried-blood-spot succinylacetone
  presence: INCREASED
  specificity: LOW
  context: >
    The screening analyte. It is sensitive for the block but not specific to it:
    the same elevation is produced by fumarylacetoacetate hydrolase deficiency,
    including partial deficiency from the pseudodeficient p.Arg341Trp allele. The
    magnitude separates them in practice — hundreds of nmol/L here against tens of
    thousands in untreated tyrosinemia type 1 — but the ranges are a guide rather
    than a boundary, and nanomolar-range quantitation by GC-MS/MS is what makes
    the distinction analytically tractable.
  biomarker_term:
    preferred_term: succinylacetone
    term:
      id: CHEBI:87897
      label: 4,6-dioxoheptanoic acid
  evidence:
  - reference: PMID:27876694
    reference_title: "Hypersuccinylacetonaemia and normal liver function in maleylacetoacetate isomerase deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Initial plasma SA levels ranged from 233 to 1282 nmol/L, greater than normal (<24 nmol/L) but less than the initial values of patients with HT1 (16 944-74 377 nmol/L, n=15)."
    explanation: Gives the observed concentration range against the normal range and against tyrosinemia type 1.
  - reference: PMID:41767123
    reference_title: "Quantitative Succinylacetone Measurement by Gas Chromatography-Tandem Mass Spectrometry (GC-MS/MS) Facilitates Diagnosis, Monitoring, and Characterization of Tyrosinemia Type 1 and Other Hypersuccinylacetonemias."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "This assay facilitates laboratory diagnosis and monitoring of HT1, permits identification and characterization of other hypersuccinylacetonemias including maleylacetoacetate isomerase deficiency"
    explanation: Establishes that nanomolar-range quantitation is what allows this disorder to be characterised biochemically.
- name: Urinary maleic acid
  presence: INCREASED
  specificity: HIGH
  context: >
    Quantitative urinary maleic acid by LC-MS/MS separated confirmed cases from
    controls cleanly in the only study to measure it: undetectable to 1.16
    mmol/mol creatinine in 66 controls against 0.95 to 192.06 in ten
    screen-positive or confirmed children, and normal in tyrosinemia type 1.
    Genetic confirmation tracked the analyte in that series — the two
    normal-maleic-acid newborns were both genetically excluded.
  biomarker_term:
    preferred_term: maleic acid
    term:
      id: CHEBI:18300
      label: maleic acid
  evidence:
  - reference: PMID:37545091
    reference_title: "Maleic acid is a biomarker for maleylacetoacetate isomerase deficiency; implications for newborn screening of tyrosinemia type 1."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "MAAI-D was genetically confirmed in 4/7 false-positive newborns, all with elevated Q-uMA, and rejected in the two newborns with normal Q-uMA."
    explanation: Shows the analyte tracking the molecular diagnosis in both directions.
genetic:
- name: GSTZ1 deficiency
  gene_term:
    preferred_term: GSTZ1
    term:
      id: hgnc:4643
      label: GSTZ1
  inheritance:
  - name: Autosomal recessive
    description: Biallelic GSTZ1 variants are required; heterozygous carriers are unaffected.
    evidence:
    - reference: PMID:38535121
      reference_title: "New Cases of Maleylacetoacetate Isomerase Deficiency with Detection by Newborn Screening and Natural History over 32 Years: Experience from a German Newborn Screening Center."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Recently, biallelic pathogenic variants in GSTZ1 underlying maleylacetoacetate isomerase (MAAI) deficiency have been described as a differential diagnosis in individuals with slightly elevated succinylacetone detected by NBS."
      explanation: States the biallelic requirement and the clinical context in which the genotype is found.
  variants:
  - name: GSTZ1 missense variants
    description: >
      c.449C>T (p.Ala150Val) was homozygous in four of the six individuals in the
      founding Québec series and c.295G>A (p.Val99Met) was seen in a further
      individual; both retained only low activity on bacterial expression.
      p.Val99Met has since recurred in trans with a splicing allele in an Italian
      infant and is classified likely pathogenic.
    evidence:
    - reference: PMID:27876694
      reference_title: "Hypersuccinylacetonaemia and normal liver function in maleylacetoacetate isomerase deficiency."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "In one, a single heterozygous GSTZ1 sequence variant was identified, c.295G>A (p.Val99Met)."
      explanation: Documents the p.Val99Met allele in the founding series.
    - reference: PMID:41009955
      reference_title: "Variants in GSTZ1 Gene Underlying Maleylacetoacetate Isomerase Deficiency: Characterization of Two New Individuals and Literature Review."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "The genetic analysis highlighted the presence of the variants c.68-12G>A and c.295G>A, p.(Val99Met), in the GSTZ1 gene."
      explanation: Documents recurrence of the same missense allele in an unrelated case.
  - name: GSTZ1 splicing variants
    description: >
      Splicing alleles account for much of the reported molecular spectrum. A
      homozygous canonical acceptor-site change, c.136-2A>G, was found in a
      German consanguineous family and predicted to trigger nonsense-mediated
      decay. The deep-intronic c.68-12G>A, shared by two unrelated Italian
      infants, creates a cryptic acceptor: RNA from a patient showed retention of
      10 bp at the exon 2 to 3 junction, which upgraded the variant from
      uncertain significance to likely pathogenic and, by trans configuration,
      upgraded the partner allele with it.
    evidence:
    - reference: PMID:38535121
      reference_title: "New Cases of Maleylacetoacetate Isomerase Deficiency with Detection by Newborn Screening and Natural History over 32 Years: Experience from a German Newborn Screening Center."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "This variant is predicted to lead to a loss of the splice acceptor site in exon 4 and therefore to aberrant splicing and presumably the nonsense-mediated mRNA decay of abnormally spliced protein."
      explanation: Documents the canonical splice-acceptor allele and its predicted consequence.
    - reference: PMID:41009955
      reference_title: "Variants in GSTZ1 Gene Underlying Maleylacetoacetate Isomerase Deficiency: Characterization of Two New Individuals and Literature Review."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "To confirm this hypothesis, we carried out patient 1 RNA sequencing, which highlighted retention of 10 bp in the exon 2-3 junction, due to the creation of a cryptic splice site in position c.68-10 (Figure 2)."
      explanation: RNA-level functional evidence establishing the cryptic-acceptor mechanism of the recurrent intronic allele.
  - name: GSTZ1 nonsense variants
    description: >
      c.259C>T (p.Arg87Ter) was found in trans with an intronic variant in one
      individual of the founding series.
    evidence:
    - reference: PMID:27876694
      reference_title: "Hypersuccinylacetonaemia and normal liver function in maleylacetoacetate isomerase deficiency."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "One was compound heterozygous for c.259C>T (p.Arg87Ter) and an intronic sequence variant."
      explanation: Documents the reported nonsense allele and its compound heterozygous context.
  features: >
    GSTZ1 is bifunctional. Besides its tyrosine-pathway role it is the principal
    enzyme metabolising dichloroacetate, so GSTZ1 genotype is an established
    pharmacogenetic determinant in its own right — haplotype governs
    dichloroacetate clearance in healthy volunteers, and clinical genotyping is
    used to individualise dosing. That second function is why loss-of-function
    genotypes here carry a drug-exposure implication that is independent of, and
    better evidenced than, any disease risk from the metabolic block itself.
  evidence:
  - reference: PMID:41009955
    reference_title: "Variants in GSTZ1 Gene Underlying Maleylacetoacetate Isomerase Deficiency: Characterization of Two New Individuals and Literature Review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The GSTZ1 gene encodes maleylacetoacetate isomerase, a bifunctional enzyme that plays a critical role in both tyrosine catabolism and detoxification of xenobiotic compounds, such as dichloroacetate."
    explanation: Establishes the gene's second, xenobiotic-metabolising function.
  - reference: PMID:29641284
    reference_title: "Personalized Dosing of Dichloroacetate Using GSTZ1 Clinical Genotyping Assay."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Variation in the GSTZ1 haplotype is the principal variable influencing DCA kinetics and dynamics in humans."
    explanation: Quantifies the pharmacogenetic consequence of GSTZ1 variation in humans.
diagnosis:
- name: Newborn screening for dried-blood-spot succinylacetone
  description: >
    Ascertainment is a by-product of screening for tyrosinemia type 1. The
    finding that brings the infant to attention is an elevated succinylacetone
    with normal tyrosine; because the elevation is mild and sometimes
    intermittent, cut-off choice determines whether the disorder is seen at all.
  diagnosis_term:
    preferred_term: newborn screening
    term:
      id: NCIT:C81178
      label: Newborn Screening
  evidence:
  - reference: PMID:41009955
    reference_title: "Variants in GSTZ1 Gene Underlying Maleylacetoacetate Isomerase Deficiency: Characterization of Two New Individuals and Literature Review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Both cases displayed elevated SA and normal Tyrosine levels at newborn screening."
    explanation: Defines the screening finding that initiates the diagnostic pathway.
- name: Coagulation and liver function testing to exclude tyrosinemia type 1
  description: >
    Normal coagulation at initial evaluation is the first discriminator, since
    newborns with tyrosinemia type 1 are clinically asymptomatic but show
    coagulation abnormalities. It is a negative finding rather than a positive
    one, and does not by itself distinguish this disorder from partial
    fumarylacetoacetate hydrolase deficiency.
  diagnosis_term:
    preferred_term: laboratory procedure
    term:
      id: NCIT:C25294
      label: Laboratory Procedure
  evidence:
  - reference: PMID:27876694
    reference_title: "Hypersuccinylacetonaemia and normal liver function in maleylacetoacetate isomerase deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Newborns with HT1 are usually clinically asymptomatic but show liver dysfunction with coagulation abnormalities (prolonged prothrombin time and/or high international normalised ratio)."
    explanation: Establishes why normal coagulation is informative at referral.
- name: Quantitative urinary maleic acid
  description: >
    LC-MS/MS quantitation of urinary maleic acid, normalised to creatinine, is
    the positive biochemical test for this disorder and separated confirmed cases
    from tyrosinemia type 1 and from controls in the study that introduced it.
    Conventional urine organic acid analysis by GC-MS detects the same
    abnormality in most but not all cases.
  diagnosis_term:
    preferred_term: laboratory procedure
    term:
      id: NCIT:C25294
      label: Laboratory Procedure
  evidence:
  - reference: PMID:37545091
    reference_title: "Maleic acid is a biomarker for maleylacetoacetate isomerase deficiency; implications for newborn screening of tyrosinemia type 1."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "This study investigated whether urine organic acid (uOA) and quantitative urine maleic acid (Q-uMA) analyses can distinguish between TT1 and MAAI-D."
    explanation: Identifies the assay and the diagnostic question it was designed to answer.
- name: GSTZ1 molecular genetic testing
  description: >
    Confirmation requires biallelic GSTZ1 variants. Both a targeted two-gene
    FAH-plus-GSTZ1 approach and a five-gene hereditary tyrosinemia panel
    (HPD, FAH, TAT, HGD, GSTZ1) have been used; the panel shortened time to
    diagnosis from months to weeks in directly compared cases, which matters
    because the interval is when unnecessary treatment is given.
  diagnosis_term:
    preferred_term: genetic testing
    term:
      id: NCIT:C15709
      label: Genetic Testing
  evidence:
  - reference: PMID:41009955
    reference_title: "Variants in GSTZ1 Gene Underlying Maleylacetoacetate Isomerase Deficiency: Characterization of Two New Individuals and Literature Review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In case 2, the molecular testing was carried out by analysis of a multigene NGS (Next Generation Sequencing) panel, including the five genes associated with hereditary tyrosinemia (i.e., HPD, FAH, TAT, HGD, and GSTZ1)"
    explanation: Documents the panel-based confirmatory approach.
  - reference: PMID:41009955
    reference_title: "Variants in GSTZ1 Gene Underlying Maleylacetoacetate Isomerase Deficiency: Characterization of Two New Individuals and Literature Review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In Case 2, the final diagnosis was reached within a few weeks, making use of an NGS multigene panel."
    explanation: Records the time-to-diagnosis advantage over sequential single-gene sequencing.
differential_diagnoses:
- name: Tyrosinemia type 1
  description: >
    The disorder this one is mistaken for. Both raise succinylacetone; only
    tyrosinemia type 1 causes liver failure, and it requires nitisinone within
    the first month of life. Distinguished by the magnitude of the
    succinylacetone elevation, by coagulation testing at referral, by normal
    urinary maleic acid, and definitively by FAH sequencing.
  disease_term:
    preferred_term: tyrosinemia type I
    term:
      id: MONDO:0010161
      label: tyrosinemia type I
  distinguishing_features:
  - Succinylacetone in the tens of thousands of nmol/L rather than the hundreds
  - Coagulation abnormality at initial evaluation
  - Urinary maleic acid not elevated
  - Biallelic FAH rather than GSTZ1 variants
  evidence:
  - reference: PMID:37545091
    reference_title: "Maleic acid is a biomarker for maleylacetoacetate isomerase deficiency; implications for newborn screening of tyrosinemia type 1."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Maleic acid was elevated in uOA of 5/7 false-positive newborns and in the three available samples of confirmed MAAI-D children, but not in TT1 patients."
    explanation: Gives the analyte that separates the two disorders.
- name: Partial fumarylacetoacetate hydrolase deficiency (FAH pseudodeficiency)
  description: >
    The other cause of mild hypersuccinylacetonaemia, and the one that this
    entry's discriminators do not fully separate: compound heterozygotes for the
    prevalent p.Arg341Trp pseudodeficient FAH allele and a severe FAH allele have
    succinylacetone three- to fivefold above normal, normal coagulation, and have
    remained well untreated to 9 and 15 years. Only FAH and GSTZ1 sequencing
    distinguishes them with confidence.
  distinguishing_features:
  - Biallelic FAH variants including the c.1021C>T (p.Arg341Trp) pseudodeficient allele, rather than biallelic GSTZ1 variants
  - Urinary maleic acid predicted normal, though this has not been directly tested in that genotype
  evidence:
  - reference: PMID:29326876
    reference_title: "Mildly elevated succinylacetone and normal liver function in compound heterozygotes with pathogenic and pseudodeficient FAH alleles."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "All newborns identified with mild hypersuccinylacetonemia in Québec have had genetic deficiencies of tyrosine degradation: either deficiency of the enzyme preceding FAH, maleylacetoacetate isomerase, or partial deficiency of FAH itself."
    explanation: States the two-way differential for mild hypersuccinylacetonaemia.
treatments:
- name: Withholding nitisinone and dietary tyrosine restriction, with structured surveillance
  description: >
    The management decision in this disorder is a decision not to treat. Every
    reported cohort has been managed without nitisinone or protein restriction,
    or has had both withdrawn once GSTZ1 variants were found, with no clinical
    or biochemical deterioration afterwards. What replaces treatment is
    surveillance — regular clinical, biochemical and imaging review — plus advice
    to seek evaluation of liver function and clotting during severe intercurrent
    illness. Note the asymmetry that makes this hard in practice: withholding is
    correct only once tyrosinemia type 1 has been excluded, and until then the
    cost of treating unnecessarily is much lower than the cost of not treating
    tyrosinemia type 1.
  therapeutic_modality: OTHER
  treatment_term:
    preferred_term: clinical and biochemical surveillance without disease-directed therapy
  evidence:
  - reference: PMID:41009955
    reference_title: "Variants in GSTZ1 Gene Underlying Maleylacetoacetate Isomerase Deficiency: Characterization of Two New Individuals and Literature Review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "we suggest regular clinical, biochemical and imaging surveillance in MAAID."
    explanation: States the surveillance recommendation that stands in place of disease-directed therapy.
  - reference: PMID:41009955
    reference_title: "Variants in GSTZ1 Gene Underlying Maleylacetoacetate Isomerase Deficiency: Characterization of Two New Individuals and Literature Review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Our data are in line with previous sparse reports (Table 2), strengthening the observation that subjects with MAAID do not develop symptoms and arguing against the need to start any treatment."
    explanation: The authors' explicit argument against initiating treatment, which is the claim this entry records as management.
- name: Avoidance of dichloroacetate, glutathione-depleting drugs and protein supplements
  description: >
    A mechanism-derived precaution rather than a therapy. Because the
    non-enzymatic rescue consumes glutathione, and because GSTZ1 is itself the
    enzyme that detoxifies dichloroacetate, exposures that either deplete
    glutathione or load the blocked step are predicted to be the circumstances
    under which this disorder could become symptomatic. The advice is standing
    clinical guidance in the human literature but rests on the mouse for its
    mechanism; no human adverse event of this kind has been reported.
  therapeutic_modality: BEHAVIORAL
  treatment_term:
    preferred_term: avoidance of glutathione-depleting and pathway-loading exposures
  target_mechanisms:
  - target: Bypass saturation under substrate overload or glutathione depletion
    treatment_effect: INHIBITS
    description: >
      Removing glutathione-depleting drugs and pathway substrate load keeps the
      non-enzymatic isomerisation from being exhausted.
    evidence:
    - reference: PMID:29641284
      reference_title: "Personalized Dosing of Dichloroacetate Using GSTZ1 Clinical Genotyping Assay."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Dichloroacetate (DCA) represents the first targeted therapy for pyruvate dehydrogenase complex deficiency; it is metabolized by glutathione transferase zeta1 (GSTZ1)."
      explanation: Establishes in humans that dichloroacetate is cleared by the enzyme this disorder disables, which is the pharmacological rationale for avoiding it in this genotype.
    - reference: PMID:12052898
      reference_title: "Maleylacetoacetate isomerase (MAAI/GSTZ)-deficient mice reveal a glutathione-dependent nonenzymatic bypass in tyrosine catabolism."
      supports: SUPPORT
      directness: INDIRECT
      evidence_source: OTHER
      snippet: "It has been shown that DCA, a compound which is in clinical trials for the treatment of lactic acidosis, is detoxified by MAAI"
      explanation: >-
        Background attribution to prior work rather than a result of the mouse study
        this sentence appears in, so it is graded OTHER rather than MODEL_ORGANISM.
  evidence:
  - reference: PMID:41009955
    reference_title: "Variants in GSTZ1 Gene Underlying Maleylacetoacetate Isomerase Deficiency: Characterization of Two New Individuals and Literature Review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In confirmed MAAID cases, Yang et al. suggested avoiding protein supplements and some medications, such as acetaminophen, dichloroacetate (DCA) and chloralhydrate"
    explanation: Records the specific avoidance advice as given in the human clinical literature.
- name: Genetic counselling and cascade testing
  description: >
    Confirming the recessive genotype allows correct counselling and identifies
    homozygous relatives who would otherwise never be found — in the German
    family, cascade testing identified a 32-year-old homozygous father whose
    screening succinylacetone was within the reference range. Because the finding
    carries no treatment implication, the counselling content is largely
    reassurance plus the avoidance advice above.
  therapeutic_modality: OTHER
  treatment_term:
    preferred_term: genetic counseling
    term:
      id: NCIT:C15240
      label: Genetic Counseling
  evidence:
  - reference: PMID:38535121
    reference_title: "New Cases of Maleylacetoacetate Isomerase Deficiency with Detection by Newborn Screening and Natural History over 32 Years: Experience from a German Newborn Screening Center."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "MAAI has to be considered a rare differential diagnosis in NBS for HT1 in cases with slight elevations of succinylacetone to allow for correct counselling and treatment decisions."
    explanation: States that recognising the diagnosis is what enables correct counselling and treatment decisions.
discussions:
- discussion_id: maai_bypass_saturation_no_human_counterpart
  kind: HUMAN_MODEL_MISMATCH
  status: OPEN
  prompt: >
    Gstz1-null mice die of hepatic and renal necrosis on a high-protein diet of
    beans and lentils, yet a homozygous human adult ate an unrestricted diet
    including dairy and meat for 32 years without a single episode of hepatic
    decompensation. Does the murine substrate-overload arm describe a real human
    vulnerability at all, and if so at what exposure?
  rationale: >
    This is not an absence of evidence but a conflict between evidence in a model
    and evidence in humans, which is why it is curated as a model mismatch rather
    than a knowledge gap. The mouse result is robust and internally controlled —
    the injury is prevented by nitisinone, so it is genuinely flux-driven — and
    it is the sole mechanistic basis for the standing advice to avoid protein
    supplements, dichloroacetate and glutathione-depleting drugs. But the murine
    loading protocols are extreme relative to human intake, mouse chow is
    unusually low in phenylalanine and tyrosine so the baseline is not the human
    baseline, and mouse survival on high phenylalanine varied by sex and strain
    by an order of magnitude, which points to modifiers that have no human
    counterpart mapped. The strain effect reaches the baseline as well as the
    challenge: a second, independently derived null on BALB/c has hepatomegaly,
    renomegaly, splenic atrophy and multifocal hepatitis on ordinary chow, where
    the line that is healthy for 22 months has none of it. So the murine arm does
    not speak with one voice about what an unstressed null looks like, and its
    human extrapolation inherits that. Two readings remain open: either humans sit permanently
    below the saturation threshold under any realistic diet, or the threshold
    exists and no ascertained individual has yet crossed it. The nine people with
    clinical follow-up are far too few to distinguish these.
  attaches_to:
  - pathophysiology#Bypass saturation under substrate overload or glutathione depletion
  - pathophysiology#Hepatorenal injury and leucopenia in the saturated state
  proposed_experiments:
  - experiment_id: exp_maai_glutathione_stress_challenge
    name: Prospective biochemical monitoring of confirmed cases through glutathione-depleting exposures
    description: >
      Register-based prospective collection of paired succinylacetone, maleic
      acid, transaminase, creatinine and tubular-function measurements in
      molecularly confirmed individuals before and during naturally occurring
      glutathione-depleting exposures — therapeutic acetaminophen courses,
      febrile intercurrent illness, high-protein dietary periods — rather than
      any deliberate challenge.
    decision_criterion: >
      A reproducible rise in succinylacetone or maleic acid with concurrent
      tubular or hepatic markers during such exposures would establish that the
      murine saturation threshold is reachable in humans and would convert the
      avoidance advice from prediction to evidence. Stable metabolites and normal
      organ markers across the exposure range would argue that human glutathione
      turnover keeps the bypass unsaturated and that the advice is precautionary
      only.
  evidence:
  - reference: PMID:12052898
    reference_title: "Maleylacetoacetate isomerase (MAAI/GSTZ)-deficient mice reveal a glutathione-dependent nonenzymatic bypass in tyrosine catabolism."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Humans, at least in developed countries, are unlikely to experience nutritional stress severe enough to be affected by MAAI deficiency if this gene defect exists in the human population."
    explanation: The originating authors' own statement of the translational limit, written before any human case was known.
  - reference: PMID:38535121
    reference_title: "New Cases of Maleylacetoacetate Isomerase Deficiency with Detection by Newborn Screening and Natural History over 32 Years: Experience from a German Newborn Screening Center."
    supports: REFUTE
    evidence_source: HUMAN_CLINICAL
    snippet: "The father was without obvious medical complaints at the age of 32 years and adhered to a regular diet including dairy and meat. He had never experienced episodes of liver disease or clinical decompensation despite having experienced several intercurrent infections."
    explanation: The longest human observation refutes a dietary-protein vulnerability at ordinary intakes, which is the specific extrapolation the mouse invites.
- discussion_id: maai_lifelong_succinylacetone_exposure_unknown
  kind: KNOWLEDGE_GAP
  status: OPEN
  prompt: >
    Succinylacetone has been characterised as an oncometabolite in
    GSTZ1-deficient hepatocellular carcinoma models. Is decades of mild,
    intermittent succinylacetone exposure in constitutional maleylacetoacetate
    isomerase deficiency genuinely inert, and does the surveillance
    recommendation have any evidential basis?
  rationale: >
    Every human observation to date says the disorder is benign, and every
    observation to date is short. Only four individuals have longitudinal
    follow-up, the longest to 32 years, in a condition whose plausible harm —
    hepatocellular carcinoma — is a late outcome. Meanwhile, somatic
    GSTZ1-1 loss in hepatocellular carcinoma drives NRF2 activation through
    succinylacetone-mediated alkylation of KEAP1 and is described as
    tumour-promoting, and the same review that argues against treating this
    disorder notes that these cancer observations would argue for lowering
    succinylacetone. The two literatures have not been reconciled, and the
    difference between them may simply be somatic loss in a transformed
    hepatocyte versus lifelong constitutional loss with an intact bypass — but
    that is a hypothesis, not a finding. Concretely: the imaging surveillance now
    recommended has no reported yield, and no cohort large or old enough to
    estimate one exists.
  attaches_to:
  - pathophysiology#Escape of succinylacetone and maleic acid into blood and urine
  - treatments#Withholding nitisinone and dietary tyrosine restriction, with structured surveillance
  proposed_experiments:
  - experiment_id: exp_maai_international_registry_longitudinal_outcome
    name: International registry of molecularly confirmed cases with standardised long-term outcome capture
    description: >
      Pooling of confirmed GSTZ1 cases across newborn screening programmes with
      a common minimum dataset — periodic transaminases, alpha-fetoprotein,
      hepatic imaging and time-integrated succinylacetone — carried into adult
      life, since no single centre has enough cases to answer the question.
    decision_criterion: >
      Any excess of hepatic nodules, alpha-fetoprotein elevation or
      hepatocellular carcinoma over an age-matched expectation would justify the
      current surveillance and reopen the case for lowering succinylacetone.
      Event-free ageing across a registry-scale cohort would support
      de-escalating surveillance to reassurance.
  evidence:
  - reference: PMID:31267557
    reference_title: "GSTZ1-1 Deficiency Activates NRF2/IGF1R Axis in HCC via Accumulation of Oncometabolite Succinylacetone."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Mechanistically, GSTZ1-1 deficiency led to succinylacetone accumulation, alkylation modification of KEAP1, and NRF2 activation, thus promoting IGF1R transcription by recruiting SP1 to its promoter."
    explanation: Gives the mechanistic reason succinylacetone cannot simply be assumed inert, and is the basis for the gap.
  - reference: PMID:38535121
    reference_title: "New Cases of Maleylacetoacetate Isomerase Deficiency with Detection by Newborn Screening and Natural History over 32 Years: Experience from a German Newborn Screening Center."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "While this suggests a benign clinical course of MAAI deficiency without specific treatment, the long-term consequences of human MAAI deficiency are currently unknown"
    explanation: States the gap directly in the human literature.
- discussion_id: maai_unconfirmed_fatal_case
  kind: CONTROVERSY
  status: OPEN
  prompt: >
    A historical patient attributed to maleylacetoacetate isomerase deficiency
    died of hepatic and renal failure but was never molecularly confirmed. Should
    that case be counted when describing the phenotypic spectrum, or excluded as
    a probable misdiagnosis?
  rationale: >
    It matters because it is the only human report inconsistent with a benign
    course, and because the reasoning is circular in both directions. Excluding
    it on the grounds that confirmed cases are benign assumes the conclusion;
    including it risks importing a case that, on today's differential, could
    equally have been tyrosinemia type 1 or partial fumarylacetoacetate hydrolase
    deficiency — both of which were unavailable as diagnoses at the time and both
    of which produce the same succinylacetone elevation. This entry describes the
    disorder from molecularly confirmed cases only and records the unconfirmed
    case here rather than in the burden assessment, but that is a curation choice
    with consequences: it is what licenses the LOW burden level, and a single
    confirmed severe case would overturn it.
  attaches_to:
  - clinical_burden#
  evidence:
  - reference: PMID:41009955
    reference_title: "Variants in GSTZ1 Gene Underlying Maleylacetoacetate Isomerase Deficiency: Characterization of Two New Individuals and Literature Review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "While Berger et al. described one patient showing fatal hepatic and renal failure, for whom molecular confirmation was not available"
    explanation: Records the single discordant report and its lack of molecular confirmation.
notes: >
  Curated as IEMbase WP-002 row 1.4.06.01 (GSTZ1-related maleylacetoacetate
  isomerase deficiency). With this entry the distal tyrosine catabolic pathway
  is curated at every enzymatic step in dismech: TAT (Tyrosinemia_Type_II), HPD
  (Tyrosinemia_Type_III), HGD (Alkaptonuria), GSTZ1 (here) and FAH
  (Tyrosinemia_Type_I). The series is worth reading as a series, because
  severity does not track position in the pathway — it tracks the chemistry of
  what accumulates behind each block, and this step is the one where a
  non-enzymatic reaction removes most of what would otherwise accumulate.

  Hawkinsinuria (MONDO:0007700), the other HPD-allelic entity, is not curated
  here and is not a member of this disorder's differential; the differential in
  practice is a three-way one among tyrosinemia type 1, partial FAH deficiency
  and this disorder, all of which raise succinylacetone.

  The entry deliberately does not populate a neurological, hepatic or renal
  phenotype. Those appear in the mouse under substrate overload and are the
  subject of a HUMAN_MODEL_MISMATCH discussion, but asserting them as human
  phenotypes on murine evidence is exactly the error the evidence_source
  discipline exists to prevent.
experimental_models: []
animal_models:
- name: Gstz1/Maai-null mouse
  species: Mouse
  genotype: Targeted deletion of Maai (Gstz1), homozygous
  background: 129SvJ and C57BL/6
  publication: PMID:12052898
  genes:
  - preferred_term: GSTZ1
    term:
      id: hgnc:4643
      label: GSTZ1
  description: >
    The defining model of this disorder, and the one that supplied its mechanism
    before any human case was known. Homozygotes are enzymatically and
    immunologically null for maleylacetoacetate isomerase, are born at Mendelian
    ratios, and remain healthy for at least 22 months on standard chow with
    normal weight, fertility and histology and no tumours — while excreting
    fumarylacetoacetate and succinylacetone in urine. That combination is the
    human phenotype in miniature and is what makes the model unusually
    informative here. Under phenylalanine, tyrosine or homogentisic acid loading,
    a high-protein bean-and-lentil diet, or pharmacological glutathione
    depletion, the same animals develop hepatic necrosis and steatosis, renal
    epithelial vacuolisation, apoptosis and necrosis, and die; nitisinone
    prevents it.
  evidence:
  - reference: PMID:12052898
    reference_title: "Maleylacetoacetate isomerase (MAAI/GSTZ)-deficient mice reveal a glutathione-dependent nonenzymatic bypass in tyrosine catabolism."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Here, we describe the phenotype of mice with a targeted deletion of the MAAI (GSTZ1) gene."
    explanation: Establishes that the model carries a targeted lesion in the orthologous gene, which is what licenses treating it as informative for this disorder.
  modeled_mechanisms:
  - target: Maleylacetoacetate isomerase deficiency
    relationship: RECAPITULATES
    fidelity: HIGH
    model_scale: ORGANISM
    description: >-
      A germline null for the orthologous gene, with complete loss of enzyme
      protein and activity in liver and kidney.
    limitations: >-
      The lesion is a targeted whole-gene deletion, whereas the reported human
      genotypes are missense and splicing alleles with residual activity, so the
      model represents the severe end of the human allelic spectrum rather than
      its centre.
    readouts:
    - name: Hepatic maleylacetoacetate isomerase activity
      target: Maleylacetoacetate isomerase deficiency
      description: >-
        Enzyme assay of liver extracts from homozygous mutants, used both to
        confirm the null and to test for a redundant isomerase.
      direction: ABOLISHED
      interpretation: >-
        Complete loss of activity with no alternative activity detectable in the
        extract is what forces the chemical rather than enzymatic reading of the
        bypass.
      evidence:
      - reference: PMID:12052898
        reference_title: "Maleylacetoacetate isomerase (MAAI/GSTZ)-deficient mice reveal a glutathione-dependent nonenzymatic bypass in tyrosine catabolism."
        supports: SUPPORT
        evidence_source: IN_VITRO
        snippet: "MAAI enzyme activity was also completely obliterated, indicating that liver cell extracts did not contain an alternate enzyme capable of metabolizing MAA to FAA in the in vitro assay."
        explanation: Reports the enzyme measurement and its negative control for a redundant enzyme.
    evidence:
    - reference: PMID:12052898
      reference_title: "Maleylacetoacetate isomerase (MAAI/GSTZ)-deficient mice reveal a glutathione-dependent nonenzymatic bypass in tyrosine catabolism."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "This test showed a complete absence of MAAI (Fig.2C), consistent with deletion of the majority of the gene."
      explanation: Confirms loss of the protein itself, establishing the model as a null for this node.
  - target: Escape of succinylacetone and maleic acid into blood and urine
    relationship: PARTIALLY_RECAPITULATES
    fidelity: MODERATE
    model_scale: ORGANISM
    description: >-
      Mutants excrete both fumarylacetoacetate and succinylacetone in urine while
      remaining well, reproducing the central paradox of the human disorder — an
      abnormal metabolite profile without disease.
    limitations: >-
      Urinary maleic acid, which is the discriminating human analyte, was not
      measured in this study, so the model covers only the succinylacetone half
      of the node. Metabolite detection was qualitative by GC-MS and the
      concentrations are not comparable with the human nmol/L ranges on which the
      clinical distinction from tyrosinemia type 1 rests.
    readouts:
    - name: Urinary fumarylacetoacetate and succinylacetone
      target: Escape of succinylacetone and maleic acid into blood and urine
      description: >-
        GC-MS analysis of urine from homozygous mutants and wild-type controls.
      direction: INCREASED
      interpretation: >-
        Appearance of metabolites absent from control urine, in an animal with no
        clinical or histological abnormality, is the model's counterpart of mild
        hypersuccinylacetonaemia.
      evidence:
      - reference: PMID:12052898
        reference_title: "Maleylacetoacetate isomerase (MAAI/GSTZ)-deficient mice reveal a glutathione-dependent nonenzymatic bypass in tyrosine catabolism."
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: "GC-MS analysis of the urine from mutant mice showed the presence of both FAA and SA (Fig.3), compounds which are not present in normal controls."
        explanation: Reports the urinary measurement against controls.
    evidence:
    - reference: PMID:12052898
      reference_title: "Maleylacetoacetate isomerase (MAAI/GSTZ)-deficient mice reveal a glutathione-dependent nonenzymatic bypass in tyrosine catabolism."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "MAAI-deficient mice accumulated FAA and succinylacetone in urine but appeared otherwise healthy."
      explanation: Pairs the metabolite finding with the absence of disease, which is the claim this node makes.
  - target: Glutathione-dependent non-enzymatic isomerisation to fumarylacetoacetate
    relationship: MEASURES
    fidelity: MODERATE
    model_scale: MOLECULAR
    description: >-
      Liver extract from mutant mice, which contains no isomerase, was the assay
      system in which the glutathione-dependent reaction was titrated, and
      glutathione-depleting agents were used in vivo to remove it.
    limitations: >-
      The in vitro titration used murine liver extract and non-physiological
      glutathione-depleting agents (diethylmaleate, phorone); human hepatic
      glutathione concentrations and turnover were not measured, so the margin by
      which the human bypass operates above its 1 mM floor is unknown. This link
      is a molecular-scale measurement cited for a molecular-scale node, so it
      carries no scale extrapolation, but it does carry a species one.
    readouts:
    - name: In vitro conversion of maleylacetoacetate to fumarylacetoacetate versus glutathione concentration
      target: Glutathione-dependent non-enzymatic isomerisation to fumarylacetoacetate
      description: >-
        Titration of the non-enzymatic isomerisation rate against glutathione
        concentration in isomerase-free mutant liver extract, with dithiothreitol
        as a chemical comparator.
      direction: INCREASED
      interpretation: >-
        A reaction rate that rises with glutathione and is undetectable below
        1 mM defines the bypass as a saturable chemical reaction rather than a
        constitutive rescue.
      evidence:
      - reference: PMID:12052898
        reference_title: "Maleylacetoacetate isomerase (MAAI/GSTZ)-deficient mice reveal a glutathione-dependent nonenzymatic bypass in tyrosine catabolism."
        supports: SUPPORT
        evidence_source: IN_VITRO
        snippet: "GSH concentrations lower than 1 mM did not result in the chemical isomerization of MAA to FAA. However, higher concentrations of GSH increased the speed of the reaction until a maximal effect was achieved with 10 mM GSH."
        explanation: Reports the concentration-response measurement that defines the bypass.
    evidence:
    - reference: PMID:12052898
      reference_title: "Maleylacetoacetate isomerase (MAAI/GSTZ)-deficient mice reveal a glutathione-dependent nonenzymatic bypass in tyrosine catabolism."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "We were able to demonstrate the enzyme-independent bypass of MAAI activity by increasing the GSH concentration in the in vitro reaction using protein extract from MAAI mutant mouse liver"
      explanation: Establishes that this model is the system in which the bypass was demonstrated.
  - target: Bypass saturation under substrate overload or glutathione depletion
    relationship: PERTURBS
    fidelity: LOW
    model_scale: ORGANISM
    description: >-
      Homogentisic acid, phenylalanine or tyrosine loading, a high-protein
      bean-and-lentil diet, and glutathione depletion by diethylmaleate or
      phorone are the interventions that drive the animal into the saturated
      state; nitisinone rescues it, confirming the injury is flux-dependent.
    limitations: >-
      Fidelity is recorded LOW because the node it perturbs has no observed human
      counterpart: the loading protocols are far outside human dietary exposure,
      laboratory chow is unusually low in aromatic amino acids so the murine
      baseline is not the human one, and survival on high phenylalanine varied
      several-fold with sex and strain, implying modifiers that are unmapped in
      humans. The model establishes that the bypass is saturable in mice; it does
      not establish the human threshold, or that one is reachable.
    readouts:
    - name: Survival and hepatic and renal injury under phenylalanine loading
      target: Bypass saturation under substrate overload or glutathione depletion
      description: >-
        Survival, transaminases, creatinine and histopathology in mutants versus
        controls on phenylalanine-supplemented food or drinking water, with
        nitisinone as the rescue arm.
      direction: DECREASED
      interpretation: >-
        Dose-dependent lethality abolished by blocking the pathway upstream shows
        the injury is caused by flux into the blocked step rather than by the
        genotype itself.
      evidence:
      - reference: PMID:12052898
        reference_title: "Maleylacetoacetate isomerase (MAAI/GSTZ)-deficient mice reveal a glutathione-dependent nonenzymatic bypass in tyrosine catabolism."
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: "With the Phe diet, blood amino acid analysis showed no differences between wild-type and mutant mice, but liver function tests indicated hepatocellular damage (elevated transaminases) and renal injury (increased creatinine)"
        explanation: Reports the hepatic and renal injury measurements under phenylalanine loading, with amino acid levels unchanged.
      - reference: PMID:12052898
        reference_title: "Maleylacetoacetate isomerase (MAAI/GSTZ)-deficient mice reveal a glutathione-dependent nonenzymatic bypass in tyrosine catabolism."
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: "to the drinking water prevented this phenotype, demonstrating the relation of this phenotype and overloading of phenylalanine catabolic pathway."
        explanation: >-
          Records the nitisinone rescue arm: the quoted clause completes the sentence
          "Addition of NTBC ... to the drinking water prevented this phenotype", so what
          it establishes is that the injury depends on flux into the blocked step rather
          than on the genotype alone. The quote begins after the drug's chemical-name
          gloss, which is bracketed in the source and so cannot be carried verbatim.
    - name: Circulating white blood cell count under high dietary phenylalanine
      target: Bypass saturation under substrate overload or glutathione depletion
      description: >-
        Total white cell counts in Gstz1-null mice on high dietary phenylalanine,
        with splenocyte cytotoxicity assays of mutant serum as the mechanistic
        follow-up.
      direction: DECREASED
      interpretation: >-
        A 60 percent white cell loss within six days, reproduced by direct
        incubation of normal splenocytes with maleylacetone, identifies a
        circulating intermediate rather than phenylalanine as the toxic species.
      evidence:
      - reference: PMID:19426674
        reference_title: "Phenylalanine-induced leucopenia in genetic and dichloroacetic acid generated deficiency of glutathione transferase Zeta."
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: "The loss was significant (P<0.05) after 2 days and total WBCs were reduced by 60% after 6 days."
        explanation: Reports the haematological measurement and its magnitude.
    evidence:
    - reference: PMID:12052898
      reference_title: "Maleylacetoacetate isomerase (MAAI/GSTZ)-deficient mice reveal a glutathione-dependent nonenzymatic bypass in tyrosine catabolism."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "To simulate nutritional conditions experienced by mice in the wild, experimental animals were fed a diet consisting of beans and lentils, which are high in protein. Under these conditions, MAAI mutant mice also developed renal and hepatic injury and had reduced survival"
      explanation: Establishes that the saturated state is reachable by dietary protein alone in this model, which is what makes the link worth curating despite its low translational fidelity.
- name: Maai/Fah double-mutant mouse
  species: Mouse
  genotype: Maai (Gstz1) and Fah double homozygous null
  publication: PMID:12052898
  genes:
  - preferred_term: GSTZ1
    term:
      id: hgnc:4643
      label: GSTZ1
  description: >
    A genetic test of the bypass rather than a model of the disease. If
    maleylacetoacetate could not reach fumarylacetoacetate without the enzyme,
    removing fumarylacetoacetate hydrolase as well should have been harmless or
    protective; instead the double mutants died within about a week of nitisinone
    withdrawal, with severe liver and kidney injury and a marked creatinine rise
    and acute renal necrosis not seen in Fah-null animals. That is the strongest
    in vivo evidence that the non-enzymatic bypass operates, and it simultaneously
    shows that maleylacetoacetate deficiency generates a toxic species distinct
    from the fumarylacetoacetate of tyrosinemia type 1.
  evidence:
  - reference: PMID:12052898
    reference_title: "Maleylacetoacetate isomerase (MAAI/GSTZ)-deficient mice reveal a glutathione-dependent nonenzymatic bypass in tyrosine catabolism."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Mice doubly mutant for MAAI and fumarylacetoacetate hydrolase (FAH) died rapidly on a normal diet, indicating that MAA could be isomerized to FAA in the absence of MAAI."
    explanation: States the genotype and the inference it licenses about the bypass.
  modeled_mechanisms:
  - target: Glutathione-dependent non-enzymatic isomerisation to fumarylacetoacetate
    relationship: PERTURBS
    fidelity: MODERATE
    model_scale: ORGANISM
    description: >-
      Removing the downstream hydrolase converts the products of the bypass into
      a lethal readout, so the double mutant reports on whether the bypass is
      carrying flux.
    limitations: >-
      The genotype has no human counterpart — no person carries biallelic null
      alleles at both loci — so this model speaks only to the existence of the
      bypass and not to any human phenotype. Its severe renal necrosis is
      evidence about maleylacetoacetate toxicity in a doubly blocked pathway, and
      must not be read as a prediction for constitutional GSTZ1 deficiency, where
      the hydrolase is intact.
    readouts:
    - name: Plasma creatinine and renal histology in double mutants
      target: Glutathione-dependent non-enzymatic isomerisation to fumarylacetoacetate
      description: >-
        Blood chemistry and kidney histopathology in Maai/Fah double mutants
        compared with Fah single mutants after nitisinone withdrawal.
      direction: INCREASED
      interpretation: >-
        Renal injury exceeding that of Fah-null animals shows the double mutant
        accumulates something the single mutant does not, which is the signature
        of maleylacetoacetate rather than fumarylacetoacetate.
      evidence:
      - reference: PMID:12052898
        reference_title: "Maleylacetoacetate isomerase (MAAI/GSTZ)-deficient mice reveal a glutathione-dependent nonenzymatic bypass in tyrosine catabolism."
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: "The marked elevation of plasma creatinine indicated severe renal glomerular dysfunction, a phenotype not seen in FAH-deficient animals."
        explanation: Reports the measurement distinguishing the double mutant from the single mutant.
    evidence:
    - reference: PMID:12052898
      reference_title: "Maleylacetoacetate isomerase (MAAI/GSTZ)-deficient mice reveal a glutathione-dependent nonenzymatic bypass in tyrosine catabolism."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "First, there is a bypass for MAAI activity in hepatocytes and renal tubular cells."
      explanation: The authors' conclusion from this genotype, which is the claim the link records.
- name: Gstz1-null BALB/c mouse
  species: Mouse
  genotype: Gstz1 homozygous null on a BALB/c background
  publication: PMID:15277241
  genes:
  - preferred_term: GSTZ1
    term:
      id: hgnc:4643
      label: GSTZ1
  description: >
    An independently derived germline Gstz1 deletion, on a different genetic
    background from the model above, and the reason the "unstressed null mouse is
    well" reading cannot be taken as general. On standard chow these animals have
    enlarged liver and kidneys, splenic atrophy, multifocal hepatitis and renal
    ultrastructural change, with constitutive induction of alpha, mu and pi class
    glutathione transferases and NQO1 — an antioxidant response consistent with
    chronic accumulation of a toxic metabolite rather than with a silent block.
    Phenylalanine loading then reproduces the same lethality, hepatic necrosis,
    steatosis, splenic atrophy and leucopenia seen in the other line, with animals
    under 28 days old dying. The strain discrepancy at baseline is itself the
    finding: whether the bypass suffices appears to be modifier-dependent in mice,
    which is one reason the murine arm is not read as a prediction for humans.
  evidence:
  - reference: PMID:15277241
    reference_title: "Mice deficient in glutathione transferase zeta/maleylacetoacetate isomerase exhibit a range of pathological changes and elevated expression of alpha, mu, and pi class glutathione transferases."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "In this study we have deleted the Gstz1 gene in BALB/c mice and characterized their phenotype."
    explanation: Establishes that this is a second, independently derived germline null in the orthologous gene, which is what makes the strain comparison meaningful.
  modeled_mechanisms:
  - target: Hepatorenal injury and leucopenia in the saturated state
    relationship: PARTIALLY_RECAPITULATES
    fidelity: LOW
    model_scale: TISSUE
    description: >-
      Reproduces the hepatic, renal, splenic and leucocyte injury of the
      saturated state, and reproduces its phenylalanine dependence, but reaches
      part of it without any loading at all.
    limitations: >-
      Baseline organ pathology on ordinary chow is not what this node describes:
      the node is defined by bypass saturation under overload, and this strain
      shows hepatomegaly, renomegaly, splenic atrophy and multifocal hepatitis
      without it. That makes the finding strain- rather than genotype-determined
      in the mouse, since the line in the entry above is healthy for 22 months on
      the same kind of diet. Neither baseline state has a human counterpart —
      no ascertained person has hepatic, renal or splenic pathology — so this
      link constrains the murine arm rather than extending it to humans.
    divergences:
    - divergence_type: POPULATION_MISMATCH
      materiality: QUALIFYING
      description: >-
        The two published Gstz1-null lines disagree at baseline on ordinary chow,
        so the murine baseline phenotype tracks genetic background. Which
        background, if either, corresponds to the human modifier landscape is
        unknown.
    - divergence_type: SPECIES_MISMATCH
      materiality: QUALIFYING
      description: >-
        Mouse chow is unusually low in phenylalanine and tyrosine relative to
        ordinary human intake, so "standard diet" in this model is not the same
        exposure as the unrestricted human diets under which affected people have
        remained well.
    readouts:
    - name: Liver, kidney and spleen morphology on standard chow
      target: Hepatorenal injury and leucopenia in the saturated state
      description: >-
        Organ weights plus light and electron microscopy of liver and kidney in
        unchallenged homozygous nulls fed a standard diet.
      direction: ALTERED
      interpretation: >-
        Pathology in the absence of any substrate load is the observation that
        separates this line from the other, and is why the saturation account is
        curated as a hypothesis rather than as settled.
      evidence:
      - reference: PMID:15277241
        reference_title: "Mice deficient in glutathione transferase zeta/maleylacetoacetate isomerase exhibit a range of pathological changes and elevated expression of alpha, mu, and pi class glutathione transferases."
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: "When fed a standard diet, the GSTZ1-1-deficient mice showed enlarged liver and kidneys as well as splenic atrophy. Light and electron microscopic examination revealed multifocal hepatitis and ultrastructural changes in the kidney."
        explanation: Reports the unchallenged organ pathology, which is the measurement this link turns on.
    - name: Circulating leukocyte count and hepatic histology under phenylalanine loading
      target: Hepatorenal injury and leucopenia in the saturated state
      description: >-
        Survival, liver histology and leukocyte counts after 3 percent
        phenylalanine in the drinking water, in young and older animals.
      direction: DECREASED
      interpretation: >-
        Independent replication of the loading phenotype in a second line, with
        an age dependence the first study did not report.
      evidence:
      - reference: PMID:15277241
        reference_title: "Mice deficient in glutathione transferase zeta/maleylacetoacetate isomerase exhibit a range of pathological changes and elevated expression of alpha, mu, and pi class glutathione transferases."
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: "The addition of 3% (w/v) phenylalanine to the drinking water was lethal for young mice (<28 days old) and caused liver necrosis, macrovesicular steatosis, splenic atrophy, and a significant loss of circulating leukocytes in older surviving mice."
        explanation: Replicates the substrate-overload injury and its haematological arm in an independent line.
    evidence:
    - reference: PMID:15277241
      reference_title: "Mice deficient in glutathione transferase zeta/maleylacetoacetate isomerase exhibit a range of pathological changes and elevated expression of alpha, mu, and pi class glutathione transferases."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "The overall response is consistent with the chronic accumulation of a toxic metabolite(s). We detected the accumulation of succinylacetone in the serum of deficient mice but cannot exclude the possibility that maleylacetoacetate and maleylacetone may also accumulate."
      explanation: The authors' own reading of the baseline phenotype as metabolite-driven, which is what makes this line informative for the injury node rather than merely an incidental strain difference.
computational_models: []
datasets: []
review_notes: >
  Curated from eleven cached PubMed references anchored to MONDO:0060527 and GSTZ1
  (hgnc:4643). Identity was confirmed before curation: MONDO:0060527
  cross-references OMIM:617596, MEDGEN:713903 and UMLS:C1291607, matching IEMbase
  WP-002 row 1.4.06.01 (GSTZ1, OMIM 617596) exactly. No named-entity confusion
  against the other tyrosine-pathway entities, all of which are separate MONDO
  terms on separate genes. Every evidence snippet is an exact substring of the
  cached record for its PMID.

  The graph is deliberately shaped around a negative claim. The disorder's
  mechanistic interest is that a block immediately upstream of the tyrosinemia
  type 1 lesion is not disease, so the central node is the glutathione-dependent
  non-enzymatic bypass, and the injury nodes downstream of bypass saturation are
  fenced into a separate EMERGING hypothesis group carrying only model-organism
  and in vitro evidence. No human phenotype is attached below that fence. The
  metabolite-swap account of why the two disorders differ (high maleylacetoacetate
  with low fumarylacetoacetate here, the reverse in tyrosinemia type 1) is curated
  with an INDIRECT evidence item quoting the source's own statement that these
  intermediates have never been measured in human tyrosinemic liver, because it is
  a pathway-position inference rather than a measurement.

  Three animal models are curated as separate entries because they answer
  different questions. Two come from the same 2002 study: the Gstz1-null mouse, a
  high-fidelity model of the enzyme block and of the metabolite-abnormality-without-disease
  phenotype, and the Maai/Fah double mutant, which is not a model of this disease
  at all but the genetic experiment that demonstrated the bypass — recorded as
  PERTURBS at MODERATE fidelity with an explicit limitation that its severe renal
  phenotype must not be read as a prediction for constitutional GSTZ1 deficiency.
  The third is the independently derived BALB/c null (PMID:15277241), added
  because it contradicts the first at baseline: it has organ pathology on ordinary
  chow where the other is healthy for 22 months. It is linked at LOW fidelity with
  a POPULATION_MISMATCH divergence, and its value here is that it stops the murine
  arm being read as one consistent prediction about unstressed nulls. No non-animal
  experimental model, computational model, or dataset with an evidence-supported
  mechanism link was identified, so those sections are empty rather than
  speculatively populated.

  Two treatments carry no ontology binding. NCIT roots TreatmentTerm at
  NCIT:C25218 (Clinical Intervention or Procedure), and neither structured
  non-treatment surveillance nor exposure avoidance has a term below that root
  that is not a distortion — the same conclusion reached for surveillance in
  Congenital_Laryngomalacia and ReNU_Syndrome, where NCIT:C15719 and NCIT:C15722
  were both rejected. Free-text preferred_term is used instead, per the ontology
  term contract's preference for no term over a bad one.

  Phenotype frequencies are omitted throughout: with fewer than twenty reported
  individuals and nine with clinical follow-up, no denominator is defensible.
references:
- reference: PMID:27876694
  title: "Hypersuccinylacetonaemia and normal liver function in maleylacetoacetate isomerase deficiency."
- reference: PMID:37545091
  title: "Maleic acid is a biomarker for maleylacetoacetate isomerase deficiency; implications for newborn screening of tyrosinemia type 1."
- reference: PMID:38535121
  title: "New Cases of Maleylacetoacetate Isomerase Deficiency with Detection by Newborn Screening and Natural History over 32 Years: Experience from a German Newborn Screening Center."
- reference: PMID:41009955
  title: "Variants in GSTZ1 Gene Underlying Maleylacetoacetate Isomerase Deficiency: Characterization of Two New Individuals and Literature Review."
- reference: PMID:41767123
  title: "Quantitative Succinylacetone Measurement by Gas Chromatography-Tandem Mass Spectrometry (GC-MS/MS) Facilitates Diagnosis, Monitoring, and Characterization of Tyrosinemia Type 1 and Other Hypersuccinylacetonemias."
- reference: PMID:29326876
  title: "Mildly elevated succinylacetone and normal liver function in compound heterozygotes with pathogenic and pseudodeficient FAH alleles."
- reference: PMID:12052898
  title: "Maleylacetoacetate isomerase (MAAI/GSTZ)-deficient mice reveal a glutathione-dependent nonenzymatic bypass in tyrosine catabolism."
- reference: PMID:19426674
  title: "Phenylalanine-induced leucopenia in genetic and dichloroacetic acid generated deficiency of glutathione transferase Zeta."
- reference: PMID:29641284
  title: "Personalized Dosing of Dichloroacetate Using GSTZ1 Clinical Genotyping Assay."
- reference: PMID:31267557
  title: "GSTZ1-1 Deficiency Activates NRF2/IGF1R Axis in HCC via Accumulation of Oncometabolite Succinylacetone."
- reference: PMID:15277241
  title: "Mice deficient in glutathione transferase zeta/maleylacetoacetate isomerase exhibit a range of pathological changes and elevated expression of alpha, mu, and pi class glutathione transferases."

📚

References & Deep Research

References

11

PMID:27876694

Hypersuccinylacetonaemia and normal liver function in maleylacetoacetate isomerase deficiency.

No top-level findings curated for this source.

PMID:37545091

Maleic acid is a biomarker for maleylacetoacetate isomerase deficiency; implications for newborn screening of tyrosinemia type 1.

No top-level findings curated for this source.

PMID:38535121

New Cases of Maleylacetoacetate Isomerase Deficiency with Detection by Newborn Screening and Natural History over 32 Years: Experience from a German Newborn Screening Center.

No top-level findings curated for this source.

PMID:41009955

Variants in GSTZ1 Gene Underlying Maleylacetoacetate Isomerase Deficiency: Characterization of Two New Individuals and Literature Review.

No top-level findings curated for this source.

PMID:41767123

Quantitative Succinylacetone Measurement by Gas Chromatography-Tandem Mass Spectrometry (GC-MS/MS) Facilitates Diagnosis, Monitoring, and Characterization of Tyrosinemia Type 1 and Other Hypersuccinylacetonemias.

No top-level findings curated for this source.

PMID:29326876

Mildly elevated succinylacetone and normal liver function in compound heterozygotes with pathogenic and pseudodeficient FAH alleles.

No top-level findings curated for this source.

PMID:12052898

Maleylacetoacetate isomerase (MAAI/GSTZ)-deficient mice reveal a glutathione-dependent nonenzymatic bypass in tyrosine catabolism.

No top-level findings curated for this source.

PMID:19426674

Phenylalanine-induced leucopenia in genetic and dichloroacetic acid generated deficiency of glutathione transferase Zeta.

No top-level findings curated for this source.

PMID:29641284

Personalized Dosing of Dichloroacetate Using GSTZ1 Clinical Genotyping Assay.

No top-level findings curated for this source.

PMID:31267557

GSTZ1-1 Deficiency Activates NRF2/IGF1R Axis in HCC via Accumulation of Oncometabolite Succinylacetone.

No top-level findings curated for this source.

PMID:15277241

Mice deficient in glutathione transferase zeta/maleylacetoacetate isomerase exhibit a range of pathological changes and elevated expression of alpha, mu, and pi class glutathione transferases.

No top-level findings curated for this source.

Deep Research

1

Deep research results are used as seeds for research; they do not undergo the same validation as the main records and may contain errors. How we use deep research.

Evaluations and curation notes (1)

Review round: answer the #11212 review findings and add the deep-research artifact · 2026-09-09T16:16:49Z · View source

Answered the four blocking findings on PR #11212 in a single push. (1) Added the missing deep-research artifact: research/Maleylacetoacetate_Isomerase_Deficiency-deep-research-falcon.md plus its .citations.md sidecar and _artifacts/ directory, generated with just research-disorder falcon (claude_code is unauthenticated on this runner; the openai provider 404s on o3-deep-research-2025-06-26). The report's own validation sections record 10/12 references verified with a 0.0 confabulation rate and 15/15 terms verified. (2) Added reference_title to the twelve evidence items that lacked it, all inside animal_models[].modeled_mechanisms[] and its nested readouts[].evidence; each title was read out of the corresponding references_cache frontmatter by script rather than transcribed. (3) Corrected the ordinal error: MAAI is the fourth step of tyrosine catabolism, not the fifth, so the ordinal was dropped in favour of 'the step immediately upstream of fumarylacetoacetate hydrolase'. (4) Fixed the claim-evidence misalignment on the NTBC rescue evidence for PMID:12052898. The review's proposed leftward extension does not validate, because conf/reference_validator_config.yaml strips bracketed spans from the snippet and the chemical-name gloss matches neither literal_bracket_patterns entry; the snippet instead starts after the bracket and the explanation names the sentence it completes. All four suggestions were also taken: directness INDIRECT on the two predictive evidence items, the DCA background sentence regraded from MODEL_ORGANISM to OTHER with a human-clinical PMID:29641284 item added ahead of it so the avoidance advice no longer rests on a mouse paper's background clause, modifier INCREASED on the HP:0031980 urinary maleic acid binding, and biological_scale MOLECULAR rather than ORGANISM on the bypass-saturation node. The deep-research cross-check the review asked to be made possible then surfaced a real content gap, so a third animal model was curated: the independently derived Gstz1-null BALB/c line (PMID:15277241), which has hepatomegaly, renomegaly, splenic atrophy and multifocal hepatitis on standard chow where the existing line is healthy for 22 months. It is linked PARTIALLY_RECAPITULATES at LOW fidelity with POPULATION_MISMATCH and SPECIES_MISMATCH divergences, and the HUMAN_MODEL_MISMATCH discussion rationale now records that the murine baseline is strain-dependent. Also resolved the branch's single merge conflict, in cache/hgnc/terms.csv, by keeping both rows in canonical CURIE order. Validation on the merged tree: just validate PASS with 85/85 snippets verified; validate-terms, check-reference-titles, check-duplicate-keys, check-entity-refs, check-causal-targets, check-qualifier-terms, check-enum-values, check-snippet-length, check-title-snippets, check-snippet-grading, check-folded-hyphens, check-environmental-evidence, check-reference-cache-frontmatter, check-term-cache-integrity, check-cache-order all PASS; model-scale-audit --strict exits 0.

Falcon ▸

Maleylacetoacetate Isomerase Deficiency: Comprehensive Disease Report

Edison Scientific Literature 29 citations 2026-09-09T16:06:52.902756

Maleylacetoacetate Isomerase Deficiency: Comprehensive Disease Report

Executive summary

Maleylacetoacetate isomerase deficiency (MAAID) is an ultra-rare autosomal-recessive disorder of phenylalanine/tyrosine degradation caused by biallelic loss-of-function variants in GSTZ1. It is usually detected incidentally by newborn screening (NBS) as mild or intermittent succinylacetone elevation. Unlike FAH-related hereditary tyrosinemia type I (HT1), currently documented MAAID is predominantly an asymptomatic biochemical trait: reported individuals generally have normal tyrosine, hepatic function, renal function, coagulation, growth, and neurodevelopment. Nevertheless, fewer than 20 individuals have been reported, so penetrance, lifetime prognosis, and responses to severe metabolic stress remain uncertain. The strongest recent developments are urinary maleic acid as a potential second-tier biomarker (2023) and a 2024 German NBS study documenting an untreated, clinically benign course in a homozygous adult through age 32. (gramer2024newcasesof pages 1-2, barretta2025variantsingstz1 pages 1-2, barretta2025variantsingstz1 pages 9-11)

Domain	Best-supported finding	Evidence type	Certainty / gap
Identity	Maleylacetoacetate isomerase deficiency (MAAID; GSTZ1/MAAI deficiency), MONDO:0060527 and OMIM phenotype #617596, is caused by deficient glutathione S-transferase zeta 1/maleylacetoacetate isomerase encoded by GSTZ1. (OpenTargets Search: Maleylacetoacetate isomerase deficiency-GSTZ1, gramer2024newcasesof pages 2-4)	Curated disease–gene association; human molecular cases	High-confidence identity and gene association; no disease-specific ICD or MeSH identifier was established in the gathered evidence.
Inheritance	Biallelic GSTZ1 variants cause autosomal-recessive MAAID. Homozygous and compound-heterozygous individuals have been reported; segregation was demonstrated in multiple families. (barretta2025variantsingstz1 pages 5-8, gramer2024newcasesof pages 2-4)	Human pedigrees and molecular testing	High confidence for autosomal-recessive inheritance; penetrance cannot be quantified and appears low for overt clinical disease.
Biochemical phenotype	Mild, persistent or intermittent elevation of succinylacetone is the principal finding, often with normal tyrosine, liver tests and coagulation. Quantitative urinary maleic acid is elevated in reported genetically confirmed cases and may distinguish MAAID from tyrosinemia type I. (gramer2024newcasesof pages 5-7, barretta2025variantsingstz1 pages 9-11)	Human newborn-screening and biomarker studies	Strong evidence for mild hypersuccinylacetonemia; maleic acid is promising but its assay, stability, reference intervals and dried-blood-spot implementation remain insufficiently standardized.
Clinical phenotype and natural history	Most molecularly confirmed individuals have been asymptomatic. Reported follow-up includes untreated children without liver or neurologic complications and an untreated homozygous adult clinically well at age 32; isolated microcephaly, short stature, obesity and mild hyperbilirubinemia have been reported without proof that they are disease-caused. (gramer2024newcasesof pages 4-5, barretta2025variantsingstz1 pages 1-2, barretta2025variantsingstz1 pages 8-9)	Small human case series and family follow-up	Evidence favors a benign or predominantly biochemical phenotype, but fewer than 20 individuals have been reported and long-term surveillance is sparse.
2024 screening statistics	In Heidelberg, 516,803 newborns were screened during August 2016–December 2020. Among 42 elevated-succinylacetone screens, two had tyrosinemia type I, two were suspected of MAAID and one MAAID case was genetically confirmed; the index value was 2.61 µmol/L. (gramer2024newcasesof pages 1-2, gramer2024newcasesof pages 2-4)	Large regional newborn-screening cohort	Reliable center-level data, not a population prevalence estimate; ascertainment depends on assay and cutoff.
Diagnostics and differential	After elevated succinylacetone, confirm with repeat dried-blood-spot/plasma testing, urine organic acids or quantitative maleic acid, liver/coagulation studies, and molecular testing. Exclude FAH-related tyrosinemia type I first, then analyze GSTZ1 by single-gene testing, a tyrosinemia panel, exome or genome sequencing. (barretta2025variantsingstz1 pages 2-4, gramer2024newcasesof pages 2-4, barretta2025variantsingstz1 pages 9-11)	Human diagnostic workflows	Molecular confirmation is decisive. Low succinylacetone cannot safely exclude mild tyrosinemia type I, so simply raising screening cutoffs risks missed cases.
Treatment	Most reported individuals received neither protein restriction nor medication and remained well. Nitisinone and tyrosine/phenylalanine restriction initiated while tyrosinemia type I was unresolved were discontinued after MAAID diagnosis without deterioration. (barretta2025variantsingstz1 pages 5-8, barretta2025variantsingstz1 pages 8-9)	Case reports and observational follow-up	Current evidence argues against routine disease-specific treatment, but there are no controlled trials or formal guidelines; surveillance and individualized intervention if liver dysfunction appears are prudent.
Mechanism	GSTZ1/MAAI normally catalyzes glutathione-dependent isomerization of maleylacetoacetate to fumarylacetoacetate in phenylalanine/tyrosine catabolism. Loss of activity permits upstream metabolites and succinylacetone to accumulate; a glutathione-dependent nonenzymatic bypass can still generate fumarylacetoacetate and probably explains the mild baseline phenotype. (fernandezcanon2002maleylacetoacetateisomerase(maaigstz)deficient pages 1-1, board2011glutathionetransferasezeta pages 7-8)	Enzyme biochemistry, in vitro experiments and knockout mice	Core enzymatic defect and bypass are well supported experimentally; their quantitative contribution in affected humans has not been directly measured.
Mouse model	Gstz1-null mice excrete fumarylacetoacetate and succinylacetone and can appear relatively healthy on standard chow, but some backgrounds show enlarged liver/kidneys, hepatitis, renal abnormalities, splenic atrophy and antioxidant-response induction. Phenylalanine, tyrosine/homogentisate challenge or glutathione depletion causes severe hepatic/renal injury and age-dependent lethality. (lim2004micedeficientin pages 1-2, board2011glutathionetransferasezeta pages 8-9, fernandezcanon2002maleylacetoacetateisomerase(maaigstz)deficient pages 7-8)	Germline knockout mouse studies	Strong evidence for conditional metabolic toxicity; severe challenged-mouse phenotypes have not been observed in the small human cohort and must not be directly extrapolated.
Major evidence gaps	No robust incidence or prevalence, carrier frequency, penetrance estimate, genotype–phenotype model, validated clinical criteria, disease-specific quality-of-life data, controlled treatment study, clinical trial, gene therapy, human tissue omics, single-cell/spatial study or proven congenital-MAAID cancer risk is available. Cancer studies of acquired GSTZ1 downregulation are mechanistically informative but not direct evidence for the inherited disorder. (barretta2025variantsingstz1 pages 1-2, barretta2025variantsingstz1 pages 11-12)	Evidence-gap assessment across retrieved literature	Very substantial uncertainty due to ultra-rarity, screening ascertainment, predominantly asymptomatic cases and limited longitudinal follow-up.

Table: Compact evidence map for GSTZ1-related maleylacetoacetate isomerase deficiency, integrating human screening and natural-history data with mechanistic and mouse-model findings. The final column highlights where evidence is strong and where ultra-rarity limits inference.

1. Disease information

Definition and identifiers

MAAID is an inborn error of metabolism in which deficient GSTZ1/MAAI activity impairs the glutathione-dependent conversion of maleylacetoacetate to fumarylacetoacetate, the penultimate reaction in tyrosine degradation. Its principal observed human phenotype is mild hypersuccinylacetonemia rather than overt hepatorenal disease. (fernandezcanon2002maleylacetoacetateisomerase(maaigstz)deficient pages 1-1, gramer2024newcasesof pages 2-4)

MONDO: MONDO:0060527.
OMIM phenotype: 617596.
Causal gene: GSTZ1, glutathione S-transferase zeta 1; Ensembl ENSG00000100577. Open Targets associates only GSTZ1 with MONDO:0060527 and cites the original human series, PMID 27876694. (OpenTargets Search: Maleylacetoacetate isomerase deficiency-GSTZ1)
Common names: maleylacetoacetate isomerase deficiency; MAAI deficiency; MAAID; GSTZ1 deficiency; glutathione transferase zeta deficiency; hypersuccinylacetonemia due to GSTZ1 deficiency. Historical “tyrosinemia type Ib” terminology is potentially confusing and is best avoided.
ICD-10/ICD-11 and MeSH: no disease-specific code or heading was established in the retrieved authoritative literature. A broad inherited amino-acid/metabolic-disorder code may be used locally but is not equivalent to a dedicated MAAID identifier.
Orphanet: no reliable disease-specific Orpha number was established from the retrieved evidence.

Evidence is mainly aggregated disease-level literature derived from a very small number of molecularly confirmed patients and families, not EHR-scale population data. The 2024 report combines NBS-cohort data with individual-level clinical and segregation findings. (gramer2024newcasesof pages 2-4, gramer2024newcasesof pages 1-2)

2. Etiology

Causal factors and genetic risk

The established cause is biallelic germline GSTZ1 dysfunction, inherited autosomal recessively. Reported disease alleles include canonical and noncanonical splice variants, missense variants, and an in-frame/complex indel. Examples are:

c.136-2A>G, homozygous: predicted exon-4 splice-acceptor loss, aberrant splicing, and nonsense-mediated decay; absent from gnomAD and ClinVar when reported and classified pathogenic under ACMG/AMP criteria.
c.68-12G>A, shown by patient RNA analysis to activate a cryptic splice site, retain 10 nucleotides, frameshift, and probably introduce premature termination.
c.295G>A (p.Val99Met), found in trans with c.68-12G>A.
c.464_471delinsCTGGG (p.Val155_Asp157delinsAlaGly), found in trans with c.68-12G>A. (barretta2025variantsingstz1 pages 5-8, gramer2024newcasesof pages 2-4, barretta2025variantsingstz1 pages 9-11)

These are constitutional/germline variants; no somatic cause of inherited MAAID is established. Acquired GSTZ1 downregulation in cancer and pharmacologic inactivation by dichloroacetate (DCA) are biologically related but are not inherited MAAID.

Environmental and gene–environment factors

No environmental exposure independently causes congenital MAAID. Mouse evidence indicates that high phenylalanine/tyrosine flux, homogentisate loading, or glutathione depletion can expose conditional toxicity. Acetaminophen or other glutathione-depleting exposures have therefore been proposed as risks, but this has not been demonstrated clinically. (board2011glutathionetransferasezeta pages 8-9, fernandezcanon2002maleylacetoacetateisomerase(maaigstz)deficient pages 7-8)

DCA is both a GSTZ1 substrate and mechanism-based inhibitor. Glutathione-dependent metabolism can produce a reactive adduct that covalently modifies Cys-16 and inactivates GSTZ1. Common GSTZ1 haplotypes alter DCA kinetics, illustrating a genuine GSTZ1–exposure interaction, but repeated DCA exposure does not fully reproduce germline knockout biology. (board2011glutathionetransferasezeta pages 8-9, board2011glutathionetransferasezeta pages 7-8, board2011glutathionetransferasezeta pages 9-10)

Protective factors

The principal mechanistic buffer is a glutathione-dependent, nonenzymatic MAA-to-FAA bypass, demonstrated in vitro and in knockout mice. An alternative, weakly expressed adrenal GSTZ1 isoform may also retain activity despite some pathogenic variants, but compensation in patients remains speculative. No validated protective allele, diet, drug, or lifestyle intervention is known. (fernandezcanon2002maleylacetoacetateisomerase(maaigstz)deficient pages 1-1, gramer2024newcasesof pages 5-7)

3. Phenotypes

The available phenotype denominator is extremely small; percentages would be misleading. Qualitative frequencies are therefore preferable.

Mild or intermittent succinylacetone elevation — characteristic/common. Usually found neonatally through HT1 screening; plasma values in six Canadian cases were 0.23–1.28 µmol/L, and German initial DBS values were 2.61 and 2.48 µmol/L. Suggested HPO: Abnormal circulating succinylacetone concentration or the nearest available abnormal-metabolite term; an exact dedicated HPO term should be verified before deposition. (gramer2024newcasesof pages 5-7)
Urinary succinylacetone — variable/trace. It may be persistent, intermittent, or undetectable in an affected adult. Suggested HPO: abnormal urinary metabolite concentration.
Elevated urinary maleic acid — apparently consistent in the 2023 tested series. Suggested HPO: abnormal urinary organic-acid concentration. It is a promising biomarker, not yet a standardized diagnostic criterion. (barretta2025variantsingstz1 pages 9-11)
Normal plasma tyrosine — typical. This helps distinguish MAAID from classic HT1 but does not alone exclude HT1. (barretta2025variantsingstz1 pages 1-2, gramer2024newcasesof pages 4-5)
Normal liver function/coagulation — typical in documented molecular cases. No consistent hepatic failure, cirrhosis, renal disease, neurologic syndrome, or developmental disorder has emerged during available follow-up. (gramer2024newcasesof pages 1-2, barretta2025variantsingstz1 pages 1-2)
Microcephaly — isolated report. One child had microcephaly at 16 months with age-appropriate development. Suggested HPO: Microcephaly (HP:0000252). Causality is uncertain. (gramer2024newcasesof pages 4-5)
Short stature — isolated report. Suggested HPO: Short stature (HP:0004322); causality uncertain.
Obesity — isolated report. Suggested HPO: Obesity (HP:0001513); causality uncertain. (barretta2025variantsingstz1 pages 8-9)
Mild hyperbilirubinemia — one adult. Suggested HPO: Hyperbilirubinemia (HP:0002904); no evidence that it resulted from MAAID. (gramer2024newcasesof pages 2-4)

Onset of the biochemical phenotype is neonatal, but overt clinical onset is generally absent. Severity is usually subclinical/mild and the biochemical course may fluctuate. No disease-specific EQ-5D, SF-36, PROMIS, disability, behavioral, or quality-of-life study exists. The principal documented burden is diagnostic uncertainty, recalls, possible unnecessary HT1 therapy, and parental anxiety. (gramer2024newcasesof pages 7-8)

4. Genetic and molecular information

GSTZ1 encodes the bifunctional cytosolic enzyme glutathione S-transferase zeta 1/maleylacetoacetate isomerase. The disease mechanism is loss of function; gain-of-function, dominant-negative, repeat-expansion, mitochondrial, or somatic mechanisms are not established. Open Targets records five evidence items linking GSTZ1 to MONDO:0060527. (OpenTargets Search: Maleylacetoacetate isomerase deficiency-GSTZ1)

Pathogenicity evidence includes trans configuration in affected individuals, segregation, rarity/absence in population databases, canonical splice disruption, predicted nonsense-mediated decay, and direct RNA confirmation for c.68-12G>A. Exact contemporary ClinVar classifications and gnomAD frequencies should be re-queried per variant at ingestion because databases change; only c.136-2A>G was explicitly reported absent from both resources in the 2024 study. (barretta2025variantsingstz1 pages 5-8, gramer2024newcasesof pages 2-4)

No validated modifier gene, epigenetic signature, recurrent copy-number abnormality, translocation, or disease-associated chromosomal lesion has been reported. The apparently healthy homozygous father indicates that biallelic loss can have very low penetrance for overt morbidity or markedly variable expressivity. (gramer2024newcasesof pages 2-4)

5. Environmental information

Smoking, alcohol, exercise, occupation, pollution, radiation, infection, and sex have not been shown to alter congenital MAAID risk. Infections were tolerated normally by the untreated homozygous adult in the 2024 family. No infectious agent causes or triggers the disorder. (gramer2024newcasesof pages 7-8, gramer2024newcasesof pages 5-7)

High protein or phenylalanine/tyrosine load and glutathione depletion are theoretical human stressors derived from animal experiments. DCA exposure is particularly relevant because GSTZ1 metabolizes DCA and is inactivated during that metabolism. DCA occurs as a water-chlorination by-product, industrial-solvent metabolite, and investigational drug, but environmentally acquired GSTZ1 inhibition must not be conflated with Mendelian MAAID. (lim2004micedeficientin pages 14-14, board2011glutathionetransferasezeta pages 7-8)

6. Mechanism and pathophysiology

Ordered causal chain

Biallelic GSTZ1 loss-of-function variants lead to reduced cytosolic GSTZ1/MAAI activity.
Reduced MAAI activity leads to impaired glutathione-dependent cis–trans isomerization of maleylacetoacetate (MAA) to fumarylacetoacetate (FAA).
The block leads to accumulation/diversion of reactive tyrosine-pathway intermediates and production of maleic acid, succinylacetoacetate, and succinylacetone.
Metabolite production leads to mild, persistent or intermittent blood/urinary succinylacetone and elevated urinary maleic acid—the principal demonstrated human manifestations.
In parallel, glutathione enables a nonenzymatic MAA-to-FAA bypass, which results in continued downstream flux and likely explains the mild baseline phenotype; its quantitative importance in humans is inferred from biochemical and mouse evidence.
Under high substrate flux or glutathione depletion, experimental metabolite accumulation leads to oxidative stress, antioxidant-response induction, cytotoxicity, and hepatic, renal, splenic, and leukocyte injury in knockout mice.
These experimental injuries could lead to human organ disease under severe stress, but this branch remains inferred: it has not been observed consistently in congenital human MAAID.

GSTZ1/MAAI is a 29-kDa cytoplasmic enzyme. Glutathione participates catalytically and is not normally consumed stoichiometrically in the isomerization. Suggested GO annotations include phenylalanine catabolic process (GO:0006559), tyrosine catabolic process, glutathione transferase activity, maleylacetoacetate isomerase activity, cellular response to oxidative stress, and xenobiotic metabolic process. Suggested GO cellular component: cytosol (GO:0005829). (fernandezcanon2002maleylacetoacetateisomerase(maaigstz)deficient pages 1-1, board2011glutathionetransferasezeta pages 7-8)

The best-supported primary cell is the hepatocyte (CL:0000182), with renal tubular epithelial cells, splenic leukocytes, neutrophils, monocytes, and lymphocytes implicated only by challenged knockout models. Oxidative responses include reduced glutathione, induction of alpha-, mu-, and pi-class GSTs, NQO1, and glutamate-cysteine ligase. (lim2004micedeficientin pages 1-2, board2011glutathionetransferasezeta pages 8-9, board2011glutathionetransferasezeta pages 9-10)

Acquired GSTZ1 loss in hepatocellular carcinoma can produce succinylacetone-dependent KEAP1 alkylation, NRF2/IGF1R signaling, or PHD2 inhibition with HIF-1α/VEGF activation. These are valuable mechanistic hypotheses but not demonstrated congenital-MAAID phenotypes or evidence of increased cancer risk. No human MAAID transcriptomic, proteomic, lipidomic, single-cell, spatial, CRISPR-screen, or integrated multi-omics dataset was identified. (barretta2025variantsingstz1 pages 1-2, barretta2025variantsingstz1 pages 11-12)

7. Anatomical structures affected

In humans, no organ is consistently clinically damaged. The liver is the main site of tyrosine catabolism and biochemical concern; the kidney is a secondary theoretical target. Mouse studies additionally implicate spleen and circulating leukocytes. Suggested anatomy terms are liver (UBERON:0002107), kidney (UBERON:0002113), renal tubule (UBERON:0001231), spleen (UBERON:0002106), and blood. (lim2004micedeficientin pages 1-2, fernandezcanon2002maleylacetoacetateisomerase(maaigstz)deficient pages 1-1)

At tissue/cell level, suggested annotations are hepatocyte (CL:0000182), kidney epithelial cell, renal tubular epithelial cell, lymphocyte (CL:0000542), neutrophil (CL:0000775), and monocyte (CL:0000576). Subcellular localization is cytosolic. There is no lateralization.

8. Temporal development

Biochemical onset is congenital/neonatal and often recognized at 48–72-hour NBS. Succinylacetone can normalize on repeat DBS, remain trace-positive in urine, or fluctuate. No validated clinical stages exist. Available untreated follow-up spans infancy through 32 years—and a summarized literature table mentions a clinically well individual at 41 years—without a demonstrated progressive course. (barretta2025variantsingstz1 pages 2-4, gramer2024newcasesof pages 2-4, gramer2024newcasesof pages 5-7)

There is no established remission concept because most individuals are never symptomatic. Potential critical periods are inferred from mice: animals under 28 days were particularly vulnerable to phenylalanine challenge. This age-dependent lethality has not been shown in human infants. (board2011glutathionetransferasezeta pages 8-9)

9. Inheritance and population

Inheritance is autosomal recessive. A child of two heterozygous carriers has the usual Mendelian 25% conception risk of biallelic disease, 50% carrier risk, and 25% chance of inheriting neither familial allele. The 2024 index case arose in a first-cousin Afghan family, illustrating the role of consanguinity but not a population-specific founder effect. (gramer2024newcasesof pages 2-4)

No robust prevalence, incidence, carrier frequency, sex ratio, ethnic enrichment, founder variant, anticipation, or germline-mosaicism estimate exists. Fewer than 20 patients were reported by 2025, with clinical follow-up for approximately nine. (barretta2025variantsingstz1 pages 1-2)

The Heidelberg experience provides only a center-level ascertainment estimate: among 516,803 screened newborns, 42 had elevated succinylacetone, two had confirmed HT1, two were suspected MAAID, and one MAAID case was genetically confirmed. One confirmed screened infant corresponds to approximately 1 per 516,803 screened births, but this is not a valid prevalence estimate because of variable biomarkers, thresholds, incomplete confirmation, and asymptomatic adults. (gramer2024newcasesof pages 1-2)

Penetrance for biochemical abnormalities appears incomplete or fluctuating; penetrance for clinically important disease appears low but cannot be quantified. Expressivity is variable. Anticipation is not applicable.

10. Diagnostics

Recommended workflow

Measure succinylacetone in NBS dried blood spots by tandem mass spectrometry.
Urgently repeat/confirm succinylacetone in DBS or plasma and perform urine organic-acid analysis; measure plasma amino acids, tyrosine, liver enzymes, bilirubin, glucose, coagulation, renal indices, and alpha-fetoprotein.
Exclude HT1 with FAH sequencing plus deletion/duplication analysis where appropriate. Treatment for possible HT1 should not be delayed if clinical/biochemical suspicion is substantial.
If succinylacetone is low-level/intermittent, tyrosine is normal, and FAH testing is negative, analyze GSTZ1 by single-gene testing or an inherited-tyrosinemia panel. One reported panel included HPD, FAH, TAT, HGD, and GSTZ1.
Use parental segregation and, for suspected splice variants, RNA analysis. WES/WGS is useful when targeted testing is unrevealing or for discovery of deep intronic/structural variants. (gramer2024newcasesof pages 2-4, barretta2025variantsingstz1 pages 2-4)

Quantitative urinary maleic acid by LC-MS/MS is the leading emerging second-tier test. In the reported study it was elevated in all tested MAAID cases and most false-positive referrals, but absent in HT1. Limitations include instability, low concentration, potential organic-acid interference, lack of age/diet-specific reference intervals, and incomplete DBS validation. (barretta2025variantsingstz1 pages 9-11)

Differential diagnosis

The critical differential is FAH-related HT1, a potentially fatal but treatable disorder. MAAID generally has much lower succinylacetone, normal tyrosine and liver function, and a benign course, but biomarker ranges overlap. Mild HT1 has been reported at succinylacetone values as low as 3.8–5.23 µmol/L or with undetectable urinary succinylacetone; therefore, raising the NBS cutoff merely to avoid MAAID can miss HT1. (gramer2024newcasesof pages 5-7)

Other differentials include transient/false-positive succinylacetone elevation, partial FAH deficiency, and other tyrosine-pathway disorders involving TAT, HPD, or HGD. CMA, karyotyping, FISH, mtDNA analysis, and repeat-expansion tests have no routine role unless another phenotype independently indicates them. Imaging, biopsy, EEG, EMG, and functional testing are not diagnostic for uncomplicated MAAID.

There are no standardized clinical diagnostic criteria or universal MAAID screening program. Detection is incidental to HT1 NBS; familial cascade testing is appropriate after molecular confirmation.

11. Outcome and prognosis

Available evidence supports a favorable prognosis. Six Canadian children reportedly remained untreated and clinically well through ages 1–13, while a homozygous father in the German family was clinically well at 32 years with essentially normal hepatic, renal, coagulation, AFP, amino-acid, and succinylacetone studies. (gramer2024newcasesof pages 1-2, gramer2024newcasesof pages 2-4)

No disease-specific deaths, survival curves, reduced life expectancy, organ-failure rates, disability estimates, validated prognostic model, or quality-of-life scores are available. Historical severe putative cases predated complete molecular confirmation and should not define the modern GSTZ1-confirmed phenotype. (fernandezcanon1998characterizationofa pages 7-8)

Potential adverse prognostic factors—high phenylalanine/tyrosine flux, glutathione depletion, or sustained high succinylacetone—are extrapolated from models. Neither congenital liver-cancer risk nor HCC surveillance beyond ordinary clinical judgment is established.

12. Treatment

No approved disease-specific treatment, formal guideline, or controlled trial exists. Most confirmed individuals have received no pharmacotherapy and no protein restriction and remained well. (gramer2024newcasesof pages 4-5, barretta2025variantsingstz1 pages 1-2)

One recent infant received nitisinone/NTBC plus tyrosine/phenylalanine restriction while HT1 remained possible. After MAAID confirmation, diet and NTBC were stopped at approximately 21–22 months; only a modest succinylacetone rise followed, and liver function and development remained normal at age four. Another untreated infant remained well at age two. These observations argue against routine NTBC or dietary restriction. (barretta2025variantsingstz1 pages 5-8)

A reasonable expert-derived strategy is:

initially manage an unresolved positive screen as possible HT1;
once biallelic GSTZ1 MAAID is confirmed and liver function is normal, stop unnecessary HT1-specific treatment under metabolic-specialist supervision;
monitor growth/development, liver and renal indices, coagulation, AFP, plasma amino acids, and blood/urinary succinylacetone periodically;
consider imaging or NTBC only for persistent substantial biochemical abnormalities or liver dysfunction, recognizing the absence of efficacy evidence. (barretta2025variantsingstz1 pages 8-9)

Suggested NCIt intervention concepts include Genetic Counseling, Clinical Observation, Laboratory Test, Nitisinone, and Dietary Intervention; exact NCIt codes should be validated against the current release. No gene, cell, RNA, surgical, immunologic, or rehabilitation therapy is indicated. ClinicalTrials.gov searching found no relevant MAAID interventional trial or NCT identifier.

13. Prevention

The germline disorder cannot be prevented by vaccination or lifestyle change. Primary reproductive prevention consists of genetic counseling, familial-variant carrier testing, prenatal diagnosis, and preimplantation genetic testing when desired. Secondary prevention is prompt molecular resolution of an elevated-succinylacetone NBS result to avoid both missed HT1 and unnecessary long-term NTBC/diet in MAAID. (gramer2024newcasesof pages 7-8)

Tertiary prevention is surveillance rather than proven prophylaxis. Avoiding extreme protein supplementation and using caution with profound glutathione-depleting exposures are biologically plausible but not evidence-based human recommendations. Standard immunization applies; no disease-specific vaccine, public-health environmental program, or prophylactic medication exists.

14. Other species and natural disease

No naturally occurring homologous veterinary disease, affected breed, zoonosis, or cross-species transmission was identified. The disorder is genetic and noninfectious.

Orthologous GSTZ/MAAI function is evolutionarily conserved. In Aspergillus nidulans, disruption of maiA prevents growth on phenylalanine/phenylacetate and causes accumulation of pathway products; the fungal phenotype demonstrates pathway conservation but is not a mammalian natural-disease model. (fernandezcanon1998characterizationofa pages 7-8)

RNAi silencing of MAAI in the blood-feeding insect Rhodnius prolixus reportedly produced no visible phenotype, consistent with possible bypass metabolism. This is mechanistically interesting but has little direct clinical fidelity.

15. Model organisms

The principal model is the germline Gstz1-null mouse (Mus musculus; NCBI Taxon 10090). On ordinary chow, one strain was relatively healthy while excreting FAA and succinylacetone, directly supporting the nonenzymatic glutathione-dependent bypass. A BALB/c knockout showed hepatomegaly and renomegaly, multifocal hepatitis, renal ultrastructural abnormalities, splenic atrophy, altered leukocytes, elevated serum succinylacetone, and constitutive induction of GST and NQO1 antioxidant defenses. (lim2004micedeficientin pages 1-2, fernandezcanon2002maleylacetoacetateisomerase(maaigstz)deficient pages 1-1)

Phenylalanine challenge caused age-dependent death in mice younger than 28 days and hepatic necrosis, macrovesicular steatosis, splenic atrophy, and leukopenia in survivors. Homogentisate, tyrosine-pathway loading, or glutathione depletion produced hepatic/renal injury; all glutathione-depleted mutants challenged with homogentisate died in one experiment. (board2011glutathionetransferasezeta pages 8-9, fernandezcanon2002maleylacetoacetateisomerase(maaigstz)deficient pages 7-8)

Applications: pathway flux, compensatory chemistry, metabolite toxicity, oxidative stress, DCA pharmacology, diet/drug interactions, and candidate interventions. Limitations: genetic background strongly changes phenotype; experimental substrate loads exceed ordinary human exposure; severe mouse hepatic, renal, immune, and lethal phenotypes have not been reproduced in confirmed human MAAID. No disease-specific human iPSC, organoid, zebrafish, rat knock-in, or humanized model was identified.

Recent developments and authoritative interpretation

2023: quantitative urinary maleic acid was reported as a potentially discriminating biomarker: elevated in tested MAAID but absent in HT1. This is promising for second-tier NBS resolution, although assay harmonization and validation remain necessary. DOI: 10.1002/jimd.12669, published August 2023. (barretta2025variantsingstz1 pages 11-12, barretta2025variantsingstz1 pages 9-11)
2024: Gramer et al. reported 516,803 screened newborns and a family containing an untreated homozygous, clinically well 32-year-old father. Their abstract concludes: “Our observation of natural history over 32 years adds evidence for a benign clinical course of MAAI deficiency without specific treatment.” DOI: 10.3390/ijns10010017, published February 2024. (gramer2024newcasesof pages 2-4, gramer2024newcasesof pages 1-2)
2025 update: two additional molecularly confirmed infants remained well, and RNA analysis established abnormal splicing from c.68-12G>A. The abstract states: “Although our data argue against medical treatment in MAAID, longer follow-up data are warranted.” DOI: 10.3390/genes16091009, published August 2025. This post-2024 evidence reinforces—but does not settle—the benign-course interpretation. (barretta2025variantsingstz1 pages 5-8, barretta2025variantsingstz1 pages 1-2)

Key evidence limitations

The evidence base consists of a handful of screen-detected patients and relatives, with ascertainment biased toward biochemical rather than clinical disease. Robust prevalence, penetrance, genotype–phenotype relationships, longitudinal organ imaging, quality of life, reproductive outcomes, standardized biomarker ranges, treatment trials, and lifetime cancer risk are unknown. The most defensible present classification is therefore an ultra-rare, usually benign or subclinical GSTZ1-related biochemical disorder that is clinically important mainly because it mimics HT1 on newborn screening. Severe organ toxicity remains a conditional model-organism concern rather than a demonstrated common human outcome. (barretta2025variantsingstz1 pages 1-2, barretta2025variantsingstz1 pages 11-12, barretta2025variantsingstz1 pages 8-9)

Principal references

Yang H, et al. Hypersuccinylacetonaemia and normal liver function in maleylacetoacetate isomerase deficiency. Journal of Medical Genetics. Published 2017;54:241–247. PMID 27876694. DOI: 10.1136/jmedgenet-2016-104289. (OpenTargets Search: Maleylacetoacetate isomerase deficiency-GSTZ1, gramer2024newcasesof pages 1-2)
van Vliet K, et al. Maleic acid is a biomarker for maleylacetoacetate isomerase deficiency; implications for newborn screening of tyrosinemia type 1. Journal of Inherited Metabolic Disease. Published August 2023. DOI: 10.1002/jimd.12669. (barretta2025variantsingstz1 pages 11-12, barretta2025variantsingstz1 pages 9-11)
Gramer G, et al. New Cases of Maleylacetoacetate Isomerase Deficiency with Detection by Newborn Screening and Natural History over 32 Years. International Journal of Neonatal Screening. Published February 2024;10:17. DOI: 10.3390/ijns10010017. (gramer2024newcasesof pages 2-4)
Fernández-Cañón JM, et al. Maleylacetoacetate Isomerase (MAAI/GSTZ)-Deficient Mice Reveal a Glutathione-Dependent Nonenzymatic Bypass in Tyrosine Catabolism. Molecular and Cellular Biology. Published July 2002;22:4943–4951. DOI: 10.1128/MCB.22.13.4943-4951.2002. (fernandezcanon2002maleylacetoacetateisomerase(maaigstz)deficient pages 1-1)
Lim CEL, et al. Mice Deficient in Glutathione Transferase Zeta/Maleylacetoacetate Isomerase Exhibit a Range of Pathological Changes. American Journal of Pathology. Published August 2004;165:679–693. DOI: 10.1016/S0002-9440(10)63332-9. (lim2004micedeficientin pages 1-2)
Barretta F, et al. Variants in GSTZ1 Gene Underlying Maleylacetoacetate Isomerase Deficiency: Characterization of Two New Individuals and Literature Review. Genes. Published August 2025;16:1009. DOI: 10.3390/genes16091009. (barretta2025variantsingstz1 pages 5-8)

References

(gramer2024newcasesof pages 1-2): Gwendolyn Gramer, Saskia B. Wortmann, Junmin Fang-Hoffmann, Dirk Kohlmüller, Jürgen G. Okun, Holger Prokisch, Thomas Meitinger, and Georg F. Hoffmann. New cases of maleylacetoacetate isomerase deficiency with detection by newborn screening and natural history over 32 years: experience from a german newborn screening center. International Journal of Neonatal Screening, 10(1):17, Feb 2024. URL: https://doi.org/10.3390/ijns10010017, doi:10.3390/ijns10010017. This article has 4 citations.
(barretta2025variantsingstz1 pages 1-2): Ferdinando Barretta, Fabiana Uomo, Alessandra Verde, Mariagrazia Fisco, Giovanna Gallo, Lucia Albano, Daniela Crisci, Cristina Mazzaccara, Pietro Strisciuglio, Margherita Ruoppolo, Simona Fecarotta, Giancarlo Parenti, Giulia Frisso, and Alessandro Rossi. Variants in gstz1 gene underlying maleylacetoacetate isomerase deficiency: characterization of two new individuals and literature review. Genes, 16(9):1009, Aug 2025. URL: https://doi.org/10.3390/genes16091009, doi:10.3390/genes16091009. This article has 0 citations.
(barretta2025variantsingstz1 pages 9-11): Ferdinando Barretta, Fabiana Uomo, Alessandra Verde, Mariagrazia Fisco, Giovanna Gallo, Lucia Albano, Daniela Crisci, Cristina Mazzaccara, Pietro Strisciuglio, Margherita Ruoppolo, Simona Fecarotta, Giancarlo Parenti, Giulia Frisso, and Alessandro Rossi. Variants in gstz1 gene underlying maleylacetoacetate isomerase deficiency: characterization of two new individuals and literature review. Genes, 16(9):1009, Aug 2025. URL: https://doi.org/10.3390/genes16091009, doi:10.3390/genes16091009. This article has 0 citations.
(OpenTargets Search: Maleylacetoacetate isomerase deficiency-GSTZ1): Open Targets Query (Maleylacetoacetate isomerase deficiency-GSTZ1, 4 results). Buniello, A. et al. (2025). Open Targets Platform: facilitating therapeutic hypotheses building in drug discovery. Nucleic Acids Research.
(gramer2024newcasesof pages 2-4): Gwendolyn Gramer, Saskia B. Wortmann, Junmin Fang-Hoffmann, Dirk Kohlmüller, Jürgen G. Okun, Holger Prokisch, Thomas Meitinger, and Georg F. Hoffmann. New cases of maleylacetoacetate isomerase deficiency with detection by newborn screening and natural history over 32 years: experience from a german newborn screening center. International Journal of Neonatal Screening, 10(1):17, Feb 2024. URL: https://doi.org/10.3390/ijns10010017, doi:10.3390/ijns10010017. This article has 4 citations.
(barretta2025variantsingstz1 pages 5-8): Ferdinando Barretta, Fabiana Uomo, Alessandra Verde, Mariagrazia Fisco, Giovanna Gallo, Lucia Albano, Daniela Crisci, Cristina Mazzaccara, Pietro Strisciuglio, Margherita Ruoppolo, Simona Fecarotta, Giancarlo Parenti, Giulia Frisso, and Alessandro Rossi. Variants in gstz1 gene underlying maleylacetoacetate isomerase deficiency: characterization of two new individuals and literature review. Genes, 16(9):1009, Aug 2025. URL: https://doi.org/10.3390/genes16091009, doi:10.3390/genes16091009. This article has 0 citations.
(gramer2024newcasesof pages 5-7): Gwendolyn Gramer, Saskia B. Wortmann, Junmin Fang-Hoffmann, Dirk Kohlmüller, Jürgen G. Okun, Holger Prokisch, Thomas Meitinger, and Georg F. Hoffmann. New cases of maleylacetoacetate isomerase deficiency with detection by newborn screening and natural history over 32 years: experience from a german newborn screening center. International Journal of Neonatal Screening, 10(1):17, Feb 2024. URL: https://doi.org/10.3390/ijns10010017, doi:10.3390/ijns10010017. This article has 4 citations.
(gramer2024newcasesof pages 4-5): Gwendolyn Gramer, Saskia B. Wortmann, Junmin Fang-Hoffmann, Dirk Kohlmüller, Jürgen G. Okun, Holger Prokisch, Thomas Meitinger, and Georg F. Hoffmann. New cases of maleylacetoacetate isomerase deficiency with detection by newborn screening and natural history over 32 years: experience from a german newborn screening center. International Journal of Neonatal Screening, 10(1):17, Feb 2024. URL: https://doi.org/10.3390/ijns10010017, doi:10.3390/ijns10010017. This article has 4 citations.
(barretta2025variantsingstz1 pages 8-9): Ferdinando Barretta, Fabiana Uomo, Alessandra Verde, Mariagrazia Fisco, Giovanna Gallo, Lucia Albano, Daniela Crisci, Cristina Mazzaccara, Pietro Strisciuglio, Margherita Ruoppolo, Simona Fecarotta, Giancarlo Parenti, Giulia Frisso, and Alessandro Rossi. Variants in gstz1 gene underlying maleylacetoacetate isomerase deficiency: characterization of two new individuals and literature review. Genes, 16(9):1009, Aug 2025. URL: https://doi.org/10.3390/genes16091009, doi:10.3390/genes16091009. This article has 0 citations.
(barretta2025variantsingstz1 pages 2-4): Ferdinando Barretta, Fabiana Uomo, Alessandra Verde, Mariagrazia Fisco, Giovanna Gallo, Lucia Albano, Daniela Crisci, Cristina Mazzaccara, Pietro Strisciuglio, Margherita Ruoppolo, Simona Fecarotta, Giancarlo Parenti, Giulia Frisso, and Alessandro Rossi. Variants in gstz1 gene underlying maleylacetoacetate isomerase deficiency: characterization of two new individuals and literature review. Genes, 16(9):1009, Aug 2025. URL: https://doi.org/10.3390/genes16091009, doi:10.3390/genes16091009. This article has 0 citations.
(fernandezcanon2002maleylacetoacetateisomerase(maaigstz)deficient pages 1-1): José Manuel Fernández-Cañón, Manfred W. Baetscher, Milton Finegold, Terry Burlingame, K. Michael Gibson, and Markus Grompe. Maleylacetoacetate isomerase (maai/gstz)-deficient mice reveal a glutathione-dependent nonenzymatic bypass in tyrosine catabolism. Molecular and Cellular Biology, 22:4943-4951, Jul 2002. URL: https://doi.org/10.1128/mcb.22.13.4943-4951.2002, doi:10.1128/mcb.22.13.4943-4951.2002. This article has 122 citations and is from a domain leading peer-reviewed journal.
(board2011glutathionetransferasezeta pages 7-8): Philip G. Board and M.W. Anders. Glutathione transferase zeta: discovery, polymorphic variants, catalysis, inactivation, and properties of gstz1−/− mice. Drug Metabolism Reviews, 43:215-225, Apr 2011. URL: https://doi.org/10.3109/03602532.2010.549132, doi:10.3109/03602532.2010.549132. This article has 33 citations and is from a peer-reviewed journal.
(lim2004micedeficientin pages 1-2): Cindy E.L. Lim, Klaus I. Matthaei, Anneke C. Blackburn, Richard P. Davis, Jane E. Dahlstrom, Mark E. Koina, M.W. Anders, and Philip G. Board. Mice deficient in glutathione transferase zeta/maleylacetoacetate isomerase exhibit a range of pathological changes and elevated expression of alpha, mu, and pi class glutathione transferases. The American Journal of Pathology, 165(2):679-693, Aug 2004. URL: https://doi.org/10.1016/s0002-9440(10)63332-9, doi:10.1016/s0002-9440(10)63332-9. This article has 75 citations.
(board2011glutathionetransferasezeta pages 8-9): Philip G. Board and M.W. Anders. Glutathione transferase zeta: discovery, polymorphic variants, catalysis, inactivation, and properties of gstz1−/− mice. Drug Metabolism Reviews, 43:215-225, Apr 2011. URL: https://doi.org/10.3109/03602532.2010.549132, doi:10.3109/03602532.2010.549132. This article has 33 citations and is from a peer-reviewed journal.
(fernandezcanon2002maleylacetoacetateisomerase(maaigstz)deficient pages 7-8): José Manuel Fernández-Cañón, Manfred W. Baetscher, Milton Finegold, Terry Burlingame, K. Michael Gibson, and Markus Grompe. Maleylacetoacetate isomerase (maai/gstz)-deficient mice reveal a glutathione-dependent nonenzymatic bypass in tyrosine catabolism. Molecular and Cellular Biology, 22:4943-4951, Jul 2002. URL: https://doi.org/10.1128/mcb.22.13.4943-4951.2002, doi:10.1128/mcb.22.13.4943-4951.2002. This article has 122 citations and is from a domain leading peer-reviewed journal.
(barretta2025variantsingstz1 pages 11-12): Ferdinando Barretta, Fabiana Uomo, Alessandra Verde, Mariagrazia Fisco, Giovanna Gallo, Lucia Albano, Daniela Crisci, Cristina Mazzaccara, Pietro Strisciuglio, Margherita Ruoppolo, Simona Fecarotta, Giancarlo Parenti, Giulia Frisso, and Alessandro Rossi. Variants in gstz1 gene underlying maleylacetoacetate isomerase deficiency: characterization of two new individuals and literature review. Genes, 16(9):1009, Aug 2025. URL: https://doi.org/10.3390/genes16091009, doi:10.3390/genes16091009. This article has 0 citations.
(board2011glutathionetransferasezeta pages 9-10): Philip G. Board and M.W. Anders. Glutathione transferase zeta: discovery, polymorphic variants, catalysis, inactivation, and properties of gstz1−/− mice. Drug Metabolism Reviews, 43:215-225, Apr 2011. URL: https://doi.org/10.3109/03602532.2010.549132, doi:10.3109/03602532.2010.549132. This article has 33 citations and is from a peer-reviewed journal.
(gramer2024newcasesof pages 7-8): Gwendolyn Gramer, Saskia B. Wortmann, Junmin Fang-Hoffmann, Dirk Kohlmüller, Jürgen G. Okun, Holger Prokisch, Thomas Meitinger, and Georg F. Hoffmann. New cases of maleylacetoacetate isomerase deficiency with detection by newborn screening and natural history over 32 years: experience from a german newborn screening center. International Journal of Neonatal Screening, 10(1):17, Feb 2024. URL: https://doi.org/10.3390/ijns10010017, doi:10.3390/ijns10010017. This article has 4 citations.
(lim2004micedeficientin pages 14-14): Cindy E.L. Lim, Klaus I. Matthaei, Anneke C. Blackburn, Richard P. Davis, Jane E. Dahlstrom, Mark E. Koina, M.W. Anders, and Philip G. Board. Mice deficient in glutathione transferase zeta/maleylacetoacetate isomerase exhibit a range of pathological changes and elevated expression of alpha, mu, and pi class glutathione transferases. The American Journal of Pathology, 165(2):679-693, Aug 2004. URL: https://doi.org/10.1016/s0002-9440(10)63332-9, doi:10.1016/s0002-9440(10)63332-9. This article has 75 citations.
(fernandezcanon1998characterizationofa pages 7-8): José Manuel Fernández-Cañón and Miguel Angel Peñalva. Characterization of a fungal maleylacetoacetate isomerase gene and identification of its human homologue*. The Journal of Biological Chemistry, 273:329-337, Jan 1998. URL: https://doi.org/10.1074/jbc.273.1.329, doi:10.1074/jbc.273.1.329. This article has 143 citations.

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Unresolved (possible confabulation)	0
Unverifiable	2
References weighed for topical relevance	10
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Unresolved (possible confabulation)	0
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Unverifiable	0
Terms whose name was checked	1
Terms named correctly	0
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MONDO:0060527 (5 mentions) - the report calls it "if available"; MONDO calls it maleylacetoacetate isomerase deficiency

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Maleylacetoacetate Isomerase Deficiency: Comprehensive Disease Report

Executive summary

1. Disease information

Definition and identifiers

2. Etiology

Causal factors and genetic risk

Environmental and gene–environment factors

Protective factors

3. Phenotypes

4. Genetic and molecular information

5. Environmental information

6. Mechanism and pathophysiology

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8. Temporal development

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10. Diagnostics

Recommended workflow

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