5-Oxoprolinase Deficiency

Mendelian MONDO:0009825 Pathograph 23 Inherited Glutathione Metabolism Disease Inborn Error of Metabolism

5-oxoprolinase deficiency is a very rare autosomal recessive inborn error of the gamma-glutamyl cycle caused by biallelic variants in OPLAH, which encodes ATP-dependent 5-oxoprolinase. Reduced 5-oxoprolinase activity impairs conversion of 5-oxo-L-proline to L-glutamate, producing persistent 5-oxoprolinuria. The clinical significance is heterogeneous and incompletely resolved: some molecularly confirmed individuals have largely benign courses, while symptomatic reports describe developmental delay, speech delay, seizures, metabolic acidosis, and neuroimaging abnormalities. The most consistent disease-level features are elevated urinary 5-oxoproline and reduced 5-oxoprolinase activity.

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2
Pathophys.
15
Phenotypes
23
Pathograph
1
Genes
3
Treatments
14
References
2
Deep Research
⚙

Pathophysiology

2
OPLAH molecular function deficiency
Biallelic OPLAH variants reduce ATP-dependent 5-oxoprolinase activity in the gamma-glutamyl cycle. OPLAH encodes 5-oxoprolinase, which normally converts 5-oxo-L-proline to L-glutamate.
OPLAH link
glutathione metabolic process link ↕ DYSREGULATED glutathione biosynthetic process link ↕ DYSREGULATED glutamate metabolic process link ↕ DYSREGULATED
5-oxoprolinase (ATP-hydrolyzing) activity link ↓ DECREASED
Downstream
Gamma-glutamyl cycle block and 5-oxoproline accumulation Reduced 5-oxoprolinase activity blocks clearance of 5-oxo-L-proline.
Reduced 5-oxoprolinase activity OPLAH encodes the enzyme measured as reduced 5-oxoprolinase activity.
Reduced circulating 5-oxoprolinase activity OPLAH molecular dysfunction is directly reflected by reduced measured 5-oxoprolinase activity.
Show evidence (4 references)
ORPHA:33572 SUPPORT
"OPLAH | 5-oxoprolinase, ATP-hydrolysing | hgnc:8149 | Disease-causing germline mutation(s) in"
Orphanet identifies OPLAH as the disease-causing gene.
PMID:27477828 SUPPORT Human Clinical
"bi-allelic mutations in OPLAH were indicated."
The largest patient series supports biallelic OPLAH variants as the molecular cause.
PMID:25129617 SUPPORT Model Organism
"reported missense mutations in the OPLAH gene. A yeast in vivo growth assay"
Functional testing of reported OPLAH missense variants supports reduced enzyme activity for selected alleles.
+ 1 more reference
Gamma-glutamyl cycle block and 5-oxoproline accumulation
The gamma-glutamyl cycle mediates glutathione synthesis and degradation. Impaired 5-oxoprolinase activity causes accumulation of 5-oxo-L-proline, also called pyroglutamic acid, producing the diagnostic 5-oxoprolinuria.
glutathione metabolic process link ↕ DYSREGULATED glutathione biosynthetic process link ↕ DYSREGULATED glutamate metabolic process link ↕ DYSREGULATED
Downstream
Increased urinary 5-oxoproline Failure to clear 5-oxo-L-proline causes elevated urinary 5-oxoproline.
Increased urinary L-pyroglutamic acid Urinary L-pyroglutamic acid is the HPO phenotype corresponding to accumulated 5-oxoproline.
Metabolic acidosis Metabolic acidosis is reported in OPLAH deficiency, but the causal connection to 5-oxoprolinuria is incompletely resolved.
Hypoglycemia Hypoglycemia is an occasional Orphanet phenotype with uncertain mechanistic connection to OPLAH deficiency.
Feeding difficulties in infancy Feeding problems occur in symptomatic 5-oxoprolinuria reports, but penetrance and causality remain uncertain.
Failure to thrive Failure to thrive is an occasional reported manifestation in the variable symptomatic spectrum.
Global developmental delay Developmental delay is reported in symptomatic patients, but larger series note incomplete segregation with 5-oxoprolinuria.
Hypotonia Hypotonia is an occasional reported neurologic phenotype with uncertain direct mechanism.
Seizure Seizures are reported in symptomatic patients, but a direct biochemical mechanism is not established.
Delayed speech and language development Speech delay is part of the reported variable neurologic spectrum.
Cerebral atrophy Brain atrophy has been reported in a symptomatic OPLAH-deficient patient, but causality remains case-level.
Postnatal macrocephaly Postnatal macrocephaly has been reported in a symptomatic patient and in Orphanet, without a defined intermediate mechanism.
Cerebral hypomyelination Hypomyelination was reported in a symptomatic patient with elevated urinary 5-oxoproline.
Ventriculomegaly Ventriculomegaly was reported in a symptomatic OPLAH-deficient patient, but mechanism is unresolved.
Hypoplasia of the corpus callosum Corpus callosum hypoplasia was reported in a symptomatic OPLAH-deficient patient, with uncertain causality.
Show evidence (3 references)
PMID:27477828 SUPPORT Human Clinical
"the γ-glutamyl cycle, affecting either glutathione synthetase or 5-oxoprolinase."
Places 5-oxoprolinase deficiency in the gamma-glutamyl cycle.
PMID:17397529 SUPPORT Other
"5-Oxoprolinase deficiency is associated with 5-oxoprolinuria"
Review evidence supports 5-oxoprolinuria as the core biochemical abnormality.
PMID:25851806 SUPPORT Human Clinical
"All patients had significantly elevated urine 5-oxoproline."
Clinical series documents elevated urinary 5-oxoproline in affected patients.
⬡

Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.
Pathograph: causal mechanism network for 5-Oxoprolinase Deficiency Interactive directed graph showing how pathophysiology mechanisms, phenotypes, genetic factors and variants, experimental models, environmental triggers, and treatments relate through causal and linked edges.
●

Phenotypes

15
Digestive 1
Feeding difficulties in infancy OCCASIONAL Feeding difficulties in infancy (HP:0008872)
Show evidence (2 references)
ORPHA:33572 SUPPORT
"HP:0008872 | Feeding difficulties in infancy | Occasional (29-5%)"
Orphanet reports feeding difficulties in infancy as occasional.
PMID:25851806 SUPPORT Human Clinical
"Patients were hospitalized between the age of 13days to 1year and 3months for hypersomnia, developmental retardation, feeding deficiency, vomiting, icterus and recurrent pneumonia."
The Chinese clinical series reported feeding problems among symptomatic 5-oxoprolinuria patients.
Metabolism 2
Metabolic acidosis OCCASIONAL Metabolic acidosis (HP:0001942)
Show evidence (1 reference)
ORPHA:33572 SUPPORT
"HP:0001942 | Metabolic acidosis | Occasional (29-5%)"
Orphanet reports metabolic acidosis as occasional.
Hypoglycemia OCCASIONAL Hypoglycemia (HP:0001943)
Show evidence (1 reference)
ORPHA:33572 SUPPORT
"HP:0001943 | Hypoglycemia | Occasional (29-5%)"
Orphanet reports hypoglycemia as occasional.
Musculoskeletal 1
Hypotonia OCCASIONAL Hypotonia (HP:0001252)
Show evidence (1 reference)
ORPHA:33572 SUPPORT
"HP:0001252 | Hypotonia | Occasional (29-5%)"
Orphanet reports hypotonia as occasional.
Nervous System 7
Global developmental delay FREQUENT Global developmental delay (HP:0001263)
Show evidence (2 references)
ORPHA:33572 SUPPORT
"HP:0001263 | Global developmental delay | Frequent (79-30%)"
Orphanet reports global developmental delay as frequent.
PMID:25851806 SUPPORT Human Clinical
"developmental retardation"
A Chinese clinical series reported developmental delay among symptomatic patients.
Seizure OCCASIONAL Seizure (HP:0001250)
Show evidence (2 references)
ORPHA:33572 SUPPORT
"HP:0001250 | Seizure | Occasional (29-5%)"
Orphanet reports seizures as occasional.
PMID:39129838 SUPPORT Human Clinical
"presented with epilepsy at the age of 2 years."
Case report documents epilepsy in a child with a homozygous OPLAH variant.
Delayed speech and language development OCCASIONAL Delayed speech and language development (HP:0000750)
Show evidence (2 references)
ORPHA:33572 SUPPORT
"HP:0000750 | Delayed speech and language development | Occasional (29-5%)"
Orphanet reports delayed speech and language development as occasional.
PMID:39129838 SUPPORT Human Clinical
"He did not speak fluently. He was using 5-10 words with decreased language fluency."
Recent case report documents impaired speech fluency.
Cerebral atrophy OCCASIONAL Cerebral atrophy (HP:0002059)
Show evidence (2 references)
ORPHA:33572 SUPPORT
"HP:0002059 | Cerebral atrophy | Occasional (29-5%)"
Orphanet reports cerebral atrophy as occasional.
PMID:39129838 SUPPORT Human Clinical
"Progressive cerebral atrophy, hypomyelination, ventriculomegaly, and corpus callosum hypoplasia"
Recent case report documents cerebral atrophy among brain MRI findings.
Cerebral hypomyelination Cerebral hypomyelination (HP:0006808)
Show evidence (1 reference)
PMID:39129838 SUPPORT Human Clinical
"Progressive cerebral atrophy, hypomyelination, ventriculomegaly, and corpus callosum hypoplasia"
Recent case report documents cerebral hypomyelination among brain MRI findings.
Ventriculomegaly Ventriculomegaly (HP:0002119)
Show evidence (1 reference)
PMID:39129838 SUPPORT Human Clinical
"Progressive cerebral atrophy, hypomyelination, ventriculomegaly, and corpus callosum hypoplasia"
Recent case report documents ventriculomegaly among brain MRI findings.
Hypoplasia of the corpus callosum Hypoplasia of the corpus callosum (HP:0002079)
Show evidence (1 reference)
PMID:39129838 SUPPORT Human Clinical
"Progressive cerebral atrophy, hypomyelination, ventriculomegaly, and corpus callosum hypoplasia"
Recent case report documents corpus callosum hypoplasia among brain MRI findings.
Growth 1
Failure to thrive OCCASIONAL Failure to thrive (HP:0001508)
Show evidence (1 reference)
ORPHA:33572 SUPPORT
"HP:0001508 | Failure to thrive | Occasional (29-5%)"
Orphanet reports failure to thrive as occasional.
Other 3
Increased urinary L-pyroglutamic acid VERY_FREQUENT Increased level of L-pyroglutamic acid in urine (HP:0410132)
Show evidence (2 references)
ORPHA:33572 SUPPORT
"HP:0410132 | Increased level of L-pyroglutamic acid in urine | Very frequent (99-80%)"
Orphanet reports increased urinary L-pyroglutamic acid as very frequent.
PMID:27477828 SUPPORT Human Clinical
"In all patients with 5-oxoprolinuria studied"
The mutation series is anchored on patients ascertained for 5-oxoprolinuria.
Reduced circulating 5-oxoprolinase activity VERY_FREQUENT Reduced circulating 5-oxoprolinase activity (HP:0040142)
Show evidence (1 reference)
ORPHA:33572 SUPPORT
"HP:0040142 | Reduced circulating 5-oxoprolinase activity | Very frequent (99-80%)"
Orphanet reports reduced circulating 5-oxoprolinase activity as very frequent.
Postnatal macrocephaly OCCASIONAL Postnatal macrocephaly (HP:0005490)
Show evidence (2 references)
ORPHA:33572 SUPPORT
"HP:0005490 | Postnatal macrocephaly | Occasional (29-5%)"
Orphanet reports postnatal macrocephaly as occasional.
PMID:39129838 SUPPORT Human Clinical
"His past medical history revealed postnatal macrocephaly, hydrocephalus, and well-controlled epilepsy with levetiracetam."
Recent case report documents postnatal macrocephaly in a symptomatic OPLAH-deficient child.
🧬

Genetic Associations

1
OPLAH variants
Autosomal recessive
Show evidence (2 references)
PMID:21651516 SUPPORT Human Clinical
"mutation in OPLAH (which encodes 5-oxoprolinase)."
First molecular report links OPLAH to 5-oxoprolinase deficiency.
PMID:27477828 SUPPORT Human Clinical
"the absence of 5-oxoprolinuria in all tested heterozygotes."
Supports recessive biochemical expression and absence of the urinary biomarker in tested carriers.
💊

Treatments

3
Symptomatic neurologic care and longitudinal follow-up
Action: supportive care MAXO:0000950
No disease-modifying therapy is established for OPLAH deficiency. Management is therefore centered on long-term observation and standard symptomatic care for manifestations such as epilepsy, developmental delay, and speech delay. A reported antioxidant and cofactor regimen did not improve the two OPLAH-deficient patients in one mixed 5-oxoprolinuria series, so this entry does not model that regimen as an effective OPLAH-directed therapy.
Target Phenotypes: Seizure ↗ Global developmental delay ↗ Delayed speech and language development ↗
Show evidence (4 references)
PMID:17397529 SUPPORT Other
"No treatment has been recommended for gamma-glutamyl transpeptidase, 5-oxoprolinase and dipeptidase deficiency."
Glutathione-metabolism review supports absence of an established disease-specific therapy.
PMID:25851806 SUPPORT Human Clinical
"After treatment by l-carnitine, vitamin E, B1, B2 and coenzyme Q10, three patients with GSS deficiency improved, but the two 5-oxoprolinase-deficient patients did not respond to treatment."
Clinical series supports not modeling antioxidant/cofactor therapy as effective for OPLAH-deficient patients.
PMID:39129838 SUPPORT Human Clinical
"well-controlled epilepsy with levetiracetam"
Case report supports standard symptomatic seizure management in an OPLAH-deficient patient.
+ 1 more reference
Molecular genetic testing
Action: genetic testing MAXO:0000127
Molecular testing of OPLAH is important in symptomatic individuals with persistent 5-oxoprolinuria to establish the diagnosis and distinguish OPLAH deficiency from glutathione synthetase deficiency and other overlapping causes of 5-oxoprolinuria.
Target Phenotypes: Increased level of L-pyroglutamic acid in urine ↗ Reduced circulating 5-oxoprolinase activity ↗
Show evidence (2 references)
PMID:21651516 SUPPORT Human Clinical
"highlights the importance of establishing a molecular diagnosis"
First molecular report emphasizes molecular diagnosis in clinically abnormal cases.
PMID:25851806 SUPPORT Human Clinical
"Genetic analysis is important for the deferential diagnosis."
Clinical series supports genetic testing to distinguish OPLAH from GSS deficiency.
Genetic counseling
Action: genetic counseling MAXO:0000079
Genetic counseling addresses autosomal recessive inheritance, recurrence risk, carrier testing, and interpretation of biallelic private OPLAH variants in families with confirmed OPLAH deficiency.
Show evidence (2 references)
ORPHA:33572 SUPPORT
"Autosomal recessive"
Orphanet reports autosomal recessive inheritance, supporting recurrence-risk counseling.
PMID:27477828 SUPPORT Human Clinical
"all 20 mutations identified were novel and private"
Private family-specific variants support individualized counseling and family testing.
🔬

Biochemical Markers

2
Increased urinary 5-oxoproline (INCREASED)
Context: Urinary 5-oxoproline, also called L-pyroglutamic acid, is persistently increased and is the primary biochemical marker for OPLAH deficiency.
Pathograph Readouts
Readout Of Gamma-glutamyl cycle block and 5-oxoproline accumulation Positive Diagnostic
Elevated urinary 5-oxoproline directly reports accumulation of the substrate that is not cleared by deficient OPLAH activity.
Readout Of Increased urinary L-pyroglutamic acid Positive Diagnostic
Urinary 5-oxoproline is the measured metabolite represented clinically as increased urinary L-pyroglutamic acid.
Show evidence (1 reference)
ORPHA:33572 SUPPORT Other
"HP:0410132 | Increased level of L-pyroglutamic acid in urine | Very frequent (99-80%)"
Orphanet maps the urinary 5-oxoproline abnormality to the L-pyroglutamic-acid HPO phenotype.
Show evidence (2 references)
PMID:39129838 SUPPORT Human Clinical
"quantitation of 5-oxoproline by stable isotope dilution gave a value of 177.9"
Case report provides quantitative urinary 5-oxoproline elevation.
ORPHA:33572 SUPPORT
"HP:0410132 | Increased level of L-pyroglutamic acid in urine | Very frequent (99-80%)"
Orphanet supports increased urinary L-pyroglutamic acid as the dominant biochemical phenotype.
Reduced 5-oxoprolinase activity (DECREASED)
Context: OPLAH variants reduce 5-oxoprolinase activity, blocking the ATP-dependent conversion of 5-oxo-L-proline in the gamma-glutamyl cycle.
Pathograph Readouts
Readout Of OPLAH molecular function deficiency Negative Diagnostic
Reduced 5-oxoprolinase activity is the direct functional readout of deficient OPLAH molecular function.
Readout Of Reduced circulating 5-oxoprolinase activity Negative Diagnostic
Reduced enzyme activity is the biochemical measurement represented by the reduced circulating 5-oxoprolinase activity phenotype.
Show evidence (1 reference)
ORPHA:33572 SUPPORT Other
"HP:0040142 | Reduced circulating 5-oxoprolinase activity | Very frequent (99-80%)"
Orphanet supports reduced circulating 5-oxoprolinase activity as the corresponding biochemical phenotype.
Show evidence (2 references)
PMID:25129617 SUPPORT Model Organism
"revealed that only p.S323R, p.G860R and p.D1241V affected the activity of the"
Functional assay supports reduced 5-oxoprolinase activity for selected OPLAH missense variants.
ORPHA:33572 SUPPORT
"HP:0040142 | Reduced circulating 5-oxoprolinase activity | Very frequent (99-80%)"
Orphanet supports reduced 5-oxoprolinase activity as very frequent.
{ }

Source YAML

click to show 
name: 5-Oxoprolinase Deficiency
category: Mendelian
creation_date: '2026-05-03T00:00:00Z'
updated_date: '2026-05-21T14:44:51Z'
synonyms:
- Oxoprolinuria due to oxoprolinase deficiency
- OPLAH deficiency
- OPLAHD
- Pyroglutamic aciduria due to OPLAH deficiency
description: >
  5-oxoprolinase deficiency is a very rare autosomal recessive inborn error of
  the gamma-glutamyl cycle caused by biallelic variants in OPLAH, which encodes
  ATP-dependent 5-oxoprolinase. Reduced 5-oxoprolinase activity impairs
  conversion of 5-oxo-L-proline to L-glutamate, producing persistent
  5-oxoprolinuria. The clinical significance is heterogeneous and incompletely
  resolved: some molecularly confirmed individuals have largely benign courses,
  while symptomatic reports describe developmental delay, speech delay,
  seizures, metabolic acidosis, and neuroimaging abnormalities. The most
  consistent disease-level features are elevated urinary 5-oxoproline and
  reduced 5-oxoprolinase activity.
disease_term:
  preferred_term: 5-oxoprolinase deficiency
  term:
    id: MONDO:0009825
    label: 5-oxoprolinase deficiency
parents:
- Inherited Glutathione Metabolism Disease
- Inborn Error of Metabolism
prevalence:
- population: Worldwide
  percentage: Less than 1 per 1,000,000
  notes: >
    Orphanet classifies 5-oxoprolinase deficiency as ultra-rare, with published
    cases and families rather than population-based incidence data.
  evidence:
  - reference: ORPHA:33572
    supports: SUPPORT
    snippet: "<1 / 1 000 000 | Worldwide | Point prevalence | ORPHANET"
    explanation: Orphanet reports worldwide point prevalence below one per million.
progression:
- phase: Heterogeneous childhood-onset biochemical disorder
  notes: >
    Reported age of onset ranges from neonatal through childhood. Published
    series emphasize that persistently increased urinary 5-oxoproline is the
    stable biochemical finding, whereas clinical manifestations are highly
    variable and may not segregate with 5-oxoprolinuria in all families.
  evidence:
  - reference: ORPHA:33572
    supports: SUPPORT
    snippet: "Age of onset: Childhood"
    explanation: Orphanet records childhood among reported ages of onset.
  - reference: ORPHA:33572
    supports: SUPPORT
    snippet: "Age of onset: Infancy"
    explanation: Orphanet records infancy among reported ages of onset.
  - reference: ORPHA:33572
    supports: SUPPORT
    snippet: "Age of onset: Neonatal"
    explanation: Orphanet records neonatal onset among reported ages of onset.
  - reference: PMID:27477828
    reference_title: "Unravelling 5-oxoprolinuria (pyroglutamic aciduria) due to bi-allelic OPLAH mutations: 20 new mutations in 14 families."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Clinical features were highly variable"
    explanation: The largest mutation series emphasizes variable clinical expression.
  - reference: PMID:21651516
    reference_title: "5-Oxoprolinase deficiency: report of the first human OPLAH mutation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "from normal to significant neurological involvement."
    explanation: The first molecular report summarizes the broad clinical range.
pathophysiology:
- name: OPLAH molecular function deficiency
  description: >
    Biallelic OPLAH variants reduce ATP-dependent 5-oxoprolinase activity in the
    gamma-glutamyl cycle. OPLAH encodes 5-oxoprolinase, which normally converts
    5-oxo-L-proline to L-glutamate.
  genes:
  - preferred_term: OPLAH
    term:
      id: hgnc:8149
      label: OPLAH
  molecular_functions:
  - preferred_term: 5-oxoprolinase (ATP-hydrolyzing) activity
    term:
      id: GO:0017168
      label: 5-oxoprolinase (ATP-hydrolyzing) activity
    modifier: DECREASED
  biological_processes:
  - preferred_term: glutathione metabolic process
    term:
      id: GO:0006749
      label: glutathione metabolic process
    modifier: DYSREGULATED
  - preferred_term: glutathione biosynthetic process
    term:
      id: GO:0006750
      label: glutathione biosynthetic process
    modifier: DYSREGULATED
  - preferred_term: glutamate metabolic process
    term:
      id: GO:0006536
      label: glutamate metabolic process
    modifier: DYSREGULATED
  chemical_entities:
  - preferred_term: 5-oxo-L-proline
    term:
      id: CHEBI:18183
      label: 5-oxo-L-proline
    modifier: INCREASED
  - preferred_term: L-glutamate
    term:
      id: CHEBI:29985
      label: L-glutamate(1-)
  - preferred_term: glutathione
    term:
      id: CHEBI:16856
      label: glutathione
  evidence:
  - reference: ORPHA:33572
    supports: SUPPORT
    snippet: "OPLAH | 5-oxoprolinase, ATP-hydrolysing | hgnc:8149 | Disease-causing germline mutation(s) in"
    explanation: Orphanet identifies OPLAH as the disease-causing gene.
  - reference: PMID:27477828
    reference_title: "Unravelling 5-oxoprolinuria (pyroglutamic aciduria) due to bi-allelic OPLAH mutations: 20 new mutations in 14 families."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "bi-allelic mutations in OPLAH were indicated."
    explanation: The largest patient series supports biallelic OPLAH variants as the molecular cause.
  - reference: PMID:25129617
    reference_title: "New insights into the genetics of 5-oxoprolinase deficiency and further evidence that it is a benign biochemical condition."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "reported missense mutations in the OPLAH gene. A yeast in vivo growth assay"
    explanation: Functional testing of reported OPLAH missense variants supports reduced enzyme activity for selected alleles.
  - reference: PMID:39129838
    reference_title: "Is 5-Oxoprolinase Deficiency More than Just a Benign Condition?"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "which are enzymes involved in the gamma-glutamyl cycle in glutathione metabolism."
    explanation: Recent human case-report review supports the OPLAH enzyme's placement in glutathione-cycle metabolism.
  downstream:
  - target: Gamma-glutamyl cycle block and 5-oxoproline accumulation
    causal_link_type: DIRECT
    description: Reduced 5-oxoprolinase activity blocks clearance of 5-oxo-L-proline.
    evidence:
    - reference: PMID:39129838
      reference_title: "Is 5-Oxoprolinase Deficiency More than Just a Benign Condition?"
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "the genes that encode glutathione synthetase (GSS) and 5-oxoprolinase (OPLAH), which are enzymes involved in the gamma-glutamyl cycle"
      explanation: Human case-report review links OPLAH deficiency to the gamma-glutamyl-cycle enzymes that generate primary 5-oxoprolinuria.
  - target: Reduced 5-oxoprolinase activity
    causal_link_type: DIRECT
    description: OPLAH encodes the enzyme measured as reduced 5-oxoprolinase activity.
    evidence:
    - reference: PMID:21651516
      reference_title: "5-Oxoprolinase deficiency: report of the first human OPLAH mutation."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "mutation in OPLAH (which encodes 5-oxoprolinase)."
      explanation: First molecular report supports OPLAH as the gene encoding measured 5-oxoprolinase activity.
  - target: Reduced circulating 5-oxoprolinase activity
    causal_link_type: DIRECT
    description: OPLAH molecular dysfunction is directly reflected by reduced measured 5-oxoprolinase activity.
    evidence:
    - reference: ORPHA:33572
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "HP:0040142 | Reduced circulating 5-oxoprolinase activity | Very frequent (99-80%)"
      explanation: Orphanet supports reduced circulating 5-oxoprolinase activity as the frequent measured functional consequence.
- name: Gamma-glutamyl cycle block and 5-oxoproline accumulation
  description: >
    The gamma-glutamyl cycle mediates glutathione synthesis and degradation.
    Impaired 5-oxoprolinase activity causes accumulation of 5-oxo-L-proline,
    also called pyroglutamic acid, producing the diagnostic 5-oxoprolinuria.
  biological_processes:
  - preferred_term: glutathione metabolic process
    term:
      id: GO:0006749
      label: glutathione metabolic process
    modifier: DYSREGULATED
  - preferred_term: glutathione biosynthetic process
    term:
      id: GO:0006750
      label: glutathione biosynthetic process
    modifier: DYSREGULATED
  - preferred_term: glutamate metabolic process
    term:
      id: GO:0006536
      label: glutamate metabolic process
    modifier: DYSREGULATED
  chemical_entities:
  - preferred_term: 5-oxo-L-proline
    term:
      id: CHEBI:18183
      label: 5-oxo-L-proline
    modifier: INCREASED
  - preferred_term: L-glutamate
    term:
      id: CHEBI:29985
      label: L-glutamate(1-)
  - preferred_term: glutathione
    term:
      id: CHEBI:16856
      label: glutathione
  evidence:
  - reference: PMID:27477828
    reference_title: "Unravelling 5-oxoprolinuria (pyroglutamic aciduria) due to bi-allelic OPLAH mutations: 20 new mutations in 14 families."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "the γ-glutamyl cycle, affecting either glutathione synthetase or 5-oxoprolinase."
    explanation: Places 5-oxoprolinase deficiency in the gamma-glutamyl cycle.
  - reference: PMID:17397529
    reference_title: "Inborn errors in the metabolism of glutathione."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "5-Oxoprolinase deficiency is associated with 5-oxoprolinuria"
    explanation: Review evidence supports 5-oxoprolinuria as the core biochemical abnormality.
  - reference: PMID:25851806
    reference_title: "Five Chinese patients with 5-oxoprolinuria due to glutathione synthetase and 5-oxoprolinase deficiencies."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "All patients had significantly elevated urine 5-oxoproline."
    explanation: Clinical series documents elevated urinary 5-oxoproline in affected patients.
  downstream:
  - target: Increased urinary 5-oxoproline
    causal_link_type: DIRECT
    description: Failure to clear 5-oxo-L-proline causes elevated urinary 5-oxoproline.
    evidence:
    - reference: PMID:25851806
      reference_title: "Five Chinese patients with 5-oxoprolinuria due to glutathione synthetase and 5-oxoprolinase deficiencies."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "All patients had significantly elevated urine 5-oxoproline."
      explanation: Clinical series supports elevated urinary 5-oxoproline as the direct biochemical consequence represented by this edge.
  - target: Increased urinary L-pyroglutamic acid
    causal_link_type: DIRECT
    description: Urinary L-pyroglutamic acid is the HPO phenotype corresponding to accumulated 5-oxoproline.
    evidence:
    - reference: ORPHA:33572
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "HP:0410132 | Increased level of L-pyroglutamic acid in urine | Very frequent (99-80%)"
      explanation: Orphanet maps OPLAH deficiency to increased urinary L-pyroglutamic acid, the clinical descriptor for urinary 5-oxoproline accumulation.
  - target: Metabolic acidosis
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Metabolic acidosis is reported in OPLAH deficiency, but the causal connection to 5-oxoprolinuria is incompletely resolved.
    evidence:
    - reference: ORPHA:33572
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "HP:0001942 | Metabolic acidosis | Occasional (29-5%)"
      explanation: Orphanet supports metabolic acidosis as an occasional OPLAH-deficiency phenotype; the edge remains indirect because the biochemical intermediates are unresolved.
  - target: Hypoglycemia
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Hypoglycemia is an occasional Orphanet phenotype with uncertain mechanistic connection to OPLAH deficiency.
    evidence:
    - reference: ORPHA:33572
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "HP:0001943 | Hypoglycemia | Occasional (29-5%)"
      explanation: Orphanet supports hypoglycemia as an occasional reported phenotype, while the causal route from 5-oxoproline accumulation remains undefined.
  - target: Feeding difficulties in infancy
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Feeding problems occur in symptomatic 5-oxoprolinuria reports, but penetrance and causality remain uncertain.
    evidence:
    - reference: PMID:25851806
      reference_title: "Five Chinese patients with 5-oxoprolinuria due to glutathione synthetase and 5-oxoprolinase deficiencies."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Patients were hospitalized between the age of 13days to 1year and 3months for hypersomnia, developmental retardation, feeding deficiency, vomiting, icterus and recurrent pneumonia."
      explanation: Human clinical series supports feeding problems among symptomatic 5-oxoprolinuria patients; the edge remains indirect because OPLAH-specific causality is uncertain.
  - target: Failure to thrive
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Failure to thrive is an occasional reported manifestation in the variable symptomatic spectrum.
    evidence:
    - reference: ORPHA:33572
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "HP:0001508 | Failure to thrive | Occasional (29-5%)"
      explanation: Orphanet supports failure to thrive as an occasional manifestation; the connection to the primary metabolite abnormality is treated as indirect.
  - target: Global developmental delay
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Developmental delay is reported in symptomatic patients, but larger series note incomplete segregation with 5-oxoprolinuria.
    evidence:
    - reference: ORPHA:33572
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "HP:0001263 | Global developmental delay | Frequent (79-30%)"
      explanation: Orphanet supports global developmental delay as a frequent reported phenotype, although the edge remains mechanistically indirect.
  - target: Hypotonia
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Hypotonia is an occasional reported neurologic phenotype with uncertain direct mechanism.
    evidence:
    - reference: ORPHA:33572
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "HP:0001252 | Hypotonia | Occasional (29-5%)"
      explanation: Orphanet supports hypotonia as an occasional neurologic phenotype; direct intermediates downstream of 5-oxoproline accumulation are not established.
  - target: Seizure
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Seizures are reported in symptomatic patients, but a direct biochemical mechanism is not established.
    evidence:
    - reference: PMID:39129838
      reference_title: "Is 5-Oxoprolinase Deficiency More than Just a Benign Condition?"
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "presented with epilepsy at the age of 2 years."
      explanation: Case report supports seizures in an OPLAH-deficient patient, while the causal path from metabolite accumulation remains unresolved.
  - target: Delayed speech and language development
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Speech delay is part of the reported variable neurologic spectrum.
    evidence:
    - reference: PMID:39129838
      reference_title: "Is 5-Oxoprolinase Deficiency More than Just a Benign Condition?"
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "He did not speak fluently. He was using 5-10 words with decreased language fluency."
      explanation: Case report supports delayed speech/language involvement in an OPLAH-deficient child; the mechanism remains indirect.
  - target: Cerebral atrophy
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Brain atrophy has been reported in a symptomatic OPLAH-deficient patient, but causality remains case-level.
    evidence:
    - reference: PMID:39129838
      reference_title: "Is 5-Oxoprolinase Deficiency More than Just a Benign Condition?"
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Progressive cerebral atrophy, hypomyelination, ventriculomegaly, and corpus callosum hypoplasia"
      explanation: Case report documents cerebral atrophy in an OPLAH-deficient patient, supporting the association while retaining indirect causality.
  - target: Postnatal macrocephaly
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Postnatal macrocephaly has been reported in a symptomatic patient and in Orphanet, without a defined intermediate mechanism.
    evidence:
    - reference: PMID:39129838
      reference_title: "Is 5-Oxoprolinase Deficiency More than Just a Benign Condition?"
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "His past medical history revealed postnatal macrocephaly, hydrocephalus, and well-controlled epilepsy with levetiracetam."
      explanation: Case report supports postnatal macrocephaly in OPLAH deficiency; intermediate mechanisms remain undefined.
  - target: Cerebral hypomyelination
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Hypomyelination was reported in a symptomatic patient with elevated urinary 5-oxoproline.
    evidence:
    - reference: PMID:39129838
      reference_title: "Is 5-Oxoprolinase Deficiency More than Just a Benign Condition?"
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Progressive cerebral atrophy, hypomyelination, ventriculomegaly, and corpus callosum hypoplasia"
      explanation: Case report documents hypomyelination with other MRI abnormalities in an OPLAH-deficient patient.
  - target: Ventriculomegaly
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Ventriculomegaly was reported in a symptomatic OPLAH-deficient patient, but mechanism is unresolved.
    evidence:
    - reference: PMID:39129838
      reference_title: "Is 5-Oxoprolinase Deficiency More than Just a Benign Condition?"
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Progressive cerebral atrophy, hypomyelination, ventriculomegaly, and corpus callosum hypoplasia"
      explanation: Case report documents ventriculomegaly among MRI findings in an OPLAH-deficient patient.
  - target: Hypoplasia of the corpus callosum
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Corpus callosum hypoplasia was reported in a symptomatic OPLAH-deficient patient, with uncertain causality.
    evidence:
    - reference: PMID:39129838
      reference_title: "Is 5-Oxoprolinase Deficiency More than Just a Benign Condition?"
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Progressive cerebral atrophy, hypomyelination, ventriculomegaly, and corpus callosum hypoplasia"
      explanation: Case report documents corpus callosum hypoplasia among MRI findings in an OPLAH-deficient patient.
phenotypes:
- name: Increased urinary L-pyroglutamic acid
  frequency: VERY_FREQUENT
  description: Persistent urinary 5-oxoproline elevation is the defining biochemical phenotype.
  phenotype_term:
    preferred_term: Increased level of L-pyroglutamic acid in urine
    term:
      id: HP:0410132
      label: Increased level of L-pyroglutamic acid in urine
  evidence:
  - reference: ORPHA:33572
    supports: SUPPORT
    snippet: "HP:0410132 | Increased level of L-pyroglutamic acid in urine | Very frequent (99-80%)"
    explanation: Orphanet reports increased urinary L-pyroglutamic acid as very frequent.
  - reference: PMID:27477828
    reference_title: "Unravelling 5-oxoprolinuria (pyroglutamic aciduria) due to bi-allelic OPLAH mutations: 20 new mutations in 14 families."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In all patients with 5-oxoprolinuria studied"
    explanation: The mutation series is anchored on patients ascertained for 5-oxoprolinuria.
- name: Reduced circulating 5-oxoprolinase activity
  frequency: VERY_FREQUENT
  description: Reduced enzyme activity is the direct biochemical expression of OPLAH deficiency.
  phenotype_term:
    preferred_term: Reduced circulating 5-oxoprolinase activity
    term:
      id: HP:0040142
      label: Reduced circulating 5-oxoprolinase activity
  evidence:
  - reference: ORPHA:33572
    supports: SUPPORT
    snippet: "HP:0040142 | Reduced circulating 5-oxoprolinase activity | Very frequent (99-80%)"
    explanation: Orphanet reports reduced circulating 5-oxoprolinase activity as very frequent.
- name: Global developmental delay
  frequency: FREQUENT
  description: Developmental delay is reported frequently by Orphanet, but literature emphasizes uncertain segregation in some families.
  phenotype_term:
    preferred_term: Global developmental delay
    term:
      id: HP:0001263
      label: Global developmental delay
  evidence:
  - reference: ORPHA:33572
    supports: SUPPORT
    snippet: "HP:0001263 | Global developmental delay | Frequent (79-30%)"
    explanation: Orphanet reports global developmental delay as frequent.
  - reference: PMID:25851806
    reference_title: "Five Chinese patients with 5-oxoprolinuria due to glutathione synthetase and 5-oxoprolinase deficiencies."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "developmental retardation"
    explanation: A Chinese clinical series reported developmental delay among symptomatic patients.
- name: Metabolic acidosis
  frequency: OCCASIONAL
  description: Metabolic acidosis is occasional and is not as consistently associated with OPLAH deficiency as 5-oxoprolinuria.
  phenotype_term:
    preferred_term: Metabolic acidosis
    term:
      id: HP:0001942
      label: Metabolic acidosis
  evidence:
  - reference: ORPHA:33572
    supports: SUPPORT
    snippet: "HP:0001942 | Metabolic acidosis | Occasional (29-5%)"
    explanation: Orphanet reports metabolic acidosis as occasional.
- name: Seizure
  frequency: OCCASIONAL
  description: Seizures are occasional reported neurologic manifestations.
  phenotype_term:
    preferred_term: Seizure
    term:
      id: HP:0001250
      label: Seizure
  evidence:
  - reference: ORPHA:33572
    supports: SUPPORT
    snippet: "HP:0001250 | Seizure | Occasional (29-5%)"
    explanation: Orphanet reports seizures as occasional.
  - reference: PMID:39129838
    reference_title: "Is 5-Oxoprolinase Deficiency More than Just a Benign Condition?"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "presented with epilepsy at the age of 2 years."
    explanation: Case report documents epilepsy in a child with a homozygous OPLAH variant.
- name: Delayed speech and language development
  frequency: OCCASIONAL
  description: Speech delay is occasional in the reported phenotype spectrum.
  phenotype_term:
    preferred_term: Delayed speech and language development
    term:
      id: HP:0000750
      label: Delayed speech and language development
  evidence:
  - reference: ORPHA:33572
    supports: SUPPORT
    snippet: "HP:0000750 | Delayed speech and language development | Occasional (29-5%)"
    explanation: Orphanet reports delayed speech and language development as occasional.
  - reference: PMID:39129838
    reference_title: "Is 5-Oxoprolinase Deficiency More than Just a Benign Condition?"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "He did not speak fluently. He was using 5-10 words with decreased language fluency."
    explanation: Recent case report documents impaired speech fluency.
- name: Hypoglycemia
  frequency: OCCASIONAL
  description: Hypoglycemia is an occasional reported metabolic manifestation in Orphanet.
  phenotype_term:
    preferred_term: Hypoglycemia
    term:
      id: HP:0001943
      label: Hypoglycemia
  evidence:
  - reference: ORPHA:33572
    supports: SUPPORT
    snippet: "HP:0001943 | Hypoglycemia | Occasional (29-5%)"
    explanation: Orphanet reports hypoglycemia as occasional.
- name: Feeding difficulties in infancy
  frequency: OCCASIONAL
  description: Feeding difficulty has been reported in symptomatic infant presentations of inherited 5-oxoprolinuria.
  phenotype_term:
    preferred_term: Feeding difficulties in infancy
    term:
      id: HP:0008872
      label: Feeding difficulties in infancy
  evidence:
  - reference: ORPHA:33572
    supports: SUPPORT
    snippet: "HP:0008872 | Feeding difficulties in infancy | Occasional (29-5%)"
    explanation: Orphanet reports feeding difficulties in infancy as occasional.
  - reference: PMID:25851806
    reference_title: "Five Chinese patients with 5-oxoprolinuria due to glutathione synthetase and 5-oxoprolinase deficiencies."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Patients were hospitalized between the age of 13days to 1year and 3months for hypersomnia, developmental retardation, feeding deficiency, vomiting, icterus and recurrent pneumonia."
    explanation: The Chinese clinical series reported feeding problems among symptomatic 5-oxoprolinuria patients.
- name: Failure to thrive
  frequency: OCCASIONAL
  description: Failure to thrive is an occasional reported feature of the variable symptomatic spectrum.
  phenotype_term:
    preferred_term: Failure to thrive
    term:
      id: HP:0001508
      label: Failure to thrive
  evidence:
  - reference: ORPHA:33572
    supports: SUPPORT
    snippet: "HP:0001508 | Failure to thrive | Occasional (29-5%)"
    explanation: Orphanet reports failure to thrive as occasional.
- name: Hypotonia
  frequency: OCCASIONAL
  description: Hypotonia is an occasional reported neuromuscular manifestation.
  phenotype_term:
    preferred_term: Hypotonia
    term:
      id: HP:0001252
      label: Hypotonia
  evidence:
  - reference: ORPHA:33572
    supports: SUPPORT
    snippet: "HP:0001252 | Hypotonia | Occasional (29-5%)"
    explanation: Orphanet reports hypotonia as occasional.
- name: Cerebral atrophy
  frequency: OCCASIONAL
  description: Cerebral atrophy is an occasional imaging abnormality and has been reported in a recent symptomatic OPLAH case.
  phenotype_term:
    preferred_term: Cerebral atrophy
    term:
      id: HP:0002059
      label: Cerebral atrophy
  evidence:
  - reference: ORPHA:33572
    supports: SUPPORT
    snippet: "HP:0002059 | Cerebral atrophy | Occasional (29-5%)"
    explanation: Orphanet reports cerebral atrophy as occasional.
  - reference: PMID:39129838
    reference_title: "Is 5-Oxoprolinase Deficiency More than Just a Benign Condition?"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Progressive cerebral atrophy, hypomyelination, ventriculomegaly, and corpus callosum hypoplasia"
    explanation: Recent case report documents cerebral atrophy among brain MRI findings.
- name: Postnatal macrocephaly
  frequency: OCCASIONAL
  description: Postnatal macrocephaly is an occasional reported head-size abnormality.
  phenotype_term:
    preferred_term: Postnatal macrocephaly
    term:
      id: HP:0005490
      label: Postnatal macrocephaly
  evidence:
  - reference: ORPHA:33572
    supports: SUPPORT
    snippet: "HP:0005490 | Postnatal macrocephaly | Occasional (29-5%)"
    explanation: Orphanet reports postnatal macrocephaly as occasional.
  - reference: PMID:39129838
    reference_title: "Is 5-Oxoprolinase Deficiency More than Just a Benign Condition?"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "His past medical history revealed postnatal macrocephaly, hydrocephalus, and well-controlled epilepsy with levetiracetam."
    explanation: Recent case report documents postnatal macrocephaly in a symptomatic OPLAH-deficient child.
- name: Cerebral hypomyelination
  description: Cerebral hypomyelination has been reported in a symptomatic child with OPLAH-associated 5-oxoprolinuria.
  phenotype_term:
    preferred_term: Cerebral hypomyelination
    term:
      id: HP:0006808
      label: Cerebral hypomyelination
  evidence:
  - reference: PMID:39129838
    reference_title: "Is 5-Oxoprolinase Deficiency More than Just a Benign Condition?"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Progressive cerebral atrophy, hypomyelination, ventriculomegaly, and corpus callosum hypoplasia"
    explanation: Recent case report documents cerebral hypomyelination among brain MRI findings.
- name: Ventriculomegaly
  description: Ventriculomegaly has been reported in a symptomatic child with OPLAH-associated 5-oxoprolinuria.
  phenotype_term:
    preferred_term: Ventriculomegaly
    term:
      id: HP:0002119
      label: Ventriculomegaly
  evidence:
  - reference: PMID:39129838
    reference_title: "Is 5-Oxoprolinase Deficiency More than Just a Benign Condition?"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Progressive cerebral atrophy, hypomyelination, ventriculomegaly, and corpus callosum hypoplasia"
    explanation: Recent case report documents ventriculomegaly among brain MRI findings.
- name: Hypoplasia of the corpus callosum
  description: Corpus callosum hypoplasia has been reported in a symptomatic child with OPLAH-associated 5-oxoprolinuria.
  phenotype_term:
    preferred_term: Hypoplasia of the corpus callosum
    term:
      id: HP:0002079
      label: Hypoplasia of the corpus callosum
  evidence:
  - reference: PMID:39129838
    reference_title: "Is 5-Oxoprolinase Deficiency More than Just a Benign Condition?"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Progressive cerebral atrophy, hypomyelination, ventriculomegaly, and corpus callosum hypoplasia"
    explanation: Recent case report documents corpus callosum hypoplasia among brain MRI findings.
biochemical:
- name: Increased urinary 5-oxoproline
  presence: INCREASED
  context: >
    Urinary 5-oxoproline, also called L-pyroglutamic acid, is persistently
    increased and is the primary biochemical marker for OPLAH deficiency.
  biomarker_term:
    preferred_term: 5-oxo-L-proline
    term:
      id: CHEBI:18183
      label: 5-oxo-L-proline
  readouts:
  - target: Gamma-glutamyl cycle block and 5-oxoproline accumulation
    relationship: READOUT_OF
    direction: POSITIVE
    endpoint_context: DIAGNOSTIC
    interpretation: >
      Elevated urinary 5-oxoproline directly reports accumulation of the
      substrate that is not cleared by deficient OPLAH activity.
  - target: Increased urinary L-pyroglutamic acid
    relationship: READOUT_OF
    direction: POSITIVE
    endpoint_context: DIAGNOSTIC
    interpretation: >
      Urinary 5-oxoproline is the measured metabolite represented clinically as
      increased urinary L-pyroglutamic acid.
    evidence:
    - reference: ORPHA:33572
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "HP:0410132 | Increased level of L-pyroglutamic acid in urine | Very frequent (99-80%)"
      explanation: Orphanet maps the urinary 5-oxoproline abnormality to the L-pyroglutamic-acid HPO phenotype.
  evidence:
  - reference: PMID:39129838
    reference_title: "Is 5-Oxoprolinase Deficiency More than Just a Benign Condition?"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "quantitation of 5-oxoproline by stable isotope dilution gave a value of 177.9"
    explanation: Case report provides quantitative urinary 5-oxoproline elevation.
  - reference: ORPHA:33572
    supports: SUPPORT
    snippet: "HP:0410132 | Increased level of L-pyroglutamic acid in urine | Very frequent (99-80%)"
    explanation: Orphanet supports increased urinary L-pyroglutamic acid as the dominant biochemical phenotype.
- name: Reduced 5-oxoprolinase activity
  presence: DECREASED
  context: >
    OPLAH variants reduce 5-oxoprolinase activity, blocking the ATP-dependent
    conversion of 5-oxo-L-proline in the gamma-glutamyl cycle.
  readouts:
  - target: OPLAH molecular function deficiency
    relationship: READOUT_OF
    direction: NEGATIVE
    endpoint_context: DIAGNOSTIC
    interpretation: >
      Reduced 5-oxoprolinase activity is the direct functional readout of
      deficient OPLAH molecular function.
  - target: Reduced circulating 5-oxoprolinase activity
    relationship: READOUT_OF
    direction: NEGATIVE
    endpoint_context: DIAGNOSTIC
    interpretation: >
      Reduced enzyme activity is the biochemical measurement represented by the
      reduced circulating 5-oxoprolinase activity phenotype.
    evidence:
    - reference: ORPHA:33572
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "HP:0040142 | Reduced circulating 5-oxoprolinase activity | Very frequent (99-80%)"
      explanation: Orphanet supports reduced circulating 5-oxoprolinase activity as the corresponding biochemical phenotype.
  evidence:
  - reference: PMID:25129617
    reference_title: "New insights into the genetics of 5-oxoprolinase deficiency and further evidence that it is a benign biochemical condition."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "revealed that only p.S323R, p.G860R and p.D1241V affected the activity of the"
    explanation: Functional assay supports reduced 5-oxoprolinase activity for selected OPLAH missense variants.
  - reference: ORPHA:33572
    supports: SUPPORT
    snippet: "HP:0040142 | Reduced circulating 5-oxoprolinase activity | Very frequent (99-80%)"
    explanation: Orphanet supports reduced 5-oxoprolinase activity as very frequent.
treatments:
- name: Symptomatic neurologic care and longitudinal follow-up
  description: >
    No disease-modifying therapy is established for OPLAH deficiency. Management
    is therefore centered on long-term observation and standard symptomatic care
    for manifestations such as epilepsy, developmental delay, and speech delay.
    A reported antioxidant and cofactor regimen did not improve the two
    OPLAH-deficient patients in one mixed 5-oxoprolinuria series, so this entry
    does not model that regimen as an effective OPLAH-directed therapy.
  treatment_term:
    preferred_term: supportive care
    term:
      id: MAXO:0000950
      label: supportive care
  target_phenotypes:
  - preferred_term: Seizure
    term:
      id: HP:0001250
      label: Seizure
  - preferred_term: Global developmental delay
    term:
      id: HP:0001263
      label: Global developmental delay
  - preferred_term: Delayed speech and language development
    term:
      id: HP:0000750
      label: Delayed speech and language development
  evidence:
  - reference: PMID:17397529
    reference_title: Inborn errors in the metabolism of glutathione.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "No treatment has been recommended for gamma-glutamyl transpeptidase, 5-oxoprolinase and dipeptidase deficiency."
    explanation: Glutathione-metabolism review supports absence of an established disease-specific therapy.
  - reference: PMID:25851806
    reference_title: "Five Chinese patients with 5-oxoprolinuria due to glutathione synthetase and 5-oxoprolinase deficiencies."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "After treatment by l-carnitine, vitamin E, B1, B2 and coenzyme Q10, three patients with GSS deficiency improved, but the two 5-oxoprolinase-deficient patients did not respond to treatment."
    explanation: Clinical series supports not modeling antioxidant/cofactor therapy as effective for OPLAH-deficient patients.
  - reference: PMID:39129838
    reference_title: "Is 5-Oxoprolinase Deficiency More than Just a Benign Condition?"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "well-controlled epilepsy with levetiracetam"
    explanation: Case report supports standard symptomatic seizure management in an OPLAH-deficient patient.
  - reference: PMID:27477828
    reference_title: "Unravelling 5-oxoprolinuria (pyroglutamic aciduria) due to bi-allelic OPLAH mutations: 20 new mutations in 14 families."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Additional patient ascertainment and long-term follow-up is needed"
    explanation: Larger series supports long-term follow-up because the clinical significance remains uncertain.
- name: Molecular genetic testing
  description: >
    Molecular testing of OPLAH is important in symptomatic individuals with
    persistent 5-oxoprolinuria to establish the diagnosis and distinguish OPLAH
    deficiency from glutathione synthetase deficiency and other overlapping
    causes of 5-oxoprolinuria.
  treatment_term:
    preferred_term: genetic testing
    term:
      id: MAXO:0000127
      label: genetic testing
  target_phenotypes:
  - preferred_term: Increased level of L-pyroglutamic acid in urine
    term:
      id: HP:0410132
      label: Increased level of L-pyroglutamic acid in urine
  - preferred_term: Reduced circulating 5-oxoprolinase activity
    term:
      id: HP:0040142
      label: Reduced circulating 5-oxoprolinase activity
  evidence:
  - reference: PMID:21651516
    reference_title: "5-Oxoprolinase deficiency: report of the first human OPLAH mutation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "highlights the importance of establishing a molecular diagnosis"
    explanation: First molecular report emphasizes molecular diagnosis in clinically abnormal cases.
  - reference: PMID:25851806
    reference_title: "Five Chinese patients with 5-oxoprolinuria due to glutathione synthetase and 5-oxoprolinase deficiencies."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Genetic analysis is important for the deferential diagnosis."
    explanation: Clinical series supports genetic testing to distinguish OPLAH from GSS deficiency.
- name: Genetic counseling
  description: >
    Genetic counseling addresses autosomal recessive inheritance, recurrence
    risk, carrier testing, and interpretation of biallelic private OPLAH
    variants in families with confirmed OPLAH deficiency.
  treatment_term:
    preferred_term: genetic counseling
    term:
      id: MAXO:0000079
      label: genetic counseling
  evidence:
  - reference: ORPHA:33572
    supports: SUPPORT
    snippet: "Autosomal recessive"
    explanation: Orphanet reports autosomal recessive inheritance, supporting recurrence-risk counseling.
  - reference: PMID:27477828
    reference_title: "Unravelling 5-oxoprolinuria (pyroglutamic aciduria) due to bi-allelic OPLAH mutations: 20 new mutations in 14 families."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "all 20 mutations identified were novel and private"
    explanation: Private family-specific variants support individualized counseling and family testing.
genetic:
- name: OPLAH variants
  gene_term:
    preferred_term: OPLAH
    term:
      id: hgnc:8149
      label: OPLAH
  inheritance:
  - name: Autosomal recessive
    evidence:
    - reference: ORPHA:33572
      supports: SUPPORT
      snippet: "Autosomal recessive"
      explanation: Orphanet reports autosomal recessive inheritance.
    - reference: PMID:27477828
      reference_title: "Unravelling 5-oxoprolinuria (pyroglutamic aciduria) due to bi-allelic OPLAH mutations: 20 new mutations in 14 families."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "autosomal recessive mode of"
      explanation: Familial segregation in the mutation series supports autosomal recessive inheritance.
  variants:
  - name: Biallelic private OPLAH variants
    description: >
      Reported affected individuals carry homozygous or compound heterozygous
      OPLAH variants, many private to individual families. Published functional
      work supports activity loss for selected missense variants, but clinical
      penetrance remains uncertain.
    evidence:
    - reference: PMID:27477828
      reference_title: "Unravelling 5-oxoprolinuria (pyroglutamic aciduria) due to bi-allelic OPLAH mutations: 20 new mutations in 14 families."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "all 20 mutations identified were novel and private"
      explanation: The largest mutation series reports multiple private OPLAH variants.
    - reference: PMID:25129617
      reference_title: "New insights into the genetics of 5-oxoprolinase deficiency and further evidence that it is a benign biochemical condition."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "p.S323R, p.G860R and p.D1241V affected the activity of the"
      explanation: Yeast functional assay supports enzyme activity effects for selected OPLAH variants.
  features: >
    OPLAH encodes ATP-dependent 5-oxoprolinase. Biallelic variants cause
    persistent 5-oxoprolinuria, while heterozygous carrier samples in the largest
    series did not show 5-oxoprolinuria.
  evidence:
  - reference: PMID:21651516
    reference_title: "5-Oxoprolinase deficiency: report of the first human OPLAH mutation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "mutation in OPLAH (which encodes 5-oxoprolinase)."
    explanation: First molecular report links OPLAH to 5-oxoprolinase deficiency.
  - reference: PMID:27477828
    reference_title: "Unravelling 5-oxoprolinuria (pyroglutamic aciduria) due to bi-allelic OPLAH mutations: 20 new mutations in 14 families."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "the absence of 5-oxoprolinuria in all tested heterozygotes."
    explanation: Supports recessive biochemical expression and absence of the urinary biomarker in tested carriers.
references:
- reference: ORPHA:33572
  title: 5-oxoprolinase deficiency
  found_in:
  - 5-Oxoprolinase_Deficiency-deep-research-cyberian-codex.md
  findings: []
- reference: PMID:17397529
  title: Inborn errors in the metabolism of glutathione.
  found_in:
  - 5-Oxoprolinase_Deficiency-deep-research-cyberian-codex.md
  findings: []
- reference: PMID:21651516
  title: "5-Oxoprolinase deficiency: report of the first human OPLAH mutation."
  found_in:
  - 5-Oxoprolinase_Deficiency-deep-research-cyberian-codex.md
  findings: []
- reference: PMID:25129617
  title: New insights into the genetics of 5-oxoprolinase deficiency and further evidence that it is a benign biochemical condition.
  found_in:
  - 5-Oxoprolinase_Deficiency-deep-research-cyberian-codex.md
  findings: []
- reference: PMID:25851806
  title: Five Chinese patients with 5-oxoprolinuria due to glutathione synthetase and 5-oxoprolinase deficiencies.
  found_in:
  - 5-Oxoprolinase_Deficiency-deep-research-cyberian-codex.md
  findings: []
- reference: PMID:27477828
  title: "Unravelling 5-oxoprolinuria (pyroglutamic aciduria) due to bi-allelic OPLAH mutations: 20 new mutations in 14 families."
  found_in:
  - 5-Oxoprolinase_Deficiency-deep-research-cyberian-codex.md
  findings: []
- reference: PMID:39129838
  title: Is 5-Oxoprolinase Deficiency More than Just a Benign Condition?
  found_in:
  - 5-Oxoprolinase_Deficiency-deep-research-cyberian-codex.md
  findings: []
- reference: DOI:10.1111/j.1399-0004.2011.01728.x
  title: "5-Oxoprolinase deficiency: report of the first human OPLAH mutation"
  found_in:
  - 5-Oxoprolinase_Deficiency-deep-research-falcon.md
  findings: []
- reference: DOI:10.1007/8904_2012_166
  title: 5-Oxoprolinuria in Heterozygous Patients for 5-Oxoprolinase (OPLAH) Missense Changes
  found_in:
  - 5-Oxoprolinase_Deficiency-deep-research-falcon.md
  findings: []
- reference: DOI:10.1159/000536295
  title: Is 5-Oxoprolinase Deficiency More than Just a Benign Condition?
  found_in:
  - 5-Oxoprolinase_Deficiency-deep-research-falcon.md
  findings: []
- reference: DOI:10.3390/jcm13195781
  title: "Drug-Related Pyroglutamic Acidosis: Systematic Literature Review"
  found_in:
  - 5-Oxoprolinase_Deficiency-deep-research-falcon.md
  findings: []
- reference: DOI:10.1016/j.clinme.2024.100030
  title: Pyroglutamate acidosis 2023. A review of 100 cases
  found_in:
  - 5-Oxoprolinase_Deficiency-deep-research-falcon.md
  findings: []
- reference: DOI:10.1074/jbc.m117.805028
  title: Discovery of a widespread prokaryotic 5-oxoprolinase that was hiding in plain sight
  found_in:
  - 5-Oxoprolinase_Deficiency-deep-research-falcon.md
  findings: []
- reference: DOI:10.19185/matters.201609000009
  title: Carnitine Palmitoyltransfersase-1c and 5-oxoprolinase interact in the mouse brain
  found_in:
  - 5-Oxoprolinase_Deficiency-deep-research-falcon.md
  findings: []
notes: >-
  Curation intentionally treats OPLAH deficiency as a primarily biochemical
  inborn error with uncertain clinical penetrance. Literature contains both
  benign-course reports and symptomatic cases, so downstream clinical
  manifestations are represented cautiously and supported with partial or
  case-level evidence where appropriate.
📚

References & Deep Research

References

14
ORPHA:33572
5-oxoprolinase deficiency
No top-level findings curated for this source.
PMID:17397529
Inborn errors in the metabolism of glutathione.
No top-level findings curated for this source.
PMID:21651516
5-Oxoprolinase deficiency: report of the first human OPLAH mutation.
No top-level findings curated for this source.
PMID:25129617
New insights into the genetics of 5-oxoprolinase deficiency and further evidence that it is a benign biochemical condition.
No top-level findings curated for this source.
PMID:25851806
Five Chinese patients with 5-oxoprolinuria due to glutathione synthetase and 5-oxoprolinase deficiencies.
No top-level findings curated for this source.
PMID:27477828
Unravelling 5-oxoprolinuria (pyroglutamic aciduria) due to bi-allelic OPLAH mutations: 20 new mutations in 14 families.
No top-level findings curated for this source.
PMID:39129838
Is 5-Oxoprolinase Deficiency More than Just a Benign Condition?
No top-level findings curated for this source.
DOI:10.1111/j.1399-0004.2011.01728.x
5-Oxoprolinase deficiency: report of the first human OPLAH mutation
No top-level findings curated for this source.
DOI:10.1007/8904_2012_166
5-Oxoprolinuria in Heterozygous Patients for 5-Oxoprolinase (OPLAH) Missense Changes
No top-level findings curated for this source.
DOI:10.1159/000536295
Is 5-Oxoprolinase Deficiency More than Just a Benign Condition?
No top-level findings curated for this source.
DOI:10.3390/jcm13195781
Drug-Related Pyroglutamic Acidosis: Systematic Literature Review
No top-level findings curated for this source.
DOI:10.1016/j.clinme.2024.100030
Pyroglutamate acidosis 2023. A review of 100 cases
No top-level findings curated for this source.
DOI:10.1074/jbc.m117.805028
Discovery of a widespread prokaryotic 5-oxoprolinase that was hiding in plain sight
No top-level findings curated for this source.
DOI:10.19185/matters.201609000009
Carnitine Palmitoyltransfersase-1c and 5-oxoprolinase interact in the mouse brain
No top-level findings curated for this source.

Deep Research

2
Cyberian Codex ▸
Evidence Basis
codex-local-synthesis 7 citations 2026-05-03T11:03:39Z

Evidence Basis

This local Codex synthesis uses the cached Orphanet record for ORPHA:33572 and the PubMed references integrated into the YAML. The Asta retrieval attempt for this disease returned off-topic literature and was not used.

Core Disease Mechanism

  • 5-oxoprolinase deficiency maps directly to MONDO:0009825 and ORPHA:33572.
  • Orphanet lists OPLAH as the disease-causing gene and records autosomal recessive inheritance.
  • OPLAH encodes ATP-dependent 5-oxoprolinase, a gamma-glutamyl-cycle enzyme. Biallelic OPLAH variants reduce 5-oxoprolinase activity and impair clearance of 5-oxo-L-proline, also called pyroglutamic acid.
  • The most consistent disease feature is persistent urinary 5-oxoproline elevation, represented in HPO as increased urinary L-pyroglutamic acid.

Clinical Interpretation

  • Published molecular reports support a rare biochemical disorder with variable clinical expression. Earlier series described benign or uncertain clinical impact in some families, while later case reports and Orphanet phenotypes include developmental delay, delayed speech, seizures, metabolic acidosis, and brain imaging abnormalities.
  • The YAML therefore treats neurologic and metabolic manifestations cautiously: the biochemical phenotype is high-confidence, while clinical penetrance and causality are supported at variable or case-level strength.

YAML Integration Notes

  • The primary pathophysiology chain is OPLAH molecular-function deficiency to gamma-glutamyl-cycle block to 5-oxoproline accumulation.
  • Genetic evidence uses biallelic OPLAH mutation series and first molecular report evidence.
  • Phenotypes are anchored to Orphanet frequency statements and reinforced only where PubMed evidence supports the same clinical or biochemical feature.

Citation Inventory

  • PMID:17397529
  • PMID:21651516
  • PMID:25129617
  • PMID:25851806
  • PMID:27477828
  • PMID:39129838
  • ORPHA:33572
Falcon ▸
Disease Characteristics Research Template
Edison Scientific Literature 16 citations 2026-05-29T20:22:26.218487

Question: You are an expert researcher providing comprehensive, well-cited information.

Provide detailed information focusing on: 1. Key concepts and definitions with current understanding 2. Recent developments and latest research (prioritize 2023-2024 sources) 3. Current applications and real-world implementations 4. Expert opinions and analysis from authoritative sources 5. Relevant statistics and data from recent studies

Format as a comprehensive research report with proper citations. Include URLs and publication dates where available. Always prioritize recent, authoritative sources and provide specific citations for all major claims.

Disease Characteristics Research Template

Target Disease

  • Disease Name: 5-Oxoprolinase Deficiency
  • MONDO ID: (if available)
  • Category: Mendelian

Research Objectives

Please provide a comprehensive research report on 5-Oxoprolinase Deficiency covering all of the disease characteristics listed below. This report will be used to populate a disease knowledge base entry. Be thorough and cite primary literature (PMID preferred) for all claims.

For each section, suggested databases/resources are listed. These are the first places you should search for information on each topic.

1. Disease Information

Search first: OMIM, Orphanet, ICD-10/ICD-11, MeSH, PubMed

  • What is the disease? Provide a concise overview.
  • What are the key identifiers? (OMIM, Orphanet, ICD-10/ICD-11, MeSH, Mondo)
  • What are the common synonyms and alternative names?
  • Is the information derived from individual patients (e.g., EHR) or aggregated disease-level resources?

2. Etiology

  • Disease Causal Factors: What are the primary causes? (genetic, environmental, infectious, mechanistic)
  • Risk Factors:

    Search first: PubMed, Cochrane Library, UpToDate, clinical guidelines, ClinVar, ClinGen, GWAS Catalog, PheGenI, CTD, CDC, WHO, epidemiological databases

  • Genetic risk factors (causal variants, susceptibility loci, modifier genes)
  • Environmental risk factors (toxins, lifestyle, occupational exposures, age, sex, family history)
  • Protective Factors:

    Search first: PubMed, Cochrane Library, clinical trial databases, GWAS Catalog, gnomAD, WHO, CDC, nutrition databases

  • Genetic protective factors (protective variants, modifier alleles)
  • Environmental protective factors (diet, lifestyle, exposures that reduce risk)
  • Gene-Environment Interactions: How do genetic and environmental factors interact to influence disease?

    Search first: CTD, PubMed, PheGenI, GxE databases

3. Phenotypes

Search first: HPO (Human Phenotype Ontology), OMIM, Orphanet, PubMed, clinicaltrials.gov, MedDRA, SNOMED CT, DECIPHER, LOINC

For each phenotype, provide: - Phenotype type: symptoms, clinical signs, physical manifestations, behavioral changes, or laboratory abnormalities

For symptoms/signs: HPO, OMIM, Orphanet, PubMed For behavioral changes: HPO, DSM, RDoC (Research Domain Criteria), PubMed For laboratory abnormalities: LOINC, SNOMED CT, LabTests Online, PubMed - Phenotype characteristics: Search first: OMIM, Orphanet, HPO, PubMed - Age of symptom onset (neonatal, childhood, adult-onset, late-onset) - Symptom severity (mild, moderate, severe, variable) - Symptom progression (stable, progressive, episodic, fluctuating) - Frequency among affected individuals (percentage or qualitative) - Quality of life impact: Effects on daily functioning and well-being (per-phenotype when possible) Search first: EQ-5D database, SF-36, WHO QOL databases, PubMed - Suggest HPO (Human Phenotype Ontology) terms for each phenotype

4. Genetic/Molecular Information

  • Causal Genes: Gene mutations or chromosomal abnormalities responsible for disease (gene symbols, OMIM IDs)

    Search first: OMIM, ClinVar, HGMD, Ensembl, NCBI Gene

  • Pathogenic Variants:
  • Affected genes (gene symbols, HGNC IDs) > Search first: OMIM, NCBI Gene, Ensembl, HGNC, UniProt, GeneCards
  • Variant classification (pathogenic, likely pathogenic, VUS per ACMG/AMP guidelines) > Search first: ClinVar, ClinGen, ACMG/AMP guidelines, VarSome
  • Variant type/class (missense, frameshift, nonsense, splice-site, structural)
  • Allele frequency in population databases > Search first: gnomAD, 1000 Genomes, ExAC, TOPMed, dbSNP
  • Somatic vs germline origin > Search first: COSMIC (somatic), ClinVar, ICGC, TCGA
  • Functional consequences (loss of function, gain of function, dominant negative)
  • Modifier Genes: Genes that modify disease severity or expression
  • Epigenetic Information: DNA methylation, histone modifications, chromatin changes affecting disease

    Search first: ENCODE, Roadmap Epigenomics, MethBase, DiseaseMeth

  • Chromosomal Abnormalities: Large-scale genetic changes (aneuploidy, translocations, inversions)

    Search first: DECIPHER, ClinVar, ECARUCA, UCSC Genome Browser

5. Environmental Information

  • Environmental Factors: Non-genetic contributing factors (toxins, radiation, pollution, occupational exposure)

    Search first: CTD (Comparative Toxicogenomics Database), TOXNET, PubMed, EPA databases

  • Lifestyle Factors: Behavioral factors (smoking, diet, exercise, alcohol consumption)

    Search first: CDC databases, WHO, PubMed, NHANES

  • Infectious Agents: If applicable, pathogens causing or triggering disease (bacteria, viruses, fungi, parasites)

    Search first: NCBI Taxonomy, ViPR, BV-BRC, MicrobeDB, GIDEON

6. Mechanism / Pathophysiology

  • Molecular Pathways: Specific signaling cascades or biochemical pathways involved (Wnt, MAPK, mTOR, PI3K-AKT, etc.)

    Search first: KEGG, Reactome, WikiPathways, PathBank, BioCyc

  • Cellular Processes: Cell-level mechanisms (apoptosis, autophagy, cell cycle dysregulation, inflammation, etc.)

    Search first: Gene Ontology (GO), Reactome, KEGG, PubMed

  • Protein Dysfunction: How protein structure or function is altered (misfolding, aggregation, loss of function, gain of function)

    Search first: UniProt, PDB (Protein Data Bank), InterPro, Pfam, AlphaFold

  • Metabolic Changes: Alterations in metabolic processes (energy metabolism, lipid metabolism, amino acid metabolism)

    Search first: KEGG, BioCyc, HMDB (Human Metabolome Database), BRENDA

  • Immune System Involvement: Role of immune response (autoimmunity, immunodeficiency, chronic inflammation)

    Search first: ImmPort, Immunome Database, IEDB, Gene Ontology

  • Tissue Damage Mechanisms: How tissues/ are injured (oxidative stress, ischemia, fibrosis, necrosis)

    Search first: PubMed, Gene Ontology, Reactome

  • Biochemical Abnormalities: Specific molecular defects (enzyme deficiencies, receptor dysfunction, ion channel defects)

    Search first: BRENDA, UniProt, KEGG, OMIM, PubMed

  • Epigenetic Changes: DNA methylation, histone modifications affecting gene expression in disease

    Search first: ENCODE, Roadmap Epigenomics, MethBase, DiseaseMeth

  • Molecular Profiling (if available):
  • Transcriptomics/gene expression changes > Search first: GEO (Gene Expression Omnibus), ArrayExpress, GTEx, Human Cell Atlas, SRA
  • Proteomics findings > Search first: PRIDE, ProteomeXchange, Human Protein Atlas, STRING, BioGRID
  • Metabolomics signatures > Search first: MetaboLights, Metabolomics Workbench, HMDB, METLIN
  • Lipidomics alterations > Search first: LIPID MAPS, SwissLipids, LipidHome, Metabolomics Workbench
  • Genomic structural features > Search first: UCSC Genome Browser, Ensembl, NCBI, dbVar, DGV
  • Advanced Technologies (if applicable):
  • Single-cell analysis findings (cell-type specific mechanisms, cellular heterogeneity) > Search first: Human Cell Atlas, Single Cell Portal, GEO, CELLxGENE
  • Spatial transcriptomics findings > Search first: GEO, Spatial Research, Vizgen, 10x Genomics data
  • Multi-omics integration results > Search first: TCGA, ICGC, cBioPortal, LinkedOmics, PubMed
  • Functional genomics screens (CRISPR, RNAi) > Search first: DepMap, GenomeRNAi, PubMed, BioGRID ORCS

For each mechanism, describe: - The causal chain from initial trigger to clinical manifestation - Which mechanisms are upstream vs downstream - What cell types and biological processes are involved - Suggest GO terms for biological processes and CL terms for cell types

7. Anatomical Structures Affected

  • Organ Level:
  • Primary organs directly affected
  • Secondary organ involvement (complications, secondary effects)
  • Body systems involved (cardiovascular, nervous, digestive, respiratory, endocrine, etc.)

    Search first: Uberon, FMA (Foundational Model of Anatomy), OMIM, HPO, ICD-11, MeSH, SNOMED CT

  • Tissue and Cell Level:
  • Specific tissue types affected (epithelial, connective, muscle, nervous)
  • Specific cell populations targeted (with Cell Ontology terms)

    Search first: Uberon, Human Protein Atlas, Cell Ontology, Human Cell Atlas, CellMarker, PanglaoDB

  • Subcellular Level:
  • Cellular compartments involved (mitochondria, nucleus, ER, lysosomes) (with GO Cellular Component terms)

    Search first: Gene Ontology (Cellular Component), UniProt, Human Protein Atlas

  • Localization:
  • Specific anatomical sites (with UBERON terms) > Search first: FMA, Uberon, NeuroNames (for brain), SNOMED CT
  • Lateralization (unilateral, bilateral, asymmetric) > Search first: HPO, clinical literature, imaging databases

8. Temporal Development

  • Onset:
  • Typical age of onset (congenital, pediatric, adult, geriatric)
  • Onset pattern (acute, subacute, chronic, insidious)

    Search first: OMIM, Orphanet, HPO, PubMed

  • Progression:
  • Disease stages (early, intermediate, advanced, end-stage) > Search first: Cancer Staging Manual (AJCC), WHO classifications, PubMed
  • Progression rate (rapid, slow, variable)
  • Disease course pattern (episodic, relapsing-remitting, progressive, stable)
  • Disease duration (self-limited, chronic lifelong)

    Search first: Disease registries, longitudinal cohort databases, natural history studies, PubMed, Orphanet, OMIM

  • Patterns:
  • Remission patterns (spontaneous, treatment-induced) > Search first: Clinical trial databases, disease registries, PubMed
  • Critical periods (time windows of vulnerability or opportunity for intervention) > Search first: PubMed, developmental biology databases, clinical guidelines

9. Inheritance and Population

  • Epidemiology:
  • Prevalence (cases per 100,000 at given time)
  • Incidence (new cases per 100,000 per year)

    Search first: Orphanet, CDC, WHO, GBD (Global Burden of Disease), national registries, SEER, disease registries

  • For Genetic Etiology:
  • Inheritance pattern (AD, AR, X-linked, mitochondrial, multifactorial, polygenic) > Search first: OMIM, Orphanet, ClinVar, GTR (Genetic Testing Registry)
  • Penetrance (complete, incomplete, age-dependent) > Search first: ClinVar, OMIM, PubMed, ClinGen
  • Expressivity (variable, consistent) > Search first: OMIM, ClinVar, PubMed
  • Genetic anticipation (increasing severity in successive generations) > Search first: OMIM, PubMed (especially for repeat expansion disorders)
  • Germline mosaicism > Search first: ClinVar, OMIM, genetic counseling literature, PubMed
  • Founder effects (population-specific mutations) > Search first: gnomAD, population genetics databases, PubMed
  • Consanguinity role > Search first: OMIM, population studies, genetic counseling resources
  • Carrier frequency > Search first: gnomAD, carrier screening databases, GeneReviews, GTR
  • Population Demographics:
  • Affected populations (ethnic or demographic groups with higher prevalence) > Search first: gnomAD, 1000 Genomes, PAGE Study, PubMed, population registries
  • Geographic distribution (endemic areas, regional variation) > Search first: WHO, CDC, GBD, Orphanet, geographic epidemiology databases
  • Geographic distribution of specific variants
  • Sex ratio (male:female) > Search first: Disease registries, OMIM, PubMed, epidemiological databases
  • Age distribution of affected individuals > Search first: CDC, disease registries, SEER, Orphanet

10. Diagnostics

  • Clinical Tests:
  • Laboratory tests (blood, urine, tissue chemistry, specific enzyme assays) > Search first: LOINC, LabTests Online, PubMed
  • Biomarkers (proteins, metabolites, genetic markers, circulating biomarkers) > Search first: FDA Biomarker List, BEST (Biomarkers, EndpointS, and other Tools), PubMed
  • Imaging studies (X-ray, CT, MRI, PET, ultrasound) > Search first: RadLex, DICOM, Radiopaedia, imaging databases
  • Functional tests (pulmonary function, cardiac stress tests) > Search first: LOINC, clinical guidelines, PubMed
  • Electrophysiology (EEG, EMG, ECG, nerve conduction studies) > Search first: LOINC, clinical neurophysiology databases, PubMed
  • Biopsy findings (histopathology, immunohistochemistry) > Search first: SNOMED CT, College of American Pathologists resources, PubMed
  • Pathology findings (microscopic examination) > Search first: SNOMED CT, Digital Pathology databases, PubMed
  • Genetic Testing:

    Search first: GTR (Genetic Testing Registry), GeneReviews, ClinGen

  • Overview of recommended genetic testing approach
  • Whole genome sequencing (WGS) utility > Search first: GTR, ClinVar, GEL (Genomics England), gnomAD
  • Whole exome sequencing (WES) utility > Search first: GTR, ClinVar, OMIM, GeneMatcher
  • Gene panels (which panels, which genes) > Search first: GTR, ClinVar, laboratory-specific databases
  • Single gene testing > Search first: GTR, ClinVar, OMIM, GeneReviews
  • Chromosomal microarray (CMA) > Search first: DECIPHER, ClinVar, dbVar, ECARUCA
  • Karyotyping > Search first: Chromosome Abnormality Database, ClinVar, cytogenetics resources
  • FISH > Search first: ClinVar, cytogenetics databases, PubMed
  • Mitochondrial DNA testing > Search first: MITOMAP, MSeqDR, ClinVar, GTR
  • Repeat expansion testing > Search first: GTR, ClinVar, repeat expansion databases, PubMed
  • Omics-Based Diagnostics (if applicable):
  • RNA sequencing / transcriptomics > Search first: GEO, ArrayExpress, GTEx, RNA-seq databases
  • Proteomics > Search first: PRIDE, ProteomeXchange, FDA Biomarker database
  • Metabolomics > Search first: MetaboLights, Metabolomics Workbench, HMDB
  • Epigenomics > Search first: GEO, ENCODE, Roadmap Epigenomics, MethBase
  • Liquid biopsy > Search first: COSMIC, ClinVar, liquid biopsy databases, PubMed
  • Clinical Criteria:
  • Standardized diagnostic criteria (DSM, ICD, society guidelines) > Search first: DSM-5, ICD-11, clinical society guidelines, UpToDate
  • Differential diagnosis (other conditions to rule out, with distinguishing features) > Search first: DynaMed, UpToDate, clinical decision support systems
  • Screening:
  • Screening methods for asymptomatic individuals (newborn screening, carrier screening, cascade screening) > Search first: ACMG recommendations, CDC newborn screening, GTR

11. Outcome/Prognosis

  • Survival and Mortality:
  • Survival rate (5-year, 10-year, overall) > Search first: SEER, cancer registries, disease-specific registries, PubMed
  • Life expectancy (with and without treatment if applicable) > Search first: Orphanet, disease registries, actuarial databases, PubMed
  • Mortality rate > Search first: CDC, WHO, GBD, national mortality databases
  • Disease-specific mortality (deaths directly attributable to disease) > Search first: Disease registries, CDC Wonder, GBD, PubMed
  • Morbidity and Function:
  • Morbidity (disease-related disability and health impacts) > Search first: GBD, WHO, disability databases, PubMed
  • Disability outcomes (long-term functional impairments) > Search first: ICF (International Classification of Functioning), disability registries
  • Quality of life measures (EQ-5D, SF-36, PROMIS, disease-specific tools) > Search first: EQ-5D database, SF-36, PROMIS, PubMed
  • Disease Course:
  • Complications (secondary problems: infections, organ failure, etc.) > Search first: ICD codes, disease registries, clinical databases, PubMed
  • Recovery potential (likelihood and extent of recovery, with vs without treatment) > Search first: Natural history studies, rehabilitation databases, PubMed
  • Prediction:
  • Prognostic factors (age, disease severity, biomarkers, treatment response) > Search first: Prognostic models databases, clinical calculators, PubMed
  • Prognostic biomarkers (molecular markers predicting disease course) > Search first: FDA Biomarker database, PubMed, cancer prognostic databases

12. Treatment

  • Pharmacotherapy:
  • Pharmacological treatments (drug names, drug classes, mechanisms of action) > Search first: DrugBank, RxNorm, ATC classification, DailyMed, FDA databases
  • Pharmacogenomics (how genetic variants affect drug metabolism, efficacy, toxicity) > Search first: PharmGKB, CPIC (Clinical Pharmacogenetics), FDA Table of PGx Biomarkers
  • Advanced Therapeutics:
  • Gene therapy (viral vectors, CRISPR, gene replacement, gene editing) > Search first: ClinicalTrials.gov, FDA gene therapy database, ASGCT resources
  • Cell therapy (stem cell transplant, CAR-T, cellular therapeutics) > Search first: ClinicalTrials.gov, FDA cell therapy database, FACT standards
  • RNA-based therapies (ASOs, siRNA, mRNA therapies) > Search first: ClinicalTrials.gov, FDA approvals, PubMed
  • Targeted therapies (treatments directed at specific molecular targets) > Search first: My Cancer Genome, OncoKB, ClinicalTrials.gov, FDA approvals
  • Immunotherapies (checkpoint inhibitors, monoclonal antibodies) > Search first: Cancer Immunotherapy Database, FDA approvals, ClinicalTrials.gov
  • Surgical and Interventional:
  • Surgical interventions (types of surgery, timing, outcomes) > Search first: CPT codes, surgical registries, clinical guidelines, PubMed
  • Supportive and Rehabilitative:
  • Supportive care (symptom management, pain control, nutrition) > Search first: Clinical guidelines, Cochrane Library, PubMed
  • Rehabilitation (physical therapy, occupational therapy, speech therapy) > Search first: Rehabilitation medicine databases, clinical guidelines, PubMed
  • Experimental:
  • Experimental treatments in clinical trials (with NCT identifiers if available) > Search first: ClinicalTrials.gov, EU Clinical Trials Register, WHO ICTRP
  • Treatment Outcomes:
  • Treatment response rates > Search first: Clinical trial databases, FDA reviews, systematic reviews, PubMed
  • Side effects and adverse events > Search first: FDA Adverse Event Reporting System (FAERS), MedWatch, PubMed
  • Treatment Strategy:
  • Treatment algorithms (clinical pathways, decision trees) > Search first: Clinical practice guidelines, NCCN Guidelines, UpToDate
  • Combination therapies > Search first: ClinicalTrials.gov, treatment guidelines, PubMed
  • Personalized medicine approaches (genotype-guided treatment) > Search first: My Cancer Genome, CIViC, PharmGKB, precision medicine databases

For each treatment, suggest MAXO (Medical Action Ontology) terms where applicable.

13. Prevention

  • Prevention Levels:
  • Primary prevention (preventing disease occurrence: vaccination, risk factor modification) > Search first: CDC, WHO, USPSTF recommendations, Cochrane Library
  • Secondary prevention (early detection and treatment: screening programs, early intervention) > Search first: USPSTF, CDC screening guidelines, WHO
  • Tertiary prevention (preventing complications in those with disease) > Search first: Clinical guidelines, disease management protocols, PubMed
  • Immunization: Vaccine strategies (if applicable)

    Search first: CDC vaccine schedules, WHO immunization, FDA vaccine database

  • Screening and Early Detection:
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  • Behavioral Interventions: Lifestyle modifications to reduce risk

    Search first: CDC, WHO, behavioral intervention databases, Cochrane Library

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    Search first: NSGC resources, ACMG guidelines, GeneReviews

  • Public Health:
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  • Environmental interventions (reducing environmental risk factors) > Search first: EPA databases, WHO environmental health, PubMed
  • Prophylaxis: Preventive medications or procedures

    Search first: Clinical guidelines, FDA approvals, PubMed

14. Other Species / Natural Disease

  • Taxonomy: Species affected (with NCBI Taxon identifiers)

    Search first: NCBI Taxonomy

  • Breed: Specific breeds affected (with VBO identifiers if applicable)

    Search first: VBO (Vertebrate Breed Ontology)

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    Search first: NCBI Gene

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  • Naturally occurring disease in other species (companion animals, wildlife) > Search first: OMIA (Online Mendelian Inheritance in Animals), VetCompass, PubMed
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  • Transmission (if applicable):
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  • Cross-species susceptibility > Search first: NCBI Taxonomy, veterinary databases, PubMed

15. Model Organisms

  • Model Types:
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  • Genetic Models:
  • Types available (knockout, knock-in, transgenic, conditional, humanized) > Search first: MGI, IMPC, KOMP, EuMMCR, IMSR
  • Model Characteristics:
  • Phenotype recapitulation (how well model reproduces human disease features) > Search first: Model organism databases, comparative studies, PubMed
  • Model limitations (aspects of human disease not captured) > Search first: Model organism databases, PubMed, review articles
  • Applications:
  • Research applications (what aspects of disease can be studied) > Search first: Model organism databases, PubMed
  • Resources:
  • Model databases > Search first: MGI, RGD, ZFIN, FlyBase, WormBase, IMSR, EMMA, MMRRC

Citation Requirements

  • Cite primary literature (PMID preferred) for all mechanistic and clinical claims
  • Prioritize recent reviews and landmark papers
  • Include direct quotes from abstracts where possible to support key statements
  • Distinguish evidence source types: human clinical, model organism, in vitro, computational

Output Format

Structure your response as a comprehensive narrative organized by the sections above. For each section, provide: - Factual content with specific details (numbers, percentages, gene names, variant nomenclature) - Ontology term suggestions (HPO, GO, CL, UBERON, CHEBI, MAXO, MONDO) where applicable - Evidence citations with PMIDs - Direct quotes from abstracts to support key claims - Clear indication when information is not available or not applicable for this disease

This report will be used to populate a disease knowledge base entry with: - Pathophysiology descriptions with causal chains - Gene/protein annotations (HGNC, GO terms) - Phenotype associations (HP terms) with frequencies - Cell type involvement (CL terms) - Anatomical locations (UBERON terms) - Chemical entities (CHEBI terms) - Treatment annotations (MAXO terms) - Evidence items with PMIDs and exact abstract quotes - Epidemiology, prognosis, diagnostic, and prevention information - Animal model descriptions with phenotype recapitulation details

Comprehensive Disease Characteristics Report: 5‑Oxoprolinase Deficiency (OPLAH deficiency)

Executive summary

Inherited 5‑oxoprolinase deficiency is a very rare Mendelian disorder of the γ‑glutamyl (glutathione) cycle caused by biallelic variants in OPLAH, leading to persistent or intermittent elevation of urinary 5‑oxoproline (pyroglutamic acid). Historically it was often described as a “benign biochemical condition,” but recent case literature (2024) reports children with epilepsy, speech delay, macrocephaly/hydrocephalus, and progressive neuroimaging abnormalities, supporting that at least a subset of patients can be symptomatic. (kasapkara2024is5oxoprolinasedeficiency pages 1-2, kasapkara2024is5oxoprolinasedeficiency pages 2-3)

A major real‑world implementation issue is differential diagnosis: elevated 5‑oxoproline is much more commonly encountered as an acquired, drug‑related high‑anion‑gap metabolic acidosis (often iatrogenic) associated with prolonged paracetamol/acetaminophen exposure, sometimes with β‑lactamase‑resistant penicillins (e.g., flucloxacillin), and risk factors such as undernutrition, infection, alcohol‑use disorder, and kidney disease. A 2024 systematic review summarized 131 reported acquired cases, with 18% fatality and commonly used interventions including drug discontinuation (100%), bicarbonate (63%), and N‑acetylcysteine (42%). (scafetta2024drugrelatedpyroglutamicacidosis pages 1-2, scafetta2024drugrelatedpyroglutamicacidosis pages 5-7)

1. Disease information

1.1 What is the disease?

Inherited 5‑oxoprolinase deficiency is an inborn error of metabolism affecting glutathione metabolism (γ‑glutamyl cycle), characterized biochemically by 5‑oxoprolinuria (markedly increased urinary 5‑oxoproline). (almaghlouth20125‐oxoprolinasedeficiencyreport pages 1-2, kasapkara2024is5oxoprolinasedeficiency pages 2-3)

1.2 Key identifiers (knowledge‑base mapping fields)

  • MONDO ID: not determined from available tool‑retrieved sources.
  • OMIM / Orphanet / ICD‑10/ICD‑11 / MeSH: not determined in this tool environment.

Implementation note: in a production curation workflow, these should be mapped by querying OMIM/Orphanet/MONDO directly using synonyms in §1.3.

1.3 Synonyms and alternative names (literature‑used)

  • 5‑oxoprolinase deficiency (OPLAH deficiency) (almaghlouth20125‐oxoprolinasedeficiencyreport pages 1-2, kasapkara2024is5oxoprolinasedeficiency pages 1-2)
  • Inherited 5‑oxoprolinuria (kasapkara2024is5oxoprolinasedeficiency pages 1-2, calpena20125oxoprolinuriainheterozygous pages 1-2)
  • Primary 5‑oxoprolinuria (as used in a 2024 case report) (kasapkara2024is5oxoprolinasedeficiency pages 1-2)
  • Pyroglutamic aciduria / pyroglutamic acidemia (context‑dependent; may refer to inherited or acquired forms) (kasapkara2024is5oxoprolinasedeficiency pages 1-2, stewart2024pyroglutamateacidosis2023. pages 1-2)

1.4 Evidence source type

For inherited OPLAH deficiency, the information base is dominated by individual patient case reports/family studies and small literature reviews (human clinical evidence). (almaghlouth20125‐oxoprolinasedeficiencyreport pages 2-3, kasapkara2024is5oxoprolinasedeficiency pages 1-2)

2. Etiology

2.1 Disease causal factors

Primary cause (genetic): biallelic pathogenic variants in OPLAH, encoding ATP‑dependent 5‑oxoprolinase, which converts 5‑oxo‑L‑proline (5‑oxoproline) to L‑glutamate in the γ‑glutamyl cycle. (kasapkara2024is5oxoprolinasedeficiency pages 2-3, almaghlouth20125‐oxoprolinasedeficiencyreport pages 1-2)

Mechanistic consequence: reduced conversion of 5‑oxoproline to glutamate leads to accumulation of 5‑oxoproline in body fluids and urine. (kasapkara2024is5oxoprolinasedeficiency pages 1-1)

2.2 Risk factors

Genetic: * Consanguinity is a recurring context in reported biallelic cases (e.g., homozygous variants in consanguineous parents). (almaghlouth20125‐oxoprolinasedeficiencyreport pages 2-3, kasapkara2024is5oxoprolinasedeficiency pages 1-2)

Environmental/clinical modifiers: evidence is limited; elevated 5‑oxoproline can occur in many acquired settings (malnutrition, drugs, pregnancy, diabetes, artificial diets), complicating recognition of inherited disease. (almaghlouth20125‐oxoprolinasedeficiencyreport pages 1-2, kasapkara2024is5oxoprolinasedeficiency pages 1-2)

2.3 Protective factors

No established genetic or environmental protective factors were identified from the retrieved literature.

2.4 Gene–environment interactions

Direct gene–environment interaction evidence for inherited OPLAH deficiency is not established in the retrieved sources; however, acquired causes of 5‑oxoproline elevation may confound phenotyping and diagnosis in genetically affected individuals. (almaghlouth20125‐oxoprolinasedeficiencyreport pages 1-2, calpena20125oxoprolinuriainheterozygous pages 1-2)

3. Phenotypes (clinical presentation)

3.1 Core phenotype and variability

The consistent feature across reports is elevated urinary 5‑oxoproline; the clinical phenotype is variable and the field has debated whether OPLAH deficiency can be purely biochemical versus symptomatic. (calpena20125oxoprolinuriainheterozygous pages 1-2, kasapkara2024is5oxoprolinasedeficiency pages 2-3)

A 2012 family study emphasized variability from apparently normal individuals to those with neurodevelopmental and systemic features reported in the literature (e.g., low IQ, delayed psychomotor development, microcephaly, failure to thrive, microcytic anemia, nephrolithiasis, enterocolitis, transient neonatal hypoglycemia). (almaghlouth20125‐oxoprolinasedeficiencyreport pages 2-3)

A 2024 case report described a 3‑year‑old with neurologic disease and brain MRI abnormalities and concluded the condition “is not a benign biochemical condition” (direct quoted phrasing as reported in the excerpt). (kasapkara2024is5oxoprolinasedeficiency pages 1-2)

3.2 Phenotype list with suggested HPO terms

Below are phenotype elements explicitly described in tool‑retrieved texts, with suggested HPO mappings:

Neurologic / developmental * Epilepsy / seizures — HP:0001250 Seizures, HP:0001270 Epilepsy (kasapkara2024is5oxoprolinasedeficiency pages 1-2, kasapkara2024is5oxoprolinasedeficiency pages 2-3) * Speech delay / language impairment — HP:0000750 Delayed speech and language development (kasapkara2024is5oxoprolinasedeficiency pages 1-2) * Developmental delay / psychomotor retardation — HP:0001263 Global developmental delay, HP:0001252 Muscular hypotonia (hypotonia reported in reviewed cases) (kasapkara2024is5oxoprolinasedeficiency pages 2-3)

Brain imaging / neuroanatomy * Progressive cerebral atrophy — HP:0002059 Cerebral atrophy (kasapkara2024is5oxoprolinasedeficiency pages 1-2) * Hypomyelination / delayed myelination — HP:0011402 Hypomyelination, HP:0003429 Delayed myelination (kasapkara2024is5oxoprolinasedeficiency pages 1-2, kasapkara2024is5oxoprolinasedeficiency pages 2-3) * Ventriculomegaly — HP:0002119 Ventriculomegaly (kasapkara2024is5oxoprolinasedeficiency pages 1-2) * Corpus callosum hypoplasia — HP:0002079 Hypoplasia of the corpus callosum (kasapkara2024is5oxoprolinasedeficiency pages 1-2)

Growth / head size * Macrocephaly (postnatal) — HP:0000256 Macrocephaly (kasapkara2024is5oxoprolinasedeficiency pages 1-2) * Microcephaly (reported in some cases) — HP:0000252 Microcephaly (almaghlouth20125‐oxoprolinasedeficiencyreport pages 2-3, kasapkara2024is5oxoprolinasedeficiency pages 1-1)

Systemic (reported across cases/literature) * Mild metabolic acidosis — HP:0001942 Metabolic acidosis (almaghlouth20125‐oxoprolinasedeficiencyreport pages 1-2, kasapkara2024is5oxoprolinasedeficiency pages 2-3) * Nephrolithiasis (kidney stones) — HP:0000787 Nephrolithiasis (almaghlouth20125‐oxoprolinasedeficiencyreport pages 2-3, kasapkara2024is5oxoprolinasedeficiency pages 1-1) * Microcytic anemia — HP:0001935 Microcytic anemia (almaghlouth20125‐oxoprolinasedeficiencyreport pages 2-3, kasapkara2024is5oxoprolinasedeficiency pages 1-1) * Enterocolitis — HP:0004386 Enterocolitis (almaghlouth20125‐oxoprolinasedeficiencyreport pages 2-3, kasapkara2024is5oxoprolinasedeficiency pages 1-1) * Neonatal hypoglycemia (transient) — HP:0001998 Neonatal hypoglycemia (almaghlouth20125‐oxoprolinasedeficiencyreport pages 2-3, kasapkara2024is5oxoprolinasedeficiency pages 1-1)

3.3 Phenotype characteristics (onset, severity, progression)

  • Age of onset: pediatric cases include infancy and early childhood; epilepsy onset at ~2 years was reported in the 2024 case. (kasapkara2024is5oxoprolinasedeficiency pages 1-2)
  • Severity: ranges from apparently asymptomatic/normal development to neurologic impairment with progressive MRI abnormalities. (almaghlouth20125‐oxoprolinasedeficiencyreport pages 2-3, kasapkara2024is5oxoprolinasedeficiency pages 1-2)
  • Course: at least some reports describe biochemical persistence; one infant in earlier literature had normalization of urinary 5‑oxoproline by ~1 year in the context of 5‑oxoprolinuria. (calpena20125oxoprolinuriainheterozygous pages 1-2, kasapkara2024is5oxoprolinasedeficiency pages 6-7)

3.4 Quality of life impact

Direct quality‑of‑life instruments (e.g., EQ‑5D/SF‑36) were not reported in retrieved sources. Functional impact is implied via seizures and speech/developmental delays. (kasapkara2024is5oxoprolinasedeficiency pages 1-2)

4. Genetic / molecular information

4.1 Causal gene

  • OPLAH (5‑oxoprolinase; ATP‑dependent 5‑oxoproline hydrolysis) (kasapkara2024is5oxoprolinasedeficiency pages 2-3, almaghlouth20125‐oxoprolinasedeficiencyreport pages 1-2)

4.2 Inheritance

Autosomal recessive inheritance is supported by homozygous affected siblings with heterozygous parents in a consanguineous family and by other homozygous/compound heterozygous cases summarized in the 2024 review. (almaghlouth20125‐oxoprolinasedeficiencyreport pages 2-3, kasapkara2024is5oxoprolinasedeficiency pages 6-7)

4.3 Pathogenic/putative pathogenic variants reported in retrieved texts

Human evidence includes: * Frameshift: NM_017570.3:c.2601_2602insC → p.(His870Profs92) (first molecularly confirmed case report). (almaghlouth20125‐oxoprolinasedeficiencyreport pages 2-3) * Homozygous missense: NM_017570.5:c.1909C>T → p.Arg637Trp (2024 case report; classified as likely pathogenic in excerpt). (kasapkara2024is5oxoprolinasedeficiency pages 1-2) * Heterozygous missense associated with massive 5‑oxoprolinuria (uncertain clinical significance): c.969C>A (p.S323R) and c.3265G>A (p.V1089I). (calpena20125oxoprolinuriainheterozygous pages 2-4) * Additional variants listed in the 2024 review excerpt: c.1562G>A (p.Gly521Glu), c.3622G>A (p.Gly1208Arg), c.2303G>A (p.Arg768His), c.1069G>C (p.Gly357Arg), c.1237_1238delGG (Gly413Argfs), plus other newly mentioned variants (c.1904G>A, c.2813_2815delGGG, c.2978G>T). (kasapkara2024is5oxoprolinasedeficiency pages 6-7)

Population frequency notes (limited): the 2024 report notes extremely low allele frequency for p.Arg637Trp and provides an example heterozygote frequency in a Turkish variome context (1/5,090) for variant context. (kasapkara2024is5oxoprolinasedeficiency pages 3-4, kasapkara2024is5oxoprolinasedeficiency pages 2-3)

4.4 Functional consequences

  • The 2012 frameshift removes the oxoprolinase domain and is expected to severely impair enzyme activity (loss of function). (almaghlouth20125‐oxoprolinasedeficiencyreport pages 2-3)

4.5 Modifier genes / epigenetics / chromosomal abnormalities

No modifier genes, epigenetic findings, or chromosomal abnormalities were identified in the retrieved evidence.

5. Environmental information

Not typically applicable as a primary driver for this Mendelian condition. However, acquired 5‑oxoproline elevation can occur due to malnutrition and drugs (e.g., vigabatrin) and other clinical states, which is critical for differential diagnosis. (almaghlouth20125‐oxoprolinasedeficiencyreport pages 1-2, kasapkara2024is5oxoprolinasedeficiency pages 1-2)

6. Mechanism / pathophysiology

6.1 Molecular pathway and causal chain

Pathway: γ‑glutamyl cycle (glutathione synthesis and degradation).

Key reaction: 5‑oxoprolinase (OPLAH) is an ATP‑dependent enzyme converting 5‑oxoproline → glutamate. (kasapkara2024is5oxoprolinasedeficiency pages 2-3, almaghlouth20125‐oxoprolinasedeficiencyreport pages 1-2)

Causal chain (inherited OPLAH deficiency): 1. Biallelic OPLAH loss‑of‑function or damaging missense variants reduce 5‑oxoprolinase activity. (almaghlouth20125‐oxoprolinasedeficiencyreport pages 2-3, kasapkara2024is5oxoprolinasedeficiency pages 1-1) 2. 5‑oxoproline cannot be efficiently converted to glutamate and accumulates, yielding 5‑oxoprolinuria on urine organic acids. (kasapkara2024is5oxoprolinasedeficiency pages 2-3, kasapkara2024is5oxoprolinasedeficiency pages 1-2) 3. Downstream clinical effects are variable; a 2024 case report emphasizes neurologic manifestations and notes that “the precise way accumulated 5‑oxoproline perturbs cellular energy metabolism and causes oxidative stress in neural cells is currently unknown” (as reported in excerpt). (kasapkara2024is5oxoprolinasedeficiency pages 1-2)

Additional mechanistic context (biochemistry / comparative biology): 5‑oxoproline is also described as an “unavoidable damage product” formed spontaneously (e.g., from glutamine cyclization), and 5‑oxoprolinase is a disposal system; accumulation has been reported to interfere with energy production and antioxidant defenses and is associated with acidosis/neurologic problems in glutathione‑metabolism inborn errors. (niehaus2017discoveryofa pages 1-2)

6.2 Suggested ontology terms

GO Biological Process (suggested): * GO:0006749 glutathione metabolic process (pathway‑level) * GO:0006750 glutathione biosynthetic process (cycle context)

GO Molecular Function (suggested): * GO:0004358 glutamate—cysteine ligase activity is not OPLAH; for OPLAH specifically use a term corresponding to 5‑oxoprolinase activity (OPLAH catalytic function) (supported conceptually by enzymatic role described). (kasapkara2024is5oxoprolinasedeficiency pages 2-3)

Cell types (CL terms; suggested, hypothesis‑driven): * Neurons (given neurologic phenotypes) — e.g., CL:0000540 neuron * Oligodendrocytes (given hypomyelination) — e.g., CL:0000128 oligodendrocyte (Clinical evidence indicates CNS involvement but does not localize to specific cell types experimentally.) (kasapkara2024is5oxoprolinasedeficiency pages 1-2)

Chemicals (ChEBI; suggested): * 5‑oxoproline / pyroglutamic acid (the metabolite measured clinically) (kasapkara2024is5oxoprolinasedeficiency pages 1-2) * L‑glutamate (product of OPLAH reaction) (kasapkara2024is5oxoprolinasedeficiency pages 2-3)

Pathway visual evidence: the γ‑glutamyl cycle depiction and the position of 5‑oxoprolinase in the cycle are shown in a figure extracted from the 2024 report. (kasapkara2024is5oxoprolinasedeficiency media cc8de042, kasapkara2024is5oxoprolinasedeficiency media c684e2b6)

7. Anatomical structures affected

Primary system implicated in symptomatic cases: central nervous system (seizures, developmental delay, brain atrophy, hypomyelination, ventriculomegaly, corpus callosum hypoplasia). (kasapkara2024is5oxoprolinasedeficiency pages 1-2)

Suggested UBERON terms (selected): * UBERON:0000955 brain * UBERON:0002285 corpus callosum * UBERON:0002113 cerebral ventricle

Systemic involvement (kidney stones, anemia, enterocolitis) is reported in some cases/literature summaries but is not consistently present. (almaghlouth20125‐oxoprolinasedeficiencyreport pages 2-3, kasapkara2024is5oxoprolinasedeficiency pages 1-1)

8. Temporal development

  • Onset: childhood onset is documented; epilepsy onset at age 2 years in the 2024 case. (kasapkara2024is5oxoprolinasedeficiency pages 1-2)
  • Progression: progressive cerebral atrophy and other progressive MRI changes were described in the 2024 case. (kasapkara2024is5oxoprolinasedeficiency pages 1-2)
  • Episodic vs stable: earlier literature includes episodic presentations and reports of normalization of 5‑oxoproline excretion in at least one child by ~1 year, suggesting biochemical and clinical variability over time. (calpena20125oxoprolinuriainheterozygous pages 1-2, kasapkara2024is5oxoprolinasedeficiency pages 6-7)

9. Inheritance and population

9.1 Epidemiology (inherited OPLAH deficiency)

Quantitative prevalence/incidence estimates were not identified in tool‑retrieved sources. Available rarity indicators are case‑count based: * By 2012, the disorder was described as “extremely rare,” with only eight patients (six families) reported previously in the 2012 paper’s framing. (almaghlouth20125‐oxoprolinasedeficiencyreport pages 1-2) * The 2024 review excerpt refers to roughly ~20 patients reported. (kasapkara2024is5oxoprolinasedeficiency pages 2-3)

9.2 Population genetics

Limited population frequency detail is available in the retrieved excerpts (e.g., extremely low allele frequency for p.Arg637Trp and a Turkish variome heterozygote frequency example). (kasapkara2024is5oxoprolinasedeficiency pages 3-4, kasapkara2024is5oxoprolinasedeficiency pages 2-3)

9.3 Prognosis

Prognosis is not well established due to few cases and variable phenotypes; the 2024 report explicitly calls for long‑term observation. (kasapkara2024is5oxoprolinasedeficiency pages 1-2)

10. Diagnostics

10.1 Clinical laboratory diagnosis (inherited)

  • Urine organic acid analysis (GC‑MS) is used to identify markedly elevated urinary 5‑oxoproline, including quantitation by stable isotope dilution in the 2024 case. (kasapkara2024is5oxoprolinasedeficiency pages 1-2)
  • 2012 and 2024 reports emphasize excluding glutathione synthetase deficiency (GSS) (e.g., normal glutathione synthase enzyme levels or normal GSS analysis) when interpreting 5‑oxoprolinuria. (almaghlouth20125‐oxoprolinasedeficiencyreport pages 1-2, kasapkara2024is5oxoprolinasedeficiency pages 1-2)

Quantitative examples: * 2024 case: urine 5‑oxoproline 177.9 mmol/mol creatinine (reference 25.8–92.2), with additional samples 105.79–243.13 mmol/mol creatinine. (kasapkara2024is5oxoprolinasedeficiency pages 2-3) * 2012 heterozygous report: values up to 13,208 mmol/mol creatinine (reference <10), with later normalization in one infant. (calpena20125oxoprolinuriainheterozygous pages 2-4)

10.2 Genetic testing

  • Molecular confirmation includes sequencing of OPLAH; examples include homozygous frameshift and homozygous missense variants. (almaghlouth20125‐oxoprolinasedeficiencyreport pages 2-3, kasapkara2024is5oxoprolinasedeficiency pages 1-2)

10.3 Differential diagnosis: inherited vs acquired 5‑oxoproline elevation

Acquired drug‑related pyroglutamic acidosis can present with severe high‑anion‑gap metabolic acidosis and (often) 5‑oxoproline positivity on urine organic acids. (scafetta2024drugrelatedpyroglutamicacidosis pages 4-5, scafetta2024drugrelatedpyroglutamicacidosis pages 5-7)

Key differentiators: * Clinical context: acquired cases typically occur in ill hospitalized adults with risk factors and drug exposure, especially prolonged paracetamol ± flucloxacillin. (scafetta2024drugrelatedpyroglutamicacidosis pages 1-2, stewart2024pyroglutamateacidosis2023. pages 2-3) * Acid–base severity (acquired): median arterial pH ~7.19 (IQR 7.12–7.29) and bicarbonate ~7 mmol/L (IQR 5–10), with anion gap elevated (median 25 meq/L [20–30]). (scafetta2024drugrelatedpyroglutamicacidosis pages 5-7) * Specimen considerations (acquired): in the 2024 review, pyroglutamate testing was mostly performed in urine (115/121 assays) rather than blood (6/121), and some series note low/normal blood pyroglutamate despite high urine excretion. (scafetta2024drugrelatedpyroglutamicacidosis pages 4-5, scafetta2024drugrelatedpyroglutamicacidosis pages 7-9)

11. Outcome / prognosis

Inherited OPLAH deficiency

Outcomes vary and are insufficiently characterized; literature describes individuals who appear clinically benign and others with neurologic impairment. (almaghlouth20125‐oxoprolinasedeficiencyreport pages 2-3, kasapkara2024is5oxoprolinasedeficiency pages 1-2)

Acquired drug‑related pyroglutamic acidosis (contextual comparator)

In the 2024 systematic review of 131 cases, mortality was 18% and median recovery time was 5 days (IQR 2–7). (scafetta2024drugrelatedpyroglutamicacidosis pages 5-7)

12. Treatment

12.1 Inherited OPLAH deficiency

No established treatment recommendations were identified in the retrieved excerpts (“There is no treatment recommendation” in the 2024 case report’s fact box). (kasapkara2024is5oxoprolinasedeficiency pages 1-1)

Management in practice (inferred from case literature): supportive neurologic management (e.g., anti‑seizure medications) and longitudinal follow‑up, with emphasis on confirming diagnosis molecularly in symptomatic patients with persistent 5‑oxoprolinuria. (kasapkara2024is5oxoprolinasedeficiency pages 1-2)

Suggested MAXO terms (for knowledge base; supportive): * Antiepileptic drug therapy (seizure management) (supported as levetiracetam use in 2024 case narrative) (kasapkara2024is5oxoprolinasedeficiency pages 1-2) * Genetic counseling (given AR inheritance/consanguinity context) (almaghlouth20125‐oxoprolinasedeficiencyreport pages 2-3, kasapkara2024is5oxoprolinasedeficiency pages 1-2)

12.2 Acquired drug‑related pyroglutamic acidosis (real‑world implementation)

From the 2024 systematic review (131 cases): * Stop offending drug(s): 100% (scafetta2024drugrelatedpyroglutamicacidosis pages 1-2) * Sodium bicarbonate: 63% (scafetta2024drugrelatedpyroglutamicacidosis pages 1-2) * N‑acetylcysteine: 42% (scafetta2024drugrelatedpyroglutamicacidosis pages 1-2) * Acute kidney replacement therapy/dialysis: 18% (scafetta2024drugrelatedpyroglutamicacidosis pages 1-2) * Case fatality: 18% (scafetta2024drugrelatedpyroglutamicacidosis pages 1-2)

This acquired condition is relevant operationally because it can be the most common clinical scenario in which 5‑oxoproline is detected, and because management is time‑sensitive. (scafetta2024drugrelatedpyroglutamicacidosis pages 1-2, scafetta2024drugrelatedpyroglutamicacidosis pages 5-7)

13. Prevention

Inherited OPLAH deficiency

No disease‑specific primary prevention is established; prevention is mainly via carrier screening/genetic counseling in affected families (consistent with AR inheritance and consanguinity in reported families). (almaghlouth20125‐oxoprolinasedeficiencyreport pages 2-3, kasapkara2024is5oxoprolinasedeficiency pages 1-2)

Acquired pyroglutamic acidosis prevention (context)

Risk mitigation includes avoiding prolonged paracetamol co‑prescription with flucloxacillin in high‑risk patients and recognizing predisposing factors (undernutrition, infection, kidney disease). (scafetta2024drugrelatedpyroglutamicacidosis pages 1-2, stewart2024pyroglutamateacidosis2023. pages 2-3)

14. Other species / natural disease

No naturally occurring veterinary syndrome analogous to human inherited OPLAH deficiency was identified in retrieved sources.

15. Model organisms

15.1 Mouse / nervous system evidence

A mouse brain study identified Oplah as a putative interacting protein with Cpt1c in vivo (co‑immunoprecipitation in transgenic mouse brain). The report notes that Oplah is enriched in the nervous system and that Oplah deletion in mice is associated with increased startle response and decreased heart rate (as summarized in the excerpt). (wolfgang2016carnitinepalmitoyltransfersase1cand pages 1-3, wolfgang2016carnitinepalmitoyltransfersase1cand pages 3-4)

15.2 Prokaryotic comparative biology

A 2017 JBC paper describes discovery of a widespread prokaryotic 5‑oxoprolinase system and highlights 5‑oxoproline as both a γ‑glutamyl cycle intermediate and a spontaneous metabolite “damage product,” supporting evolutionary conservation of 5‑oxoproline disposal. (niehaus2017discoveryofa pages 1-2)

Recent developments and latest research (2023–2024 emphasis)

  1. Symptomatic inherited OPLAH deficiency case report (2024): A 3‑year‑old with epilepsy, speech difficulty, macrocephaly/hydrocephalus, and progressive MRI abnormalities had persistently elevated urine 5‑oxoproline and a novel homozygous OPLAH variant (c.1909C>T; p.Arg637Trp). (kasapkara2024is5oxoprolinasedeficiency pages 1-2, kasapkara2024is5oxoprolinasedeficiency pages 2-3)
  2. Drug‑related pyroglutamic acidosis systematic review (2024): 131 cases; predominant association with therapeutic paracetamol exposure and identifiable risk‑factor cluster; provides quantitative acid–base descriptors and management/outcome statistics. (scafetta2024drugrelatedpyroglutamicacidosis pages 1-2, scafetta2024drugrelatedpyroglutamicacidosis pages 5-7)

Evidence table (curated)

The following table summarizes key human evidence (inherited OPLAH deficiency / 5‑oxoprolinuria) available from tool‑retrieved full texts.

Study (first author, year) Publication type URL/DOI Patient count / families Inheritance / genotype Key phenotypes Key biochemical findings (urine 5-oxoproline values/units) Key interpretation
Almaghlouth, 2012 Human case report / family study https://doi.org/10.1111/j.1399-0004.2011.01728.x 2 homozygous siblings in 1 consanguineous family; paper notes only 8 patients from 6 families had been reported previously Autosomal recessive; first molecularly confirmed human OPLAH defect: NM_017570.3:c.2601_2602insC, p.(His870Profs*92); parents heterozygous, sister homozygous Variable spectrum in literature from apparently asymptomatic/developmentally normal to low IQ, delayed psychomotor development, microcephaly, failure to thrive, microcytic anemia, nephrolithiasis, enterocolitis, transient neonatal hypoglycemia; index case had mild indirect hyperbilirubinemia, mild metabolic acidosis, eczema/food allergies, slowed head growth but normal motor/social/cognitive development (almaghlouth20125‐oxoprolinasedeficiencyreport pages 2-3, almaghlouth20125‐oxoprolinasedeficiencyreport pages 1-2) Markedly elevated urinary 5-oxoproline by GC-MS; index ratio 7.60 vs average control 0.06; homozygous sister 3.76 vs 0.06 control; prior reports had high urinary 5-oxoproline with normal glutathione synthase levels and usually no metabolic acidemia (almaghlouth20125‐oxoprolinasedeficiencyreport pages 2-3, almaghlouth20125‐oxoprolinasedeficiencyreport pages 1-2) Supports true inherited OPLAH deficiency with highly variable expression; authors note debate over whether some prior neurologic findings were due solely to OPLAH deficiency versus overlapping defects (almaghlouth20125‐oxoprolinasedeficiencyreport pages 2-3, almaghlouth20125‐oxoprolinasedeficiencyreport pages 1-2)
Calpena, 2012 Human case report / short series https://doi.org/10.1007/8904_2012_166 2 unrelated probands Expected AR disorder overall; prior homozygous p.H870Pfs truncating mutation noted in literature; in this report only single heterozygous missense OPLAH changes found: c.969C>A (p.S323R) and c.3265G>A (p.V1089I) (calpena20125oxoprolinuriainheterozygous pages 2-4, calpena20125oxoprolinuriainheterozygous pages 1-2) Clinical significance uncertain; literature cited as inconsistent, with renal stones, mental retardation, neonatal hypoglycaemia, microcytic anemia, microcephaly, and episodic seizures in an infant; present series did not clearly support symptomatic enzymopathy, and one infant’s oxoprolinuria normalized by age 1 year (calpena20125oxoprolinuriainheterozygous pages 2-4, calpena20125oxoprolinuriainheterozygous pages 1-2) Very high urinary pyroglutamic acid/5-oxoproline: one proband 13,208 mmol/mol creatinine, second sample 7,931 mmol/mol creatinine; decompensation examples 7,828 and 3,255 mmol/mol creatinine; later normalization example 9 mmol/mol creatinine at 1 year (reference <10); blood glutathione within reference range (e.g., 3.2 mmol/L, 2.45 mmol/L) (calpena20125oxoprolinuriainheterozygous pages 2-4, calpena20125oxoprolinuriainheterozygous pages 1-2) Interpreted largely as a benign biochemical condition / uncertain pathogenic significance, especially for isolated heterozygous missense findings; authors suggest oxoprolinuria may sometimes be an epiphenomenon (calpena20125oxoprolinuriainheterozygous pages 2-4, calpena20125oxoprolinuriainheterozygous pages 1-2)
Kasapkara, 2024 Human case report with literature review https://doi.org/10.1159/000536295 1 symptomatic child; review text notes roughly 20 patients reported overall Homozygous OPLAH variant NM_017570.5:c.1909C>T (p.Arg637Trp) in child of consanguineous parents; ACMG classification reported as likely pathogenic; review also lists additional reported homozygous/compound heterozygous/heterozygous variants in prior patients (kasapkara2024is5oxoprolinasedeficiency pages 3-4, kasapkara2024is5oxoprolinasedeficiency pages 1-2, kasapkara2024is5oxoprolinasedeficiency pages 6-7, kasapkara2024is5oxoprolinasedeficiency pages 2-3) Epilepsy, speech difficulty/delay, developmental delay, postnatal macrocephaly, hydrocephalus, progressive cerebral atrophy, hypomyelination, ventriculomegaly, corpus callosum hypoplasia; review notes broader spectrum including psychomotor retardation, hypotonia, feeding problems, vomiting, recurrent pneumonia, severe respiratory events, microcephaly or macrocephaly, leukodystrophy/delayed myelination, mild metabolic acidosis (kasapkara2024is5oxoprolinasedeficiency pages 1-2, kasapkara2024is5oxoprolinasedeficiency pages 6-7, kasapkara2024is5oxoprolinasedeficiency pages 2-3) Urine 5-oxoproline 177.9 mmol/mol creatinine (reference 25.8–92.2); three additional samples ranged 105.79–243.13 mmol/mol creatinine; diagnosis supported by persistent 5-oxoprolinuria and normal GSS analysis (kasapkara2024is5oxoprolinasedeficiency pages 1-2, kasapkara2024is5oxoprolinasedeficiency pages 2-3) Authors argue inherited OPLAH deficiency is “not a benign biochemical condition” and recommend molecular testing/screening in symptomatic patients with persistent 5-oxoprolinuria (kasapkara2024is5oxoprolinasedeficiency pages 3-4, kasapkara2024is5oxoprolinasedeficiency pages 1-2, kasapkara2024is5oxoprolinasedeficiency pages 2-3)

Table: This table summarizes the key published human evidence for inherited OPLAH deficiency/5-oxoprolinuria from the three provided studies. It highlights the shift from viewing the condition as a potentially benign biochemical finding toward recognition that some patients have clear neurologic and structural brain manifestations.

Visual evidence (figure/table)

The 2024 case report includes (i) a figure diagramming the γ‑glutamyl cycle and the OPLAH step, and (ii) a table summarizing published OPLAH variants and associated clinical findings. (kasapkara2024is5oxoprolinasedeficiency media cc8de042, kasapkara2024is5oxoprolinasedeficiency media f8f7f3ad)

Key limitations of this report (data gaps)

  • Cross‑ontology identifiers (MONDO/OMIM/Orphanet/ICD/MeSH) could not be programmatically retrieved with the available tools; they should be added via direct database lookups in the curation pipeline.
  • Phenotype frequencies (percent of affected individuals) and robust natural history are not well established for inherited OPLAH deficiency due to very small numbers and heterogeneous reporting. (almaghlouth20125‐oxoprolinasedeficiencyreport pages 1-2, kasapkara2024is5oxoprolinasedeficiency pages 2-3)
  • ClinVar‑level variant classifications and population allele frequencies (gnomAD) were not accessible via direct database tools here; only limited frequency commentary in the 2024 case report excerpt was available. (kasapkara2024is5oxoprolinasedeficiency pages 3-4, kasapkara2024is5oxoprolinasedeficiency pages 2-3)

References

  1. (kasapkara2024is5oxoprolinasedeficiency pages 1-2): Çiğdem Seher Kasapkara, Oya Kıreker Köylü, Aysenur Engin Erdal, Burak Yürek, Nesrin Ceylan, and Serdar Ceylaner. Is 5-oxoprolinase deficiency more than just a benign condition? Molecular Syndromology, 15:303-310, Feb 2024. URL: https://doi.org/10.1159/000536295, doi:10.1159/000536295. This article has 1 citations and is from a peer-reviewed journal.

  2. (kasapkara2024is5oxoprolinasedeficiency pages 2-3): Çiğdem Seher Kasapkara, Oya Kıreker Köylü, Aysenur Engin Erdal, Burak Yürek, Nesrin Ceylan, and Serdar Ceylaner. Is 5-oxoprolinase deficiency more than just a benign condition? Molecular Syndromology, 15:303-310, Feb 2024. URL: https://doi.org/10.1159/000536295, doi:10.1159/000536295. This article has 1 citations and is from a peer-reviewed journal.

  3. (scafetta2024drugrelatedpyroglutamicacidosis pages 1-2): Tessa Scafetta, Orsolya Kovacs, Gregorio P. Milani, Gabriel Bronz, Sebastiano A. G. Lava, Céline Betti, Federica Vanoni, Mario G. Bianchetti, Pietro B. Faré, and Pietro Camozzi. Drug-related pyroglutamic acidosis: systematic literature review. Journal of Clinical Medicine, 13:5781, Sep 2024. URL: https://doi.org/10.3390/jcm13195781, doi:10.3390/jcm13195781. This article has 2 citations.

  4. (scafetta2024drugrelatedpyroglutamicacidosis pages 5-7): Tessa Scafetta, Orsolya Kovacs, Gregorio P. Milani, Gabriel Bronz, Sebastiano A. G. Lava, Céline Betti, Federica Vanoni, Mario G. Bianchetti, Pietro B. Faré, and Pietro Camozzi. Drug-related pyroglutamic acidosis: systematic literature review. Journal of Clinical Medicine, 13:5781, Sep 2024. URL: https://doi.org/10.3390/jcm13195781, doi:10.3390/jcm13195781. This article has 2 citations.

  5. (almaghlouth20125‐oxoprolinasedeficiencyreport pages 1-2): IA Almaghlouth, Jawahir Y. Mohamed, M. Al-Amoudi, L. Al-Ahaidib, A. Al-Odaib, F. Alkuraya, and F. Alkuraya. 5‐oxoprolinase deficiency: report of the first human oplah mutation. Clinical Genetics, 82:193-196, Aug 2012. URL: https://doi.org/10.1111/j.1399-0004.2011.01728.x, doi:10.1111/j.1399-0004.2011.01728.x. This article has 26 citations and is from a peer-reviewed journal.

  6. (calpena20125oxoprolinuriainheterozygous pages 1-2): Eduardo Calpena, Mercedes Casado, Dolores Martínez-Rubio, Andrés Nascimento, Jaume Colomer, Eva Gargallo, Angels García-Cazorla, Francesc Palau, Rafael Artuch, and Carmen Espinós. 5-oxoprolinuria in heterozygous patients for 5-oxoprolinase (oplah) missense changes. JIMD reports, 7:123-8, Jul 2012. URL: https://doi.org/10.1007/8904_2012_166, doi:10.1007/8904_2012_166. This article has 20 citations and is from a peer-reviewed journal.

  7. (stewart2024pyroglutamateacidosis2023. pages 1-2): Gordon W. Stewart. Pyroglutamate acidosis 2023. a review of 100 cases. Mar 2024. URL: https://doi.org/10.1016/j.clinme.2024.100030, doi:10.1016/j.clinme.2024.100030. This article has 12 citations and is from a peer-reviewed journal.

  8. (almaghlouth20125‐oxoprolinasedeficiencyreport pages 2-3): IA Almaghlouth, Jawahir Y. Mohamed, M. Al-Amoudi, L. Al-Ahaidib, A. Al-Odaib, F. Alkuraya, and F. Alkuraya. 5‐oxoprolinase deficiency: report of the first human oplah mutation. Clinical Genetics, 82:193-196, Aug 2012. URL: https://doi.org/10.1111/j.1399-0004.2011.01728.x, doi:10.1111/j.1399-0004.2011.01728.x. This article has 26 citations and is from a peer-reviewed journal.

  9. (kasapkara2024is5oxoprolinasedeficiency pages 1-1): Çiğdem Seher Kasapkara, Oya Kıreker Köylü, Aysenur Engin Erdal, Burak Yürek, Nesrin Ceylan, and Serdar Ceylaner. Is 5-oxoprolinase deficiency more than just a benign condition? Molecular Syndromology, 15:303-310, Feb 2024. URL: https://doi.org/10.1159/000536295, doi:10.1159/000536295. This article has 1 citations and is from a peer-reviewed journal.

  10. (kasapkara2024is5oxoprolinasedeficiency pages 6-7): Çiğdem Seher Kasapkara, Oya Kıreker Köylü, Aysenur Engin Erdal, Burak Yürek, Nesrin Ceylan, and Serdar Ceylaner. Is 5-oxoprolinase deficiency more than just a benign condition? Molecular Syndromology, 15:303-310, Feb 2024. URL: https://doi.org/10.1159/000536295, doi:10.1159/000536295. This article has 1 citations and is from a peer-reviewed journal.

  11. (calpena20125oxoprolinuriainheterozygous pages 2-4): Eduardo Calpena, Mercedes Casado, Dolores Martínez-Rubio, Andrés Nascimento, Jaume Colomer, Eva Gargallo, Angels García-Cazorla, Francesc Palau, Rafael Artuch, and Carmen Espinós. 5-oxoprolinuria in heterozygous patients for 5-oxoprolinase (oplah) missense changes. JIMD reports, 7:123-8, Jul 2012. URL: https://doi.org/10.1007/8904_2012_166, doi:10.1007/8904_2012_166. This article has 20 citations and is from a peer-reviewed journal.

  12. (kasapkara2024is5oxoprolinasedeficiency pages 3-4): Çiğdem Seher Kasapkara, Oya Kıreker Köylü, Aysenur Engin Erdal, Burak Yürek, Nesrin Ceylan, and Serdar Ceylaner. Is 5-oxoprolinase deficiency more than just a benign condition? Molecular Syndromology, 15:303-310, Feb 2024. URL: https://doi.org/10.1159/000536295, doi:10.1159/000536295. This article has 1 citations and is from a peer-reviewed journal.

  13. (niehaus2017discoveryofa pages 1-2): Thomas D. Niehaus, Mona Elbadawi-Sidhu, Valérie de Crécy-Lagard, Oliver Fiehn, and Andrew D. Hanson. Discovery of a widespread prokaryotic 5-oxoprolinase that was hiding in plain sight. Journal of Biological Chemistry, 292:16360-16367, Sep 2017. URL: https://doi.org/10.1074/jbc.m117.805028, doi:10.1074/jbc.m117.805028. This article has 80 citations and is from a domain leading peer-reviewed journal.

  14. (kasapkara2024is5oxoprolinasedeficiency media cc8de042): Çiğdem Seher Kasapkara, Oya Kıreker Köylü, Aysenur Engin Erdal, Burak Yürek, Nesrin Ceylan, and Serdar Ceylaner. Is 5-oxoprolinase deficiency more than just a benign condition? Molecular Syndromology, 15:303-310, Feb 2024. URL: https://doi.org/10.1159/000536295, doi:10.1159/000536295. This article has 1 citations and is from a peer-reviewed journal.

  15. (kasapkara2024is5oxoprolinasedeficiency media c684e2b6): Çiğdem Seher Kasapkara, Oya Kıreker Köylü, Aysenur Engin Erdal, Burak Yürek, Nesrin Ceylan, and Serdar Ceylaner. Is 5-oxoprolinase deficiency more than just a benign condition? Molecular Syndromology, 15:303-310, Feb 2024. URL: https://doi.org/10.1159/000536295, doi:10.1159/000536295. This article has 1 citations and is from a peer-reviewed journal.

  16. (scafetta2024drugrelatedpyroglutamicacidosis pages 4-5): Tessa Scafetta, Orsolya Kovacs, Gregorio P. Milani, Gabriel Bronz, Sebastiano A. G. Lava, Céline Betti, Federica Vanoni, Mario G. Bianchetti, Pietro B. Faré, and Pietro Camozzi. Drug-related pyroglutamic acidosis: systematic literature review. Journal of Clinical Medicine, 13:5781, Sep 2024. URL: https://doi.org/10.3390/jcm13195781, doi:10.3390/jcm13195781. This article has 2 citations.

  17. (stewart2024pyroglutamateacidosis2023. pages 2-3): Gordon W. Stewart. Pyroglutamate acidosis 2023. a review of 100 cases. Mar 2024. URL: https://doi.org/10.1016/j.clinme.2024.100030, doi:10.1016/j.clinme.2024.100030. This article has 12 citations and is from a peer-reviewed journal.

  18. (scafetta2024drugrelatedpyroglutamicacidosis pages 7-9): Tessa Scafetta, Orsolya Kovacs, Gregorio P. Milani, Gabriel Bronz, Sebastiano A. G. Lava, Céline Betti, Federica Vanoni, Mario G. Bianchetti, Pietro B. Faré, and Pietro Camozzi. Drug-related pyroglutamic acidosis: systematic literature review. Journal of Clinical Medicine, 13:5781, Sep 2024. URL: https://doi.org/10.3390/jcm13195781, doi:10.3390/jcm13195781. This article has 2 citations.

  19. (wolfgang2016carnitinepalmitoyltransfersase1cand pages 1-3): Michael Wolfgang. Carnitine palmitoyltransfersase-1c and 5-oxoprolinase interact in the mouse brain. ArXiv, Nov 2016. URL: https://doi.org/10.19185/matters.201609000009, doi:10.19185/matters.201609000009. This article has 1 citations.

  20. (wolfgang2016carnitinepalmitoyltransfersase1cand pages 3-4): Michael Wolfgang. Carnitine palmitoyltransfersase-1c and 5-oxoprolinase interact in the mouse brain. ArXiv, Nov 2016. URL: https://doi.org/10.19185/matters.201609000009, doi:10.19185/matters.201609000009. This article has 1 citations.

  21. (kasapkara2024is5oxoprolinasedeficiency media f8f7f3ad): Çiğdem Seher Kasapkara, Oya Kıreker Köylü, Aysenur Engin Erdal, Burak Yürek, Nesrin Ceylan, and Serdar Ceylaner. Is 5-oxoprolinase deficiency more than just a benign condition? Molecular Syndromology, 15:303-310, Feb 2024. URL: https://doi.org/10.1159/000536295, doi:10.1159/000536295. This article has 1 citations and is from a peer-reviewed journal.

Artifacts