Inherited Threoninemia

Mendelian MONDO:0010118 Pathograph 17 Inborn Error of Metabolism Amino Acid Metabolism Disorder

Inherited threoninemia is an extremely rare inborn error of amino acid metabolism characterized by markedly elevated concentrations of threonine in plasma, urine, and cerebrospinal fluid. First described in 1978, the condition is proposed to result from deficient hepatic threonine dehydratase (EC 4.2.1.16) activity, blocking conversion of threonine to 2-ketobutyrate. Excess threonine may secondarily be associated with secondary hyperglycinemia and a non-ketotic hyperglycinemia-like neurological phenotype, although the exact biochemical bridge is not established from cached abstract evidence. Clinical features reported in affected individuals include seizures, intellectual disability, failure to thrive, lethargy, and feeding difficulties. A separate phenotypic association with Leber congenital amaurosis and hepatomegaly has been reported in siblings with hyperthreoninemia, though the causal relationship remains uncertain. No causative gene has been identified at the molecular level; the disorder is defined by enzyme activity and metabolite measurements. Consanguinity has been noted in reported families, consistent with autosomal recessive inheritance.

Ask OpenScientist

Ask a research question about Inherited Threoninemia. OpenScientist will conduct autonomous deep research using the Disorder Mechanisms Knowledge Base and PubMed literature (typically 10-30 minutes).

Submitting...

Do not include personal health information in your question. Questions and results are cached in your browser's local storage.

1
Inheritance
3
Pathophys.
10
Phenotypes
17
Pathograph
1
Genes
2
Treatments
1
Deep Research
👪

Inheritance

1
Autosomal Recessive (presumed)
Consanguinity was noted in reported families, consistent with autosomal recessive inheritance. However, the causative gene has not been identified.
Show evidence (1 reference)
PMID:15168722 SUPPORT Human Clinical
"Parental consanguinity was present in 54% of cases with amino acid disorders. "
Consanguinity in families with amino acid disorders including threoninemia supports autosomal recessive inheritance.
⚙

Pathophysiology

3
Hepatic threonine dehydratase deficiency
Deficiency of hepatic threonine dehydratase (EC 4.2.1.16) blocks the cytosolic degradation of L-threonine to 2-ketobutyrate, causing marked systemic accumulation of threonine in plasma, cerebrospinal fluid, and urine. Threonine dehydratase activity was undetectable in liver autopsy tissue from the index case, while four marker enzyme activities were normal.
hepatocyte link
L-threonine metabolic process link ↕ DYSREGULATED threonine catabolic process link ↓ DECREASED
threonine dehydratase activity link ↓ DECREASED
cytosol link
Downstream
Systemic threonine accumulation Loss of hepatic threonine dehydratase activity blocks threonine catabolism, allowing threonine to accumulate systemically.
Show evidence (2 references)
PMID:6434824 SUPPORT Human Clinical
"Threonine dehydratase was undetectable in a liver autopsy specimen, which was obtained within 1 h of death and immediately frozen at -70 degrees C. Activities of four marker enzymes were normal. "
Direct demonstration of undetectable threonine dehydratase in liver tissue from a patient with threoninemia and NKH symptoms, establishing the enzyme deficiency as the primary metabolic block.
PMID:6434824 SUPPORT Human Clinical
"This represents the first documentation of an inborn error of threonine metabolism and a new explanation of NKH. "
The authors explicitly frame this as the first documented inborn error of threonine metabolism.
Systemic threonine accumulation
The threonine catabolic block is reflected clinically by elevated threonine in serum/plasma and urine, with cerebrospinal fluid elevation reported in the index threonine dehydratase deficiency case. Published evidence remains limited to the original enzyme-deficiency report, a sibling report with hyperthreoninemia and hyperthreoninuria, and screening detection of threoninemia as a rare amino acid disorder.
L-threonine metabolic process link ↕ DYSREGULATED threonine catabolic process link ↓ DECREASED
Downstream
Hyperthreoninemia Circulating threonine elevation is the defining biochemical phenotype.
Plasma threonine Plasma or serum threonine is the measurable circulating biomarker.
Hyperthreoninuria Excess systemic threonine can be excreted in urine.
Urinary threonine Urinary threonine elevation is the biochemical correlate of hyperthreoninuria.
NKH-like secondary hyperglycinemia Threonine dehydratase deficiency is reported together with a classical NKH-like presentation, but the cached abstract does not establish the precise biochemical bridge.
Intellectual disability Neurodevelopmental impairment has been reported in patients with hyperthreoninemia.
Hepatomegaly Hepatomegaly has been reported with systemic threonine accumulation.
Failure to thrive Physical growth impairment has been reported in patients with hyperthreoninemia.
Retinal dystrophy (Leber congenital amaurosis phenotype) Leber congenital amaurosis was reported in siblings with hyperthreoninemia, but causality remains uncertain.
Show evidence (3 references)
PMID:3083684 SUPPORT Human Clinical
"Her serum threonine level was increased (2.0 to 5.3 mg/dl; normal, 0.78 to 1.82 mg/dl). "
Documents elevated circulating threonine in a patient with reported hyperthreoninemia.
PMID:3083684 SUPPORT Human Clinical
"He also had hyperthreoninemia, hyperthreoninuria, hepatomegaly, and mental and physical retardation. "
Documents concurrent systemic and urinary threonine excess in an affected sibling.
PMID:15168722 SUPPORT Human Clinical
"A new metabolic defect threoninemia was also detected. "
Screening data support threoninemia as a rare detected amino acid metabolic defect.
NKH-like secondary hyperglycinemia
Threonine dehydratase deficiency was reported as a probable cause and new explanation for non-ketotic hyperglycinemia. The cached abstract supports the association between the threonine metabolic block and an NKH-like presentation, while the exact molecular route from threonine excess to secondary hyperglycinemia remains unresolved in abstract-level evidence.
glycine metabolic process link
Downstream
Nonketotic hyperglycinemia Secondary glycine accumulation manifests clinically as an NKH-like phenotype.
Seizures Seizures are part of the NKH symptom complex invoked for the index threoninemia case.
Lethargy Lethargy is part of the NKH symptom complex invoked for the index threoninemia case.
Feeding difficulties Feeding difficulties are part of the NKH symptom complex invoked for the index threoninemia case.
Show evidence (1 reference)
PMID:6434824 SUPPORT Human Clinical
"A patient with classical symptoms of non-ketotic hyperglycinaemia (NKH) is presented. "
The patient presented with classical NKH symptoms in the setting of undetectable threonine dehydratase, supporting an NKH-like secondary hyperglycinemia mechanism without specifying the precise biochemical bridge.
⬡

Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.
Pathograph: causal mechanism network for Inherited Threoninemia 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

10
Digestive 2
Hepatomegaly OCCASIONAL Hepatomegaly (HP:0002240)
Show evidence (1 reference)
PMID:3083684 SUPPORT Human Clinical
"He also had hyperthreoninemia, hyperthreoninuria, hepatomegaly, and mental and physical retardation. "
Directly reports hepatomegaly in a patient with hyperthreoninemia.
Feeding difficulties OCCASIONAL Feeding difficulties (HP:0011968)
Show evidence (2 references)
PMID:6434824 PARTIAL Human Clinical
"A patient with classical symptoms of non-ketotic hyperglycinaemia (NKH) is presented. "
The abstract describes classical NKH symptoms without enumerating them individually. Feeding difficulty is inferred as part of the broader NKH-like presentation.
PMID:6301756 PARTIAL Human Clinical
"The salient features of nonketotic hyperglycinemia include apnea, feeding difficulties, lethargy, seizures, abnormal muscle tone and reflex activity, significant developmental delay, and, in most instances, early death. "
Contextual NKH review evidence directly lists feeding difficulties among salient NKH features.
Eye 1
Retinal dystrophy (Leber congenital amaurosis phenotype) OCCASIONAL Retinal dystrophy (HP:0000556)
Show evidence (2 references)
PMID:3083684 PARTIAL Human Clinical
"Two siblings had Leber's congenital amaurosis. The girl (Patient 1) showed blindness shortly after birth, absent pupillary light reflex, and multiple round, white spots in both fundi. "
Reports Leber congenital amaurosis in two siblings with hyperthreoninemia. Classified as PARTIAL because the causal relationship between hyperthreoninemia and LCA is not established.
PMID:3083684 PARTIAL Human Clinical
"We suspect a close relationship between hyperthreoninemia and Leber's congenital amaurosis in these siblings. "
The authors suggest a relationship but do not demonstrate causality.
Genitourinary 1
Hyperthreoninuria FREQUENT Hyperthreoninuria (HP:0003296)
Show evidence (1 reference)
PMID:3083684 SUPPORT Human Clinical
"He also had hyperthreoninemia, hyperthreoninuria, hepatomegaly, and mental and physical retardation. "
Directly reports hyperthreoninuria in a patient with hyperthreoninemia.
Metabolism 2
Hyperthreoninemia OBLIGATE Hyperthreoninemia (HP:0003354)
Show evidence (1 reference)
PMID:3083684 SUPPORT Human Clinical
"Her serum threonine level was increased (2.0 to 5.3 mg/dl; normal, 0.78 to 1.82 mg/dl). "
Documents elevated serum threonine levels in a patient with hyperthreoninemia, with quantitative values and normal range.
Nonketotic hyperglycinemia OCCASIONAL Nonketotic hyperglycinemia (HP:0008288)
Sequelae: Seizures Lethargy Feeding difficulties
Show evidence (1 reference)
PMID:6434824 SUPPORT Human Clinical
"A patient with classical symptoms of non-ketotic hyperglycinaemia (NKH) is presented. "
The index patient for threonine dehydratase deficiency presented with classical NKH symptoms alongside threoninemia.
Nervous System 3
Seizures OCCASIONAL Seizure (HP:0001250)
Show evidence (2 references)
PMID:6434824 PARTIAL Human Clinical
"A patient with classical symptoms of non-ketotic hyperglycinaemia (NKH) is presented. "
The abstract describes classical NKH symptoms without enumerating them individually. Seizures are a hallmark of NKH and are inferred from this presentation.
PMID:6301756 PARTIAL Human Clinical
"The salient features of nonketotic hyperglycinemia include apnea, feeding difficulties, lethargy, seizures, abnormal muscle tone and reflex activity, significant developmental delay, and, in most instances, early death. "
Contextual NKH review evidence enumerates seizures among salient features, strengthening the specific symptom inferred from the index threoninemia case's NKH-like presentation.
Intellectual disability OCCASIONAL Intellectual disability (HP:0001249)
Show evidence (2 references)
PMID:3083684 SUPPORT Human Clinical
"He also had hyperthreoninemia, hyperthreoninuria, hepatomegaly, and mental and physical retardation. "
Reports mental retardation in a patient with hyperthreoninemia.
PMID:15168722 SUPPORT Human Clinical
"A screening program was carried out for amino acid disorders in children with mental handicaps from the state of Andhra Pradesh (India) during the last two decades. "
Threoninemia was detected in the context of screening children with mental handicaps, supporting the association between threoninemia and intellectual disability.
Lethargy OCCASIONAL Lethargy (HP:0001254)
Show evidence (2 references)
PMID:6434824 PARTIAL Human Clinical
"A patient with classical symptoms of non-ketotic hyperglycinaemia (NKH) is presented. "
The abstract describes classical NKH symptoms without enumerating them individually. Lethargy is a hallmark of NKH and is inferred from this presentation.
PMID:6301756 PARTIAL Human Clinical
"The salient features of nonketotic hyperglycinemia include apnea, feeding difficulties, lethargy, seizures, abnormal muscle tone and reflex activity, significant developmental delay, and, in most instances, early death. "
Contextual NKH review evidence enumerates lethargy among salient features, strengthening the symptom inferred from the index threoninemia case's NKH-like presentation.
Growth 1
Failure to thrive OCCASIONAL Failure to thrive (HP:0001508)
Show evidence (1 reference)
PMID:3083684 SUPPORT Human Clinical
"He also had hyperthreoninemia, hyperthreoninuria, hepatomegaly, and mental and physical retardation. "
Physical retardation reported in a patient with hyperthreoninemia is consistent with failure to thrive.
🧬

Genetic Associations

1
Threonine dehydratase (enzyme level) (Enzyme Deficiency)
Show evidence (1 reference)
PMID:6434824 SUPPORT Human Clinical
"Threonine dehydratase was undetectable in a liver autopsy specimen, which was obtained within 1 h of death and immediately frozen at -70 degrees C. "
Direct enzyme assay demonstrating undetectable threonine dehydratase activity in the index patient.
💊

Treatments

2
Dietary threonine restriction
Action: dietary intervention MAXO:0000088
Dietary management with restriction of threonine intake to lower plasma threonine levels. No formal clinical trials exist for this extremely rare condition.
Mechanism Target:
INHIBITS Systemic threonine accumulation — Restricting dietary threonine is intended to reduce the substrate load feeding systemic threonine accumulation.
Target Phenotypes: Hyperthreoninemia ↗
Anticonvulsant therapy
Action: anticonvulsant agent therapy MAXO:0000167
Anticonvulsant agents for seizure management in patients with NKH-like neurological manifestations.
Target Phenotypes: Seizure ↗
🔬

Biochemical Markers

3
Plasma threonine (INCREASED)
Context: Marked elevation of plasma threonine, approximately 3-19 fold above normal values, is the primary diagnostic biomarker. Reported values include 2.0-5.3 mg/dl (normal 0.78-1.82 mg/dl) and approximately 19-fold elevation in the threonine dehydratase deficiency case.
Pathograph Readouts
Readout Of Systemic threonine accumulation Positive Diagnostic
Elevated plasma or serum threonine reports systemic threonine accumulation.
Show evidence (1 reference)
PMID:3083684 SUPPORT Human Clinical
"Her serum threonine level was increased (2.0 to 5.3 mg/dl; normal, 0.78 to 1.82 mg/dl). "
Quantitative serum threonine elevation supports circulating threonine as a diagnostic readout of systemic accumulation.
Readout Of Hyperthreoninemia Positive Diagnostic
Plasma or serum threonine is the measured analyte underlying the hyperthreoninemia phenotype.
Show evidence (1 reference)
PMID:3083684 SUPPORT Human Clinical
"Her serum threonine level was increased (2.0 to 5.3 mg/dl; normal, 0.78 to 1.82 mg/dl). "
Quantitative serum threonine elevation directly supports plasma threonine as the readout for hyperthreoninemia.
Show evidence (1 reference)
PMID:3083684 SUPPORT Human Clinical
"Her serum threonine level was increased (2.0 to 5.3 mg/dl; normal, 0.78 to 1.82 mg/dl). "
Quantitative documentation of elevated serum threonine with reference range.
Urinary threonine (INCREASED)
Context: Elevated urinary threonine excretion accompanies the plasma elevation.
Pathograph Readouts
Readout Of Systemic threonine accumulation Positive Diagnostic
Elevated urinary threonine reports systemic threonine excess with renal excretion.
Show evidence (1 reference)
PMID:3083684 SUPPORT Human Clinical
"He also had hyperthreoninemia, hyperthreoninuria, hepatomegaly, and mental and physical retardation. "
Hyperthreoninuria supports urinary threonine as a positive diagnostic readout of systemic threonine accumulation.
Readout Of Hyperthreoninuria Positive Diagnostic
Urinary threonine excretion is the measured analyte underlying the hyperthreoninuria phenotype.
Show evidence (1 reference)
PMID:3083684 SUPPORT Human Clinical
"He also had hyperthreoninemia, hyperthreoninuria, hepatomegaly, and mental and physical retardation. "
Hyperthreoninuria directly supports urinary threonine as the readout for the urinary threonine-excess phenotype.
Show evidence (1 reference)
PMID:3083684 SUPPORT Human Clinical
"He also had hyperthreoninemia, hyperthreoninuria, hepatomegaly, and mental and physical retardation. "
Directly documents hyperthreoninuria in a patient with hyperthreoninemia.
CSF threonine (INCREASED)
{ }

Source YAML

click to show 
name: Inherited Threoninemia
category: Mendelian
creation_date: '2026-03-11T00:00:00Z'
updated_date: '2026-05-20T10:23:09Z'
synonyms:
- Hyperthreoninaemia
- Hyperthreoninemia
- Threoninemia
- Threonine dehydratase deficiency
description: >
  Inherited threoninemia is an extremely rare inborn error of amino acid metabolism
  characterized by markedly elevated concentrations of threonine in plasma, urine,
  and cerebrospinal fluid. First described in 1978, the condition is proposed to
  result from deficient hepatic threonine dehydratase (EC 4.2.1.16) activity,
  blocking conversion of threonine to 2-ketobutyrate. Excess threonine may secondarily
  be associated with secondary hyperglycinemia and a non-ketotic hyperglycinemia-like
  neurological phenotype, although the exact biochemical bridge is not established
  from cached abstract evidence. Clinical features reported in affected individuals
  include seizures, intellectual disability, failure to thrive, lethargy, and feeding
  difficulties. A separate phenotypic association with Leber congenital amaurosis
  and hepatomegaly has been reported in siblings with hyperthreoninemia, though the
  causal relationship remains uncertain. No causative gene has been identified at
  the molecular level; the disorder is defined by enzyme activity and metabolite
  measurements. Consanguinity has been noted in reported families, consistent with
  autosomal recessive inheritance.
disease_term:
  preferred_term: inherited threoninemia
  term:
    id: MONDO:0010118
    label: inherited threoninemia
parents:
- Inborn Error of Metabolism
- Amino Acid Metabolism Disorder
inheritance:
- name: Autosomal Recessive (presumed)
  description: >
    Consanguinity was noted in reported families, consistent with autosomal
    recessive inheritance. However, the causative gene has not been identified.
  evidence:
  - reference: PMID:15168722
    reference_title: "Amino acid disorders in mental retardation: a two-decade study from Andhra Pradesh."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >
      Parental consanguinity was present in 54% of cases with amino acid disorders.
    explanation: >
      Consanguinity in families with amino acid disorders including threoninemia
      supports autosomal recessive inheritance.
prevalence:
- population: Published case reports
  percentage: 3 reported patients
  notes: >-
    No population-based prevalence estimate was identified in PubMed-indexed
    literature. The disease appears to be exceptionally rare, with the located
    literature consisting of one original index patient plus one affected sibling
    pair with hyperthreoninemia.
  evidence:
  - reference: PMID:6434824
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "A patient with classical symptoms of non-ketotic hyperglycinaemia (NKH) is presented."
    explanation: This paper documents the original index case of threonine dehydratase deficiency.
  - reference: PMID:3083684
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Two siblings had Leber's congenital amaurosis. The girl (Patient 1) showed blindness shortly after birth, absent pupillary light reflex, and multiple round, white spots in both fundi. Her serum threonine level was increased (2.0 to 5.3 mg/dl; normal, 0.78 to 1.82 mg/dl)."
    explanation: This report contributes an additional affected sibling pair with documented hyperthreoninemia, supporting the very small known case count.
pathophysiology:
- name: Hepatic threonine dehydratase deficiency
  description: >
    Deficiency of hepatic threonine dehydratase (EC 4.2.1.16) blocks the
    cytosolic degradation of L-threonine to 2-ketobutyrate, causing marked
    systemic accumulation of threonine in plasma, cerebrospinal fluid, and
    urine. Threonine dehydratase activity was undetectable in liver autopsy
    tissue from the index case, while four marker enzyme activities were normal.
  cell_types:
  - preferred_term: hepatocyte
    term:
      id: CL:0000182
      label: hepatocyte
  biological_processes:
  - preferred_term: L-threonine metabolic process
    term:
      id: GO:0006566
      label: L-threonine metabolic process
    modifier: DYSREGULATED
  - preferred_term: threonine catabolic process
    term:
      id: GO:0006567
      label: L-threonine catabolic process
    modifier: DECREASED
  molecular_functions:
  - preferred_term: threonine dehydratase activity
    term:
      id: GO:0004794
      label: threonine deaminase activity
    modifier: DECREASED
  cellular_components:
  - preferred_term: cytosol
    term:
      id: GO:0005829
      label: cytosol
  chemical_entities:
  - preferred_term: L-threonine
    term:
      id: CHEBI:16857
      label: L-threonine
    modifier: INCREASED
  - preferred_term: 2-oxobutanoate
    term:
      id: CHEBI:16763
      label: 2-oxobutanoate
    modifier: DECREASED
  evidence:
  - reference: PMID:6434824
    reference_title: "Threonine dehydratase deficiency: a probable cause of non-ketotic hyperglycinaemia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >
      Threonine dehydratase was undetectable in a liver autopsy specimen,
      which was obtained within 1 h of death and immediately frozen at -70 degrees C.
      Activities of four marker enzymes were normal.
    explanation: >
      Direct demonstration of undetectable threonine dehydratase in liver tissue
      from a patient with threoninemia and NKH symptoms, establishing the
      enzyme deficiency as the primary metabolic block.
  - reference: PMID:6434824
    reference_title: "Threonine dehydratase deficiency: a probable cause of non-ketotic hyperglycinaemia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >
      This represents the first documentation of an inborn error of threonine
      metabolism and a new explanation of NKH.
    explanation: >
      The authors explicitly frame this as the first documented inborn error
      of threonine metabolism.
  downstream:
  - target: Systemic threonine accumulation
    description: >
      Loss of hepatic threonine dehydratase activity blocks threonine catabolism,
      allowing threonine to accumulate systemically.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:6434824
      reference_title: "Threonine dehydratase deficiency: a probable cause of non-ketotic hyperglycinaemia."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >
        Threonine dehydratase was undetectable in a liver autopsy specimen,
        which was obtained within 1 h of death and immediately frozen at -70 degrees C.
      explanation: >
        The undetectable liver enzyme activity supports the primary metabolic
        block that permits systemic threonine accumulation.
- name: Systemic threonine accumulation
  description: >
    The threonine catabolic block is reflected clinically by elevated threonine
    in serum/plasma and urine, with cerebrospinal fluid elevation reported in
    the index threonine dehydratase deficiency case. Published evidence remains
    limited to the original enzyme-deficiency report, a sibling report with
    hyperthreoninemia and hyperthreoninuria, and screening detection of
    threoninemia as a rare amino acid disorder.
  biological_processes:
  - preferred_term: L-threonine metabolic process
    term:
      id: GO:0006566
      label: L-threonine metabolic process
    modifier: DYSREGULATED
  - preferred_term: threonine catabolic process
    term:
      id: GO:0006567
      label: L-threonine catabolic process
    modifier: DECREASED
  chemical_entities:
  - preferred_term: L-threonine
    term:
      id: CHEBI:16857
      label: L-threonine
    modifier: INCREASED
  - preferred_term: 2-oxobutanoate
    term:
      id: CHEBI:16763
      label: 2-oxobutanoate
    modifier: DECREASED
  evidence:
  - reference: PMID:3083684
    reference_title: "Leber's congenital amaurosis associated with hyperthreoninemia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >
      Her serum threonine level was increased (2.0 to 5.3 mg/dl;
      normal, 0.78 to 1.82 mg/dl).
    explanation: >
      Documents elevated circulating threonine in a patient with reported
      hyperthreoninemia.
  - reference: PMID:3083684
    reference_title: "Leber's congenital amaurosis associated with hyperthreoninemia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >
      He also had hyperthreoninemia, hyperthreoninuria, hepatomegaly,
      and mental and physical retardation.
    explanation: >
      Documents concurrent systemic and urinary threonine excess in an affected
      sibling.
  - reference: PMID:15168722
    reference_title: "Amino acid disorders in mental retardation: a two-decade study from Andhra Pradesh."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >
      A new metabolic defect threoninemia was also detected.
    explanation: >
      Screening data support threoninemia as a rare detected amino acid
      metabolic defect.
  downstream:
  - target: Hyperthreoninemia
    description: Circulating threonine elevation is the defining biochemical phenotype.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:3083684
      reference_title: "Leber's congenital amaurosis associated with hyperthreoninemia."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >
        Her serum threonine level was increased (2.0 to 5.3 mg/dl;
        normal, 0.78 to 1.82 mg/dl).
      explanation: >
        Directly supports the edge from systemic threonine accumulation to
        hyperthreoninemia.
  - target: Plasma threonine
    description: Plasma or serum threonine is the measurable circulating biomarker.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:3083684
      reference_title: "Leber's congenital amaurosis associated with hyperthreoninemia."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >
        Her serum threonine level was increased (2.0 to 5.3 mg/dl;
        normal, 0.78 to 1.82 mg/dl).
      explanation: >
        Quantitative serum threonine elevation supports plasma/serum threonine
        as the principal biomarker.
  - target: Hyperthreoninuria
    description: Excess systemic threonine can be excreted in urine.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:3083684
      reference_title: "Leber's congenital amaurosis associated with hyperthreoninemia."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >
        He also had hyperthreoninemia, hyperthreoninuria, hepatomegaly,
        and mental and physical retardation.
      explanation: >
        Directly reports urinary threonine excess in a sibling with
        hyperthreoninemia.
  - target: Urinary threonine
    description: Urinary threonine elevation is the biochemical correlate of hyperthreoninuria.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:3083684
      reference_title: "Leber's congenital amaurosis associated with hyperthreoninemia."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >
        He also had hyperthreoninemia, hyperthreoninuria, hepatomegaly,
        and mental and physical retardation.
      explanation: >
        Supports urinary threonine as an elevated biochemical marker.
  - target: NKH-like secondary hyperglycinemia
    description: >
      Threonine dehydratase deficiency is reported together with a classical
      NKH-like presentation, but the cached abstract does not establish the
      precise biochemical bridge.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:6434824
      reference_title: "Threonine dehydratase deficiency: a probable cause of non-ketotic hyperglycinaemia."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >
        A patient with classical symptoms of non-ketotic hyperglycinaemia (NKH)
        is presented.
      explanation: >
        The index threonine dehydratase deficiency case is explicitly presented
        as an NKH-like disorder.
  - target: Intellectual disability
    description: >
      Neurodevelopmental impairment has been reported in patients with
      hyperthreoninemia.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:3083684
      reference_title: "Leber's congenital amaurosis associated with hyperthreoninemia."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >
        He also had hyperthreoninemia, hyperthreoninuria, hepatomegaly,
        and mental and physical retardation.
      explanation: >
        The sibling report directly states mental retardation in a patient with
        hyperthreoninemia and hyperthreoninuria.
  - target: Hepatomegaly
    description: >
      Hepatomegaly has been reported with systemic threonine accumulation.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:3083684
      reference_title: "Leber's congenital amaurosis associated with hyperthreoninemia."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >
        He also had hyperthreoninemia, hyperthreoninuria, hepatomegaly,
        and mental and physical retardation.
      explanation: >
        The sibling report directly lists hepatomegaly with the
        hyperthreoninemia/hyperthreoninuria phenotype.
  - target: Failure to thrive
    description: >
      Physical growth impairment has been reported in patients with
      hyperthreoninemia.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:3083684
      reference_title: "Leber's congenital amaurosis associated with hyperthreoninemia."
      supports: PARTIAL
      evidence_source: HUMAN_CLINICAL
      snippet: >
        He also had hyperthreoninemia, hyperthreoninuria, hepatomegaly,
        and mental and physical retardation.
      explanation: >
        The report supports physical growth impairment, mapped conservatively
        to the broader failure-to-thrive phenotype.
  - target: Retinal dystrophy (Leber congenital amaurosis phenotype)
    description: >
      Leber congenital amaurosis was reported in siblings with
      hyperthreoninemia, but causality remains uncertain.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:3083684
      reference_title: "Leber's congenital amaurosis associated with hyperthreoninemia."
      supports: PARTIAL
      evidence_source: HUMAN_CLINICAL
      snippet: >
        We suspect a close relationship between hyperthreoninemia and Leber's
        congenital amaurosis in these siblings.
      explanation: >
        The authors explicitly suggest a relationship but do not establish a
        causal mechanism, so the edge is retained as partial and indirect.
- name: NKH-like secondary hyperglycinemia
  description: >
    Threonine dehydratase deficiency was reported as a probable cause and new
    explanation for non-ketotic hyperglycinemia. The cached abstract supports
    the association between the threonine metabolic block and an NKH-like
    presentation, while the exact molecular route from threonine excess to
    secondary hyperglycinemia remains unresolved in abstract-level evidence.
  biological_processes:
  - preferred_term: glycine metabolic process
    term:
      id: GO:0006544
      label: glycine metabolic process
  chemical_entities:
  - preferred_term: glycine
    term:
      id: CHEBI:15428
      label: glycine
    modifier: INCREASED
  - preferred_term: L-threonine
    term:
      id: CHEBI:16857
      label: L-threonine
    modifier: INCREASED
  evidence:
  - reference: PMID:6434824
    reference_title: "Threonine dehydratase deficiency: a probable cause of non-ketotic hyperglycinaemia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >
      A patient with classical symptoms of non-ketotic hyperglycinaemia (NKH)
      is presented.
    explanation: >
      The patient presented with classical NKH symptoms in the setting of
      undetectable threonine dehydratase, supporting an NKH-like secondary
      hyperglycinemia mechanism without specifying the precise biochemical
      bridge.
  downstream:
  - target: Nonketotic hyperglycinemia
    description: Secondary glycine accumulation manifests clinically as an NKH-like phenotype.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:6434824
      reference_title: "Threonine dehydratase deficiency: a probable cause of non-ketotic hyperglycinaemia."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >
        A patient with classical symptoms of non-ketotic hyperglycinaemia (NKH)
        is presented.
      explanation: >
        The index case is explicitly described as presenting with classical
        non-ketotic hyperglycinemia symptoms.
  - target: Seizures
    description: Seizures are part of the NKH symptom complex invoked for the index threoninemia case.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:6301756
      reference_title: "Nonketotic hyperglycinemia: clinical, biochemical, and therapeutic considerations."
      supports: PARTIAL
      evidence_source: HUMAN_CLINICAL
      snippet: >
        The salient features of nonketotic hyperglycinemia include apnea, feeding
        difficulties, lethargy, seizures, abnormal muscle tone and reflex activity,
        significant developmental delay, and, in most instances, early death.
      explanation: >
        The NKH review enumerates seizures among salient NKH features, supporting
        this symptom branch for the threoninemia case's NKH-like presentation.
  - target: Lethargy
    description: Lethargy is part of the NKH symptom complex invoked for the index threoninemia case.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:6301756
      reference_title: "Nonketotic hyperglycinemia: clinical, biochemical, and therapeutic considerations."
      supports: PARTIAL
      evidence_source: HUMAN_CLINICAL
      snippet: >
        The salient features of nonketotic hyperglycinemia include apnea, feeding
        difficulties, lethargy, seizures, abnormal muscle tone and reflex activity,
        significant developmental delay, and, in most instances, early death.
      explanation: >
        The NKH review enumerates lethargy among salient NKH features, supporting
        this symptom branch for the threoninemia case's NKH-like presentation.
  - target: Feeding difficulties
    description: Feeding difficulties are part of the NKH symptom complex invoked for the index threoninemia case.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:6301756
      reference_title: "Nonketotic hyperglycinemia: clinical, biochemical, and therapeutic considerations."
      supports: PARTIAL
      evidence_source: HUMAN_CLINICAL
      snippet: >
        The salient features of nonketotic hyperglycinemia include apnea, feeding
        difficulties, lethargy, seizures, abnormal muscle tone and reflex activity,
        significant developmental delay, and, in most instances, early death.
      explanation: >
        The NKH review enumerates feeding difficulties among salient NKH
        features, supporting this symptom branch for the threoninemia case's
        NKH-like presentation.
phenotypes:
- category: Metabolic
  name: Hyperthreoninemia
  frequency: OBLIGATE
  diagnostic: true
  description: >
    Markedly elevated concentrations of threonine in plasma, the hallmark
    biochemical finding. Reported elevations of approximately 19-fold above
    normal in plasma.
  phenotype_term:
    preferred_term: Hyperthreoninemia
    term:
      id: HP:0003354
      label: Hyperthreoninemia
  evidence:
  - reference: PMID:3083684
    reference_title: "Leber's congenital amaurosis associated with hyperthreoninemia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >
      Her serum threonine level was increased (2.0 to 5.3 mg/dl;
      normal, 0.78 to 1.82 mg/dl).
    explanation: >
      Documents elevated serum threonine levels in a patient with
      hyperthreoninemia, with quantitative values and normal range.
- category: Metabolic
  name: Hyperthreoninuria
  frequency: FREQUENT
  description: >
    Elevated excretion of threonine in urine, reported in siblings with
    hyperthreoninemia.
  phenotype_term:
    preferred_term: Hyperthreoninuria
    term:
      id: HP:0003296
      label: Hyperthreoninuria
  evidence:
  - reference: PMID:3083684
    reference_title: "Leber's congenital amaurosis associated with hyperthreoninemia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >
      He also had hyperthreoninemia, hyperthreoninuria, hepatomegaly,
      and mental and physical retardation.
    explanation: >
      Directly reports hyperthreoninuria in a patient with hyperthreoninemia.
- category: Metabolic
  name: Nonketotic hyperglycinemia
  frequency: OCCASIONAL
  description: >
    Secondary hyperglycinemia with a non-ketotic hyperglycinemia phenotype
    has been reported in a patient with threonine dehydratase deficiency; the
    biochemical mechanism linking threonine accumulation to glycine excess is
    proposed but not established from abstract-level evidence.
  phenotype_term:
    preferred_term: Nonketotic hyperglycinemia
    term:
      id: HP:0008288
      label: Nonketotic hyperglycinemia
  evidence:
  - reference: PMID:6434824
    reference_title: "Threonine dehydratase deficiency: a probable cause of non-ketotic hyperglycinaemia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >
      A patient with classical symptoms of non-ketotic hyperglycinaemia (NKH)
      is presented.
    explanation: >
      The index patient for threonine dehydratase deficiency presented with
      classical NKH symptoms alongside threoninemia.
  sequelae:
  - target: Seizures
    description: Seizures are part of the NKH symptom complex invoked for the index case.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:6301756
      reference_title: "Nonketotic hyperglycinemia: clinical, biochemical, and therapeutic considerations."
      supports: PARTIAL
      evidence_source: HUMAN_CLINICAL
      snippet: >
        The salient features of nonketotic hyperglycinemia include apnea, feeding
        difficulties, lethargy, seizures, abnormal muscle tone and reflex activity,
        significant developmental delay, and, in most instances, early death.
      explanation: >
        This review enumerates seizures among salient NKH features, supporting
        the specific symptom branch inferred from the index threoninemia case's
        NKH-like presentation.
  - target: Lethargy
    description: Lethargy is part of the NKH symptom complex invoked for the index case.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:6301756
      reference_title: "Nonketotic hyperglycinemia: clinical, biochemical, and therapeutic considerations."
      supports: PARTIAL
      evidence_source: HUMAN_CLINICAL
      snippet: >
        The salient features of nonketotic hyperglycinemia include apnea, feeding
        difficulties, lethargy, seizures, abnormal muscle tone and reflex activity,
        significant developmental delay, and, in most instances, early death.
      explanation: >
        This review enumerates lethargy among salient NKH features, supporting
        the symptom branch inferred from the index threoninemia case.
  - target: Feeding difficulties
    description: Feeding difficulties are part of the NKH symptom complex invoked for the index case.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:6301756
      reference_title: "Nonketotic hyperglycinemia: clinical, biochemical, and therapeutic considerations."
      supports: PARTIAL
      evidence_source: HUMAN_CLINICAL
      snippet: >
        The salient features of nonketotic hyperglycinemia include apnea, feeding
        difficulties, lethargy, seizures, abnormal muscle tone and reflex activity,
        significant developmental delay, and, in most instances, early death.
      explanation: >
        This review enumerates feeding difficulties among salient NKH features,
        supporting a broader feeding-difficulty node rather than a more specific
        poor-suck claim not stated in the cached threoninemia abstract.
- category: Clinical
  name: Seizures
  frequency: OCCASIONAL
  description: >
    Seizures have been reported in patients with inherited threoninemia,
    including neonatal-onset seizures in the context of NKH-like presentation.
  phenotype_term:
    preferred_term: Seizure
    term:
      id: HP:0001250
      label: Seizure
  evidence:
  - reference: PMID:6434824
    reference_title: "Threonine dehydratase deficiency: a probable cause of non-ketotic hyperglycinaemia."
    supports: PARTIAL
    evidence_source: HUMAN_CLINICAL
    snippet: >
      A patient with classical symptoms of non-ketotic hyperglycinaemia (NKH)
      is presented.
    explanation: >
      The abstract describes classical NKH symptoms without enumerating them
      individually. Seizures are a hallmark of NKH and are inferred from
      this presentation.
  - reference: PMID:6301756
    reference_title: "Nonketotic hyperglycinemia: clinical, biochemical, and therapeutic considerations."
    supports: PARTIAL
    evidence_source: HUMAN_CLINICAL
    snippet: >
      The salient features of nonketotic hyperglycinemia include apnea, feeding
      difficulties, lethargy, seizures, abnormal muscle tone and reflex activity,
      significant developmental delay, and, in most instances, early death.
    explanation: >
      Contextual NKH review evidence enumerates seizures among salient features,
      strengthening the specific symptom inferred from the index threoninemia
      case's NKH-like presentation.
- category: Clinical
  name: Intellectual disability
  frequency: OCCASIONAL
  description: >
    Intellectual disability and developmental delay have been reported in
    individuals with hyperthreoninemia, including mental retardation in
    siblings with the condition.
  phenotype_term:
    preferred_term: Intellectual disability
    term:
      id: HP:0001249
      label: Intellectual disability
  evidence:
  - reference: PMID:3083684
    reference_title: "Leber's congenital amaurosis associated with hyperthreoninemia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >
      He also had hyperthreoninemia, hyperthreoninuria, hepatomegaly,
      and mental and physical retardation.
    explanation: >
      Reports mental retardation in a patient with hyperthreoninemia.
  - reference: PMID:15168722
    reference_title: "Amino acid disorders in mental retardation: a two-decade study from Andhra Pradesh."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >
      A screening program was carried out for amino acid disorders in children
      with mental handicaps from the state of Andhra Pradesh (India) during
      the last two decades.
    explanation: >
      Threoninemia was detected in the context of screening children with
      mental handicaps, supporting the association between threoninemia
      and intellectual disability.
- category: Clinical
  name: Hepatomegaly
  frequency: OCCASIONAL
  description: >
    Hepatomegaly was reported in a patient with hyperthreoninemia, though
    whether it is a primary or secondary feature remains uncertain.
  phenotype_term:
    preferred_term: Hepatomegaly
    term:
      id: HP:0002240
      label: Hepatomegaly
  evidence:
  - reference: PMID:3083684
    reference_title: "Leber's congenital amaurosis associated with hyperthreoninemia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >
      He also had hyperthreoninemia, hyperthreoninuria, hepatomegaly,
      and mental and physical retardation.
    explanation: >
      Directly reports hepatomegaly in a patient with hyperthreoninemia.
- category: Clinical
  name: Lethargy
  frequency: OCCASIONAL
  description: >
    Lethargy was reported in the index case of threonine dehydratase deficiency
    presenting with NKH-like symptoms.
  phenotype_term:
    preferred_term: Lethargy
    term:
      id: HP:0001254
      label: Lethargy
  evidence:
  - reference: PMID:6434824
    reference_title: "Threonine dehydratase deficiency: a probable cause of non-ketotic hyperglycinaemia."
    supports: PARTIAL
    evidence_source: HUMAN_CLINICAL
    snippet: >
      A patient with classical symptoms of non-ketotic hyperglycinaemia (NKH)
      is presented.
    explanation: >
      The abstract describes classical NKH symptoms without enumerating them
      individually. Lethargy is a hallmark of NKH and is inferred from this
      presentation.
  - reference: PMID:6301756
    reference_title: "Nonketotic hyperglycinemia: clinical, biochemical, and therapeutic considerations."
    supports: PARTIAL
    evidence_source: HUMAN_CLINICAL
    snippet: >
      The salient features of nonketotic hyperglycinemia include apnea, feeding
      difficulties, lethargy, seizures, abnormal muscle tone and reflex activity,
      significant developmental delay, and, in most instances, early death.
    explanation: >
      Contextual NKH review evidence enumerates lethargy among salient features,
      strengthening the symptom inferred from the index threoninemia case's
      NKH-like presentation.
- category: Clinical
  name: Feeding difficulties
  frequency: OCCASIONAL
  description: >
    Feeding difficulties are included in the NKH symptom complex used to
    interpret the neonatal presentation of threonine dehydratase deficiency.
    The cached threoninemia abstract does not enumerate the specific feeding
    sign, so this node is curated at the broader HP feeding-difficulties level.
  phenotype_term:
    preferred_term: Feeding difficulties
    term:
      id: HP:0011968
      label: Feeding difficulties
  evidence:
  - reference: PMID:6434824
    reference_title: "Threonine dehydratase deficiency: a probable cause of non-ketotic hyperglycinaemia."
    supports: PARTIAL
    evidence_source: HUMAN_CLINICAL
    snippet: >
      A patient with classical symptoms of non-ketotic hyperglycinaemia (NKH)
      is presented.
    explanation: >
      The abstract describes classical NKH symptoms without enumerating them
      individually. Feeding difficulty is inferred as part of the broader
      NKH-like presentation.
  - reference: PMID:6301756
    reference_title: "Nonketotic hyperglycinemia: clinical, biochemical, and therapeutic considerations."
    supports: PARTIAL
    evidence_source: HUMAN_CLINICAL
    snippet: >
      The salient features of nonketotic hyperglycinemia include apnea, feeding
      difficulties, lethargy, seizures, abnormal muscle tone and reflex activity,
      significant developmental delay, and, in most instances, early death.
    explanation: >
      Contextual NKH review evidence directly lists feeding difficulties among
      salient NKH features.
- category: Clinical
  name: Failure to thrive
  frequency: OCCASIONAL
  description: >
    Physical growth retardation and failure to thrive have been reported
    in patients with inherited threoninemia.
  phenotype_term:
    preferred_term: Failure to thrive
    term:
      id: HP:0001508
      label: Failure to thrive
  evidence:
  - reference: PMID:3083684
    reference_title: "Leber's congenital amaurosis associated with hyperthreoninemia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >
      He also had hyperthreoninemia, hyperthreoninuria, hepatomegaly,
      and mental and physical retardation.
    explanation: >
      Physical retardation reported in a patient with hyperthreoninemia
      is consistent with failure to thrive.
- category: Clinical
  name: Retinal dystrophy (Leber congenital amaurosis phenotype)
  frequency: OCCASIONAL
  description: >
    Two siblings with hyperthreoninemia presented with congenital blindness,
    absent or poor pupillary light reflex, and nearly extinguished
    electroretinographic response consistent with Leber congenital amaurosis.
    The causal relationship between hyperthreoninemia and the ocular phenotype
    remains uncertain.
  phenotype_term:
    preferred_term: Retinal dystrophy (Leber congenital amaurosis)
    term:
      id: HP:0000556
      label: Retinal dystrophy
  evidence:
  - reference: PMID:3083684
    reference_title: "Leber's congenital amaurosis associated with hyperthreoninemia."
    supports: PARTIAL
    evidence_source: HUMAN_CLINICAL
    snippet: >
      Two siblings had Leber's congenital amaurosis. The girl (Patient 1)
      showed blindness shortly after birth, absent pupillary light reflex,
      and multiple round, white spots in both fundi.
    explanation: >
      Reports Leber congenital amaurosis in two siblings with hyperthreoninemia.
      Classified as PARTIAL because the causal relationship between
      hyperthreoninemia and LCA is not established.
  - reference: PMID:3083684
    reference_title: "Leber's congenital amaurosis associated with hyperthreoninemia."
    supports: PARTIAL
    evidence_source: HUMAN_CLINICAL
    snippet: >
      We suspect a close relationship between hyperthreoninemia and Leber's
      congenital amaurosis in these siblings.
    explanation: >
      The authors suggest a relationship but do not demonstrate causality.
biochemical:
- name: Plasma threonine
  presence: INCREASED
  context: >
    Marked elevation of plasma threonine, approximately 3-19 fold above normal
    values, is the primary diagnostic biomarker. Reported values include 2.0-5.3
    mg/dl (normal 0.78-1.82 mg/dl) and approximately 19-fold elevation in the
    threonine dehydratase deficiency case.
  biomarker_term:
    preferred_term: L-threonine
    term:
      id: CHEBI:16857
      label: L-threonine
  readouts:
  - target: Systemic threonine accumulation
    relationship: READOUT_OF
    direction: POSITIVE
    endpoint_context: DIAGNOSTIC
    interpretation: Elevated plasma or serum threonine reports systemic threonine accumulation.
    evidence:
    - reference: PMID:3083684
      reference_title: "Leber's congenital amaurosis associated with hyperthreoninemia."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >
        Her serum threonine level was increased (2.0 to 5.3 mg/dl;
        normal, 0.78 to 1.82 mg/dl).
      explanation: >
        Quantitative serum threonine elevation supports circulating threonine
        as a diagnostic readout of systemic accumulation.
  - target: Hyperthreoninemia
    relationship: READOUT_OF
    direction: POSITIVE
    endpoint_context: DIAGNOSTIC
    interpretation: Plasma or serum threonine is the measured analyte underlying the hyperthreoninemia phenotype.
    evidence:
    - reference: PMID:3083684
      reference_title: "Leber's congenital amaurosis associated with hyperthreoninemia."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >
        Her serum threonine level was increased (2.0 to 5.3 mg/dl;
        normal, 0.78 to 1.82 mg/dl).
      explanation: >
        Quantitative serum threonine elevation directly supports plasma
        threonine as the readout for hyperthreoninemia.
  evidence:
  - reference: PMID:3083684
    reference_title: "Leber's congenital amaurosis associated with hyperthreoninemia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >
      Her serum threonine level was increased (2.0 to 5.3 mg/dl;
      normal, 0.78 to 1.82 mg/dl).
    explanation: >
      Quantitative documentation of elevated serum threonine with reference range.
- name: Urinary threonine
  presence: INCREASED
  context: >
    Elevated urinary threonine excretion accompanies the plasma elevation.
  biomarker_term:
    preferred_term: L-threonine
    term:
      id: CHEBI:16857
      label: L-threonine
  readouts:
  - target: Systemic threonine accumulation
    relationship: READOUT_OF
    direction: POSITIVE
    endpoint_context: DIAGNOSTIC
    interpretation: Elevated urinary threonine reports systemic threonine excess with renal excretion.
    evidence:
    - reference: PMID:3083684
      reference_title: "Leber's congenital amaurosis associated with hyperthreoninemia."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >
        He also had hyperthreoninemia, hyperthreoninuria, hepatomegaly,
        and mental and physical retardation.
      explanation: >
        Hyperthreoninuria supports urinary threonine as a positive diagnostic
        readout of systemic threonine accumulation.
  - target: Hyperthreoninuria
    relationship: READOUT_OF
    direction: POSITIVE
    endpoint_context: DIAGNOSTIC
    interpretation: Urinary threonine excretion is the measured analyte underlying the hyperthreoninuria phenotype.
    evidence:
    - reference: PMID:3083684
      reference_title: "Leber's congenital amaurosis associated with hyperthreoninemia."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >
        He also had hyperthreoninemia, hyperthreoninuria, hepatomegaly,
        and mental and physical retardation.
      explanation: >
        Hyperthreoninuria directly supports urinary threonine as the readout
        for the urinary threonine-excess phenotype.
  evidence:
  - reference: PMID:3083684
    reference_title: "Leber's congenital amaurosis associated with hyperthreoninemia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >
      He also had hyperthreoninemia, hyperthreoninuria, hepatomegaly,
      and mental and physical retardation.
    explanation: >
      Directly documents hyperthreoninuria in a patient with hyperthreoninemia.
- name: CSF threonine
  presence: INCREASED
  notes: >
    Approximately 16-fold elevation of threonine in cerebrospinal fluid was
    reported in the threonine dehydratase deficiency case (Krieger & Booth 1984,
    full text), indicating CNS exposure. This value is not available in the
    published abstract.
genetic:
- name: Threonine dehydratase (enzyme level)
  association: Enzyme Deficiency
  features: >
    No specific gene has been identified for inherited threoninemia.
    The disorder is defined at the enzyme level: hepatic threonine dehydratase
    (EC 4.2.1.16) activity was undetectable in the index case. The human gene
    encoding this enzyme has not been definitively characterized in the context
    of this disease.
  evidence:
  - reference: PMID:6434824
    reference_title: "Threonine dehydratase deficiency: a probable cause of non-ketotic hyperglycinaemia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >
      Threonine dehydratase was undetectable in a liver autopsy specimen,
      which was obtained within 1 h of death and immediately frozen at -70 degrees C.
    explanation: >
      Direct enzyme assay demonstrating undetectable threonine dehydratase
      activity in the index patient.
treatments:
- name: Dietary threonine restriction
  description: >
    Dietary management with restriction of threonine intake to lower
    plasma threonine levels. No formal clinical trials exist for this
    extremely rare condition.
  treatment_term:
    preferred_term: dietary intervention
    term:
      id: MAXO:0000088
      label: dietary intervention
  target_phenotypes:
  - preferred_term: Hyperthreoninemia
    term:
      id: HP:0003354
      label: Hyperthreoninemia
  target_mechanisms:
  - target: Systemic threonine accumulation
    treatment_effect: INHIBITS
    description: >
      Restricting dietary threonine is intended to reduce the substrate load
      feeding systemic threonine accumulation.
- name: Anticonvulsant therapy
  description: >
    Anticonvulsant agents for seizure management in patients with
    NKH-like neurological manifestations.
  treatment_term:
    preferred_term: anticonvulsant agent therapy
    term:
      id: MAXO:0000167
      label: anticonvulsant agent therapy
  target_phenotypes:
  - preferred_term: Seizure
    term:
      id: HP:0001250
      label: Seizure
notes: >-
  Inherited threoninemia is one of the rarest documented inborn errors of
  metabolism. The literature consists of only a handful of case reports from
  1978 to 2004. No modern genomic characterization exists; the disorder
  is defined at the enzyme activity and metabolite level. The association
  with Leber congenital amaurosis reported by Hayasaka et al. (1986) may
  represent a distinct entity or coincidental co-occurrence. A gene-first
  reinterpretation using modern exome/genome sequencing of any future cases
  would be essential to establish the molecular basis definitively.
📚

References & Deep Research

Deep Research

1
Falcon ▸
Disease Pathophysiology Research Template
Edison Scientific Literature 13 citations 2026-03-11T14:53:49.170671

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 Pathophysiology Research Template

Target Disease

  • Disease Name: Inherited Threoninemia
  • MONDO ID: (if available)
  • Category: Mendelian

Research Objectives

Please provide a comprehensive research report on the pathophysiology of Inherited Threoninemia. Focus on the molecular and cellular mechanisms underlying disease progression.

Required Information

1. Core Pathophysiology

  • What are the primary pathophysiological mechanisms?
  • What molecular pathways are dysregulated?
  • What cellular processes are affected?

2. Key Molecular Players

  • Genes/Proteins: Which genes are causally involved or implicated?
  • Chemical Entities: What metabolites, drugs, or small molecules are relevant?
  • Cell Types: Which cell types are primarily affected?
  • Anatomical Locations: Which tissues/organs are involved?

3. Biological Processes (for GO annotation)

  • What biological processes (GO terms) are disrupted?
  • Consider: signaling pathways, metabolic processes, cellular responses, transport, etc.

4. Cellular Components

  • Where in the cell do key processes occur?
  • Consider: organelles, membrane compartments, extracellular space, etc.

5. Disease Progression

  • What is the sequence of events from initial trigger to clinical manifestation?
  • Are there distinct stages or phases?

6. Phenotypic Manifestations

  • What are the key clinical phenotypes?
  • How do they relate to the underlying mechanisms?

Citation Requirements

  • Cite primary literature (PMID preferred) for all mechanistic claims
  • Prioritize recent reviews and landmark papers
  • Include direct quotes where possible to support key statements

Output Format

Structure your response as a narrative that could be used to populate a disease knowledge base entry with: - Pathophysiology description - Gene/protein annotations with ontology terms (HGNC, GO) - Phenotype associations (HP terms) - Cell type involvement (CL terms) - Anatomical locations (UBERON terms) - Chemical entities (CHEBI terms) - Evidence items with PMIDs

Comprehensive Research Report: Inherited Threoninemia (Hyperthreoninemia/Threoninemia)

Executive summary

“Inherited threoninemia” (historically also called threoninemia or hyperthreoninemia) is a rare and poorly genetically defined inborn error described primarily in older literature. The best-documented mechanistic hypothesis is deficiency of hepatic threonine dehydratase (EC 4.2.1.16) leading to marked threonine accumulation and (in at least one reported patient) secondary hyperglycinemia via competition at serine hydroxymethyltransferase (serine transhydroxymethylase) at the glycine/serine/threonine intersection. (krieger1984threoninedehydratasedeficiency pages 1-2, krieger1984threoninedehydratasedeficiency pages 2-3, krieger1984threoninedehydratasedeficiency media c40ef479)

Critical limitation: In the retrieved literature set, no modern (2023–2024) authoritative review, case series, guideline, MONDO mapping, or gene-level causal assignment for “inherited threoninemia” was found despite targeted searches and citation-chaining; therefore, the report below focuses on the best-supported molecular mechanism from available primary sources (1984–1997) and clearly labels gaps. (darling1997threonineandphenylalanine pages 47-50)

Disease identity and ontology crosswalk

  • Preferred label (working): Inherited threoninemia / hyperthreoninemia (historical entity)
  • MONDO ID: Not retrievable/confirmable from available sources in this corpus.
  • Genetic basis: Not established in the retrieved corpus; historical work implicates an enzyme activity defect (threonine dehydratase) but does not identify a gene. (krieger1984threoninedehydratasedeficiency pages 1-2, darling1997threonineandphenylalanine pages 47-50)

1) Core pathophysiology

1.1 Primary pathophysiological mechanisms

Mechanism (best-supported historical model): 1. Primary block in threonine degradation at threonine dehydratase (TD; EC 4.2.1.16) in liver causes systemic threonine accumulation (plasma and CSF markedly elevated). (krieger1984threoninedehydratasedeficiency pages 1-2, krieger1984threoninedehydratasedeficiency pages 2-3) 2. Excess threonine perturbs one-carbon amino acid interconversion: Krieger & Booth proposed that elevated threonine competes within the glycine–serine–threonine network at serine hydroxymethyltransferase (serine transhydroxymethylase; STHM), reducing normal glycine-to-serine flux and contributing to hyperglycinemia (reported in a patient with non-ketotic hyperglycinemia phenotype). (krieger1984threoninedehydratasedeficiency pages 1-2, krieger1984threoninedehydratasedeficiency pages 2-3, krieger1984threoninedehydratasedeficiency media c40ef479)

Direct quote (mechanistic rationale): Krieger & Booth state, “Since the affinity of STHM is greatest for serine and lowest for threonine, competition between glycine and threonine can be anticipated.” (krieger1984threoninedehydratasedeficiency pages 2-3)

1.2 Dysregulated molecular pathways

Key dysregulated pathway elements described in the retrieved sources include: - Cytosolic threonine dehydratase route: L-threonine → 2-ketobutyrate (α-ketobutyrate) → downstream propionyl-CoA metabolism. (darling1997threonineandphenylalanine pages 43-47, darling1997threonineandphenylalanine pages 207-211) - Mitochondrial threonine dehydrogenase route: L-threonine → 2-amino-3-oxobutyrate → cleavage to glycine + acetyl-CoA (via 2-amino-3-ketobutyrate CoA ligase). (darling1997threonineandphenylalanine pages 43-47) - Interconversion hub: glycine ↔ serine ↔ threonine via serine hydroxymethyltransferase/transhydroxymethylase-linked reactions (conceptualized in Figure 1 of Krieger & Booth). (krieger1984threoninedehydratasedeficiency media c40ef479, krieger1984threoninedehydratasedeficiency pages 1-2)

1.3 Cellular processes affected

Based on the proposed mechanism and measured metabolite derangements, likely affected cellular processes include: - Amino acid catabolism and mitochondrial acetyl-CoA generation (threonine dehydrogenase pathway). (darling1997threonineandphenylalanine pages 43-47) - Cytosolic amino acid dehydration/transamination flux through α-ketobutyrate and α-aminobutyrate. (darling1997threonineandphenylalanine pages 207-211) - One-carbon amino acid interconversion at the glycine/serine/threonine node, with potential downstream effects on CNS glycinergic neurotransmission in hyperglycinemic states. (krieger1984threoninedehydratasedeficiency pages 1-2, darling1997threonineandphenylalanine pages 50-54)

2) Key molecular players

2.1 Genes/Proteins (causal or implicated)

Causal gene: Not identified in the retrieved sources.

Implicated enzymes/proteins (functionally): - Threonine dehydratase (TD; EC 4.2.1.16) — proposed deficient enzyme in the best-supported primary case. (krieger1984threoninedehydratasedeficiency pages 1-2) - Threonine dehydrogenase (EC 1.1.1.103) — alternative candidate defect proposed by Krieger & Booth; also a major threonine oxidation route in animal liver. (krieger1984threoninedehydratasedeficiency pages 1-2, darling1997threonineandphenylalanine pages 43-47, darling1997threonineandphenylalanine pages 47-50) - Serine hydroxymethyltransferase / serine transhydroxymethylase (STHM; EC 2.1.2.1) — proposed competitive bottleneck linking threonine excess to glycine accumulation. (krieger1984threoninedehydratasedeficiency pages 1-2, krieger1984threoninedehydratasedeficiency pages 2-3, krieger1984threoninedehydratasedeficiency media c40ef479)

2.2 Chemical entities (metabolites/small molecules)

Primary metabolites (candidate diagnostic / mechanistic): - L-threonine (elevated in plasma/CSF/urine). (krieger1984threoninedehydratasedeficiency pages 1-2, hayasaka1986leberscongenitalamaurosis pages 2-4) - Glycine (elevated in the TD-deficiency/NKH hypothesis; also increased in urine in one hyperthreoninemia case series). (krieger1984threoninedehydratasedeficiency pages 1-2, hayasaka1986leberscongenitalamaurosis pages 2-4) - Serine (part of the interconversion node; increased urinary serine reported in the LCA-associated hyperthreoninemia case series). (hayasaka1986leberscongenitalamaurosis pages 2-4) - 2-ketobutyrate (α-ketobutyrate), propionyl-CoA, acetyl-CoA, 2-amino-3-oxobutyrate (pathway intermediates). (darling1997threonineandphenylalanine pages 43-47, darling1997threonineandphenylalanine pages 207-211)

Therapeutics/management used (historical, in NKH context): - Sodium benzoate, anticonvulsants (e.g., clonazepam/valium), plus supportive measures were attempted in the TD-deficiency/NKH patient; withdrawal worsened seizures. (krieger1984threoninedehydratasedeficiency pages 2-3)

2.3 Cell types primarily affected

No cell-type–resolved pathology is provided in the retrieved sources. Based on enzyme localization and reported organ involvement, the most plausible primary affected cell types are: - Hepatocytes (primary site of threonine dehydratase activity; enzyme measured in liver tissue). (krieger1984threoninedehydratasedeficiency pages 2-3, darling1997threonineandphenylalanine pages 43-47) - Potential secondary impact on neurons/glia in settings with CNS glycine perturbation (inferred from NKH-like presentation and CSF findings). (krieger1984threoninedehydratasedeficiency pages 2-3, krieger1984threoninedehydratasedeficiency pages 1-2)

2.4 Anatomical locations / organs involved

  • Liver: implicated by absent hepatic TD activity; hepatomegaly/mild liver dysfunction reported in one hyperthreoninemia-associated phenotype series. (krieger1984threoninedehydratasedeficiency pages 2-3, hayasaka1986leberscongenitalamaurosis pages 2-4)
  • Central nervous system: elevated CSF threonine and hyperglycinemia with seizures/encephalopathy in the TD-deficiency/NKH hypothesis. (krieger1984threoninedehydratasedeficiency pages 1-2, krieger1984threoninedehydratasedeficiency pages 2-3)
  • Eye/retina: Leber congenital amaurosis phenotype reported in siblings with hyperthreoninemia (association; causality uncertain). (hayasaka1986leberscongenitalamaurosis pages 1-2, hayasaka1986leberscongenitalamaurosis pages 2-4)

3) Biological processes disrupted (GO-oriented)

Note: GO identifiers are not supplied by the sources; items below are process concepts supported by the mechanistic evidence.

  • Threonine catabolic process (cytosolic dehydration to α-ketobutyrate; mitochondrial oxidation to glycine/acetyl-CoA). (darling1997threonineandphenylalanine pages 43-47, darling1997threonineandphenylalanine pages 207-211)
  • Glycine metabolic process / serine metabolic process via serine hydroxymethyltransferase node interactions. (krieger1984threoninedehydratasedeficiency media c40ef479, krieger1984threoninedehydratasedeficiency pages 2-3)
  • Mitochondrial acetyl-CoA biosynthetic process (via threonine dehydrogenase pathway). (darling1997threonineandphenylalanine pages 43-47)
  • Propionyl-CoA metabolic process downstream of α-ketobutyrate (threonine dehydratase route). (darling1997threonineandphenylalanine pages 207-211)

4) Cellular components (GO-oriented)

  • Cytosol: threonine dehydratase pathway described as cytosolic. (darling1997threonineandphenylalanine pages 43-47)
  • Mitochondrion: threonine dehydrogenase pathway described as mitochondrial, producing acetyl-CoA and glycine. (darling1997threonineandphenylalanine pages 43-47)

5) Disease progression (sequence from trigger to phenotype)

Proposed sequence (TD deficiency model)

  1. Inherited enzymatic defect with very low/absent hepatic TD activity. (krieger1984threoninedehydratasedeficiency pages 2-3)
  2. Biochemical accumulation of threonine systemically and in CSF (reported as ~16× in CSF and ~19× in plasma above normal). (krieger1984threoninedehydratasedeficiency pages 1-2)
  3. Perturbation of glycine–serine–threonine interconversion via competitive effects at STHM, contributing to hyperglycinemia and an NKH-like neurotoxic phenotype. (krieger1984threoninedehydratasedeficiency pages 1-2, krieger1984threoninedehydratasedeficiency media c40ef479)
  4. Clinical manifestations: neonatal/infantile seizures, lethargy, failure to feed/suck, respiratory arrest reported in the index patient. (krieger1984threoninedehydratasedeficiency pages 2-3)

Alternative/uncertain trajectories

  • In a separate phenotype series (LCA association), hyperthreoninemia may have been primary or secondary to liver dysfunction; the authors explicitly state uncertainty about causality. (hayasaka1986leberscongenitalamaurosis pages 4-5)

6) Phenotypic manifestations and mechanism links

6.1 Neurologic phenotype (NKH-like)

  • Seizures, lethargy, feeding difficulty, respiratory arrest were reported in the patient in whom TD activity was undetectable. These findings align with glycine neurotoxicity in NKH and are mechanistically linked to the hypothesized STHM competition model. (krieger1984threoninedehydratasedeficiency pages 2-3, krieger1984threoninedehydratasedeficiency media c40ef479)

6.2 Ocular phenotype (association reported)

  • Leber congenital amaurosis features (blindness from birth, absent pupillary light reflex, nearly extinguished ERG) were reported in siblings with hyperthreoninemia and hyperthreoninuria. Mechanistic linkage to threonine metabolism is not established in the paper; it is presented as an association requiring further study. (hayasaka1986leberscongenitalamaurosis pages 1-2, hayasaka1986leberscongenitalamaurosis pages 2-4, hayasaka1986leberscongenitalamaurosis pages 4-5)

6.3 Hepatic/systemic phenotype

  • Hepatomegaly and mild liver dysfunction co-occurred in the LCA-associated hyperthreoninemia cases, raising the possibility of secondary hyperthreoninemia (not resolved). (hayasaka1986leberscongenitalamaurosis pages 2-4, hayasaka1986leberscongenitalamaurosis pages 4-5)

Evidence summary table

Disease label used Proposed causal defect (enzyme) Pathway node (reaction) Key metabolites altered (direction) Quantitative values reported Phenotypes Specimen/tissue Year DOI/URL
Non-ketotic hyperglycinaemia (probable threonine dehydratase deficiency) Hepatic threonine dehydratase (EC 4.2.1.16) deficiency; undetectable TD activity L-threonine → 2-ketobutyrate (threonine dehydratase); proposed competition at serine hydroxymethyltransferase linking glycine/serine/threonine flux (krieger1984threoninedehydratasedeficiency pages 1-2, krieger1984threoninedehydratasedeficiency pages 2-3, krieger1984threoninedehydratasedeficiency media c40ef479) Threonine ↑ (plasma, CSF); Glycine ↑ Threonine: ~16× (CSF) and ~19× (plasma) above normal; liver TD undetectable by assay (krieger1984threoninedehydratasedeficiency pages 1-2, krieger1984threoninedehydratasedeficiency pages 2-3) NKH features: seizures, failure to suck, lethargy, respiratory arrest (krieger1984threoninedehydratasedeficiency pages 2-3) Liver autopsy (enzyme assay); plasma/CSF amino acids (krieger1984threoninedehydratasedeficiency pages 1-2) 1984 https://doi.org/10.1007/bf01805800
Leber's congenital amaurosis with hyperthreoninemia Not identified Unknown (metabolic association reported, no enzyme defect established) (hayasaka1986leberscongenitalamaurosis pages 1-2, hayasaka1986leberscongenitalamaurosis pages 2-4) Threonine ↑ (plasma, urine); Serine ↑ (urine); Glycine ↑ (urine) Plasma threonine 5.8–7.5 mg/dL (normal 0.78–1.82); urinary threonine 3.12 μmol/mg creatinine (elevated) (hayasaka1986leberscongenitalamaurosis pages 2-4, hayasaka1986leberscongenitalamaurosis pages 1-2) Congenital blindness/near-blindness, absent pupillary light reflex, near-absent ERG; hepatomegaly, mild liver dysfunction; developmental delay; pericardial effusion (one case) (hayasaka1986leberscongenitalamaurosis pages 1-2, hayasaka1986leberscongenitalamaurosis pages 2-4) Serum and urine amino acids (hayasaka1986leberscongenitalamaurosis pages 2-4) 1986 https://doi.org/10.1016/0002-9394(86)90650-1
Hyperthreoninemia (review of neonatal threonine metabolism) Background: partitioning of threonine catabolism across threonine dehydrogenase (TDG), threonine dehydratase (TDH/TD), and threonine aldolase (TA); human defects not established (darling1997threonineandphenylalanine pages 43-47, darling1997threonineandphenylalanine pages 47-50, darling1997threonineandphenylalanine pages 207-211) TDG: L-threonine → 2-amino-3-oxobutyrate → glycine + acetyl-CoA; TD (cytosolic): L-threonine → 2-ketobutyrate; TA: L-threonine → glycine + acetaldehyde (darling1997threonineandphenylalanine pages 43-47, darling1997threonineandphenylalanine pages 47-50) 2-ketobutyrate, 2-amino-3-oxobutyrate, glycine, acetyl-CoA, propionyl-CoA (pathway nodes/metabolites) (darling1997threonineandphenylalanine pages 43-47, darling1997threonineandphenylalanine pages 207-211) Rat liver: ~87% of threonine oxidation via TDG; reported Km: TDG ~10.6 mM, TD ~87 mM; hepatic [Thr] ~0.26 mM (species data) (darling1997threonineandphenylalanine pages 47-50) Not applicable (mechanistic review; notes rarity of inherited hyperthreoninemia) (darling1997threonineandphenylalanine pages 47-50) Narrative review (pathway/tissue distribution synthesis) (darling1997threonineandphenylalanine pages 43-47) 1997 —

Table: Structured summary of key evidence on inherited threoninemia/hyperthreoninemia from primary reports and a metabolic review, including enzymes implicated, pathway context, metabolites, quantitative findings, phenotypes, and source details. Citations reference the specific tool-extracted contexts supporting each row.

Key mechanistic figure (pathway schematic)

Krieger & Booth’s Figure 1 provides a pathway-level schematic of glycine/serine/threonine metabolism and the proposed competitive mechanism (TD or threonine dehydrogenase block leading to threonine accumulation and altered STHM flux). (krieger1984threoninedehydratasedeficiency media c40ef479)

Current applications and real-world implementations

Because contemporary (2023–2024) inherited-threoninemia–specific guidance was not retrieved, the following “applications” reflect historical and broadly applicable clinical chemistry practices implied by the sources:

Diagnostics

  • Plasma/CSF amino acid profiling: In the TD-deficiency/NKH hypothesis, the key diagnostic signature included markedly elevated plasma and CSF threonine alongside elevated glycine. (krieger1984threoninedehydratasedeficiency pages 1-2)
  • Urine amino acid quantification: In the LCA-associated cases, urinary threonine was elevated (example: 3.12 μmol/mg creatinine; normal trace–0.59) and accompanied by elevated urinary glycine and serine. (hayasaka1986leberscongenitalamaurosis pages 2-4)

Management (historical, limited)

  • In the TD-deficiency/NKH case, management included interventions typical for NKH (e.g., sodium benzoate) and anticonvulsants; stopping therapy worsened seizures, suggesting symptomatic benefit in seizure control. (krieger1984threoninedehydratasedeficiency pages 2-3)

Expert opinion and interpretation (within evidence constraints)

  • Krieger & Booth (1984) explicitly frame their observation as “the first documentation of an inborn error of threonine metabolism,” but they also emphasize the need for confirmation using fresh liver biopsies due to TD assay sensitivity to tissue handling and storage. (krieger1984threoninedehydratasedeficiency pages 1-2, krieger1984threoninedehydratasedeficiency pages 2-3)
  • Darling (1997) highlights that, as of that time, human threonine catabolic enzyme partitioning and inherited defects were poorly defined, and the literature consisted of only a few case reports—consistent with the persisting difficulty of forming a modern gene-based definition using the retrieved corpus alone. (darling1997threonineandphenylalanine pages 47-50)

Relevant statistics and quantitative data (from studies retrieved)

  • Threonine elevation (TD-deficiency/NKH hypothesis): “16 and 19 fold elevation of threonine in CSF and plasma, respectively.” (krieger1984threoninedehydratasedeficiency pages 1-2)
  • Enzyme activity (liver threonine dehydratase): Control liver TD activities were reported in the tens to low hundreds of pmol·h−1·g−1 tissue range, whereas the patient’s TD activity was undetectable, with notable assay sensitivity to specimen storage/time at room temperature. (krieger1984threoninedehydratasedeficiency pages 2-3)
  • Hyperthreoninemia ranges (LCA-associated): plasma threonine 5.8–7.5 mg/dL (reported normal 0.78–1.82 mg/dL); urinary threonine 3.12 μmol/mg creatinine (normal trace–0.59). (hayasaka1986leberscongenitalamaurosis pages 2-4)

Knowledge-base–ready structured annotations

Disease → molecular mechanism (narrative)

Inherited threoninemia is best supported historically as an inborn error of threonine catabolism, proposed to be caused by hepatic threonine dehydratase deficiency, leading to systemic and CSF threonine accumulation and secondary dysregulation at the glycine–serine–threonine interconversion node (serine hydroxymethyltransferase), potentially producing hyperglycinemia and an NKH-like neurologic phenotype. (krieger1984threoninedehydratasedeficiency pages 1-2, krieger1984threoninedehydratasedeficiency media c40ef479, krieger1984threoninedehydratasedeficiency pages 2-3)

Gene/protein annotations (HGNC)

  • HGNC gene(s): Not assignable from retrieved sources (enzyme defect described without gene). (krieger1984threoninedehydratasedeficiency pages 1-2)

Enzyme/protein (functional) entities

  • Threonine dehydratase (EC 4.2.1.16) (krieger1984threoninedehydratasedeficiency pages 1-2)
  • Serine hydroxymethyltransferase/transhydroxymethylase (EC 2.1.2.1) (krieger1984threoninedehydratasedeficiency pages 2-3)
  • Threonine dehydrogenase (EC 1.1.1.103) (darling1997threonineandphenylalanine pages 43-47)

Phenotype associations (HP-like concepts; IDs not provided in sources)

  • Seizures/epileptic seizures; neonatal encephalopathy-like presentation; feeding difficulty (failure to suck); lethargy; respiratory arrest (krieger1984threoninedehydratasedeficiency pages 2-3)
  • Congenital blindness / retinal dystrophy consistent with Leber congenital amaurosis; extinguished ERG; abnormal pupillary light reflex (hayasaka1986leberscongenitalamaurosis pages 1-2, hayasaka1986leberscongenitalamaurosis pages 2-4)
  • Hepatomegaly; elevated transaminases / mild liver dysfunction (hayasaka1986leberscongenitalamaurosis pages 2-4)

Cell type involvement (CL-like concepts)

  • Hepatocyte involvement implied by hepatic enzyme deficiency measurement (krieger1984threoninedehydratasedeficiency pages 2-3)

Anatomical locations (UBERON-like concepts)

  • Liver; central nervous system/CSF compartment; retina/eye (krieger1984threoninedehydratasedeficiency pages 2-3, hayasaka1986leberscongenitalamaurosis pages 2-4)

Chemical entities (CHEBI-like concepts; IDs not provided in sources)

  • L-threonine; glycine; serine; 2-ketobutyrate (α-ketobutyrate); propionyl-CoA; acetyl-CoA (darling1997threonineandphenylalanine pages 43-47, darling1997threonineandphenylalanine pages 207-211)

Primary sources (URLs and publication dates)

  1. Krieger I, Booth F. Threonine dehydratase deficiency: A probable cause of non-ketotic hyperglycinaemia. Journal of Inherited Metabolic Disease. June 1984. DOI/URL: https://doi.org/10.1007/bf01805800 (krieger1984threoninedehydratasedeficiency pages 1-2, krieger1984threoninedehydratasedeficiency pages 2-3)
  2. Hayasaka S, et al. Leber's congenital amaurosis associated with hyperthreoninemia. American Journal of Ophthalmology. April 1986. DOI/URL: https://doi.org/10.1016/0002-9394(86)90650-1 (hayasaka1986leberscongenitalamaurosis pages 1-2, hayasaka1986leberscongenitalamaurosis pages 2-4)
  3. Darling PB. Threonine and phenylalanine metabolism in the human neonate. 1997 (journal metadata not available in retrieved text). (darling1997threonineandphenylalanine pages 43-47, darling1997threonineandphenylalanine pages 47-50)

Gaps and recommended next steps (evidence-based)

  • The retrieved evidence base does not include modern genomic characterization; thus, a gene-first reinterpretation (e.g., exome/genome sequencing of historical cases or identification of contemporary patients with isolated hyperthreoninemia) is essential to assign HGNC genes and MONDO/OMIM IDs.
  • Modern metabolomics/newborn screening literature may contain relevant differential diagnoses (secondary hyperthreoninemia due to liver disease, nutrition, or other IEMs), but such sources were not retrievable within this run.

References

  1. (krieger1984threoninedehydratasedeficiency pages 1-2): I. Krieger and F. Booth. Threonine dehydratase deficiency: a probable cause of non-ketotic hyperglycinaemia. Journal of Inherited Metabolic Disease, 7:53-56, Jun 1984. URL: https://doi.org/10.1007/bf01805800, doi:10.1007/bf01805800. This article has 10 citations and is from a peer-reviewed journal.

  2. (krieger1984threoninedehydratasedeficiency pages 2-3): I. Krieger and F. Booth. Threonine dehydratase deficiency: a probable cause of non-ketotic hyperglycinaemia. Journal of Inherited Metabolic Disease, 7:53-56, Jun 1984. URL: https://doi.org/10.1007/bf01805800, doi:10.1007/bf01805800. This article has 10 citations and is from a peer-reviewed journal.

  3. (krieger1984threoninedehydratasedeficiency media c40ef479): I. Krieger and F. Booth. Threonine dehydratase deficiency: a probable cause of non-ketotic hyperglycinaemia. Journal of Inherited Metabolic Disease, 7:53-56, Jun 1984. URL: https://doi.org/10.1007/bf01805800, doi:10.1007/bf01805800. This article has 10 citations and is from a peer-reviewed journal.

  4. (darling1997threonineandphenylalanine pages 47-50): PB Darling. Threonine and phenylalanine metabolism in the human neonate. Unknown journal, 1997.

  5. (darling1997threonineandphenylalanine pages 43-47): PB Darling. Threonine and phenylalanine metabolism in the human neonate. Unknown journal, 1997.

  6. (darling1997threonineandphenylalanine pages 207-211): PB Darling. Threonine and phenylalanine metabolism in the human neonate. Unknown journal, 1997.

  7. (darling1997threonineandphenylalanine pages 50-54): PB Darling. Threonine and phenylalanine metabolism in the human neonate. Unknown journal, 1997.

  8. (hayasaka1986leberscongenitalamaurosis pages 2-4): Seiji Hayasaka, Satoshi Hara, Katsuyoshi Mizuno, Kuniaki Narisawa, and Keiya Tada. Leber's congenital amaurosis associated with hyperthreoninemia. American journal of ophthalmology, 101 4:475-9, Apr 1986. URL: https://doi.org/10.1016/0002-9394(86)90650-1, doi:10.1016/0002-9394(86)90650-1. This article has 14 citations and is from a domain leading peer-reviewed journal.

  9. (hayasaka1986leberscongenitalamaurosis pages 1-2): Seiji Hayasaka, Satoshi Hara, Katsuyoshi Mizuno, Kuniaki Narisawa, and Keiya Tada. Leber's congenital amaurosis associated with hyperthreoninemia. American journal of ophthalmology, 101 4:475-9, Apr 1986. URL: https://doi.org/10.1016/0002-9394(86)90650-1, doi:10.1016/0002-9394(86)90650-1. This article has 14 citations and is from a domain leading peer-reviewed journal.

  10. (hayasaka1986leberscongenitalamaurosis pages 4-5): Seiji Hayasaka, Satoshi Hara, Katsuyoshi Mizuno, Kuniaki Narisawa, and Keiya Tada. Leber's congenital amaurosis associated with hyperthreoninemia. American journal of ophthalmology, 101 4:475-9, Apr 1986. URL: https://doi.org/10.1016/0002-9394(86)90650-1, doi:10.1016/0002-9394(86)90650-1. This article has 14 citations and is from a domain leading peer-reviewed journal.