Tyrosinemia Type II

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Mappings

MONDO

MONDO:0010160 tyrosinemia type II

MONDO:0010160 (tyrosinemia type II) cross-references OMIM:276600 (TYRSN2) and Orphanet:28378, the authoritative entries for TAT-deficiency Richner-Hanhart syndrome.

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Inheritance

1

Autosomal recessive HP:0000007

Tyrosinemia type II is caused by biallelic pathogenic variants in TAT; heterozygous carriers are asymptomatic and each sib of an affected individual has a 25% recurrence risk.

Autosomal recessive inheritance

Show evidence (2 references)

PMID:39446998 SUPPORT Other

"Tyrosinemia type II is inherited in an autosomal recessive manner."

GeneReviews states the autosomal recessive inheritance pattern.

PMID:1357662 SUPPORT Human Clinical

"Tyrosinemia type II (Richner-Hanhart syndrome, RHS) is a disease of autosomal recessive inheritance characterized by keratitis, palmoplantar hyperkeratosis, mental retardation, and elevated blood tyrosine levels."

Confirms autosomal recessive inheritance and the defining clinical tetrad.

⚙

Pathophysiology

3

Tyrosine aminotransferase deficiency

Biallelic loss-of-function TAT variants reduce hepatic cytosolic tyrosine aminotransferase activity, blocking the first (transamination) step of tyrosine catabolism that converts L-tyrosine to 4-hydroxyphenylpyruvate.

TAT hgnc:11573

L-tyrosine catabolic process GO:0006572 ↓ DECREASED

tyrosine aminotransferase activity GO:0004838 ↓ DECREASED

liver UBERON:0002107

Downstream

Hypertyrosinemia and systemic tyrosine accumulation Loss of tyrosine aminotransferase activity prevents normal tyrosine degradation, causing tyrosine to accumulate in blood and tissues.

Show evidence (3 references)

PMID:1357662 SUPPORT Human Clinical

"The disease results from deficiency in hepatic tyrosine aminotransferase (TAT; L-tyrosine:2-oxoglutarate aminotransferase, EC 2.6.1.5), a 454-amino acid protein encoded by a gene with 12 exons."

Identifies deficiency of hepatic tyrosine aminotransferase as the causal enzymatic lesion.

PMID:39446998 SUPPORT Other

"The diagnosis of tyrosinemia type II is established in a proband by identification of biallelic pathogenic variants in TAT on molecular genetic testing"

Confirms biallelic TAT pathogenic variants as the molecular basis of the disease.

PMID:31603991 SUPPORT Other

"Tyrosine aminotransferase (TAT) transaminates tyrosine, forming p‐hydroxyphenylpyruvate and glutamate."

Defines the biochemical reaction catalyzed by TAT.

Hypertyrosinemia and systemic tyrosine accumulation

The upstream enzymatic block produces increased tyrosine in plasma and cerebrospinal fluid and increased tyrosine catabolic metabolites in plasma and urine. Tyrosine crystal deposition is implicated in the characteristic eye and skin lesions.

Downstream

Oculocutaneous tyrosine deposition Elevated intracellular tyrosine deposits in the cornea and in palmoplantar epidermis, triggering the inflammatory and hyperkeratotic tissue response.

Intellectual disability Sustained untreated hypertyrosinemia is associated with variable cognitive manifestations through unresolved neurologic intermediates.

Seizures Hypertyrosinemia is associated with reported seizures through unresolved neurologic intermediates.

Self-injurious behavior Hypertyrosinemia is associated with reported self-injurious behavior through unresolved neurologic intermediates.

Show evidence (2 references)

PMID:22389994 SUPPORT Human Clinical

"Blood tests showed a tyrosine level of 508 micromol/L (normal range: 30-150)."

Documents the marked hypertyrosinemia (508 vs normal 30-150 micromol/L) that defines the biochemical phenotype.

PMID:31603991 SUPPORT Other

"TAT deficiency leads to increased levels of tyrosine in plasma and CSF together with increased levels of its catabolic metabolites in plasma and urine."

Review supports the compartments and metabolite classes affected by TAT deficiency.

Oculocutaneous tyrosine deposition

Tyrosine crystal deposition in eye and skin tissues produces infancy-onset ophthalmologic and dermatologic lesions. Clinically, these include pseudodendritic corneal lesions and painful palmoplantar hyperkeratosis.

cornea UBERON:0000964 skin of palmar/plantar part of autopod UBERON:0013776

Downstream

Keratitis Corneal tyrosine deposition drives an inflammatory pseudodendritic keratitis.

Corneal dystrophy Corneal crystal deposition produces the characteristic corneal dystrophy and opacity.

Palmoplantar hyperkeratosis Epidermal tyrosine deposition in the palms and soles produces painful focal hyperkeratosis.

Show evidence (3 references)

PMID:31603991 SUPPORT Other

"Deposition of tyrosine crystals leads to eye and skin lesions in patients with TAT deficiency, resulting in infancy‐onset ophthalmological and dermatological symptoms."

Review directly supports the tissue-deposition mechanism and its eye and skin consequences.

PMID:22389994 SUPPORT Human Clinical

"Biomicroscopic examination revealed bilateral circular corneal opacities on the inferior quadrant and small dendritic lesions at the center of the circular opacities."

Documents the corneal (pseudodendritic) lesions produced by ocular tyrosine deposition.

PMID:22389994 SUPPORT Human Clinical

"Tyrosinemia type II should be suspected in patients demonstrating dermatologic signs, especially palmoplantar keratosis, associated with bilateral pseudodendritic corneal lesions unresponsive to antiviral therapy."

Ties the palmoplantar keratosis and antiviral-unresponsive pseudodendritic keratitis together as the hallmark oculocutaneous syndrome.

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Pathograph

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

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Phenotypes

8

Eye 3

Keratitis HP:0000491

Show evidence (1 reference)

PMID:1357662 SUPPORT Human Clinical

"characterized by keratitis, palmoplantar hyperkeratosis, mental retardation, and elevated blood tyrosine levels."

Keratitis is a defining feature of tyrosinemia type II.

Corneal dystrophy HP:0001131

Show evidence (1 reference)

PMID:39446998 SUPPORT Other

"Tyrosinemia type II is characterized by corneal dystrophy, painful palmoplantar hyperkeratosis, and variable intellectual disability."

GeneReviews lists corneal dystrophy as a characteristic feature.

Photophobia HP:0000613

Show evidence (1 reference)

PMID:22389994 SUPPORT Human Clinical

"We report a 15-year-old female patient with complaints of bilateral photophobia and tearing, which started during the infancy period."

Documents bilateral photophobia and tearing beginning in infancy.

Integument 1

Palmoplantar hyperkeratosis HP:0000972

Show evidence (1 reference)

PMID:39446998 SUPPORT Other

"Tyrosinemia type II is characterized by corneal dystrophy, painful palmoplantar hyperkeratosis, and variable intellectual disability."

GeneReviews lists painful palmoplantar hyperkeratosis as a characteristic feature.

Metabolism 1

Hypertyrosinemia HP:0003231

Show evidence (1 reference)

PMID:22389994 SUPPORT Human Clinical

"Blood tests showed a tyrosine level of 508 micromol/L (normal range: 30-150)."

Documents hypertyrosinemia (508 micromol/L vs normal 30-150).

Nervous System 3

Intellectual disability HP:0001249

Show evidence (1 reference)

PMID:39446998 SUPPORT Other

"Tyrosinemia type II is characterized by corneal dystrophy, painful palmoplantar hyperkeratosis, and variable intellectual disability."

GeneReviews lists variable intellectual disability as a feature.

Seizures HP:0001250

Show evidence (1 reference)

PMID:31603991 SUPPORT Other

"The phenotype is further characterised by seizures and self‐injuring and difficult behaviour."

Review identifies seizures among reported TAT-deficiency manifestations.

Self-injurious behavior HP:0100716

Show evidence (1 reference)

PMID:31603991 SUPPORT Other

"The phenotype is further characterised by seizures and self‐injuring and difficult behaviour."

Review identifies self-injurious behavior among reported TAT-deficiency manifestations.

🧬

Genetic Associations

1

TAT deficiency

Gene: TAT hgnc:11573

Autosomal recessive

Show evidence (2 references)

PMID:1357662 SUPPORT Human Clinical

"The disease results from deficiency in hepatic tyrosine aminotransferase (TAT; L-tyrosine:2-oxoglutarate aminotransferase, EC 2.6.1.5), a 454-amino acid protein encoded by a gene with 12 exons."

Describes the TAT gene product and structure.

PMID:1357662 SUPPORT Human Clinical

"DNA sequence analysis of the regions identified as nonfunctional revealed six different point mutations."

Documents causative point mutations in patient TAT alleles.

Variants (1)

TAT point mutations

Nonsense, missense, and splice-site point mutations in TAT abolish tyrosine aminotransferase activity; nonsense mutations at codons 57, 223, and 417 and splice-donor/acceptor mutations were among the first characterized.

Show evidence (2 references)

PMID:1357662 SUPPORT Human Clinical

"Three RHS alleles have nonsense mutations at codons 57, 223, and 417, respectively."

Patient-allele sequencing directly documents three early nonsense variants.

PMID:1357662 SUPPORT Human Clinical

"One "complex" RHS allele carries a GT----GG splice donor mutation in intron 8 together with a Gly----Val substitution at amino acid 362."

Patient-allele sequencing documents a splice-donor variant with a missense substitution.

💊

Medical Actions

3

Dietary tyrosine and phenylalanine restriction

Action: dietary intervention Ontology label: Dietary Intervention NCIT:C15447

Platform: Behavioral / lifestyle

Lifelong low-protein diet restricting dietary tyrosine and phenylalanine, combined with phenylalanine-free/tyrosine-free amino acid, vitamin, and mineral supplements. Lowering plasma tyrosine produces rapid resolution of the corneal and cutaneous lesions. Early-treated individuals may be asymptomatic or have only mild ocular and skin manifestations.

Mechanism Target:

INHIBITS Hypertyrosinemia and systemic tyrosine accumulation — Dietary restriction reduces the systemic tyrosine burden.

Show evidence (1 reference)

PMID:22389994 SUPPORT Human Clinical

"One and a half months after the tyrosine- and phenylalanine-restricted diet, her tyrosine level dropped to 395 micromol/L level, her corneal lesions subsided, and a symptomatic relief was achieved."

Human treatment response directly supports diet lowering tyrosine and improving corneal disease.

Show evidence (2 references)

PMID:39446998 SUPPORT Other

"Lifelong restriction of dietary tyrosine and phenylalanine with low-protein diet combined with age-appropriate amino acid (phenylalanine-free and tyrosine-free), vitamin, and mineral supplements."

GeneReviews specifies dietary tyrosine/phenylalanine restriction as targeted therapy.

PMID:22389994 SUPPORT Human Clinical

"One and a half months after the tyrosine- and phenylalanine-restricted diet, her tyrosine level dropped to 395 micromol/L level, her corneal lesions subsided, and a symptomatic relief was achieved."

Demonstrates biochemical and clinical response to dietary restriction.

Supportive ocular care

Action: supportive care Ontology label: Supportive Care NCIT:C15747

Lubricating eye drops and ointment, with ocular surgery as needed for bilateral corneal ulceration.

Show evidence (1 reference)

PMID:39446998 SUPPORT Other

"Lubricating eye drops and ointment; ocular surgery as needed to treat bilateral corneal ulcers"

GeneReviews lists supportive ocular care in management.

Supportive skin and developmental care

Action: supportive care Ontology label: Supportive Care NCIT:C15747

Pyridoxine phosphate or a systemic retinoid may benefit skin manifestations; developmental and educational support is provided according to need.

Show evidence (1 reference)

PMID:39446998 SUPPORT Other

"pyridoxine phosphate or a systemic retinoid may be beneficial for skin manifestations; developmental and educational support."

GeneReviews separately supports dermatologic and developmental supportive management.

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Biochemical Markers

1

Plasma tyrosine (INCREASED)

Context: Plasma tyrosine is markedly elevated and serves as a biochemical marker for recognition and monitoring. One delayed-diagnosis case reported 508 micromol/L against a 30-150 micromol/L reference interval, with a fall after tyrosine- and phenylalanine-restricted diet.

Show evidence (1 reference)

PMID:22389994 SUPPORT Human Clinical

"Blood tests showed a tyrosine level of 508 micromol/L (normal range: 30-150)."

Provides a quantified plasma tyrosine elevation with its reference interval.

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Diagnosis

3

TAT molecular genetic testing

Identification of biallelic pathogenic TAT variants establishes the diagnosis and enables family-based carrier and reproductive testing.

genetic testing NCIT:C15709

Show evidence (1 reference)

PMID:39446998 SUPPORT Other

"The diagnosis of tyrosinemia type II is established in a proband by identification of biallelic pathogenic variants in TAT on molecular genetic testing"

GeneReviews defines biallelic TAT variant detection as the principal diagnostic route.

Hepatic tyrosine aminotransferase activity assay

In limited instances, substantially reduced TAT enzyme activity measured in liver can establish the diagnosis.

laboratory procedure NCIT:C25294

Show evidence (1 reference)

PMID:39446998 SUPPORT Other

"or – in limited instances – significantly reduced activity of the enzyme tyrosine aminotransferase in liver."

GeneReviews describes reduced hepatic enzyme activity as a limited alternative route to diagnosis.

Plasma amino-acid analysis

Quantitative plasma amino-acid analysis identifies marked hypertyrosinemia and supports biochemical recognition and monitoring, with molecular testing used for definitive diagnosis.

laboratory procedure NCIT:C25294

Show evidence (1 reference)

PMID:22389994 SUPPORT Human Clinical

"Blood tests showed a tyrosine level of 508 micromol/L (normal range: 30-150)."

A delayed-diagnosis case demonstrates the diagnostic biochemical abnormality.

📈

Progression

2

Early-treated course

Age: Infancy onward

Individuals diagnosed and treated from early infancy may remain asymptomatic or have only mild eye and skin manifestations.

Show evidence (1 reference)

PMID:39446998 SUPPORT Other

"Individuals diagnosed and treated from early infancy may be asymptomatic or have only mild ocular and skin manifestations."

GeneReviews describes the attenuated course associated with early diagnosis and treatment.

Delayed or untreated presentation

Age: Infancy through later childhood or adulthood

Delayed diagnosis or absence of treatment is associated with ocular and skin disease and variable cognitive manifestations; painful eye disease may be mistaken for herpetic keratitis.

Show evidence (1 reference)

PMID:39446998 SUPPORT Other

"Individuals with delayed diagnosis or lack of treatment present with ocular, skin, and variable cognitive manifestations."

GeneReviews states the manifestations associated with delayed diagnosis or no treatment.

⚖️

Clinical Burden

Moderate

Untreated disease can cause painful keratitis, corneal injury, painful palmoplantar hyperkeratosis, and variable cognitive disability. The burden is substantially modifiable because early diagnosis and lifelong dietary therapy can produce an asymptomatic or mild course, although sustained diet, biochemical monitoring, and multidisciplinary surveillance are required.

Show evidence (1 reference)

PMID:39446998 SUPPORT Other

"Tyrosinemia type II is characterized by corneal dystrophy, painful palmoplantar hyperkeratosis, and variable intellectual disability."

The characteristic painful, ocular, cutaneous, and cognitive manifestations support a moderate untreated burden.

{ }

Source YAML

click to show

name: Tyrosinemia Type II
category: Mendelian
creation_date: '2026-07-07T00:00:00Z'
synonyms:
- Richner-Hanhart syndrome
- Oculocutaneous tyrosinemia
- Tyrosine aminotransferase deficiency
- TAT deficiency
- Keratosis palmoplantaris-corneal dystrophy syndrome
- TYRSN2
description: >
  Tyrosinemia type II (Richner-Hanhart syndrome) is a rare autosomal recessive
  inborn error of tyrosine metabolism caused by deficiency of hepatic cytosolic
  tyrosine aminotransferase (TAT), the first enzyme of the tyrosine degradation
  pathway. Loss of TAT activity blocks transamination of tyrosine to
  4-hydroxyphenylpyruvate, producing marked hypertyrosinemia and systemic
  accumulation of tyrosine in plasma, cerebrospinal fluid, and tissues. Tyrosine
  crystal deposition in eye and skin tissues drives the disorder's characteristic
  oculocutaneous phenotype: a pseudodendritic, herpetiform keratitis with
  corneal dystrophy, and painful palmoplantar hyperkeratosis. Variable
  intellectual disability may occur, particularly with delayed diagnosis or
  untreated disease. Dietary restriction of tyrosine and phenylalanine lowers
  plasma tyrosine and can rapidly improve ocular and cutaneous lesions.
disease_term:
  preferred_term: tyrosinemia type II
  term:
    id: MONDO:0010160
    label: tyrosinemia type II
parents:
- Disorder of Tyrosine Metabolism
- Inborn Error of Metabolism
mappings:
  mondo_mappings:
  - term:
      id: MONDO:0010160
      label: tyrosinemia type II
    mapping_predicate: skos:exactMatch
    mapping_source: OMIM:276600
    mapping_justification: >
      MONDO:0010160 (tyrosinemia type II) cross-references OMIM:276600 (TYRSN2)
      and Orphanet:28378, the authoritative entries for TAT-deficiency
      Richner-Hanhart syndrome.
inheritance:
- name: Autosomal recessive
  description: >
    Tyrosinemia type II is caused by biallelic pathogenic variants in TAT;
    heterozygous carriers are asymptomatic and each sib of an affected
    individual has a 25% recurrence risk.
  inheritance_term:
    preferred_term: Autosomal recessive inheritance
    term:
      id: HP:0000007
      label: Autosomal recessive inheritance
  evidence:
  - reference: PMID:39446998
    reference_title: "Tyrosinemia Type II."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Tyrosinemia type II is inherited in an autosomal recessive manner."
    explanation: GeneReviews states the autosomal recessive inheritance pattern.
  - reference: PMID:1357662
    reference_title: "Point mutations in the tyrosine aminotransferase gene in tyrosinemia type II."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Tyrosinemia type II (Richner-Hanhart syndrome, RHS) is a disease of autosomal recessive inheritance characterized by keratitis, palmoplantar hyperkeratosis, mental retardation, and elevated blood tyrosine levels."
    explanation: Confirms autosomal recessive inheritance and the defining clinical tetrad.
progression:
- phase: Early-treated course
  age_range: Infancy onward
  notes: >
    Individuals diagnosed and treated from early infancy may remain asymptomatic
    or have only mild eye and skin manifestations.
  evidence:
  - reference: PMID:39446998
    reference_title: "Tyrosinemia Type II."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Individuals diagnosed and treated from early infancy may be asymptomatic or have only mild ocular and skin manifestations."
    explanation: GeneReviews describes the attenuated course associated with early diagnosis and treatment.
- phase: Delayed or untreated presentation
  age_range: Infancy through later childhood or adulthood
  notes: >
    Delayed diagnosis or absence of treatment is associated with ocular and
    skin disease and variable cognitive manifestations; painful eye disease may
    be mistaken for herpetic keratitis.
  evidence:
  - reference: PMID:39446998
    reference_title: "Tyrosinemia Type II."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Individuals with delayed diagnosis or lack of treatment present with ocular, skin, and variable cognitive manifestations."
    explanation: GeneReviews states the manifestations associated with delayed diagnosis or no treatment.
clinical_burden:
  burden_level: MODERATE
  rationale: >
    Untreated disease can cause painful keratitis, corneal injury, painful
    palmoplantar hyperkeratosis, and variable cognitive disability. The burden
    is substantially modifiable because early diagnosis and lifelong dietary
    therapy can produce an asymptomatic or mild course, although sustained diet,
    biochemical monitoring, and multidisciplinary surveillance are required.
  evidence:
  - reference: PMID:39446998
    reference_title: "Tyrosinemia Type II."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Tyrosinemia type II is characterized by corneal dystrophy, painful palmoplantar hyperkeratosis, and variable intellectual disability."
    explanation: The characteristic painful, ocular, cutaneous, and cognitive manifestations support a moderate untreated burden.
pathophysiology:
- name: Tyrosine aminotransferase deficiency
  role: TRIGGER
  biological_scale: MOLECULAR
  description: >
    Biallelic loss-of-function TAT variants reduce hepatic cytosolic tyrosine
    aminotransferase activity, blocking the first (transamination) step of
    tyrosine catabolism that converts L-tyrosine to 4-hydroxyphenylpyruvate.
  genes:
  - preferred_term: TAT
    term:
      id: hgnc:11573
      label: TAT
  molecular_functions:
  - preferred_term: tyrosine aminotransferase activity
    term:
      id: GO:0004838
      label: L-tyrosine:2-oxoglutarate transaminase activity
    modifier: DECREASED
  biological_processes:
  - preferred_term: L-tyrosine catabolic process
    term:
      id: GO:0006572
      label: L-tyrosine catabolic process
    modifier: DECREASED
  locations:
  - preferred_term: liver
    term:
      id: UBERON:0002107
      label: liver
  evidence:
  - reference: PMID:1357662
    reference_title: "Point mutations in the tyrosine aminotransferase gene in tyrosinemia type II."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The disease results from deficiency in hepatic tyrosine aminotransferase (TAT; L-tyrosine:2-oxoglutarate aminotransferase, EC 2.6.1.5), a 454-amino acid protein encoded by a gene with 12 exons."
    explanation: Identifies deficiency of hepatic tyrosine aminotransferase as the causal enzymatic lesion.
  - reference: PMID:39446998
    reference_title: "Tyrosinemia Type II."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "The diagnosis of tyrosinemia type II is established in a proband by identification of biallelic pathogenic variants in TAT on molecular genetic testing"
    explanation: Confirms biallelic TAT pathogenic variants as the molecular basis of the disease.
  - reference: PMID:31603991
    reference_title: "Inborn errors of enzymes in glutamate metabolism."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Tyrosine aminotransferase (TAT) transaminates tyrosine, forming p‐hydroxyphenylpyruvate and glutamate."
    explanation: Defines the biochemical reaction catalyzed by TAT.
  downstream:
  - target: Hypertyrosinemia and systemic tyrosine accumulation
    description: >
      Loss of tyrosine aminotransferase activity prevents normal tyrosine
      degradation, causing tyrosine to accumulate in blood and tissues.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:22389994
      reference_title: "Richner-Hanhart syndrome (tyrosinemia type II): a case report of delayed diagnosis with pseudodendritic corneal lesion."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Richner-Hanhart syndrome (tyrosinemia type II) is a rare autosomal recessive disease associated with high serum tyrosine levels caused by the deficiency of tyrosine aminotransferase enzyme."
      explanation: Directly links tyrosine aminotransferase deficiency to elevated serum tyrosine.
- name: Hypertyrosinemia and systemic tyrosine accumulation
  role: CENTRAL_EFFECTOR
  biological_scale: ORGANISM
  description: >
    The upstream enzymatic block produces increased tyrosine in plasma and
    cerebrospinal fluid and increased tyrosine catabolic metabolites in plasma
    and urine. Tyrosine crystal deposition is implicated in the characteristic
    eye and skin lesions.
  chemical_entities:
  - preferred_term: L-tyrosine
    term:
      id: CHEBI:17895
      label: L-tyrosine
    modifier: INCREASED
  evidence:
  - reference: PMID:22389994
    reference_title: "Richner-Hanhart syndrome (tyrosinemia type II): a case report of delayed diagnosis with pseudodendritic corneal lesion."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Blood tests showed a tyrosine level of 508 micromol/L (normal range: 30-150)."
    explanation: Documents the marked hypertyrosinemia (508 vs normal 30-150 micromol/L) that defines the biochemical phenotype.
  - reference: PMID:31603991
    reference_title: "Inborn errors of enzymes in glutamate metabolism."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "TAT deficiency leads to increased levels of tyrosine in plasma and CSF together with increased levels of its catabolic metabolites in plasma and urine."
    explanation: Review supports the compartments and metabolite classes affected by TAT deficiency.
  downstream:
  - target: Oculocutaneous tyrosine deposition
    description: >
      Elevated intracellular tyrosine deposits in the cornea and in palmoplantar
      epidermis, triggering the inflammatory and hyperkeratotic tissue response.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:31603991
      reference_title: "Inborn errors of enzymes in glutamate metabolism."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "Deposition of tyrosine crystals leads to eye and skin lesions in patients with TAT deficiency, resulting in infancy‐onset ophthalmological and dermatological symptoms."
      explanation: Review directly attributes eye and skin lesions to tyrosine crystal deposition.
  - target: Intellectual disability
    description: >
      Sustained untreated hypertyrosinemia is associated with variable cognitive
      manifestations through unresolved neurologic intermediates.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:39446998
      reference_title: "Tyrosinemia Type II."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "Individuals with delayed diagnosis or lack of treatment present with ocular, skin, and variable cognitive manifestations."
      explanation: The treatment-timing association supports a link while leaving the neurologic intermediates unresolved.
  - target: Seizures
    description: Hypertyrosinemia is associated with reported seizures through unresolved neurologic intermediates.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:31603991
      reference_title: "Inborn errors of enzymes in glutamate metabolism."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "The phenotype is further characterised by seizures and self‐injuring and difficult behaviour."
      explanation: Establishes the TAT-deficiency neurologic endpoint but not the route from tyrosine elevation.
  - target: Self-injurious behavior
    description: Hypertyrosinemia is associated with reported self-injurious behavior through unresolved neurologic intermediates.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:31603991
      reference_title: "Inborn errors of enzymes in glutamate metabolism."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "The phenotype is further characterised by seizures and self‐injuring and difficult behaviour."
      explanation: Establishes the TAT-deficiency neurologic endpoint but not the route from tyrosine elevation.
- name: Oculocutaneous tyrosine deposition
  role: DOWNSTREAM
  biological_scale: TISSUE
  description: >
    Tyrosine crystal deposition in eye and skin tissues produces infancy-onset
    ophthalmologic and dermatologic lesions. Clinically, these include
    pseudodendritic corneal lesions and painful palmoplantar hyperkeratosis.
  locations:
  - preferred_term: cornea
    term:
      id: UBERON:0000964
      label: cornea
  - preferred_term: skin of palmar/plantar part of autopod
    term:
      id: UBERON:0013776
      label: skin of palmar/plantar part of autopod
  evidence:
  - reference: PMID:31603991
    reference_title: "Inborn errors of enzymes in glutamate metabolism."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Deposition of tyrosine crystals leads to eye and skin lesions in patients with TAT deficiency, resulting in infancy‐onset ophthalmological and dermatological symptoms."
    explanation: Review directly supports the tissue-deposition mechanism and its eye and skin consequences.
  - reference: PMID:22389994
    reference_title: "Richner-Hanhart syndrome (tyrosinemia type II): a case report of delayed diagnosis with pseudodendritic corneal lesion."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Biomicroscopic examination revealed bilateral circular corneal opacities on the inferior quadrant and small dendritic lesions at the center of the circular opacities."
    explanation: Documents the corneal (pseudodendritic) lesions produced by ocular tyrosine deposition.
  - reference: PMID:22389994
    reference_title: "Richner-Hanhart syndrome (tyrosinemia type II): a case report of delayed diagnosis with pseudodendritic corneal lesion."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Tyrosinemia type II should be suspected in patients demonstrating dermatologic signs, especially palmoplantar keratosis, associated with bilateral pseudodendritic corneal lesions unresponsive to antiviral therapy."
    explanation: Ties the palmoplantar keratosis and antiviral-unresponsive pseudodendritic keratitis together as the hallmark oculocutaneous syndrome.
  downstream:
  - target: Keratitis
    description: Corneal tyrosine deposition drives an inflammatory pseudodendritic keratitis.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:31603991
      reference_title: "Inborn errors of enzymes in glutamate metabolism."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "herpetiform corneal ulcerations in patients with TAT deficiency"
      explanation: Directly names the characteristic inflammatory corneal lesion in TAT deficiency.
  - target: Corneal dystrophy
    description: Corneal crystal deposition produces the characteristic corneal dystrophy and opacity.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:31603991
      reference_title: "Inborn errors of enzymes in glutamate metabolism."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "Deposition of tyrosine crystals leads to eye and skin lesions in patients with TAT deficiency, resulting in infancy‐onset ophthalmological and dermatological symptoms."
      explanation: Supports eye tissue lesions as a consequence of tyrosine crystal deposition; GeneReviews identifies corneal dystrophy as the characteristic lesion.
    - reference: PMID:39446998
      reference_title: "Tyrosinemia Type II."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "Tyrosinemia type II is characterized by corneal dystrophy, painful palmoplantar hyperkeratosis, and variable intellectual disability."
      explanation: Identifies corneal dystrophy as the characteristic ocular outcome paired with the deposition mechanism.
  - target: Palmoplantar hyperkeratosis
    description: Epidermal tyrosine deposition in the palms and soles produces painful focal hyperkeratosis.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:31603991
      reference_title: "Inborn errors of enzymes in glutamate metabolism."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "Deposition of tyrosine crystals leads to eye and skin lesions in patients with TAT deficiency, resulting in infancy‐onset ophthalmological and dermatological symptoms."
      explanation: Directly supports the deposition-to-skin-lesion route; GeneReviews identifies painful palmoplantar hyperkeratosis as the characteristic skin lesion.
    - reference: PMID:39446998
      reference_title: "Tyrosinemia Type II."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "Tyrosinemia type II is characterized by corneal dystrophy, painful palmoplantar hyperkeratosis, and variable intellectual disability."
      explanation: Identifies painful palmoplantar hyperkeratosis as the characteristic skin outcome paired with the deposition mechanism.
phenotypes:
- name: Keratitis
  category: Ocular
  description: >
    Painful, bilateral, often pseudodendritic (herpetiform) keratitis presenting
    with photophobia and tearing, characteristically unresponsive to antiviral
    therapy and improving with tyrosine-lowering diet.
  phenotype_term:
    preferred_term: Keratitis
    term:
      id: HP:0000491
      label: Keratitis
  evidence:
  - reference: PMID:1357662
    reference_title: "Point mutations in the tyrosine aminotransferase gene in tyrosinemia type II."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "characterized by keratitis, palmoplantar hyperkeratosis, mental retardation, and elevated blood tyrosine levels."
    explanation: Keratitis is a defining feature of tyrosinemia type II.
- name: Corneal dystrophy
  category: Ocular
  description: >
    Corneal involvement manifests as bilateral corneal opacities/dystrophy with
    pseudodendritic lesions.
  phenotype_term:
    preferred_term: Corneal dystrophy
    term:
      id: HP:0001131
      label: Corneal dystrophy
  evidence:
  - reference: PMID:39446998
    reference_title: "Tyrosinemia Type II."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Tyrosinemia type II is characterized by corneal dystrophy, painful palmoplantar hyperkeratosis, and variable intellectual disability."
    explanation: GeneReviews lists corneal dystrophy as a characteristic feature.
- name: Photophobia
  category: Ocular
  description: Bilateral photophobia and tearing, often beginning in infancy, from the keratitis.
  phenotype_term:
    preferred_term: Photophobia
    term:
      id: HP:0000613
      label: Photophobia
  evidence:
  - reference: PMID:22389994
    reference_title: "Richner-Hanhart syndrome (tyrosinemia type II): a case report of delayed diagnosis with pseudodendritic corneal lesion."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We report a 15-year-old female patient with complaints of bilateral photophobia and tearing, which started during the infancy period."
    explanation: Documents bilateral photophobia and tearing beginning in infancy.
- name: Palmoplantar hyperkeratosis
  category: Dermatologic
  description: Painful focal hyperkeratosis of the palms and soles.
  phenotype_term:
    preferred_term: Palmoplantar hyperkeratosis
    term:
      id: HP:0000972
      label: Palmoplantar hyperkeratosis
  evidence:
  - reference: PMID:39446998
    reference_title: "Tyrosinemia Type II."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Tyrosinemia type II is characterized by corneal dystrophy, painful palmoplantar hyperkeratosis, and variable intellectual disability."
    explanation: GeneReviews lists painful palmoplantar hyperkeratosis as a characteristic feature.
- name: Intellectual disability
  category: Neurologic
  description: >
    Variable intellectual disability, more likely with delayed diagnosis or
    untreated disease.
  phenotype_term:
    preferred_term: Intellectual disability
    term:
      id: HP:0001249
      label: Intellectual disability
  evidence:
  - reference: PMID:39446998
    reference_title: "Tyrosinemia Type II."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Tyrosinemia type II is characterized by corneal dystrophy, painful palmoplantar hyperkeratosis, and variable intellectual disability."
    explanation: GeneReviews lists variable intellectual disability as a feature.
- name: Seizures
  category: Neurologic
  description: Seizures have been reported as part of the neurologic phenotype.
  phenotype_term:
    preferred_term: Seizure
    term:
      id: HP:0001250
      label: Seizure
  evidence:
  - reference: PMID:31603991
    reference_title: "Inborn errors of enzymes in glutamate metabolism."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "The phenotype is further characterised by seizures and self‐injuring and difficult behaviour."
    explanation: Review identifies seizures among reported TAT-deficiency manifestations.
- name: Self-injurious behavior
  category: Neurologic
  description: Self-injurious and difficult behavior has been reported.
  phenotype_term:
    preferred_term: Self-injurious behavior
    term:
      id: HP:0100716
      label: Self-injurious behavior
  evidence:
  - reference: PMID:31603991
    reference_title: "Inborn errors of enzymes in glutamate metabolism."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "The phenotype is further characterised by seizures and self‐injuring and difficult behaviour."
    explanation: Review identifies self-injurious behavior among reported TAT-deficiency manifestations.
- name: Hypertyrosinemia
  category: Biochemical
  description: Marked elevation of plasma tyrosine, with increased tyrosine also reported in cerebrospinal fluid.
  phenotype_term:
    preferred_term: Hypertyrosinemia
    term:
      id: HP:0003231
      label: Hypertyrosinemia
  evidence:
  - reference: PMID:22389994
    reference_title: "Richner-Hanhart syndrome (tyrosinemia type II): a case report of delayed diagnosis with pseudodendritic corneal lesion."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Blood tests showed a tyrosine level of 508 micromol/L (normal range: 30-150)."
    explanation: Documents hypertyrosinemia (508 micromol/L vs normal 30-150).
biochemical:
- name: Plasma tyrosine
  presence: INCREASED
  context: >
    Plasma tyrosine is markedly elevated and serves as a biochemical marker for
    recognition and monitoring. One delayed-diagnosis case reported 508
    micromol/L against a 30-150 micromol/L reference interval, with a fall after
    tyrosine- and phenylalanine-restricted diet.
  biomarker_term:
    preferred_term: L-tyrosine
    term:
      id: CHEBI:17895
      label: L-tyrosine
  evidence:
  - reference: PMID:22389994
    reference_title: "Richner-Hanhart syndrome (tyrosinemia type II): a case report of delayed diagnosis with pseudodendritic corneal lesion."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Blood tests showed a tyrosine level of 508 micromol/L (normal range: 30-150)."
    explanation: Provides a quantified plasma tyrosine elevation with its reference interval.
genetic:
- name: TAT deficiency
  gene_term:
    preferred_term: TAT
    term:
      id: hgnc:11573
      label: TAT
  inheritance:
  - name: Autosomal recessive
    description: Biallelic pathogenic TAT variants are required; carriers are asymptomatic.
    evidence:
    - reference: PMID:39446998
      reference_title: "Tyrosinemia Type II."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "Tyrosinemia type II is inherited in an autosomal recessive manner."
      explanation: States autosomal recessive inheritance.
  variants:
  - name: TAT point mutations
    description: >
      Nonsense, missense, and splice-site point mutations in TAT abolish tyrosine
      aminotransferase activity; nonsense mutations at codons 57, 223, and 417
      and splice-donor/acceptor mutations were among the first characterized.
    evidence:
    - reference: PMID:1357662
      reference_title: "Point mutations in the tyrosine aminotransferase gene in tyrosinemia type II."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Three RHS alleles have nonsense mutations at codons 57, 223, and 417, respectively."
      explanation: Patient-allele sequencing directly documents three early nonsense variants.
    - reference: PMID:1357662
      reference_title: "Point mutations in the tyrosine aminotransferase gene in tyrosinemia type II."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "One \"complex\" RHS allele carries a GT----GG splice donor mutation in intron 8 together with a Gly----Val substitution at amino acid 362."
      explanation: Patient-allele sequencing documents a splice-donor variant with a missense substitution.
  features: >
    TAT encodes hepatic cytosolic tyrosine aminotransferase, a 454-amino acid
    protein encoded by a gene with 12 exons. Biallelic loss-of-function variants
    cause the enzyme deficiency.
  evidence:
  - reference: PMID:1357662
    reference_title: "Point mutations in the tyrosine aminotransferase gene in tyrosinemia type II."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The disease results from deficiency in hepatic tyrosine aminotransferase (TAT; L-tyrosine:2-oxoglutarate aminotransferase, EC 2.6.1.5), a 454-amino acid protein encoded by a gene with 12 exons."
    explanation: Describes the TAT gene product and structure.
  - reference: PMID:1357662
    reference_title: "Point mutations in the tyrosine aminotransferase gene in tyrosinemia type II."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "DNA sequence analysis of the regions identified as nonfunctional revealed six different point mutations."
    explanation: Documents causative point mutations in patient TAT alleles.
diagnosis:
- name: TAT molecular genetic testing
  description: >
    Identification of biallelic pathogenic TAT variants establishes the
    diagnosis and enables family-based carrier and reproductive testing.
  diagnosis_term:
    preferred_term: genetic testing
    term:
      id: NCIT:C15709
      label: Genetic Testing
  evidence:
  - reference: PMID:39446998
    reference_title: "Tyrosinemia Type II."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "The diagnosis of tyrosinemia type II is established in a proband by identification of biallelic pathogenic variants in TAT on molecular genetic testing"
    explanation: GeneReviews defines biallelic TAT variant detection as the principal diagnostic route.
- name: Hepatic tyrosine aminotransferase activity assay
  description: >
    In limited instances, substantially reduced TAT enzyme activity measured in
    liver can establish the diagnosis.
  diagnosis_term:
    preferred_term: laboratory procedure
    term:
      id: NCIT:C25294
      label: Laboratory Procedure
  evidence:
  - reference: PMID:39446998
    reference_title: "Tyrosinemia Type II."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "or – in limited instances – significantly reduced activity of the enzyme tyrosine aminotransferase in liver."
    explanation: GeneReviews describes reduced hepatic enzyme activity as a limited alternative route to diagnosis.
- name: Plasma amino-acid analysis
  description: >
    Quantitative plasma amino-acid analysis identifies marked hypertyrosinemia
    and supports biochemical recognition and monitoring, with molecular testing
    used for definitive diagnosis.
  diagnosis_term:
    preferred_term: laboratory procedure
    term:
      id: NCIT:C25294
      label: Laboratory Procedure
  evidence:
  - reference: PMID:22389994
    reference_title: "Richner-Hanhart syndrome (tyrosinemia type II): a case report of delayed diagnosis with pseudodendritic corneal lesion."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Blood tests showed a tyrosine level of 508 micromol/L (normal range: 30-150)."
    explanation: A delayed-diagnosis case demonstrates the diagnostic biochemical abnormality.
treatments:
- name: Dietary tyrosine and phenylalanine restriction
  description: >
    Lifelong low-protein diet restricting dietary tyrosine and phenylalanine,
    combined with phenylalanine-free/tyrosine-free amino acid, vitamin, and
    mineral supplements. Lowering plasma tyrosine produces rapid resolution of
    the corneal and cutaneous lesions. Early-treated individuals may be
    asymptomatic or have only mild ocular and skin manifestations.
  therapeutic_modality: BEHAVIORAL
  treatment_term:
    preferred_term: dietary intervention
    term:
      id: NCIT:C15447
      label: Dietary Intervention
  target_mechanisms:
  - target: Hypertyrosinemia and systemic tyrosine accumulation
    treatment_effect: INHIBITS
    description: Dietary restriction reduces the systemic tyrosine burden.
    evidence:
    - reference: PMID:22389994
      reference_title: "Richner-Hanhart syndrome (tyrosinemia type II): a case report of delayed diagnosis with pseudodendritic corneal lesion."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "One and a half months after the tyrosine- and phenylalanine-restricted diet, her tyrosine level dropped to 395 micromol/L level, her corneal lesions subsided, and a symptomatic relief was achieved."
      explanation: Human treatment response directly supports diet lowering tyrosine and improving corneal disease.
  evidence:
  - reference: PMID:39446998
    reference_title: "Tyrosinemia Type II."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Lifelong restriction of dietary tyrosine and phenylalanine with low-protein diet combined with age-appropriate amino acid (phenylalanine-free and tyrosine-free), vitamin, and mineral supplements."
    explanation: GeneReviews specifies dietary tyrosine/phenylalanine restriction as targeted therapy.
  - reference: PMID:22389994
    reference_title: "Richner-Hanhart syndrome (tyrosinemia type II): a case report of delayed diagnosis with pseudodendritic corneal lesion."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "One and a half months after the tyrosine- and phenylalanine-restricted diet, her tyrosine level dropped to 395 micromol/L level, her corneal lesions subsided, and a symptomatic relief was achieved."
    explanation: Demonstrates biochemical and clinical response to dietary restriction.
- name: Supportive ocular care
  description: >
    Lubricating eye drops and ointment, with ocular surgery as needed for
    bilateral corneal ulceration.
  treatment_term:
    preferred_term: supportive care
    term:
      id: NCIT:C15747
      label: Supportive Care
  evidence:
  - reference: PMID:39446998
    reference_title: "Tyrosinemia Type II."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Lubricating eye drops and ointment; ocular surgery as needed to treat bilateral corneal ulcers"
    explanation: GeneReviews lists supportive ocular care in management.
- name: Supportive skin and developmental care
  description: >
    Pyridoxine phosphate or a systemic retinoid may benefit skin manifestations;
    developmental and educational support is provided according to need.
  treatment_term:
    preferred_term: supportive care
    term:
      id: NCIT:C15747
      label: Supportive Care
  evidence:
  - reference: PMID:39446998
    reference_title: "Tyrosinemia Type II."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "pyridoxine phosphate or a systemic retinoid may be beneficial for skin manifestations; developmental and educational support."
    explanation: GeneReviews separately supports dermatologic and developmental supportive management.
notes: >
  Unlike tyrosinemia type I, the metabolic block is at the first step of
  tyrosine degradation, so tyrosine itself accumulates rather than
  fumarylacetoacetate or succinylacetone. Nitisinone, the principal therapy for
  type I, acts downstream of TAT and is not used in type II because it would
  further increase tyrosine.
  Surveillance described by GeneReviews includes quantitative plasma tyrosine
  and phenylalanine at each visit, annual or clinically indicated ophthalmology
  and skin assessments, annual developmental and neuropsychological review, and
  nutritional monitoring including calcium, phosphorus, and 25-hydroxyvitamin D.
  Increased dietary protein should be avoided. The causal route from systemic
  tyrosine elevation to variable cognitive manifestations remains unresolved;
  neurologic outcomes are therefore linked only through unknown intermediates.
experimental_models: []
animal_models: []
datasets: []
review_notes: >
  Review used four cached sources anchored to MONDO:0010160 and TAT. No
  disease-specific public molecular dataset or model with an evidence-supported
  mechanism link was identified in the repository, so those sections are
  explicitly empty. Phenotype frequencies were omitted because the cited
  sources do not provide defensible denominators or qualitative bands. Direct
  evidence supports TAT deficiency causing hypertyrosinemia and tyrosine crystal
  deposition causing eye and skin lesions. Neurologic phenotypes are linked with
  INDIRECT_UNKNOWN_INTERMEDIATES edges because association and treatment timing
  support a relationship while the causal route remains unresolved.
references:
- reference: PMID:39446998
  title: "Tyrosinemia Type II."
  tags:
  - GeneReviews
- reference: PMID:1357662
  title: "Point mutations in the tyrosine aminotransferase gene in tyrosinemia type II."
- reference: PMID:22389994
  title: "Richner-Hanhart syndrome (tyrosinemia type II): a case report of delayed diagnosis with pseudodendritic corneal lesion."
- reference: PMID:31603991
  title: "Inborn errors of enzymes in glutamate metabolism."

📚

References & Deep Research

References

4

PMID:39446998

Tyrosinemia Type II.

No top-level findings curated for this source.

PMID:1357662

Point mutations in the tyrosine aminotransferase gene in tyrosinemia type II.

No top-level findings curated for this source.

PMID:22389994

Richner-Hanhart syndrome (tyrosinemia type II): a case report of delayed diagnosis with pseudodendritic corneal lesion.

No top-level findings curated for this source.

PMID:31603991

Inborn errors of enzymes in glutamate metabolism.

No top-level findings curated for this source.

Tyrosinemia Type II

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