Hartnup Disease

Mendelian MONDO:0009324 Pathograph 36 Renal aminoaciduria Inborn error of metabolism

Hartnup disease is an autosomal recessive neutral aminoaciduria caused mainly by biallelic loss-of-function variants in SLC6A19, which encodes the sodium-dependent neutral amino acid transporter B0AT1. Impaired B0AT1-mediated transport in renal proximal tubule and intestinal epithelial cells causes urinary loss and reduced gastrointestinal uptake of neutral amino acids, including tryptophan. Reduced tryptophan availability can limit endogenous nicotinamide synthesis, producing episodic pellagra-like photosensitive rash and neuropsychiatric manifestations such as ataxia, emotional lability, hallucinations, anxiety, hypotonia, and seizures. Most molecular evidence centers on SLC6A19/B0AT1, while Orphanet also lists CLTRN, an amino acid transport regulator, as a disease-associated gene.

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1
Inheritance
6
Pathophys.
21
Phenotypes
36
Pathograph
2
Genes
4
Treatments
8
References
1
Deep Research
👪

Inheritance

1
Autosomal recessive inheritance HP:0000007
autosomal recessive inheritance
Show evidence (2 references)
ORPHA:2116 SUPPORT Other
"Autosomal recessive"
Orphanet records autosomal recessive inheritance for Hartnup disease.
PMID:15286787 SUPPORT Human Clinical
"Hartnup disorder, an autosomal recessive defect"
The original-family SLC6A19 paper describes Hartnup disorder as autosomal recessive.
⚙

Pathophysiology

6
SLC6A19 B0AT1 transporter loss of function
Pathogenic SLC6A19 variants impair the sodium-dependent neutral amino acid transporter B0AT1. The transporter is normally expressed in intestinal and renal epithelial cells, where it mediates uptake or reabsorption of neutral amino acids.
epithelial cell of proximal tubule link intestinal epithelial cell link
SLC6A19 link
neutral amino acid transport link ↓ DECREASED tryptophan transport link ↓ DECREASED
neutral L-amino acid transmembrane transporter activity link ↓ DECREASED amino acid:sodium symporter activity link ↓ DECREASED
proximal tubule link intestinal mucosa link
Downstream
Renal and intestinal neutral amino acid transport defect Reduced B0AT1 activity impairs reabsorption and absorption of neutral amino acids in kidney and intestine.
B0AT1 endoplasmic-reticulum retention Some disease-causing variants impair trafficking of B0AT1 to the plasma membrane.
Show evidence (4 references)
PMID:15286787 SUPPORT Human Clinical
"then identified mutations in SLC6A19 in members of the original family in whom"
The original-family study identified SLC6A19 mutations in affected families.
PMID:15286788 SUPPORT In Vitro
"reduced neutral amino acid transport"
Functional testing showed reduced neutral amino acid transport for disease-causing SLC6A19 variants.
PMID:16052352 SUPPORT Other
"caused by mutations in the neutral amino acid transporter B(0) AT1 (SLC6A19)."
Review evidence identifies B0AT1/SLC6A19 mutation as the molecular basis of Hartnup disorder.
+ 1 more reference
CLTRN amino acid transport regulator involvement
CLTRN encodes collectrin, an amino-acid transport regulator listed by Orphanet as a disease-causing gene for Hartnup disease. The available cached evidence supports a gene association, while the better-supported disease-defining transporter mechanism remains SLC6A19/B0AT1.
CLTRN link
amino acid transmembrane transport link ⚠ ABNORMAL
Downstream
Renal and intestinal neutral amino acid transport defect CLTRN is modeled as an auxiliary amino-acid transport regulator that converges on the epithelial neutral amino acid transport phenotype.
Show evidence (2 references)
ORPHA:2116 PARTIAL Other
"CLTRN | collectrin, amino acid transport regulator | hgnc:29437 | Disease-causing germline mutation(s) in"
Orphanet lists CLTRN as a disease-causing germline amino acid transport regulator for Hartnup disease.
PMID:19472175 SUPPORT Other
"SLC6A19 requires either collectrin or angiotensin-converting enzyme 2 for surface expression in the kidney and intestine, respectively."
The Hartnup-specific review supports collectrin as a regulator of SLC6A19/B0AT1 surface expression in kidney, consistent with CLTRN convergence on the epithelial amino-acid transport defect.
B0AT1 endoplasmic-reticulum retention
Several Hartnup disease-causing B0AT1 variants are retained in the endoplasmic reticulum rather than reaching the plasma membrane, providing a variant-level mechanism for loss of transporter function.
SLC6A19 link
endoplasmic reticulum link plasma membrane link
Downstream
Renal and intestinal neutral amino acid transport defect ER retention reduces delivery of functional B0AT1 to the epithelial cell surface.
Show evidence (2 references)
PMID:40852587 SUPPORT In Vitro
"were found to be retained in the endoplasmic reticulum"
Functional cell studies showed ER retention of multiple Hartnup-associated B0AT1 variants.
PMID:40852587 SUPPORT In Vitro
"by impairing amino acid transport and may influence ACE2-mediated physiological"
The trafficking study supports ER-retained B0AT1 variants as pathogenic because they impair amino acid transport and may disrupt ACE2-related physiology.
Renal and intestinal neutral amino acid transport defect
Defective B0AT1-mediated transport causes impaired renal reabsorption and gastrointestinal absorption of neutral amino acids. The resulting biochemical signature is neutral hyperaminoaciduria, often including elevated urinary indican from unabsorbed tryptophan metabolism.
amino acid transmembrane transport link ↓ DECREASED neutral amino acid transport link ↓ DECREASED tryptophan transport link ↓ DECREASED
Downstream
Neutral hyperaminoaciduria Failed renal reabsorption produces excessive urinary neutral amino acids.
Malabsorption Impaired intestinal neutral amino acid transport contributes to reduced nutrient absorption.
Tryptophan and nicotinamide availability reduction Reduced intestinal tryptophan absorption can limit niacin/nicotinamide availability.
Low systemic tryptophan availability Impaired intestinal neutral amino acid transport can reduce systemic and CSF tryptophan availability.
Increased urinary indican Abnormal tryptophan transport and handling is reflected by elevated urinary indican.
Elevated urinary indican level Elevated urinary indican is the phenotype-level expression of abnormal tryptophan handling.
Abnormal urinary color Abnormal urinary color is grouped with abnormal urinary amino-acid and tryptophan-derived metabolites.
Show evidence (3 references)
PMID:15286787 SUPPORT Human Clinical
"results from impaired transport of neutral amino"
The SLC6A19 discovery paper states the epithelial neutral amino acid transport defect.
PMID:16052352 SUPPORT Other
"resorption of all neutral amino acids."
Review evidence places B0AT1 in renal and intestinal neutral amino acid resorption.
ORPHA:2116 SUPPORT Other
"abnormal renal and gastrointestinal transport of neutral amino acids"
Orphanet's definition describes the renal and gastrointestinal transport defect.
Tryptophan and nicotinamide availability reduction
Tryptophan is a neutral amino acid and a precursor for nicotinamide synthesis. Reduced tryptophan uptake can produce a functional pellagra-like state even when dietary niacin intake is adequate.
L-tryptophan metabolic process link ↓ DECREASED nicotinamide metabolic process link ↓ DECREASED
Downstream
Pellagra-like neurocutaneous manifestations Functional niacin/nicotinamide deficiency can drive photosensitive rash and neurologic or psychiatric features.
Show evidence (2 references)
PMID:2472426 SUPPORT Human Clinical
"6 microM) and cerebrospinal fluid (1.0 +/- 0.2 microM) were persistently less"
The treatment case documented low serum and CSF tryptophan before bypass therapy.
PMID:7955499 SUPPORT Human Clinical
"prolonged lactation and increased activity. Dietary intake of niacin was within"
Pellagra developed despite adequate niacin intake, consistent with Hartnup-related precursor limitation.
Pellagra-like neurocutaneous manifestations
In susceptible patients, the transport defect manifests as photosensitive pellagra-like dermatitis together with neurologic and psychiatric signs such as ataxia, tremor, hypotonia, emotional lability, hallucinations, anxiety, and psychosis.
Downstream
Cutaneous photosensitivity Pellagra-like skin disease includes photosensitivity.
Ataxia Cerebellar manifestations include ataxia.
Psychosis Neuropsychiatric manifestations can include psychosis.
Skin rash Pellagra-like dermatitis includes rash.
Emotional lability Emotional lability is grouped with Hartnup neuropsychiatric manifestations.
Hallucinations Hallucinations are grouped with Hartnup neuropsychiatric manifestations.
Anxiety Anxiety is grouped with Hartnup neuropsychiatric manifestations.
Hypotonia Hypotonia is grouped with Hartnup neurologic manifestations.
Hyperreflexia Hyperreflexia is grouped with Hartnup neurologic manifestations.
Tremor Tremor is grouped with Hartnup neurologic manifestations.
Migraine Migraine is grouped with Hartnup neurologic manifestations.
EEG abnormality EEG abnormality is grouped with Hartnup neurologic manifestations.
Seizure Seizures are grouped with occasional Hartnup neurologic manifestations.
Photophobia Photophobia is grouped with Hartnup ocular features.
Nystagmus Nystagmus is grouped with Hartnup ocular-neurologic features.
Strabismus Strabismus is grouped with Hartnup ocular features.
Abnormality of vision Visual abnormality is grouped with Hartnup ocular features.
Show evidence (2 references)
PMID:15286787 SUPPORT Human Clinical
"Symptoms include transient manifestations of pellagra (rashes), cerebellar"
The SLC6A19 discovery paper summarizes the pellagra-like and cerebellar clinical expression.
ORPHA:2116 SUPPORT Other
"mainly characterized by skin photosensitivity, ocular and neuropsychiatric features"
Orphanet describes the major neurocutaneous and ocular disease manifestations.
⬡

Pathograph

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

21
Digestive 1
Malabsorption FREQUENT Malabsorption (HP:0002024)
Show evidence (1 reference)
ORPHA:2116 SUPPORT Other
"HP:0002024 | Malabsorption | Frequent (79-30%)"
Orphanet records malabsorption as frequent.
Eye 3
Photophobia FREQUENT Photophobia (HP:0000613)
Show evidence (1 reference)
ORPHA:2116 SUPPORT Other
"HP:0000613 | Photophobia | Frequent (79-30%)"
Orphanet records photophobia as frequent.
Nystagmus FREQUENT Nystagmus (HP:0000639)
Show evidence (1 reference)
ORPHA:2116 SUPPORT Other
"HP:0000639 | Nystagmus | Frequent (79-30%)"
Orphanet records nystagmus as frequent.
Strabismus FREQUENT Strabismus (HP:0000486)
Show evidence (1 reference)
ORPHA:2116 SUPPORT Other
"HP:0000486 | Strabismus | Frequent (79-30%)"
Orphanet records strabismus as frequent.
Immune 1
Skin rash FREQUENT Skin rash (HP:0000988)
Show evidence (2 references)
ORPHA:2116 SUPPORT Other
"HP:0000988 | Skin rash | Frequent (79-30%)"
Orphanet records skin rash as frequent.
PMID:15286787 SUPPORT Human Clinical
"pellagra (rashes), cerebellar"
The SLC6A19 discovery paper lists pellagra-like rashes.
Integument 1
Cutaneous photosensitivity VERY_FREQUENT Cutaneous photosensitivity (HP:0000992)
Show evidence (2 references)
ORPHA:2116 SUPPORT Other
"HP:0000992 | Cutaneous photosensitivity | Very frequent (99-80%)"
Orphanet records cutaneous photosensitivity as very frequent.
PMID:7955499 SUPPORT Human Clinical
"A young woman presented with pellagra."
Adult case report documents a pellagra presentation.
Musculoskeletal 1
Hypotonia VERY_FREQUENT Hypotonia (HP:0001252)
Show evidence (1 reference)
ORPHA:2116 SUPPORT Other
"HP:0001252 | Hypotonia | Very frequent (99-80%)"
Orphanet records hypotonia as very frequent.
Nervous System 9
Ataxia VERY_FREQUENT Ataxia (HP:0001251)
Show evidence (2 references)
ORPHA:2116 SUPPORT Other
"HP:0001251 | Ataxia | Very frequent (99-80%)"
Orphanet records ataxia as very frequent.
PMID:15286787 SUPPORT Human Clinical
"ataxia and psychosis."
The SLC6A19 discovery paper lists ataxia and psychosis among symptoms.
Hallucinations VERY_FREQUENT Hallucinations (HP:0000738)
Show evidence (1 reference)
ORPHA:2116 SUPPORT Other
"HP:0000738 | Hallucinations | Very frequent (99-80%)"
Orphanet records hallucinations as very frequent.
Anxiety VERY_FREQUENT Anxiety (HP:0000739)
Show evidence (1 reference)
ORPHA:2116 SUPPORT Other
"HP:0000739 | Anxiety | Very frequent (99-80%)"
Orphanet records anxiety as very frequent.
Hyperreflexia VERY_FREQUENT Hyperreflexia (HP:0001347)
Show evidence (1 reference)
ORPHA:2116 SUPPORT Other
"HP:0001347 | Hyperreflexia | Very frequent (99-80%)"
Orphanet records hyperreflexia as very frequent.
Migraine VERY_FREQUENT Migraine (HP:0002076)
Show evidence (1 reference)
ORPHA:2116 SUPPORT Other
"HP:0002076 | Migraine | Very frequent (99-80%)"
Orphanet records migraine as very frequent.
EEG abnormality VERY_FREQUENT EEG abnormality (HP:0002353)
Show evidence (1 reference)
ORPHA:2116 SUPPORT Other
"HP:0002353 | EEG abnormality | Very frequent (99-80%)"
Orphanet records EEG abnormality as very frequent.
Tremor FREQUENT Tremor (HP:0001337)
Show evidence (1 reference)
ORPHA:2116 SUPPORT Other
"HP:0001337 | Tremor | Frequent (79-30%)"
Orphanet records tremor as frequent.
Psychosis OCCASIONAL Psychosis (HP:0000709)
Show evidence (2 references)
ORPHA:2116 SUPPORT Other
"HP:0000709 | Psychosis | Occasional (29-5%)"
Orphanet records psychosis as occasional.
PMID:15286787 SUPPORT Human Clinical
"ataxia and psychosis."
The SLC6A19 discovery paper lists psychosis among symptoms.
Seizure OCCASIONAL Seizure (HP:0001250)
Show evidence (1 reference)
ORPHA:2116 SUPPORT Other
"HP:0001250 | Seizure | Occasional (29-5%)"
Orphanet records seizures as occasional.
Other 5
Neutral hyperaminoaciduria VERY_FREQUENT Neutral hyperaminoaciduria (HP:0008353)
Show evidence (2 references)
ORPHA:2116 SUPPORT Other
"HP:0008353 | Neutral hyperaminoaciduria | Very frequent (99-80%)"
Orphanet records neutral hyperaminoaciduria as very frequent.
PMID:7955499 SUPPORT Human Clinical
"Chromatography of urinary amino acids was diagnostic of"
Urinary amino acid chromatography established the biochemical diagnosis in an adult case.
Emotional lability VERY_FREQUENT Emotional lability (HP:0000712)
Show evidence (1 reference)
ORPHA:2116 SUPPORT Other
"HP:0000712 | Emotional lability | Very frequent (99-80%)"
Orphanet records emotional lability as very frequent.
Abnormal urinary color VERY_FREQUENT Abnormal urinary color (HP:0012086)
Show evidence (1 reference)
ORPHA:2116 SUPPORT Other
"HP:0012086 | Abnormal urinary color | Very frequent (99-80%)"
Orphanet records abnormal urinary color as very frequent.
Elevated urinary indican level FREQUENT Elevated urinary indican level (HP:6000130)
Show evidence (1 reference)
ORPHA:2116 SUPPORT Other
"HP:6000130 | Elevated urinary indican level | Frequent (79-30%)"
Orphanet records elevated urinary indican level as frequent.
Abnormality of vision FREQUENT Abnormality of vision (HP:0000504)
Show evidence (1 reference)
ORPHA:2116 SUPPORT Other
"HP:0000504 | Abnormality of vision | Frequent (79-30%)"
Orphanet records abnormality of vision as frequent.
🧬

Genetic Associations

2
Hartnup disease gene associations (Causative biallelic pathogenic variants)
Autosomal recessive inheritance
Show evidence (3 references)
ORPHA:2116 SUPPORT Other
"SLC6A19 | solute carrier family 6 member 19 | hgnc:27960 | Disease-causing germline mutation(s) in"
Orphanet lists SLC6A19 as a disease-causing germline gene.
ORPHA:2116 SUPPORT Other
"CLTRN | collectrin, amino acid transport regulator | hgnc:29437 | Disease-causing germline mutation(s) in"
Orphanet also lists CLTRN as an amino acid transport regulator associated with Hartnup disease.
CGGV:assertion_44c34762-450b-4abd-8fe4-3f17ff700630-2020-05-07T160000.000Z SUPPORT Other
"SLC6A19 | HGNC:27960 | Hartnup disease | MONDO:0009324 | AR | Definitive"
ClinGen classifies the SLC6A19-Hartnup disease gene-disease relationship as definitive with autosomal recessive inheritance.
CLTRN disease association (Orphanet-listed disease-causing germline association; auxiliary amino acid transport regulator)
Show evidence (1 reference)
ORPHA:2116 SUPPORT Other
"CLTRN | collectrin, amino acid transport regulator | hgnc:29437 | Disease-causing germline mutation(s) in"
Orphanet lists CLTRN as a disease-causing germline gene for Hartnup disease.
💊

Treatments

4
Oral nicotinamide
Action: Pharmacotherapy NCIT:C15986
Agent: nicotinamide ↗
Oral nicotinamide can resolve pellagra-like symptoms in symptomatic patients by bypassing reduced tryptophan-derived nicotinamide availability.
Mechanism Target:
MODULATES Tryptophan and nicotinamide availability reduction — Nicotinamide supplies vitamin B3 activity downstream of impaired tryptophan uptake.
Show evidence (1 reference)
PMID:7955499 SUPPORT Human Clinical
"symptoms resolved with oral nicotinamide."
Adult pellagra symptoms resolved with oral nicotinamide.
Show evidence (1 reference)
PMID:7955499 SUPPORT Human Clinical
"symptoms resolved with oral nicotinamide."
Adult case report supports oral nicotinamide for symptomatic pellagra-like disease.
Tryptophan ethyl ester bypass therapy
Action: Pharmacotherapy NCIT:C15986
Tryptophan ethyl ester has been reported as an experimental strategy to bypass defective gastrointestinal neutral amino acid transport and normalize tryptophan availability.
Mechanism Target:
MODULATES Renal and intestinal neutral amino acid transport defect — The ester bypasses defective neutral amino acid transport in the gut.
Show evidence (1 reference)
PMID:2472426 SUPPORT Human Clinical
"bypass defective gastrointestinal neutral amino acid transport in a child with"
The study explicitly used tryptophan ethyl ester to bypass the intestinal transport defect.
Show evidence (1 reference)
PMID:2472426 SUPPORT Human Clinical
"tryptophan ethyl ester is effective at circumventing defective gastrointestinal"
The authors concluded tryptophan ethyl ester may be useful by circumventing defective transport.
Sunlight avoidance for photosensitivity
Action: sunlight avoidance MAXO:0000055
Avoidance of sunlight and photoprotection are supportive measures for the photosensitive pellagra-like skin component.
Target Phenotypes: Cutaneous photosensitivity ↗
Show evidence (1 reference)
ORPHA:2116 PARTIAL Other
"HP:0000992 | Cutaneous photosensitivity | Very frequent (99-80%)"
Orphanet supports the photosensitivity target for photoprotective care.
Genetic counseling
Action: genetic counseling MAXO:0000079
Genetic counseling is appropriate because Hartnup disease is inherited as an autosomal recessive disorder caused by germline variants.
Mechanism Target:
SLC6A19 B0AT1 transporter loss of function — Genetic counseling is anchored to the autosomal recessive SLC6A19 transport defect and supports recurrence-risk counseling; it does not directly alter metabolism.
Show evidence (1 reference)
PMID:15286787 SUPPORT Human Clinical
"Hartnup disorder, an autosomal recessive defect"
The SLC6A19 discovery paper supports autosomal recessive inheritance for counseling around the causal transport defect.
CLTRN amino acid transport regulator involvement — Genetic counseling also covers the Orphanet-listed CLTRN association when familial variants are identified.
Show evidence (1 reference)
ORPHA:2116 PARTIAL Other
"CLTRN | collectrin, amino acid transport regulator | hgnc:29437 | Disease-causing germline mutation(s) in"
Orphanet lists CLTRN as a disease-causing germline gene, supporting inclusion in counseling discussions.
Show evidence (1 reference)
ORPHA:2116 SUPPORT Other
"Autosomal recessive"
Autosomal recessive inheritance supports recurrence-risk counseling.
🔬

Biochemical Markers

3
Neutral hyperaminoaciduria (INCREASED)
Context: Urine amino acid analysis shows excessive excretion of neutral amino acids, reflecting failed renal proximal tubular reabsorption.
Pathograph Readouts
Readout Of Renal and intestinal neutral amino acid transport defect Positive Diagnostic
Excess urinary neutral amino acids report failed renal reabsorption through the Hartnup transport defect.
Show evidence (2 references)
ORPHA:2116 SUPPORT Other
"HP:0008353 | Neutral hyperaminoaciduria | Very frequent (99-80%)"
Orphanet supports neutral hyperaminoaciduria as the defining biochemical phenotype.
PMID:7955499 SUPPORT Human Clinical
"Chromatography of urinary amino acids was diagnostic of"
Urinary amino acid chromatography supported diagnosis in a clinical case.
Increased urinary indican (INCREASED)
Context: Elevated urinary indican is a frequent biochemical correlate of abnormal tryptophan handling in Hartnup disease.
Pathograph Readouts
Readout Of Renal and intestinal neutral amino acid transport defect Positive Diagnostic
Increased urinary indican reflects abnormal tryptophan handling downstream of the neutral amino acid transport defect.
Show evidence (1 reference)
ORPHA:2116 SUPPORT Other
"HP:6000130 | Elevated urinary indican level | Frequent (79-30%)"
Orphanet records elevated urinary indican level as frequent.
Low systemic tryptophan availability (DECREASED)
Context: Some symptomatic patients have reduced serum and CSF tryptophan, consistent with inadequate neutral amino acid absorption.
Pathograph Readouts
Readout Of Renal and intestinal neutral amino acid transport defect Negative Diagnostic
Low serum and CSF tryptophan reports the absorptive component of the neutral amino acid transport defect.
Readout Of Tryptophan and nicotinamide availability reduction Negative Monitoring
Low tryptophan availability reports reduced precursor supply for nicotinamide synthesis.
Show evidence (1 reference)
PMID:2472426 SUPPORT Human Clinical
"baseline tryptophan concentrations in serum"
The treatment study measured low baseline serum and CSF tryptophan.
{ }

Source YAML

click to show 
name: Hartnup Disease
category: Mendelian
creation_date: '2026-05-04T00:00:00Z'
updated_date: '2026-05-21T19:29:29Z'
synonyms:
- Hartnup disorder
- Aminoaciduria, Hartnup type
description: >
  Hartnup disease is an autosomal recessive neutral aminoaciduria caused mainly
  by biallelic loss-of-function variants in SLC6A19, which encodes the
  sodium-dependent neutral amino acid transporter B0AT1. Impaired B0AT1-mediated
  transport in renal proximal tubule and intestinal epithelial cells causes
  urinary loss and reduced gastrointestinal uptake of neutral amino acids,
  including tryptophan. Reduced tryptophan availability can limit endogenous
  nicotinamide synthesis, producing episodic pellagra-like photosensitive rash
  and neuropsychiatric manifestations such as ataxia, emotional lability,
  hallucinations, anxiety, hypotonia, and seizures. Most molecular evidence
  centers on SLC6A19/B0AT1, while Orphanet also lists CLTRN, an amino acid
  transport regulator, as a disease-associated gene.
disease_term:
  preferred_term: Hartnup disease
  term:
    id: MONDO:0009324
    label: Hartnup disease
parents:
- Renal aminoaciduria
- Inborn error of metabolism
inheritance:
- name: Autosomal recessive inheritance
  inheritance_term:
    preferred_term: autosomal recessive inheritance
    term:
      id: HP:0000007
      label: Autosomal recessive inheritance
  evidence:
  - reference: ORPHA:2116
    reference_title: "Hartnup disease (Orphanet structured-database record)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Autosomal recessive"
    explanation: Orphanet records autosomal recessive inheritance for Hartnup disease.
  - reference: PMID:15286787
    reference_title: "Mutations in SLC6A19, encoding B0AT1, cause Hartnup disorder."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Hartnup disorder, an autosomal recessive defect"
    explanation: The original-family SLC6A19 paper describes Hartnup disorder as autosomal recessive.
prevalence:
- population: Worldwide
  percentage: 1-9 per 100,000
  notes: >
    Orphanet reports worldwide point prevalence in the 1-9 per 100,000 range,
    with several country or population-specific estimates in the same class.
  evidence:
  - reference: ORPHA:2116
    reference_title: "Hartnup disease (Orphanet structured-database record)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "1-9 / 100 000 | Worldwide | Point prevalence"
    explanation: Orphanet provides the worldwide point-prevalence class.
progression:
- phase: Episodic all-age metabolic and neurocutaneous disorder
  notes: >
    Orphanet records all-age onset. Clinical expression is variable, with some
    patients presenting in childhood and occasional adult presentation during
    physiologic stress such as lactation and increased activity.
  evidence:
  - reference: ORPHA:2116
    reference_title: "Hartnup disease (Orphanet structured-database record)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Age of onset: All ages"
    explanation: Orphanet records all-age onset.
  - reference: PMID:15286788
    reference_title: "Hartnup disorder is caused by mutations in the gene encoding the neutral amino acid transporter SLC6A19."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "and gastrointestinal neutral amino acid transport noted for its clinical"
    explanation: The SLC6A19 discovery paper emphasizes clinical variability.
  - reference: PMID:7955499
    reference_title: "Hartnup disease presenting in an adult."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "A young woman presented with pellagra."
    explanation: Adult case report supports presentation outside childhood.
pathophysiology:
- name: SLC6A19 B0AT1 transporter loss of function
  description: >
    Pathogenic SLC6A19 variants impair the sodium-dependent neutral amino acid
    transporter B0AT1. The transporter is normally expressed in intestinal and
    renal epithelial cells, where it mediates uptake or reabsorption of neutral
    amino acids.
  genes:
  - preferred_term: SLC6A19
    term:
      id: hgnc:27960
      label: SLC6A19
  molecular_functions:
  - preferred_term: neutral L-amino acid transmembrane transporter activity
    term:
      id: GO:0015175
      label: neutral L-amino acid transmembrane transporter activity
    modifier: DECREASED
  - preferred_term: amino acid:sodium symporter activity
    term:
      id: GO:0005283
      label: amino acid:sodium symporter activity
    modifier: DECREASED
  biological_processes:
  - preferred_term: neutral amino acid transport
    term:
      id: GO:0015804
      label: neutral amino acid transport
    modifier: DECREASED
  - preferred_term: tryptophan transport
    term:
      id: GO:0015827
      label: tryptophan transport
    modifier: DECREASED
  cell_types:
  - preferred_term: epithelial cell of proximal tubule
    term:
      id: CL:0002306
      label: epithelial cell of proximal tubule
  - preferred_term: intestinal epithelial cell
    term:
      id: CL:0002563
      label: intestinal epithelial cell
  locations:
  - preferred_term: proximal tubule
    term:
      id: UBERON:0004134
      label: proximal tubule
  - preferred_term: intestinal mucosa
    term:
      id: UBERON:0001242
      label: intestinal mucosa
  evidence:
  - reference: PMID:15286787
    reference_title: "Mutations in SLC6A19, encoding B0AT1, cause Hartnup disorder."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "then identified mutations in SLC6A19 in members of the original family in whom"
    explanation: The original-family study identified SLC6A19 mutations in affected families.
  - reference: PMID:15286788
    reference_title: "Hartnup disorder is caused by mutations in the gene encoding the neutral amino acid transporter SLC6A19."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "reduced neutral amino acid transport"
    explanation: Functional testing showed reduced neutral amino acid transport for disease-causing SLC6A19 variants.
  - reference: PMID:16052352
    reference_title: "The molecular basis of neutral aminoacidurias."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "caused by mutations in the neutral amino acid transporter B(0) AT1 (SLC6A19)."
    explanation: Review evidence identifies B0AT1/SLC6A19 mutation as the molecular basis of Hartnup disorder.
  - reference: PMID:19472175
    reference_title: "The role of the neutral amino acid transporter B0AT1 (SLC6A19) in Hartnup disorder and protein nutrition."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "The disorder is caused by mutations in the neutral amino acid transporter B(0)AT1 (SLC6A19)."
    explanation: This Hartnup-specific review independently supports SLC6A19/B0AT1 transporter mutation as the disease-defining molecular mechanism.
  downstream:
  - target: Renal and intestinal neutral amino acid transport defect
    description: Reduced B0AT1 activity impairs reabsorption and absorption of neutral amino acids in kidney and intestine.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:15286788
      reference_title: "Hartnup disorder is caused by mutations in the gene encoding the neutral amino acid transporter SLC6A19."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "reduced neutral amino acid transport"
      explanation: Functional testing links SLC6A19/B0AT1 variants to reduced neutral amino acid transport.
  - target: B0AT1 endoplasmic-reticulum retention
    description: Some disease-causing variants impair trafficking of B0AT1 to the plasma membrane.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:40852587
      reference_title: "Hartnup disease-causing SLC6A19 mutations lead to B0AT1 aberrant trafficking and ACE2 mis-localisation implicating the endoplasmic reticulum protein quality control."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "were found to be retained in the endoplasmic reticulum"
      explanation: The trafficking study directly supports ER retention of Hartnup-associated B0AT1 variants.
- name: CLTRN amino acid transport regulator involvement
  description: >
    CLTRN encodes collectrin, an amino-acid transport regulator listed by Orphanet
    as a disease-causing gene for Hartnup disease. The available cached evidence
    supports a gene association, while the better-supported disease-defining
    transporter mechanism remains SLC6A19/B0AT1.
  genes:
  - preferred_term: CLTRN
    term:
      id: hgnc:29437
      label: CLTRN
  biological_processes:
  - preferred_term: amino acid transmembrane transport
    term:
      id: GO:0003333
      label: amino acid transmembrane transport
    modifier: ABNORMAL
  evidence:
  - reference: ORPHA:2116
    reference_title: "Hartnup disease (Orphanet structured-database record)"
    supports: PARTIAL
    evidence_source: OTHER
    snippet: "CLTRN | collectrin, amino acid transport regulator | hgnc:29437 | Disease-causing germline mutation(s) in"
    explanation: Orphanet lists CLTRN as a disease-causing germline amino acid transport regulator for Hartnup disease.
  - reference: PMID:19472175
    reference_title: "The role of the neutral amino acid transporter B0AT1 (SLC6A19) in Hartnup disorder and protein nutrition."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "SLC6A19 requires either collectrin or angiotensin-converting enzyme 2 for surface expression in the kidney and intestine, respectively."
    explanation: The Hartnup-specific review supports collectrin as a regulator of SLC6A19/B0AT1 surface expression in kidney, consistent with CLTRN convergence on the epithelial amino-acid transport defect.
  downstream:
  - target: Renal and intestinal neutral amino acid transport defect
    description: CLTRN is modeled as an auxiliary amino-acid transport regulator that converges on the epithelial neutral amino acid transport phenotype.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - collectrin-dependent SLC6A19/B0AT1 surface expression in kidney epithelium
    evidence:
    - reference: ORPHA:2116
      reference_title: "Hartnup disease (Orphanet structured-database record)"
      supports: PARTIAL
      evidence_source: OTHER
      snippet: "CLTRN | collectrin, amino acid transport regulator | hgnc:29437 | Disease-causing germline mutation(s) in"
      explanation: The structured source supports CLTRN as an amino acid transport regulator, but stronger mechanistic evidence in this entry remains SLC6A19-centered.
    - reference: PMID:19472175
      reference_title: "The role of the neutral amino acid transporter B0AT1 (SLC6A19) in Hartnup disorder and protein nutrition."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "SLC6A19 requires either collectrin or angiotensin-converting enzyme 2 for surface expression in the kidney and intestine, respectively."
      explanation: Collectrin-dependent SLC6A19 surface expression supports the modeled edge from CLTRN involvement to defective renal and intestinal neutral amino acid transport.
- name: B0AT1 endoplasmic-reticulum retention
  description: >
    Several Hartnup disease-causing B0AT1 variants are retained in the
    endoplasmic reticulum rather than reaching the plasma membrane, providing a
    variant-level mechanism for loss of transporter function.
  genes:
  - preferred_term: SLC6A19
    term:
      id: hgnc:27960
      label: SLC6A19
  locations:
  - preferred_term: endoplasmic reticulum
    term:
      id: GO:0005783
      label: endoplasmic reticulum
    modifier: INCREASED
  - preferred_term: plasma membrane
    term:
      id: GO:0005886
      label: plasma membrane
    modifier: DECREASED
  evidence:
  - reference: PMID:40852587
    reference_title: "Hartnup disease-causing SLC6A19 mutations lead to B0AT1 aberrant trafficking and ACE2 mis-localisation implicating the endoplasmic reticulum protein quality control."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "were found to be retained in the endoplasmic reticulum"
    explanation: Functional cell studies showed ER retention of multiple Hartnup-associated B0AT1 variants.
  - reference: PMID:40852587
    reference_title: "Hartnup disease-causing SLC6A19 mutations lead to B0AT1 aberrant trafficking and ACE2 mis-localisation implicating the endoplasmic reticulum protein quality control."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "by impairing amino acid transport and may influence ACE2-mediated physiological"
    explanation: The trafficking study supports ER-retained B0AT1 variants as pathogenic because they impair amino acid transport and may disrupt ACE2-related physiology.
  downstream:
  - target: Renal and intestinal neutral amino acid transport defect
    description: ER retention reduces delivery of functional B0AT1 to the epithelial cell surface.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:40852587
      reference_title: "Hartnup disease-causing SLC6A19 mutations lead to B0AT1 aberrant trafficking and ACE2 mis-localisation implicating the endoplasmic reticulum protein quality control."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "by impairing amino acid transport and may influence ACE2-mediated physiological"
      explanation: ER-retained B0AT1 variants impair amino acid transport, supporting the edge to the epithelial transport defect.
- name: Renal and intestinal neutral amino acid transport defect
  description: >
    Defective B0AT1-mediated transport causes impaired renal reabsorption and
    gastrointestinal absorption of neutral amino acids. The resulting biochemical
    signature is neutral hyperaminoaciduria, often including elevated urinary
    indican from unabsorbed tryptophan metabolism.
  biological_processes:
  - preferred_term: amino acid transmembrane transport
    term:
      id: GO:0003333
      label: amino acid transmembrane transport
    modifier: DECREASED
  - preferred_term: neutral amino acid transport
    term:
      id: GO:0015804
      label: neutral amino acid transport
    modifier: DECREASED
  - preferred_term: tryptophan transport
    term:
      id: GO:0015827
      label: tryptophan transport
    modifier: DECREASED
  chemical_entities:
  - preferred_term: L-tryptophan
    term:
      id: CHEBI:57912
      label: L-tryptophan zwitterion
    modifier: DECREASED
  - preferred_term: indican
    term:
      id: CHEBI:16700
      label: indican
    modifier: INCREASED
  evidence:
  - reference: PMID:15286787
    reference_title: "Mutations in SLC6A19, encoding B0AT1, cause Hartnup disorder."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "results from impaired transport of neutral amino"
    explanation: The SLC6A19 discovery paper states the epithelial neutral amino acid transport defect.
  - reference: PMID:16052352
    reference_title: "The molecular basis of neutral aminoacidurias."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "resorption of all neutral amino acids."
    explanation: Review evidence places B0AT1 in renal and intestinal neutral amino acid resorption.
  - reference: ORPHA:2116
    reference_title: "Hartnup disease (Orphanet structured-database record)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "abnormal renal and gastrointestinal transport of neutral amino acids"
    explanation: Orphanet's definition describes the renal and gastrointestinal transport defect.
  downstream:
  - target: Neutral hyperaminoaciduria
    description: Failed renal reabsorption produces excessive urinary neutral amino acids.
    causal_link_type: DIRECT
    evidence:
    - reference: ORPHA:2116
      reference_title: "Hartnup disease (Orphanet structured-database record)"
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "HP:0008353 | Neutral hyperaminoaciduria | Very frequent (99-80%)"
      explanation: Orphanet records neutral hyperaminoaciduria as the common biochemical phenotype of the transport defect.
  - target: Malabsorption
    description: Impaired intestinal neutral amino acid transport contributes to reduced nutrient absorption.
    causal_link_type: DIRECT
    evidence:
    - reference: ORPHA:2116
      reference_title: "Hartnup disease (Orphanet structured-database record)"
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "HP:0002024 | Malabsorption | Frequent (79-30%)"
      explanation: Orphanet records malabsorption as a frequent phenotype of Hartnup disease.
  - target: Tryptophan and nicotinamide availability reduction
    description: Reduced intestinal tryptophan absorption can limit niacin/nicotinamide availability.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - reduced intestinal tryptophan absorption and reduced niacin precursor supply
    evidence:
    - reference: PMID:2472426
      reference_title: "Circumvention of defective neutral amino acid transport in Hartnup disease using tryptophan ethyl ester."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "baseline tryptophan concentrations in serum"
      explanation: Low baseline serum tryptophan supports reduced systemic tryptophan availability downstream of the transport defect.
  - target: Low systemic tryptophan availability
    description: Impaired intestinal neutral amino acid transport can reduce systemic and CSF tryptophan availability.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:2472426
      reference_title: "Circumvention of defective neutral amino acid transport in Hartnup disease using tryptophan ethyl ester."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "baseline tryptophan concentrations in serum"
      explanation: A symptomatic child had low baseline serum and CSF tryptophan before transport-bypass therapy.
  - target: Increased urinary indican
    description: Abnormal tryptophan transport and handling is reflected by elevated urinary indican.
    causal_link_type: DIRECT
    evidence:
    - reference: ORPHA:2116
      reference_title: "Hartnup disease (Orphanet structured-database record)"
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "HP:6000130 | Elevated urinary indican level | Frequent (79-30%)"
      explanation: Orphanet records elevated urinary indican as a frequent biochemical phenotype.
  - target: Elevated urinary indican level
    description: Elevated urinary indican is the phenotype-level expression of abnormal tryptophan handling.
    causal_link_type: DIRECT
    evidence:
    - reference: ORPHA:2116
      reference_title: "Hartnup disease (Orphanet structured-database record)"
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "HP:6000130 | Elevated urinary indican level | Frequent (79-30%)"
      explanation: Orphanet records elevated urinary indican as frequent.
  - target: Abnormal urinary color
    description: Abnormal urinary color is grouped with abnormal urinary amino-acid and tryptophan-derived metabolites.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: ORPHA:2116
      reference_title: "Hartnup disease (Orphanet structured-database record)"
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "HP:0012086 | Abnormal urinary color | Very frequent (99-80%)"
      explanation: Orphanet records abnormal urinary color as very frequent.
- name: Tryptophan and nicotinamide availability reduction
  description: >
    Tryptophan is a neutral amino acid and a precursor for nicotinamide
    synthesis. Reduced tryptophan uptake can produce a functional pellagra-like
    state even when dietary niacin intake is adequate.
  chemical_entities:
  - preferred_term: L-tryptophan
    term:
      id: CHEBI:57912
      label: L-tryptophan zwitterion
    modifier: DECREASED
  - preferred_term: nicotinamide
    term:
      id: CHEBI:17154
      label: nicotinamide
    modifier: DECREASED
  biological_processes:
  - preferred_term: L-tryptophan metabolic process
    term:
      id: GO:0006568
      label: L-tryptophan metabolic process
    modifier: DECREASED
  - preferred_term: nicotinamide metabolic process
    term:
      id: GO:0006769
      label: nicotinamide metabolic process
    modifier: DECREASED
  evidence:
  - reference: PMID:2472426
    reference_title: "Circumvention of defective neutral amino acid transport in Hartnup disease using tryptophan ethyl ester."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "6 microM) and cerebrospinal fluid (1.0 +/- 0.2 microM) were persistently less"
    explanation: The treatment case documented low serum and CSF tryptophan before bypass therapy.
  - reference: PMID:7955499
    reference_title: "Hartnup disease presenting in an adult."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "prolonged lactation and increased activity. Dietary intake of niacin was within"
    explanation: Pellagra developed despite adequate niacin intake, consistent with Hartnup-related precursor limitation.
  downstream:
  - target: Pellagra-like neurocutaneous manifestations
    description: Functional niacin/nicotinamide deficiency can drive photosensitive rash and neurologic or psychiatric features.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - functional niacin or nicotinamide deficiency from reduced tryptophan precursor supply
    evidence:
    - reference: PMID:7955499
      reference_title: "Hartnup disease presenting in an adult."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "A young woman presented with pellagra."
      explanation: The adult case links Hartnup disease to pellagra-like manifestations.
- name: Pellagra-like neurocutaneous manifestations
  description: >
    In susceptible patients, the transport defect manifests as photosensitive
    pellagra-like dermatitis together with neurologic and psychiatric signs such
    as ataxia, tremor, hypotonia, emotional lability, hallucinations, anxiety,
    and psychosis.
  evidence:
  - reference: PMID:15286787
    reference_title: "Mutations in SLC6A19, encoding B0AT1, cause Hartnup disorder."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Symptoms include transient manifestations of pellagra (rashes), cerebellar"
    explanation: The SLC6A19 discovery paper summarizes the pellagra-like and cerebellar clinical expression.
  - reference: ORPHA:2116
    reference_title: "Hartnup disease (Orphanet structured-database record)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "mainly characterized by skin photosensitivity, ocular and neuropsychiatric features"
    explanation: Orphanet describes the major neurocutaneous and ocular disease manifestations.
  downstream:
  - target: Cutaneous photosensitivity
    description: Pellagra-like skin disease includes photosensitivity.
    causal_link_type: DIRECT
    evidence:
    - reference: ORPHA:2116
      reference_title: "Hartnup disease (Orphanet structured-database record)"
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "mainly characterized by skin photosensitivity, ocular and neuropsychiatric features"
      explanation: Orphanet identifies skin photosensitivity as a core Hartnup disease manifestation.
  - target: Ataxia
    description: Cerebellar manifestations include ataxia.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:15286787
      reference_title: "Mutations in SLC6A19, encoding B0AT1, cause Hartnup disorder."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "ataxia and psychosis."
      explanation: The SLC6A19 discovery paper lists ataxia among Hartnup disease symptoms.
  - target: Psychosis
    description: Neuropsychiatric manifestations can include psychosis.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:15286787
      reference_title: "Mutations in SLC6A19, encoding B0AT1, cause Hartnup disorder."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "ataxia and psychosis."
      explanation: The SLC6A19 discovery paper lists psychosis among Hartnup disease symptoms.
  - target: Skin rash
    description: Pellagra-like dermatitis includes rash.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:15286787
      reference_title: "Mutations in SLC6A19, encoding B0AT1, cause Hartnup disorder."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "pellagra (rashes), cerebellar"
      explanation: The SLC6A19 discovery paper includes pellagra-like rashes among Hartnup symptoms.
  - target: Emotional lability
    description: Emotional lability is grouped with Hartnup neuropsychiatric manifestations.
    causal_link_type: DIRECT
    evidence:
    - reference: ORPHA:2116
      reference_title: "Hartnup disease (Orphanet structured-database record)"
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "HP:0000712 | Emotional lability | Very frequent (99-80%)"
      explanation: Orphanet records emotional lability as very frequent.
  - target: Hallucinations
    description: Hallucinations are grouped with Hartnup neuropsychiatric manifestations.
    causal_link_type: DIRECT
    evidence:
    - reference: ORPHA:2116
      reference_title: "Hartnup disease (Orphanet structured-database record)"
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "HP:0000738 | Hallucinations | Very frequent (99-80%)"
      explanation: Orphanet records hallucinations as very frequent.
  - target: Anxiety
    description: Anxiety is grouped with Hartnup neuropsychiatric manifestations.
    causal_link_type: DIRECT
    evidence:
    - reference: ORPHA:2116
      reference_title: "Hartnup disease (Orphanet structured-database record)"
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "HP:0000739 | Anxiety | Very frequent (99-80%)"
      explanation: Orphanet records anxiety as very frequent.
  - target: Hypotonia
    description: Hypotonia is grouped with Hartnup neurologic manifestations.
    causal_link_type: DIRECT
    evidence:
    - reference: ORPHA:2116
      reference_title: "Hartnup disease (Orphanet structured-database record)"
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "HP:0001252 | Hypotonia | Very frequent (99-80%)"
      explanation: Orphanet records hypotonia as very frequent.
  - target: Hyperreflexia
    description: Hyperreflexia is grouped with Hartnup neurologic manifestations.
    causal_link_type: DIRECT
    evidence:
    - reference: ORPHA:2116
      reference_title: "Hartnup disease (Orphanet structured-database record)"
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "HP:0001347 | Hyperreflexia | Very frequent (99-80%)"
      explanation: Orphanet records hyperreflexia as very frequent.
  - target: Tremor
    description: Tremor is grouped with Hartnup neurologic manifestations.
    causal_link_type: DIRECT
    evidence:
    - reference: ORPHA:2116
      reference_title: "Hartnup disease (Orphanet structured-database record)"
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "HP:0001337 | Tremor | Frequent (79-30%)"
      explanation: Orphanet records tremor as frequent.
  - target: Migraine
    description: Migraine is grouped with Hartnup neurologic manifestations.
    causal_link_type: DIRECT
    evidence:
    - reference: ORPHA:2116
      reference_title: "Hartnup disease (Orphanet structured-database record)"
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "HP:0002076 | Migraine | Very frequent (99-80%)"
      explanation: Orphanet records migraine as very frequent.
  - target: EEG abnormality
    description: EEG abnormality is grouped with Hartnup neurologic manifestations.
    causal_link_type: DIRECT
    evidence:
    - reference: ORPHA:2116
      reference_title: "Hartnup disease (Orphanet structured-database record)"
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "HP:0002353 | EEG abnormality | Very frequent (99-80%)"
      explanation: Orphanet records EEG abnormality as very frequent.
  - target: Seizure
    description: Seizures are grouped with occasional Hartnup neurologic manifestations.
    causal_link_type: DIRECT
    evidence:
    - reference: ORPHA:2116
      reference_title: "Hartnup disease (Orphanet structured-database record)"
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "HP:0001250 | Seizure | Occasional (29-5%)"
      explanation: Orphanet records seizures as occasional.
  - target: Photophobia
    description: Photophobia is grouped with Hartnup ocular features.
    causal_link_type: DIRECT
    evidence:
    - reference: ORPHA:2116
      reference_title: "Hartnup disease (Orphanet structured-database record)"
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "HP:0000613 | Photophobia | Frequent (79-30%)"
      explanation: Orphanet records photophobia as frequent.
  - target: Nystagmus
    description: Nystagmus is grouped with Hartnup ocular-neurologic features.
    causal_link_type: DIRECT
    evidence:
    - reference: ORPHA:2116
      reference_title: "Hartnup disease (Orphanet structured-database record)"
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "HP:0000639 | Nystagmus | Frequent (79-30%)"
      explanation: Orphanet records nystagmus as frequent.
  - target: Strabismus
    description: Strabismus is grouped with Hartnup ocular features.
    causal_link_type: DIRECT
    evidence:
    - reference: ORPHA:2116
      reference_title: "Hartnup disease (Orphanet structured-database record)"
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "HP:0000486 | Strabismus | Frequent (79-30%)"
      explanation: Orphanet records strabismus as frequent.
  - target: Abnormality of vision
    description: Visual abnormality is grouped with Hartnup ocular features.
    causal_link_type: DIRECT
    evidence:
    - reference: ORPHA:2116
      reference_title: "Hartnup disease (Orphanet structured-database record)"
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "HP:0000504 | Abnormality of vision | Frequent (79-30%)"
      explanation: Orphanet records abnormality of vision as frequent.
phenotypes:
- name: Neutral hyperaminoaciduria
  frequency: VERY_FREQUENT
  description: >
    Neutral hyperaminoaciduria is the core biochemical phenotype caused by
    impaired renal reabsorption of neutral amino acids.
  phenotype_term:
    preferred_term: Neutral hyperaminoaciduria
    term:
      id: HP:0008353
      label: Neutral hyperaminoaciduria
  evidence:
  - reference: ORPHA:2116
    reference_title: "Hartnup disease (Orphanet structured-database record)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0008353 | Neutral hyperaminoaciduria | Very frequent (99-80%)"
    explanation: Orphanet records neutral hyperaminoaciduria as very frequent.
  - reference: PMID:7955499
    reference_title: "Hartnup disease presenting in an adult."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Chromatography of urinary amino acids was diagnostic of"
    explanation: Urinary amino acid chromatography established the biochemical diagnosis in an adult case.
- name: Cutaneous photosensitivity
  frequency: VERY_FREQUENT
  description: Photosensitive skin disease reflects the pellagra-like manifestation of Hartnup disease.
  phenotype_term:
    preferred_term: Cutaneous photosensitivity
    term:
      id: HP:0000992
      label: Cutaneous photosensitivity
  evidence:
  - reference: ORPHA:2116
    reference_title: "Hartnup disease (Orphanet structured-database record)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0000992 | Cutaneous photosensitivity | Very frequent (99-80%)"
    explanation: Orphanet records cutaneous photosensitivity as very frequent.
  - reference: PMID:7955499
    reference_title: "Hartnup disease presenting in an adult."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "A young woman presented with pellagra."
    explanation: Adult case report documents a pellagra presentation.
- name: Ataxia
  frequency: VERY_FREQUENT
  description: Ataxia is a very frequent neurologic manifestation.
  phenotype_term:
    preferred_term: Ataxia
    term:
      id: HP:0001251
      label: Ataxia
  evidence:
  - reference: ORPHA:2116
    reference_title: "Hartnup disease (Orphanet structured-database record)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0001251 | Ataxia | Very frequent (99-80%)"
    explanation: Orphanet records ataxia as very frequent.
  - reference: PMID:15286787
    reference_title: "Mutations in SLC6A19, encoding B0AT1, cause Hartnup disorder."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "ataxia and psychosis."
    explanation: The SLC6A19 discovery paper lists ataxia and psychosis among symptoms.
- name: Emotional lability
  frequency: VERY_FREQUENT
  description: Emotional lability is included in Orphanet's very frequent neuropsychiatric phenotype set.
  phenotype_term:
    preferred_term: Emotional lability
    term:
      id: HP:0000712
      label: Emotional lability
  evidence:
  - reference: ORPHA:2116
    reference_title: "Hartnup disease (Orphanet structured-database record)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0000712 | Emotional lability | Very frequent (99-80%)"
    explanation: Orphanet records emotional lability as very frequent.
- name: Hallucinations
  frequency: VERY_FREQUENT
  description: Hallucinations are included in Orphanet's very frequent neuropsychiatric phenotype set.
  phenotype_term:
    preferred_term: Hallucinations
    term:
      id: HP:0000738
      label: Hallucinations
  evidence:
  - reference: ORPHA:2116
    reference_title: "Hartnup disease (Orphanet structured-database record)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0000738 | Hallucinations | Very frequent (99-80%)"
    explanation: Orphanet records hallucinations as very frequent.
- name: Anxiety
  frequency: VERY_FREQUENT
  description: Anxiety is included in Orphanet's very frequent neuropsychiatric phenotype set.
  phenotype_term:
    preferred_term: Anxiety
    term:
      id: HP:0000739
      label: Anxiety
  evidence:
  - reference: ORPHA:2116
    reference_title: "Hartnup disease (Orphanet structured-database record)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0000739 | Anxiety | Very frequent (99-80%)"
    explanation: Orphanet records anxiety as very frequent.
- name: Hypotonia
  frequency: VERY_FREQUENT
  description: Hypotonia is a very frequent neurologic manifestation in Orphanet.
  phenotype_term:
    preferred_term: Hypotonia
    term:
      id: HP:0001252
      label: Hypotonia
  evidence:
  - reference: ORPHA:2116
    reference_title: "Hartnup disease (Orphanet structured-database record)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0001252 | Hypotonia | Very frequent (99-80%)"
    explanation: Orphanet records hypotonia as very frequent.
- name: Hyperreflexia
  frequency: VERY_FREQUENT
  description: Hyperreflexia is a very frequent neurologic sign in Orphanet.
  phenotype_term:
    preferred_term: Hyperreflexia
    term:
      id: HP:0001347
      label: Hyperreflexia
  evidence:
  - reference: ORPHA:2116
    reference_title: "Hartnup disease (Orphanet structured-database record)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0001347 | Hyperreflexia | Very frequent (99-80%)"
    explanation: Orphanet records hyperreflexia as very frequent.
- name: Migraine
  frequency: VERY_FREQUENT
  description: Migraine is recorded as very frequent in Orphanet's phenotype table.
  phenotype_term:
    preferred_term: Migraine
    term:
      id: HP:0002076
      label: Migraine
  evidence:
  - reference: ORPHA:2116
    reference_title: "Hartnup disease (Orphanet structured-database record)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0002076 | Migraine | Very frequent (99-80%)"
    explanation: Orphanet records migraine as very frequent.
- name: EEG abnormality
  frequency: VERY_FREQUENT
  description: EEG abnormality is recorded as very frequent in Orphanet's phenotype table.
  phenotype_term:
    preferred_term: EEG abnormality
    term:
      id: HP:0002353
      label: EEG abnormality
  evidence:
  - reference: ORPHA:2116
    reference_title: "Hartnup disease (Orphanet structured-database record)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0002353 | EEG abnormality | Very frequent (99-80%)"
    explanation: Orphanet records EEG abnormality as very frequent.
- name: Abnormal urinary color
  frequency: VERY_FREQUENT
  description: Abnormal urinary color is recorded as very frequent and is consistent with abnormal urinary amino acid metabolites.
  phenotype_term:
    preferred_term: Abnormal urinary color
    term:
      id: HP:0012086
      label: Abnormal urinary color
  evidence:
  - reference: ORPHA:2116
    reference_title: "Hartnup disease (Orphanet structured-database record)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0012086 | Abnormal urinary color | Very frequent (99-80%)"
    explanation: Orphanet records abnormal urinary color as very frequent.
- name: Elevated urinary indican level
  frequency: FREQUENT
  description: Elevated urinary indican reflects altered tryptophan handling and intestinal metabolism.
  phenotype_term:
    preferred_term: Elevated urinary indican level
    term:
      id: HP:6000130
      label: Elevated urinary indican level
  evidence:
  - reference: ORPHA:2116
    reference_title: "Hartnup disease (Orphanet structured-database record)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:6000130 | Elevated urinary indican level | Frequent (79-30%)"
    explanation: Orphanet records elevated urinary indican level as frequent.
- name: Malabsorption
  frequency: FREQUENT
  description: Malabsorption reflects impaired gastrointestinal neutral amino acid transport.
  phenotype_term:
    preferred_term: Malabsorption
    term:
      id: HP:0002024
      label: Malabsorption
  evidence:
  - reference: ORPHA:2116
    reference_title: "Hartnup disease (Orphanet structured-database record)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0002024 | Malabsorption | Frequent (79-30%)"
    explanation: Orphanet records malabsorption as frequent.
- name: Skin rash
  frequency: FREQUENT
  description: Skin rash is part of the pellagra-like photosensitive phenotype.
  phenotype_term:
    preferred_term: Skin rash
    term:
      id: HP:0000988
      label: Skin rash
  evidence:
  - reference: ORPHA:2116
    reference_title: "Hartnup disease (Orphanet structured-database record)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0000988 | Skin rash | Frequent (79-30%)"
    explanation: Orphanet records skin rash as frequent.
  - reference: PMID:15286787
    reference_title: "Mutations in SLC6A19, encoding B0AT1, cause Hartnup disorder."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "pellagra (rashes), cerebellar"
    explanation: The SLC6A19 discovery paper lists pellagra-like rashes.
- name: Photophobia
  frequency: FREQUENT
  description: Photophobia is part of the ocular phenotype set recorded by Orphanet.
  phenotype_term:
    preferred_term: Photophobia
    term:
      id: HP:0000613
      label: Photophobia
  evidence:
  - reference: ORPHA:2116
    reference_title: "Hartnup disease (Orphanet structured-database record)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0000613 | Photophobia | Frequent (79-30%)"
    explanation: Orphanet records photophobia as frequent.
- name: Nystagmus
  frequency: FREQUENT
  description: Nystagmus is an ocular neurologic manifestation in Orphanet.
  phenotype_term:
    preferred_term: Nystagmus
    term:
      id: HP:0000639
      label: Nystagmus
  evidence:
  - reference: ORPHA:2116
    reference_title: "Hartnup disease (Orphanet structured-database record)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0000639 | Nystagmus | Frequent (79-30%)"
    explanation: Orphanet records nystagmus as frequent.
- name: Strabismus
  frequency: FREQUENT
  description: Strabismus is part of the frequent ocular phenotype set recorded by Orphanet.
  phenotype_term:
    preferred_term: Strabismus
    term:
      id: HP:0000486
      label: Strabismus
  evidence:
  - reference: ORPHA:2116
    reference_title: "Hartnup disease (Orphanet structured-database record)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0000486 | Strabismus | Frequent (79-30%)"
    explanation: Orphanet records strabismus as frequent.
- name: Abnormality of vision
  frequency: FREQUENT
  description: Abnormality of vision is part of the frequent ocular phenotype set recorded by Orphanet.
  phenotype_term:
    preferred_term: Abnormality of vision
    term:
      id: HP:0000504
      label: Abnormality of vision
  evidence:
  - reference: ORPHA:2116
    reference_title: "Hartnup disease (Orphanet structured-database record)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0000504 | Abnormality of vision | Frequent (79-30%)"
    explanation: Orphanet records abnormality of vision as frequent.
- name: Tremor
  frequency: FREQUENT
  description: Tremor is a frequent neurologic manifestation recorded by Orphanet.
  phenotype_term:
    preferred_term: Tremor
    term:
      id: HP:0001337
      label: Tremor
  evidence:
  - reference: ORPHA:2116
    reference_title: "Hartnup disease (Orphanet structured-database record)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0001337 | Tremor | Frequent (79-30%)"
    explanation: Orphanet records tremor as frequent.
- name: Psychosis
  frequency: OCCASIONAL
  description: Psychosis is an occasional neuropsychiatric manifestation.
  phenotype_term:
    preferred_term: Psychosis
    term:
      id: HP:0000709
      label: Psychosis
  evidence:
  - reference: ORPHA:2116
    reference_title: "Hartnup disease (Orphanet structured-database record)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0000709 | Psychosis | Occasional (29-5%)"
    explanation: Orphanet records psychosis as occasional.
  - reference: PMID:15286787
    reference_title: "Mutations in SLC6A19, encoding B0AT1, cause Hartnup disorder."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "ataxia and psychosis."
    explanation: The SLC6A19 discovery paper lists psychosis among symptoms.
- name: Seizure
  frequency: OCCASIONAL
  description: Seizures are occasional neurologic manifestations.
  phenotype_term:
    preferred_term: Seizure
    term:
      id: HP:0001250
      label: Seizure
  evidence:
  - reference: ORPHA:2116
    reference_title: "Hartnup disease (Orphanet structured-database record)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0001250 | Seizure | Occasional (29-5%)"
    explanation: Orphanet records seizures as occasional.
biochemical:
- name: Neutral hyperaminoaciduria
  presence: INCREASED
  context: >
    Urine amino acid analysis shows excessive excretion of neutral amino acids,
    reflecting failed renal proximal tubular reabsorption.
  readouts:
  - target: Renal and intestinal neutral amino acid transport defect
    relationship: READOUT_OF
    direction: POSITIVE
    endpoint_context: DIAGNOSTIC
    interpretation: Excess urinary neutral amino acids report failed renal reabsorption through the Hartnup transport defect.
  evidence:
  - reference: ORPHA:2116
    reference_title: "Hartnup disease (Orphanet structured-database record)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0008353 | Neutral hyperaminoaciduria | Very frequent (99-80%)"
    explanation: Orphanet supports neutral hyperaminoaciduria as the defining biochemical phenotype.
  - reference: PMID:7955499
    reference_title: "Hartnup disease presenting in an adult."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Chromatography of urinary amino acids was diagnostic of"
    explanation: Urinary amino acid chromatography supported diagnosis in a clinical case.
- name: Increased urinary indican
  presence: INCREASED
  context: >
    Elevated urinary indican is a frequent biochemical correlate of abnormal
    tryptophan handling in Hartnup disease.
  biomarker_term:
    preferred_term: indican
    term:
      id: CHEBI:16700
      label: indican
  readouts:
  - target: Renal and intestinal neutral amino acid transport defect
    relationship: READOUT_OF
    direction: POSITIVE
    endpoint_context: DIAGNOSTIC
    interpretation: Increased urinary indican reflects abnormal tryptophan handling downstream of the neutral amino acid transport defect.
  evidence:
  - reference: ORPHA:2116
    reference_title: "Hartnup disease (Orphanet structured-database record)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:6000130 | Elevated urinary indican level | Frequent (79-30%)"
    explanation: Orphanet records elevated urinary indican level as frequent.
- name: Low systemic tryptophan availability
  presence: DECREASED
  context: >
    Some symptomatic patients have reduced serum and CSF tryptophan, consistent
    with inadequate neutral amino acid absorption.
  biomarker_term:
    preferred_term: L-tryptophan
    term:
      id: CHEBI:57912
      label: L-tryptophan zwitterion
  readouts:
  - target: Renal and intestinal neutral amino acid transport defect
    relationship: READOUT_OF
    direction: NEGATIVE
    endpoint_context: DIAGNOSTIC
    interpretation: Low serum and CSF tryptophan reports the absorptive component of the neutral amino acid transport defect.
  - target: Tryptophan and nicotinamide availability reduction
    relationship: READOUT_OF
    direction: NEGATIVE
    endpoint_context: MONITORING
    interpretation: Low tryptophan availability reports reduced precursor supply for nicotinamide synthesis.
  evidence:
  - reference: PMID:2472426
    reference_title: "Circumvention of defective neutral amino acid transport in Hartnup disease using tryptophan ethyl ester."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "baseline tryptophan concentrations in serum"
    explanation: The treatment study measured low baseline serum and CSF tryptophan.
genetic:
- name: Hartnup disease gene associations
  gene_term:
    preferred_term: SLC6A19
    term:
      id: hgnc:27960
      label: SLC6A19
  association: Causative biallelic pathogenic variants
  relationship_type: CAUSATIVE
  variant_origin: GERMLINE
  inheritance:
  - name: Autosomal recessive inheritance
    inheritance_term:
      preferred_term: autosomal recessive inheritance
      term:
        id: HP:0000007
        label: Autosomal recessive inheritance
    evidence:
    - reference: ORPHA:2116
      reference_title: "Hartnup disease (Orphanet structured-database record)"
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "Autosomal recessive"
      explanation: Orphanet records autosomal recessive inheritance.
    - reference: PMID:15286788
      reference_title: "Hartnup disorder is caused by mutations in the gene encoding the neutral amino acid transporter SLC6A19."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "cosegregated with disease in the predicted recessive"
      explanation: The SLC6A19 mutation study showed recessive segregation.
  variants:
  - name: Biallelic SLC6A19 pathogenic variants
    description: >
      Reported disease-causing SLC6A19 alleles include compound heterozygous and
      homozygous variants that reduce B0AT1-mediated neutral amino acid
      transport or impair trafficking to the plasma membrane.
    evidence:
    - reference: PMID:15286788
      reference_title: "Hartnup disorder is caused by mutations in the gene encoding the neutral amino acid transporter SLC6A19."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "in kidney and intestine, with properties of system B(0). We identified six"
      explanation: The study identified multiple SLC6A19 mutations in affected individuals.
    - reference: PMID:40852587
      reference_title: "Hartnup disease-causing SLC6A19 mutations lead to B0AT1 aberrant trafficking and ACE2 mis-localisation implicating the endoplasmic reticulum protein quality control."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "Hartnup disease-causing B0AT1 variants using experimental approaches including"
      explanation: The 2025 functional study tested disease-causing B0AT1 variants.
  evidence:
  - reference: ORPHA:2116
    reference_title: "Hartnup disease (Orphanet structured-database record)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "SLC6A19 | solute carrier family 6 member 19 | hgnc:27960 | Disease-causing germline mutation(s) in"
    explanation: Orphanet lists SLC6A19 as a disease-causing germline gene.
  - reference: ORPHA:2116
    reference_title: "Hartnup disease (Orphanet structured-database record)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "CLTRN | collectrin, amino acid transport regulator | hgnc:29437 | Disease-causing germline mutation(s) in"
    explanation: Orphanet also lists CLTRN as an amino acid transport regulator associated with Hartnup disease.
  - reference: CGGV:assertion_44c34762-450b-4abd-8fe4-3f17ff700630-2020-05-07T160000.000Z
    reference_title: "SLC6A19 / Hartnup disease (Definitive)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "SLC6A19 | HGNC:27960 | Hartnup disease | MONDO:0009324 | AR | Definitive"
    explanation: ClinGen classifies the SLC6A19-Hartnup disease gene-disease relationship as definitive with autosomal recessive inheritance.
- name: CLTRN disease association
  gene_term:
    preferred_term: CLTRN
    term:
      id: hgnc:29437
      label: CLTRN
  association: Orphanet-listed disease-causing germline association; auxiliary amino acid transport regulator
  relationship_type: CAUSATIVE
  variant_origin: GERMLINE
  notes: >
    CLTRN encodes collectrin, an amino acid transport regulator. Orphanet lists
    CLTRN as a disease-causing germline gene for Hartnup disease, while the
    cached PubMed evidence used here primarily supports SLC6A19/B0AT1 as the
    disease-defining transporter mechanism.
  evidence:
  - reference: ORPHA:2116
    reference_title: "Hartnup disease (Orphanet structured-database record)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "CLTRN | collectrin, amino acid transport regulator | hgnc:29437 | Disease-causing germline mutation(s) in"
    explanation: Orphanet lists CLTRN as a disease-causing germline gene for Hartnup disease.
treatments:
- name: Oral nicotinamide
  description: >
    Oral nicotinamide can resolve pellagra-like symptoms in symptomatic patients
    by bypassing reduced tryptophan-derived nicotinamide availability.
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: nicotinamide
      term:
        id: CHEBI:17154
        label: nicotinamide
  target_mechanisms:
  - target: Tryptophan and nicotinamide availability reduction
    treatment_effect: MODULATES
    description: Nicotinamide supplies vitamin B3 activity downstream of impaired tryptophan uptake.
    evidence:
    - reference: PMID:7955499
      reference_title: "Hartnup disease presenting in an adult."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "symptoms resolved with oral nicotinamide."
      explanation: Adult pellagra symptoms resolved with oral nicotinamide.
  evidence:
  - reference: PMID:7955499
    reference_title: "Hartnup disease presenting in an adult."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "symptoms resolved with oral nicotinamide."
    explanation: Adult case report supports oral nicotinamide for symptomatic pellagra-like disease.
- name: Tryptophan ethyl ester bypass therapy
  description: >
    Tryptophan ethyl ester has been reported as an experimental strategy to
    bypass defective gastrointestinal neutral amino acid transport and normalize
    tryptophan availability.
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
  target_mechanisms:
  - target: Renal and intestinal neutral amino acid transport defect
    treatment_effect: MODULATES
    description: The ester bypasses defective neutral amino acid transport in the gut.
    evidence:
    - reference: PMID:2472426
      reference_title: "Circumvention of defective neutral amino acid transport in Hartnup disease using tryptophan ethyl ester."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "bypass defective gastrointestinal neutral amino acid transport in a child with"
      explanation: The study explicitly used tryptophan ethyl ester to bypass the intestinal transport defect.
  evidence:
  - reference: PMID:2472426
    reference_title: "Circumvention of defective neutral amino acid transport in Hartnup disease using tryptophan ethyl ester."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "tryptophan ethyl ester is effective at circumventing defective gastrointestinal"
    explanation: The authors concluded tryptophan ethyl ester may be useful by circumventing defective transport.
- name: Sunlight avoidance for photosensitivity
  description: >
    Avoidance of sunlight and photoprotection are supportive measures for the
    photosensitive pellagra-like skin component.
  treatment_term:
    preferred_term: sunlight avoidance
    term:
      id: MAXO:0000055
      label: sunlight avoidance
  target_phenotypes:
  - preferred_term: Cutaneous photosensitivity
    term:
      id: HP:0000992
      label: Cutaneous photosensitivity
  evidence:
  - reference: ORPHA:2116
    reference_title: "Hartnup disease (Orphanet structured-database record)"
    supports: PARTIAL
    evidence_source: OTHER
    snippet: "HP:0000992 | Cutaneous photosensitivity | Very frequent (99-80%)"
    explanation: Orphanet supports the photosensitivity target for photoprotective care.
- name: Genetic counseling
  description: >
    Genetic counseling is appropriate because Hartnup disease is inherited as an
    autosomal recessive disorder caused by germline variants.
  treatment_term:
    preferred_term: genetic counseling
    term:
      id: MAXO:0000079
      label: genetic counseling
  evidence:
  - reference: ORPHA:2116
    reference_title: "Hartnup disease (Orphanet structured-database record)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Autosomal recessive"
    explanation: Autosomal recessive inheritance supports recurrence-risk counseling.
  target_mechanisms:
  - target: SLC6A19 B0AT1 transporter loss of function
    description: Genetic counseling is anchored to the autosomal recessive SLC6A19 transport defect and supports recurrence-risk counseling; it does not directly alter metabolism.
    evidence:
    - reference: PMID:15286787
      reference_title: "Mutations in SLC6A19, encoding B0AT1, cause Hartnup disorder."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Hartnup disorder, an autosomal recessive defect"
      explanation: The SLC6A19 discovery paper supports autosomal recessive inheritance for counseling around the causal transport defect.
  - target: CLTRN amino acid transport regulator involvement
    description: Genetic counseling also covers the Orphanet-listed CLTRN association when familial variants are identified.
    evidence:
    - reference: ORPHA:2116
      reference_title: "Hartnup disease (Orphanet structured-database record)"
      supports: PARTIAL
      evidence_source: OTHER
      snippet: "CLTRN | collectrin, amino acid transport regulator | hgnc:29437 | Disease-causing germline mutation(s) in"
      explanation: Orphanet lists CLTRN as a disease-causing germline gene, supporting inclusion in counseling discussions.
diagnosis:
- name: Urinary amino acid chromatography
  diagnosis_term:
    preferred_term: disease screening
    term:
      id: MAXO:0000124
      label: disease screening
  description: >
    Urine amino acid analysis or chromatography detects neutral
    hyperaminoaciduria and can establish the biochemical diagnosis.
  results: Excess urinary neutral amino acids support Hartnup disease.
  evidence:
  - reference: PMID:7955499
    reference_title: "Hartnup disease presenting in an adult."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Chromatography of urinary amino acids was diagnostic of"
    explanation: Urinary amino acid chromatography diagnosed Hartnup disease in the adult case.
  - reference: ORPHA:2116
    reference_title: "Hartnup disease (Orphanet structured-database record)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0008353 | Neutral hyperaminoaciduria | Very frequent (99-80%)"
    explanation: Orphanet supports neutral hyperaminoaciduria as the expected biochemical screening result.
- name: SLC6A19 molecular testing
  diagnosis_term:
    preferred_term: genetic testing
    term:
      id: MAXO:0000127
      label: genetic testing
  description: >
    Molecular testing for biallelic SLC6A19 pathogenic variants confirms the
    genetic diagnosis, especially in variable or late-presenting cases.
  results: Biallelic pathogenic SLC6A19 variants support diagnosis.
  evidence:
  - reference: PMID:15286788
    reference_title: "Hartnup disorder is caused by mutations in the gene encoding the neutral amino acid transporter SLC6A19."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "SLC6A19 is the long-sought gene that is mutated in Hartnup disorder"
    explanation: The SLC6A19 discovery paper supports molecular confirmation.
  - reference: PMID:15286787
    reference_title: "Mutations in SLC6A19, encoding B0AT1, cause Hartnup disorder."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "product of SLC6A19, the Hartnup transporter, is expressed primarily in intestine"
    explanation: The original-family study identifies SLC6A19 as the Hartnup transporter gene.
references:
- reference: ORPHA:2116
  title: Hartnup disease
  found_in:
  - Hartnup_Disease-deep-research-fallback.md
- reference: PMID:15286787
  title: "Mutations in SLC6A19, encoding B0AT1, cause Hartnup disorder."
  found_in:
  - Hartnup_Disease-deep-research-fallback.md
- reference: PMID:15286788
  title: Hartnup disorder is caused by mutations in the gene encoding the neutral amino acid transporter SLC6A19.
  found_in:
  - Hartnup_Disease-deep-research-fallback.md
- reference: PMID:16052352
  title: The molecular basis of neutral aminoacidurias.
  found_in:
  - Hartnup_Disease-deep-research-fallback.md
- reference: PMID:19472175
  title: The role of the neutral amino acid transporter B0AT1 (SLC6A19) in Hartnup disorder and protein nutrition.
  findings:
  - statement: Hartnup disorder is a neutral aminoaciduria with photosensitive rash and cerebellar ataxia manifestations.
    supporting_text: "Hartnup disorder (OMIM 234500) is an autosomal recessive disorder, which was first described in 1956 as an aminoaciduria of neutral amino acids accompanied by a variety of symptoms, such as a photo-sensitive skin-rash and cerebellar ataxia."
  - statement: SLC6A19/B0AT1 mutation and collectrin-dependent surface expression are central to the Hartnup mechanism.
    supporting_text: "The disorder is caused by mutations in the neutral amino acid transporter B(0)AT1 (SLC6A19)."
  found_in:
  - Hartnup_Disease-deep-research-fallback.md
- reference: PMID:2472426
  title: Circumvention of defective neutral amino acid transport in Hartnup disease using tryptophan ethyl ester.
  found_in:
  - Hartnup_Disease-deep-research-fallback.md
- reference: PMID:40852587
  title: Hartnup disease-causing SLC6A19 mutations lead to B0AT1 aberrant trafficking and ACE2 mis-localisation implicating the endoplasmic reticulum protein quality control.
  found_in:
  - Hartnup_Disease-deep-research-fallback.md
- reference: PMID:7955499
  title: Hartnup disease presenting in an adult.
  found_in:
  - Hartnup_Disease-deep-research-fallback.md
notes: >-
  The entry prioritizes the disease-defining SLC6A19/B0AT1 transport mechanism.
  CLTRN is included because it is listed in the structured Orphanet gene table,
  but the cached PubMed evidence used here primarily supports SLC6A19.
review_notes: >-
  GeneReviews baseline was checked during PR review. PubMed searches for
  Hartnup-specific GeneReviews records returned no Hartnup GeneReviews PMID, and
  the NCBI GeneReviews title search for Hartnup returned unrelated chapters
  rather than a Hartnup chapter. The review-mentioned NBK1215 / PMID:20301394 is
  SHOX Deficiency Disorders, not Hartnup disease, so it is intentionally not
  tagged here. PMID:19472175 is included instead as a Hartnup-specific narrative
  review baseline.
📚

References & Deep Research

References

8
ORPHA:2116
Hartnup disease
No top-level findings curated for this source.
PMID:15286787
Mutations in SLC6A19, encoding B0AT1, cause Hartnup disorder.
No top-level findings curated for this source.
PMID:15286788
Hartnup disorder is caused by mutations in the gene encoding the neutral amino acid transporter SLC6A19.
No top-level findings curated for this source.
PMID:16052352
The molecular basis of neutral aminoacidurias.
No top-level findings curated for this source.
PMID:19472175
The role of the neutral amino acid transporter B0AT1 (SLC6A19) in Hartnup disorder and protein nutrition.
2 findings
Hartnup disorder is a neutral aminoaciduria with photosensitive rash and cerebellar ataxia manifestations.
"Hartnup disorder (OMIM 234500) is an autosomal recessive disorder, which was first described in 1956 as an aminoaciduria of neutral amino acids accompanied by a variety of symptoms, such as a photo-sensitive skin-rash and cerebellar ataxia."
SLC6A19/B0AT1 mutation and collectrin-dependent surface expression are central to the Hartnup mechanism.
"The disorder is caused by mutations in the neutral amino acid transporter B(0)AT1 (SLC6A19)."
PMID:2472426
Circumvention of defective neutral amino acid transport in Hartnup disease using tryptophan ethyl ester.
No top-level findings curated for this source.
PMID:40852587
Hartnup disease-causing SLC6A19 mutations lead to B0AT1 aberrant trafficking and ACE2 mis-localisation implicating the endoplasmic reticulum protein quality control.
No top-level findings curated for this source.
PMID:7955499
Hartnup disease presenting in an adult.
No top-level findings curated for this source.

Deep Research

1
Hartnup Disease Deep Research Fallback ▸

Hartnup Disease Deep Research Fallback

Date: 2026-05-04

Provider Attempts

  • timeout 120 just research-disorder falcon Hartnup_Disease
  • Result: timed out after the bounded 120-second run and was terminated by signal 15.
  • Completed artifact: none.
  • timeout 120 just research-disorder openai Hartnup_Disease
  • Result: timed out after the bounded 120-second run and was terminated by signal 15.
  • Completed artifact: none.

Evidence Scope Used For Curation

The YAML curation therefore used structured Orphanet evidence plus cached PubMed records with exact snippet audit coverage.

Structured Source

  • ORPHA:2116 Hartnup disease structured record
  • Exact MONDO cross-reference: MONDO:0009324
  • Exact OMIM cross-reference: OMIM:234500
  • Inheritance: autosomal recessive
  • Genes: SLC6A19 and CLTRN
  • Phenotypes: neutral hyperaminoaciduria, cutaneous photosensitivity, ataxia, neuropsychiatric features, ocular findings, malabsorption, elevated urinary indican, and other HPO annotations

PubMed Records

  • PMID:15286787 Kleta et al. 2004
  • Identifies SLC6A19/B0AT1 mutations in the original Hartnup family and Japanese families.
  • Supports impaired neutral amino acid transport across renal proximal tubule and intestinal mucosa.
  • PMID:15286788 Seow et al. 2004
  • Independently identifies SLC6A19 as the Hartnup gene.
  • Shows tested disease-causing mutations reduce neutral amino acid transport in vitro.
  • PMID:16052352 Broer et al. 2006
  • Reviews the molecular basis of neutral aminoacidurias and B0AT1/SLC6A19 involvement in kidney and intestine.
  • PMID:2472426 Jonas and Butler 1989
  • Reports tryptophan ethyl ester bypass of defective gastrointestinal neutral amino acid transport in a child with Hartnup disease.
  • PMID:40852587 Alkhofash and Ali 2025
  • Tests Hartnup disease-causing B0AT1 variants and supports ER retention / plasma membrane trafficking defects as a mechanism for transport loss.
  • PMID:7955499 Oakley and Wallace 1994
  • Reports adult pellagra presentation diagnosed by urinary amino acid chromatography and responsive to oral nicotinamide.

Integration Notes

The YAML integrates the evidence into a mechanism chain:

  1. SLC6A19/B0AT1 transporter loss of function.
  2. Variant trafficking defects for selected B0AT1 alleles.
  3. Renal and intestinal neutral amino acid transport defect.
  4. Neutral hyperaminoaciduria, malabsorption, elevated urinary indican, and reduced tryptophan availability.
  5. Pellagra-like neurocutaneous manifestations responsive to nicotinamide in symptomatic disease and experimentally bypassed by tryptophan ethyl ester.

The provider timeouts mean no additional narrative deep-research synthesis was available beyond the evidence-backed curation and local audits.