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PubMed This is a summary of 15 peer-reviewed journal articles Updated
Medical Genetics

The Biology and Genetics of Hartnup Disease

At a Glance

Hartnup disease is a genetic disorder caused by mutations in the SLC6A19 gene, which stops the intestines and kidneys from properly absorbing neutral amino acids like tryptophan. This prevents the body from making enough niacin (vitamin B3), leading to symptoms like a sun-sensitive rash.

To understand Hartnup disease, it helps to think of the body’s cells as a busy factory that needs specific building blocks to function. These building blocks are called amino acids, which we get from the protein in our food [1][2]. In Hartnup disease, the “machinery” responsible for moving these building blocks into the factory is broken.

The Defective ‘Pump’: SLC6A19 and B0AT1

Every person has a gene called SLC6A19 [3][4]. This gene acts as a blueprint for a protein called B0AT1, which functions as a “pump” or transporter [3][5].

These pumps are located in two critical places:

  • The Intestines: Here, the pumps pull neutral amino acids (a specific group of protein building blocks) from the food you eat into your bloodstream [5][6].
  • The Kidneys: As your blood is filtered, the kidneys try to “catch” these same amino acids before they are lost in your urine. The B0AT1 pump is what catches them and puts them back into the body [5][1].

In Hartnup disease, the SLC6A19 gene has a mutation that causes these pumps to be misshapen or missing entirely [7][4]. As a result, the body cannot absorb enough neutral amino acids from food, and it accidentally flushes the ones it already has out through the urine. This is why doctors call the condition a neutral aminoaciduria—meaning “neutral amino acids in the urine” [8][9].

The Niacin Chain Reaction

The most important amino acid affected by this defect is tryptophan [6][10]. Tryptophan is an “essential” amino acid, meaning the body cannot make it on its own; it must come from diet [11].

Tryptophan is famous for being the starting material for a critical chain reaction:

  1. Tryptophan Absorption: Normally, the body absorbs tryptophan through the B0AT1 pump [10][6].
  2. Niacin Production: Inside the body, about 95% of the tryptophan that is not used for building new proteins is broken down through a process called the kynurenine pathway [12][13].
  3. Vitamin B3 (Niacin): This pathway is the body’s only way to create its own niacin (Vitamin B3) and a molecule called NAD+, which cells use for energy [11][6].

Because a person with Hartnup disease cannot absorb tryptophan properly, their body cannot produce enough niacin [6][14]. This lack of niacin is what causes the classic symptoms, such as the sun-sensitive rash and neurological changes [10][14].

How It Is Inherited: Autosomal Recessive

Hartnup disease is an autosomal recessive condition [3][7]. For a child to have the disease, they must inherit the mutated gene from both parents. When two carriers have a child, there is a 25% chance the child will have Hartnup disease, a 50% chance they will be a carrier like their parents, and a 25% chance they will have two healthy genes [15].

What Hartnup Disease is NOT

It is important to distinguish Hartnup disease from other “aminoacidurias.” For example, Cystinuria is a different condition involving a different transporter that affects cystine and basic amino acids, which leads to kidney stones [3]. Hartnup disease specifically involves neutral amino acids and typically does not cause kidney stones; instead, its main “side effect” is the vitamin deficiency described above [9][8].

Return to the Home Page or read about How Hartnup Disease is Diagnosed.

Common questions in this guide

What gene mutation causes Hartnup disease?
Hartnup disease is caused by mutations in the SLC6A19 gene. This gene provides the blueprint for a protein pump called B0AT1, which normally helps the intestines and kidneys absorb specific protein building blocks from your food and blood.
Why does Hartnup disease cause a vitamin B3 (niacin) deficiency?
The mutated gene prevents the body from properly absorbing an amino acid called tryptophan. Since the body uses tryptophan to create its own niacin (vitamin B3), the poor absorption leads directly to a niacin deficiency, which causes the disease's classic symptoms.
How is Hartnup disease inherited?
Hartnup disease is an autosomal recessive condition, which means a child must inherit the mutated gene from both parents to develop the disorder. If both parents are carriers, there is a 25 percent chance with each pregnancy that their child will have the disease.
Should siblings be tested for the SLC6A19 mutation?
Yes, if both parents are known carriers of the mutated gene, siblings have a 25 percent chance of having the condition as well. Genetic testing can determine if they have the disease or if they are carriers of the gene, even if they currently show no symptoms.
How does Hartnup disease differ from Cystinuria?
Both conditions involve issues with how the body handles amino acids, but they affect different types. Cystinuria affects basic amino acids and cystine, frequently causing kidney stones. Hartnup disease affects neutral amino acids and causes a vitamin deficiency rather than kidney stones.

Questions to Ask Your Doctor

Curated prompts to bring to your next appointment.

  1. 1.Can you explain my child's specific SLC6A19 mutation and if it typically leads to a more or less severe form of the disease?
  2. 2.How does Hartnup disease differ from other amino acid disorders like Cystinuria?
  3. 3.Should our other children be tested for this mutation, even if they show no symptoms?

Questions For You

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References

References (15)
  1. 1

    CRRT 2023 Meeting: Targeting Amino Acid Transport to Improve Acute Kidney Injury Outcome.

    Oe Y, Vallon V

    Nephron 2023; (147(12)):774-777 doi:10.1159/000531918.

    PMID: 37490876
  2. 2

    Expression of SARS-CoV-2 entry factors, electrolyte, and mineral transporters in different mouse intestinal epithelial cell types.

    Pearce SC, Suntornsaratoon P, Kishida K, et al.

    Physiological reports 2021; (9(21)):e15061 doi:10.14814/phy2.15061.

    PMID: 34755492
  3. 3

    Accurate discrimination of Hartnup disorder from other aminoacidurias using a diagnostic ratio.

    Haijes HA, Prinsen HCMT, de Sain-van der Velden MGM, et al.

    Molecular genetics and metabolism reports 2020; (22()):100551 doi:10.1016/j.ymgmr.2019.100551.

    PMID: 31908951
  4. 4

    Study of Seizure-Manifested Hartnup Disorder Case Induced By Novel Mutations in SLC6A19.

    Zhu Y, Chen L, He J, et al.

    Open life sciences 2018; (13()):22-27 doi:10.1515/biol-2018-0003.

    PMID: 33817063
  5. 5

    Identification of novel inhibitors of the amino acid transporter B0 AT1 (SLC6A19), a potential target to induce protein restriction and to treat type 2 diabetes.

    Cheng Q, Shah N, Bröer A, et al.

    British journal of pharmacology 2017; (174(6)):468-482 doi:10.1111/bph.13711.

    PMID: 28176326
  6. 6

    New aspects for the brain in Hartnup disease based on mining of high-resolution cellular mRNA expression data for SLC6A19.

    Kravetz Z, Schmidt-Kastner R

    IBRO neuroscience reports 2023; (14()):393-397 doi:10.1016/j.ibneur.2023.03.010.

    PMID: 37101820
  7. 7

    Hartnup disease-causing SLC6A19 mutations lead to B0AT1 aberrant trafficking and ACE2 mis-localisation implicating the endoplasmic reticulum protein quality control.

    Alkhofash NF, Ali BR

    Frontiers in cell and developmental biology 2025; (13()):1589534 doi:10.3389/fcell.2025.1589534.

    PMID: 40852587
  8. 8

    Excretion of excess nitrogen and increased survival by loss of SLC6A19 in a mouse model of ornithine transcarbamylase deficiency.

    Belanger AJ, Gefteas E, Przybylska M, et al.

    Journal of inherited metabolic disease 2023; (46(1)):55-65 doi:10.1002/jimd.12568.

    PMID: 36220785
  9. 9

    Loss of CLTRN function produces a neuropsychiatric disorder and a biochemical phenotype that mimics Hartnup disease.

    Pillai NR, Yubero D, Shayota BJ, et al.

    American journal of medical genetics. Part A 2019; (179(12)):2459-2468 doi:10.1002/ajmg.a.61357.

    PMID: 31520464
  10. 10

    ACE2 and gut amino acid transport.

    Camargo SMR, Vuille-Dit-Bille RN, Meier CF, Verrey F

    Clinical science (London, England : 1979) 2020; (134(21)):2823-2833 doi:10.1042/CS20200477.

    PMID: 33140827
  11. 11

    Kynurenine pathway, NAD+ synthesis, and mitochondrial function: Targeting tryptophan metabolism to promote longevity and healthspan.

    Castro-Portuguez R, Sutphin GL

    Experimental gerontology 2020; (132()):110841 doi:10.1016/j.exger.2020.110841.

    PMID: 31954874
  12. 12

    Emerging effects of tryptophan pathway metabolites and intestinal microbiota on metabolism and intestinal function.

    Hyland NP, Cavanaugh CR, Hornby PJ

    Amino acids 2022; (54(1)):57-70 doi:10.1007/s00726-022-03123-x.

    PMID: 35038025
  13. 13

    Tryptophan-derived serotonin-kynurenine balance in immune activation and intestinal inflammation.

    Haq S, Grondin JA, Khan WI

    FASEB journal : official publication of the Federation of American Societies for Experimental Biology 2021; (35(10)):e21888 doi:10.1096/fj.202100702R.

    PMID: 34473368
  14. 14

    Association of Schizophrenia Risk With Disordered Niacin Metabolism in an Indian Genome-wide Association Study.

    Periyasamy S, John S, Padmavati R, et al.

    JAMA psychiatry 2019; (76(10)):1026-1034 doi:10.1001/jamapsychiatry.2019.1335.

    PMID: 31268507
  15. 15

    Establishment of the induced pluripotent stem cell line (NCKDi005-A) from a male patient with Alport syndrome carrying a homozygous frameshift mutation in the COL4A4 gene.

    Wang G, Gao E, Wu H, et al.

    Stem cell research 2022; (58()):102628 doi:10.1016/j.scr.2021.102628.

    PMID: 34942480

This page provides educational information about the genetics and biology of Hartnup disease. It is not intended as medical advice. Always consult a genetic counselor or healthcare provider to discuss specific genetic mutations, testing, or family inheritance risks.

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