Can niacin deficiency occur in Hartnup disease?

December 26, 2025 •

4 min read

Hartnup disease is a rare autosomal recessive disorder involving the malabsorption of certain amino acids, and as a direct result, niacin deficiency can occur. This genetic condition disrupts the body's ability to properly utilize tryptophan, a key precursor for vitamin B3 synthesis.

Quick Summary

Hartnup disease, a rare genetic disorder affecting amino acid transport, causes niacin deficiency due to the malabsorption of tryptophan, leading to pellagra-like symptoms that affect the skin and nervous system.

Key Points

Genetic Defect: Hartnup disease is caused by a mutation in the SLC6A19 gene, disrupting the B0AT1 transporter for neutral amino acids, including tryptophan.
Tryptophan Malabsorption: The genetic defect leads to malabsorption of tryptophan from the intestine and increased loss via the kidneys, significantly reducing tryptophan availability.
Niacin Synthesis Impairment: Since tryptophan is a precursor for niacin, the body's inability to absorb it leads directly to a functional niacin deficiency, particularly during periods of increased metabolic demand.
Pellagra-like Symptoms: The resulting niacin deficiency causes symptoms resembling pellagra, such as a sun-sensitive rash, diarrhea, neurological issues like ataxia, and psychiatric disturbances.
Treatment and Prognosis: Symptoms are often episodic and can be managed effectively with niacin/nicotinamide supplements and a high-protein diet, leading to a good prognosis for most patients.

The Genetic Cause of Tryptophan Malabsorption

Hartnup disease is a metabolic disorder caused by mutations in the SLC6A19 gene. This gene provides instructions for creating the B0AT1 transport protein, which is essential for the absorption of neutral amino acids, including tryptophan, from the small intestine and for their reabsorption in the kidneys. When the SLC6A19 gene is mutated, the B0AT1 transporter functions improperly, leading to a deficiency of these amino acids in the body. As a consequence, excessive amounts of neutral amino acids are lost through urination and stool.

The Niacin Connection

Tryptophan is not only a building block for proteins but also a critical precursor for the body's synthesis of niacin (vitamin B3). Under normal circumstances, the body can produce some of its niacin from tryptophan. However, in individuals with Hartnup disease, the systemic deficiency of tryptophan severely impairs this conversion process. This creates a state of functional niacin deficiency, especially during periods of stress, illness, or poor nutrition when the demand for vitamins is higher. The resulting lack of niacin can manifest as pellagra-like symptoms.

Manifestations of Niacin Deficiency in Hartnup Disease

The symptoms of niacin deficiency in Hartnup disease mirror those of classic nutritional pellagra, often described as the "4 D's": Dermatitis, Diarrhea, Dementia, and potentially Death. These symptoms are often intermittent and triggered by specific environmental or physiological stressors.

Dermatological Symptoms

Photosensitive Rash: A hallmark sign is a red, scaly, and hyperpigmented rash that appears on sun-exposed areas of the body, such as the face, neck, and limbs. This rash can resemble sunburn and may feature distinctive patterns, like Casal's collar around the neck.
Skin Changes: Over time, the skin can become rough, dry, and thickened.

Neurological and Psychiatric Symptoms

Cerebellar Ataxia: Episodes of unsteady gait and poor coordination are common neurological manifestations. This is thought to be linked to niacin's role in cellular energy production in the nervous system.
Mental Health Issues: Psychiatric symptoms can include emotional lability, anxiety, rapid mood changes, depression, and even psychosis or delusions.
Other Neurological Effects: Headaches, tremors, and fainting are also frequently reported.

Gastrointestinal Symptoms

Diarrhea: Chronic or intermittent diarrhea can occur due to inflammation of the gastrointestinal tract, a classic symptom of pellagra.
Mouth Sores: Inflammation can also cause sores and a red, swollen tongue (glossitis).

Contributing Factors and Triggers

Certain factors are known to precipitate or exacerbate symptomatic episodes in people with Hartnup disease. These triggers include:

Fever and infections
Poor nutrition, especially low-protein diets
Exposure to sunlight
Emotional or physical stress
Specific medications, such as sulfonamides

Management and Treatment of Niacin Deficiency

The primary goal of managing Hartnup disease is to prevent symptomatic episodes, which can be achieved by addressing the underlying nutritional deficiencies.

Treatment Strategies for Hartnup Disease

Niacin Supplementation: Oral niacin or niacinamide supplements are a cornerstone of treatment. Dosages are adjusted based on the severity of symptoms.
High-Protein Diet: A high-protein diet can help compensate for the defective amino acid transport, providing the body with more tryptophan.
Trigger Avoidance: Patients should minimize sun exposure, wear protective clothing, and avoid medications known to increase photosensitivity.
Symptomatic Support: Neurological and psychiatric symptoms require appropriate specialized medical attention.

Hartnup-Induced vs. Nutritional Pellagra

Although the symptoms of niacin deficiency are similar, the underlying causes for Hartnup disease and nutritional pellagra are distinct. The following table highlights the key differences:


Feature	Hartnup Disease	Nutritional Pellagra
Cause	Genetic mutation in the SLC6A19 gene affecting tryptophan transport.	Inadequate dietary intake of niacin and tryptophan.
Symptom Triggers	Illness, stress, fever, sun exposure, poor nutrition.	Chronically low dietary intake.
Underlying Defect	Impaired intestinal absorption and renal reabsorption of neutral amino acids.	Simple dietary deficiency of vitamin B3.
Biochemical Hallmark	Excess neutral amino acids (including tryptophan) in the urine.	Low circulating niacin levels due to dietary lack.
Frequency	Rare, affecting approximately 1 in 15,000 to 30,000 people.	Uncommon in developed countries due to fortified foods; more prevalent in areas with limited dietary variety.

Conclusion

Yes, niacin deficiency can and does occur in Hartnup disease as a direct consequence of the genetic defect causing impaired tryptophan metabolism. The mutated SLC6A19 gene prevents the body from adequately absorbing the amino acid tryptophan, a crucial precursor for niacin synthesis. This leads to pellagra-like symptoms, including dermatitis, neurological issues, and gastrointestinal problems, which are often episodic and triggered by environmental factors. With proper diagnosis through urine analysis and a comprehensive management plan involving niacin supplementation, a high-protein diet, and trigger avoidance, most individuals with Hartnup disease can lead a normal life. This highlights the complex link between genetic factors and nutritional status.

Visit the NIH for more information on Hartnup disease.

Frequently Asked Questions

The primary cause is a genetic mutation in the SLC6A19 gene, which impairs the transport of neutral amino acids, including tryptophan. Since the body uses tryptophan to synthesize niacin, the malabsorption of this key amino acid leads to a functional niacin deficiency.

No, symptoms of Hartnup disease are often intermittent and appear in episodes or 'attacks.' Many individuals with the genetic defect remain asymptomatic. Symptomatic episodes are frequently triggered by factors such as stress, fever, illness, or poor nutrition.

Diagnosis is typically confirmed through urine analysis, which reveals high levels of neutral amino acids. Genetic testing for mutations in the SLC6A19 gene can also be used to confirm the diagnosis.

Niacin supplementation does not cure the underlying genetic disorder but effectively treats and prevents the symptoms related to niacin deficiency. A high-protein diet also helps manage the condition by providing alternative sources of amino acids.

Symptoms resemble pellagra because the core issue in both conditions is a deficiency of niacin. In Hartnup disease, the deficiency is a secondary effect of poor tryptophan absorption rather than a primary dietary lack, but the physiological consequences are similar.

In addition to being a precursor for niacin, tryptophan is involved in the synthesis of other important molecules like serotonin. Its malabsorption can contribute to both the physical and psychiatric symptoms seen in the disease.

No, many individuals who carry the gene mutation never develop symptoms and are only identified through routine screening. The severity and manifestation of symptoms vary widely and are often influenced by diet and other environmental triggers.