Hartnup disease is a condition caused by the body's inability to absorb certain protein building blocks (amino acids) from the diet. As a result, affected individuals are not able to use these amino acids to produce other substances, such as vitamins and proteins. Most people with Hartnup disease are able to get the vitamins and other substances they need with a well-balanced diet.

People with Hartnup disease have high levels of various amino acids in their urine (aminoaciduria). For most affected individuals, this is the only sign of the condition. However, some people with Hartnup disease have episodes during which they exhibit other signs, which can include skin rashes; difficulty coordinating movements (cerebellar ataxia); and psychiatric symptoms, such as depression or psychosis. These episodes are typically temporary and are often triggered by illness, stress, nutrient-poor diet, or fever. These features tend to go away once the trigger is remedied, although the aminoaciduria remains. In affected individuals, signs and symptoms most commonly occur in childhood.

Hartnup disease is caused by mutations in the SLC6A19 gene. This gene provides instructions for making a protein called B0AT1, which is primarily found embedded in the membrane of intestine and kidney cells. The function of this protein is to transport certain amino acids into cells. In the intestines, amino acids from food are transported into intestinal cells then released into the bloodstream so the body can use them. In the kidneys, amino acids are reabsorbed into the bloodstream instead of being removed from the body in urine. In the body, these amino acids are used in the production of many other substances, including vitamins and proteins. One particular amino acid transported by B0AT1, tryptophan, is needed to produce vitamin B3 (also known as niacin).

SLC6A19 gene mutations result in the production of a B0AT1 protein with reduced activity. As a result, specific amino acids cannot be taken in by cells and are instead removed from the body as waste. Because these amino acids are removed from the body without being used, people with this condition may be lacking (deficient) in certain amino acids and vitamins. However, individuals who are nutrient-deficient due to their diet, illness, stress, or a variety of other reasons, can develop serious signs and symptoms of this condition including rashes, cerebellar ataxia, and psychiatric symptoms. Researchers believe that many of these features are related to a deficiency of tryptophan and niacin, specifically.

Normal Function

The SLC6A19 gene provides instructions for making a protein called system B(0) neutral amino acid transporter 1 (B0AT1). This protein transports certain protein building blocks (amino acids), namely those with a neutral charge, into cells. B0AT1 is found primarily in the membrane of intestinal cells that make up the brush border, which lines the walls of the intestine and absorbs nutrients from food. B0AT1 transports the neutral amino acids from food into intestinal cells; from there the amino acids are released into the bloodstream to be used by the body. B0AT1 is also found in the membrane of kidney cells, specifically in cells of the proximal tubules, which are structures that help to reabsorb nutrients and other materials into the blood and excrete unneeded substances into the urine. In the kidneys, B0AT1 reabsorbs neutral amino acids into the bloodstream so they are not released in urine.

Health Conditions Related to Genetic Changes

Hartnup disease

At least 23 mutations in the SLC6A19 gene have been found to cause Hartnup disease. This condition is characterized by increased levels of amino acids in the urine (aminoaciduria). Some individuals have episodes during which they exhibit skin rashes or movement or cognitive problems. Most of the mutations that cause Hartnup disease change single amino acids in the B0AT1 protein, reducing its activity. A mutation that has been identified in multiple affected families replaces the amino acid aspartic acid with the amino acid asparagine at position 173 in the protein (written as Asp173Asn or D173N).

The reduced B0AT1 activity leads to large amounts of neutral amino acids being removed from the body as waste. As a result, affected individuals are lacking (deficient) in certain amino acids and vitamins. Most affected people get the nutrients they need from a well-balanced diet. However, some individuals are nutrient-deficient due to their diet, illness, stress, or a variety of other reasons and can develop skin rashes or movement or psychiatric problems. Researchers believe that many of these features are related to a deficiency of vitamin B3 (niacin) and one of its main components, the amino acid tryptophan.

Other Names for This Gene

• B0AT1
• HND
• sodium-dependent amino acid transporter system B0
• sodium-dependent neutral amino acid transporter B(0)AT1
• solute carrier family 6 (neutral amino acid transporter), member 19
• system B(0) neutral amino acid transporter AT1
• system B0 neutral amino acid transporter

Genomic Location

This condition is inherited in an autosomal recessive pattern, which means both copies of the gene in each cell have mutations. The parents of an individual with an autosomal recessive condition each carry one copy of the mutated gene, but they typically do not show signs and symptoms of the condition.

The signs and symptoms of Hartnup disease may vary and include the following:

• Skin findings: sensitivity to sunlight
• Neurologic symptoms: ataxia, spasticity, headaches, and hypotonia
• Psychiatric symptoms: anxiety, emotional instability, mood changes
• Ocular findings: double vision, nystagmus, strabismus, photophobia

Symptoms may be triggered by sunlight exposure, fever, drugs, and emotional or physical stress. The episodes of skin and neurologic findings may last for 1-4 weeks before spontaneous remission occurs.