Hartnup Disease
Diseases

Definition

Hartnup disease (also known as "Pellagra-like dermatosis) is an autosomal recessive metabolic disorder affecting the absorption of nonpolar amino acids (particularly tryptophan that can be, in turn, converted into Serotonin, Melatonin and Niacin). Niacin is a precursor to nicotinamide, a necessary component of NAD+.

Hartnup Disease

Epidemiology

Hartnup disorder (OMIM 234500) is an autosomal recessive disorder occurring at a frequency of about 1:30,000 in European populations. The disorder was first described in 1956 by Baron et al. Hartnup disorder received its name from the first described case Eddie Hartnup (Eddie H. in the original publication).
Hartnup disease is manifested by a wide clinical spectrum. Most patients remain asymptomatic, but, in a minority of patients, skin photosensitivity and neurologic and psychiatric symptoms may have a considerable influence on quality of life. Rarely, severe CNS involvement may lead to death. Mental retardation and short stature have been described in a few patients. Malnutrition and a low-protein diet are the primary factors that contribute to morbidity. The is no racial and sexual predilection. The onset of Hartnup disease is in childhood, usually in children aged 3-9 years, but it may present as early as 10 days after birth. In addition, a case of Hartnup disease presenting for the first time in an adult female, after prolonged lactation and increased physical activity, is described.

Symptoms

Hereditary pellagra-like skin rash with temporary cerebellar ataxia, constant renal aminoaciduria and other bizarre biochemical features.
Although these clinical symptoms were recorded in Eddie Hartnup’s case, these days most cases are asymptomatic. If symptoms do occur, they usually appear in childhood and may include:

1. Diarrhea
2. Mood changes
3. Nervous system (neurologic) problems, such as abnormal muscle tone
4. Red, scaly skin rash, usually when skin is exposed to sunlight
5. Sensitivity to light (photosensitivity)
6. Short stature
7. Uncoordinated movements

The renal aminoaciduria is the hallmark of the disorder, because of the variability of other symptoms, and most if not all patients were diagnosed by urine analysis. The aminoaciduria is restricted to neutral amino acids although slightly elevated amounts of glutamate are often found as well. Particularly relevant are the increased amounts of tryptophan pointing to a lack of tryptophan reabsorption. The clinical symptoms of Hartnup disorder are remarkably similar to pellagra or niacin deficiency. This vitamin deficiency is characterized by a photosensitive dermatitis. Advanced pellagra is accompanied by depressive psychosis and diarrhea. It has been noted that clinical symptoms are more likely to occur in individuals with low plasma amino acid levels . Alternatively it has been proposed that toxic bacterial degradation products of tryptophan might be involved .

Hartnup Disorder, 2010

Diagnosis

The symptoms of this disease suggest a deficiency of a B vitamin called niacin. A detailed diet history can be used to assess if there is adequate protein and vitamins in the diet. The diagnosis of Hartnup disease is confirmed by a laboratory test of the urine which will contain an abnormally high amount of amino acids (aminoaciduria).

Pathogenesis

The aminoaciduria and clinical symptoms are caused by a defect of the major renal and intestinal transporter for neutral amino acids, which has been termed B0 (Denoting a transporter for neutral amino acids (0) with broad specificity; the upper case is used to indicate Na1-dependence) or neutral brush border (NBB). Niacin comprises nicotinic acid and nicotinamide, the two compounds having the biological activity of this vitamin. Nicotinic acid is used as a precursor for NADH biosynthesis . Although niacin is considered a vitamin, the body can synthesize significant amounts of NADH from tryptophan.

Aminoacidurias,Clinical and molecular aspects, 2008

• The biochemical basis of the skin rash is still understood, but in Hartnup disorder it appears to respond to niacin supplementation, suggesting that the reduced availability of tryptophan is the most likely cause for the skin-rash. In addition reduced amounts of the histidine metabolite urocanic acid have been reported in the skin of pellagrins. The compound is important for the absorption of UV light in normal skin and histidine transport is impaired in Hartnup disorder . Reduced levels of urocanic acid are also observed in hereditary zinc deficiency causing acrodermatities hepatica, which has been observed in one case of Hartnup disorder as mentioned above.

• In addition, mammalian skin contains the entire metabolic pathway to convert L-tryptophan to melatonin. Melatonin exerts a variety of skin protective effects and is considered to be an important regulator of skin function and structure.

• The ataxia might also be related to tryptophan metabolism and its conversion to serotonin (5-hydroxytryptamine). Serotonin plays an important role as a neurotransmitter in the modulation of anger, aggression, body temperature, mood, sleep, sexuality, appetite, and metabolism. Although low levels of B0AT1 are found in the brain, its main site of expression is the brushborder of kidney and intestinal epithelial cells. Serotonin levels in the brain, however, correspond to the levels of tryptophan in the blood because the Km of tryptophan hydroxylase, the rate limiting step of serotonin biosynthesis, is higher than tryptophan concentrations in the brain or the circulation . As a result, tryptophan has antidepressive properties and its metabolite 5- hydroxytryptophan causes regression of various forms of cerebellar ataxia. Little is known whether changed plasma levels of other neurotransmitter precursor amino acids, such as tyrosine or histidine may contribute to neurological symptoms.

The role of the neutral amino acid transporter B0AT1 (SLC6A19) in Hartnup disorder and protein nutrition, 2009

• Bacterial degradation products of tryptophan such as indole-compounds (indoxyl sulfate, indole acetic acid, indolylacetyl glutamine) and other amino acids have been identified in the urine of individuals with Hartnup disorder, demonstrating that they are absorbed in the intestine and distributed throughout the body. The occurrence of these bacterial degradation products were indeed the first evidence that amino acid transport is impaired in the intestine . The involvement of indole compounds in the onset of ataxia, however, appears unlikely in view of the asymptotic cases of Hartnup disorder, in which the degradation products of tryptophan would still be produced.

Neutral amino acid transport in the kidney and intestine

Amino acids involved:

1. Serine
2. Threonine
3. Glutamine
4. Asparagine
5. Alanine
6. Valine
7. Leucine
8. Isoleucine
9. Phenylalanine
10. Tyrosine
11. Tryptophan
12. Histidine

It is clinically comparable to pellagra (caused by defects in the metabolism of tryptophan) but due to a defective absorption of tryptophan in the intestine resulting in inability of synthesis of nicotinamide derived from it.
Nicotinamide (also known as vitamin PP = Preventing Pellagra) is the amide of nicotinic acid (niacin) and belongs, with the latter group of vitamin B3, is involved in bioenergetic processes as a constituent of NAD and NADP. They are found in the urine several indole derivatives of tryptophan due to its catabolism by intestinal bacteria. This is a vicious circle because the indole inhibit the enzyme systems that convert tryptophan to vitamin PP and vitamin deficiency depresses further the already deficient intestinal absorption of tryptophan. It has an aminoaciduria with pathological urinary excretion up to 10 times the norm of many aminoacids as serine, threonine, leucine and high amounts of indole bodies. The block of tryptophan can also cause defects in the absorption of other amino acids for competitive inhibition of tryptophan occupying cellular sites of absorption also useful for other amino acids and for a more specific metabolic defect that involves many cellular carriers.
Amino acids are retained within the intestinal lumen, where they are converted by bacteria to indolic compounds that can be toxic to the CNS. Tryptophan is converted to indole in the intestine. Following absorption, indole is converted to 3-hydroxyindole (ie, indoxyl, indican) in the liver, where it is conjugated with potassium sulfate or glucuronic acid. Subsequently, it is transported to the kidneys for excretion (ie, indicanuria). Other tryptophan degradation products, including kynurenine and serotonin, are also excreted in the urine. Tubular renal transport is also defective, contributing to gross aminoaciduria. Neutral amino acids are also found in the feces.
Proteins from up to 30% of our nutrition are hydrolysed into peptides and amino acids (in stomach and intestine), both of which are absorbed by specific transport systems located in the apical membrane of intestinal enterocytes. Subsequently, they are released into the portal venous system by a set of different basolateral transport systems. In the kidney, an ultrafiltrate is produced that contains all low molecular weight compounds present in the blood plasma. To avoid wastage of valuable nutrients into the urine, all nutrients are reabsorbed by the epithelial cells of the proximal tubule and returned to the blood. More than 95% of filtered amino acids are cleared in the S1–S3 segments of the proximal tubule. Generally, it appears that similar transport systems are expressed in intestinal enterocytes and kidney epithelial cells.

Treatment

Treatment of aminoaciduria depends on the underlying cause. Treatment focuses on reducing the intake of the amino acid, providing the body with a way to utilize the amino acid more effectively, or allowing the kidneys to clear the amino acid more effectively.
Treatment of aminoaciduria may include:

• Diet restrictions:
  • Reduces the amount of a particular amino acid in the diet

• Increase liquids in the diet:
  • Allows the kidney to clear excess amino acids more easily

• Medications that alkalinize the urine:
  • Allows the kidney to clear excess amino acids more easily
  • Sodium bicarbonate
  • Sodium citrate

• Vitamin supplements:
  • May help the body utilize amino acids more effectively

Other symptoms can be treated :

• Avoiding sun exposure by wearing protective clothing and using a sunscreen of factor 15 or higher

• Taking supplements containing nicotinamide

• Undergoing psychiatric treatment, such as the use of antidepressants or mood stabilizers, if mood swings or psychiatric problems occur

• The vitamin niacin is given as a treatment. The typical dosage ranges from 40-200 mg of nicotinamide per day to prevent pellagra-like symptoms. Some patients may require dietary supplements of tryptophan.

• Eating a healthy, high protein diet can relieve the symptoms and prevent them from recurring.

Hartnup Disease Treatment

Gene

The causative gene, SLC6A19, is located on chromosome 5.

Genomic Location

• SLC6A19 is a sodium-dependent and chloride-independent neutral amino acid transporter, expressed predominately in kidney and intestine, with properties of system B0.

• Hartnup disorder is an autosomal recessive impairment of amino acid transport in kidney and intestine. Mutations in SLC6A19 have been shown to cosegregate with the disease in the predicted recessive manner; however, in two previous studies (Seow et al., Nat Genet 2004;36:1003-1007; Kleta et al., Nat Genet 2004;36:999-1002), not all causative alleles were identified in all affected individuals, raising the possibility that other genes may contribute to Hartnup disorder. Have been now investigated six newly acquired families of Australian and Canadian (Province of Quebec) origin and resequenced the entire coding region of SLC6A19 in families with only a single disease allele identified. Has been also studied one American family in whom no mutations had been identified in a previous study (Kleta et al., Nat Genet 2004;36:999-1002). In addition have been identified seven novel mutations in SLC6A19 that show functional obliteration of the protein in vitro, explaining Hartnup disorder in all reported families so far. We demonstrate that Hartnup disorder is allelically heterogeneous with two mutated SLC6A19 alleles, whether identical or not, necessary for manifestation of the characteristic aminoaciduria in affected individuals. This study resolves the previous hypothesis that other genes contribute to the Hartnup phenotype.

Hartnup disorder is caused by mutations in the gene encoding the neutral amino acid transporter SLC6A19, 2004

Further evidence for allelic heterogeneity in Hartnup disorder, 2008