Hartnup Disease

Disease Overview

Hartnup disease is a rare genetic disorder that involves an inborn error of amino acid metabolism. The disorder is characterized by a distinctive skin rash and in a few reported patients was accompanied by episodes of neurological involvement including an inability to coordinate voluntary movements (ataxia), vision problems and cognitive delays. The symptoms associated with this disorder may be triggered by fever, drugs or situations when an affected individual is under emotional or physical stress such as during an illness. Generally, the frequency of such episodes usually diminishes with age. Hartnup disease is caused by changes (variants or mutations) in the SLC6A19 gene and is inherited in an autosomal recessive pattern.

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Synonyms

• Hartnup disorder
• Hartnup syndrome
• pellagra-cerebellar ataxia-renal aminoaciduria syndrome

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Signs & Symptoms

The symptoms of Hartnup disease vary greatly from one person to another. Most affected individuals do not have any apparent symptoms (asymptomatic). When symptoms do develop, they most often occur between the ages of 3-9. In rare instances, symptoms first appear in adulthood.

The most common symptoms are red, scaly light-sensitive (photosensitive) rashes on the face, arms, extremities and other exposed areas of skin.

A wide variety of neurological abnormalities can occur including sudden episodes of impaired muscle coordination (ataxia), an unsteady walk (gait), impaired articulation of speech (dysarthria), occasional tremors of the hands and tongue, and spasticity, a condition marked by increased muscle tone and stiffness of the muscles, particularly in the legs.
There have been reports of delayed cognitive development and, in rare instances, mild intellectual disability in some children. However, it’s unclear whether these symptoms are related to Hartnup disease or incidentally occurred in the same individual and were therefore attributed to Hartnup disease. Similarly, seizures, fainting, trembling, lack of muscle tone (hypotonia), headaches, dizziness and/or vertigo and delays in motor development have been observed but may be unrelated. Some affected individuals may experience psychiatric problems including emotional instability such as rapid mood changes, depression, confusion, anxiety, delusions and/or hallucinations.

Some children experience growth delays and may be shorter than would be expected based upon age and gender (short stature). In some people, the eyes may be affected, and individuals may experience double vision (diplopia), involuntary rhythmic movements of the eyes (nystagmus) and droopy upper eyelids (ptosis).

Diarrhea may precede or follow an episode of this disorder. Some adults with Hartnup disease have been reported whose initial symptom was the onset of seizures during adulthood. Heartburn has been reported in adults with the disorder.

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Causes

Hartnup disease is caused by disease-causing variants in the SLC6A19 gene. Genes provide instructions for creating proteins that play a critical role in many functions of the body. When a mutation of a gene occurs, the protein product may be faulty, inefficient, or absent. Depending upon the functions of the protein, this can affect many organ systems of the body.

The SLC6A19 gene produces a protein known as an amino acid transporter, which serves to assist the movement (or transport) of specific amino acids within the body. This protein is especially active within the kidneys and the intestines, although these organs are otherwise unaffected and function normally. The amino acids affected include tryptophan, alanine, asparagine, glutamine, histidine, isoleucine, leucine, phenylalanine, serine, threonine, tyrosine and valine.

Amino acids are the chemical building blocks of proteins and are essential for proper growth and development. Because of the SLC6A19 gene variant in Hartnup disease, the intestines cannot properly absorb amino acids and the kidney cannot properly reabsorb them, leading to excessive amounts of amino acids being lost through the passage of urine. This leaves the body with reduced amounts of amino acids to serve as the building blocks of proteins. Deficiency of the amino acid tryptophan is believed to account for the symptoms associated with Hartnup disease. Tryptophan is essential for the creation (synthesis) of nicotinamide, which is also supplemented through nutrition as a vitamin (also known as vitamin B3).

This deficiency is most problematic during times of illness or stress. Precipitating factors that may cause acute episodes of Hartnup disease may include a period of poor nutrition, fever, exposure to sunlight, sulphonamide medications, illness and/or psychological stress.

Hartup disease is inherited in an autosomal recessive pattern. Recessive genetic disorders occur when an individual inherits a mutated gene from each parent. If an individual receives one normal gene and one mutated gene for the disease, the person will be a carrier for the disease, but usually will not show symptoms. The risk for two carrier parents to both pass the mutated gene and have an affected child is 25% with each pregnancy. The risk of having a child who is a carrier like the parents is 50% with each pregnancy. The chance for a child to receive normal genes from both parents is 25%. The risk is the same for males and females.

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Affected populations

Hartnup disease affects both males and females in equal numbers. The disorder usually begins in childhood and continues into adulthood. The number of people affected by Hartnup disease is unknown. It has been estimated to occur at a frequency of approximately one in 30,000 individuals based upon newborn screening results in the United States and Australia.

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Disorders with Similar Symptoms

Symptoms of the following disorders can be similar to those of Hartnup disease. Comparisons may be useful for a differential diagnosis:

Loss of collectrin, which is required for transportation and activation of SLC6A19 in the kidney has been reported in two patients with symptoms that are very similar to Hartnup disease. Both presented with neuropsychiatric symptoms including autistic features, anxiety, depression, compulsions and motor tics. Due to amino acids appearing in urine, both were initially diagnosed with Hartnup disease.

Pellagra is an illness that results from a deficiency of nicotinic acid and occasionally tryptophan. This disorder is characterized by lack of appetite, weakness, discomfort, emotional instability, insomnia, bouts of diarrhea or constipation, a burning or stinging sensation of the skin (especially following exposure to the sun) and a sore mouth. The skin may become reddish-brown, scaly and rough. This disorder usually occurs from deficiencies in the diet such as those that occur in countries where corn or maize is the staple food. It is very rare in the United States.

In addition to pellagra, the skin rash associated with Hartnup disease can be similar to the malar rash seen in lupus, infantile atopic dermatitis, seborrheic dermatitis, carcinoid syndrome, xeroderma pigmentosum and a variety of other metabolic disorders including phenylketonuria and blue diaper syndrome. The neurological symptoms of Hartnup disease can resemble those seen in other metabolic disorders and ataxia-telangiectasia and other forms of ataxia.

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Diagnosis

Due to the variability of symptoms, diagnosis can only be made through urine analysis for detection of elevated amino acids by chromatography and mass spectroscopy.

Molecular genetic testing can confirm a diagnosis of Hartnup disease in some patients. Molecular genetic testing can detect variants in the SLC6A19 gene known to cause the disorder, but usually is not necessary to make a diagnosis. Testing for variants in the CLTRN gene may be considered if disease-causing variants in SLC6A19 are not detected.

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Standard Therapies

Treatment
Individuals with Hartnup disease who do not develop symptoms will usually not require any treatment. Low protein diets (vegan or similar) may trigger symptomatic episodes, which can be reduced or avoided by maintaining good nutrition including a high protein diet, avoiding excess sun exposure and avoiding certain drugs such as sulphonamide drugs. Supplementing the diet with nicotinamide or niacin may help to prevent Hartnup disease episodes.

In some instances, during a symptomatic episode, treatment with nicotinamide may be recommended.

According to the medical literature, at least one individual showed improvement of symptoms after treatment with the compound L-tryptophan ethyl ester, which restored tryptophan levels in both the serum and cerebrospinal fluid. Because intestinal absorption of di- and tripeptides remains intact in Hartnup disease, commercially available protein hydrolysates should also be beneficial.
Other treatment is symptomatic and supportive.

Genetic counseling is recommended for affected families.

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Clinical Trials and Studies

Information on current clinical trials is posted on the Internet at www.clinicaltrials.gov. All studies receiving U.S. government funding, and some supported by private industry, are posted on this government web site.

For information about clinical trials being conducted at the NIH Clinical Center in Bethesda, MD, contact the NIH Patient Recruitment Office:

Toll-free: (800) 411-1222
TTY: (866) 411-1010
Email: [email protected]

Some current clinical trials also are posted on the following page on the NORD website:
https://rarediseases.org/for-patients-and-families/information-resources/info-clinical-trials-and-research-studies/

For information about clinical trials sponsored by private sources, contact:
www.centerwatch.com

For more information about clinical trials conducted in Europe, contact:
https://www.clinicaltrialsregister.eu/

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References

TEXTBOOKS
Buist NRM, Winter SC. Hartnup Disease. In: NORD Guide to Rare Disorders. Lippincott Williams & Wilkins. Philadelphia, PA. 2003:458.

JOURNAL ARTICLES
Pillai NR, Yubero D, Shayota BJ, et al. Loss of CLTRN function produces a neuropsychiatric disorder and a biochemical phenotype that mimics Hartnup disease. Am J Med Genet A. 2019;179(12):2459-2468. doi:10.1002/ajmg.a.61357

Broer S. Diseases associated with general amino acid transporters of the solute carrier 6 family (SLC6). Curr Mol Phamacol. 2013;6:74-87. https://www.ncbi.nlm.nih.gov/pubmed/23876153

Cheon CK, Lee BH, Ko JM, Kim HJ, Yoo HW. Novel mutation in SLC6A19 causing late-onset seizures in Hartnup disorder. Pediatr Neurol. 2010;42:369-371. https://www.ncbi.nlm.nih.gov/pubmed/20399395

Azmanov DN, Kowalczuk S, Rodgers H, et al. Further evidence for allelic heterogeneity in Hartnup disorder. Hum Mutat. 2008;29:1217-1221. https://www.ncbi.nlm.nih.gov/pubmed/18484095

Seow HF, Broer S, Broer A, et al. Hartnup disease is caused by mutations in the gene encoding the natural amino acid transporter SLC6A19. Nat Genet. 2004;36:1003-1007. https://www.ncbi.nlm.nih.gov/pubmed/15286788

Kleta R, Romeo E, Ristic Z, et al. Mutations in SLC6A19, encoding B0AT1, cause Hartnup disorder. Nat Genet. 2004;36:999-1002. https://www.ncbi.nlm.nih.gov/pubmed/15286787
INTERNET
McKusick VA, ed. Online Mendelian Inheritance in Man (OMIM). Baltimore. MD: The Johns Hopkins University; Entry No: 234500; Last Update: 06/03/2020. Available at: https://omim.org/entry/234500 Accessed October 25, 2023.

Wendel U. Hartnup Disease. Orphanet Encyclopedia. Last update: July 2019. Available at: https://www.orpha.net/consor/cgi-bin/OC_Exp.php?Expert=2116 Accessed October 25, 2023

Sekulovic LK, Karadaglic D, Stojanov L. Hartnup Disease. Medscape. Updated:Nov 12, 2021. Available at: https://emedicine.medscape.com/article/1115549-overview Accessed October 25, 2023.

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