NORD gratefully acknowledges Professor Stefan Broer, College of Science, The Australian National University, for assistance in the preparation of this report.
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 cases was accompanied by episodes of neurological involvement that can include 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 during 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 mutations in the SLC6A19 gene and is inherited in an autosomal recessive manner.
The symptoms of Hartnup disease vary greatly from one person to another. The majority of 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 symptom 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 those of the legs.
There have been reports of delayed cognitive development and, in rare instances, mild intellectual disability in some children. It is, however, unclear whether these symptoms are related to Hartnup disorder or incidentally occurred in the same individual and were therefore attributed to Hartnup disorder. 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 abnormalities 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 instances, 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.
Hartnup disease is caused by alterations (mutations) 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 particular protein, this can affect many organ systems of the body.
These alterations are inherited in an autosomal recessive manner. Most genetic diseases are determined by the status of the two copies of a gene, one received from the father and one from the mother. Recessive genetic disorders occur when an individual inherits two copies of an abnormal gene for the same trait, one from each parent. If an individual inherits one normal gene and one 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 altered gene and have an affected child is 25% with each pregnancy. The risk to have 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.
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 underlying genetic defect 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.
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.
Due to the variability of symptoms, unambiguous diagnosis can only be made through urine analysis. Pediatricians can request this analysis from selected pathology centers. The test is based on the detection of elevated amino acids in the urine by chromatography and mass spectroscopy.
Molecular genetic testing can confirm a diagnosis of Hartnup disease in some cases. Molecular genetic testing can detect genetic alterations in the SLC19A6 gene known to cause the disorder, but usually is not necessary to obtain a diagnosis.
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 exposure the sun, and avoiding certain drugs such as sulphonamide drugs. Supplementing the diet with nicotinamide or niacin is also of benefit in preventing 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 an improvement of symptoms after treatment with the compound L-tryptophan ethyl ester, which restored tryptophan levels in both the serum and cerebrospinal fluid.
Other treatment is symptomatic and supportive. Genetic counseling may be helpful for affected families.
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