What is Hartnup Disease?
Amino acids are the components that make up protein. There are three types of amino acids, classified based on how they interact with water – acidic, basic, and neutral. Hartnup disease is a genetic disorder that’s passed down through families. It’s characterized by the body’s decreased ability to absorb neutral amino acids from the gut and kidneys.
It manifests in a variety of symptoms including an excess of neutral amino acids in urine, a substance called indican in urine, a skin rash that worsens with sun exposure, coordination problems, anxiety, depression, and mild intellectual disability. These symptoms can come and go, and their intensity can be influenced by things like one’s environment, seasons, stress levels, and nutrition.
Interestingly, some people with Hartnup disease may not show any symptoms and their condition could be discovered accidentally during routine medical check-ups.
What Causes Hartnup Disease?
Hartnup disease is caused by a change or mutation in a person’s genes. It affects a gene known as SLC6A19, which is found on the short arm of chromosome 5. This specific gene is involved in making a protein called B0AT1. This protein is located on the surface of cells in the small intestine and kidneys and is indicated to be most active in certain parts of the kidneys and the small intestine called the early proximal convoluted tubules and the jejunum respectively.
When there is a mutation in the SLC6A19 gene, it can lead to Hartnup disease. The mutations that can cause this disease vary and may include missense, splice site, frameshift, and nonsense mutations. The protein B0AT1 is moved to the cell surface by specific membrane proteins. These are collectrin in the kidneys and angiotensin-converting enzyme 2 in the intestines. These proteins activate B0AT1 through specific chemical reactions and then transport B0AT1 to the surface of the cell.
Both the angiotensin-converting enzyme and the collectrin protein are encoded by genes found on the X chromosome band Xp22.2. If there’s a mutation in these genes, it can result in less B0AT1 transporter protein on the cell surface, causing the symptoms of Hartnup disease.
Hartnup disease can be the result of a mutation in the protein B0AT1 or in the co-receptors collectrin and ACE2. The symptoms can therefore vary widely based on where exactly the mutation is.
Risk Factors and Frequency for Hartnup Disease
Hartnup disease is not very common, occurring in 1 out of every 15,000 live births. The disease was first identified in 1956 in England, within a family with four children who all had the disease. The initial cases were recognized due to symptoms such as rash that gets worse when exposed to the sun, loss of full control of bodily movements, shaky hands, and problems with walking. Each of the four children experienced different severities of these symptoms. Typically, Hartnup disease starts in early childhood. It is passed down through families, which means both boys and girls can inherit the disease.
Signs and Symptoms of Hartnup Disease
People with this condition often have on-and-off skin and neurological symptoms, which can get worse with sunlight, hot weather, and lack of proper nutrition. The skin symptoms often look like pellagra, a disease caused by lack of niacin. These symptoms often show up on parts of the skin that get lots of sun and look red and scaly. There have been cases where these skin symptoms improved when treated with nicotinamide, a form of vitamin B3.
The neurological symptoms can range from:
- Tremors (shaking)
- Ataxia (loss of coordination)
- Mood disorders
- Depression
- Convulsions (seizures)
- Psychosis (losing touch with reality)
Children with this condition usually reach developmental milestones at normal ages, but they may perform below average in school and may be shorter than their peers. The symptoms can improve as they get older and their bodies’ need for protein decreases. If their diets include enough niacin, these individuals might not show any symptoms throughout their lives.
Testing for Hartnup Disease
Hartnup disease is a condition that affects how the body absorbs and processes certain proteins. This disease is diagnosed through a urine test that looks for certain types of amino acids, which are the building blocks of proteins. The amino acids that are usually searched for during the test are neutral amino acids such as valine, serine, phenylalanine, histidine, glutamine, leucine, asparagine, citrulline, isoleucine, threonine, alanine, tyrosine, and tryptophan. The presence of these in the urine can highlight a problem with the body’s ability to properly absorb them from food.
The test uses a method called paper chromatography, which helps separate and identify these different types of amino acids. In addition to the amino acids, the urine test also checks for a substance called indican. Indican is produced when tryptophan, one of the amino acids, is broken down by bacteria in the colon. If there’s too much indican in the urine, it may be a sign of Hartnup disease.
Treatment Options for Hartnup Disease
The main goal of treatment is to prevent clinical episodes or symptoms from occurring. Hartnup disease, a rare genetic disorder, can be managed through a specific diet high in protein. It’s important for patients to have a balanced diet, as symptoms are more frequent in individuals who are malnourished or who rely heavily on corn-based foods.
Supplementing with nicotinamide, a form of vitamin B3, can help improve skin problems and neurological symptoms in patients who are deficient in niacin, another type of B3 vitamin. If a patient with Hartnup disease is experiencing neurological symptoms, a complete neurological exam is necessary. Depending on the specific neuropsychiatric symptoms, certain treatments for mental health and neurological conditions might be needed.
What else can Hartnup Disease be?
When diagnosing Hartnup disease, it’s important to differentiate it from other conditions that can cause a skin rash that is sensitive to sunlight. The usual suspects include:
- Nutritional pellagra
- Lupus erythematosus
- Congenital poikiloderma
- Carcinoid syndrome
- Seborrheic eczema
These conditions can be differentiated by additional symptoms and test results. For instance, nutritional pellagra doesn’t alter the results of a urine analysis, while lupus would show specific antibodies in a blood test. Carcinoid syndrome comes with flushing and diarrhea and would increase the levels of specific acid in the urine test. Seborrheic eczema, on the other hand, shows yellow crusting on skin lesions and is often associated with a history of allergies.
What to expect with Hartnup Disease
The symptoms of this condition have been observed to lessen with age. Consuming a diet rich in protein and supplemented with niacin – a type of Vitamin B, often decreases the chances of symptoms recurring. Overall, the prognosis, or the likely outcome of the disease, is typically positive. Patients can expect to live a normal lifespan with minimal health complications or altered quality of life.
Possible Complications When Diagnosed with Hartnup Disease
The difficulties that might arise include:
- Severe brain damage symptoms, such as sudden, uncontrolled electrical disturbances in the brain, illusions, and severe confusion or disturbed thought processes.
- Excessive darkening of the skin and extreme dryness at the location of emerging skin sores.
- Reports indicate delays in mental and physical growth, leading to poor academic performance.
Preventing Hartnup Disease
It’s important for people with Hartnup disease to take steps to avoid triggers for possible episodes. One major step is protecting themselves from the sun, as warmer weather and direct sunlight can make skin symptoms worse. This can include wearing sun-protective clothing, seeking shade when outdoors, and regularly applying a good quality sunblock.
There are also certain types of medications that can make the skin more sensitive to light, such as sulfonamides, nonsteroidal anti-inflammatory drugs, tetracyclines, and oral contraceptives. People with Hartnup disease should therefore avoid these types of medications where possible to reduce their risk of triggering an episode of the disease.
