Hartnups Disease: Causes, Symptoms & Treatment

Hartnup disease is a rare and autosomal recessive inherited metabolic disorder that blocks the transport of amino acids in cell membranes through an allele mutation. The disease is highly variable and can affect the skin, kidneys, liver, and even the central nervous system.

What is Hartnup disease?

Hartnup disease, or Hartnup syndrome, is a medical term for a metabolic disorder that affects the transport of amino acids across cell membranes. It is a hereditary disease that is passed on in an autosomal recessive manner. This means that both homologous chromosomes must carry the defective allele for the disease to occur. Therefore, Hartnup disease is rather rare. Not all carriers of the gene develop symptoms at all. Because up to six different gene variants are affected by the disease, the metabolic disorder is extremely variable. For example, the disease can manifest itself exclusively in a difficulty in transporting amino acids in the kidneys, but it can also affect only the intestines. The disease is often compared with the so-called pellagra, a hypovitaminosis due to malnutrition, which causes similar symptoms. The disease was first documented in 1956 in children of the Hartnup family in London. Today, experts believe that Julius Caesar already suffered from the metabolic disorder.

Causes

The cause of Hartnup syndrome is a gene mutation. In this context, medicine assumes a total of 21 different mutations of SLC6A19 in chromosome five gene locus p15.33, each of which has different effects on the transport of amino acids in the body. As a rule, patients of Hartnup syndrome suffer from two different mutations, with a large proportion of them having allele D173N as their gene carrier. Mutations of the alleles D173N or P265L have transport channels in direct dependence of ACE2 in the intestine or Tmem27 in the kidneys. The gene defect results in a deficiency of certain membrane proteins in the body, which in healthy individuals appear as neutral amino acid transporters. These amino acid transporters transport both neutral and aromatic amino acids through the body cells. In body tissues of increased amino acid uptake, the effects of the gene defect are most apparent, although they are not limited in principle to these tissues.

Symptoms, complaints, and signs

Hartnup disease manifests itself in a wide variety of symptoms, depending on severity, and progresses in episodes. In particular, fever, stress, and medications can trigger an episode. On the skin, erythematous eczema, specific skin lesions, appear during an episode. The gastrointestinal tract is affected by symptoms such as recurrent or even persistent diarrhea. Under certain circumstances, accompanied by psychiatric disorders, neurological symptoms also occur, such as ataxia or paralysis, but these usually disappear again. In most cases, it is above all the immune system that is permanently damaged, so that those affected by Hartnup syndrome become ill more quickly, for example. Apart from this, hypersensitivity to insulin can be symptomatic of the disease. The same applies to anatomical damage to the adrenal glands or liver. In some circumstances, headache and photosensitivity may also occur during a disease episode.

Diagnosis and course

Because Hartnup disease is variable, it is difficult to make sweeping statements about the course of the disease. Ultimately, the metabolic disorder primarily affects the upper small intestine and certain cells of the kidneys. The effects of Hartnup’s disease on the kidneys usually consist of reduced absorption, i.e. an inability to retain amino acids in the bloodstream. Amino acids are thus lost as they accumulate in the urine instead of the blood. However, if the affected person takes in sufficient protein, then this loss is not significant and does not cause any symptoms. However, since those affected by Hartnup’s disease often also have a resorption disorder in the small intestine, there are usually serious losses overall, because certain essential amino acids are simply necessary for life support, and a healthy body obtains a large proportion of these vital substances in the intestine through amino acid recycling. If left untreated, Hartnup syndrome therefore often leads to serious damage and can even have fatal consequences.Nevertheless, medical science today generally assumes a rather benign course of the disease, since suitable treatment methods are available to compensate for the amino acid loss even in severe cases of Harntup syndrome. Detecting the disease is relatively difficult because of the many mutations. Usually, when the genetic defect is suspected, physicians order a urinalysis, which may confirm the presence of amino acids in the urine, thus confirming the initial suspicion. If the initial suspicion cannot be confirmed by the urine sample, however, the disease is not necessarily ruled out. In this case, reliable diagnosis is also difficult or impossible using blood values. Under certain circumstances, however, a test for porphyrogens can provide indications, in which hydrochloric acid is added to the morning urine. If the urine is then heated, porphyrogens form a red color, which corresponds to a positive test result. However, this test is also rather nonspecific.

Complications

Hartnup disease can affect various internal organs of the body and cause discomfort or complications in them. However, in most cases, Hartnup disease affects the liver, kidneys, and skin. Furthermore, there may also be restrictions and complaints on the central nervous system. The patient primarily suffers from stress and fever. Likewise, diarrhea occurs, which not infrequently can be accompanied by vomiting and severe nausea. Due to the impairment of the central nervous system, the patient sometimes suffers from paralysis or sensory disturbances. These can further lead to psychological complaints and depression. The patient’s immune system is usually weakened by Hartnup’s disease, so that inflammations and various infections develop more often. Damage to the liver and kidneys occurs. In the worst case, the patient suffers complete renal failure and is thus dependent on dialysis or a donor organ. The symptoms of Hartnup’s disease are treated with the help of medication. No further complications occur. Likewise, psychological measures are also necessary for usually.

When should one go to the doctor?

Unfortunately, the symptoms of Hartnup’s disease are not particularly specific, so no general prediction can be made about when to see a doctor. The symptoms often occur in episodes, which can be indicative of the disease. This usually involves severe diarrhea or other discomfort in the stomach and intestines. Skin complaints may also indicate Hartnup’s disease and should be investigated. Furthermore, paralysis is also a typical symptom of the disease, and its severity can vary greatly. Frequently, affected individuals also suffer from a weakened immune system and become ill relatively often or suffer from infections and inflammations. In some cases, Hartnup’s disease can also lead to high sensitivity to insulin, which should also be investigated. The initial examination can be done by a pediatrician or by a general practitioner. Since the disease cannot be completely cured and is treated only symptomatically, the general practitioner can usually provide this treatment as well.

Treatment and therapy

Patients with Hartnup disease are usually treated with replacement therapy. This means that they are provided with a daily dietary supplement in the form of niacin. They take up to three grams of the substance daily in the initial phase, with the dose being regulated to 500 milligrams per day in the maintenance phase. A particularly high-protein diet with plenty of tryptophan complements this method of therapy. Dairy products, poultry, potatoes and nuts form the core of the dietary measures. In severe courses of the disease, these methods are not sufficient to compensate for the transport defect, so that intravenous substitutions with chemically modified amino acid must be used. Depending on the symptoms caused by an episode of the disease, physiotherapeutic measures may also be used to combat the symptoms of paralysis, in addition to ointments for the skin symptoms.

Outlook and prognosis

The outlook for Hartnup disease varies. They depend on the extent of loss of neutral and essential amino acids.If only the kidneys are affected by the disorder, the loss can be well compensated by diet. Hartnup’s disease is genetic. But it develops a great variability. Thus, several possible mutations are suspected. As a result, there is a wide range of the disease, from asymptomatic to severe. Most affected individuals develop no symptoms and achieve a normal life expectancy even without treatment. However, the severe forms of Hartnup’s disease often lead to death if left untreated. Many organs of the body can be affected by the deterioration. Neutral and aromatic amino acids are insufficiently or not at all transported through the cells due to a lack of transport proteins. They are lost to the body through excretion in the urine. In severe cases, amino acids from degraded body cells can no longer be used at all. This can lead to a situation where even essential and non-essential amino acids supplied through the diet are no longer sufficient to maintain vital functions. Many organs and organ systems such as the liver, pancreas, adrenal glands, skin, intestines, central nervous system or immune system are weakened. Administration of niacin can improve transport problems in some cases. In particularly severe cases of Hartnup’s disease, the important amino acids must be substituted intravenously for life to increase life expectancy.

Prevention

Hartnup disease cannot be prevented because the metabolic disease is a hereditary genetic defect. However, with a prevalence of 1:24,000, the disease is relatively rare.

Follow-up

In Hartnup disease, very few measures of direct follow-up are available to the patient. However, in this disease, early detection and treatment of the disease is very important to prevent further complications or discomfort. The affected person should seek medical attention for Hartnup’s disease at the first symptoms and signs to prevent further worsening of the symptoms. There can be no cure on its own. Therefore, in most cases, the treatment of this disease is done by taking various medications. The patient should always pay attention to a correct dosage and also to a regular intake in order to alleviate the symptoms. In many cases, it is necessary to change the diet, and a doctor can also prepare a diet plan. Furthermore, with Hartnup’s disease, some sufferers rely on the measures of physiotherapy to treat the symptoms. Many exercises from such therapy can also be performed in the patient’s own home. Loving care and support for those affected also have a positive effect on the course of this disease. Above all, depression or psychological upsets can be prevented as a result.

What you can do yourself

Since Hartnup disease is a hereditary defect, the disease can usually not be prevented. Affected individuals are always dependent on treatment by a physician. For this reason, there is no direct possibility of self-help for the disease. In most cases, those affected are dependent on substitution therapy to alleviate the symptoms. Regular and correctly dosed intake must be ensured. In case of doubt, a doctor must always be consulted. Furthermore, a diet with tryptophan can also have a very good effect on Hartnup’s disease. For this reason, potatoes, poultry and dairy products are particularly suitable. Nuts also represent an important part of this diet. If paralysis or sensory disturbances occur, they are usually treated therapeutically. These exercises can often be done at home to speed up the healing of Hartnup’s disease. In case of severe paralysis, however, the affected persons depend on loving support in their everyday life. Contact with other sufferers of the disease can possibly prevent psychological discomfort.