Hartnup disease is a rare hereditary disease characterized by a violation of the metabolism of amino acids, mainly tryptophan. The main symptoms are pellagra–like skin rashes on the face and exposed areas of the body, photosensitivity, neurological disorders. The diagnosis is made when an increased concentration of neutral amino acids and their breakdown products is detected in the urine, confirmed by a molecular genetic study. Therapeutic measures include changes in diet, protection of the skin from sunlight, the appointment of nicotinic acid preparations.
E72.0 Amino acid transport disorders
Hartnup disease (aminoaciduria of dicarboxylic acids) is named after the first patient in whom it was diagnosed. The disease was first described by the English doctor D. Baron in 1956. Clinical manifestations resemble the picture of pellagra − a pathological condition caused by nicotinic acid deficiency. According to various statistics, the prevalence of Hartnup disease ranges from 1:18,000 to 1:54,000 people. There are no significant gender differences.
The development of Hartnup disease is associated with a genetic mutation of the SLC6A19 gene located at the 5p15.33 locus of chromosome 5. This gene encodes a sodium-dependent carrier protein involved in the transport of neutral amino acids (tryptophan, tyrosine, histidine, etc.). This protein is mainly localized in the epithelium of the small intestine and renal tubules. The inheritance of the disease occurs in an autosomal recessive type. The parents of a sick child are healthy carriers of the mutant gene.
The basis for triggering pathological manifestations is an imbalance in the metabolism of tryptophan. Due to malabsorption, tryptophan is retained in the intestine, where, under the influence of bacterial microflora, they turn into decay products – indole, kynurenine. These compounds, getting into the systemic circulation, have a toxic effect on the central nervous system. Their inactivation occurs in the liver, where they combine with sulfuric acid and are excreted in the urine as conjugates.
Violation of the reabsorption of amino acids in the renal tubules leads to their additional loss with urine. Tryptophan is the main substrate for the synthesis of nicotinic acid (vitamin PP), which is part of enzymes involved in tissue respiration and other processes of energy metabolism. Also, melatonin is formed from tryptophan – the main hormone that regulates sleep and wakefulness cycles.
The disease has a chronic course with periods of relapses and remissions. The first clinical signs can occur at any age. Manifestations and exacerbation are promoted by insufficient nutrition, emotional or physical stress, taking medications, etc. The most striking symptom of Hartnup disease is the staining of urine in blue or blue. This is due to the presence in the urine of oxidized products of indole neutralized by the liver.
The skin and nervous system suffer the most. In open areas of the body (face, neck, hands) after prolonged exposure, the skin becomes covered with red spots, becomes rough, bubbles with serous contents appear. Subjectively, the patient experiences itching and burning in the places of rashes. After a few days, the skin in the affected areas acquires a brownish hue, begins to peel off, thin out.
The most common nonspecific neurological symptoms are headache, dizziness, insomnia. Fainting often happens. In severe cases, there is a violation of coordination of movements, instability when walking, tremor of the hands and head. There are often deviations in the mental sphere, for example, constant mood swings, tearfulness. Strabismus, involuntary oscillatory eye movements are very rare.
Any serious adverse consequences that pose an immediate threat to the life of a patient suffering from Hartnup disease are extremely rare. Only with a very severe course of pathology, in isolated cases in young children, a deep lesion of the central nervous system is possible, which leads to a fatal outcome. Also, children sometimes have a lag in mental development.
There are complications from the mental sphere – depression, acute psychoses with visual and auditory hallucinations. After opening, the blisters on the skin leave ulcerative surfaces, which creates favorable conditions for the attachment of secondary bacterial flora (staphylococci, streptococci). Frequent falls due to imbalance and loss of consciousness increase the risk of traumatic brain injuries and various fractures.
Patients with Hartnup disease are supervised by pediatricians, neurologists. Anamnestic data (the presence of a close relative with confirmed Hartnup disease) are of great help in establishing the diagnosis. When questioning the patient, it is clarified what preceded the onset of symptoms (violation of diet, infectious disease, stress).
During neurological examination, the patient demonstrates difficulties in performing coordination tests – the Romberg pose, heel-knee, finger-nasal test. To confirm the diagnosis, the following additional examination methods are prescribed:
- Determination of amino acid excretion. Urine analysis reveals high concentrations of neutral amino acids, their breakdown products (indole, indican). There is also an increase in the content of 5-hydroxyindolacetic acid in the urine after oral tryptophan loading.
- Skin biopsy. Histological examination of the biopsy of the affected area of the skin reveals nonspecific changes, such as hyperkeratosis, atrophy of the epidermis, moderate lymphocytic infiltration.
- Molecular genetic analysis. The genetic mutation SLC6A19 is determined by polymerase chain reaction in the blood.
To exclude other types of aminoaciduria, for example, Fanconi syndrome, a urine test for hydroxyproline, arginine is performed. These indicators for Hartnup’s disease remain normal. Also, the differential diagnosis is carried out with dermatological diseases (eczema, atopic dermatitis), hereditary ataxia-telangiectasia.
Depending on the severity of the patient’s condition, treatment can be carried out both on an outpatient basis and in a hospital setting. The patient is advised to avoid factors contributing to the exacerbation of the disease, especially with regard to insolation; consume sufficient amounts of protein and vitamin c. Protective measures include wearing closed clothing, using sunscreens in the summer. For pharmacotherapy of Hartnup disease are used:
- Nicotinic acid. During an attack, parenteral administration of large doses of nicotinic acid is prescribed, which allows for a rapid regression of neurological and dermatological symptoms. In the future, the patient should take nicotinic acid preparations in oral form.
- Amino acids. Severe patients may need infusion of amino acid mixtures containing a high amount of tryptophan to quickly restore the level of tryptophan in the blood.
- Glucocorticosteroids. With a pronounced skin lesion, ointments or creams containing GCS (prednisolone, triamcinolone) are used to relieve inflammation.
- Psychotropic drugs. If mental disorders have developed, neuroleptics (aminazine), antidepressants (fluoxetine), tranquilizers (diazepam) are used.
Prognosis and prevention
In the vast majority of cases, Hartnup disease has a benign course and a favorable prognosis. The life expectancy of patients with timely diagnosis and the appointment of treatment practically does not differ from the general population. There are isolated situations with a fatal outcome due to generalized damage to the nervous system.
There are no methods of primary prevention. A balanced diet high in protein and vitamin PP helps prevent seizures. If there are relatives in the family with diagnosed Hartnup disease, it is recommended to do a urine test to determine the concentration of amino acids and undergo medical and genetic counseling for early detection of the disease.