Hereditary disease, characterized by metabolic disorders, which is based on excessive formation of uric acid, disorders of neuropsychiatric functions reminiscent of the symptomatology of cerebral palsy, behavioral anomalies manifested in the propensity to self-harm and obsessive aggressiveness in combination with mental retardation was called Lesch-Nihan syndrome.
This is not a very common disease attracted attention for a long time, its first description refers to the middle of the XIII century. And only in 1964 medical student M.Lesh and his teacher U. Nihan, describing this disease as an independent, immortalized their names in his name. And three years later, a group of scientists found that it was caused by the lack of enzymatic activity of the purine metabolism catalyst.
The epidemiology of this disease in the classical form is estimated as one case from 200-380 thousand of the population. The frequency of variations in the syndrome is unknown. Almost all episodes are recorded in men, rare episodes of the syndrome among women are explained by a non-random inactivation of the X chromosome. Currently, more than 600 mutations of the HGFR gene are known.
Causes of the lesha-Nihan syndrome
This disease is determined by the pathology of the exchange process of purine nucleotides, caused by a hereditary enzymatic deficiency of GFRT (second phosphoribosyltransferase), which catalyzes the secondary conversion of guanine and hypoxanthine into the corresponding mononucleotides.
The GFRT gene is located on the long arm of the X chromosome, is passed on to the next generation of men from the mother, i.e. Risk factors - episodes of this syndrome in previous generations.
The absence of hypoxanthine-guanine phosphoribosyltransferase is the main moment of the pathogenesis of this disease. Under such conditions, purines are decomposed and isolated in the form of uric acid. The body includes a compensatory mechanism that accelerates the synthesis of purine bases to make up for the losses from their destruction. The speed of biosynthesis of purines exceeds the rate of their destruction, which is the main cause of overproduction of uric acid and leads to supersaturation of blood plasma with urate sodium.
As a result, they crystallize in different organs and tissues of the body with the formation of tofus (gouty formations). Crystals of uric acid, appearing in the joints, cause inflammation and gouty arthritis.
The kidneys also respond to hyperuricemia by accelerating the excretion of uric acid, which can lead to the formation of urate formations. It can be not only sand, but also stones that can block the excretion of urine and provoke hematuria and infection of the urinary system.
In the part of the pathogenesis of nervous system disorders and behavior in the Lesch-Nihan syndrome, there are still many questions. Chemical and visualization studies of neuroprocesses suggest that in patients, there are significant decreases (up to 90%) in the level of dopamine in the basal nuclei, the link between the cortical areas responsible for associative thinking and coordination of movements. This can explain the occurrence of motor disorders and behavioral abnormalities.
The biochemical processes resulting from the absence of hypoxanthine-guanine phosphoribosyltransferase and affecting basal nuclei and, in particular, dopamine, have not yet been elucidated. Because of the enzymatic deficiency in the cerebrospinal fluid, not uric acid, but, hypoxanthine, is concentrated. Acid in the brain tissue is not synthesized and does not get through the blood-brain barrier. Anomalies of behavior, apparently, are not caused by supersaturation of blood plasma with urate sodium or concentration of hypoxanthine. Here there are other circumstances, since partial loss of enzyme activity causes only gout, and the development of Lesch-Nihan syndrome occurs with the absolute absence of enzymatic activity of GFRT.
Symptoms of the lesha-Nihan syndrome
A significant part of patients already in the first year of their life are found motor disorders, from 0.5 to 1.5 years they become noticeable uncoordinated involuntary movements, characteristic of extrapyramidal disorders. Relying on the clinical picture, children often erroneously diagnose infantile cerebral palsy.
A small number of patients with this pathology are symptomatic, indicating an increased production of uric acid. Mom babies can see in diapers "orange sand", that is precipitation of salts of uric acid (crystalluria) or erythrocytes in the urine (microhematuria). The first signs of this syndrome can be expressed by complete or partial renal dysfunction or hematuria due to the formation of stones in the urinary system.
In infancy, aggression to oneself is almost not observed, however, with age this symptom is characteristic for all patients. By the presence of self-aggression in combination with intellectual backwardness and hyperuricemia, and diagnose this disease.
External symptoms, which allow to diagnose this genetic pathology, are classified into the following groups:
disorders of the nervous system - hypertension of the muscles, convulsive alertness, hyperkinesis, frequent vomiting for no apparent reason, slow development, both physical and mental (children begin to sit down, walk, speak with a backwardness from the norm), dysarthria, may occur episyndrom, paresis of the upper or lower limbs;
metabolic disorders - constant thirst, frequent and profuse urination, arthritis (mainly affected by the joints of the toes), gouty nodes in the ear lobes, crystalluria, stunting and puberty;
anomalies of behavior - increased nervousness, a sharp change in mood with the prevalence of an aggressive attitude towards oneself, things that surround people, traces of injuries on the body, inside the cheeks, fingers appear from the moment of teething.
The initial stage of the disease is characterized by psychomotor backwardness, later it adds muscle hypertonicity and a combination of hyperkinesis and hypokinesia. With the appearance of teeth, a pronounced tendency to self-harm becomes pronounced. Autoaggression manifests itself in the biting of the lips, nails, fingers, scratching the skin of the face to the blood. The pain threshold is not reduced, so self-mutilation is accompanied by screams caused by pain. Patients at this stage are aggressive not only to themselves, but also to surrounding people, animals, things.
The clinical types of Lesch-Nihan syndrome are classified according to the degree of activity of hypoxanthine-guanine phosphoribosyltransferase. A classic type of disease is observed in the absence of enzymatic activity of GFRT.
With its partial deficit (1.5-2% of the norm), symptomatology predominates from the side of the central nervous system.
If the insufficiency exceeds 8% of the norm, then the mental capacity is practically without deviations, but this type is accompanied by severe manifestations of gout.
Autoaggression for erased variants of the disease is not typical, but sometimes a small dystonia is observed in patients.
Complications and consequences
Consequences and complications of the syndrome in the classical form are associated with a variety of psychological and neurological problems, patients are deprived of the opportunity to move independently, can not engage in self-care, most often in psychiatric hospitals. Physical condition is unsatisfactory (gout, kidney stones), life expectancy is low.
Diagnostics of the lesha-Nihan syndrome
Diagnosis of the disease in the clinical triad: hyperuricemia, nervous system disorders; mental retardation in combination with abnormal behavior. To establish the diagnosis requires a consultation of a neurologist, rheumatologist, genetics.
The correspondence of physical development to the age of the patient is examined. The syndrome is characterized by a lag in growth, sexual development, which may not occur at all. Usually, when checking the physical condition, traces of injuries are found in most patients - scars, scars, amputation of parts of the lips, tongue, fingers. Patients demonstrate obsessive irrational behavior, which turns into aggression to inanimate objects and to other people.
There are violations of intelligence (IQ≈60), neurological functions - with normal sensitivity, coordination disorders, neurocirculatory dystonia, convulsive muscle contractions, choreoathetical movements are noticeable. The severity of disorders of the nervous system deprives patients of the opportunity to move independently.
Patients under the diagnostic measures are assigned clinical analyzes of urine and blood, blood biochemistry - to establish the level of uric acid. The main instrumental diagnostics is ultrasound examination of the kidneys.
Diagnosis of the syndrome at an early stage is difficult, because all three features have not yet emerged. It is possible to suspect its presence by noticing physical and intellectual backwardness, which is accompanied by hyperproduction of uric acid, leading to nephrolithiasis or hematuria. Later, when the teeth erupt, self-evaluation of the patient may lead to the thought of Lesch-Nyhen syndrome. But since auto-aggression is also characteristic of other mental pathologies, a line of differential diagnosis is coming.
From other syndromes, which are characterized by self-inflicted injuries, this pathology is distinguished by the localization of wounds - skins, lips, mucous membranes of the oral cavity. The facts of self-harm are necessarily accompanied by hyperuricemia and nervous system disorders similar in the clinic with infantile cerebral palsy. Differential diagnosis allows for a combination of symptoms to accurately distinguish Lesch-Nyhen syndrome from other diseases.
The decisive point in the diagnostic activities is the genetic study - the establishment of the level of GFWR and recognition of the mutations of its gene.
Patients with a classical form of the disease are recommended to be placed in a hospital. In the treatment of this disease, the focus is on the normalization of the synthesis of uric acid in order to prevent negative consequences from the genitourinary system and inflammatory processes in the joints. At the same time, medicinal preparations that slow down the process of overproduction of uric acid are used and compensate for fluid losses, especially during periods of intense loss, for example, with frequent recurrence of vomiting.
With hyperuricosuria, stones are removed by medication or by surgical intervention. With gouty arthritis, non-steroidal anti-inflammatory drugs are used.
Medicinal treatment must be combined with observance of a non-purpinic diet, while patients should drink as much pure water as possible. As an additional factor, only plant food can be used, which helps alkalinize urine and dissolve uric acid crystals.
To reduce the level of uric acid and, consequently, to reduce inflammation in the gouty nodes and the deposition of salts, a noticeable effect is provided by therapy with Allopurinol. This drug, frustrating the process of overproduction of uric acid. The urostatic effect is achieved due to its ability to inhibit the enzymatic activity of xanthine oxidase, a catalyst for oxidation of hypoxanthine. Preventing the production of uric acid, Allopurinol reduces its content in the blood and promotes the dissolution of its salts. The duration and schedule of treatment is prescribed by the doctor depending on the level of uric acid.
The average daily dosage of Allopurinol is from 100 to 300 mg, it can be taken once. The recommended initial dosage is 100 mg / day, its adjustment is performed no more often than once a week as needed. The daily dosage, maintaining the level of uric acid, on the average from 200mg to 600mg, when treated with high dosages - from 600mg to 800mg. When the dosage is more than 300 mg / day, the drug is taken in equal parts (one dose does not exceed 300 mg).
Correction of dosing toward the increase implies control of the level of oxypurinol in the blood plasma (the main metabolite of Allopurinol).
Children from 15 years of age are prescribed a drug at a rate of 10-20 mg per 1 kg of weight (divided into three doses). The greatest infant dosage is 400 mg / day.
Allopurinol is not prescribed for severe kidney and liver pathologies, allergies, during gout exacerbation, with caution in heart disease and hypertension.
This drug, in general, does not cause side effects, but they can not be excluded from any organs and body systems.
As an alternative to Allopurinol (with its intolerance), prescribe Probenecid, which prevents the reverse absorption of uric acid, which increases its excretion.
In cases of chronic course gout for therapy with Probenecid starts with a dosage of 250 mg twice a day for a month. A week after the start of treatment, the dosage can be increased to 500 mg twice a day. The greatest dosage is 2000 mg / day. Provided that during ½ year of taking Probenecid the patient did not experience gout exacerbation, and also, the uric acid content in the blood plasma is not more than the permissible level, the dosage is reduced every six months by 500 mg to the lowest active dose. Probenecid is prescribed to children from two years of age, therapy starts with a dosage of 25 mg / kg of weight with an increase of up to 40 mg / kg, taken intermittently for at least 6 hours.
It should be borne in mind that the action of Probenecid, leading to the release of uric acid, can cause gouty paroxysm. Also, this drug prevents urinary excretion of certain drugs, for example, antibiotics, NSAIDs, sulfonylurea derivatives, increasing their accumulation in the blood plasma.
Probenecid is not prescribed for gouty paroxysms; stones, especially urate; porphyria; pathology of hematopoiesis; at the age of up to two years; secondary hyperuricemia due to neoplasms or chemotherapy; allergies.
Patients with nephrolithiasis should maintain a large volume of urine with a neutral acidity level. In this case, use balanced mixtures of salts, for example, Polycitra.
The importance of a neutral acidity level of urine is proved by the fact that with acid urine (for example, pH 5,0), the ability of uric acid to dissolve is 0.15 g / l, and at neutral - 2 g / l.
Hyperuricemia needs to be corrected, since no correction is made with probenecid, but overproduction of uric acid is well inhibited by Allopurinol.
Neurological disorders are treated based on symptoms, for example, alprazolam, baclofen or diazepam can reduce anxiety, eliminate convulsions, and reduce motor function disorders.
Alprazolam is a psychotropic drug that exerts a moderate hypnotic effect, which removes manifestations of depression, which has a slight anticonvulsant effect.
In patients taking this drug, there is a decrease in anxiety and feelings of fear, as well as stabilization of the emotional state.
The effect of Alprazolam on the cardiovascular and respiratory systems in patients without these pathologies is not observed.
Treatment of adult patients begins with a dosage of 0.1-0.2 mg two or three times a day. After a week from the start of therapy, the dosage is started, if necessary, from the evening reception. The average daily dosage is from 3 to 6 mg, the largest is 10 mg.
Duration of treatment in acute cases - from three to five days, the maximum can be taken no more than three months.
To cancel the drug, the dosage is reduced every 0.5 days by 0.5 mg, as a sharp cessation of treatment leads to the formation of withdrawal syndrome. At the beginning of treatment there is drowsiness, lethargy, loss of strength, decreased concentration of attention and psychomotor and other negative reactions. The drug is not prescribed in cases of lactose intolerance, with respiratory, liver and kidney dysfunctions.
Diazepam - a tranquilizer of the benzodiazepine series, promotes muscle relaxation, relieves convulsive readiness, has a pronounced soothing effect, enhances the effect of γ-aminobutyric acid, which functions as a mediator of inhibition of the central nervous system.
Diazepam increases the stability of the tissues of the nervous system in oxygen starvation, thereby increasing the pain threshold, inhibits vegetative attacks.
Has an effect on the central nervous system depending on the dosage taken: up to 15 mg per day stimulating, more than 15 mg - hypno-sedative.
As a result of taking the drug in patients, anxiety, a sense of fear, emotional stress decreases. Occasionally there is a decrease in affectation.
As a psychotropic drug apply from 2.5 to 10 mg two, three or four times a day. In psychiatry, when dysphoric conditions are dosed from 5 to 10 mg two to three times a day. If necessary, the daily dosage is gradually increased to a maximum (60 mg).
In pediatrics in the treatment of jet and psychosomatic disorders, as well as spastic conditions, children up to 3 years of age are recommended parenteral administration (dosed individually), older than 3 years - orally with 2.5 mg per day. If necessary, the dosage is gradually increased, while the child's condition is controlled by the medical staff.
Diazepam in most cases is well tolerated, but the treatment should take into account the likelihood of undesirable effects of its use as a decline in strength, confused consciousness, drowsiness, emotional, visual, motor, speech disorders. The drug may be addictive.
Diazepam is not recommended for persons prone to suicide, with pathological muscle fatigue, with epilepsy. It is not used for violations of external respiration, glaucoma, ataxia, porphyria,
With the anomalies of behavior, mainly with self-aggression, the most difficult to cope with, the most effective methods are complex methods, including behavioral and drug therapy. Apply gabapentin and benzodiazepines, in the most severe cases, you can use neuroleptics, they are used to relieve exacerbation.
In complex therapy, vitamins and trace elements are necessarily present, in case of hyperuricemia, vitamin B, vitamin C, potassium, neuroprotectors - vitamin A, D, folic acid, biotin are prescribed.
Practically in all cases of genetic pathologies in a complex of therapeutic measures, physiotherapeutic treatment is used. Lesha-Nihan syndrome uses a wide variety of physiotherapeutic methods of treatment - electrosleep, galvanization, massages, coniferous baths. To prevent gouty attacks, physiobalneotherapy is recommended, in particular, radon baths have a good uricosuric effect. For the removal of inflammation, mud applications are used, as well as paraffin-ozokeritotherapy.
For the excretion of uric acid and the prevention of stone formation, it is advisable to ingest low mineralized mineral waters having alkaline pH values.
The curative gymnastics is included in the general complex of treatment.
In addition to medication, physiological and psychological therapy, you can consult with your doctor to use alternative drugs and take some tips:
be sure to stick to the disupuncture diet and drink a lot, about 18 glasses of liquid a day;
the favorite soups should be pea, lentil, bean, porridge - wheat, oat, buckwheat, rice, millet, carrots (raw and boiled), corn, raspberries and pistachios - these products contain molybdenum, which promotes the excretion of uric acid and thereby prevents the development of gout;
buckwheat, barley and oat porridge, lentils are also rich in copper, which controls the presence of uric acid in the blood and is involved in creating a sheath of nerve fibers.
In dietary nutrition, molybdenum and copper are preferably consumed together, they seem to be created for each other. Copper is rich - nuts, rye bread, yogurt, yolks of eggs (raw), spinach and lettuce leaves, asparagus, parsley, potatoes.
In alternative medicine, various not very complex decoctions and infusions are used, removing the deposition of salts.
For example, a decoction of celery and parsley : take 100g of stems with leaves and roots of these plants for half a liter of water, boil the mixture for at least five minutes, set aside for half an hour, then strain and squeeze; add the juice of one lemon and two tablespoons of honey; drink everything during the day.
Duration of treatment - one month, repeat with an interval of one week.
Or a decoction of the bean pods : a well-crushed dry pods (one tablespoon) brew with one liter of boiling water and two hours of boiling in a water bath. Strain and drink one tablespoon three times a day.
Apples are on sale all year round. Cut three large or five smaller apples into slices (do not peel off the peel). Pour water, boil for a quarter of an hour under the lid. The broth should be infused for 4 hours, it should be drunk in small portions during the day.
Trays of herbs : 200 grams of chamomile, calendula or sage to brew 1.5 liters of boiling water, insist for at least two hours, strain and add to a bath for feet with a temperature of 34 ° C, lower the temperature to 26 ° C, lower your legs and take a bath for 20 minutes. The procedures are good before bedtime, the recommended course duration is 20 days, after 20 days, repeat the course of procedures.
Cleansing of salts for lazy people. Buy 1kg of honey and raisins. In the morning on an empty stomach to eat a handful of raisins and two hours more nothing to drink or eat. The next day in the morning on an empty stomach to eat one tablespoon of honey and two hours more nothing to drink or eat. And so - every day, until the honey with raisins, will not end.
Only herbal treatment, of course, will not be able to defeat such a serious genetic defect as Lesha-Nihan syndrome. And not every herb can be combined with a set of medications, so a doctor's advice before applying is mandatory
Part of medical science, like modern traditional medicine, and not one of the types of alternative medicine, homeopathy obeys certain principles of treatment.
A homoeopathic doctor, like any other, should find out what happens to the patient and prescribe a treatment. The examination is done in a traditional way - collecting an anamnesis, examining and evaluating the results of diagnostic procedures. These data are compared with drug pathogenesis - the more similar the pathogenesis of the drug to the diagnostic data, the greater the effect of the selected drug.
The appointment of a homeopathic preparation occurs on the basis of the amount of pathological manifestations with their individual course in conjunction with the constitution, taking into account the lifestyle and heredity of the patient. A homoeopathic doctor must determine an individual drug for a particular organism.
Properly selected homeopathic drug helps to significantly improve health and get rid of chronic diseases. The therapeutic effect of homeopathic treatment comes, as a rule, in the interval from three months to two years.
In homeopathy there are preparations for conditions, the description of which is similar to the Lesch-Nihan syndrome. The most suitable preparation is Lithium carbonicum:
Lithium carbonate got into the homeopathic pharmacy, as antipodegric. Lithium salts convert the salts of uric acid into soluble, then they are excreted from the body. The patient has deformed joints with gouty nodes, painful, swollen, sensitive to touch. In all joints, in particular, knee and small on the toes, the stiffness is almost paralytic. Arthritis, acute and chronic.
Also, the drug is used for urolithiasis (oxolates and urates). Calculous colic, frequent pain in the heart zone, especially in the morning. Passes after visiting the toilet. Symptoms include headache, decreased visual acuity and clarity, rapid eye fatigue.
Depending on the symptoms, you can choose other drugs, for example:
Kolhikum (Colchicum) or saffron meadow, is also used in phytotherapy as a remedy for gout. Symptoms include gouty paroxysms with characteristic localization in small joints. "Arthritic" foot: arthritis of the big toe, pain in the heels. Edema, pain in bones and muscles, colic, digestive disorders, blurred vision. Soreness increases in the evening and night, its strengthening is facilitated by cold and motor activity. Painful sensations decrease with heat and rest.
Aconite Gouty paroxysms with soreness, anxiety, anxiety, panic, neuralgia, nervous overexcitation, wounds, muscular weakness of the lower limbs.
Ledum (Ledum) or Ledum, marsh soreness and inflammation of small and large joints, injuries and wounds and their consequences.
Guaiacum. Education of tofus, painful spasms, muscle cramps, a regular need to stretch and spread the stiff muscles, the need for apples, stubbornness, a diathesis of gouty genesis.
Dosages and treatment regimens are prescribed only individually, the recommended doses of the drug, as in traditional medicine, are not found in classical homeopathy.
Surgical operations are performed by such a patient about urolithiasis in cases of ineffective therapeutic treatment. Indications for surgery are: stopping the urine entering the bladder due to a blockage of the ureter with a stone, septicemia caused by calculous pyelonephritis; frequent paroxysms of renal colic in the absence of a tendency to independent release of stones; hematuria, which threatens life.
Operative treatment includes both open surgical interventions and instrumental ones, including crushing stones in the bladder with a cystolithotriptor, laser, ultrasound, and endoscope.
The presence in previous generations of the Lesch-Nihan syndrome requires compulsory medical genetic counseling.
Getting the necessary medical care, the life expectancy of patients with this syndrome, usually 30-40 years, some manage to live up to 50 years. Quality of life is low, complete lack of independence and disability.
The cause of death of patients often are complications of calculous pyelonephritis, renal dysfunction, aspiration pneumonia, at the same time, many patients die suddenly, and even autopsy does not reveal the cause of death.
Last update: 26.06.2018
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Medical expert editor
Portnov Alexey Alexandrovich
Education: Kiev National Medical University. A.A. Bogomolets, Specialty - "General Medicine"