Lesch-Nyhan syndrome

A hereditary disease characterized by metabolic disorders based on excessive formation of uric acid, disorders of neuropsychiatric functions resembling cerebral palsy in symptoms, behavioral anomalies manifested in a tendency to self-harm and obsessive aggressiveness in combination with mental retardation is called Lesch-Nyhan syndrome.

This not very common disease has attracted attention for a long time, its first description dates back to the middle of the 13th century. And only in 1964, medical student M. Lesch and his teacher W. Nyhan, having described this disease as an independent one, immortalized their names in its name. And three years later, a group of scientists found that it is caused by the lack of enzymatic activity of the purine metabolism catalyst.

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Epidemiology

The epidemiology of this disease in its classical form is estimated as one case out of 200–380 thousand of the population. The frequency of variations of the syndrome is unknown. Almost all episodes are registered in men, rare episodes of the syndrome among women are explained by non-random inactivation of the X chromosome. Currently, more than 600 cases of mutation of the GPRT gene are known.

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Causes of Lesch-Nyhan syndrome

This disease is determined by the pathology of the metabolic process of purine nucleotides, caused by a hereditary enzymatic deficiency of GPRT (second phosphoribosyltransferase), which catalyzes the secondary conversion of guanine and hypoxanthine into the corresponding mononucleotides.

The GPRT gene is located on the long arm of the X chromosome and is transmitted to men of subsequent generations from the mother, i.e. risk factors are episodes of this syndrome in previous generations.

The absence of hypoxanthine-guanine phosphoribosyltransferase is the main point of the pathogenesis of this disease. Under such conditions, purines are decomposed and released in the form of uric acid. The body includes a compensatory mechanism that accelerates the synthesis of purine bases to compensate for the losses from their destruction. The rate of purine biosynthesis exceeds the rate of their destruction, which is the main reason for the overproduction of uric acid and leads to oversaturation of blood plasma with sodium urates.

As a result, they crystallize in various organs and tissues of the body, forming tophi (gouty formations). Uric acid crystals, ending up in joints, cause inflammation and gouty arthritis.

The kidneys also react to hyperuricemia by accelerating the excretion of uric acid, which can lead to the formation of urate formations. This may be not only sand, but also stones that can block the excretion of urine and provoke hematuria and infection of the urinary system.

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Pathogenesis

There are still many questions regarding the pathogenesis of nervous system and behavioral disorders in Lesch-Nyhan syndrome. Chemical and visualization studies of neuroprocesses indicate that patients have significant decreases (up to 90%) in the level of dopamine in the basal ganglia, the link between the areas of the cerebral cortex responsible for associative thinking and coordination of movements. This can explain the occurrence of movement disorders and behavioral deviations.

The biochemical processes that occur as a result of the absence of hypoxanthine-guanine phosphoribosyltransferase and affect the basal ganglia and, in particular, dopamine, have not yet been elucidated. Due to the enzymatic deficiency, hypoxanthine, rather than uric acid, is concentrated in the cerebrospinal fluid. The acid is not synthesized in the brain tissue and does not penetrate the blood-brain barrier. The behavioral anomalies are apparently not caused by the supersaturation of the blood plasma with sodium urates or the concentration of hypoxanthine. Here, other circumstances are at play, since partial loss of enzyme activity causes only gout, and the development of Lesch-Nyhan syndrome occurs with the absolute absence of the enzymatic activity of GPRT.

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Symptoms of Lesch-Nyhan syndrome

A significant proportion of patients already in the first year of life show motor disorders, from 0.5 to 1.5 years they begin to notice uncoordinated involuntary movements, characteristic of extrapyramidal disorders. Based on the clinical picture, children are often mistakenly diagnosed with cerebral palsy.

A small number of patients with this pathology have symptoms indicating increased production of uric acid. Mothers of babies may see "orange sand" in diapers, that is, precipitation of uric acid salts (crystalluria) or red blood cells in the urine (microhematuria). The first signs of this syndrome may be expressed by complete or partial dysfunction of the kidneys or hematuria due to the formation of stones in the urinary system.

In infancy, aggression towards oneself is almost not observed, however, with age, this symptom is characteristic of all patients. The presence of self-aggression in combination with intellectual retardation and hyperuricemia is the diagnosis of this disease.

External symptoms that allow diagnosis of this genetic pathology are classified into the following groups:

• nervous system disorders - hypertonicity of muscles, convulsive readiness, hyperkinesis, frequent vomiting without apparent cause, delayed development, both physical and mental (children begin to sit, walk, speak with a delay from the norm), dysarthria, epilepsy syndrome, paresis of the upper or lower extremities may be observed;
• metabolic disorders – constant thirst, frequent and profuse urination, arthritis (mostly affecting the joints of the toes), gouty nodes in the earlobes, crystalluria, delayed growth and puberty;
• behavioral anomalies - increased nervousness, sudden mood swings with a predominance of aggressive attitude towards oneself, things, people around one; from the moment of teething, traces of injuries appear on the body, the inside of the cheeks, fingers.

The initial stage of the disease is characterized by psychomotor retardation, subsequently muscle hypertonicity and a combination of hyperkinesis and hypokinesis are added. With the appearance of teeth, a tendency to self-harm becomes pronounced. Autoaggression manifests itself in biting lips, nails, fingers, scratching the skin of the face until it bleeds. The pain threshold is not reduced, so self-harm is accompanied by screams caused by pain. Patients at this stage are aggressive not only to themselves, but also to people around them, animals, and things.

Clinical types of Lesch-Nyhan syndrome are classified according to the degree of hypoxanthine-guanine phosphoribosyltransferase activity. The classic type of the disease is observed in the absence of enzymatic activity of HPRT.

With its partial deficiency (1.5-2% of the norm), symptoms from the central nervous system predominate.

If the deficiency exceeds 8% of the norm, then mental abilities are practically without deviations, but this type is accompanied by severe manifestations of gout.

Autoaggression is not typical for latent variants of the disease, but sometimes patients experience mild dystonia.

Complications and consequences

The consequences and complications of the syndrome in its classical form are associated with many psychological and neurological problems, patients are unable to move independently, cannot take care of themselves, and are most often in psychiatric hospitals. The physical condition is unsatisfactory (gout, kidney stones), life expectancy is low.

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Diagnostics of Lesch-Nyhan syndrome

The disease is diagnosed by the clinical triad: hyperuricemia, nervous system disorders; mental retardation in combination with abnormal behavior. Consultations with a neurologist, rheumatologist, and geneticist are required to establish a diagnosis.

The patient's physical development is examined to see if it corresponds to his age. The syndrome is characterized by growth retardation, sexual development, which may not occur at all. Usually, when examining the physical condition, traces of trauma are found in most patients - scars, cicatrices, amputations of parts of the lips, tongue, fingers. Patients demonstrate obsessive irrational behavior, turning into aggression towards inanimate objects and other people.

There are violations of intelligence (IQ≈60), neurological functions - with normal sensitivity, coordination disorders, neurocirculatory dystonia, convulsive muscle contractions, choreoathetic movements are noticeable. The severity of nervous system disorders deprives patients of the ability to move independently.

As part of diagnostic measures, patients are prescribed clinical urine and blood tests, blood biochemistry - to determine the level of uric acid. The main instrumental diagnostics is an ultrasound examination of the kidneys.

Diagnosis of the syndrome at an early stage is difficult because all three features have not yet manifested themselves. Its presence can be suspected by noticing physical and intellectual retardation, which is accompanied by hyperproduction of uric acid, leading to nephrolithiasis or hematuria. Later, when teeth are erupting, self-injury of the patient may prompt the idea of Lesch-Nyhan syndrome. But since autoaggression is also characteristic of other mental pathologies, it is time for differential diagnostics.

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Differential diagnosis

This pathology differs from other syndromes characterized by self-inflicted injuries by the localization of the wounds - bitten fingers, lips, oral mucosa. Self-injuries are necessarily accompanied by hyperuricemia and nervous system disorders, similar in clinical features to cerebral palsy. Differential diagnostics allows for a fairly accurate distinction between Lesch-Nyhan syndrome and other diseases based on the totality of symptoms.

The decisive point in diagnostic measures is genetic research – establishing the level of GPRT and recognizing mutations of its gene.

Treatment of Lesch-Nyhan syndrome

Patients with the classic form of the disease are recommended to be hospitalized. In the treatment of this disease, the main focus is on normalizing the synthesis of uric acid in order to prevent negative consequences from the genitourinary system and inflammatory processes in the joints. In this case, medications are used that slow down the process of overproduction of uric acid and compensate for fluid loss, especially during periods of its intense loss, for example, with frequent vomiting.

In hyperuricosuria, stones are removed with medication or surgery. In gouty arthritis, nonsteroidal anti-inflammatory drugs are used.

Medicinal treatment is necessarily combined with a purine-free diet, and patients should drink as much clean water as possible. As an additional factor, only plant-based nutrition can be used, which helps alkalize urine and dissolve uric acid crystals.

To reduce the level of uric acid and, as a consequence, reduce inflammatory processes in gouty nodes and salt deposits, Allopurinol therapy gives a noticeable effect. This is a drug that disrupts 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 the oxidation reaction of hypoxanthine. By preventing the production of uric acid, Allopurinol reduces its content in the blood and promotes the dissolution of its salts. The duration and treatment regimen are prescribed by a 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 made no more than once a week if necessary. The daily dosage that maintains the level of uric acid, on average, from 200 mg to 600 mg, when treating with high doses - from 600 mg to 800 mg. When the dosage is more than 300 mg / day, the drug is taken in equal parts (one dose does not exceed 300 mg).

Adjustment of the dosage upward involves monitoring the level of oxypurinol in the blood plasma (the main metabolite of Allopurinol).
Children over 15 years of age are prescribed the drug per day at a rate of 10-20 mg per 1 kg of weight (divided into three doses). The highest pediatric dosage is 400 mg/day.

Allopurinol is not prescribed for severe kidney and liver pathologies, allergies, during an exacerbation of gout, and with caution for heart disease and hypertension.

This drug generally does not cause side effects, but they cannot be ruled out from any organs and systems of the body.

As an alternative to Allopurinol (if it is not tolerated), Probenecid is prescribed, which prevents the reabsorption of uric acid, which increases its excretion.

In cases of chronic gout, Probenecid therapy is started 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 highest dosage is 2000 mg / day. Provided that during ½ a year of taking Probenecid, the patient has not had an exacerbation of gout, and also, the content of uric acid in the blood plasma is not more than the permissible level, the dosage is reduced every six months by 500 mg to the lowest effective. Probenecid is prescribed to children from two years old, therapy begins with a dosage of 25 mg / kg of weight with an increase to 40 mg / kg, taken with breaks of at least 6 hours.

It is necessary to take into account that the action of Probenecid, leading to the release of uric acid, can cause gout paroxysm. Also, this drug prevents the excretion of some drugs with urine, for example, antibiotics, NSAIDs, sulfonylurea derivatives, increasing their accumulation in the blood plasma.

Probenecid is not prescribed for gout paroxysms; stones, especially urate stones; porphyria; hematopoietic pathology; under two years of age; secondary hyperuricemia as a result of neoplasms or chemotherapy; allergies.

Patients with kidney stones need to maintain a large volume of urine with a neutral acidity level. In this case, balanced salt mixtures are used, for example, Polycitra.

The importance of a neutral urine acidity level is demonstrated by the fact that in acidic urine (for example, pH≈5.0), the ability of uric acid to dissolve is 0.15 g/l, and in neutral urine – 2 g/l.

Hyperuricemia must be corrected, since no correction occurs when taking 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 seizures, and reduce motor function disorders.

Alprazolam is a psychotropic drug that has a moderate hypnotic effect, relieves symptoms of depression, and has a mild anticonvulsant effect.

Patients taking this drug experience a decrease in anxiety and 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 increased, if necessary, starting with an evening dose. The average daily dosage is from 3 to 6 mg, the highest is 10 mg.

The duration of treatment in acute cases is from three to five days; the maximum duration of treatment is three months.

To stop taking the drug, the dosage is reduced by 0.5 mg every three days, since abrupt cessation of treatment leads to the formation of withdrawal syndrome. At the beginning of treatment, drowsiness, lethargy, loss of strength, decreased concentration and psychomotor skills, and other negative reactions are observed. The drug is not prescribed in cases of lactose intolerance, with dysfunction of the respiratory organs, liver and kidneys.

Diazepam is a benzodiazepine tranquilizer that promotes muscle relaxation, relieves convulsive readiness, has a pronounced calming effect, and enhances the action of γ-aminobutyric acid, which functions as a CNS inhibitory mediator.

Diazepam increases the stability of nervous system tissues during oxygen starvation, thereby increasing the pain threshold and suppressing vegetative attacks.

It has a dose-dependent effect on the central nervous system: up to 15 mg per day - stimulating, more than 15 mg - hypnosedative.
As a result of taking the drug, patients experience reduced anxiety, fear, and emotional tension. Occasionally, a decrease in affectivity is observed.

As a psychotropic drug, 2.5 to 10 mg is used two, three or four times a day. In psychiatry, for dysphoric conditions, 5 to 10 mg is dosed two to three times a day. If necessary, the daily dosage is gradually increased to the maximum (60 mg).

In pediatrics, for the treatment of reactive and psychosomatic disorders, as well as spastic conditions, parenteral administration is recommended for children under 3 years of age (dosed individually), and for children over 3 years of age, orally, starting at 2.5 mg per day. If necessary, the dosage is gradually increased, while the child's condition is monitored by medical personnel.

Diazepam is well tolerated in most cases, but when treating it is necessary to take into account the possibility of undesirable consequences of its use such as loss of strength, confusion, drowsiness, emotional, visual, motor, speech disorders. The drug can be addictive.

Diazepam is not recommended for use by people prone to suicide, with pathological muscle fatigue, with epilepsy. It is not used for respiratory disorders, glaucoma, ataxia, porphyria,
heart failure.

Behavioral anomalies, mainly self-aggression, are the most difficult to deal with; complex methods, including behavioral and drug therapy, are most effective. Gabapentin and benzodiazepines are used; in the most severe cases, neuroleptics can be used; they are used to relieve exacerbations.

Complex therapy necessarily includes vitamins and microelements; for hyperuricemia, B vitamins, vitamin C, potassium, neuroprotectors – vitamin A, D, folic acid, biotin are prescribed.

In almost all cases of genetic pathologies, physiotherapy is used as part of a complex of treatment measures. In the case of Lesch-Nyhan syndrome, a wide variety of physiotherapeutic treatment methods are used - electrosleep, galvanization, massages, pine baths. Physiobalneotherapy is recommended to prevent gout attacks, in particular, radon baths have a good uricosuric effect. Mud applications and paraffin-ozokerite therapy are used to relieve inflammation.

To remove uric acid and prevent the formation of stones, it is recommended to drink weakly mineralized mineral waters with alkaline pH values.

The general treatment complex also includes therapeutic exercises.

Folk remedies

In addition to drug, physiological and psychological therapy, you can, after consulting with your doctor, use folk remedies and take advantage of some tips:

• Be sure to follow a purine-free diet and drink plenty of fluids, about 18 glasses a day;
• favorite soups should be pea, lentil, bean, porridges - wheat, oatmeal, buckwheat, rice, millet, barley, carrots (raw and boiled), corn, raspberries and pistachios - these products contain molybdenum, which helps remove uric acid and thereby prevents the development of gout;
• Buckwheat, barley and oatmeal, lentils are also rich in copper, which controls the presence of uric acid in the blood and is involved in the creation of the sheath of nerve fibers.

In dietary nutrition, molybdenum and copper are preferably consumed together, as if they were made for each other. Copper is rich in nuts, rye bread, sour milk, egg yolks (raw), spinach and lettuce leaves, asparagus, parsley, potatoes.

In folk medicine, various not very complex decoctions and infusions are used to remove salt deposits.

For example, a decoction of celery and parsley: take 100 g of stems with leaves and roots of these plants per 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 is one month, repeat at intervals of one week.

Or a decoction of bean pods: finely crushed dry pods (one tablespoon) brew one liter of boiling water and boil for two hours in a water bath. Strain and drink one tablespoon three times a day.

Apples are available all year round. Cut three large or five smaller apples into slices (do not peel). Pour water over them and boil for a quarter of an hour under a lid. The decoction should be left to brew for 4 hours and should be drunk in small portions throughout the day.

Herbal baths: brew 200g of chamomile, calendula or sage flowers in 1.5l of boiling water, leave for at least two hours, strain and add to a foot bath at 34ºC, reduce the temperature to 26ºC, lower your feet and take a bath for 20 minutes. It is good to do the procedures before going to bed, the recommended course duration is 20 days, after 20 days repeat the course of procedures.

Cleansing from salts for the lazy. Buy 1 kg of honey and raisins. In the morning on an empty stomach eat a handful of raisins and do not drink or eat anything else for two hours. The next day in the morning on an empty stomach eat one tablespoon of honey and do not drink or eat anything else for two hours. And so on - every day, until the honey and raisins run out.

Herbal treatment alone, of course, cannot overcome such a serious genetic defect as Lesch-Nyhan syndrome. And not every herb can be combined with a complex of medications, so a doctor's consultation before use is mandatory

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Homeopathy

Part of medical science, like modern traditional medicine, and not one of the types of folk medicine, homeopathy is subject to certain principles of treatment.

A homeopathic doctor, like any other, must find out what is happening to the patient and prescribe treatment. The examination is done in the traditional way - collecting anamnesis, examination and evaluation of the results of diagnostic procedures. These data are compared with the drug pathogenesis - the more similar the pathogenesis of the drug is with the diagnostic data, the greater the effect of the selected drug.

The prescription of a homeopathic medicine is based on the sum of pathological manifestations with their individual course in combination with the constitution, taking into account the patient's lifestyle and heredity. A homeopathic doctor must determine an individual medicine for a specific organism.

A properly selected homeopathic preparation helps to significantly improve health and get rid of chronic diseases. The therapeutic effect of homeopathic treatment usually occurs within three months to two years.

In homeopathy there are remedies for conditions that are described as similar to Lesch-Nyhan syndrome. The most suitable remedy is Lithium carbonicum:

Lithium carbonate entered the homeopathic pharmacy as an anti-gout remedy. Lithium salts transform uric acid salts into soluble ones, which are then excreted from the body. The patient has deformed joints with gouty nodes, painful, swollen, sensitive to touch. In all joints, especially the knees and small toes, there is a feeling of almost paralytic stiffness. Arthritis, acute and chronic.

The drug is also used for urolithiasis (oxalates and urates). Calculous colic, frequent pain in the heart area, especially in the morning. It goes away after going to the toilet. The symptoms include headache, decreased visual acuity and clarity, and rapid eye fatigue.

Depending on the symptoms, other medications can be selected, for example:

• Colchicum (Colchicum) or meadow saffron is also used in phytotherapy as a remedy for gout. The symptoms include gouty paroxysms with a characteristic localization in small joints. "Gouty" foot: arthritis of the big toe, pain in the heels. Swelling, pain in the bones and muscles, colic, digestive disorders, blurred vision. The pain intensifies in the evening and at night, and is aggravated by cold and physical activity. The pain is reduced by warmth and rest.
• Aconite (Aconite) Gouty paroxysms with pain, anxiety, restlessness, panic, neuralgia, nervous overexcitement, wounds, muscle weakness of the lower extremities.
• Ledum (Ledum) or marsh wild rosemary pain and inflammation of small and large joints, injuries and wounds and their consequences.
• Guayacum (Guaiacum) Formation of tophi, painful spasms, muscle cramps, regular need to stretch and straighten stiff muscles, need for apples, stubbornness, gouty diathesis.

Dosages and treatment regimens are prescribed only individually; there are no recommended doses of the drug, as in traditional medicine, in classical homeopathy.

Surgical treatment

Surgical operations are performed on such patients for urolithiasis in cases of ineffective therapeutic treatment. Indications for surgery are: cessation of urine flow into the bladder due to blockage of the ureter by a stone, septicemia caused by calculous pyelonephritis; frequent paroxysms of renal colic in the absence of a tendency for spontaneous passage of stones; life-threatening hematuria.

Surgical treatment includes both open and instrumental surgical interventions, including crushing stones in the bladder with a cystolithotripter, laser, ultrasound, and endoscope.

Prevention

The presence of Lesch-Nyhan syndrome in previous generations requires mandatory medical genetic counseling.

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Forecast

With the necessary medical care, the life expectancy of patients with this syndrome is usually 30-40 years, some manage to live to 50 years. The quality of life is low, there is complete lack of independence and disability.

The cause of death of patients is often 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.

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