Lesch-Nyhan syndrome is a hereditary disease that occurs when there is a violation of purine metabolism, excessive accumulation of uric acid in the body. It develops due to a genetic mutation that causes a deficiency of the enzyme HGPRT. It is manifested by attacks of gout, severe neurological deficiency, self-harming behavior. Diagnosis of the disease is carried out by biochemical analyses, genetic research, neuroimaging methods. Treatment of the syndrome is symptomatic: selection of a diet, anti-gouty drugs, psychotropic drugs and complex neurorehabilitation.
E79.1 Lesch-Nyhan syndrome
The syndrome is named after the American pediatrician and geneticist William Nihan and his student Michael Lesh, who in 1964 were the first to describe the typical clinical picture of two brothers with gout, central nervous system damage, and self-aggression. Taking into account the peculiarities of transcription, variations of the name “Lesch-Nyhan syndrome”, “Lesch-Nyhan” are found in Russian-language sources. The disease is registered with a frequency of 1 case per 235-380 thousand of the population, mainly men are ill. Despite the rarity, the problem is relevant in modern genetics, which is associated with the difficulties of its diagnosis, difficulties in the selection of therapy.
The disease occurs due to mutations of the HGPRT1 gene, which is responsible for the formation of the enzyme hypoxanthine-guanine phosphoribosyltransferase (HGPRT). More than 400 variants of genetic code defects causing Lesha-Nihan’s disease have been described. The mutation is located on the X chromosome at the Xq26.2-q26.3 locus. The inheritance of the syndrome occurs according to the X-linked type, so almost all patients are male, and women are mostly asymptomatic carriers of the gene.
The main role in the pathogenesis of the disease is played by the increased formation of uric acid. It is synthesized from guanine and hypoxanthine, which accumulate inside cells due to a deficiency of HGPRT, and then undergo biochemical transformation under the action of the enzyme xanthine oxidase. Leading in the development of the syndrome is the increased formation of new purines, which, in combination with violations of the reutilization of existing purine compounds, makes the patient’s condition heavier.
The mechanism of the appearance of neurological disorders in Lesha-Nihan’s disease has not yet been disclosed. Experimental studies suggest the defeat of the central nervous system due to metabolic disorders of neurotransmitters – dopamine, serotonin, adenosine. Especially important in the pathogenesis of the syndrome is the lesion of the basal cerebral ganglia, where a large number of dopaminergic neurons are located.
In practice, 3 forms of the syndrome are conditionally distinguished, according to the degree of residual activity of the HGPRT enzyme. With an indicator of less than 1.5%, a full range of disorders develops, including severe disorders of purine metabolism and neurological symptoms. A value of 1.5-8% corresponds to less intense neurological manifestations, and with a HGPRT level of more than 8%, uric acid metabolism disorders prevail with normal functioning of the central nervous system.
The first signs of Lesha-Nihan syndrome appear in 3-6 month-old infants. There is a decrease in muscle tone, sluggish movements of the arms and legs, a delay in psychomotor skills (smiling, fixing the gaze, holding the head). In the second half of the baby’s life, involuntary movements of the limbs, head, and trunk begin. After 1 year, pronounced hyperkinesis is formed with concomitant muscular hypotension.
Motor disorders are steadily progressing. When a child tries to learn to sit or stand, there is often an arched deflection of the trunk and neck, which is accompanied by tremor. Outwardly, such symptoms resemble a convulsive seizure. With a severe deficiency of HGPRT, patients lose the ability to purposeful movements, independent movement. The clinical picture is similar to the symptoms of cerebral palsy.
The syndrome is necessarily accompanied by autoaggressive behavior when the patient injures himself. This usually manifests itself in the form of constant biting of the lips, biting of one’s own fingers, attempts to injure the eyes. Occasionally aggression is projected onto other people: patients try to hit others, use obscene expressions in speech.
An integral component of the clinical picture is hyperuricemia and hyperuricosuria. In young children, parents may notice a yellow precipitate on diapers, which is uric acid crystals. Lesch-Nyhan syndrome is characterized by the development of urate nephropathy, episodes of micro- or macrohematuria occur. In severe cases, nephrolithiasis, acute renal failure occurs.
All patients with Lesha-Nihan syndrome have intellectual disabilities of the type of mild or moderate mental retardation. The most important problem is attention deficit, as a result of which such children are extremely difficult to learn. Due to severe violations of motor functions, early disability of patients occurs, they spend most of the time in special wheelchairs with fixation.
In rare cases, the pathology is complicated by gastroesophageal reflux and frequent vomiting, which makes feeding difficult. Also, with Leshi-Nihan’s disease, megaloblastic or microcytic anemia may appear. Some patients have congenital malformations: deformity of the auricles, atresia of the anus, absence of testicles. Sometimes there are attacks of apnea, which may be associated with sudden death syndrome.
The initial examination is carried out by a pediatric neurologist or pediatrician, after which a consultation with a geneticist is appointed. It is possible to suspect the disease by signs of hyperuricemia, which is combined with episodes of autoaggression, delayed psychomotor development, hyperkinesis. To confirm the diagnosis of Lesch-Nyhan syndrome, the following diagnostic methods are used:
- Biochemical analyses. A blood test reveals a suspended uric acid content, and a urine test determines its increased excretion through the kidneys. The ratio of urates to creatinine of more than 2 unmistakably indicates hyperproduction of uric acid.
- Genetic research. For 100% accurate diagnosis of the syndrome, direct automatic sequencing of the coding region of the gene is performed, which demonstrates a typical HGPRT1 mutation.
- Neuroimaging. CT or MRI of the brain reveals moderate atrophic changes of the large hemispheres specific for the syndrome, a decrease in the volume of the basal nuclei. Positron emission tomography is recommended to evaluate the parameters of dopamine metabolism.
- Ultrasound of the kidneys. Ultrasound scanning is shown to all patients in order to quickly assess the structure, identify stones, hydronephrosis. Excretory urography is used to clarify the diagnosis.
Maintenance therapy begins with a special diet to limit the intake of purines into the body. Meat and fish broths, smoked meats, canned food are excluded from the diet, and it is also forbidden to give chocolate, coffee, salted cheeses to patients. The basis of nutrition consists of vegetables, dairy products, proper drinking regime (decoctions of dried fruits, alkaline mineral waters). Drug therapy of Lesch-Nyhan syndrome includes:
- Anti-gouty drugs. To reduce the formation of uric acid from hypoxanthine, allopurinol is prescribed, which is taken in long courses, dosed individually according to the severity of hyperuricemia.
- Anticonvulsants. Anticonvulsant medications are used to reduce the hyperkinesis and tremor characteristic of the syndrome, reduce muscle tone, and improve the quality of life.
- Neuroleptics. With pronounced manifestations of autoaggression, medications help prevent severe damage to the body, stabilize the psycho-emotional state. Antidepressants are also indicated for this purpose.
Proper care is of great importance in Lesha-Nihan syndrome. At home, you need to create a safe environment, cover sharp corners in the child’s accessibility area with soft materials, remove traumatic objects. In case of motor disorders, a special wheelchair with wide locking straps is used to protect the patient from self-harm. To protect the lips and tongue from biting, special plates are put on the teeth.
Since many patients with Nihan’s disease retain speech development and the ability to memorize, it is possible to teach such children. Given the pronounced attention deficit, classes are required according to a special program with correctional teachers. Rehabilitation is complemented by physical therapy programs, massage for the correction of hypertension, physiotherapy techniques.
Prognosis and prevention
Lesch-Nyhan syndrome refers to incurable diseases, so the prognosis is relatively unfavorable. Life expectancy correlates with the level of HGPRT: patients with an enzyme content of less than 1.5% and a detailed clinical picture often die at the age of 20-30 years. With a higher content of the enzyme, patients live longer. Prevention of the syndrome consists in medical and genetic counseling of families with burdened heredity.