Lesch-Nihan syndrome: what is it, symptoms, treatment, prognosis

What is Lesch-Nihan syndrome?

Lesch-Nihan syndrome (or Nehena) is a rare congenital error in purine metabolism, characterized by the absence or deficiency of the activity of the enzyme hypoxanthine-guanine phosphoribosyltransferase (HGFT or Eng. HPRT). Purines are nitrogen-containing compounds found in many foods (such as organic meat, poultry, and legumes).

In the absence of HPRT, the purines hypoxanthine and guanine are not incorporated into nucleotides. People with Lesch-Nuhan syndrome have abnormally high levels of uric acid, and sodium urate crystals can build up abnormally in joints and kidneys.

Lesch-Nyhan syndrome is inherited as an X-linked recessive genetic disorder, which, with the rare exception of women, most often affects men. Symptoms of Lesch-Nihan syndrome include impaired renal function, acute gouty arthritis, and self-deprecating behaviors such as biting lips and fingers and / or banging the head.

Signs and symptoms

Symptoms of Lesch-Nihan syndrome can appear as early as the age of 6 months. Earlier formation of urate crystals as a result of abnormally high levels of uric acid in the urine leads to deposits of orange ("orange sand") in diapers in babies with this disorder. This may be the first manifestation of Lesch-Nihan syndrome, but it is rarely recognized in early childhood.

Excessive amounts of uric acid secreted as sodium urate in the kidneys of infants with Lesch-Nyhan syndrome can lead to the development of urinary calculi (stones). These stones can cause the appearance blood in urine (hematuria) and increase the risk urinary tract infections. Urate crystals can also be found in joints, but usually only in late adolescence or In adulthood, untreated patients with Lesch-Nyhan syndrome experience recurrent episodes of pain and joint swelling, such as adults with gout. These episodes may become more frequent after they start.

In older children with this condition, sodium urate deposits can accumulate in the cartilage tissues of the joints and ears; in the ears, they form visible "bulges" called tofus. This symptom is also commonly known as gouty tofus.

The neurological symptoms associated with Lesch-Nyhan syndrome usually begin before 12 months of age. These can include involuntary writhing movements of the arms and legs (dystonia) and aimless repetitive movements (chorea) such as flexing the fingers, raising and lowering the shoulders, and / or making grimaces on the face. Babies who were previously able to sit upright usually lose this ability. Initially, the muscles can be soft and make it difficult to keep the head upright. Affected children may not achieve developmental milestones such as crawling, sitting or walking (i.e., experiencing developmental delays). After all, most children with Lesch-Nihan syndrome experience abnormally increased muscle tone (hypertension) and muscle stiffness (spasticity). Deep tendon reflexes are increased (hyperreflexia). Intellectual disability can also occur and is usually mild. However, an accurate assessment of intelligence can be difficult due to poorly articulated speech (dysarthria). Some patients have normal intelligence.

The most striking feature of Lesch-Nihan syndrome, which occurs in about 85 percent of patients, is self-harm. This behavior most often begins between the ages of two and three. However, they can also develop during the first year of life or much later in childhood. Self-harm can include repeated biting of the lips, fingers and / or hands, and repeated head banging on hard objects. Some children may scratch their face multiple times. However, people with Lesch-Nihan syndrome are not sensitive to pain. Additional behavioral disorders include aggressiveness, vomiting, and spitting. Regular self-harm leads to tissue loss.

Children with Lesch-Nyhan syndrome may have difficulty swallowing (dysphagia) and may have difficulty feeding. Vomiting is common and most affected children are underweight for their age. Additional symptoms may include irritability or screaming. Some children with Lesch-Nihan syndrome may also develop a rare anemiaknown as pernicious anemia.

Another symptom of Lesch-Nyhan syndrome can be severe muscle spasm, which causes severe flexion of the back and tilt of the head and heel back (opisthotonus). Affected children may also experience hip dislocation, fractures, abnormal curvature of the spine (scoliosis) and / or permanent fixation of several joints in a flexed position (contractures).

Carrier women usually do not have symptoms of the disorder, but can develop gout later in life as a result of untreated excess uric acid in the blood (hyperuricemia).

Causes

The only gene known to be associated with Lesch-Nihan syndrome is located on the X chromosome and is called HPRT1. Disorders (mutations) in a gene HPRT1 lead to the absence or deficiency of the enzyme hypoxanthine-guanine-phosphoribosyltransferase (HGFT or Eng. HPRT) and abnormal accumulation of uric acid in the blood.

Lesch-Nyhan syndrome is inherited in an X-linked pattern. X-linked genetic disorders are conditions caused by an abnormal gene on the X chromosome and occur primarily in males. Women with an abnormal gene on one of their X chromosomes are carriers of this disorder. Carrier women usually show no symptoms because women have two X chromosomes and only one carries the abnormal gene. Men have one X chromosome that is inherited from their mother, and if a man inherits an X chromosome that contains an abnormal gene, he will develop the disease.

Women carriers of X-related disorder have a 25% risk with each pregnancy to have a carrier daughter similar to themselves, 25% risk giving birth to a non-carrier daughter, 25% chance of having a son affected by the disease and 25% risk of having an unaffected healthy son.

If a man with an X-linked disorder is fertile, he will pass the abnormal gene on to all of his daughters who will be carriers. A man cannot pass the X-linked gene to his sons because men always pass on their Y chromosome instead of their X chromosome to male offspring.

Affected populations

Lesch-Nihan syndrome is a rare disease that affects men. Rarely, women can be affected by the disorder. However, in most cases, women can be carriers of the disease gene, but are asymptomatic. One estimate is that the disease occurs in about 1 in 380,000 live births.

Symptomatic disorders

Symptoms of the following disorders may be similar to those of Lesch-Nyhan syndrome in the sense that self-injurious behavior may occur. Comparisons can be useful for differential diagnosis:

• Riley-Day syndrome (familial dysautonomy) is a rare genetic disorder of the autonomic nervous system that primarily affects people of Eastern European Jewish heritage. It is characterized by a decrease in sensitivity to pain, lack of tearing in the eyes, a decrease in the number of protrusions in the form papillae that cover the tongue (mushroom papillae), unusual fluctuations in body temperature and unstable blood pressure. The symptoms of this disorder are obvious at birth. The autonomic nervous system controls the body's vital involuntary functions.
• Cornelia de Lange syndrome (Brahman-Lange syndrome) is a rare genetic disorder that manifests itself at birth. Associated symptoms and signs usually include delays in physical development before and after birth; characteristic anomalies of the head and facial (craniofacial) region, leading to a characteristic facial appearance; malformations of the hands and arms (upper limbs); and mild to severe mental retardation. Children with Cornelia de Lange syndrome may also have eating and breathing problems; increased susceptibility to respiratory infections; quiet "growling" cry; heart defects; delayed maturation of the skeleton; hearing loss; or other physical abnormalities. The range and severity of associated symptoms and signs can be extremely different for each person.

Diagnostics

The diagnosis of Lesch-Nyhan syndrome can be confirmed by careful clinical evaluation, including a detailed medical history and specific blood tests. Children with this disorder have abnormally high concentrations of uric acid in their blood. The absence of the HPRT enzyme in the cells of any tissue confirms the diagnosis. Molecular genetic testing for the gene is also available to identify the specific mutation causing the disease. HPRT1.

Prenatal diagnosis and preimplantation genetic diagnosis are possible if the affected family member has a gene mutation HPRT1, causing the disease. Prenatal diagnosis can also be done with an enzyme test.

Standard treatments

Treatment for Lesch-Nihan syndrome focuses on the specific symptoms that each person experiences. Treatment may require the coordinated efforts of a team of specialists. Pediatricians, specialists in the diagnosis and treatment of skeletal disorders (orthopedists), physiotherapists and others health-care workers may need to systematically and comprehensively plan the treatment of the victim child.

Allopurinol is used to control excess uric acid associated with Lesch-Nihan syndrome and control symptoms associated with excess uric acid. However, this treatment does not affect the neurological or behavioral symptoms associated with this disorder.

In the presence of kidney stones they can be treated with extracorporeal shock wave lithotripsy (ESWL). During this procedure, the patient is immersed in water and high energy shock waves are sent to the body in the area of ​​the kidney stone. The stone breaks up into small pieces, and these small pieces come out in the urine.

No long-term treatment or drug therapy has proven to be as effective in treating the neurological problems associated with Lesch-Nihan syndrome. Baclofen or benzodiazepines have been used to treat spasticity. Diazepam can also be helpful.

People with Lesch-Nihan syndrome have been reported to benefit from behavior modification techniques developed to reduce self-injurious behavior, but real success is unusual. Children with Lesch-Nyhan syndrome usually need physical restraint in the hips, chest and elbows so that they do not injure themselves. The armrests keep your hands free. Finger and / or lip bites, which can lead to irreversible perversion, can be prevented by using a mouth protectant (oral prosthetics) or tooth extraction. Many affected people demand restrictions themselves. As they grow older, the self-injurious behavior of some victims may improve or cease.

In some patients, medications have been used to treat behavioral disorders associated with Lesch-Nihan syndrome. These include Apilepsin, Depakine, Orfiril, Konvulex, Enkorat (Valproic acid), Gabapentin, Baclofen, and Carbamazepine. Benzodiazepines can also be helpful in treating anxiety symptoms sometimes associated with Lesch-Nihan syndrome.

Forecast

Patients can die from aspiration pneumonia or complications from chronic nephrolithiasis and renal failure. With optimal care, few patients live beyond 40 years, and most are wheelchair-bound.