Lesch-Nyhan syndrome is a genetic and metabolic disorder that affects children from birth and causes severe neurological disorders, cognitive impairment and various behavioural problems.

This article discusses this syndrome, its symptoms, how it is diagnosed, and the main treatments available.

What is Lesch-Nyhan syndrome?

Lesch-Nyhan syndrome is an inherited disease, described in 1964, that affects the metabolism of purines (nitrogenous compounds that form, along with other nucleotides such as pyrimidines, nucleic acids such as DNA and RNA). The cause of the disease is a mutation of a gene located on the X chromosome, which is recessive in inheritance (meaning that both genes must be abnormal to cause the disorder).

The genetic error produced by this syndrome generates a deficit of the enzyme – hypoxatin – guanine – phosphoribosyl – transferase (HPRT), whose most prominent consequence at the metabolic level is a marked overproduction of uric acid levels in the body, as well as a whole series of neurological and behavioural problems.

The prevalence of Lesch-Nyhan syndrome has been estimated at around 1 in 380,000 and 1 in 235,000 newborns. This disease mainly affects men , although heterozygous women (who have two different alleles of the gene) are also carriers (and usually asymptomatic).

The onset of the disorder occurs in childhood and, so far, two forms of the disease have been described: LNS (the more severe variant), which causes a total absence of HPRT) and Lesch-Nyhan variants, which result in a partial deficit of the enzyme. The LNS variant produces urolithiasis (presence of stones in the kidneys or urinary tract) and gout, which are associated with overproduction of uric acid, as well as serious neurological disorders, haematological alterations and self-injurious behaviour.

In the less severe form of LNS, also known as Kelley-Seegmiller syndrome , although most of the clinical manifestations of Lesch-Nyhan syndrome occur, self-injurious behaviors are not present and patients have a normal life expectancy.

Symptoms

Lesch-Nyhan syndrome is characterized by three main symptoms: neurological problems, cognitive disorders and uric acid overproduction .

One of the first symptoms of this disease is the appearance of uric acid crystals, which are orange in colour and usually soak the affected child’s diaper. The overproduction of this compound later causes the formation of stones in the kidneys, urethra or bladder, which are deposited in the joints and, over time, produce arthritis and other conditions (gout, joint pain, etc.).

Another of the most common symptoms of this disorder is the self-injurious behaviour of patients , who need to compulsively bite their fingertips and lips; a behaviour very similar to the compulsions that occur in obsessive-compulsive disorder. These symptoms of self-mutilation may be exacerbated by stress.

Children with Lesch-Nyhan syndrome also present psychomotor retardation , which is usually evident between 3 and 6 months of age: delayed seating, inability to hold the head, hypotonia and athetoid-like movements. This disorder also causes children to be unable to stand and walk, or to make involuntary movements triggered by voluntary acts (choreathetosis and ballism).

It is also common for patients to suffer from dysarthria (difficulty in articulating sounds), dysphagia (alterations in swallowing food) and muscle-type problems, such as opisthotonos. Spasticity, hyperreflexia or Babinski’s sign (the dorsal extension of the big toe, accompanied by the fanning of the rest of the toes) usually appear late.

Diagnosis

A possible Lesch-Nyhan syndrome is often suspected when the child has psychomotor retardation, with elevated uric acid levels in the blood and urine. As the activity of the HPRT enzyme is undetectable in the peripheral blood or in healthy cells (erythrocytes or fibroblasts), the diagnosis is usually made by molecular genetic testing .

Prenatal diagnosis is possible if the gene mutation has also been identified in the family, since inheritance is recessive and X-linked. In this respect, genetic counselling is important.

On the other hand, when making the differential diagnosis of this disease, the following disorders should be taken into account: cerebral palsy, dystonia, other causes of intellectual deficit, autism, Tourette’s syndrome, Cornelia de Lange syndrome, idiopathic intellectual deficit and severe psychiatric disorders.

Treatment

The neurological disorders and behavioural problems caused by Lesch-Nyhan syndrome generate, in the child and his family, important problems at the motor level, since the child will not be able to stand, crawl or move around , nor will he be able to grasp or hold objects with weight, with the consequences that this entails. This can be treated with an expert in psychomotor skills and with physiotherapy.

As the syndrome can cause intellectual disability, this can make it difficult for the child to fix his attention correctly, thus generating serious learning problems , as his capacity for analysis and understanding is compromised. In this sense, it is necessary that an occupational therapist intervenes and a speech and educational approach is made.

Medical follow-up is also important . Drug treatment is usually done with allopurinol, a medication used to treat hyperuricemia and its complications.

It is also essential to emphasize emotional and social needs, which must be properly addressed. Children affected by Lesch-Nyhan syndrome need constant supervision and someone to guide them to make their day-to-day life more bearable. It is also important that family members are cared for and accompanied, as the impact on their daily functioning will be considerable.

Finally, as far as schooling is concerned, it is often difficult to include these children in an ordinary school . The children concerned have special educational needs that cannot be addressed within the framework of the measures to address the diversity of ordinary schools, and it is therefore common to propose that the child be placed in a special education centre or a similar centre.

Bibliographic references:

  • Campolo González, A., Vargas Díaz, A., Fontboté Riesco, D., & Hernández Chávez, M. (2018). Lesch-Nyhan syndrome and oral self-mutilation. Case report. Chilean Journal of Pediatrics, 89(1), 86-91.
  • Jiménez, R. T., Antón, F. M., Hernández, T. R., Martínez, J. A., Soto, A. B., & Puig, J. G. (1998). Biochemical, enzymatic and genetic study of hypoxanthine guanine phosphoribosyltransferase (HPRT) deficiency. Spanish Annals of Pediatrics, 48, 355-362.
  • Torres, R. J., & Puig, J. G. (2007). Hypoxanthine-guanine phosphoribosyltransferase (HPRT) deficiency: Lesch-Nyhan syndrome. Orphanet journal of rare diseases, 2(1), 48.