Lesch Nyhan syndrome: Hypoxanthine Guanine Phosphoribosyl Transferase Deficiency: HPRT Deficiency

Lesch Nyhan syndrome was first described in 1964. It is a very rare genetic metabolic disorder usually occurring in boys but carried by females. A few affected females have also been reported. It is caused by virtually complete deficiency of the enzyme Hypoxanthine Guanine Phosphoribosyl Transferase (HPRT) which is important in purine metabolism. Cases have been described where HPRT deficiency was incomplete and associated with no obvious neurological or behavioural abnormalities.

Affected males inherit the gene mutation (change) that results in HPRT deficiency from females who show no symptoms of disease, or as a result of a new mutation.

The full spectrum of disease associated with HPRT deficiency is now recognised as ranging from isolated hyperuricaemia (excess uric acid in the blood) resulting in gout to hyperuricaemia associated with profound neurobehavioral dysfunction. In recognition of the careful early clinical description the full spectrum of clinical abnormalities associated with HPRT deficiency have been designated Lesch Nyhan disease (LND). Patients who lack the full clinical manifestations as a result of partial HPRT deficiency are designated LND variants in which case patients may only have kidney problems and gout as a result of the high level of uric acid in the blood though some also have mild neurological problems.

Diagnosis should be carried out in a specialist centre as it depends on a careful examination of HPRT activity in the blood. Uric acid levels will usually be raised in blood and urine but levels may be misleading causing missed diagnosis.

Infants with Lesch-Nyhan syndrome appear normal at birth; motor delay and low muscle tone become apparent within the first few months. Dystonia and choreoathetosis (involuntary jerky movement of the body) usually develop towards the end of the first year. Dystonia is a disorder of muscle tone producing typical contractile spasms or fixed postures in the limbs or trunk, which interfere with purposeful movements and speech development. The condition may be misdiagnosed as cerebral palsy. Feeding difficulties and hiatus hernia are common. About half the children have seizures. There may be testicular damage causing small size and delayed puberty.

Intellectual development is impaired, most affected individuals have moderate or severe learning difficulties, although some have low average intellectual abilities and attain age appropriate reading skills.

A build up of uric acid in the blood and urine results in kidney damage and production of kidney stones. Some infants have severe kidney problems and may present in kidney failure. Allopurinol is a drug used to reduce uric acid production but the dose must be carefully monitored as too much can produce xanthine, which is more insoluble than uric acid and will also cause kidney damage and stones.

Compulsive self-injurious behaviour (see An introduction to behavioural phenotypes) is reported in eighty-five per cent of cases. It usually starts in the second year though can be as late as ten years. Biting of the lips, inside the mouth and tongue or of the fingers is common. Marked dystonic spasm with arching of the back and neck that may cause spinal cord damage is also common. This behaviour fluctuates and may be associated with aggressive outbursts towards carers and anxiety and depression in boys. Restraints such as arm splints and neck support may be required and requested. The effectiveness of medication in treating the self-injurious behaviour has been variable. Behaviour modification techniques can be helpful in some cases. Stress reduction is generally viewed as a useful and effective method of intervention. The mechanism of the neurological impairments is not fully understood and there are as yet no effective treatments for these neurological complications. Life expectancy is reduced. In many cases death occurs in the twenties or thirties but some men are living beyond forty.

Inheritance patterns
X-linked recessive. Up to four boys will be born annually in the UK and one third of cases will be new mutations. Carrier detection is not perfect, only eighty-five per cent can be identified positively using DNA probes. However, genetic counselling and investigation is important for the wider family. In 2004 a database of three hundred and two mutations associated with both full and partial phenotypes was described. Prenatal diagnosis
Detection of HPRT deficiency is possible in the first twelve weeks of pregnancy using chorionic biopsy material.

Medical text written May 2002 by Dr G T McCarthy. Last updated February 2006 by Dr G T McCarthy FRCP FRCPCH, Honorary Consultant Neuropaediatrician, Chailey Heritage Clinical Services, Lewes, UK.

Further Online Resources
Medical texts in The Contact a Family Directory are designed to give a short, clear description of specific conditions and rare disorders. More extensive information on this condition can be found on a range of reliable, validated web sites and links to them are included in the CD-ROM version of this Directory. Further information on these resources can be found in our Medical Information on the Internet article.

As Lesch Nyhan syndrome is a purine metabolic disorder, support and information can be obtained from PUMPA (see, Purine and Pyrimidine Metabolic diseases) Support is also available from a group of families under the umbrella of Climb (see entry, Metabolic diseases)