Lesch-Nyhan Syndrome (LNS)

Synonyms: LNS, hypoxanthine-guanine phosphoribosyl transferase (HPRT) deficiency, Kelley-Seegmiller syndrome (milder form)

Lesch-Nyhan syndrome (LNS) is a rare hereditary disorder caused by a deficiency of the enzyme hypoxanthine-guanine phosphoribosyl transferase (HPRT). The 3 main features of the disease are:

• Excessive production of uric acid
• Neurological problems, especially mental retardation, spastic cerebral palsy and choreoathetosis
• Behavioural disorders

It is an x-linked condition with a defect at the chromosome point Xq26-q27.2.¹ There is virtually no HPRT, with levels below 1.5% in Lesch-Nyhan syndrome but in Kelley-Seegmiller syndrome levels are at least 8%. The gene locus of this condition is identical but it has a different OMIM listing at #300323.² The problems here seem to be limited to the excessive production of uric acid without the neurological and behavioural disorders. Although chromosome point Xq26-q27.2 is involved in both disorders, the exact point of mutation varies, even within Lesch-Nyhan disease, and with it the clinical manifestation.

The incidence seems fairly uniform worldwide at about 1 in 380,000 births. Being an x-linked recessive it is unsurprising that it affects almost exclusively males with female cases being a rarity. Two cases have been described in the literature.³ In a population at equilibrium for a sex-linked lethal genetic abnormality, one-third of the genes would be expected to arise by spontaneous mutation. Evidence suggests a very much lower rate of spontaneous mutation.⁴

History

• It tends to be noticed between 3 to 12 months old as there is delay in motor development and usually hypotonia at first, although spasticity may sometimes be a presenting feature.
• Involuntary movements usually start between 6 and 18 month old.
• Rather less often the presenting feature relates to the hyperuricaemia. There may be "orange sand" in nappies, due to urate crystals and some microscopic haematuria but sometimes renal stones can produce gross haematuria or even chronic renal failure. The hyperuricaemia tends to produce renal rather than joint problems as in gout.
• Behavioural disorder and self injury develop but are not usually a presenting feature but tend to start after the second birthday. Rarely it may not start until 10.

Examination

• Growth is delayed and head circumference to a lesser extent.
• Testicular atrophy is common. Puberty is delayed or absent.
• Mental handicap is usual and IQ is typically around 60.
• Sensation is normal but motor skills are markedly impaired. Extrapyramidal features may include dystonia, choreoathetosis, opisthotonic spasms, and ballismus. Many also show pyramidal features, including hyperreflexia and ankle clonus. Delay in walking is noted and eventually all patients require a wheelchair.
• Behavioural disorders are not uncommon in children but these are of a severity that is unusual and shocking. Self-injury may result in partial amputations of the fingers, lips, tongue, or oral mucosa, from biting. Serious injuries or scarring from repetitive self-abrasion or hitting are seen. In addition there is often compulsive behaviours that may appear as signs of aggression. These include hitting, spitting, coprolalia, copropraxia, and manipulative behaviour.

• Uric acid levels in both blood and urine are usually raised but can fall transiently into the normal range and hence be misleading. Urinary excretion of uric acid, especially if corrected for weight, is elevated but collecting a 24 hours sample from a small child is very difficult and a spot test may be unsatisfactory.
• There is often a macrocytic anaemia although folate and vitamin B12 levels are normal, as is iron. The problem appears to be reduced ability to utilise vitamin B12.
• Definitive diagnosis is often by measurement of HPRT enzyme activity in blood or tissue. Blood samples are often used but intact fibroblasts or lymphocytes give more precise information.
• Identification of a molecular genetic mutation in the HPRT gene confirms the diagnosis. This permits carrier detection and prenatal screening of at-risk pregnancies.
• Imaging studies of the brain and spinal cord tend to show little or no abnormality. Minimal atrophy may be noted.
• Imaging of the urinary tract is usually by ultrasound, especially as urate stones are radiolucent. It may be conducted periodically in case of stones or obstruction of the urinary tract.
• Bone age is a slightly delayed.

• Cerebral palsy
• Chorea
• Other metabolic disorders

Treatment of the condition is limited. In outline:

• Allopurinol is useful for hyperuricaemia and reduces complications (nephrolithiasis and gouty arthritis). Maintaining good hydration also helps but despite these measures nephrolithiasis still occurs.
• Few treatments have proved helpful for neurological or behavioral difficulties.
• Spasticity can be helped with a combination of baclofen and benzodiazepines. Tizanidine is also used. Diazepam and alprazolam are most commonly used. They may also help some of the extrapyramidal features.
• Behavioral abnormalities are best managed using a behavioral modification techniques together with medication. Behavioural modification can be successful in this condition.⁵ It works on the basis of reward or reinforcement of good behaviour. Punishment or negative reinforcement of bad behaviour may exacerbate problems. Intelligence is low but cognitive ability is better than may be expected.⁶ Gabapentin and carbamazepine may help reduce some behaviour problems.
• If other techniques fail to control self-injury by biting, dental extraction may be required. Biting does seem to be especially difficult to control.
• Other surgery may be required for muscular and joint problems due to the neurological problem.
• Intervention may be required for stones in the urinary tract.
• Diet is normal and continued activity should be encouraged.
• Use of restraints, especially at night, may be justified, even long term, to prevent self-injury.

• Quite severe self injury may occur
• There may be complications from the neuromuscular imbalance
• Problems of stones in the renal tract
• The joint manifestations of gout may occur

Death is usual in the 20s or 30s with few reaching their 40th birthday. Death is usually from aspiration pneumonia or complications of nephrolithiasis. Sometimes there is sudden death of unknown cause.

In view of the possibility of genetic mosaicism, gene testing can be performed before pregnancy to assess risk and also to assess more distant relatives.⁷ Hair roots may be used for this purpose. This may be followed by chorionic villus sampling and ultimately termination of the pregnancy.⁸

The condition was described by Lesch and Nyhan as recently as 1964.⁹ The enzymatic defect (deficiency of the enzyme hypoxanthine-guanine phosphoribosyl transferase) was discovered by Seegmiller and colleagues in 1967. The gene encoding the enzyme was cloned and sequenced by Friedmann and colleagues in 1985.¹⁰

Michael Lesch was born in 1939 in New York and was still a medical student at the John Hopkins in Baltimore, Maryland in 1964 when he described the condition. He has since become Professor of Medicine at Columbia University and is a cardiologist.

William Nyhan was a paediatrician who was born in 1926 and was a faculty member at the John Hopkins in 1964, before becoming Professor of Paediatrics at the University of California.

William Kelley was also born in 1939. He had an illustrious medical career, including spending some time at the Sir William Dunn School of Pathology in Oxford and eventually became CEO of the University of Pennsylvania Medical Center and Health System and Dean of the School of Medicine, and the Robert G. Dunlop Professor of Medicine and Biochemistry and Biophysics. He was the first to suggest in vitro gene therapy as we understand it today. He described a gene defect in gout associated with the overproduction of uric acid in 1967.¹¹

Jarvis Seegmiller was born in 1920. He was initially a biochemistry graduate but after army service studied medicine. After internship at the John Hopkins he became chief of human biochemical genetics at the National Institute of Health.