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Monday, December 23, 2013

Lesch-Nyhan syndrome (LNS)

Lesch-Nyhan syndrome (LNS) is a rare hereditary disorder caused by a deficiency of the enzyme hypoxanthine-guanine phosphoribosyl transferase (HPRT).

There is a spectrum of clinical features associated with HPRT deficiency. At one end of the spectrum are patients with classic Lesch-Nyhan syndrome and the full clinical phenotype. At the other end of the spectrum are patients with overproduction of uric acid but no apparent neurological or behavioural deficits, eg Kelley-Seegmiller syndrome. In between are patients with varying degrees of motor, cognitive, or behavioural abnormalities.

The 3 main features of the disease are:
This is an X-linked condition with a defect at the chromosome point Xq26-q27.2.[1]

There is virtually no HPRT in Lesch-Nyhan syndrome, with levels below 1.5% 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]

Although chromosome point Xq26-q27.2 is involved in both disorders, the exact point of mutation varies, even within Lesch-Nyhan syndrome, and with it the clinical manifestation.

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.[3]
The incidence seems fairly uniform worldwide at about 1 in 380,000 births. As an X-linked recessive disorder it affects almost exclusively males, with female cases being a rarity. Two cases have been described in the literature.[4]

History

  • Symptoms are first noticed between 3 to 12 months old. There is delay in motor development and usuallyhypotonia at first, although spasticity may sometimes be a presenting feature.
  • Involuntary movements usually start between 6 and 18 months old.
  • Less often, the presenting feature relates to thehyperuricaemia. There may be 'orange sand' in nappies, due to urate crystals and some microscopichaematuria 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 disorders and self-injury are not usually presenting features until after the second birthday. Rarely, it may not start until the age of 10.

Examination

  • Growth (and head circumference, to a lesser extent) is delayed.
  • Testicular atrophy is common. Puberty is delayed or absent.
  • General learning difficulties are 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 are often compulsive behaviours that may appear as signs of aggression. These include hitting, spitting, coprolalia, copropraxia, and manipulative behaviour.
  • Uric acid levels (in blood and urine) are usually raised but can fall transiently into the normal range and be misleading. Urinary excretion of uric acid, especially if corrected for weight, is elevated but collecting a 24-hour 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 use 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.
Treatment of the condition is limited:
  • Allopurinol is useful for hyperuricaemia and reduces complications (nephrolithiasis andgouty arthritis). Maintaining good hydration also helps but despite these measures nephrolithiasis still occurs.
  • Few treatments have proved helpful for the neurological or behavioural difficulties.
  • Spasticity can be helped with a combination of baclofen and benzodiazepines.Tizanidine is also used. Diazepam is most commonly used. They may also help some of the extrapyramidal features.
  • Behavioural abnormalities are best managed using a behavioural modification technique 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] Gabapentinand carbamazepine may help reduce some behavioural 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.
  • There may be 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 issudden 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 in 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.[
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