Lesch Nyhan Syndrome


What is Lesch Nyhan syndrome?

Lesch Nyhan syndrome is an inherited disorder and can transmit via families. Lesch-Nyhan syndrome is first described by Michael Lesch and William Nyhan in 1964.


In this condition, purine, the normal component of the human tissue become abnormally constructed and breaking down. Therefore, the normal functioning of the purines i.e. providing a base of genetic materials become hampers1.

Facts/Pathophysiology

In the human body, HPRT (Hypoxanthine-guanine phosphoribosyl transferase) usually acting as a prime role in the salvage of the hypoxanthine and guanine, purine bases, into the purine nucleotide bands. The absence of HPRT causes hampering of recycling of purine bases, as an alternative, they become metabolized and excretes as uric acid. The malfunctioning of the purine salvage leads to increased rate of purine synthesis and also enhance the rate of purine synthesis to compensate the excessive loss of purine due to excessive degradation. The consequence of this leads to the overproduction of uric acid and cause hyperuricemia.

Hyperuricemia increases the risk of precipitation of uric acid or tophi of uric acid into the different tissues. Deposition of uric acid in the joints causes inflammation or gout, in renal system urate stone may form in the urinary tract. Urate stone in the urinary tract also causes hematuria and urinary tract infections.

Furthermore, HPRT deficiency also influences dopamine neuron function abnormality and affects neurologic and behavioral features due to neurodevelopmental defect, but the precise mechanism is unknown2.

Etiology

Lesch Nyhan disease is caused by abnormal mutation of the HPRTgene on the X- linked chromosome. The involvement of the X- linked chromosome signify the sex-linked trait. Mostly male gender affects with this disease. The abnormal mutation is basically heterogeneous in nature and more than 600 different substitutions, deletions, insertions possible including single base3.

Epidemiology

Lesch Nyhan disease does not frequently occur disease the incidence rate can be illustrated as 1 in 3 lakhs 80 thousand population. The predominance of the disease is same for almost all ethnic group. Mostly all the incidence is reported with a male, as Lesch-Nyhan ailment is an X-linked recessive disorder and rare incidence reported with females. The life span is less and only a few affected individual can survive beyond 40 years2,3.

Symptoms

The most remarkable characteristic of Lesch-Nyhan is self-destructive behavior, which includes chomping off lips, fingertips. The behavioral disorder may occur due to dopaminergic neurotransmitter disorder. Other included symptoms are


  • Delayed motor development, which causes abnormal movements
  • Reflex actions increased
  • Increased uric acid level and that causes joint inflammation and pain, clinically termed as gout
  • Stone formation in the urogenital system due to uric acid crystallization4

Treatment

There is no specific treatment available for Lesch Nyhan syndrome. The basic aim of the treatment plan for Lesch-Nyhan syndrome is to control uric acid level. Enhancement of uric acid causes joint complications including gout. Controlling of uric acid level can also cause oxypurine stones formation and that causes urological problems.

The uric acid level can be controlled by inhibiting the breakdown of hypoxanthine and xanthine to uric acid and for this allopurinol, medication can be given. Another approach is to maintain the hydration level in the body system that can resolve urological complications. But both these approaches unable to improve the neurological problems.

The unfamiliar environment must be avoided for a patient suffering from Lesch-Nyhan syndrome, as it may exacerbate behavioral troubles like the tendency of self-harm.

Different protective devices, like splints or straps, must be applied to prevent self-injury.

Allopurinol is the fundamental treatment approach to regulating the uric acid level. recent drug development also provides novel drug-like febuxostat is also available in the market for normalizing the uric acid level. But this medication unable to prevent stone formation in the urogenital system.

Different medications also available to control the neuro-behavioral problems. The drugs classified under benzodiazepines like alprazolam, diazepam can able to control attenuate anxiety. Baclofen, which is acts as an antispasticity agent is also prescribed in Lesch-Nyhan syndrome.

Behavioral problems, mainly the self-injurious behavior is very difficult to manage. Medication alone cannot provide long term benefits. But medication along with behavioral modification techniques provide better management. Behavioral extinction methods along with positive support are most beneficial. Adjunctive medications, such as gabapentin and benzodiazepines are also used for attenuating problem behaviors. Neuroleptics are prescribed for the severe neurological behavioral problem, but these drugs are not prescribed frequently or long term uses also not preferable due to their side effect3,5.

Prevention

Hereditary history of Lesch Nyhan syndrome needs genetic counseling for getting useful preventive information and knowledge.

Genetic testing of women can also perform before the plan for the child to check the carrier of this syndrome1,2.

Life Expectancy

Patient with Lesch Nyhan disease has no longer life span. The patient can survive 30 to 40 years of their life span, rarely survival duration exceed beyond 40 years.

The cause of early mortality may due to aspiration pneumonia or impediments arise from chronic nephrolithiasis and renal failure. However, there is also many death occurs due to unexplained sudden basis. The possibility of sudden death may due to respiratory failure arises from cervical pathology or laryngospasm3,5.


References

  1. Lesch-Nyhan Syndrome; Health Guide; The New York Times; http://www.nytimes.com/health/guides/disease/lesch-nyhan-syndrome/overview.html
  2. Jinnah HA. Friedmann T. Lesch-Nyhan Disease and its variants Scriver CR, Sly WS, et.al, eds. The molecular and metabolic Bases of Inherited Disease. 6th ed. New York Ny: Mc Graw-Hill 2000. Chapter107.
  3. H A Jinnah; Lesch-Nyhan Disease; Online available at http://emedicine.medscape.com/article/1181356-overview#a4
  4. Lesch-Nyhan Syndrome; National Organization for Rare Disorder; Online available at https://rarediseases.org/rare-diseases/lesch-nyhan-syndrome/
  5. Lesch-Nyhan syndrome; Genetic Home References; Online available at https://ghr.nlm.nih.gov/condition/lesch-nyhan-syndrome

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