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Lesch Nyhan Syndrome

Lesch-Nyhan Syndrome

Lesch Nyhan syndrome (LNS) is a hereditary disorder of purine metabolism which consists in a severe form of hypoxanthine-guanine phosphoribosyltransferase (HPRT) deficiency that leads to a characteristic uric acid overproduction (UAO), as well as neurological and behavioral problems.


The clinical manifestation of LNS has an early onset, as many patients begin to show clear signs within the first six months of life. Urate crystal formation, the direct consequence of increased uric acid levels, is the first sign to appear, manifesting itself indirectly through the appearance of orange colored deposits called “orange sands” in the diapers of affected children. Unfortunately, even though this can be an important significant clue for the future manifestation of the disorder, it is rarely diagnosed and taken into consideration. The appearance of crystals, in fact, occurs later during late teenagerhood or early adulthood after distressful episodes of pain and swelling, especially in the joints [7], which tend to increase in frequency as the disorder progresses on. It is important to note that in older children the development of sodium urate in cartilaginous tissues can also be observed.

Stone formation is another sign which appears very early. The stones in the urinary tracts might determine the presence of blood in the urine, in a condition known as hematuria, as well as the occurrence of infections.

Other musculoskeletal problems include the appearance of severe muscle spasms, characterized by the tendency of the back to severely arch, combined with the tendency of head and heels to bend backward, in a condition known as opisthotonos. These are associated with other characteristic events such as hip dislocation, fractures, abnormal spine curvature (scoliosis), and permanent joint fixation in flexed positions.

The neurological signs of LNS usually appears later in life, at around 12 years of age. They classically include involuntary writhing movements of arms and legs (dystonia) as well as repetitive movements performed with no apparent reason such as flexing the fingers, raising or lowering shoulders, and grimacing the face. Other neurological signs include those which show the failure of the correct developmental process, such as delays in reaching important stages like crawling, sitting upright and walking. Many also show problems correlated with muscle tone, with muscles appearing with either an abnormally high tone (hypertonia) or an abnormally high rigidity (spasticity). It is also possible to observe deep tendon reflexes (hyperreflexia) or the incapability by the side of the children of holding the head in an upright position. Mental retardation can also appear after a while, but this important sign might be difficult to detect due to poorly articulated speech (dysarthria).

One of the most important behavioral problems, observed in around 85% of the cases, is self-mutilation, which tends to appear very early usually within the first 2-3 years of life. These behavioral problems can include repeated biting of lips, fingers, and hands, frequent banging of the head on walls or other hard objects, and scratching of the face, which are often combined with aggressiveness, vomiting, and spitting. Irritability and screaming are also frequent.

AS previously indicated, the clinical signs of LNS mostly appear in men, even though many females might develop gout later in life as a result of untreated uric acid accumulation in the blood [8].

Cerebral Palsy
  • We report on a 7-year-old boy with Lesch-Nyhan syndrome, lacking self-mutilative behavior, who was erroneously diagnosed as having athetotic cerebral palsy.[ncbi.nlm.nih.gov]
  • Because a lack of HPRT causes the body to poorly utilize vitamin B12, some boys may develop a rare disorder called megaloblastic anemia.[ninds.nih.gov]
  • 2016 2017 2018 2019 Billable/Specific Code Applicable To Amino-acid deficiency anemia Orotaciduric anemia Type 1 Excludes Lesch-Nyhan syndrome ( E79.1 ) Arthropathy M12.9 - see also Arthritis ICD-10-CM Diagnosis Code M12.9 Arthropathy, unspecified 2016[icd10data.com]
  • Another issue is anemia with very large red cells in the blood (megaloblastic anemia). Fortunately, this does not usually cause problems or require treatment.[thinkgenetic.com]
  • Some individuals may develop a rare disorder called megaloblastic anemia. Is there any treatment? Treatment for LNS is symptomatic. The drug allopurinol may be used to control excessive amounts of uric acid.[web.archive.org]
  • Some may also be afflicted with macrocytic anemia. Virtually all patients are males; males suffer delayed growth and puberty, and most develop shrunken testicles or testicular atrophy.[namrata.co]
Prolonged Immobilization
  • The presence of pulmonary embolism is unusual and may be the consequence of prolonged immobilization.[ncbi.nlm.nih.gov]
Cutaneous Manifestation
  • Hobbs, Bitemarks, Cutaneous Manifestations of Child Abuse and Their Differential Diagnosis, 10.1007/978-3-642-29287-3_8, (219-244), (2012). R.A.C. Bilo and A.P.[doi.org]
Muscle Hypotonia
  • These include uncontrollable movements in the arms and legs (dystonia), repetitive movements (chorea) such as raising and lowering of the shoulders, and/or facial grimacing, and low muscle tone or soft muscles (hypotonia).[thinkgenetic.com]
  • It affects males and is characterized by neurologic defects, moderate mental retardation, muscle hypotonia, and a tendency for self-mutilation (self-biting of lips, tongue, and fingertips).[icd10data.com]
Self Mutilation
  • Lesch-Nyhan syndrome is a very rare X-linked recessive disorder characterized by mental retardation, spasticity resembling cerebral palsy, choreo-athetosis, self-mutilation and hyperuricemia. Self-mutilative behavior is a hallmark of the disease.[ncbi.nlm.nih.gov]
Self-Inflicted Wound
  • He was referred to the Dental Unit from the Department of Pediatric Neurology for evaluation and management of self-inflicted wounds on fingers, lips and cheeks associated with weight loss and decreased food intake.[ncbi.nlm.nih.gov]
  • Main symptoms and co-morbidities for Lesch-Nyhan syndrome include: Various degree of physical disability Delayed growth and puberty Gouty arthritis with flare-ups Kidney and bladder stones Infections of self-inflicted wounds Megaloblastic anaemia Cardiovascular[gii.co.jp]
  • Periods of relative dehydration are to be avoided because they could concentrate the purine metabolites in the urinary system and increase the risk for renal stones or urate nephropathy with resulting oliguria/anuria.[ncbi.nlm.nih.gov]
  • This syndrome is characterized clinically by mental retardation, chorea, athetosis, hyperuricemia, uricosuria and self-mutilation.[ncbi.nlm.nih.gov]
  • […] uncontrolled aggressive and/or compulsive actions, muscle weakness (hypotonia), uncontrolled spastic muscle movements, and neurological problems such as involuntary writhing movements of the arms and legs (athetosis) and purposeless repetitive movements (chorea[web.archive.org]
  • Chorea — Involuntary, rapid, jerky movements. Chorionic villus sampling (CVS) — A procedure used for prenatal diagnosis at 10-12 weeks gestation.[medical-dictionary.thefreedictionary.com]
Spastic Gait
  • Page TNyhan WLMorena de Vega V Syndrome of mild mental retardation, spastic gait, and skeletal malformations in a family with partial deficiency of hypoxanthine-guanine phosphoribosyltransferase.[dx.doi.org]
  • Syndrome of mild mental retardation, spastic gait, and skeletal malformations in a family with partial deficiency of hypoxanthine-guanine phosphoribosyltransferase. Pediatrics 79: 713-717, 1987. [PubMed: 3575027] [Full Text: ] Preston, R.[ncbi.nlm.nih.gov]
Choreoathetoid Movements
  • They have in addition a variety of neurological abnormalities including mental retardation, spastic cerebral palsy, and involuntary, choreoathetoid movements. Involved patients have unusual, compulsive, aggressive behavior.[link.springer.com]


Measurement of HPRT enzyme and its function in blood and tissues is the definitive diagnosis for LNS. This is usually confirmed by the identification of mutations in the HPRT1 gene.

Lab Studies
Uric acid overproduction can be easily revealed with blood and urine studies usually performed in clinical practices. However, it has to be remembered that sometime hyperuricemia can be caused by other conditions, while many patients affected by LNS might have levels of uric acid within the normal ranges. Therefore, uric acid levels cannot be used to confirm the disorder. Particularly in use are the 24-hour samples, even though they can be very difficult to collect. The calculation of the ratio between urinary uric acid and creatinine from urine specimen can be used as alternative method, but this approach is not as informative as the previous one.

Imaging studies
No evident structural malformation in the brain of the patients affected by LNS can be detected by using neuroimaging studies such as CT scan and MRI [6]. However, they might reveal small reductions in brain volume, which frequently go unnoticed in routine imaging studies. The brain volume loss especially occurs in the area of the basal ganglia and frontal cortex, without involving occipital lobes and cerebellum [9]. Sometime, complications can reach the spinal cord, especially in the cervical portions, causing degenerative joint disease that damage the spinal cord itself and the emerging nerve roots nearby.

Experts also recommend the use of noninvasive imaging studies for the kidneys and the urogenital system, especially to detect in advance the occurrence of infections and stone formation when they still remain asymptomatic. On this regard, ultrasonography is highly recommended in most of the cases.

  • Death is usually from aspiration pneumonia or complications of nephrolithiasis. Sometimes there is sudden death of unknown cause.[patient.info]
  • Hyperuricemia leads to hyperuricuria and uric acid nephrolithiasis. The underlying defect is a deficiency of hypoxanthine-guanine-phosphoribosyl transferase.[ncbi.nlm.nih.gov]
Small Kidney
  • Radiographic findings described in Lesch-Nyhan syndrome include faintly radio-opaque stones on abdominal radiographs or, if renal disease is present, small kidneys with poor function on intravenous urogram.[ncbi.nlm.nih.gov]
  • We report on a 16-day-old male with metabolic acidosis, hyperuricemia, hyperuricosuria, and nephrocalcinosis caused by Lesch-Nyhan syndrome.[ncbi.nlm.nih.gov]
  • After pyelolithotomy for a left renal stone, made up of ammonium urate, associated with urinary tract infection, a high dose of allopurinol was given because of the persistence of pyuria.[ncbi.nlm.nih.gov]
  • Dihydropyrimidinase deficiency Dihydrouracil dehydrogenase deficiency Disorder of purine and pyrimidine metabolism Disorder of purine metabolism Disorder of pyrimidine metabolism Hereditary orotic aciduria, type 2 Hereditary xanthinuria Hooft's syndrome Hyperuricuria Hypouricemia[icd9data.com]


Treatment is mostly aimed at addressing specific symptoms, through a strategy of coordinated efforts performed with the intervention of several specialists.

The pharmacological approach is mostly based on the use of allopurinol, which helps control the excessive amounts of uric acid in the blood and tissues [10]. However, this drug has no influence on the behavior and the neurological state of the patient, which remains negatively affected.

Stone formation can be treated using extracorporeal shock wave lithotripsy [11], a particular procedure which consists in immersing patients in water and treating them with high energy shock waves. Thanks to this approach, stones eventually dissolve and the many little pieces produced are finally eliminated through urine.

Neurological problems are usually addressed by using baclofen, benzodiazepines, or diazepam. However, no drug treatment has proved to be fully and evenly effective so far in dealing with this clinical side of LNS. On the contrary, behavior modification techniques have turned out to be useful in dealing with self-injurious behavior, especially when combined with the use of physical restrain of hips, chest, and elbows, or the use of mouth guards to avoid biting fingers and lips. Behavioral abnormalities can some time be treated with drugs. On this regard, it is important to remember depakote (sodium valproate), gabapentin, baclofen, and carbamazepine. Benzodiazepines should also be added to this list, as it can effectively treat the anxiety frequently associated with LNS.


The clinical consequences of LNS are very severe. Many patients die after aspiration pneumonia and the aftermaths of chronic nephrolithiasis and renal failure. Even with the best clinical treatment, just a few patients reach 40 years of age and many remain confined to wheelchairs [4].


LNS is a classical X-linked disorder, in other words a pathological condition which is caused by one or more mutations of the genes present in the X chromosome [3], one of the two sex-determining chromosomes (or allosomes) in many animal species. These types of genetic disorders mostly occur in males, as they have one single X chromosome. Therefore, to see the phenotypic expression of these mutations, it is sufficient to have one single mutated gene. On the contrary, LSN appears much less frequently in females, as they mostly have two X chromosomes. Therefore, in a female the expression of a X-linked mutation, which appears as a recessive character, occurs only when the two copies of the gene in both X chromosomes are mutated. Thus, females more frequently end up becoming simple carriers of the disorder.

As previously stated, the gene involved in the development of LNS is HPRT1, located on the long arm of the X chromosome in the Xq27 position. Its mutations inevitably result into a severe deficiency of HPRT and an abnormally high uric acid accumulation in the blood.


The prevalence of LNS has been estimated over the years to vary in the range going from 1 case for every 235,000 to 1 case for every 380,000 live births [4]. The disorder has been observed in all races and ethnic groups, with no particular predilection. As stated above, because of its X-linked nature, the disorder mostly appears in males rather than females, which mainly remain simple carriers. Affected individuals are diagnosed very early in life, usually before the age of 4. It is important to note that at the moment the prevalence of the HPRT deficiency is still unknown.

Sex distribution
Age distribution


HPRT is involved in the recycling process of purine bases. If the function of this enzyme is compromised, the purine recycling process is compromised as well, and as a result the purine bases are degraded and excreted as uric acid. This then leads to an increase in the synthesis of the purines, perhaps for some still undetected compensation mechanism. These two factors combined, the failure of the recycling process and the increased purine synthesis, are lastly responsible for the uric acid overproduction [1].

The direct consequence of uric acid overproduction is persistent hyperuricemia which, as the uric acid is already near the solubility limit, finally causes uric acid precipitation and the subsequent crystallization in the several tissues in the body. Crystallization, in turn, leads to the formation of the tophi along skin surface, especially in the joints, and the inflammatory reaction called gouty arthritis. Another direct consequence to remember is the increased excretion by the side of kidneys into the urogenital system, which in turn increases the risk of stone formation into the urinary tracts, and therefore the risk of the associated urine flow blocks and infections.

As to the pathogenesis of the behavioral and neurological signs, the mechanism that finally leads to these problems have not been completely understood yet [5]. However, some neurochemical and neuroimaging studies have underlined the presence of significant abnormalities associated with the dopamine neuron function in the basal ganglia. In addition, neuropathological studies suggest the presence of a neurodevelopmental defect with no signs of degenerative process [6], that must somehow be connected with the behavioral and neurological profile. Nevertheless, the question about the mechanism underlying the effects of the HPRT over the dopamine systems and therefore the appearance of the behavioral and neurological consequences is still hotly debated among experts.


As LNS is a genetic disorder, no specific measure can be suggested to prevent it. However, genetic counseling is highly recommended, as it might allow parents and physicians to organize a treatment plan in advance.


Lesch Nyhan Syndrome (LNS) is a genetic disorder which is characterized by three major symptoms, as indicted previously: a characteristic overproduction of uric acid, combined with neurological and behavioral problems [1]. The over production of uric acid is usually associated with hyperuricemia and on the long run, if left untreated, it might lead to nephrolithiasis and associated complications such as renal failure, gouty arthritis, and deposits of uric acid on the surface of the skin called tophi. Dystonia appears to be the main neurological complications, but it can be combined with other problems such as spasticity, ballismus, choreoathetosis, and hyperreflexia. Lastly, the behavioral problems include intellectual disability, often combined with aggressive and impulsive behaviors which often cause self-injuries.

In addition to the full form of the disorder, characterized by the full manifestation of all the clinical signs underlined, milder forms have also been observed over the years [2]. In these milder variants, while uric acid overproduction is likely to be always present, affected individuals can show no self-injurious behaviors, normal levels of cognition, and no dystonia at all. These cases are collectively referred to as LNS variants and their occurrence can only be diagnosed by screening HPRT gene and revealing HPRT deficiency.

Unfortunately, treatment is limited and mainly based on the use of products such as allopurinol which controls uric acid overproduction and reduces the possibility of developing nephrolithiasis and gouty arthritis. Neurological and behavioral problems, instead, are frequently addressed with a combination of behavioral modification techniques and pharmacological treatment based on drugs like baclofen and benzodiazepines.

Patient Information

Lesch Nyhan syndrome (LNS) is a genetic disorder which consists in a disruption of the normal mechanism to build and break down purines, one of the components of DNA and RNA.

LNS is caused by mutations of the gene for hypoxanthine guanine phosphoribosyltransferase, one of the enzyme responsible for purine recycle process. If its function is compromised, purines can no longer be recycled, and as consequence are turned into uric acid which begins to build up throughout the body. The hypoxanthine guanine phosphoribosyltransferase gene can be found as recessive train carried by the X chromosome. For this reason, the disorder is predominantly observed in males.

Motor symptoms are the first to be noticed, usually between the first months of life, especially as delays in motor development, hypotonia, or spasticity. These are then followed by involuntary movements, especially between the sixth and the eighteenth month of age.

Hyperuricaemia, the abnormally high level of uric acid in the blood, is another important clinical sign of LNS. This is usually associated with the appearance of orange sands throughout the skin surface, as a consequences of the formation of uric acid crystals and gout.

These initial signs are then followed by neurological and behavioral problems, which eventually lead to the appearance of self-injurious behaviors towards the age of 12 years.

The diagnosis of LNS is largely made with a thorough clinical evaluation based on the history of the patient and specialized blood tests. The tests are used especially to detect the high concentration of uric acid in the blood, even though the final diagnosis has to be confirmed with a genetic analysis to reveal the mutations on the HPRT 1 gene associated with LNS.

The most important drug used against LNS is allopurinol, employed to treat hyperuricaemia and its complications. Other important drugs include baclofen and benzodiazepines, used in combination to treat spasticity, and diazepam.
No treatment has proved to be fully effective against neurological and behavioral problems, which can be best addressed by using behavioral modification techniques. Furthermore, while treating the patient it is very useful to use physical restrains and month guards to avoid physical damages due to self-injurious behaviors.



  1. Jinnah HA, Friedmann T. Lesch-Nyhan disease and its variants. Scriver CR, Sly WS, Childs B, Beaudet AL, et al, eds. The Molecular and Metabolic Bases of Inherited Disease. 6th ed. New York, NY: McGraw-Hill; 2000. Chapter 107.
  2. Jinnah HA, Ceballos-Picot I, Torres RJ, et al. Attenuated variants of Lesch-Nyhan disease. Brain. 2010 Feb 22.
  3. Jinnah HA, De Gregorio L, Harris JC, et al. The spectrum of inherited mutations causing HPRT deficiency: 75 new cases and a review of 196 previously reported cases. Mutat Res. 2000 Oct; 463(3):309-26.
  4. Torres RJ, Puig JG. Hypoxanthine-guanine phosophoribosyltransferase (HPRT) deficiency: Lesch-Nyhan syndrome. Orphanet J Rare Dis. 2007 Dec 8; 2:48.
  5. Visser JE, Bar PR, Jinnah HA. Lesch-Nyhan disease and the basal ganglia. Brain Res Brain Res Rev. 2000 Apr; 32(2-3):449-75.
  6. Jinnah HA, Visser JE, Harris JC, et al. Delineation of the motor disorder of Lesch-Nyhan disease. Brain. 2006 May; 129(Pt 5):1201-17.
  7. van der Zee SP, Schretlen ED, Monnens LA. Megaloblastic anaemia in the Lesch-Nyhan syndrome. Lancet. 1968 Jun 29; 1(7557):1427.
  8. Jinnah H A, Friedmann T. Lesch-Nyhan disease and its variants.In: Scriver C R, Beaudet A L, Sly W S, Valle D. (eds.) : The Metabolic & Molecular Bases of Inherited Disease. Vol. II. 8th ed. New York: McGraw-Hill 2001. P. 2537.
  9. Bakay B, Nissinen E, Sweetman L, et al. Utilization of purines by an HPRT variant in an intelligent, nonmutilative patient with features of the Lesch-Nyhan syndrome. Pediat Res. 1979; 13:1365-1370.
  10. Torres RJ, Prior C, Puig JG. Efficacy and safety of allopurinol in patients with hypoxanthine-guanine phosphoribosyltransferase deficiency. Metabolism. 2007; 56:1179-1186.
  11. Morino M, Shiigai N, Kusuyama H, et al. Extracorporeal shock wave lithotripsy and xanthine calculi in Lesch-Nyhan syndrome. Pediatr Radiol. 1992; 22:304.

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Last updated: 2019-07-11 21:12