Lesch�Nyhan syndrome (LNS) is a rare inherited disorder caused by a deficiency of the enzyme hypoxanthine-guanine phosphoribosyltransferase (HGPRT).
The defective gene is that for hypoxanthine-guanine phosphoribosyltransferase (HPRT), needed for the recycling of purine nucleotides.
This enzyme is involved in the biochemical pathways the body uses to produce purines, one of the components of DNA and RNA.
Defects of this enzyme lead to increased production of uric acid.
A partial HPRT deficiency, is known as Kelley-Seegmiller syndrome, is a less severe form of LNS.
Kelley-Seegmiller syndrome symptoms generally involve less neurological involvement but the disease still causes gout and kidney stones.male
LNS associated with an increased synthesis and decreased utilization of purines leads to high levels of uric acid production.
High levels of uric acid in the blood and urine occur and is associated with severe gout and kidney problems.
Hyperuricemia may lead to the development of uric acid crystals or stones in the kidneys, ureters, or bladder, and later in the disease gout-like arthritis, with swelling and tenderness.
The overproduction of uric acid is present at birth, but may not be clinically recognized.
The serum uric acid concentration is often normal, as the excess purines are promptly eliminated in the urine.
Uric acid does not penetrate the blood–brain barrier well.
Oxidative stress due to uric acid is now thought to figure in metabolic syndrome, atherosclerosis, and stroke, all syndromes associated with high uric acid levels.
It is characterized by: neurologic dysfunction, cognitive and behavioral disturbances including self-mutilation, and uric acid overproduction.
Uric acid is a possible cause of neurotoxicity, but this is unproven.
Lesions in striatal dopaminergic pathways may be central to the neurological deficits in LNS especially for choreoathetoid dyskinesia and self-mutilation.
A lack of HGPRT enzyme may produce a nucleotide deficiency disorder, resulting in dopamine deficiency.
Uric acid is a powerful reducing agent and likely an important antioxidant, suggesting that free radicals, oxidative stress, and reactive oxygen species may play some role in the neuropathology of LNS.
However, hyperuricemia associated with primary gout, which is caused by low uric acid renal clearance rather than uric acid overproduction, is not associated with neuropathology.
Behaviors may be seen as a psychological extension of the compulsion to cause self-injury, and socialization rejection.
Compulsive behaviors including aggressiveness, vomiting, spitting, and coprolalia occur.
The development of this type of behavior is sometimes seen within the first year, or in early childhood, but others may not develop it until later in life.
The majority of individuals are cognitively impaired.
Self-harm is characteristic of the disease and is apparent in 85% of affected males.
Self-harm increases with stress.
The symptoms caused by the buildup of uric acid, gout and kidney symptoms, respond well to allopurinol that reduces the levels of uric acid in the blood.
The mental deficits and self-mutilating behavior do not respond well to treatment.
No known cure exists,but many affected people live to adulthood.
Some patients may also be afflicted with macrocytic anemia.
The gene mutation is usually carried by the mother and passed on to her son, although one-third of all cases arise from new mutations and do not have a family history.
LNS affects about 1 in 380,000 live births.
LNS is present at birth in baby boys.
The most common presenting findings are abnormally decreased muscle tone
and developmental delay.
These findings are evident by three to six months of age, when infants
are late in sitting up, never crawl or walk.
Lack of speech is also a very common trait associated with LNS.
One of the first signs of nervous system impairment is irritability.
Most people with this deficiency have severe mental and physical problems throughout life.
A few rare cases reported affecting females.
The father of an affected male will not be the carrier of the mutant allele, and will not have LNS.
A woman who has an affected son and one other affected relative in the maternal line is an obligate carrier of the disease.
Statistically if a woman is the first in her family with an affected son, it is predicted there is a 2/3 chance that she is a carrier and a 1/3 chance that the son has a new germline mutation.
With each pregnancy, a carrier female has a 25% chance of having a male that is affected, a 25% chance of having a female that is a carrier, and a 50% chance of having a normal male or female.
Males with LNS do not reproduce due to the characteristics of the disease.
If a male with a less severe phenotype reproduces, all of his daughters are carriers, and none of his sons will be affected.
Female carriers are at an increased risk for gouty arthritis but are usually otherwise unaffected.
Female carriers are generally asymptomatic, but they do experience an increase in uric acid excretion, and some may develop symptoms of hyperuricemia, and suffer from gout in their later years.
Testing may reveal the possibility of transmitting the trait to male children.
Females who carry one copy of the defective gene are carriers with a 50% chance of passing the disease on to their sons.
In order for a female to be affected, she would need to have two copies of the mutated gene, one of which would be inherited from her father.
Males affected with LNS do not usually have children due to the debilitating effects of the disease.
Males are affected because they only have one copy of the X chromosome.
Female carriers have a second X chromosome, containing a normal copy of HPRT gene, preventing the disease from developing.
Female carriers may have increased risk of hyperuricemia.
It is possible for a female to inherit an X chromosome from her unaffected father, who carries a new mutation of the HGPRT gene.
Under these circumstances, a girl could be born with LNS, and though there are a few reports of this happening, it is very rare.
Siblings risk of an affected individual depends upon the carrier status of the mother.
There is a 50% chance of any female who is a carrier to transmit the HPRT1 mutation in each pregnancy.
Sons who inherit the mutation will be affected while daughters who inherit the mutation are carriers.
The HGPRT deficiency causes a build-up of uric acid in all body fluids.
HGPRT channels hypoxanthine and guanine back into DNA synthesis.
When HGPRT enzyme fails it results in cell breakdown products that cannot be reused, and are therefore degraded.
The fault gives rise to increased uric acid, a purine breakdown product.
Hypouricemia seen in a number of purine disorders, in particular xanthinuria.
Xanthinuria, a complete absence of blood uric acid, with no neuropathology, but with kidney stones caused by accumulation of insoluble xanthine.
The HPRT gene is located on the X chromosome, LNS is an X-linked inherited disease.
Other name Is Juvenile gout.
LNS deficiency of HGPRT occurs due to mutations in the HPRT1 gene located on the X chromosome.
A number of mutations of HGPRT exist: those that only mildly decrease the enzyme’s function do not normally cause the severe form of LNS, but do produce a milder form of the disease.
Milder forms of the disease have features purine overproduction, with susceptibility to gout and uric acid nephrolithiasis.
LNS is inherited in an X-linked recessive manner.
Hypoxanthine-guanine phosphoribosyltransferase deficiency associated with deafness and self-mutilation.
Characterized by elevated uric acid, severe neurologic impairments, mental retardation, self-mutilation in males.
Virtually all patients are male.
Males suffer with delayed growth and delayed puberty.
Males develop testicular atrophy.
Early findings include the presence of sand-like crystals of uric acid in the diapers of the affected infant.
Some patients with Lesch-Nyhan syndrome have gouty arthritis.
In the first year of life neurological signs, poor muscle control and moderate intellectual disability occur.
In the second year of life self-mutilating behaviors, characterized by lip and finger biting occur.
Extreme nail biting is sometimes related by Lesch-Nyhan Syndrome.
Uncontrollable self-injury associated with LNS also usually begins at three years of age: biting of the lips and tongue, finger biting and head banging.
Also, neurological symptoms including grimacing, writhing, and repetitive movements of the arms and legs similar to those seen in Huntington’s disease occur.
Extrapyramidal involvement causes abnormal involuntary muscle contractions such as loss of motor control, writhing motions known as choreoathetosis, and arching of the spine.
Pyramidal system involvement of spasticity, hyperreflexia and extensor plantar reflexes, occur.
It resembles athetoid cerebral palsy,and
most individuals are initially diagnosed as having CP.
Most individuals with LN Sx never walk, and become lifelong wheelchair users.
Damage to the basal ganglia causes patients to adopt a characteristic fencing stance due to the nature of the lesion.
A lack of HGPRT causes the body to poorly utilize vitamin B12, some males may develop megaloblastic anemia.
Diagnosis:
When the three clinical elements of uric acid overproduction, neurologic dysfunction, and cognitive and behavioral disturbances, the diagnosis is easily made.
Early diagnosis is more difficult, when the 3 elements to diagnosis are not fully appreciated.
Signs of self injury behavior and genetic testing and evaluation can confirm the diagnosis.
Suspicion for the diagnosis comes with developmental delay, and the presence of hyperuricemia.
Developmental delay and an association with the manifestations of kidney stones suggest the diagnosis.
Generally, the diagnosis of LNS is suspected when there is self injurious behavior.
Biting the fingers and lips is a definitive feature of Lesch–Nyhan syndrome.
Other syndromes associated with self-injury consist of head banging and nonspecific self-mutilation, but not biting of the cheeks, lips and fingers.
Lesch–Nyhan syndrome ought to be clearly considered only when self-injurious behavior takes place in conjunction with hyperuricemia and neurological dysfunction.
Self-injurious behaviors occurs in: Lesch-Nyhan syndrome, nonspecific intellectual disability, autism, Rett syndrome, Cornelia de Lange syndrome, Tourette syndrome, familial dysautonomia, choreoacanthocytosis, sensory neuropathy including hereditary sensory neuropathy type 1, and several psychiatric conditions.
Diagnostic findings:
The urate to creatinine concentration ratio in urine is elevated, an indicator of acid overproduction.
For children under ten years of age with LNS, a urate to creatinine ratio above two is typically found.
Twenty-four-hour urate excretion of more than 20 mg/kg is also typical.
Hyperuricemia (serum uric acid concentration of >8 mg/dL) is often present but not reliable enough for diagnosis.
The activity of the HGPRT enzyme in cells from any type of tissue: blood, fibroblasts, or lymphoblasts, that is less than 1.5% of normal enzyme activity confirms the diagnosis of Lesch–Nyhan syndrome.
Diagnosis is confirmed by molecular genetic studies of the HPRT gene mutations.
Subsequent carrier testing in at-risk females such as close family relatives on the female side is helpful.
A mutant frequency of 0.5–5.0 × 10−2 is found in carrier females, while a non-carrier female has a frequency of 1–20 × 10−6.
HPRT1 is the only gene known to be associated with LNS.
Treatment for LNS is symptomatic.
Gout can be treated with allopurinol to control excessive amounts of uric acid.
Treatment for the neurological symptoms of LNS, includes carbidopa/levodopa, diazepam, phenobarbital, or haloperidol.
No medication is effective in controlling the extrapyramidal motor abnormalities of the disease.
Spasticity, however, can be reduced by the administration of baclofen or benzodiazepines.
The overproduction of uric acid is controlled in order to reduce the risk of nephropathy, nephrolithiasis, and gouty arthritis: allopurinol is utilized to stop the conversion of oxypurines into uric acid, and prevent the development of subsequent arthritic tophi, kidney stones, and nephropathy, the resulting kidney disease.
Allopurinol is taken orally, at a typical dose of 3–20 mg/kg per day , and the dose is adjusted to bring the uric acid level down into the normal range.
Most affected patients can be treated with allopurinol all through life.
Self-injurious behavior is best managed by a combination of medical, physical, and behavioral interventions.
Using restraints can reduce self mutilation and 60% of affected individuals have the teeth extracted to avoid self injury.
Restraints are commonly used to prevent self injury, and more than 75% of the time patients are restrained.
Restraints put the patients at ease.
The prognosis for individuals with severe LNS is poor.
LNS deaths are usually due to kidney failure or complications from hypotonia, in the first or second decade of life.
Less severe forms have better prognoses.