Lavoro svolto da Elena Asteggiano ed Elena Banino
DEFINITION
Lesch-Nyhan syndrome (LNS), also known as Nyhan's syndrome, Kelley-Seegmiller syndrome and Juvenile gout, is a rare inherited disorder transmitted as a sex-linked trait and caused by a deficiency of an enzyme of purine metabolism:hypoxanthine-guanine phosphoribosyltransferase (HGPRT).
Affected individuals are normal in the first year of life and then develop psychomotor retardation, extrapyramidal movement disorders, progressive spasticity, and seizures. Self-destructive behaviours such as biting of fingers and lips are seen frequently. Intellectual impairment may also occur but is typically not severe. Elevation of uric acid in the serum leads to the development of renal calculi and gouty arthritis.
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EPIDEMIOLOGY
LNS is a rare disease, estimated prevalence at birth is between 1/380,000 and 1/235,000 live births.
LNS is an X-linked recessive disease: the gene mutation is usually carried by the mother and passed on to her son.
Males get Lesch-Nyhan disease when there is a mutation of the HPRT gene on the X-chromosome. Females do not get the disease because the normal X-chromosome protects them. These females are known as silent carriers, because they carry the disease, but it remains silent.
If they pass the good one along, their children are healthy. If they pass the bad one along, the result depends on whether they have a boy or a girl. If the bad chromosome is passed along to a daughter, the daughter is normal but becomes a silent carrier like her mother. If the bad chromosome is passed to a son, he gets Lesch-Nyhan disease. Because every boy inherits his X-chromosome from his mother, only mothers can transmit the disease. Fathers cannot pass the disease to their sons.
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.
Lesch-Nyhan boys do not always get their condition from their mothers. One-third of all cases arise de novo (from new mutations) and do not have a family history. These boys got their disease when a mutation in the HPRT gene occurred very early during their development. Genetic testing is required to determine if the mutation came from the mother or not.
Lesch-Nyhan disease is a rare condition that affects children at a very young age, from the first year of life.
The disease has been reported for most races, with approximately equal rates for most ethnic groups.
Hypoxanthine-Guanine Phosophoribosyltransferase (HPRT) Deficiency: Lesch-Nyhan Syndrome, 2007
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Genetic Home Reference URL
SYMPTOMS
Lesch-Nyhan syndrome is characterized by:
- uric acid overproduction,
- neurologic dysfunction,
- cognitive and behavioural disturbances.
Overproduction of uric acid
One of the first symptoms of the disease is the presence of sand-like crystals of uric acid in the diapers of the affected infant. Overproduction of uric acid may lead to the development of uric acid crystals or stones. The crystals usually appear as an orange grainy material, or they may coalesce to form either multiple tiny stones ("gravel") or distinct large stones that are difficult to pass.
These crystals and stones like to form in three main areas of the body.
The first area is the joints between bones, especially those of the toes or fingers. When this happens, the crystals cause irritation of the joints, a problem known as gout. Gout can be seen as a finger or toe that becomes swollen, red, and painful.
The second area that crystals and stones form is just under the skin in cool parts of the body. When they form here, they can be seen through the skin as tophi.
The last area crystals and stones form is in the kidney. These are the most dangerous stones. Sometimes a stone will pass out of the kidney to show up in the urine, where it can actually be seen. Sometimes a stone will get stuck on its way to the bladder. This often causes pain in the belly, back, or upper leg. A trapped stone can also block the flow of urine. If a large stone gets stuck in the kidney or on its way to the bladder, it can prevent the kidney from doing its job and cause kidney failure.
End-stage renal disease (ESRD), which prior to the availability of allopurinol was the rule in this disease, is less common now but still occurs. ESRD may be a special risk for variant patients with variant forms in whom neurologic or behavioural features do not lead to early recognition
This photograph shows uric acid crystals in urine, when viewed using a microscope. Their birefringence under a polarizing microscope helps to discriminate uric acid crystals from other types of crystals, but biochemical analysis is required to reveal the chemical composition.
Nervous system impairment
The periods before and surrounding birth are typically normal in individuals with LNS.
The most common presenting features are abnormally decreased muscle tone (hypotonia) and developmental delay, which are evident by three to six months of age. Affected individuals fail to reach normal milestones such as sitting, crawling, and walking.
Irritability is most often noticed along with the first signs of nervous system impairment. Within the first few years of life, extrapyramidal involvement causes abnormal involuntary muscle contractions such as loss of motor control . Their muscles seem stiff, particularly when they try to use them. This problem is known as dystonia, and all have it. These problems are severe enough that they often prevent walking or using hands for feeding.
Some with Lesch-Nyhan disease also have spasticity. This is also a form of muscle stiffness, and it can be difficult to distinguish it from dystonia. A few also have choreoathetosis or ballismus, motor disorders characterized by wiggling, writhing and flinging movements.
Signs of pyramidal system involvement, including spasticity, overactive reflexes (hyperreflexia) and extensor plantar reflexes, also occur. The resemblance to athetoid cerebral palsy is apparent in the neurologic aspects of LNS. As a result, most individuals are initially diagnosed as having cerebral palsy. The motor disability is so extensive that most individuals never walk, and are confined to a wheelchair for life.
Cognitive and behavioural disturbances
Patients with Lesch-Nyhan disease almost always have behaviour problems. Some of these troublesome behaviours include attempting to hit others, spitting on others, or using foul language.
These behaviours may look like acts of aggression towards others, but they are not. Many admit that they are impulsive and cannot control these acts.
Other compulsive behaviours may include aggressiveness, vomiting, spitting, and coprolalia.
Early studies of cognitive function suggested that all people with Lesch-Nyhan disease had severe mental retardation. This is not true. Recent studies have suggested much less severe cognitive disability. IQ testing reveals a wide range in scores with some falling in the normal range. The IQ scores usually fall between 60-70, which is classified as mild or moderate cognitive impairment.
More importantly, recent studies have addressed different cognitive domains, such as memory or language skills, to determine the reason IQ scores are low. Individuals with Lesch-Nyhan disease have relatively good memories and language, but their attention spans are terrible, and they have difficulty with complex planning and predicting the consequences of future events.
The Lesch-Nyhan variants do not have behaviour problems.
Self-injuring behaviour
Children with Lesch-Nyhan disease often develop problem behaviours. The most troublesome of these involve repeated attempts to injure themselves, known as self-injurious behaviour. These problems may start during the first year of life, but more commonly appear between 2-4 years of age. Biting of the lips and tongue is the most common problem behaviour, but biting of fingers and other body parts may also occur. Others try to hit themselves or injure their own eyes.
The self-injury can increase during times of stress. Self-mutilation is a distinguishing characteristic of the disease and is apparent in 85% of affected males.
The behaviours are very disturbing to anyone who may witness them. It is very unhelpful to yell at the boy who is engaging in these behaviours. The impulses that force these behaviours to occur are too strong, and the boys cannot control them. It is necessary to restrain boys with Lesch-Nyhan disease when these behaviours appear, or they may cause serious injuries. In most cases, boys with Lesch-Nyhan disease prefer being restrained, because they are comforted by the knowledge that they will not hurt themselves.
A small portion of the lower lip has been disfigured by persistent self-biting.
The distal portions of several fingers are shortened by prior uncontrolled self-biting
Other issues
Several other problems may also occur in Lesch-Nyhan disease. One of these is recurrent vomiting. This is sometimes severe enough to impair nutrition and growth. If it is severe, a feeding tube may have to be inserted into the stomach.
Another problem is anaemia with very large red cells in the blood. This problem is usually caused by dietary deficiency of vitamin B12 or folic acid, and sometimes by other problems. However, patients with Lesch-Nyhan disease do not usually have such deficiencies, and supplements do not correct the anaemia. Fortunately, it does not usually cause significant disability, so it does not need to be treated.
Affected males suffer delayed growth and puberty and most develop shrunken testicles or testicular atrophy.
EEG may show nonspecific changes of slowing or disorganization. Both CT and MRI show nonspecific changes of atrophy in the central nervous system with reduced cerebral volume and reduced caudate nucleus volume.
Lesch-Nyhan Syndrome. 2000
Database LINK
Lesch-Nyhan.org URL
Lesch-Nyhan syndrome in females
While carrier females are generally an asymptomatic condition, 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 in this context has no clinical consequence, but it may reveal the possibility of transmitting the trait to male children. Women may also require testing if a male child develops LNS. In this instance, a negative test means the son's disease is the result of a new mutation, and the risk in siblings is not increased.
DIAGNOSIS
Because Lesch-Nyhan disease is so rare, it can be difficult to find a specialist who is experienced in making the diagnosis. The diagnosis can usually be made by following three simple steps:
1.Clinical assessment
2.Confirmatory testing
3.Checking the family
1.Clinical assessment
The first step in diagnosis involves a thorough medical evaluation. This usually includes collecting a detailed summary of the child’s development and performing a physical examination. There are three important clinical elements to address in the medical evaluation:
1. Evidence that suggests developmental delay
2. Any occurrence of self-biting or other types of self-injurious behaviour
3. Clues that suggest uric acid overproduction
Difficulties of diagnosis are abundant in the early stages when the three features are not yet obvious. Suspicion often comes about when the developmental delay of the individual is associated with hyperuricemia. Otherwise, the diagnosis should be alleged when developmental delay is associated with kidney stones (nephrolithiasis) or blood in the urine (hematuria), caused by uric acid stones. For the most part, Lesch–Nyhan syndrome is first suspected when self-inflicted injury behavior develops. However, self-injurious behaviours occur also in other conditions. Biting the fingers and lips is a definitive feature of Lesch–Nyhan syndrome.
Lesch–Nyhan syndrome ought to be clearly considered only when self-injurious behaviour takes place in conjunction with hyperuricemia and neurological dysfunction.
2.Confirmatory testing
The second step in diagnosis requires certain tests to confirm the diagnosis and rule out other possible diseases.
The tests include blood and urine samples for uric acid. If these tests reveal high uric acid levels, then suspicion for Lesch-Nyhan disease goes up. Uric acid is considered a screening test for Lesch-Nyhan disease. Uric acid levels alone are not sufficient for definitive diagnosis.
- The urate-to- creatinine ratio, calculated from the concentration of uric acid and creatinine in the urine, provides a reliable measure of uric acid overproduction. A urate-to-creatinine ratio greater than 2.0 is characteristic for affected males younger than age ten years, but is not considered diagnostic.
- Twenty-four-hour urate excretion of more than 20 mg/kg is characteristic but not diagnostic.
- Hyperuricemia (serum uric acid concentration >8 mg/dL) is often present but not sensitive or specific enough for diagnostic purposes.
3.Checking the family
If the tests lead to a definite diagnosis of Lesch-Nyhan disease, it becomes very important to check family members as a third step, by a genetic counselling.
Genetic counselling is the process of providing individuals and families with information on the nature, inheritance, and implications of genetic disorders to help them make informed medical and personal decisions
At a minimum, the child’s mother should be checked. The disease shows up in males but stays silently hidden in females. A mother who carries the disease will seem completely normal.
If a woman is the first in her family with an affected son, Haldane's rule predicts a 2/3 chance that she is a carrier and a 1/3 chance that the son has a new germ line mutation.
When an affected male is the only affected individual in the family, several possibilities regarding his mother's carrier status need to be considered:
-The son has a de novo disease-causing mutation in the HPRT1 gene and his mother is not a carrier.
-His mother has a de novo disease-causing mutation in the HPRT1 gene, either (a) as a germline mutation" (i.e., occurring at the time of her conception and thus present in every cell of her body); or (b) as germ line mosaicism" (i.e., present in a certain percentage of her germ cells only).
-His mother has a disease-causing mutation that she inherited from a maternal female ancestor.
Prenatal Testing
Prenatal testing is available for at-risk pregnancies (i.e., pregnancies of women who are carriers or who may have germ line mosaicism).
When the HPRT1 disease-causing mutation is known in a family, HPRT enzyme activity or molecular genetic testing are performed to confirm the diagnosis in the fetus.
The usual procedure is to determine fetal sex by performing chromosome analysis on fetal cells obtained by chorionic villus sampling (CVS) at approximately ten to 12 weeks' gestation or by amniocentesis usually performed at approximately 15 to 18 weeks' gestation.
If the karyotype is 46,XY, DNA from fetal cells can be analyzed for the known disease-causing mutation. 46,XX cells can be tested for mutation carrier status as well.
Biochemical genetic testing. Assay of HPRT enzyme activity in cultured amniocytes or chorionic villus cells is the preferred method if the HPRT1 mutation has not been identified in the family. No false positive or false negative diagnoses have been encountered in prenatal testing, but it is possible that maternal cells could contaminate and overgrow the culture.
Preimplantation genetic diagnosis (PGD) may be available for families in which the disease-causing mutation has been identified.
DIFFERENTIAL DIAGNOSIS
The main diagnostic difficulties for LND arise during early stages when all the features are not yet apparent, or in individuals who have partial deficiency of HPRT enzyme activity.
Lesch-Nyhan syndrome is often first suspected when self-injurious behaviour develops. However, self-injurious behaviours occur in other conditions, including:
-nonspecific mental retardation:
- autism,
- Rett syndrome,
- Cornelia de Lange syndrome,
- Tourette syndrome,
- familial dysautonomia,
- choreoacanthocytosis.
-sensory neuropathy including:
- hereditary sensory neuropathy type 1,
- several psychiatric conditions.
Of these, only individuals with Lesch-Nyhan syndrome, Cornelia de Lange syndrome, and familial dysautonomia regularly display loss of tissue as a result of the behaviour. Finger and lip biting is so characteristic of Lesch-Nyhan syndrome that it is referred to as a behavioural phenotype.
PATHOGENESIS
LNS is due to mutations in the HPRT1 gene, so named because it codes for the enzyme hypoxanthine-guanine phosphoribosyltransferase. HPRT normally plays a key role in the recycling of the purine bases, hypoxanthine and guanine, into the purine nucleotide pools.
In the absence of HPRT, these purine bases cannot be salvaged, and instead are degraded and excreted as uric acid. In addition to the failure of purine recycling, the synthetic rate for purines is accelerated, presumably to compensate for purines lost by the failure of the salvage process. The failure of recycling together with the increased synthesis of purines is the basis for the overproduction of uric acid. The increased production of uric acid leads to hyperuricemia.
The pathogenesis of the neurological and behavioural features is incompletely understood. Neurochemical and neuroimaging studies have demonstrated significant abnormalities of dopamine neuron function in the basal ganglia that might account for the abnormal extrapyramidal neurological signs and many of the behavioural anomalies. Neuropathological studies suggest a neurodevelopmental defect, with no signs of a degenerative process. The current studies demonstrate that HPRT deficiency influences early developmental processes controlling the dopaminergic phenotype.
The En1 and En2 genes encode two closely related transcription factors that are part of a large family of homeobox transcription factors responsible for many developmental processes. The engrailed products have specific roles in two events during neural development. They function as nuclear transcription factors that alter the expression of multiple other genes, but they also can be released from cells and internalized by neighbours, where they are thought to exert paracrine-like activities. There is good evidence that alterations in the expression of the engrailed genes influence dopamine neuron development and survival. The mechanisms by which HPRT deficiency influences the expression of the engrailed genes remain to be determined. One possibility is that engrailed expression may be affected directly by HPRT. HPRT may have a moonlighting function beyond its role in purine recycling. Alternatively, HPRT deficiency may influence engrailed pathways indirectly, through the secondary changes in purine metabolism that occur when HPRT is missing. It also is possible that over-expression of engrailed genes reflects a compensatory developmental response to a defect elsewhere in the developmental programs of these neurons.
Hypoxanthine-guanine phosphoribosyl transferase regulates early developmental programming of dopamine neurons: implications for Lesch-Nyhan disease pathogenesis.2009.
Dopamine function in Lesch-Nyhan disease,2000
VARIANTS
The clinical picture of the classic form of Lesch-Nyhan disease usually includes three things: uric acid crystals or stones, neurological disability, and difficult behaviours. But not all patients have all three problems. Some are spared the behavioural problems and self-injury. Others have only uric acid problems. These individuals with less severe problems are called the Lesch-Nyhan variants (LNV), to distinguish them from the more severely affected patients: the condition with only problems due to too much uric acid is called 'HPRT-related hyperuricemia' (HRH) and patients who also have neurological problems, but no behavioural symptoms and self-injury, have 'HPRT-related hyperuricemia with neurological dysfunction' (HND).
The reasons that some patients are less severely affected are an important area of current research. They may hold clues for how to spare others from getting all three of the problems.
Schematic representation of the spectrum of clinical features in LND and its variants. Patients are divided into subgroups with the most severe being LND, the intermediate form being HPRT-related neurological dysfunction (HND), and the least severely affected being HPRT-related hyperuricemia (HRH). The frequency or severity of each problem is depicted by the thickness of the tapering bar, with description of the spectrum of the problem across the groups.
IQ scores according to patient subgroup. Patient subgroups include LND, HPRT-related neurological dysfunction (HND), and HPRT-related hyperuricemia (HRH). Patients with LND and HPRT-related neurological dysfunction were distinguished by the presence of self-injurious behaviour. Individual scores are overlaid with a box-whisker plot, where the middle horizontal line in each box shows the median. The upper and lower limits of the box define the upper and lower quartiles. Whiskers span the entire data range excepting outliers, defined as values that fell outside the upper or lower quartile plus 1.5 times the inter-quartile distance.
Severity of dystonia according to patient subgroup. Patient subgroups are LND, HPRT-related neurological dysfunction (HND), and HPRT-related hyperuricemia (HRH). Patients with LND and HPRT-related neurological dysfunction were distinguished by the presence of self-injurious behaviour.
Attenuated variants of Lesch-Nyhan disease, 2010.
Database LINK
Lesch-Nyhan.org URL
COMPLICATIONS AND PROGNOSIS
Life expectancy
The prognosis for individuals with severe LNS is poor, few patients live beyond 40 years.
If symptoms are properly managed, most individuals survive into the second or third decade of life. There may be slow progression of disease in adulthood.
Death is usually due to :
- renal failure,
- nephrolithiasis,
- urosepsis,
- complications from hypotonia,
- forcible opisthotonus,
- respiratory abnormalities,
- laryngospasm,
- dysphagia,
- aspiration and pneumonia,
- gout.
A significant proportion of patients die suddenly and unexpectedly from unknown causes, even on a background of an apparently stable medical condition.
Less severe forms have better prognosis.
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eMedicine URL
TREATMENT
Medical Care
The gross overproduction of uric acid must be controlled to prevent the development of urologic or articular complications. The goal is to maintain uric acid levels in the normal range. A common error is to attempt to suppress uric acid below normal levels, but this approach risks the development of oxypurine stones instead. The control of uric acid requires two important components:
-"Allopurinol":http://en.wikipedia.org/wiki/Allopurinol, which inhibits the metabolism of hypoxanthine and xanthine to uric acid by the enzyme xanthine oxidase, is generally effective in limiting hyperuricemia and its consequences. The dose is titrated with the goal of bringing serum uric acid levels into the normal range.
-Generous hydration at all times is essential. Hydration should be increased during periods of increased fluid loss, such as a febrile illness or recurrent emesis.
Despite the combined use of allopurinol and generous hydration, nephrolithiasis still may occur.
Several medications are available to mitigate the severity of the neurological features, though no agent has proved consistently efficacious in all cases. Benzodiazepines, such as diazepam or alprazolam, reduce severity and help attenuate anxiety that may indirectly exacerbate the extrapyramidal abnormalities. Antispasticity agents such as baclofen can also be helpful.
Management of the behavioural problems, and particularly the self-injurious behaviour, can be very difficult. In general, behavioural problems are best managed with a combination of behavioural modification techniques and medication. Behavioural extinction methods with positive reinforcement are most beneficial; techniques involving negative reinforcement are not helpful and may even exacerbate the behaviour problems. Adjunctive medications, sometimes useful for attenuating problem behaviours, include gabapentin and benzodiazepines. Neuroleptics are sometimes used when problems are particularly severe, although long-term use is discouraged due to side effects.
A model of behavioural treatments for self-mutilation behaviour in Lesch-Nyhan syndrome,2008
Surgical Care
The metabolic defect does not preclude safe application of standard anaesthetic or surgical procedures when indicated.
Dental work is perhaps the most commonly required surgical intervention in this disease. Dental extraction may be the only procedure for preventing serious tissue injury, if self-injurious biting cannot be controlled with behavioural and/or medical therapy.
Orthopaedic intervention often is required for management of the consequences of the neurological disorder. Procedures may be required for release of contractures, reduction of subluxed joints, or stabilization of spinal deformity.
Nephrolithiasis may require surgical intervention for extraction of stones or relief from urogenital obstruction.
Recent studies have provided a promising suggestion that deep brain stimulation surgery may be useful for controlling both dystonia and self-injury. The procedure is considered experimental, and further studies are needed before the procedure can be broadly recommended because the brain targets seem to differ from those used for other disorders of dystonia or for Parkinson’s disease.
Consultations
Genetic counselling is essential for informing the family of the risk of additional children with the disorder.
Consultations with specialists in the motor disorder (Neurology, Physiatry) and the behavioural disorder (Psychiatry, Psychology) are nearly universally required.
Surgical specialists may be required for joint complications (Orthopaedics) or large kidney stones (Urology).
Diet
Most patients can eat a normal diet. Dysphagia may be a significant problem, particularly with aging. Some patients respond to changes in the consistency of the diet, while others may require gastrostomy.
Activity
Despite their profound motor handicap, most patients prefer to remain actively engaged in their environments.
FOLLOW-UP
Further Inpatient Care
Inpatient admissions should be limited to those absolutely necessary for medical interventions, since moving these patients into an unfamiliar environment will exacerbate behavioural problems such as self-injury.
Protective devices such as straps or splints should be applied at all times to prevent self-injury; this includes night time sleeping periods and also during transfer for any tests. These devices should be viewed as protective devices (rather than restraints) that are permitted in hospitals for patients with developmental disorders. Most patients and families will request them, and they become upset if they are removed.
Deterrence/Prevention
Since few reliable treatments are available for the condition, genetic counselling is critical for prevention. Mothers and sisters of patients should be tested to determine if they are carriers.
Prenatal testing should be offered to all pregnant women known to be carriers. Because of the rare potential for gonadal mosaicism, prenatal testing should also be offered to mothers who have previously given birth to an affected individual, even if she does not appear to be a carrier.
