Lesch-Nyhan syndrome (LNS), also known as Nyhan’s syndrome, is a rare, inherited disorder caused by a deficiency of the enzyme
hypoxanthine-guanine phosphoribosyltransferase (HGPRT).
LNS is an X-linked recessive disease: the gene is
carried by the mother and passed on to her son. LNS is present at birth in baby boys.
Patients have severe mental and physical problems throughout life. The lack of HPRT causes a build-up of uric acid in all body fluids, and leads to problems such as severe gout, poor
muscle control, and moderate mental retardation, which appear in the first year of
life. A striking feature of LNS is self-mutilating behaviors, characterized by lip and
finger biting, that begin in the second year of life. Abnormally high uric acid levels can cause sodium urate crystals to form in
the joints, kidneys, central nervous system and other tissues of the body, leading to gout-like swelling in the joints
and severe kidney problems. Neurological symptoms include facial grimacing, involuntary writhing, and repetitive movements of the
arms and legs similar to those seen in Huntington's disease. The direct cause of
the neurological abnormalities remains unknown. Because a lack of HPRT causes the body to poorly utilize vitamin B12, some boys may develop a rare disorder called megaloblastic anemia.[1]
The symptoms caused by the buildup of uric acid (arthritis and renal symptoms) respond well to treatment with drugs such as allopurinol
that reduce the levels of uric acid in the blood. The mental deficits and self-mutilating behavior do not respond to treatment.
There is no cure, but many patients live to adulthood. LNS is rare, affecting about one in 380,000 live births.[2] It was first described in 1964 by Dr. Michael Lesch and Dr. William Nyhan.[3]
Signs and symptoms
LNS is characterized by three major hallmarks: neurologic dysfunction, cognitive and behavioral disturbances, as well as uric acid overproduction (hyperuricemia). Damage to the basal ganglia causes victims to adopt
a characteristic fencing stance due to the nature of the lesion. Some may also be afflicted with anemia (macrocytic). Virtually all patients are male, and male victims suffer delayed growth and puberty, and most develop shrunken testicles or testicular atrophy.
Female carriers are at an increased risk for gouty arthritis, but are usually otherwise
unaffected.
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 in
the kidneys, ureters, or bladder. Such crystals deposited in joints later in the disease may produce gout-like arthritis, with swelling and tenderness.
The overproduction of uric acid is present at birth, but may not be recognized by routine clinical laboratory testing methods.
The serum uric acid concentration is often normal, as the excess purines are promptly eliminated in the urine. The crystals
usually appear as an orange grainy material, or they may coalesce to form either multiple tiny stones, or distinct large stones
that are difficult to pass. The stones, or calculi, usually cause hematuria (blood in the
urine) and increase the risk of urinary tract infection. Some victims suffer
kidney damage due to such kidney stones. Stones may be the presenting feature of the
disease, but can go undetected for months or even years.
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 are late in sitting up, while most never crawl or
walk. Lack of speech is also a very common trait
associated with LNS.
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 (dystonia), writhing motions (choreoathetosis), and arching of the spine (opisthotonus). 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.
Self-injuring behavior
Persons affected are cognitively impaired and have behavioral disturbances that emerge between two and three years of age. The
uncontrollable self-injury associated with LNS also usually begins at three years of age. The self-injury begins with biting of
the lips and tongue and as the disease progresses, affected individuals frequently develop finger biting and head banging. 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 majority of individuals are cognitively impaired, which is not easy to determine because of the behavioral disturbances
and motor deficits associated with the syndrome. In many ways, the behaviors may be seen as a psychological extension of the
compulsion to cause self-injury: rejecting desired treats or travel, repaying kindness with coldness or rage, failing to answer
test questions correctly despite study and a desire to succeed, provoking anger from caregivers when affection is desired, and so
on.
Compulsive behaviors also occur, including aggressiveness, vomiting, spitting, and
involuntary swearing, or coprolalia. 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.
LNS in females
While carrier females are generally asymptomatic, 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.
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. It is possible
for a female to inherit an X chromosome from her unaffected father, who carries a new mutation of the HPRT 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. The
overwhelming majority of patients with LNS are male.
Diagnosis
When an affected individual has fully developed the three clinical elements of uric acid overproduction, neurologic
dysfunction, and cognitive and behavioral disturbances, diagnosis of LNS is easily made. 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 behaviors 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, and several psychiatric conditions. Of these, only individuals
with Lesch-Nyhan syndrome, de Lange syndrome, and familial dysautonomia recurrently display loss of tissue as a consequence.
Biting the fingers and lips is a definitive feature of Lesch-Nyhan syndrome; in other syndromes associated with self-injury, the
behaviors usually 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.
Diagnostic approach
The urate to creatinine (breakdown product of creatine phosphate in muscle) concentration
ratio in urine is elevated. This is a good indicator of acid overproduction. For children under ten years of age with Lesch-Nyhan
syndrome, a urate to creatinine ratio above two is typically found. Twenty-four-hour urate excretion of more than 20 mg/kg is
also typical but is not diagnostic. Hyperuricemia (serum uric acid concentration of >8
mg/dL) is often present but not reliable enough for diagnosis. Activity of the HPRT enzyme in cells from any type of tissue (e.g., blood, cultured fibroblasts, or lymphoblasts) that is less than 1.5% of normal enzyme activity confirms the diagnosis of Lesch-Nyhan
syndrome.
Testing
The use of biochemical testing for the detection of carriers is technically demanding
and not often used. Biochemical analyses that have been performed on hair bulbs from at risk women have had a small number of
both false positive and false negative outcomes. If only a suspected carrier
female is available for HPRT1 mutation testing, it is appropriate to grow her lymphocytes in
6-thioguanine (a purine analogue), which allows only HPRT-deficient cells to survive. A mutant
frequency of 0.5-5.0 x 10-2 is found in carrier females, while a non-carrier female has a frequency of 1-20 x 10-6. This
frequency is usually diagnostic by itself.
Molecular genetic testing is the most effective method of testing, as HPRT1 is the only gene known to be associated with LNS.
Individuals who display the full Lesch-Nyhan phenotype all have mutations in the HPRT1 gene.
Sequence analysis of mRNA is available clinically and can be utilized in order to detect
HPRT1 mutations in males affected with Lesch-Nyhan syndrome. Techniques such as RT-PCR, multiplex genomic PCR, and sequence
analysis (cDNA and genomic DNA), used for the diagnosis of genetic diseases, are performed on a research basis. If RT-PCR tests
result in cDNA showing the absence of an entire exon or exons, then multiplex genomic PCR testing
is performed. Multiplex genomic PCR testing amplifies the nine exons of the HPRT1 gene as eight PCR products. If the exon in
question is deleted, the corresponding band will be missing from the multiplex PCR. However if the exon is present, the exon is
sequenced to identify the mutation, therefore causing exclusion of the exon from cDNA. If no cDNA is created by RT-PCR, then
multiplex PCR is performed on the notion that most or all of the gene is obliterated.
Genetics
LNS is due to mutations in the HPRT1 gene,[4][2] so named because it codes for the enzyme hypoxanthine-guanine phosphoribosyltransferase (HPRT or HGPRT,
EC 2.4.2.8). 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. Since the HPRT gene is located on the X chromosome, LNS is an X-linked inherited disease.
The father of an affected male will not be the carrier of the mutant allele, and will not have
the disease. An obligate carrier would be a woman who has an affected son and one other affected relative in the maternal
line.
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 germline
mutation. However, in this case Haldane's prediction is incorrect due to an increased risk of mutation arising from the
father when compared to the mother.
The risk to siblings of an affected individual depends upon the carrier status of the mother herself. A 50% chance is given to
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. Therefore, 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. However, if a male with a less severe
phenotype reproduces, all of his daughters are carriers, and none of his sons will be
affected.
Pathophysiology
As in other X-linked diseases, males are affected because they only have one copy of the
X chromosome. In Lesch-Nyhan syndrome, the defective gene is that for hypoxanthine-guanine phosphoribosyltransferase (HPRT), a participant in
the purine metabolism. Female carriers have a second X chromosome, which contains a "normal" copy
of HPRT, preventing the disease from developing, though they may have increased risk of hyperuricemia.
Various mutations of HPRT are known. Mutations that only mildly decrease the enzyme's function do not normally cause LNS, but
do increase susceptibility to gout and nephrolithiasis.
Formation of DNA (during cell division) requires nucleosides, molecules that are the building blocks for DNA. The purines (adenine and guanine) and pyrimidines
(thymidine and cytosine) are bound to deoxyribose and
phosphate and incorporated as necessary. Normally, the nucleosides are synthetized de novo from amino acids and other precursors. A small part, however, is generated from the degraded DNA of broken-down
cells. This is termed the "salvage pathway".
HPRT is the "salvage enzyme" for the purines: it channels adenosine (in its hypoxanthine form) and guanine back into DNA
synthesis. Failure of this enzyme has two results:
- Cell breakdown products cannot be reused, and are therefore degraded. This gives rise to increased uric acid, a purine breakdown product.
- The de novo pathway is stimulated due to an excess of PRPP (5-phospho-D-ribosyl-1-pyrophosphate or simply
phosphoribosyl-pyrophosphate).
It is unclear whether the neurological abnormalities in LNS are due to uric acid neurotoxicity or to a relative shortage in
"new" purines during essential steps. Polymorphisms for enzymes in the de novo pathway may contribute to the disease, but
this would not be the case if uric acid neurotoxicity were the main cause of the symptoms.
Moreover, evidence suggests that one or more lesions in striatal dopaminergic pathways is at least partially responsible for the neurological deficits, especially the
choreoathetoid dyskinesia and self-mutilation [1] [2][5].
Thus, 6-hydroxydopamine toxicity in rodents is a useful animal model for the syndrome
[3]. Another putative animal model, Hyperuricemic syndrome in Dalmatian dogs, presents with the characteristic arthritis and kidney failure, but not the neurological
findings.
6-hydroxydopamine damages neurons by oxidative mechanisms. Similarly, Hyperuricemic syndrome in Dalmatians responds to
treatment with Orgotein, the veterinary formulation of the antioxidant enzyme superoxide
dismutase [4] ]. Uric acid is a powerful reducing agent and likely an important human antioxidant. E.g.,
urate is the antioxidant in highest concentration in blood. However, uric acid can also act as a pro-oxidant [5], particularly at high concentrations like those produced in LNS. Thus,
free radicals, oxidative stress, and
reactive oxygen species may play some role in the etiology of Lesch-Nyhan's
syndrome.[6] Significantly, while first proposed for LNS
and hyperuricemia in Dalmatian dogs [6], urate-induced oxidative stress is now thought to also figure in
metabolic syndrome, atherosclerosis, and
stroke.
Treatment
Treatment for LNS is symptomatic. Gout can be treated with allopurinol to control
excessive amounts of uric acid. Kidney stones may be treated with lithotripsy, a technique for breaking up kidney stones using shock waves or laser beams. There is no
standard treatment for the neurological symptoms of LNS. Some may be relieved with the drugs carbidopa/levodopa, diazepam,
phenobarbital, or haloperidol.[1]
It is essential that the overproduction of uric acid be controlled in order to reduce the risk of nephropathy,
nephrolithiasis, and gouty arthritis. The drug allopurinol is utilized to stop the
conversion of oxypurines into uric acid, and prevent the development of subsequent
arthritic tophi (produced after having chronic gout), renal
stones (also known as kidney stones), and nephropathy, the resulting kidney disease.
Allopurinol is taken orally, at a typical dose of 3–20 mg/kg per day. The dose is then adjusted to bring the uric acid level down
into the normal range (<3 mg/dL). Most affected individuals can be treated with allopurinol all through life.
No medication is effective in controlling the extrapyramidal motor features of
the disease. Spasticity, however, can be reduced by the administration of baclofen or
benzodiazepines.
No method of treatment for the neurobehavioral aspects of the disease has been effective. Even children treated from birth
with allopurinol develop behavioral and neurologic problems, despite never having had high serum concentrations of uric acid.
Self-injurious and other behaviors are best managed by a combination of medical, physical, and behavioral interventions. The
self-mutilation is often reduced by using restraints. Sixty percent of individuals have their teeth extracted in order to avoid
self-injury, which families have found to be an effective management technique. Because stress increases self-injury, behavioral
management through aversive techniques (which would normally reduce self-injury) actually increases self-injury in individuals
with LNS. Nearly all affected individuals need restraints to prevent self-injury, and are restrained more than 75% of the time.
This is often at their own request, and occasionally involves restraints that would appear to be ineffective, as they do not
physically prevent biting. Families report that affected individuals are more at ease when restrained.
An article in the August 13, 2007 issue of New Yorker magazine, written by Richard Preston, discusses "Deep-brain
stimulation," as a possible treatment. It has been performed on a few patients with Lesch-Nyhan syndrome by Dr. Takaomi Taira in
Tokyo and by a group in France led by Dr. Philippe Coubes. Some patients experienced a decrease in spastic self-injurious
symptoms. The technique was developed for treating people with Parkinson's disease, according to Preston, over 20 years ago. The
treatment involves invasive surgery to place wires that carry a continuous electric current into a specific region of the
brain.
http://www.newyorker.com/reporting/2007/08/13/070813fa_fact_preston
Prognosis
The prognosis for individuals with LNS is poor. Death is usually due to renal failure in the first or second decade of
life.[1]
History
Michael Lesch was a medical student at Johns Hopkins Hospital, where
pediatrician Bill Nyhan was a faculty member, when the
two identified LNS and its associated hyperuricemia in two affected brothers, ages 4 and 8.[7] Lesch and Nyhan published their findings in 1964.[8] Within three years, the metabolic cause was identified by J. Edwin Seegmiller and his colleagues at NIH.[9]
Less severe forms
A less severe related disease is partial HPRT deficiency is known as Kelley-Seegmiller
Syndrome (Lesch-Nyhan Syndrome involves total HPRT deficiency). Symptoms generally involve less neurological involvement
but the disease still causes gout and kidney stones.[7][8]
LNS in popular culture
LNS is one of the subjects treated in Richard Preston's fictional account of a
biological-weapons attack on the New York subway system, The Cobra Event.
Richard Preston, An Error in the Code -- A syndrome poses questions about free
will, The New Yorker, August 13, 2007, p. 30, is a report examining developments in
medicine’s understanding of LNS, with stories of some patients' experiences. Abstract: [9]
References
- ^ a b c
- ^ a b
- ^ Ole Daniel Enersen. Lesch-Nyhan syndrome or disease.
Who Named It. Retrieved on 2007-05-27.
- ^ Lesch-Nyhan syndrome. NCBI Genes and disease. Retrieved on 2007-04-12
- ^ Visser J, Smith D, Moy S, Breese G,
Friedmann T, Rothstein J, Jinnah H (2002). "Oxidative stress and dopamine deficiency in a genetic mouse model of Lesch-Nyhan
disease". Brain Res Dev Brain Res 133 (2): 127-39. PMID 11882343.
- ^ Bavaresco C, Chiarani F, Matté C, Wajner M,
Netto C, de Souza Wyse A (2005). "Effect of hypoxanthine on Na+,K+-ATPase activity and some parameters of oxidative stress in rat
striatum". Brain Res 1041 (2): 198–204. PMID 15829228.
- Visser J, Smith D, Moy S, Breese G, Friedmann T, Rothstein J, Jinnah H (2002).
"Oxidative
stress and dopamine deficiency in a genetic mouse model of Lesch-Nyhan disease". Brain Res Dev Brain Res 133 (2):
127-39. PMID 11882343.
- Saugstad O, Marklund S (1988). "High activities of erythrocyte glutathione peroxidase
in
patients with the Lesch-Nyhan syndrome". Acta Med Scand 224 (3): 281-5. PMID 3239456.
- ^ Nyhan WL. The recognition of Lesch-Nyhan syndrome as an inborn error of
purine metabolism. J Inher Metab Dis 1997;20:171-8. PMID 9211189.
- ^ Lesch M, Nyhan WL. A familial disorder of uric acid metabolism and central
nervous system function. Am J Med 1964;36:561-70. PMID 14142409.
- ^ Seegmiller JE, Rosenbloom FM, Kelley WN. Enzyme defect associated with a
sex-linked human neurological disorder and excessive purine synthesis. Science
1967;155:1682–4. PMID 6020292.
External links
|
Metabolic pathology
/ Inborn error of metabolism (E70-90, 270-279) |
| Amino acid |
Aromatic
(Phenylketonuria, Alkaptonuria, Ochronosis, Tyrosinemia, Albinism,
Histidinemia) - Branched chain
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acidemia, Methylmalonic acidemia, Isovaleric acidemia, 3-Methylcrotonyl-CoA carboxylase deficiency) - Transport
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aciduria, Hyperammonemia) - Glutaric
acidemia type 1 - Sarcosinemia |
| Carbohydrate |
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(type I, type
II, type III, type IV, type V,
type VI, type
VII) - fructose metabolism (Fructose intolerance,
Fructose bisphosphatase deficiency, Essential fructosuria) - galactose metabolism (Galactosemia, Galactose-1-phosphate uridylyltransferase galactosemia,
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(Glucose-galactose malabsorption, Sucrose intolerance) - pyruvate metabolism and gluconeogenesis (PCD, PDHA) - Pentosuria - Renal glycosuria |
| Lipid
storage |
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Niemann-Pick disease - Farber disease -
Fabry's disease - Metachromatic
leukodystrophy - Krabbe disease
Neuronal ceroid lipofuscinosis (Batten
disease) - Cerebrotendineous xanthomatosis - Cholesteryl ester storage disease (Wolman
disease) |
| Other lipid |
Lipoprotein/lipidemias:
Hyperlipidemia - Hypercholesterolemia -
Familial hypercholesterolemia - Xanthoma
- Combined hyperlipidemia - Lecithin cholesterol acyltransferase deficiency - Tangier disease - Abetalipoproteinemia
Fatty acid: Adrenoleukodystrophy - Carnitine (Primary, I, II) |
| Mineral |
Cu Wilson's
disease/Menkes disease - Fe Haemochromatosis - Zn Acrodermatitis
enteropathica - PO43− Hypophosphatemia/Hypophosphatasia - Mg2+
Hypermagnesemia/Hypomagnesemia -
Ca2+ Hypercalcaemia/Hypocalcaemia/Disorders of calcium
metabolism |
Fluid, electrolyte
and acid-base balance |
Electrolyte disturbance - Na+ Hypernatremia/Hyponatremia - Acidosis (Metabolic, Respiratory, Lactic) - Alkalosis (Metabolic, Respiratory) - Mixed disorder of acid-base
balance - H2O Dehydration/Hypervolemia - K+ Hypokalemia/Hyperkalemia - Cl− Hyperchloremia/Hypochloremia |
| Purine and pyrimidine |
Hyperuricemia -
Lesch-Nyhan syndrome - Xanthinuria |
| Porphyrin |
Acute intermittent, Gunther's, Cutanea tarda, Erythropoietic,
Hepatoerythropoietic, Hereditary copro-, Variegate |
| Bilirubin |
Unconjugated (Gilbert's syndrome, Crigler-Najjar syndrome) -
Conjugated (Dubin-Johnson syndrome, Rotor
syndrome) |
| Glycosaminoglycan |
Mucopolysaccharidosis - 1:Hurler/Hunter - 3:Sanfilippo - 4:Morquio - 6:Maroteaux-Lamy - 7:Sly |
| Glycoprotein |
Mucolipidosis -
I-cell disease - Pseudo-Hurler
polydystrophy - Aspartylglucosaminuria - Fucosidosis - Alpha-mannosidosis - Sialidosis |
| Other |
Alpha 1-antitrypsin deficiency - Cystic fibrosis
- Amyloidosis (Familial Mediterranean
fever) - Acatalasia |
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