Lesch-Nyhan syndrome
Encyclopedia
Lesch–Nyhan syndrome also known as Nyhan's syndrome, Kelley-Seegmiller syndrome and Juvenile gout, is a rare inherited disorder caused by a deficiency of the enzyme
hypoxanthine-guanine phosphoribosyltransferase
(HGPRT), produced by mutation
s in the HPRT gene
located on (the) X chromosome
. LNS affects about one in 380,000 live births. The disorder was first recognized and clinically characterized by medical student Michael Lesch
and his mentor, pediatrician Bill Nyhan
, who published their findings in 1964.
The HGPRT deficiency causes a build-up of uric acid
in all body fluids. This results in both hyperuricemia
and hyperuricosuria
, associated with severe gout
and kidney problems. Neurological signs include poor muscle control and moderate mental retardation
. These complications usually appear in the first year of life. Beginning in the second year of life, a particularly striking feature of LNS is self-mutilating behaviors, characterized by lip and finger biting. 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 HGPRT causes the body to poorly utilize vitamin B12
, some boys may develop megaloblastic anemia
.
LNS is an X-linked recessive
disease: the gene mutation is usually carried by the mother and passed on to her son, although one-third of all cases arise de novo (from new mutations) and do not have a family history. LNS is present at birth
in baby boys. Most, but not all, persons with this deficiency have severe mental and physical problems throughout life. There are a few rare cases in the world of affected females.
The symptoms caused by the buildup of uric acid (gout
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 well to treatment. There is no cure, but many patients live to adulthood. Several new experimental treatments may alleviate symptoms.
dysfunction, cognitive
and behavioral
disturbances
including self-mutilation, and uric acid
overproduction (hyperuricemia
). Damage to the basal ganglia
causes sufferers to adopt a characteristic fencing stance due to the nature of the lesion. Some may also be afflicted with macrocytic anemia. Virtually all patients are male; males 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.
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 stone
s. Stones may be the presenting feature of the disease, but can go undetected for months or even years.
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 reflex
es, 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 become lifelong wheelchair users.
The majority of individuals are cognitively impaired, which is sometimes difficult to distinguish from other symptoms 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, and include 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.
Compulsive behaviors also occur, including aggressiveness, vomiting
, spitting, and coprolalia
(involuntary swearing). 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.
, 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.
), 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.
(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 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 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 HGPRT enzyme in cells
from any type of tissue
(e.g., blood
, cultured fibroblast
s, or lymphoblast
s) that is less than 1.5% of normal enzyme activity confirms the diagnosis of Lesch–Nyhan syndrome. Molecular genetic studies of the HPRT gene mutations may confirm diagnosis, and are particularly helpful for subsequent 'carrier testing' in at-risk females such as close family relatives on the female side.
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 mutation testing, it may be appropriate to grow her lymphocytes in 6-thioguanine (a purine analogue
), which allows only HGPRT-deficient cells to survive. 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. 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.
LNS is due to mutation
s in the HPRT1 gene
, so named because it codes for the enzyme
hypoxanthine-guanine phosphoribosyltransferase
(HPRT or HGPRT). This enzyme is involved in the biochemical pathways the body uses to produce purine
s, 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.
(HPRT), a participant in the 'recycling' of purine
nucleotide
s. 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.
A large number of mutations of HPRT are known. Mutations 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 which still features purine overproduction accompanied by susceptibility to gout
and uric acid
nephrolithiasis.
Formation of DNA (during cell division
) requires nucleotide
s, molecules that are the building blocks for DNA. The purine bases (adenine
and guanine
) and pyrimidine
bases (thymidine
and cytosine
) are bound to deoxyribose and phosphate and incorporated as necessary. Normally, the nucleotides are synthetized de novo from amino acid
s and other precursors. A small part, however, is 'recycled' from degraded DNA of broken-down cells. This is termed the "salvage pathway".
HGPRT is the "salvage enzyme" for the purines: it channels hypoxanthine
and guanine
back into DNA synthesis. Failure of this enzyme has two results:
It was previously unclear whether the neurological abnormalities in LNS were due to uric acid neurotoxicity or to a relative shortage in "new" purine nucleotide
s during essential synthesis steps. Genetic mutations affecting the enzymes of the de novo synthesis pathway may possibly contribute to the disease, although these are rare or unknown. Uric acid has been suggested as a possible cause of neurotoxicity but this is unproven.
Importantly, evidence suggests that one or more lesions in striatal
dopamine
rgic pathways may be central to the neurological deficits, especially the choreoathetoid dyskinesia and self-mutilation.
6-hydroxydopamine toxicity in rodents may be a useful animal model for the syndrome, although this is not proven.
However, the link between dopamine and purine synthesis is a nucleotide called guanosine triphosphate
or 'GTP'. The first step of dopamine synthesis is GTP cyclohydrolase, and significantly a deficiency of this step produces a syndrome that has a neuropathology similar to LNS. Thus a lack of HGPRT may produce a nucleotide deficiency (specifically: GTP deficiency) disorder, resulting in dopamine deficiency.
Another putative animal model for LNS has been proposed to arise from oxidative damage, caused by the hyperuricemia
accompanying LNS. This is based on the theory that uric acid
is a powerful reducing agent
and likely an important human antioxidant
, in high concentration in blood. On the other hand, uric acid may also act as a pro-oxidant
, Thus, it has been suggested that free radicals, oxidative stress
, and reactive oxygen species
may play some role in the neuropathology of LNS.
However, some evidence argues against a role for uric acid in the neuropathology of Lesch-Nyhans:
Similarly, uric acid does not penetrate the blood-brain barrier well. However, 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. Similarly, Superoxide dismutase
( "SOD" ) and SOD-mimetics such as TEMPOL ameliorate the effects of hyperuricemia. Likewise, 6-hydroxydopamine (the putative animal model for Lesch-Nyhan's neuropathy) apparently acts as a neurotoxin by generation of active oxygen species. It may be that oxidative stress induced by some other oxypurine such as xanthine causes the disease. See Barrasco et al. above.
Thus, evidence points to the pathophysiology of LNS arising from nucleotide deficiency, rather than oxidative damage. This has important implications for treatment. "Antioxidant therapy" has not been found to provide any relief for LNS symptoms. This may be because ectopic urate-like reducing antioxidants such as ascorbate must compete as antioxidants and neuroprotectants with order-of-magnitude higher levels of uric acid itself http://stroke.ahajournals.org/cgi/content/full/39/8/e126. On the other hand, supplementation of nucleotides with an orally-delivered precursor drug (SAMe) has shown encouraging results, as described below.
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
.
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), kidney stone
s, 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.
There has previously been no effective method of treatment for the neurobehavioral aspects of the disease. 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.
The Matheny Medical and Educational Center http://www.matheny.org in Peapack, NJ, has nine Lesch-Nyhan patients, believed to be the largest concentration of LNS cases in one location, and is recognized as the leading source of information on care issues.
Treatment for LNS patients, according to Gary E. Eddey, MD, medical director, should include: 1) Judicious use of protective devices; 2) Utilization of a behavioral technique commonly referred to as 'selective ignoring' with redirection of activities; and 3) Occasional use of medications.
An article in the August 13, 2007 issue of The 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.
An encouraging advance in the treatment of the neurobehavioural aspects of LNS was the publication in the October, 2006 issue of Journal of Inherited Metabolic Disease
of an experimental therapy giving oral S-adenosyl-methionine (SAMe).
This drug is a nucleotide precursor
that provides a readily absorbed purine, which is known to be transported across the blood-brain barrier
. Administration of SAMe to adult LNS patients was shown to provide improvement in neurobehavioural and other neurological attributes. The drug is available without prescription and has been widely used for depression, but its use for treating LNS should be undertaken only under strict medical supervision, as side effects are known.
SAMe has also been used recently to treat another purine nucleotide disease, "Art's Syndrome" (which is a PRPP disorder in common with LNS), with encouraging results.
Thus SAMe may be useful for treating purine nucleotide diseases, which include LNS.
was a medical student at Johns Hopkins University
and Bill Nyhan, a pediatrician
and biochemical geneticist, was his mentor, when the two identified LNS and its associated hyperuricemia in two affected brothers, ages 4 and 8. Lesch and Nyhan published their findings in 1964. Within three years, the metabolic cause was identified by J. Edwin Seegmiller
and his colleagues at NIH.
's 1998 fictional work, The Cobra Event
. It is the focus of one chapter in his nonfiction work Panic in Level 4.
In 2009, an experimental stageplay entitled Chewing Your Fingers to the Bone was devised by a Professor of Theatre, a local artist, and a company of undergraduate students at Allegheny College
in Meadville, Pennsylvania
. The piece involves a number of separate yet related storylines, several of which depict the stories of people living with Lesch-Nyhan Syndrome. Much of the original material was inspired by Richard Preston's An Error in the Code, originally published in The New Yorker
.
In Mystery Diagnosis
(season 6, episode 8, titled The Boy Hit Bit Himself), a true story of a little boy with Lesch-Nyhan Syndrome.
In Nip/Tuck
(season 6, episode 11), the patient Dan Daly suffers from Lesch-Nyhan Syndrome and requires plastic surgery on his lips after having chewed them off.
In House
(season 3, episode 23, titled The Jerk), Kelley-Seegmiller syndrome is considered as a diagnosis for a teen-aged chess prodigy after he is found to have an HPRT enzyme deficiency. The script errs in having one of the doctors erroneously describing Kelley-Seegmiller syndrome victims as prone to self-mutilation, chewing their lips and banging their heads against the wall.
Enzyme
Enzymes are proteins that catalyze chemical reactions. In enzymatic reactions, the molecules at the beginning of the process, called substrates, are converted into different molecules, called products. Almost all chemical reactions in a biological cell need enzymes in order to occur at rates...
hypoxanthine-guanine phosphoribosyltransferase
Hypoxanthine-guanine phosphoribosyltransferase
Hypoxanthine-guanine phosphoribosyltransferase is an enzyme encoded in humans by the HPRT1 gene.HGPRT is a transferase that catalyzes conversion of hypoxanthine to inosine monophosphate and guanine to guanosine monophosphate. This reaction transfers the 5-phosphoribosyl group from...
(HGPRT), produced by mutation
Mutation
In molecular biology and genetics, mutations are changes in a genomic sequence: the DNA sequence of a cell's genome or the DNA or RNA sequence of a virus. They can be defined as sudden and spontaneous changes in the cell. Mutations are caused by radiation, viruses, transposons and mutagenic...
s in the HPRT gene
Gene
A gene is a molecular unit of heredity of a living organism. It is a name given to some stretches of DNA and RNA that code for a type of protein or for an RNA chain that has a function in the organism. Living beings depend on genes, as they specify all proteins and functional RNA chains...
located on (the) X chromosome
X chromosome
The X chromosome is one of the two sex-determining chromosomes in many animal species, including mammals and is common in both males and females. It is a part of the XY sex-determination system and X0 sex-determination system...
. LNS affects about one in 380,000 live births. The disorder was first recognized and clinically characterized by medical student Michael Lesch
Michael Lesch
Dr. Michael Lesch was a distinguished American physician and medical educator who helped identify an important genetic disorder associated with retardation and self-mutilation. This disease is now known as the Lesch-Nyhan syndrome...
and his mentor, pediatrician Bill Nyhan
William Nyhan
Dr. William Leo Nyhan, MD PhD is currently Professor of Pediatrics at UC San Diego School of Medicine in La Jolla, CA. He has also held positions at Johns Hopkins University School of Medicine, University of Miami School of Medicine...
, who published their findings in 1964.
The HGPRT deficiency causes a build-up of uric acid
Uric acid
Uric acid is a heterocyclic compound of carbon, nitrogen, oxygen, and hydrogen with the formula C5H4N4O3. It forms ions and salts known as urates and acid urates such as ammonium acid urate. Uric acid is created when the body breaks down purine nucleotides. High blood concentrations of uric acid...
in all body fluids. This results in both hyperuricemia
Hyperuricemia
Hyperuricemia is a level of uric acid in the blood that is abnormally high. In humans, the upper end of the normal range is 360 µmol/L for women and 400 µmol/L for men.-Causes:...
and hyperuricosuria
Hyperuricosuria
Hyperuricosuria is a medical term referring to the presence of excessive amounts of uric acid in the urine. Notable direct causes of hyperuricosuria are dissolution of uric acid crystals in the kidneys or urinary bladder, and hyperuricemia...
, associated with severe gout
Gout
Gout is a medical condition usually characterized by recurrent attacks of acute inflammatory arthritis—a red, tender, hot, swollen joint. The metatarsal-phalangeal joint at the base of the big toe is the most commonly affected . However, it may also present as tophi, kidney stones, or urate...
and kidney problems. Neurological signs include poor muscle control and moderate mental retardation
Mental retardation
Mental retardation is a generalized disorder appearing before adulthood, characterized by significantly impaired cognitive functioning and deficits in two or more adaptive behaviors...
. These complications usually appear in the first year of life. Beginning in the second year of life, a particularly striking feature of LNS is self-mutilating behaviors, characterized by lip and finger biting. Neurological symptoms include facial grimacing, involuntary writhing, and repetitive movements of the arms and legs similar to those seen in Huntington's disease
Huntington's disease
Huntington's disease, chorea, or disorder , is a neurodegenerative genetic disorder that affects muscle coordination and leads to cognitive decline and dementia. It typically becomes noticeable in middle age. HD is the most common genetic cause of abnormal involuntary writhing movements called chorea...
. The direct cause of the neurological abnormalities remains unknown. Because a lack of HGPRT causes the body to poorly utilize vitamin B12
Vitamin B12
Vitamin B12, vitamin B12 or vitamin B-12, also called cobalamin, is a water-soluble vitamin with a key role in the normal functioning of the brain and nervous system, and for the formation of blood. It is one of the eight B vitamins...
, some boys may develop megaloblastic anemia
Megaloblastic anemia
Megaloblastic anemia is an anemia that results from inhibition of DNA synthesis in red blood cell production. When DNA synthesis is impaired, the cell cycle cannot progress from the G2 growth stage to the mitosis stage...
.
LNS is an X-linked recessive
X-linked recessive
X-linked recessive inheritance is a mode of inheritance in which a mutation in a gene on the X chromosome causes the phenotype to be expressed in males and in females who are homozygous for the gene mutation X-linked recessive inheritance is a mode of inheritance in which a mutation in a gene on...
disease: the gene mutation is usually carried by the mother and passed on to her son, although one-third of all cases arise de novo (from new mutations) and do not have a family history. LNS is present at birth
Childbirth
Childbirth is the culmination of a human pregnancy or gestation period with the birth of one or more newborn infants from a woman's uterus...
in baby boys. Most, but not all, persons with this deficiency have severe mental and physical problems throughout life. There are a few rare cases in the world of affected females.
The symptoms caused by the buildup of uric acid (gout
Gout
Gout is a medical condition usually characterized by recurrent attacks of acute inflammatory arthritis—a red, tender, hot, swollen joint. The metatarsal-phalangeal joint at the base of the big toe is the most commonly affected . However, it may also present as tophi, kidney stones, or urate...
and renal symptoms) respond well to treatment with drugs such as allopurinol
Allopurinol
Allopurinol is a drug used primarily to treat hyperuricemia and its complications, including chronic gout.- Mechanism of action :...
that reduce the levels of uric acid in the blood. The mental deficits and self-mutilating behavior do not respond well to treatment. There is no cure, but many patients live to adulthood. Several new experimental treatments may alleviate symptoms.
Signs and symptoms
LNS is characterized by three major hallmarks: neurologicNeurology
Neurology is a medical specialty dealing with disorders of the nervous system. Specifically, it deals with the diagnosis and treatment of all categories of disease involving the central, peripheral, and autonomic nervous systems, including their coverings, blood vessels, and all effector tissue,...
dysfunction, cognitive
Cognition
In science, cognition refers to mental processes. These processes include attention, remembering, producing and understanding language, solving problems, and making decisions. Cognition is studied in various disciplines such as psychology, philosophy, linguistics, and computer science...
and behavioral
Human behavior
Human behavior refers to the range of behaviors exhibited by humans and which are influenced by culture, attitudes, emotions, values, ethics, authority, rapport, hypnosis, persuasion, coercion and/or genetics....
disturbances
Deviant Behavior
Deviant Behavior is an interdisciplinary journal which focuses on social deviance, including criminal, sexual, and narcotic behaviors.The journal is published by Taylor and Francis, Inc., and was ranked 41st out of 46 psychology journals and 46th out of 90 sociology journals in 2004 by the...
including self-mutilation, and uric acid
Uric acid
Uric acid is a heterocyclic compound of carbon, nitrogen, oxygen, and hydrogen with the formula C5H4N4O3. It forms ions and salts known as urates and acid urates such as ammonium acid urate. Uric acid is created when the body breaks down purine nucleotides. High blood concentrations of uric acid...
overproduction (hyperuricemia
Hyperuricemia
Hyperuricemia is a level of uric acid in the blood that is abnormally high. In humans, the upper end of the normal range is 360 µmol/L for women and 400 µmol/L for men.-Causes:...
). Damage to the basal ganglia
Basal ganglia
The basal ganglia are a group of nuclei of varied origin in the brains of vertebrates that act as a cohesive functional unit. They are situated at the base of the forebrain and are strongly connected with the cerebral cortex, thalamus and other brain areas...
causes sufferers to adopt a characteristic fencing stance due to the nature of the lesion. Some may also be afflicted with macrocytic anemia. Virtually all patients are male; males suffer delayed growth and puberty
Puberty
Puberty is the process of physical changes by which a child's body matures into an adult body capable of reproduction, as initiated by hormonal signals from the brain to the gonads; the ovaries in a girl, the testes in a boy...
, and most develop shrunken testicles or testicular atrophy
Testicular atrophy
Testicular atrophy is a medical condition in which the male reproductive organs diminish in size and may be accompanied by loss of function. This does not refer to temporary changes, such as those brought on by cold.Some medications can cause testicular atrophy...
. Female carriers are at an increased risk for gouty arthritis
Gout
Gout is a medical condition usually characterized by recurrent attacks of acute inflammatory arthritis—a red, tender, hot, swollen joint. The metatarsal-phalangeal joint at the base of the big toe is the most commonly affected . However, it may also present as tophi, kidney stones, or urate...
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 acidUric acid
Uric acid is a heterocyclic compound of carbon, nitrogen, oxygen, and hydrogen with the formula C5H4N4O3. It forms ions and salts known as urates and acid urates such as ammonium acid urate. Uric acid is created when the body breaks down purine nucleotides. High blood concentrations 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
Urinary bladder
The urinary bladder is the organ that collects urine excreted by the kidneys before disposal by urination. A hollow muscular, and distensible organ, the bladder sits on the pelvic floor...
. Such crystals deposited in joints later in the disease may produce gout
Gout
Gout is a medical condition usually characterized by recurrent attacks of acute inflammatory arthritis—a red, tender, hot, swollen joint. The metatarsal-phalangeal joint at the base of the big toe is the most commonly affected . However, it may also present as tophi, kidney stones, or urate...
-like arthritis
Arthritis
Arthritis is a form of joint disorder that involves inflammation of one or more joints....
, 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
Hematuria
In medicine, hematuria, or haematuria, is the presence of red blood cells in the urine. It may be idiopathic and/or benign, or it can be a sign that there is a kidney stone or a tumor in the urinary tract , ranging from trivial to lethal...
(blood in the urine) and increase the risk of urinary tract infection
Urinary tract infection
A urinary tract infection is a bacterial infection that affects any part of the urinary tract. Symptoms include frequent feeling and/or need to urinate, pain during urination, and cloudy urine. The main causal agent is Escherichia coli...
. Some victims suffer kidney damage due to such kidney stone
Kidney stone
A kidney stone, also known as a renal calculus is a solid concretion or crystal aggregation formed in the kidneys from dietary minerals in the urine...
s. 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 muscleMuscle
Muscle is a contractile tissue of animals and is derived from the mesodermal layer of embryonic germ cells. Muscle cells contain contractile filaments that move past each other and change the size of the cell. They are classified as skeletal, cardiac, or smooth muscles. Their function is to...
tone (hypotonia
Hypotonia
Hypotonia is a state of low muscle tone , often involving reduced muscle strength. Hypotonia is not a specific medical disorder, but a potential manifestation of many different diseases and disorders that affect motor nerve control by the brain or muscle strength...
) 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
Walking
Walking is one of the main gaits of locomotion among legged animals, and is typically slower than running and other gaits. Walking is defined by an 'inverted pendulum' gait in which the body vaults over the stiff limb or limbs with each step...
. 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
Extrapyramidal
Extrapyramidal can refer to:* Extrapyramidal system* Extrapyramidal symptoms...
involvement causes abnormal involuntary muscle contractions such as loss of motor control (dystonia
Dystonia
Dystonia is a neurological movement disorder, in which sustained muscle contractions cause twisting and repetitive movements or abnormal postures. The disorder may be hereditary or caused by other factors such as birth-related or other physical trauma, infection, poisoning or reaction to...
), writhing motions (choreoathetosis
Choreoathetosis
Choreoathetosis is the occurrence of involuntary movements in a combination of chorea and athetosis ....
), and arching of the spine (opisthotonus
Opisthotonus
Opisthotonus or opisthotonos, from Greek roots, opistho meaning "behind" and tonos meaning "tension", is a state of a severe hyperextension and spasticity in which an individual's head, neck and spinal column enter into a complete "bridging" or "arching" position...
). Signs of pyramidal system involvement, including spasticity, overactive reflexes (hyperreflexia
Hyperreflexia
Hyperreflexia is defined as overactive or overresponsive reflexes. Examples of this can include twitching or spastic tendencies, which are indicative of upper motor neuron disease as well as the lessening or loss of control ordinarily exerted by higher brain centers of lower neural pathways...
) and extensor plantar reflex
Plantar reflex
The plantar reflex is a reflex elicited when the sole of the foot is stimulated with a blunt instrument. The reflex can take one of two forms. In normal adults the plantar reflex causes a downward response of the hallux...
es, also occur. The resemblance to athetoid cerebral palsy
Cerebral palsy
Cerebral palsy is an umbrella term encompassing a group of non-progressive, non-contagious motor conditions that cause physical disability in human development, chiefly in the various areas of body movement....
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 become lifelong wheelchair users.
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; as the disease progresses, affected individuals frequently develop finger biting and head banging. The self-injury can increase during times of stress. Self-harm is a distinguishing characteristic of the disease and is apparent in 85% of affected males.The majority of individuals are cognitively impaired, which is sometimes difficult to distinguish from other symptoms 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, and include 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.
Compulsive behaviors also occur, including aggressiveness, vomiting
Vomiting
Vomiting is the forceful expulsion of the contents of one's stomach through the mouth and sometimes the nose...
, spitting, and coprolalia
Coprolalia
Coprolalia is involuntary swearing or the involuntary utterance of obscene words or socially inappropriate and derogatory remarks. Coprolalia comes from the Greek κόπρος meaning "feces" and λαλιά from lalein, "to talk"...
(involuntary swearing). 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 an asymptomatic condition, they do experience an increase in uric acid excretion, and some may develop symptoms of hyperuricemiaHyperuricemia
Hyperuricemia is a level of uric acid in the blood that is abnormally high. In humans, the upper end of the normal range is 360 µmol/L for women and 400 µmol/L for men.-Causes:...
, 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 (hematuriaHematuria
In medicine, hematuria, or haematuria, is the presence of red blood cells in the urine. It may be idiopathic and/or benign, or it can be a sign that there is a kidney stone or a tumor in the urinary tract , ranging from trivial to lethal...
), 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
Mental retardation
Mental retardation is a generalized disorder appearing before adulthood, characterized by significantly impaired cognitive functioning and deficits in two or more adaptive behaviors...
, autism
Autism
Autism is a disorder of neural development characterized by impaired social interaction and communication, and by restricted and repetitive behavior. These signs all begin before a child is three years old. Autism affects information processing in the brain by altering how nerve cells and their...
, Rett syndrome
Rett syndrome
Rett syndrome is a neurodevelopmental disorder of the grey matter of the brain that almost exclusively affects females. The clinical features include small hands and feet and a deceleration of the rate of head growth . Repetitive hand movements, such as wringing and/or repeatedly putting hands into...
, Cornelia de Lange syndrome
Cornelia de Lange Syndrome
Cornelia de Lange Syndrome often termed as Bushy Syndrome is a genetic disorder that can lead to severe developmental anomalies. It affects the physical and intellectual development of a child. Exact incidence is unknown, but it is estimated at 1 in 10,000 to 30,000.! Appx...
, Tourette syndrome
Tourette syndrome
Tourette syndrome is an inherited neuropsychiatric disorder with onset in childhood, characterized by multiple physical tics and at least one vocal tic; these tics characteristically wax and wane...
, familial dysautonomia
Familial dysautonomia
Familial dysautonomia is a disorder of the autonomic nervous system which affects the development and survival of sensory, sympathetic and some parasympathetic neurons in the autonomic and sensory nervous system resulting in variable symptoms including: insensitivity to pain, inability to produce...
, 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 creatinineCreatinine
Creatinine is a break-down product of creatine phosphate in muscle, and is usually produced at a fairly constant rate by the body...
(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 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 but is not diagnostic
Medical diagnosis
Medical diagnosis refers both to the process of attempting to determine or identify a possible disease or disorder , and to the opinion reached by this process...
. Hyperuricemia (serum uric acid concentration of >8 mg/dL) is often present but not reliable enough for diagnosis. Activity of the HGPRT enzyme in cells
Cell (biology)
The cell is the basic structural and functional unit of all known living organisms. It is the smallest unit of life that is classified as a living thing, and is often called the building block of life. The Alberts text discusses how the "cellular building blocks" move to shape developing embryos....
from any type of tissue
Biological tissue
Tissue is a cellular organizational level intermediate between cells and a complete organism. A tissue is an ensemble of cells, not necessarily identical, but from the same origin, that together carry out a specific function. These are called tissues because of their identical functioning...
(e.g., blood
Blood
Blood is a specialized bodily fluid in animals that delivers necessary substances such as nutrients and oxygen to the cells and transports metabolic waste products away from those same cells....
, cultured fibroblast
Fibroblast
A fibroblast is a type of cell that synthesizes the extracellular matrix and collagen, the structural framework for animal tissues, and plays a critical role in wound healing...
s, or lymphoblast
Lymphoblast
Lymphoblasts are immature cells which typically differentiate to form mature lymphocytes. Normally lymphoblasts are found in the bone marrow, but in acute lymphoblastic leukemia , lymphoblasts proliferate uncontrollably and are found in large numbers in the peripheral blood.The size is between 10...
s) that is less than 1.5% of normal enzyme activity confirms the diagnosis of Lesch–Nyhan syndrome. Molecular genetic studies of the HPRT gene mutations may confirm diagnosis, and are particularly helpful for subsequent 'carrier testing' in at-risk females such as close family relatives on the female side.
Testing
The use of biochemicalBiochemistry
Biochemistry, sometimes called biological chemistry, is the study of chemical processes in living organisms, including, but not limited to, living matter. Biochemistry governs all living organisms and living processes...
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
Type I and type II errors
In statistical test theory the notion of statistical error is an integral part of hypothesis testing. The test requires an unambiguous statement of a null hypothesis, which usually corresponds to a default "state of nature", for example "this person is healthy", "this accused is not guilty" or...
and false negative outcomes. If only a suspected carrier female is available for mutation testing, it may be appropriate to grow her lymphocytes in 6-thioguanine (a purine analogue
Purine
A purine is a heterocyclic aromatic organic compound, consisting of a pyrimidine ring fused to an imidazole ring. Purines, including substituted purines and their tautomers, are the most widely distributed kind of nitrogen-containing heterocycle in nature....
), which allows only HGPRT-deficient cells to survive. 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. 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
Phenotype
A phenotype is an organism's observable characteristics or traits: such as its morphology, development, biochemical or physiological properties, behavior, and products of behavior...
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
Exon
An exon is a nucleic acid sequence that is represented in the mature form of an RNA molecule either after portions of a precursor RNA have been removed by cis-splicing or when two or more precursor RNA molecules have been ligated by trans-splicing. The mature RNA molecule can be a messenger RNA...
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
Mutation
In molecular biology and genetics, mutations are changes in a genomic sequence: the DNA sequence of a cell's genome or the DNA or RNA sequence of a virus. They can be defined as sudden and spontaneous changes in the cell. Mutations are caused by radiation, viruses, transposons and mutagenic...
s in the HPRT1 gene
Gene
A gene is a molecular unit of heredity of a living organism. It is a name given to some stretches of DNA and RNA that code for a type of protein or for an RNA chain that has a function in the organism. Living beings depend on genes, as they specify all proteins and functional RNA chains...
, so named because it codes for the enzyme
Enzyme
Enzymes are proteins that catalyze chemical reactions. In enzymatic reactions, the molecules at the beginning of the process, called substrates, are converted into different molecules, called products. Almost all chemical reactions in a biological cell need enzymes in order to occur at rates...
hypoxanthine-guanine phosphoribosyltransferase
Hypoxanthine-guanine phosphoribosyltransferase
Hypoxanthine-guanine phosphoribosyltransferase is an enzyme encoded in humans by the HPRT1 gene.HGPRT is a transferase that catalyzes conversion of hypoxanthine to inosine monophosphate and guanine to guanosine monophosphate. This reaction transfers the 5-phosphoribosyl group from...
(HPRT or HGPRT). This enzyme is involved in the biochemical pathways the body uses to produce purine
Purine
A purine is a heterocyclic aromatic organic compound, consisting of a pyrimidine ring fused to an imidazole ring. Purines, including substituted purines and their tautomers, are the most widely distributed kind of nitrogen-containing heterocycle in nature....
s, one of the components of DNA
DNA
Deoxyribonucleic acid is a nucleic acid that contains the genetic instructions used in the development and functioning of all known living organisms . The DNA segments that carry this genetic information are called genes, but other DNA sequences have structural purposes, or are involved in...
and RNA
RNA
Ribonucleic acid , or RNA, is one of the three major macromolecules that are essential for all known forms of life....
. Defects of this enzyme lead to increased production of uric acid
Uric acid
Uric acid is a heterocyclic compound of carbon, nitrogen, oxygen, and hydrogen with the formula C5H4N4O3. It forms ions and salts known as urates and acid urates such as ammonium acid urate. Uric acid is created when the body breaks down purine nucleotides. High blood concentrations of uric acid...
. Since the HPRT gene is located on the X chromosome
XY sex-determination system
The XY sex-determination system is the sex-determination system found in humans, most other mammals, some insects and some plants . In this system, females have two of the same kind of sex chromosome , and are called the homogametic sex. Males have two distinct sex chromosomes , and are called...
, LNS is an X-linked inherited disease.
The father of an affected male will not be the carrier of the mutant allele
Allele
An allele is one of two or more forms of a gene or a genetic locus . "Allel" is an abbreviation of allelomorph. Sometimes, different alleles can result in different observable phenotypic traits, such as different pigmentation...
, 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
Haldane's rule
Haldane's rule or Haldane's law was formulated in 1922 by the British evolutionary biologist J.B.S. Haldane. It describes hybrid sterility in species and is extended to describe speciation in evolutionary theory, in two parts: the rule of hybrid sterility and the rule of hybrid inviability...
predicts a 2/3 chance that she is a carrier and a 1/3 chance that the son has a new germline mutation
Germline mutation
A germline mutation is any detectable and heritable variation in the lineage of germ cells. Mutations in these cells are transmitted to offspring, while, on the other hand, those in somatic cells are not. A germline mutation gives rise to a constitutional mutation in the offspring, that is, a...
. 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
Pregnancy
Pregnancy refers to the fertilization and development of one or more offspring, known as a fetus or embryo, in a woman's uterus. In a pregnancy, there can be multiple gestations, as in the case of twins or triplets...
. 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
Phenotype
A phenotype is an organism's observable characteristics or traits: such as its morphology, development, biochemical or physiological properties, behavior, and products of behavior...
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 phosphoribosyltransferaseHypoxanthine-guanine phosphoribosyltransferase
Hypoxanthine-guanine phosphoribosyltransferase is an enzyme encoded in humans by the HPRT1 gene.HGPRT is a transferase that catalyzes conversion of hypoxanthine to inosine monophosphate and guanine to guanosine monophosphate. This reaction transfers the 5-phosphoribosyl group from...
(HPRT), a participant in the 'recycling' of purine
Purine
A purine is a heterocyclic aromatic organic compound, consisting of a pyrimidine ring fused to an imidazole ring. Purines, including substituted purines and their tautomers, are the most widely distributed kind of nitrogen-containing heterocycle in nature....
nucleotide
Nucleotide
Nucleotides are molecules that, when joined together, make up the structural units of RNA and DNA. In addition, nucleotides participate in cellular signaling , and are incorporated into important cofactors of enzymatic reactions...
s. 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.
A large number of mutations of HPRT are known. Mutations 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 which still features purine overproduction accompanied by susceptibility to gout
Gout
Gout is a medical condition usually characterized by recurrent attacks of acute inflammatory arthritis—a red, tender, hot, swollen joint. The metatarsal-phalangeal joint at the base of the big toe is the most commonly affected . However, it may also present as tophi, kidney stones, or urate...
and uric acid
Uric acid
Uric acid is a heterocyclic compound of carbon, nitrogen, oxygen, and hydrogen with the formula C5H4N4O3. It forms ions and salts known as urates and acid urates such as ammonium acid urate. Uric acid is created when the body breaks down purine nucleotides. High blood concentrations of uric acid...
nephrolithiasis.
Formation of DNA (during cell division
Cell division
Cell division is the process by which a parent cell divides into two or more daughter cells . Cell division is usually a small segment of a larger cell cycle. This type of cell division in eukaryotes is known as mitosis, and leaves the daughter cell capable of dividing again. The corresponding sort...
) requires nucleotide
Nucleotide
Nucleotides are molecules that, when joined together, make up the structural units of RNA and DNA. In addition, nucleotides participate in cellular signaling , and are incorporated into important cofactors of enzymatic reactions...
s, molecules that are the building blocks for DNA. The purine bases (adenine
Adenine
Adenine is a nucleobase with a variety of roles in biochemistry including cellular respiration, in the form of both the energy-rich adenosine triphosphate and the cofactors nicotinamide adenine dinucleotide and flavin adenine dinucleotide , and protein synthesis, as a chemical component of DNA...
and guanine
Guanine
Guanine is one of the four main nucleobases found in the nucleic acids DNA and RNA, the others being adenine, cytosine, and thymine . In DNA, guanine is paired with cytosine. With the formula C5H5N5O, guanine is a derivative of purine, consisting of a fused pyrimidine-imidazole ring system with...
) and pyrimidine
Pyrimidine
Pyrimidine is a heterocyclic aromatic organic compound similar to benzene and pyridine, containing two nitrogen atoms at positions 1 and 3 of the six-member ring...
bases (thymidine
Thymidine
Thymidine is a chemical compound, more precisely a pyrimidine deoxynucleoside. Deoxythymidine is the DNA nucleoside T, which pairs with deoxyadenosine in double-stranded DNA...
and cytosine
Cytosine
Cytosine is one of the four main bases found in DNA and RNA, along with adenine, guanine, and thymine . It is a pyrimidine derivative, with a heterocyclic aromatic ring and two substituents attached . The nucleoside of cytosine is cytidine...
) are bound to deoxyribose and phosphate and incorporated as necessary. Normally, the nucleotides are synthetized de novo from amino acid
Amino acid
Amino acids are molecules containing an amine group, a carboxylic acid group and a side-chain that varies between different amino acids. The key elements of an amino acid are carbon, hydrogen, oxygen, and nitrogen...
s and other precursors. A small part, however, is 'recycled' from degraded DNA of broken-down cells. This is termed the "salvage pathway".
HGPRT is the "salvage enzyme" for the purines: it channels hypoxanthine
Hypoxanthine
Hypoxanthine is a naturally occurring purine derivative. It is occasionally found as a constituent of nucleic acids where it is present in the anticodon of tRNA in the form of its nucleoside inosine. It has a tautomer known as 6-Hydroxypurine. Hypoxanthine is a necessary additive in certain cell,...
and guanine
Guanine
Guanine is one of the four main nucleobases found in the nucleic acids DNA and RNA, the others being adenine, cytosine, and thymine . In DNA, guanine is paired with cytosine. With the formula C5H5N5O, guanine is a derivative of purine, consisting of a fused pyrimidine-imidazole ring system with...
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 acidUric acidUric acid is a heterocyclic compound of carbon, nitrogen, oxygen, and hydrogen with the formula C5H4N4O3. It forms ions and salts known as urates and acid urates such as ammonium acid urate. Uric acid is created when the body breaks down purine nucleotides. High blood concentrations of 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 was previously unclear whether the neurological abnormalities in LNS were due to uric acid neurotoxicity or to a relative shortage in "new" purine nucleotide
Nucleotide
Nucleotides are molecules that, when joined together, make up the structural units of RNA and DNA. In addition, nucleotides participate in cellular signaling , and are incorporated into important cofactors of enzymatic reactions...
s during essential synthesis steps. Genetic mutations affecting the enzymes of the de novo synthesis pathway may possibly contribute to the disease, although these are rare or unknown. Uric acid has been suggested as a possible cause of neurotoxicity but this is unproven.
Importantly, evidence suggests that one or more lesions in striatal
Striatum
The striatum, also known as the neostriatum or striate nucleus, is a subcortical part of the forebrain. It is the major input station of the basal ganglia system. The striatum, in turn, gets input from the cerebral cortex...
dopamine
Dopamine
Dopamine is a catecholamine neurotransmitter present in a wide variety of animals, including both vertebrates and invertebrates. In the brain, this substituted phenethylamine functions as a neurotransmitter, activating the five known types of dopamine receptors—D1, D2, D3, D4, and D5—and their...
rgic pathways may be central to the neurological deficits, especially the choreoathetoid dyskinesia and self-mutilation.
6-hydroxydopamine toxicity in rodents may be a useful animal model for the syndrome, although this is not proven.
However, the link between dopamine and purine synthesis is a nucleotide called guanosine triphosphate
Guanosine triphosphate
Guanosine-5'-triphosphate is a purine nucleoside triphosphate. It can act as a substrate for the synthesis of RNA during the transcription process...
or 'GTP'. The first step of dopamine synthesis is GTP cyclohydrolase, and significantly a deficiency of this step produces a syndrome that has a neuropathology similar to LNS. Thus a lack of HGPRT may produce a nucleotide deficiency (specifically: GTP deficiency) disorder, resulting in dopamine deficiency.
Another putative animal model for LNS has been proposed to arise from oxidative damage, caused by the hyperuricemia
Hyperuricemia
Hyperuricemia is a level of uric acid in the blood that is abnormally high. In humans, the upper end of the normal range is 360 µmol/L for women and 400 µmol/L for men.-Causes:...
accompanying LNS. This is based on the theory that uric acid
Uric acid
Uric acid is a heterocyclic compound of carbon, nitrogen, oxygen, and hydrogen with the formula C5H4N4O3. It forms ions and salts known as urates and acid urates such as ammonium acid urate. Uric acid is created when the body breaks down purine nucleotides. High blood concentrations of uric acid...
is a powerful reducing agent
Reducing agent
A reducing agent is the element or compound in a reduction-oxidation reaction that donates an electron to another species; however, since the reducer loses an electron we say it is "oxidized"...
and likely an important human antioxidant
Antioxidant
An antioxidant is a molecule capable of inhibiting the oxidation of other molecules. Oxidation is a chemical reaction that transfers electrons or hydrogen from a substance to an oxidizing agent. Oxidation reactions can produce free radicals. In turn, these radicals can start chain reactions. When...
, in high concentration in blood. On the other hand, uric acid may also act as a pro-oxidant
Pro-oxidant
Pro-oxidants are chemicals that induce oxidative stress, through either creating reactive oxygen species or inhibiting antioxidant systems. The oxidative stress produced by these chemicals can damage cells and tissues...
, Thus, it has been suggested that free radicals, oxidative stress
Oxidative stress
Oxidative stress represents an imbalance between the production and manifestation of reactive oxygen species and a biological system's ability to readily detoxify the reactive intermediates or to repair the resulting damage...
, and reactive oxygen species
Reactive oxygen species
Reactive oxygen species are chemically reactive molecules containing oxygen. Examples include oxygen ions and peroxides. Reactive oxygen species are highly reactive due to the presence of unpaired valence shell electrons....
may play some role in the neuropathology of LNS.
However, some evidence argues against a role for uric acid in the neuropathology of Lesch-Nyhans:
- Hyperuricaemia associated with classic primary gout, which is caused by low uric acid renal clearance rather than uric acid overproduction, is not associated with neuropathology.
- Hypouricaemia occurs in a number of purine disorders, in particular xanthinuriaXanthinuriaXanthinuria, also known as xanthine oxidase deficiency, is a rare genetic disorder causing the accumulation of xanthine. It is caused by a deficiency of the enzyme xanthine oxidase.It was first formally characterized in 1954.-Causes:...
. Despite having complete absence of blood uric acid, xanthinuria patients do not have any neuropathology, nor any other disease states - other than the kidney stones caused by accumulation of insoluble xanthine in lieu of uric acid.
Similarly, uric acid does not penetrate the blood-brain barrier well. However, oxidative stress due to uric acid is now thought to figure in metabolic syndrome
Metabolic syndrome
Metabolic syndrome is a combination of medical disorders that, when occurring together, increase the risk of developing cardiovascular disease and diabetes. It affects one in five people in the United States and prevalence increases with age...
, atherosclerosis
Atherosclerosis
Atherosclerosis is a condition in which an artery wall thickens as a result of the accumulation of fatty materials such as cholesterol...
, and stroke
Stroke
A stroke, previously known medically as a cerebrovascular accident , is the rapidly developing loss of brain function due to disturbance in the blood supply to the brain. This can be due to ischemia caused by blockage , or a hemorrhage...
, all syndromes associated with high uric acid levels. Similarly, Superoxide dismutase
Superoxide dismutase
Superoxide dismutases are a class of enzymes that catalyze the dismutation of superoxide into oxygen and hydrogen peroxide. As such, they are an important antioxidant defense in nearly all cells exposed to oxygen...
( "SOD" ) and SOD-mimetics such as TEMPOL ameliorate the effects of hyperuricemia. Likewise, 6-hydroxydopamine (the putative animal model for Lesch-Nyhan's neuropathy) apparently acts as a neurotoxin by generation of active oxygen species. It may be that oxidative stress induced by some other oxypurine such as xanthine causes the disease. See Barrasco et al. above.
Thus, evidence points to the pathophysiology of LNS arising from nucleotide deficiency, rather than oxidative damage. This has important implications for treatment. "Antioxidant therapy" has not been found to provide any relief for LNS symptoms. This may be because ectopic urate-like reducing antioxidants such as ascorbate must compete as antioxidants and neuroprotectants with order-of-magnitude higher levels of uric acid itself http://stroke.ahajournals.org/cgi/content/full/39/8/e126. On the other hand, supplementation of nucleotides with an orally-delivered precursor drug (SAMe) has shown encouraging results, as described below.
Treatment
Treatment for LNS is symptomatic. Gout can be treated with allopurinolAllopurinol
Allopurinol is a drug used primarily to treat hyperuricemia and its complications, including chronic gout.- Mechanism of action :...
to control excessive amounts of uric acid
Uric acid
Uric acid is a heterocyclic compound of carbon, nitrogen, oxygen, and hydrogen with the formula C5H4N4O3. It forms ions and salts known as urates and acid urates such as ammonium acid urate. Uric acid is created when the body breaks down purine nucleotides. High blood concentrations of uric acid...
. Kidney stones may be treated with lithotripsy
Lithotripsy
Lithotripsy refers to the physical destruction of gallstones or kidney stones. The term is derived from the Greek words meaning "breaking stones" .Forms include:* Extracorporeal shock wave 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
Carbidopa
Carbidopa is a drug given to people with Parkinson's disease in order to inhibit peripheral metabolism of levodopa.- Pharmacology :...
/levodopa
Levodopa
L-DOPA is a chemical that is made and used as part of the normal biology of some animals and plants. Some animals including humans make it via biosynthesis from the amino acid L-tyrosine. L-DOPA is the precursor to the neurotransmitters dopamine, norepinephrine , and epinephrine collectively...
, diazepam
Diazepam
Diazepam , first marketed as Valium by Hoffmann-La Roche is a benzodiazepine drug. Diazepam is also marketed in Australia as Antenex. It is commonly used for treating anxiety, insomnia, seizures including status epilepticus, muscle spasms , restless legs syndrome, alcohol withdrawal,...
, phenobarbital
Phenobarbital
Phenobarbital or phenobarbitone is a barbiturate, first marketed as Luminal by Friedr. Bayer et comp. It is the most widely used anticonvulsant worldwide, and the oldest still commonly used. It also has sedative and hypnotic properties but, as with other barbiturates, has been superseded by the...
, or haloperidol
Haloperidol
Haloperidol is a typical antipsychotic. It is in the butyrophenone class of antipsychotic medications and has pharmacological effects similar to the phenothiazines....
.
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
Allopurinol
Allopurinol is a drug used primarily to treat hyperuricemia and its complications, including chronic gout.- Mechanism of action :...
is utilized to stop the conversion of oxypurines into uric acid, and prevent the development of subsequent arthritic tophi (produced after having chronic gout), kidney stone
Kidney stone
A kidney stone, also known as a renal calculus is a solid concretion or crystal aggregation formed in the kidneys from dietary minerals in the urine...
s, and nephropathy
Nephropathy
Nephropathy refers to damage to or disease of the kidney. An older term for this is nephrosis.-Causes:Causes of nephropathy include administration of analgesics, xanthine oxidase deficiency, and long-term exposure to lead or its salts...
, 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
Extrapyramidal
Extrapyramidal can refer to:* Extrapyramidal system* Extrapyramidal symptoms...
motor features of the disease. Spasticity, however, can be reduced by the administration of baclofen
Baclofen
Baclofen is a derivative of gamma-aminobutyric acid . It is primarily used to treat spasticity and is under investigation for the treatment of alcoholism....
or benzodiazepines.
There has previously been no effective method of treatment for the neurobehavioral aspects of the disease. 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.
The Matheny Medical and Educational Center http://www.matheny.org in Peapack, NJ, has nine Lesch-Nyhan patients, believed to be the largest concentration of LNS cases in one location, and is recognized as the leading source of information on care issues.
Treatment for LNS patients, according to Gary E. Eddey, MD, medical director, should include: 1) Judicious use of protective devices; 2) Utilization of a behavioral technique commonly referred to as 'selective ignoring' with redirection of activities; and 3) Occasional use of medications.
An article in the August 13, 2007 issue of The New Yorker
The New Yorker
The New Yorker is an American magazine of reportage, commentary, criticism, essays, fiction, satire, cartoons and poetry published by Condé Nast...
magazine, written by Richard Preston
Richard Preston
Richard Preston, born August 5, 1954 in Cambridge, Massachusetts, U.S., is a New Yorker writer and bestselling author perhaps best-known for his books about infectious disease epidemics and bioterrorism, although he has written other non-fiction works...
, 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
Parkinson's disease
Parkinson's disease is a degenerative disorder of the central nervous system...
, 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.
An encouraging advance in the treatment of the neurobehavioural aspects of LNS was the publication in the October, 2006 issue of Journal of Inherited Metabolic Disease
Journal of Inherited Metabolic Disease
The Journal of Inherited Metabolic Disease is a peer-reviewed medical journal covering inherited metabolic disorders. It was established in 1978 and is the official journal of the Society for the Study of Inborn Errors of Metabolism.- External links :*...
of an experimental therapy giving oral S-adenosyl-methionine (SAMe).
This drug is a nucleotide precursor
Precursor (chemistry)
In chemistry, a precursor is a compound that participates in the chemical reaction that produces another compound. In biochemistry, the term "precursor" is used more specifically to refer to a chemical compound preceding another in a metabolic pathway....
that provides a readily absorbed purine, which is known to be transported across the blood-brain barrier
Blood-brain barrier
The blood–brain barrier is a separation of circulating blood and the brain extracellular fluid in the central nervous system . It occurs along all capillaries and consists of tight junctions around the capillaries that do not exist in normal circulation. Endothelial cells restrict the diffusion...
. Administration of SAMe to adult LNS patients was shown to provide improvement in neurobehavioural and other neurological attributes. The drug is available without prescription and has been widely used for depression, but its use for treating LNS should be undertaken only under strict medical supervision, as side effects are known.
SAMe has also been used recently to treat another purine nucleotide disease, "Art's Syndrome" (which is a PRPP disorder in common with LNS), with encouraging results.
Thus SAMe may be useful for treating purine nucleotide diseases, which include LNS.
Prognosis
The prognosis for individuals with severe LNS is poor. Death is usually due to renal failure or complications from hypotonia, in the first or second decade of life. Less severe forms (see below) have better prognoses.History
Michael LeschMichael Lesch
Dr. Michael Lesch was a distinguished American physician and medical educator who helped identify an important genetic disorder associated with retardation and self-mutilation. This disease is now known as the Lesch-Nyhan syndrome...
was a medical student at Johns Hopkins University
Johns Hopkins University
The Johns Hopkins University, commonly referred to as Johns Hopkins, JHU, or simply Hopkins, is a private research university based in Baltimore, Maryland, United States...
and Bill Nyhan, a pediatrician
Pediatrics
Pediatrics or paediatrics is the branch of medicine that deals with the medical care of infants, children, and adolescents. A medical practitioner who specializes in this area is known as a pediatrician or paediatrician...
and biochemical geneticist, was his mentor, when the two identified LNS and its associated hyperuricemia in two affected brothers, ages 4 and 8. Lesch and Nyhan published their findings in 1964. Within three years, the metabolic cause was identified by J. Edwin Seegmiller
J. Edwin Seegmiller
J Edwin Seegmiller, or Jay Seegmiller, was an American physician and biochemical geneticist best known for his role in discovering the biochemical basis of the Lesch-Nyhan syndrome. He was a rheumatologist and a pioneer in research on arthritic diseases and on aging.-Life:Jay Seegmiller was born...
and his colleagues at NIH.
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.In popular culture
Lesch-Nyhan Syndrome is mentioned in Richard PrestonRichard Preston
Richard Preston, born August 5, 1954 in Cambridge, Massachusetts, U.S., is a New Yorker writer and bestselling author perhaps best-known for his books about infectious disease epidemics and bioterrorism, although he has written other non-fiction works...
's 1998 fictional work, The Cobra Event
The Cobra Event
The Cobra Event is a 1998 thriller novel by Richard Preston describing a terror attempt on the United States by a lone man, the creator of a virus, called "Cobra", that mixes the incurable common cold with one of the world's most deadly diseases, smallpox...
. It is the focus of one chapter in his nonfiction work Panic in Level 4.
In 2009, an experimental stageplay entitled Chewing Your Fingers to the Bone was devised by a Professor of Theatre, a local artist, and a company of undergraduate students at Allegheny College
Allegheny College
Allegheny College is a private liberal arts college located in northwestern Pennsylvania in the town of Meadville. Founded in 1815, the college has about 2,100 undergraduate students.-Early history:...
in Meadville, Pennsylvania
Meadville, Pennsylvania
Meadville is a city in and the county seat of Crawford County, Pennsylvania, United States. The city is generally considered part of the Pittsburgh Tri-State and is within 40 miles of Erie, Pennsylvania. It was the first permanent settlement in northwest Pennsylvania...
. The piece involves a number of separate yet related storylines, several of which depict the stories of people living with Lesch-Nyhan Syndrome. Much of the original material was inspired by Richard Preston's An Error in the Code, originally published in The New Yorker
The New Yorker
The New Yorker is an American magazine of reportage, commentary, criticism, essays, fiction, satire, cartoons and poetry published by Condé Nast...
.
In Mystery Diagnosis
Mystery Diagnosis
Mystery Diagnosis is a television program that airs on the OWN: Oprah Winfrey Network. Each episode focuses on two or more individuals and their struggles to find out what ailments they suffer from....
(season 6, episode 8, titled The Boy Hit Bit Himself), a true story of a little boy with Lesch-Nyhan Syndrome.
In Nip/Tuck
Nip/Tuck
Nip/Tuck is an American drama series created by Ryan Murphy, which aired on FX in the United States. The series focuses on McNamara/Troy, a plastic surgery practice, and follows its founders, Sean McNamara and Christian Troy...
(season 6, episode 11), the patient Dan Daly suffers from Lesch-Nyhan Syndrome and requires plastic surgery on his lips after having chewed them off.
In House
House (TV series)
House is an American television medical drama that debuted on the Fox network on November 16, 2004. The show's central character is Dr. Gregory House , an unconventional and misanthropic medical genius who heads a team of diagnosticians at the fictional Princeton-Plainsboro Teaching Hospital in...
(season 3, episode 23, titled The Jerk), Kelley-Seegmiller syndrome is considered as a diagnosis for a teen-aged chess prodigy after he is found to have an HPRT enzyme deficiency. The script errs in having one of the doctors erroneously describing Kelley-Seegmiller syndrome victims as prone to self-mutilation, chewing their lips and banging their heads against the wall.
External links
- CLIMB (Children Living with Inherited Metabolic Diseases)
- Lesch-Nyhan Syndrome Registry
- GeneReview/NIH/UW entry on Lesch-Nyhan Syndrome
- National Institute of Child Health and Human Development (NICHD)
- Philip Baker's Homepage
- Lesch-Nyhan Syndrome. The Cleveland clinic. Retrieved on 2007-04-12.
- Lesch-Nyhan Syndrome. Joseph F. Smith medical library. Retrieved from the internet archive, April 3, 2005 version on 2007-04-12.