Lesch-Nyhan syndrome Classification and external resources
Philip Baker, an adult with Lesch-Nyhan Syndrome. Visible in this picture are the restraints on Philip's chair that he must use to control his involuntary movement.
ICD-10	E79.1
ICD-9	277.2
OMIM	308000 300322
DiseasesDB	7415
MedlinePlus	001655
eMedicine	neuro/630
MeSH	D007926

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). The International Statistical Classification of Diseases and Related Health Problems (most commonly known by the abbreviation ICD) provides codes to classify Diseases The International Statistical Classification of Diseases and Related Health Problems 10th Revision ( ICD -10) is a coding of diseases and signs symptoms abnormal findings E00-E35 - Endocrine diseases (E00-E07 Thyroid gland / Thyroid hormone ( Congenital iodine-deficiency syndrome ( The International Statistical Classification of Diseases and Related Health Problems (most commonly known by the abbreviation ICD) provides codes to classify Diseases The following is a list of codes for International Statistical Classification of Diseases and Related Health Problems. The Mendelian Inheritance in Man project is a Database that catalogues all the known Diseases with a genetic component, and—when possible—links them The Diseases Database is a free Website that provides information about the relationships between medical conditions Symptoms, and Medications. MedlinePlus, with the MedlinePlus Medical Encyclopedia, is a website network containing Health information from the world's largest medical Library eMedicine is an online clinical medical knowledge base that was founded in 1996 by Scott Plantz and Richard Lavely two medical doctors Medical Subject Headings ( MeSH) is a huge Controlled vocabulary (or metadata system for the purpose of indexing journal articles and books A genetic disorder is a condition caused by abnormalities in Genes or Chromosomes While some diseases such as Cancer, are due to genetic abnormalities acquired Enzymes are Biomolecules that catalyze ( ie increase the rates of Chemical reactions Almost all enzymes are Proteins Hypoxanthine-guanine phosphoribosyltransferase ( HPRT LNS is an X-linked recessive disease: the gene is carried by the mother and passed on to her son. X-linked recessive is a mode of inheritance in which a mutation in a Gene on the X chromosome causes the phenotype to be expressed (1 in males (who are History See also History of genetics The existence of genes was first suggested by Gregor Mendel (1822-1884 who in the 1860s studied inheritance LNS is present at birth in baby boys. Childbirth (also called labour, birth, partus or parturition) is the culmination of a Human Pregnancy or Patients have severe mental and physical problems throughout life. The lack of HGPRT 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. Uric acid (or urate) is an Organic compound of Carbon, Nitrogen, Oxygen and Hydrogen with the formula C5H4N4O3 Gout (also called metabolic arthritis) is a disease created by a buildup of Uric acid. Mental retardation is a generalized triarchic disorder characterized by subaverage cognitive functioning and deficits in two or more adaptive behaviors with onset before the age A striking feature of LNS is self-mutilating behaviors, characterized by lip and finger biting, that begin in the second year of life. Self-injury ( SI) or self-harm ( SH) is deliberate Injury inflicted by a person upon their own body without suicidal intent 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. A joint is the location at which two or more Bones make contact The kidneys are complicated organs that have numerous biological roles In Vertebrates the central nervous system ( CNS) is the part of the Nervous system which is enclosed in the Meninges. 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, also called Huntington's chorea, chorea major, or HD, is a genetic neurological disorder characterized after 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 a disorder called megaloblastic anemia. Megaloblastic anemia is an Anemia (of macrocytic classification which results from inhibition of DNA synthesis in red blood cell production ^[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. Arthritis (from Greek arthro-, joint + -itis, inflammation plural arthritides is a group of conditions involving damage to the Joints of the body The kidneys are complicated organs that have numerous biological roles Allopurinol is a drug used primarily to treat conditions arising from excess Uric acid, most notably chronic Gout. 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] The disorder was first recognized and clinically characterized by medical student Michael Lesch and his pediatric mentor Bill Nyhan, who published their findings in 1964. Michael Lesch ( June 30, 1939 &ndash March 19, 2008) was a distinguished American physician and medical educator who helped identify a genetic Dr William Leo Nyhan MD PhD (born March 13, 1926) currently holds the position of Professor of Pediatrics at UC San Diego School of Medicine ^[3]

Contents 1 Signs and symptoms 1.1 Overproduction of uric acid 1.2 Nervous system impairment 1.3 Self-injuring behavior 1.4 LNS in females 2 Diagnosis 2.1 Diagnostic approach 2.2 Testing 3 Genetics 4 Pathophysiology 5 Treatment 6 Prognosis 7 History 8 Less severe forms 9 LNS in popular culture 10 References 11 External links

Signs and symptoms

LNS is characterized by three major hallmarks: neurologic dysfunction, cognitive and behavioral disturbances, as well as uric acid overproduction (hyperuricemia). Cognition is a concept used in different ways by different disciplines but is generally accepted to mean the process of awareness or thought For the Björk song see Human Behaviour Human behavior is the collection of Behaviors exhibited by Human beings and influenced by Deviance describes actions or behaviors that violate cultural norms including formally-enacted rules (e Uric acid (or urate) is an Organic compound of Carbon, Nitrogen, Oxygen and Hydrogen with the formula C5H4N4O3 Hyperuricemia ( American English) or hyperuricaemia ( British English) is the presence of high levels of Uric acid in the blood Damage to the basal ganglia causes victims to adopt a characteristic fencing stance due to the nature of the lesion. The basal ganglia (or basal nuclei) are a group of nuclei in the Brain interconnected with the Cerebral cortex, Thalamus and Some may also be afflicted with anemia (macrocytic). Anemia ( AmE) or anæmia/anaemia ( BrE) (from the Ancient Greek grc-Latn anaîmia, meaning “without blood” is defined as a qualitative Virtually all patients are male, and male victims suffer delayed growth and puberty, and most develop shrunken testicles or testicular atrophy. Testicular atrophy is a medical condition in which the Male Reproductive organs (the Testes, which in humans are located in the Scrotum Female carriers are at an increased risk for gouty arthritis, but are usually otherwise unaffected. Gout (also called metabolic arthritis) is a disease created by a buildup of Uric acid.

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. Uric acid (or urate) is an Organic compound of Carbon, Nitrogen, Oxygen and Hydrogen with the formula C5H4N4O3 Overproduction of uric acid may lead to the development of uric acid crystals or stones in the kidneys, ureters, or bladder. The kidneys are complicated organs that have numerous biological roles In human Anatomy, the ureters are muscular ducts that propel Urine from the Kidneys to the Urinary bladder. In Anatomy, the urinary bladder is a hollow muscular, and distensible (or elastic organ that sits on the Pelvic floor in Mammals It is the Such crystals deposited in joints later in the disease may produce gout-like arthritis, with swelling and tenderness. Gout (also called metabolic arthritis) is a disease created by a buildup of Uric acid. Arthritis (from Greek arthro-, joint + -itis, inflammation plural arthritides is a group of conditions involving damage to the Joints of the body

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. In Medicine, hematuria (or "haematuria" is the presence of Red blood cells (erythrocytes in the Urine. A urinary tract infection ( UTI) is a bacterial Infection that affects any part of the Urinary tract. Some victims suffer kidney damage due to such kidney stones. Kidney stones, also called renal calculi, are solid concretions (crystal aggregations of dissolved minerals in Urine; calculi typically form 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. Muscle (from Latin musculus, diminutive of mus "mouse" is contractile tissue of the body and is derived from the Hypotonia is a condition of abnormally low Muscle tone (the amount of tension or resistance to movement in a muscle often involving reduced muscle strength Affected individuals are late in sitting up, while most never crawl or walk. Walking (also called ambulation) is the main form of Animal Locomotion on land, distinguished from Running and crawling Lack of speech is also a very common trait associated with LNS. Speech refers to the processes associated with the production and perception of Sounds used in Spoken language.

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). In Human anatomy, the extrapyramidal system is a Neural network located in the brain that is part of the Motor system involved in the coordination Dystonia is a neurological Movement disorder in which sustained muscle contractions cause twisting and repetitive movements or abnormal postures Choreoathetosis is the occurrence of involuntary movements in a combination of chorea and Athetosis. Opisthotonus or opisthotonos, from Greek roots opistho meaning "behind" and tonos meaning "tension" is a state of a severe Signs of pyramidal system involvement, including spasticity, overactive reflexes (hyperreflexia) and extensor plantar reflexes, also occur. The corticospinal or pyramidal tract is a massive collection of Axons that travel between the Cerebral cortex of the Brain and the Spinal Hyperreflexia is defined as overactive or overresponsive Reflexes. In Medicine and Neurology, the Babinski response to the plantar reflex is a Reflex, named after Joseph Babinski ( 1857 - 1932) (a French The resemblance to athetoid cerebral palsy is apparent in the neurologic aspects of LNS. Cerebral palsy ( CP) is an Umbrella term encompassing a group of non-progressive, non- contagious conditions that cause Physical disability 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. Vomiting (also called throwing up, emesis) is the forceful expulsion of the contents of one's Stomach through the Mouth and sometimes the Coprolalia is involuntary Swearing or the involuntary utterance of obscene words or socially inappropriate and derogatory remarks 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. Kidney stones, also called renal calculi, are solid concretions (crystal aggregations of dissolved minerals in Urine; calculi typically form In Medicine, hematuria (or "haematuria" is the presence of Red blood cells (erythrocytes in the Urine. 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. Mental retardation is a generalized triarchic disorder characterized by subaverage cognitive functioning and deficits in two or more adaptive behaviors with onset before the age Language development. The terminology Rett syndrome (also called Rett disorder) is a neurodevelopmental disorder that is classified as a Pervasive developmental disorder by the DSM-IV. Cornelia de Lange Syndrome aka CdLS is a little known Genetic disorder that can lead to severe developmental anomalies Tourette syndrome (also called Tourette's syndrome, Tourette's disorder, Gilles de la Tourette syndrome, GTS or more commonly simply Tourette's Familial dysautonomia, or FD, sometimes called Riley-Day syndrome is a disorder of the Autonomic nervous system which affects the development and survival Neuroacanthocytosis (also known as Levine-Critchley syndrome or chorea-acanthocytosis) is a rare movement disorder marked by progressive muscle weakness and Atrophy Neuropathy is a medical term usually short for Peripheral neuropathy. 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. Creatinine is a break-down product of Creatine phosphate in Muscle, and is usually produced at a fairly constant rate by the body (depending on muscle mass 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. Diagnosis is the identification by Process of elimination, of the nature of anything 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. The cell is the structural and functional unit of all known living Organisms It is the smallest unit of an organism that is classified as living and is often called Tissue is a cellular organizational level intermediate between cells and a complete organism g. , blood, cultured fibroblasts, or lymphoblasts) that is less than 1. Blood is a specialized Bodily fluid that delivers necessary substances to the body's cells ��such as nutrients and oxygen—and transports Waste products A fibroblast is a type of cell that synthesizes and maintains the Extracellular matrix of many Animal tissues Lymphoblasts are immature cells which typically differentiate to form mature Lymphocytes Normally lymphoblasts are found in the bone marrow but in Acute lymphoblastic 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. Biochemistry is the study of the chemical processes in living Organisms It deals with the Structure and function of cellular components such as 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. In Statistics, the terms Type I error (also α error, or false positive) and type II error ( β error, or a false negative 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 lymphocyte is a type of White blood cell in the Vertebrate Immune system. Purine ( 1) is a heterocyclic Aromatic Organic compound, consisting of a Pyrimidine ring fused to an Imidazole ring 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. A phenotype is any observable characteristic of an Organism, such as its morphology, Development, biochemical or physiological properties Sequence analysis of mRNA is available clinically and can be utilized in order to detect HPRT1 mutations in males affected with Lesch-Nyhan syndrome. Messenger ribonucleic acid ( mRNA) is a molecule of RNA encoding a chemical "blueprint" for a Protein product 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. An exon is a Nucleic acid sequence that is represented in the mature form of an RNA molecule after a portions of a precursor RNA Introns have been 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). In biology mutations are changes to the Nucleotide sequence of the Genetic material of an organism History See also History of genetics The existence of genes was first suggested by Gregor Mendel (1822-1884 who in the 1860s studied inheritance Enzymes are Biomolecules that catalyze ( ie increase the rates of Chemical reactions Almost all enzymes are Proteins Hypoxanthine-guanine phosphoribosyltransferase ( HPRT This article is about the Enzyme Commission codes For the European Commission system for coding chemicals see EC-No. This enzyme is involved in the biochemical pathways the body uses to produce purines, one of the components of DNA and RNA. Purine ( 1) is a heterocyclic Aromatic Organic compound, consisting of a Pyrimidine ring fused to an Imidazole ring Deoxyribonucleic acid ( DNA) is a Nucleic acid that contains the genetic instructions used in the development and functioning of all known Ribonucleic acid ( RNA) is a Nucleic acid that consists of a long chain of Nucleotide units Defects of this enzyme lead to increased production of uric acid. Uric acid (or urate) is an Organic compound of Carbon, Nitrogen, Oxygen and Hydrogen with the formula C5H4N4O3 Since the HPRT gene is located on the X chromosome, LNS is an X-linked inherited disease. Hypoxanthine-guanine phosphoribosyltransferase ( HPRT The XY sex-determination system is the Sex-determination system found in Humans most other Mammals some insects ( Drosophila) and some Sex linkage is the phenotypic expression of an Allele that is related to the chromosomal sex of the individual

The father of an affected male will not be the carrier of the mutant allele, and will not have the disease. An allele (ˈæliːl (UK /əˈliːl/ (US (from the Greek αλληλος allelos, meaning each other) is one member of a pair or series of different forms 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. Haldane's rule relating to hybrids of Species and extended to Speciation in Evolutionary theory is easily stated When in the offspring of A Germline Mutation is any detectable and heritable variation in the lineage of germ cells. 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 ( Latin graviditas) is the carrying of one or more offspring known as a Fetus or Embryo, inside the Uterus of a Female 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. A phenotype is any observable characteristic of an Organism, such as its morphology, Development, biochemical or physiological properties

Pathophysiology

As in other X-linked diseases, males are affected because they only have one copy of the X chromosome. Sex linkage is the phenotypic expression of an Allele that is related to the chromosomal sex of the individual In Lesch-Nyhan syndrome, the defective gene is that for hypoxanthine-guanine phosphoribosyltransferase (HPRT), a participant in the purine metabolism. Hypoxanthine-guanine phosphoribosyltransferase ( HPRT Purine ( 1) is a heterocyclic Aromatic Organic compound, consisting of a Pyrimidine ring fused to an Imidazole ring 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. Gout (also called metabolic arthritis) is a disease created by a buildup of Uric acid. Kidney stones, also called renal calculi, are solid concretions (crystal aggregations of dissolved minerals in Urine; calculi typically form

Formation of DNA (during cell division) requires nucleosides, molecules that are the building blocks for DNA. Cell division is a process by which a cell, called the parent cell divides into two or more cells called daughter cells. See also Adenosine triphosphate (ATP The purines (adenine and guanine) and pyrimidines (thymidine and cytosine) are bound to deoxyribose and phosphate and incorporated as necessary. Adenine is a Purine with a variety of roles in Biochemistry including Cellular respiration, in the form of both the energy-rich Adenosine Guanine is one of the five main Nucleobases found in the Nucleic acids DNA and RNA, the others being Adenine, Cytosine, Pyrimidine is a Heterocyclic Aromatic Organic compound similar to Benzene and Pyridine, containing two Nitrogen Atoms Thymidine (more precisely called deoxythymidine; can also be labelled deoxyribosylthymine, and thymine deoxyriboside) is a Chemical compound Cytosine is one of the five main bases found in DNA and RNA. It is a Pyrimidine derivative with a Heterocyclic Aromatic ring Normally, the nucleosides are synthetized de novo from amino acids and other precursors. In Chemistry, an amino acid is a Molecule containing both Amine and Carboxyl Functional groups In Biochemistry, this 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. Uric acid (or urate) is an Organic compound of Carbon, Nitrogen, Oxygen and Hydrogen with the formula C5H4N4O3
• 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. The striatum is a subcortical (ie inside rather than on the outside part of the Telencephalon. Dopamine is a Hormone and Neurotransmitter occurring in a wide variety of animals including both vertebrates and invertebrates ^[5][6][7] Thus, 6-hydroxydopamine toxicity in rodents is a useful animal model for the syndrome. 6-Hydroxydopamine, or 6-OHDA is a neurotoxin used by neurobiologists to selectively kill Dopaminergic and Noradrenergic neurons ^[8] 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. The enzyme superoxide dismutase ( SOD,) catalyzes the Dismutation of Superoxide into Oxygen and Hydrogen peroxide. ^[9] Uric acid is a powerful reducing agent and likely an important human antioxidant. Uric acid (or urate) is an Organic compound of Carbon, Nitrogen, Oxygen and Hydrogen with the formula C5H4N4O3 A reducing agent (also called a reductant or reducer) is the element or a compound in a Redox (reduction-oxidation reaction (see Electrochemistry An antioxidant is a Molecule capable of slowing or preventing the oxidation of other molecules E. g. , urate is the antioxidant in highest concentration in blood. However, uric acid can also act as a pro-oxidant,^[10] particularly at high concentrations like those produced in LNS. Pro-oxidants are chemicals that induce Oxidative stress, either through creating Reactive oxygen species or inhibiting Antioxidant systems Thus, free radicals, oxidative stress, and reactive oxygen species may play some role in the etiology of Lesch-Nyhan's syndrome. In Chemistry, radicals (often referred to as free radicals) are atoms molecules or ions with Unpaired electrons on an otherwise Open shell Oxidative stress is caused by an imbalance between the production of reactive oxygen and a biological system's ability to readily detoxify the reactive intermediates or easily Reactive oxygen species (ROS are ions or very small molecules that include Oxygen Ions free radicals, and Peroxides both inorganic and ^[11] Significantly, while first proposed for LNS and hyperuricemia in Dalmatian dogs,^[12] urate-induced oxidative stress is now thought to also figure in metabolic syndrome, atherosclerosis, and stroke. Metabolic syndrome is a combination of medical disorders that increase the risk of developing Cardiovascular disease and diabetes. Atherosclerosis is a Disease affecting arterial Blood vessels It is a chronic inflammatory response in the walls of arteries in large part due to the accumulation A stroke is the rapidly developing loss of brain functions due to a disturbance in the blood vessels supplying blood to the brain

Treatment

Treatment for LNS is symptomatic. Gout can be treated with allopurinol to control excessive amounts of uric acid. Allopurinol is a drug used primarily to treat conditions arising from excess Uric acid, most notably chronic Gout. Uric acid (or urate) is an Organic compound of Carbon, Nitrogen, Oxygen and Hydrogen with the formula C5H4N4O3 Kidney stones may be treated with lithotripsy, a technique for breaking up kidney stones using shock waves or laser beams. A lithotriptor is a Medical device used in the non-invasive treatment of Kidney stones (urinary calculosis and Biliary calculi (stones in the There is no standard treatment for the neurological symptoms of LNS. Some may be relieved with the drugs carbidopa/levodopa, diazepam, phenobarbital, or haloperidol. Carbidopa (MK-486 tradename Lodosyn) is a drug given to people with Parkinson's disease in order to inhibit peripheral Metabolism of Levodopa Diazepam (daɪˈæzɨpæm first marketed as Valium by Hoffmann-La Roche, is a Benzodiazepine derivative Drug. Phenobarbital ( INN) or phenobarbitone (former BAN) is a Barbiturate, first marketed as Luminal by Friedr Haloperidol is a Typical antipsychotic. It is in the Butyrophenone class of Antipsychotic medications and has pharmacological effects similar ^[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 a drug used primarily to treat conditions arising from excess Uric acid, most notably chronic Gout. Purine ( 1) is a heterocyclic Aromatic Organic compound, consisting of a Pyrimidine ring fused to an Imidazole ring A tophus (Latin "stone" plural tophi) is a deposit of Crystallised monosodium urate in people with longstanding Hyperuricemia Kidney stones, also called renal calculi, are solid concretions (crystal aggregations of dissolved minerals in Urine; calculi typically form Nephropathy refers to damage to or disease of the Kidney. An older term for this is nephrosis. 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. In Human anatomy, the extrapyramidal system is a Neural network located in the brain that is part of the Motor system involved in the coordination Spasticity, however, can be reduced by the administration of baclofen or benzodiazepines. Baclofen (brand names Kemstro and Lioresal) is a derivative of gamma-aminobutyric acid (GABA primarily used to treat Spasticity. The benzodiazepines (pronounced, often abbreviated to "benzos") are a class of Psychoactive drugs with varying Hypnotic

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 The New Yorker magazine, written by Richard Preston, discusses "Deep-brain stimulation," as a possible treatment. Events 3114 BC - According to the Lounsbury correlation the start of the Maya calendar. Year 2007 ( MMVII) was a Common year starting on Monday of the Gregorian calendar in the 21st century. The New Yorker is an American Magazine that publishes reportage commentary criticism essays fiction satire cartoons and poetry Richard Preston (b August 5, 1954) is a New Yorker writer and bestselling Author best-known for his alarming books about Infectious 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. Parkinson's disease (also known as Parkinson disease or PD) is a degenerative disorder of the Central nervous system that often impairs the sufferer's The treatment involves invasive surgery to place wires that carry a continuous electric current into a specific region of the brain. ^[13]

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 Hopkins 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. Michael Lesch ( June 30, 1939 &ndash March 19, 2008) was a distinguished American physician and medical educator who helped identify a genetic Dr William Leo Nyhan MD PhD (born March 13, 1926) currently holds the position of Professor of Pediatrics at UC San Diego School of Medicine Pediatrics (also spelled paediatrics) is the branch of Medicine that deals with the medical care of Infants Children and Adolescents ^[14] Lesch and Nyhan published their findings in 1964. ^[15] Within three years, the metabolic cause was identified by J. Edwin Seegmiller and his colleagues at NIH. J(arvis Edwin Seegmiller, or Jay Seegmiller, (June 22 1920 - May 31 2006 was an American Physician and biochemical geneticist best known for his role "NIH" redirects here For other meanings of NIH see NIH (disambiguation. ^[16]

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. ^[17][18]

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 (b August 5, 1954) is a New Yorker writer and bestselling Author best-known for his alarming books about Infectious The Cobra Event is a 1998 bio-thriller Novel by Richard Preston describing a terror attempt on the United States by a man known only

Richard Preston, An Error in the Code -- A syndrome poses questions about free will, The New Yorker, August 13, 2007, p. Richard Preston (b August 5, 1954) is a New Yorker writer and bestselling Author best-known for his alarming books about Infectious The New Yorker is an American Magazine that publishes reportage commentary criticism essays fiction satire cartoons and poetry Events 3114 BC - According to the Lounsbury correlation the start of the Maya calendar. Year 2007 ( MMVII) was a Common year starting on Monday of the Gregorian calendar in the 21st century. 30, is a report examining developments in medicine’s understanding of LNS, with stories of some patients' experiences. ^[19]

References

External links

• CLIMB (Children Living with Inherited Metabolic Diseases)
• Lesch-Nyhan Syndrome Registry
• National Organization for Rare Disorders (NORD)
• National Institute of Child Health and Human Development (NICHD)
• Philip Baker's Homepage
• Lesch-Nyhan Syndrome. The Cleveland clinic. Retrieved on 2007-04-12. Year 2007 ( MMVII) was a Common year starting on Monday of the Gregorian calendar in the 21st century. Events 467 - Anthemius is elevated to Emperor of the Western Roman Empire.
• Lesch-Nyhan Syndrome. Joseph F. Smith medical library. Retrieved from the internet archive, April 3, 2005 version on 2007-04-12. Events 1043 - Edward the Confessor is crowned King of England. Year 2005 ( MMV) was a Common year starting on Saturday (link displays full calendar of the Gregorian calendar. Year 2007 ( MMVII) was a Common year starting on Monday of the Gregorian calendar in the 21st century. Events 467 - Anthemius is elevated to Emperor of the Western Roman Empire.

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