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Rare genetic syndrome

Medical condition

Lesch–Nyhan syndrome
Other names	Juvenile gout,[1] Primary hyperuricemia syndrome, Choreoathetosis self-mutilation syndrome, X-linked primary hyperuricemia, HGPRT deficiency
Extreme blast biting is sometimes caused by Lesch-Nyhan Syndrome.
Specialty	Endocrinology
Symptoms	self harm, dystonia, chorea, spasticity, intellectual inability, hyperuricemia,
Complications	kidney failure, megaloblastic anemia
Differential diagnosis	cerebral palsy, dystonia, Cornelia de Lange syndrome, autism, famillial dysautonomia, Tourette syndrome
Frequency	1 in 380,000[2]

Lesch–Nyhan syndrome (LNS) is a rare inherited disorder acquired by a deficiency of the enzyme hypoxanthine-guanine phosphoribosyltransferase (HGPRT). This deficiency occurs due to mutations in the HPRT1 cistron located on the X chromosome. LNS affects about 1 in 380,000 live births.^[3] The disorder was first recognized and clinically characterized past American medical educatee Michael Lesch and his mentor, pediatrician William Nyhan, at Johns Hopkins.^[iv]

The HGPRT deficiency causes a build-upwardly of uric acid in all body fluids. The combination of increased synthesis and decreased utilization of purines leads to loftier levels of uric acid production. This results in both loftier levels of uric acid in the blood and urine, associated with severe gout and kidney problems. Neurological signs include poor musculus control and moderate intellectual inability. These complications usually announced in the first year of life. Commencement in the second twelvemonth of life, a specially striking feature of LNS is self-mutilating behaviors, characterized past lip and finger biting. Neurological symptoms include facial grimacing, involuntary writhing, and repetitive movements of the arms and legs like to those seen in Huntington's disease. The cause of the neurological abnormalities remains unknown. Because a lack of HGPRT causes the body to poorly utilize vitamin B₁₂, some males may develop megaloblastic anemia.^[5]

LNS is inherited in an X-linked recessive manner; the factor mutation is usually carried by the mother and passed on to her son, although 1-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, just not all, persons with this deficiency take severe mental and physical problems throughout life. Cases in females are very rare.^[6]

The symptoms acquired by the buildup of uric acid (gout and kidney symptoms) respond well to treatment with medications such every bit allopurinol that reduce the levels of uric acrid in the blood. The mental deficits and cocky-mutilating behavior do not respond well to treatment. In that location is no cure, but many affected people live to machismo. Several new experimental treatments may convalesce symptoms.

Signs and symptoms [edit]

LNS is characterized past three major hallmarks: neurologic dysfunction, cerebral and behavioral disturbances including cocky-mutilation, and uric acid overproduction (hyperuricemia). Damage to the basal ganglia causes afflicted individuals to adopt a feature fencing stance due to the nature of the lesion. Some may too accept macrocytic anemia^[seven] due to the faulty DNA synthesis, most likely due to deficient purine synthesis that lead to a lag of cell division with respect to increases in prison cell mass.^{[viii] [9]} Nigh all patients are male; males experience delayed growth and puberty, and nearly develop shrunken testicles or testicular atrophy. Female carriers are at an increased gamble for gouty arthritis but are usually otherwise unaffected.^[two]

Overproduction of uric acid [edit]

Ane of the starting time symptoms of the affliction is the presence of sand-like crystals of uric acrid 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 float. 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 oftentimes normal, as the excess purines are promptly eliminated in the urine. The crystals unremarkably appear equally an orange grainy material, or they may coalesce to form either multiple tiny stones or distinct large stones that are difficult to laissez passer. The stones, or calculi, usually cause hematuria (blood in the urine) and increase the risk of urinary tract infection. Some affected people have kidney damage due to such kidney stones. Stones may exist the presenting feature of the affliction, just can get undetected for months or fifty-fifty years.^{[ commendation needed ]}

Nervous system impairment [edit]

The periods earlier and surrounding nativity are typically normal in individuals with LNS. The almost common presenting features are abnormally decreased musculus tone (hypotonia) and developmental delay, which are evident by three to 6 months of age. Affected individuals are late in sitting upwardly, while most never clamber or walk. Lack of speech is besides a very common trait associated with LNS.^{[ citation needed ]}

Irritability is nigh often noticed along with the first signs of nervous system damage. Inside the start few years of life, extrapyramidal involvement causes abnormal involuntary muscle contractions such as loss of motor control (dystonia), writhing motions (choreoathetosis), and arching of the spine (opisthotonus). Signs of pyramidal system involvement, including spasticity, overactive reflexes (hyperreflexia) and extensor plantar reflexes, also occur. The resemblance to athetoid cerebral palsy is apparent in the neurologic aspects of LNS. As a result, virtually individuals are initially diagnosed as having cerebral palsy. The motor disability is and so extensive that most individuals never walk, and become lifelong wheelchair users.^{[ citation needed ]}

Cocky-injuring behavior [edit]

Persons affected are cognitively dumb 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 bitter of the lips and tongue; as the disease progresses, afflicted individuals frequently develop finger biting and headbanging.^[10] The self-injury tin can increase during times of stress. Self-impairment is a distinguishing characteristic of the illness and is apparent in 85% of affected males.^[11]

The majority of individuals are cognitively dumb, which is sometimes hard 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.^[xi]

Compulsive behaviors as well occur, including aggressiveness, vomiting, spitting, and coprolalia (involuntary swearing). The evolution of this type of behavior is sometimes seen within the first twelvemonth, or in early on childhood, just others may not develop it until later in life.^{[ citation needed ]}

LNS in females [edit]

While carrier females are generally an asymptomatic condition, they practise experience an increase in uric acrid excretion, and some may develop symptoms of hyperuricemia, and experience gout in their after years. Testing in this context has no clinical consequence, simply 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 examination means the son'due south disease is the upshot of a new mutation, and the risk in siblings is not increased.^{[ commendation needed ]}

Females who carry i copy of the defective gene are carriers with a 50% take chances of passing the illness on to their sons. In order for a female person to be affected, she would need to have ii copies of the mutated gene, i of which would be inherited from her father. Males affected with LNS exercise not usually take children due to the debilitating effects of the disease. Information technology is possible for a female to inherit an X chromosome from her unaffected begetter, who carries a new mutation of the HGPRT gene. Nether 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.^{[ citation needed ]}

Less severe forms [edit]

A less severe, related affliction, partial HPRT deficiency, is known as Kelley–Seegmiller syndrome (Lesch–Nyhan syndrome involves total HPRT deficiency). Symptoms by and large involve less neurological involvement but the disease still causes gout and kidney stones.^[12]

Genetics [edit]

LNS is due to mutations in the HPRT1 gene,^{[three] [13]} and so named because it codes for the enzyme hypoxanthine-guanine phosphoribosyltransferase (HPRT or HGPRT, EC 2.four.two.8). This enzyme is involved in the biochemical pathways the trunk uses to produce purines, one of the components of Dna and RNA. Defects of this enzyme lead to increased production of uric acid. Since the HPRT factor is located on the X chromosome, LNS is an X-linked inherited affliction.^{[ citation needed ]}

The father of an afflicted male will not exist the carrier of the mutant allele, and will not have the disease. An obligate carrier would exist a woman who has an affected son and ane other affected relative in the maternal line.^{[ citation needed ]}

If a woman is the first in her family with an affected son, Haldane'south rule predicts a ii/3 chance that she is a carrier and a ane/3 chance that the son has a new germline mutation.^{[ citation needed ]}

The risk to siblings of an affected individual depends upon the carrier status of the mother herself. A l% take a chance is given to any female who is a carrier to transmit the HPRT1 mutation in each pregnancy. Sons who inherit the mutation volition exist affected while daughters who inherit the mutation are carriers. Therefore, with each pregnancy, a carrier female has a 25% hazard of having a male that is affected, a 25% take a chance of having a female that is a carrier, and a l% chance of having a normal male or female.^{[ citation needed ]}

Males with LNS practice not reproduce due to the characteristics of the disease. Notwithstanding, if a male person with a less severe phenotype reproduces, all of his daughters are carriers, and none of his sons volition exist affected.^{[ citation needed ]}

Pathophysiology [edit]

As in other X-linked diseases, males are affected because they merely have 1 copy of the Ten chromosome. In Lesch–Nyhan syndrome, the defective gene is that for hypoxanthine-guanine phosphoribosyltransferase (HGPRT), a participant in the 'recycling' of purine nucleotides. Female carriers have a 2d X chromosome, which contains a "normal" re-create of HPRT, preventing the affliction from developing, though they may take increased adventure of hyperuricemia.^{[ citation needed ]}

A large number of mutations of HPRT are known. Mutations that but mildly decrease the enzyme'southward function do not usually cause the astringent form of LNS, simply do produce a milder course of the disease which nevertheless features purine overproduction accompanied by susceptibility to gout and uric acid nephrolithiasis.^{[ commendation needed ]}

Formation of Deoxyribonucleic acid (during cell division) requires nucleotides, molecules that are the edifice blocks for Deoxyribonucleic acid. The purine bases (adenine and guanine) and pyrimidine bases (thymine and cytosine) are bound to deoxyribose and phosphate and incorporated as necessary. Normally, the nucleotides are synthetized de novo from amino acids and other precursors. A pocket-sized part, however, is 'recycled' from degraded DNA of cleaved-down cells. This is termed the "relieve pathway".^{[ commendation needed ]}

HGPRT is the "salve enzyme" for the purines: it channels hypoxanthine and guanine back into Dna synthesis. Failure of this enzyme has two results:^{[ citation needed ]}

• Cell breakdown products cannot be reused, and are therefore degraded. This gives rise to increased uric acid, a purine breakdown product.
• The de novo pathway is stimulated due to an backlog of PRPP (five-phospho-D-ribosyl-one-pyrophosphate or simply phosphoribosyl-pyrophosphate).

It was previously unclear whether the neurological abnormalities in LNS were due to uric acrid neurotoxicity or to a relative shortage in "new" purine nucleotides during essential synthesis steps. Genetic mutations affecting the enzymes of the de novo synthesis pathway may perhaps contribute to the disease, although these are rare or unknown. Uric acid has been suggested as a possible cause of neurotoxicity just this is unproven.^{[ citation needed ]}

Importantly, evidence suggests that one or more lesions in striatal dopaminergic pathways may exist key to the neurological deficits, particularly the choreoathetoid dyskinesia and self-mutilation.^{[14] [15] [16]} 6-hydroxydopamine toxicity in rodents may be a useful animal model for the syndrome, although this is non proven.^[17] However, the link between dopamine and purine synthesis is a nucleotide chosen guanosine triphosphate or 'GTP'. The kickoff step of dopamine synthesis is GTP cyclohydrolase, and significantly a deficiency of this pace 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.^[xviii]

Another animal model for LNS has been proposed to arise from oxidative damage, caused past the hyperuricemia accompanying LNS. This is based on the theory that uric acid is a powerful reducing amanuensis and likely an of import human antioxidant, in loftier concentration in claret. Thus, information technology has been suggested that free radicals, oxidative stress, and reactive oxygen species may play some function in the neuropathology of LNS.^{[16] [xix] [20] [ not-primary source needed ]}

Still, some prove suggests against a role for uric acid in the neuropathology of Lesch–Nyhan syndrome:

• Hyperuricemia associated with classic primary gout, which is caused by low uric acrid renal clearance rather than uric acid overproduction, is not associated with neuropathology.
• Hypouricemia occurs in a number of purine disorders, in particular xanthinuria. 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.^[21]

Similarly, uric acid does not penetrate the blood–brain barrier well. Nevertheless, oxidative stress due to uric acid is now idea 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'south neuropathy) apparently acts as a neurotoxin past generation of reactive oxygen species. Information technology may be that oxidative stress induced by some other oxypurine such as xanthine causes the illness.^{[ commendation needed ]}

Diagnosis [edit]

When an afflicted private has fully developed the three clinical elements of uric acid overproduction, neurologic dysfunction, and cognitive and behavioral disturbances, diagnosis of LNS is easily made. Diagnosis is less piece of cake in the early stages, when the 3 features are not withal obvious. Signs of self-injurious behavior (SIB), results of pedigree analysis and novel molecular biology with genetic testing (called every bit Diagnostic triad for LNS), often confirms the diagnosis.^[22] Suspicion oft comes about when the developmental delay of the private is associated with hyperuricemia. Otherwise, the diagnosis should be alleged when developmental filibuster is associated with kidney stones (nephrolithiasis) or blood in the urine (hematuria), acquired by uric acid stones. For the almost part, Lesch–Nyhan syndrome is beginning suspected when cocky-inflicted injury behavior develops. However, self-injurious behaviors occur in other conditions, including nonspecific intellectual disability, autism, Rett syndrome, Cornelia de Lange syndrome, Tourette syndrome, familial dysautonomia, choreoacanthocytosis, sensory neuropathy including hereditary sensory neuropathy type 1, and several psychiatric conditions. Of these, only individuals with Lesch–Nyhan syndrome, de Lange syndrome, and familial dysautonomia recurrently display loss of tissue every bit a result. Biting the fingers and lips is a definitive feature of Lesch–Nyhan syndrome; in other syndromes associated with self-injury, the behaviors ordinarily consist of head banging and nonspecific self-mutilation, just not biting of the cheeks, lips and fingers. Lesch–Nyhan syndrome ought to be conspicuously considered only when self-injurious behavior takes identify in conjunction with hyperuricemia and neurological dysfunction.^[23]

Diagnostic approach [edit]

The urate to creatinine (breakdown production 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 ii is typically plant. Twenty-four-hour urate excretion of more 20 mg/kg is also typical only 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 whatsoever type of tissue (eastward.g., blood, cultured fibroblasts, or lymphoblasts) 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.^{[ citation needed ]}

Testing [edit]

The employ of biochemical testing for the detection of carriers is technically demanding and not often used. Biochemical analyses that have been performed on hair bulbs from at risk women have had a small number of both fake positive and false negative outcomes. If only a suspected carrier female is available for mutation testing, it may exist appropriate to abound her lymphocytes in half-dozen-thioguanine (a purine analogue), which allows only HGPRT-deficient cells to survive. A mutant frequency of 0.5–v.0 × ten^−two is plant in carrier females, while a non-carrier female person has a frequency of 1–xx × 10⁻⁶. This frequency is unremarkably diagnostic past itself.^{[ citation needed ]}

Molecular genetic testing is the nearly 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 bachelor clinically and can exist utilized in order to detect HPRT1 mutations in males affected with Lesch–Nyhan syndrome. Techniques such equally RT-PCR, multiplex genomic PCR, and sequence analysis (cDNA and genomic Deoxyribonucleic acid), used for the diagnosis of genetic diseases, are performed on a research basis. If RT-PCR tests consequence in cDNA showing the absence of an unabridged exon or exons, then multiplex genomic PCR testing is performed. Multiplex genomic PCR testing amplifies the nine exons of the HPRT1 gene equally 8 PCR products. If the exon in question is deleted, the respective band will be missing from the multiplex PCR. However, if the exon is present, the exon is sequenced to place 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 near or all of the gene is obliterated.^{[ citation needed ]}

Treatment [edit]

Handling for LNS is symptomatic. Gout can be treated with allopurinol to control excessive amounts of uric acid. Kidney stones may exist treated with lithotripsy, a technique for breaking up kidney stones using shock waves or laser beams. At that place is no standard treatment for the neurological symptoms of LNS. Some may exist relieved with the drugs carbidopa/levodopa, diazepam, phenobarbital, or haloperidol.^[5]

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 stones, and nephropathy, the resulting kidney disease. Allopurinol is taken orally, at a typical dose of iii–twenty mg/kg per day. The dose is then adjusted to bring the uric acid level downwards into the normal range (<three mg/dL). Most affected individuals tin exist treated with allopurinol all through life.^{[ citation needed ]}

No medication is effective in controlling the extrapyramidal motor features of the disease. Spasticity, nonetheless, can be reduced past the administration of baclofen or benzodiazepines.^{[ citation needed ]}

There has previously been no effective method of treatment for the neurobehavioral aspects of the disease. Even children treated from nascency with allopurinol develop behavioral and neurologic bug, 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 cocky-mutilation is ofttimes reduced past using restraints. Lx percent of individuals have their teeth extracted^{[ citation needed ]} in order to avoid self-injury, which families accept found to be an effective management technique.^{[ citation needed ]} Because stress increases self-injury, behavioral management through aversive techniques (which would normally reduce self-injury) actually increases cocky-injury in individuals with LNS. Nearly all afflicted individuals need restraints to forestall self-injury, and are restrained more 75% of the time. This is often at their own asking, and occasionally involves restraints that would appear to exist ineffective, as they do not physically foreclose biting. Families written report that affected individuals are more than at ease when restrained.^{[ commendation needed ]}

The Matheny Medical and Educational Centre [2] in Peapack, NJ, has^{[ when? ]} six Lesch–Nyhan syndrome patients, believed to be the largest concentration of LNS cases in 1 location, and is recognized as the leading source of data on care issues.

Treatment for LNS patients, according to Gary E. Eddey, MD, medical director^{[ clarification needed ]}, should include: i) Judicious utilise of protective devices; two) Utilization of a behavioral technique usually referred to as 'selective ignoring' with redirection of activities; and 3) Occasional use of medications.^{[ commendation needed ]}

An article in the August xiii, 2007 issue of The New Yorker magazine, written by Richard Preston, discusses "deep-encephalon 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 French republic 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, co-ordinate to Preston, over 20 years agone. The treatment involves invasive surgery to place wires that carry a continuous electrical electric current into a specific region of the brain.^[24]

An encouraging advance in the treatment of the neurobehavioural aspects of LNS was the publication in the October, 2006 result of Journal of Inherited Metabolic Affliction of an experimental therapy giving oral S-adenosyl-methionine (Same).^[25] This drug is a nucleotide precursor that provides a readily captivated purine, which is known to exist transported across the blood–brain bulwark. Administration of Aforementioned 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, simply its employ for treating LNS should exist undertaken simply nether strict medical supervision, as side furnishings are known.^{[ citation needed ]}

Prognosis [edit]

The prognosis for individuals with astringent LNS is poor. Death is ordinarily due to kidney failure or complications from hypotonia, in the first or second decade of life. Less severe forms have better prognoses.^[5]

History [edit]

Michael Lesch was a medical student at Johns Hopkins and William Nyhan, a pediatrician and biochemical geneticist, was his mentor when the two identified LNS and its associated hyperuricemia in ii affected brothers, ages 4 and viii.^[26] Lesch and Nyhan published their findings in 1964.^[27] Within three years, the metabolic cause was identified by J. Edwin Seegmiller and his colleagues at the NIH.^[28]

References [edit]

1. ^ James, William D.; Berger, Timothy G.; et al. (2006). Andrews' Diseases of the Pare: clinical Dermatology. Saunders Elsevier. p. 546. ISBN978-0-7216-2921-6.
2. ^ ^{a b} "Lesch Nyhan Syndrome". Retrieved 24 February 2022.
3. ^ ^{a b} Lesch–Nyhan syndrome. Genetics Abode Reference. Retrieved on 2007-05-24.
4. ^ Ole Daniel Enersen. Lesch-Nyhan syndrome at Who Named It?
5. ^ ^{a b c} lesch_nyhan at NINDS
6. ^ Hladnik U, Nyhan WL, Bertelli 1000 (September 2008). "Variable expression of HPRT deficiency in 5 members of a family with the same mutation". Curvation. Neurol. 65 (9): 1240–3. doi:ten.1001/archneur.65.nine.1240. PMID 18779430.
7. ^ Cakmakli, H. F.; Torres, R. J.; Menendez, A.; Yalcin-Cakmakli, K.; Porter, C. C.; Puig, J. Thou.; Jinnah, H. A. (2019). "Macrocytic anemia in Lesch-Nyhan disease and its variants". Genetics in Medicine. 21 (2): 353–360. doi:10.1038/s41436-018-0053-1. PMC6281870. PMID 29875418.
8. ^ Cakmakli, H. F.; Torres, R. J.; Menendez, A.; Yalcin-Cakmakli, G.; Porter, C. C.; Puig, J. G.; Jinnah, H. A. (2018). "Macrocytic Anemia in Lesch-Nyhan Disease and its Variants". Genetics in Medicine. 21 (2): 353–360. doi:10.1038/s41436-018-0053-1. PMC6281870. PMID 29875418.
9. ^ Nagao, T.; Hirokawa, K. (2017). "Diagnosis and handling of macrocytic anemias in adults". Periodical of General and Family unit Medicine. 18 (5): 200–204. doi:10.1002/jgf2.31. PMC5689413. PMID 29264027.
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11. ^ ^{a b} Gualtieri, C. Thomas (2002). Brain Injury and Mental Retardation: Psychopharmacology and Neuropsychiatry, p. 257. Lippincott Williams & Wilkins. ISBN 0-7817-3473-8. [1]
12. ^ Augoustides-Savvopoulou P, Papachristou F, Fairbanks LD, Dimitrakopoulos Grand, Marinaki AM, Simmonds HA (2002). "Partial hypoxanthine-Guanine phosphoribosyltransferase deficiency every bit the unsuspected cause of renal disease spanning three generations: a cautionary tale". Pediatrics. 109 (one): E17. doi:10.1542/peds.109.1.e17. PMID 11773585.
13. ^ Lesch–Nyhan syndrome. NCBI Genes and disease. Retrieved on 2007-04-12
14. ^ Proctor, P (26 December 1970). "Levodopa Side-effects and the Lesch-Nyhan Syndrome". Lancet. 296 (7687): 1367. doi:10.1016/S0140-6736(seventy)92399-viii. PMID 4098945.
15. ^ Nyhan WL (2000). "Dopamine office in Lesch–Nyhan disease". Environ. Health Perspect. 108 (Suppl 3): 409–11. doi:10.2307/3454529. JSTOR 3454529. PMC1637829. PMID 10852837.
16. ^ ^{a b} Visser J, Smith D, Moy Due south, Breese G, Friedmann T, Rothstein J, Jinnah H (2002). "Oxidative stress and dopamine deficiency in a genetic mouse model of Lesch–Nyhan disease". Brain Res Dev Brain Res. 133 (ii): 127–39. doi:ten.1016/S0165-3806(02)00280-eight. PMID 11882343.
17. ^ Breese GR, Knapp DJ, Criswell HE, Moy SS, Papadeas ST, Blake BL (2005). "The neonate-half-dozen-hydroxydopamine-lesioned rat: a model for clinical neuroscience and neurobiological principles". Brain Res. Brain Res. Rev. 48 (1): 57–73. doi:10.1016/j.brainresrev.2004.08.004. PMID 15708628. S2CID 22599841.
18. ^ Deutsch SI; Long KD; Rosse RB; Mastropaolo J; Eller J. (Jan–Feb 2005). "Hypothesized deficiency of guanine-based purines may contribute to abnormalities of neurodevelopment, neuromodulation, and neurotransmission in Lesch–Nyhan syndrome". Clin. Neuropharmacol. 28 (1): 28–37. doi:10.1097/01.wnf.0000152043.36198.25. PMID 15711436. S2CID 36457793.
19. ^ Saugstad O, Marklund Southward (1988). "Loftier activities of erythrocyte glutathione peroxidase in patients with the Lesch–Nyhan syndrome". Acta Med Scand. 224 (3): 281–5. doi:10.1111/j.0954-6820.1988.tb19374.x. PMID 3239456.
20. ^ Bavaresco C, Chiarani F, Matté C, Wajner K, Netto C, de Souza Wyse A (2005). "Effect of hypoxanthine on Na+,K+-ATPase activity and some parameters of oxidative stress in rat striatum". Encephalon Res. 1041 (two): 198–204. doi:x.1016/j.brainres.2005.02.012. PMID 15829228. S2CID 22575382.
21. ^ Kudo Chiliad; Moteki T; Sasaki T; Konno Y; Ujiie South; Onose A; Mizugaki M; Ishikawa M; Hiratsuka M. (March 2008). "Functional characterization of human xanthine oxidase allelic variants". Pharmacogenet Genomics. xviii (3): 243–51. doi:10.1097/FPC.0b013e3282f55e2e. PMID 18300946. S2CID 8140455.
22. ^ https://www.jstage.jst.go.jp/article/irdr/vi/one/6_2016.01076/_pdf^{[ bare URL PDF ]}
23. ^ Tewari N, Mathur VP, Sardana D, Bansal K (February 2017). "Lesch-Nyhan syndrome: The saga of metabolic abnormalities and self-injurious behavior". Intractable Rare Dis Res. 6 (1): 65–68. doi:x.5582/irdr.2016.01076. PMC5359358. PMID 28357186.
24. ^ Preston, Richard (August 2007). "An Error in the Code". The New Yorker. p. 30. Retrieved 2008-09-14 .
25. ^ Glick N (October 2006). "Dramatic reduction in cocky-injury in Lesch–Nyhan disease following S-adenosylmethionine administration". J. Inherit. Metab. Dis. 29 (5): 687. doi:10.1007/s10545-006-0229-8. PMID 16906475. S2CID 33099025.
26. ^ Nyhan WL (1997). "The recognition of Lesch–Nyhan syndrome as an inborn error of purine metabolism" (PDF). J. Inherit. Metab. Dis. xx (2): 171–viii. doi:10.1023/A:1005348504512. PMID 9211189. S2CID 37373603. ^{[ permanent dead link ]}
27. ^ Lesch M, Nyhan WL (1964). "A familial disorder of uric acid metabolism and cardinal nervous organization function". Am. J. Med. 36 (4): 561–lxx. doi:10.1016/0002-9343(64)90104-4. PMID 14142409.
28. ^ Seegmiller JE, Rosenbloom FM, Kelley WN (1967). "Enzyme defect associated with a sex-linked human neurological disorder and excessive purine synthesis". Scientific discipline. 155 (770): 1682–4. Bibcode:1967Sci...155.1682S. doi:10.1126/scientific discipline.155.3770.1682. PMID 6020292. S2CID 45609754.

External links [edit]

• Lesch-Nyhan Syndrome at NIH's Office of Rare Diseases
• GeneReview/NIH/UW entry on Lesch–Nyhan syndrome
• National Found of Child Health and Human Development (NICHD)

Source: https://en.wikipedia.org/wiki/Lesch%E2%80%93Nyhan_syndrome

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