biochem assignment- Lesh Nyhan Syndrome

8/7/2019 biochem assignment- Lesh Nyhan Syndrome

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Purines are key components of cellular energy systems (eg, ATP, NAD),signaling (eg,

GTP, cAMP, cGMP), and, along with pyrimidines, RNA and DNA production. Purines

may be synthesized de novo or recycled by a salvage pathway from normal catabolism.

The end product of complete catabolism of purines is uric acid.

DISORDER OF PURINE SALVAGE

SALVAGE REACTIONS CONVERT PURINES & THEIR NUCLEOSIDES TO

MONONUCLEOTIDE.

Conversion of purines, their ribonucleosides, and their deoxyribonucleosides tomononucleotides involves socalled salvage reactions that require far less energy thande novo synthesis. The more important mechanism involves phosphoribosylation byPRPP of a free purine (Pu) to form a purine 5-mononucleotide (Pu-RP). Twophosphoribosyl transferases then convert adenine to AMP and hypoxanthine andguanine to IMP or GMP. A second salvage mechanism involves phosphoryl transferfrom ATP to a purine ribonucleoside(PuR): Adenosine kinase catalyzes phosphorylationof adenosineand deoxyadenosine to AMP and dAMP, and deoxycytidine kinasephosphorylates deoxycytidine and 2-deoxyguanosine to dCMP and dGMP. Liver, themajor site of purine nucleotide biosynthesis, provides purines and purine nucleosides forsalvage and utilization by tissues incapable of their biosynthesis. For example, human

brain has a low level of PRPP amidotransferase and hence depends in part onexogenous purines. Erythrocytes and polymorphonuclear leukocytes cannot synthesize5-phosphoribosylamine

Lesch-Nyhan syndrome:

Introduction

Purine Metabolism Disorder


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This is a rare, X-linked, recessive disorder caused by deficiency of hypoxanthine-guanine

phosphoribosyl transferase (HPRT); degree of deficiency (and hence manifestations) vary with

the specific mutation. HPRT deficiency results in failure of the salvage pathway for hypoxanthine

and guanine.These purines are instead degraded to uric acid. Additionally, a decrease in inositol

monophosphate and guanosyl monophosphate leads to an increase in conversion of 5-phosphoribosyl-1-pyrophosphate (PRPP) to 5-phosphoribosylamine, which further exacerbates

uric acid overproduction. Hyperuricemia predisposes to gout and its complications. Patients also

have a number of cognitive and behavioral dysfunctions, etiology of which is unclear; they do not

seem related to uric acid.


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The disease usually manifests between 3 months and 12 months of age with the appearance of

orange sandy precipitate (xanthine) in the urine; it progresses to CNS involvement with

intellectual disability, spastic cerebral palsy, involuntary movements, and self-mutilating

behavior (particularly biting). Later, chronic hyperuricemia causes symptoms of gout (eg,

urolithiasis, nephropathy, gouty arthritis, tophi).

The main features of the disease are:

Excessive production of uric acid.

Neurological problems,especially mental retardation,spastic cerebral palsy and

choreoathetosis .

Behavioral disorders- confusion, anxiety, fear,secrecy and obsession.

Hyperuricemia (overproduction of uric acid) -Uric acid is a chemical created when the

body breaks down substances called purines. Purines are found in some foods and drinks,

such as liver, anchovies, mackerel, dried beans and peas, beer, and wine.

Most uric acid dissolves in blood and travels to the kidneys, where it passes out in urine.

If your body produces too much uric acid or doesn't remove enough if it, you can get

sick.

Urate crystal formation (orange, crystal-like deposits found in the urine, caused by the

overproduction of uric acid).

Mental retardation (typically in the moderate range).

Aggressive and impulsive behaviors (always including self-injurious behaviors) lip

biting, finger biting, and head banging kicking, spitting or vomiting on care providers

Choreoathetosis (involuntary writhing movements of the arms and legs and purposeless

repetitive movements).

Spasticity- is stiff or rigid muscles with exaggerated, deep tendon reflexes (for example, a

knee-jerk reflex). The condition can interfere with walking, movement, or speech.

Dystonia (involuntary spasms and muscle contractions).

Ballismus (violent flinging movements of the limbs).

Muscle weakness (hypotonia).

Speech impairment

Hyperrefelxia (exaggeration of reflexes).

Kidney stones.

Blood in the urine.


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Gouty Arthiritis caused by uric acid in the joints(prevelant in females).

Pain and swelling in the joints.

Difficulty swallowing and eating.

Vomiting.

Impaired kidney function. Irritability.

Abnormal involuntary muscle movements such as flexing, jerking, flinging, and flailing

are often displayed.

Trait

This condition is inherited in an X-linked recessive pattern. A condition is considered X-linked if the mutated gene that causes the disorder is located on the X chromosome (one

of the two sex chromosomes). In males, who have only one X chromosome, one altered

copy of the gene is sufficient to cause the condition. In females, who have two X

chromosomes, a mutation must usually be present in both copies of the gene to cause the

disorder. Males are affected by X-linked recessive disorders much more frequently than

females. A striking characteristic of X-linked inheritance is that fathers cannot pass X-

linked traits to their sons.

Among males with Lesch-Nyhan, the X chromosome that carries the mutation is

inherited from the mother, who is referred to as an unaffected carrier. Other females in

the mother's family may also carry the mutation.

Diagonosis

Diagnosis is suggested by the combination of dystonia, intellectual disability, and self-

mutilation. Serum uric acid levels are usually elevated, but confirmation by HPRT

enzyme assay is usually done.

The diagnosis of Lesch-Nyhan syndrome is based initially on the distinctive pattern of

the child's symptoms, most commonly involuntary muscle movements or failure to crawl

and walk at the usual ages. In some cases the first symptom is related to overproduction

of uric acid; the parents notice "orange sand" in the child's diapers. The "sand" is actually

crystals of uric acid tinged with blood. Measuring the amount of uric acid in a person's


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blood or urine can not definitively diagnose Lesch-Nyhan syndrome. It is diagnosed by

measuring the activity of the HPRT enzyme through a blood test. When the activity of the

enzyme is very low it is diagnostic of Lesch-Nyhan syndrome.

Treatment: CNS dysfunction has no known treatment; management is supportive. Self-mutilation

may require physical restraint, dental extraction, and sometimes drug therapy; a variety of

drugs has been used.

Hyperuricemia is treated with a low-purine diet (eg, avoiding organ meats, beans,

sardines) and allopurinol ,a xanthine oxidase inhibitor (the last enzyme in the purine

catabolic pathway). Allopurinol PREVENTS conversion of accumulated hypoxanthine to

uric acid; because hypoxanthine is highly soluble, it is excreted. Allopurinol may beused to control excessive amounts of uric acid. Kidney stones may be treated with

lithotripsy. There is no standard treatment for the neurological symptoms of LNS. Some

symptoms may be relieved with the drugs carbidopa/levodopa, diazepam, phenobarbital,

orhaloperidol test.There are no known treatments for the neurological defects of Lesch-

Nyhan. Allopurinol (Aloprim, Zyloprim), a drug usually prescribed to lower the risk of

gout attacks,can lower blood uric acid levels. This medication is a preventive; it does not

correct many of the symptoms of Lesch-Nyhan. Other drugs that are given to manage

spasticity include baclofen (Lioresal), which is a muscle relaxant, and benzodiazepine

tranquilizers. Some patients with Lesch-Nyhan syndrome have their teeth removed to

prevent self-injury. Restraints may be recommended to reduce self-destructive behaviors,

although some patients can be managed with a combination of behavioral modification

therapy.

Prognosis

With strong supportive care, infants born with Lesch-Nyhan can live into adulthood with

symptoms continuing throughout life. Few live beyond 40, however, with death usually

resulting either from kidney failure or from aspiration pneumonia. Sudden unexpected

death from respiratory failure is common in these patients.

At present, there are no preventive measures for Lesch-Nyhan syndrome. However,

recent studies have indicated that this genetic disorder may be a good candidate for


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treatment with gene replacement therapy. Unfortunately, the technology necessary to

implement this therapy has not yet been perfected.

Demographics

The prevalence of Lesch-Nyhan syndrome is approximately 1 in 380,000 individuals.

This condition occurs with a similar frequency in all populations.

Prevention

Genetic Counseling for prospective parents with a family history of Lesch-Nyhan

syndrome is recommended. The carrier state of the mother may be determined by culture

of skin fibroblasts. Half the fibroblasts will have normal levels of the HGP enzyme and

the remaining half will have deficient or absent HGP.

Genetic Counseling-Genetic counseling and prenatal diagnosis provides parents with the

knowledge to make intelligent, informed decisions regarding possible pregnancy and its

outcome. Some parents choose to become pregnant and have the disease status of the

fetus determined early in the pregnancy. The pregnancy is continued if the fetus is

disease-free. If a genetic defect is identified in the fetus, parents who decide to continuethe pregnancy may be better prepared to care for the infant by educating themselves

about the disease in advance. For example, if a baby is born with a genetic disease that

leads to diet problems, both the mother and baby may need to be treated with specialized

diets.

However, until science has the knowledge to treat some of the more serious, sometimes

deadly genetic disorders, the best option is prevention. Based on genetic counseling,

some parents (in the face of possibly deadly genetic disease) have chosen to adopt instead

of getting pregnant, while others have opted for egg or sperm donation from ananonymous donor who is not likely to be a carrier of the specific disease.


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Pictures:

The photo below is that of a child with the Lesch-Nyhan syndrome. Note the mutilation of the

lower lip and also on the index finger of his right hand. These mutilations were inflicted by self-

biting. The photo to the right is the hand of another patient with the Lesch-Nyhan syndrome. Note

the bite marks on the dorsum of his hand.

A small portion of the lower lip has been disfigured by persistent self biting.

The distal portions of several fingers are shortened by prior uncontrolled self-biting.


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Recent Research Article

Hypoxanthine-guanine phosophoribosyltransferase (HPRT) deficiency:Lesch-Nyhan syndrome.

Torres RJ, Puig JG.

Division of Clinical Biochemistry, La Paz University Hospital, Madrid, Spain. [email protected]

Abstract

Deficiency of hypoxanthine-guanine phosphoribosyltransferase (HPRT) activity is an inborn error of purine

metabolism associated with uric acid overproduction and a continuum spectrum of neurological

manifestations depending on the degree of the enzymatic deficiency. The prevalence is estimated at

1/380,000 live births in Canada, and 1/235,000 live births in Spain. Uric acid overproduction is present inall

HPRT-deficient patients and is associated with lithiasis and gout. Neurological manifestations include severe

action dystonia, choreoathetosis, ballismus, cognitive and attention deficit, and self-injurious behaviour. The

most severe forms are known as Lesch-Nyhan syndrome (patients are normal at birth and diagnosis can be

accomplished when psychomotor delay becomes apparent). Partial HPRT-deficient patients present thesesymptoms with a different intensity, and in the least severe forms symptoms may be unapparent.

Megaloblastic anaemia is also associated with the disease. Inheritance of HPRT deficiency is X-linked

recessive, thus males are generally affected and heterozygous female are carriers (usually asymptomatic).

Human HPRT is encoded by a single structural gene on the long arm of the X chromosome at Xq26. To

date, more than 300 disease-associated mutations in the HPRT1 gene have been identified. The diagnosis

is based on clinical and biochemical findings (hyperuricemia and hyperuricosuria associated with

psychomotor delay), and enzymatic (HPRT activity determination in haemolysate, intact erythrocytes or

fibroblasts) and molecular tests. Molecular diagnosis allows faster and more accurate carrier and prenatal

diagnosis. Prenatal diagnosis can be performed with amniotic cells obtained by amniocentesis at about 15-

18 weeks' gestation, or chorionic villus cells obtained at about 10-12 weeks' gestation. Uric acid

overproduction can be managed by allopurinol treatment. Doses must be carefully adjusted to avoidxanthine lithiasis. The lack of precise understanding of the neurological dysfunction has precluded

development of useful therapies. Spasticity, when present, and dystonia can be managed with

benzodiazepines and gamma-aminobutyric acid inhibitors such as baclofen. Physical rehabilitation, including

management of dysarthria and dysphagia, special devices to enable hand control, appropriate walking aids,

and a programme of posture management to prevent deformities are recommended. Self-injurious

behaviour must be managed by a combination of physical restraints, behavioural and pharmaceutical

treatments.
http://www.ncbi.nlm.nih.gov/pubmed?term=%22Torres%20RJ%22%5BAuthor%5Dhttp://www.ncbi.nlm.nih.gov/pubmed?term=%22Puig%20JG%22%5BAuthor%5Dhttp://www.ncbi.nlm.nih.gov/pubmed?term=%22Torres%20RJ%22%5BAuthor%5Dhttp://www.ncbi.nlm.nih.gov/pubmed?term=%22Puig%20JG%22%5BAuthor%5D


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References

emedicine, Inc. http://www.emedicine.com/NEURO/topic630.htm

Harpers Illustrated Biochemistry,chapter 33 Metabolism of purine & Pyrimidine

Nucleotides.

U.S. National Library of Medicinehttp://medlineplus.nlm.nih.gov/cgi/jablonski/syndrome_cgi?index=398

Matheny School and Hospital http://www.matheny.org/about/ab_les.html

National Institutes of Health http://www.ninds.nih.gov/patients/Disorder/Lesch-

Nyhan/Lesch-Nyhan.htm

Pediatric Database (PEDBASE) http://www.icondata.com/health/pedbase/files/LESCH-

NY.HTM

abcNIH/NINDS Lesch-Nyhan Information Page.NIH/NINDS (February 13, 2007).

abLesch-Nyhan syndrome. Genetics Home Reference.

Lesch-Nyhan syndrome.NCBI Genes and disease.

Visser J, Smith D, Moy S, Breese G, Friedmann T, Rothstein J, Jinnah H (2002)."Oxidative stress and dopamine deficiency in a genetic mouse model of Lesch-Nyhan

disease".Brain Res Dev Brain Res133 (2): 127-39. PMID 11882343.

Bavaresco C, Chiarani F, Matt C, Wajner M, Netto C, de Souza Wyse A (2005). "Effect

of hypoxanthine on Na+,K+-ATPase activity and some parameters of oxidative stress inrat striatum".Brain Res1041 (2): 198204. PMID 15829228.

Visser J, Smith D, Moy S, Breese G, Friedmann T, Rothstein J, Jinnah H (2002).

"Oxidative stress and dopamine deficiency in a genetic mouse model of Lesch-Nyhan

disease".Brain Res Dev Brain Res133 (2): 127-39. PMID 11882343.* Saugstad O, Marklund S (1988). "High activities of erythrocyte glutathione peroxidase

in patients with the Lesch-Nyhan syndrome".Acta Med Scand224 (3): 281-5. PMID3239456.

Nyhan WL. The recognition of Lesch-Nyhan syndrome as an inborn error of purine

metabolism.J Inher Metab Dis 1997;20:171-8. PMID 9211189.

Lesch M, Nyhan WL. A familial disorder of uric acid metabolism and central nervous

system function.Am J Med1964;36:561-70. PMID 14142409.

Seegmiller JE, Rosenbloom FM, Kelley WN. Enzyme defect associated with a sex-

linked human neurological disorder and excessive purine synthesis. Science1967;155:16824. PMID
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Advance Biochemistry Assignment

Lesch-Nyhan Syndrome

Submitted By: Submitted To:

Hema Negi Dr.Girish Sharma

M.Sc Biotechnology Sem I

Sec-B

Roll No: 214


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Contents

1. Introduction

2. Pathway

3. Disease Characterstics

4. Trait

5. Diagonosis

6. Treatment

7. Prognosis

8. Demographics

9. Prevention

10. .Pictures

11. Recent Research Article

12. References

biochem assignment- Lesh Nyhan Syndrome

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