Documente Academic
Documente Profesional
Documente Cultură
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.
Lesch-Nyhan syndrome:
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.
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).
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.
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 be
used 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,
or haloperidol 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.
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 continue
the 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 an
anonymous donor who is not likely to be a carrier of the specific disease.
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.
Recent Research Article
Hypoxanthine-guanine phosophoribosyltransferase (HPRT) deficiency:
Lesch-Nyhan syndrome.
Torres RJ, Puig JG.
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 these
symptoms 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 avoid
xanthine 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.
References
emedicine, Inc. http://www.emedicine.com/NEURO/topic630.htm
Harper’s Illustrated Biochemistry,chapter 33 Metabolism of purine & Pyrimidine
Nucleotides.
U.S. National Library of Medicine
http://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
a b c NIH/NINDS Lesch-Nyhan Information Page. NIH/NINDS (February 13, 2007).
a b Lesch-Nyhan syndrome. Genetics Home Reference.
Lesch-Nyhan syndrome. NCBI Genes and disease.
Lesch-Nyhan Syndrome
2. Pathway
3. Disease Characterstics
4. Trait
5. Diagonosis
6. Treatment
7. Prognosis
8. Demographics
9. Prevention
10. .Pictures
12. References