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Lesch-Nyhan Syndrome
In 1964, Lesch and Nyhan provided the first detailed clini- cal description of Lesch-Nyhan syndrome with a report of two brothers with hyperuricemia and a characteristic neurobehavioral syndrome that included motor dysfunction and self-injurious behavior. The prevalence of the syndrome is estimated to be approximately 1:380,000.
GENETICS/BASIC DEFECTS
1. Inheritance: X-linked recessive
2. Enzymatic defect: caused by deficiency of the enzyme hypoxanthine-guanine phosphoribosyltransferase (HPRT), which catalyzes the conversion of hypoxanthine to inosine monophosphate and guanine to guanine monophosphate in the presence of phosphoribosylpyrophosphate
3. Hypoxanthine-guanine phosphoribosyltransferase gene (HPRT1)
a. Mapped to chromosome Xq26-q27.2
b. The only gene known to be associated with Lesch- Nyhan syndrome
c. Heterogeneous mutations i. Single base substitutions ii. Deletions
iii. Insertion iv. Substitutions 4. Pathogenesis
a. Metabolic basis of overproduction of uric acid: results from changes in the regulation of purine synthesis and degradation
b. Pathogenesis of neurologic and behavioral features remains incompletely understood. Growing evidence suggests that these features result from dysfunction of the dopamine transmitter systems of the basal ganglia
CLINICAL FEATURES
1. Normal prenatal and perinatal course 2. Early developmental milestones
a. Hypotonia and developmental delay: most common presenting features evident by 3–6 months of age b. Failure to reach normal motor milestones, such as
delayed in crawling, sitting, and walking 3. Within the first few years
a. Extrapyramidal involvement i. Dystonia
ii. Choreoathetosis iii. Opisthotonus
iv. Ballismus
b. Pyramidal involvement i. Spasticity
ii. Hyperreflexia
iii. Extensor plantar reflexes iv. Ankle clonus
v. Scissoring of the legs
4. Between 2 to 3 years a. Impaired cognition
i. Moderate to severe mental retardation in most patients
ii. Varying degree of impairment
iii. Difficult to obtain adequate assessments of cog- nitive abilities
b. Compulsive behavioral disturbances i. Aggressiveness
ii. Vomiting iii. Spitting
iv. Coprolalia v. Copropraxis
vi. Manipulative behavior
c. Persistent self-injurious behavior: a hallmark of the disease
i. Biting the fingers, hands, lips, and buccal mucosa
ii. Banging the head or limbs 5. Overproduction of uric acid
a. Uric acid crystalluria noted as orange crystals in the diaper during the first weeks of life
b. Deposition of uric acid crystals or calculi in the kid- neys, ureters, or bladder
c. Leading to nephrolithiasis, obstructive uropathy, and azotemia, if untreated
d. Gouty arthritis develops later in the course of the disease 6. Other features
a. Delayed growth and puberty
b. Testicular atrophy in most affected males c. Associated orthopedic problems
i. Hip subluxation or dislocation ii. Fractures
iii. Autoamputation iv. Infections
v. Minor scoliosis vi. Contractures 7. Life expectancy
a. Most surviving into the second or third decade of life if properly managed
b. No evidence suggesting disease progression over time c. Complications
i. Aspiration pneumonia ii. Chronic nephrolithiasis iii. Renal failure
iv. Sudden unexpected death 8. Lesch-Nyhan syndrome in females
a. Extremely rare b. Female carriers
i. Generally considered to be asymptomatic ii. Have increased uric acid excretion
iii. Develop symptoms of hyperuricemia in later years
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c. Affected females
i. Affected carrier females: considered to have non- random X-chromosome inactivation or skewed inactivation of the normal HPRT1 allele ii. The first female case reported was caused by a
microdeletion of the maternally derived HPRT gene and nonrandom inactivation of the paternally derived X chromosome
iii. Two additional cases were caused by a point mutation in one allele and markedly reduced mRNA expression from the other allele
DIAGNOSTIC INVESTIGATIONS
1. EEG: nonspecific changes of slowing or disorganization 2. CT and MRI of the brain: nonspecific changes of atrophy
of the basal ganglia or cerebrum
3. Positron emission tomography to demonstrate a selective decrease of 50–70% in dopamine transporters in the cau- date and putamen
4. Hyperuricuria or hyperuricemia (serum uric aid concen- tration >8mg/dL): often present but not sensitive or spe- cific enough for diagnosis
5. 24 Hour uric acid excretion (>20 mg/kg): characteristic but not diagnostic
6. Uric acid to creatinine ratio >2.0: characteristic for patients under 10 years of age
7. Hypoxanthine-guanine phosphoribosyltransferase enzyme activity <1.5% of normal enzyme activity in cells from any tissue (blood, cultured fibroblasts, or lymphoblasts):
establishes the diagnosis
8. Molecular genetic testing of the HPRT1 gene a. Purposes
i. To define the mutation in the affected males ii. To determine carrier status in at-risk females b. Sequence analysis to detect HPRT1 mutations in
males affected with Lesch-Nyhan syndrome: avail- able on clinical basis
c. Direct DNA analysis using RT-PCR, multiplex genom- ic PCR, and sequence analysis performed on research basis
GENETIC COUNSELING
1. Recurrence risk a. Patient’s sib
i. When the mother is not a carrier: not increased unless the mother has germline mosaicism in which case there is an undetermined, but real, risk of having future affected sons or carrier daughters
ii. When the mother is a carrier
a) A 25% risk of having an affected male b) A 25% risk of having a carrier female c) A 50% risk of having an unaffected male or
female b. Patient’s offspring
i. Severely affected males: not surviving to repro- ductive age
ii. Less severely affected males: all of his daughters are obligatory carriers and none of his sons affected
2. Prenatal diagnosis available to at-risk pregnancies a. Fetal sex determination by amniocentesis or CVS b. Confirmation of a previously known HPRT1 disease-
causing mutation in a male fetus i. Perform HPRT enzyme activity ii. Perform molecular genetic testing
c. Assay of HPRT enzyme activity in cultured amnio- cytes or chorionic villus cells: the method of choice if the HPRT1 mutation has not been identified in the family
d. Preimplantation genetic diagnosis possible for a pre- viously characterized disease-causing mutation 3. Management
a. Hyperuricemia
i. Control hyperuricemia to reduce the risk of nephropathy, nephrolithiasis, and gouty arthritis ii. Allopurinol
a) To block the conversion of oxypurines into uric acid
b) To prevent uric acid accumulation and sub- sequent arthritic tophi, renal stones, and nephropathy
b. Neurologic dysfunction
i. No medication known to be consistently effective in controlling the extrapyramidal motor features ii. Baclofen or benzodiazepine for spasticity c. Neurobehavioral symptoms
i. No effective intervention available ii. Use behavioral modification techniques iii. Control self-injurious behavior
a) Require physical restraints b) Removal of teeth
c) A noninvasive approach with a special appli- ance fabricated for the prevention of damage to oral and perioral soft tissues
d) Carbamezapine to attenuate the behavioral manifestations
d. Surgery for orthopedic problems
e. Bone marrow transplantation or red blood cell trans- fusions not significantly ameliorate the neurologic disorder
REFERENCES
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Baumeister AA, Frye GD: The biochemical basis of the behavioral disorder in the Lesch-Nyhan syndrome. Neurosci Biobehav Rev 9:169–178, 1985.
Crawhall JC, Henderson JF, Kelley WN: Diagnosis and treatment of the Lesch- Nyhan syndrome. Pediatr Res 6:504–513, 1972.
Fardi K, Topouzelis N, Kotsanos N: Lesch-Nyhan syndrome: a preventive approach to self-mutilation. Int J Paediatr Dent 13:51–56, 2003.
Graham GW, Aitken DA, Connor JM: Prenatal diagnosis by enzyme analysis in 15 pregnancies at risk for the Lesch-Nyhan syndrome. Prenat Diagn 16:647–651, 1996.
Jinnah HA: Lesch-Nyhan syndrome. 2002. http://www.emedicine.com Jinnah HA, Friedman T: Lesch-Nyhan disease and its variants. In Scriver CR,
Beaudet al., Sly WS, Valle D (eds): The Metabolic & Molecular Bases of Inherited Disease. 8th ed. New York: McGraw-Hill, 2001.
Jinnah HA, De Gregorio L, Harris JC, et al.: The spectrum of inherited muta- tions causing HPRT deficiency: 75 new cases and a review of 196 previ- ously reported cases. Mutat Res 463:309–326, 2000.
Lesch M and Nyhan WL: A familial disorder of uric acid metabolism and cen- tral nervous system function. Am J Med Genet 36:561–570, 1964.
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380, 1978.
Nyhan WL: The recognition of Lesch-Nyhan syndrome as an inborn error of purine metabolism. J Inherit Metab Dis 20:171–178, 1997.
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Sponseller PD, Ahn NU, Choi JC, et al.: Orthopedic problems in Lesch-Nyhan syndrome. J Pediatr Orthop 19:596–602, 1999.
Watts RW, Spellacy E, Gibbs DA, et al.: Clinical, post-mortem, biochemical and therapeutic observations on the Lesch-Nyhan syndrome with particular reference to the Neurological manifestations. Q J Med 51:
43–78, 1982.
Fig. 1. Two boys with Lesch-Nyhan syndrome showing severe mental retardation and self-mutilation of the lips and tongue.
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