Wallach's Interpretation of Diagnostic Tests: Pathways to Arriving at a Clinical Diagnosis (442 page)

Lesch-Nyhan syndrome is an X-linked recessive disorder with almost complete absence of hypoxanthine–guanine phosphoribosyltransferase (HGPRT), which catalyzes hypoxanthine and guanine to their nucleotides. Mutations in
HPRT1
(Xq26-q27.2) cause an accumulation of purines.

   Who Should Be Suspected?

Affected males manifest with neurologic dysfunction, cognitive and behavioral disturbances (choreoathetosis, mental retardation, and tendency to self-mutilation), and uric acid overproduction. Clinical manifestations are due to secondary gout (tophi after 10 years, crystalluria, hematuria, urinary calculi, UTI, gouty arthritis, response to colchicine). Patients die of renal failure by age 10 years unless treated. Orange crystals or sand is seen in infants’ diapers.

   Relevant Tests and Diagnostic Value

   A urinary urate-to-creatinine ratio >2.0 is characteristic for affected male patients who are younger than 10 years of age but is not considered diagnostic. Neither hyperuricuria nor hyperuricemia (serum uric acid >8 mg/ dL; 600–1,000 mg/24 hour in patients weighing ≥15 kg) is specific for diagnosis.

   Hypoxanthine–guanine phosphoribosyltransferase (HPRT) enzyme activity in male patients <1.5% of normal in blood cells, cultured fibroblasts, amniocytes, or lymphoblasts is diagnostic. The assay is possible on erythrocytes in anticoagulant or on dried blood spots on filter paper. Enzyme assay is not helpful in female patients.

   Sequence analysis of the
HPRT1
gene is available. More than 200 mutations (primarily missense and nonsense mutations and small deletions/insertions) have been identified.

   Other Considerations

   Variants with partial deficiency of HGPRT show 0–50% of normal activity in RBC hemolysates and >1.2% in fibroblasts; accumulate purines but no orange sand in diapers or abnormality of CNS or behavior.

   Probenecid and other uricosuric drugs designed to reduce the serum concentration of uric acid are contraindicated because they augment the delivery of uric acid into the urinary system and raise the risk of acute anuria from deposition of uric acid crystals in the renal collecting system.

Suggested Readings

Jinnah HA, Harris JC, Nyhan WL, et al. The spectrum of mutations causing HPRT deficiency: an update.
Nucleosides Nucleotides Nucleic Acids.
2004;23:1153–1160.

Lesch M, Nyhan WL. A familial disorder of uric acid metabolism and central nervous system function.
Am J Med.
1964;36:561–570.

MENKES SYNDROME (KINKY HAIR)

MIM #309400

   Definition

Menkes syndrome is an X-linked recessive disorder of copper metabolism caused by gene mutations in the gene encoding Cu
²⁺
-transporting ATPase, alpha polypeptide (ATP7A) that result in a block of copper transport from intestinal mucosa cells to blood, causing generalized copper deficiency.

   Who Should Be Suspected?

It is a syndrome of neonatal hypothermia, feeding difficulties, and sometimes prolonged jaundice; at 2–3 months, seizures and progressive hair depigmentation and twisting take place. The syndrome also includes a striking facial appearance, increasing mental deterioration, infections, failure to thrive, death in early infancy, and changes in the elastica interna of arteries.

   Relevant Tests and Diagnostic Value