Tetrahydrobiopterin May Obviate Dietary Restriction for Hyperphenylalaninemia

Laurie Barclay, MD

December 26, 2002

Dec. 26, 2002 -- Tetrahydrobiopterin may be a useful alternative to dietary restriction for mild hyperphenylalanemia or mild phenylketonuria (PKU), according to a preliminary report published in the Dec. 26 issue of the New England Journal of Medicine.

"Hyperphenylalanemia is a common inherited metabolic disease that is due to phenylalanine hydroxylase deficiency, and at least half the patients have mild clinical phenotypes," write Ania C. Muntau, MD, and colleagues from Ludwig Maximilians University in Munich, Germany. "Treatment with a low phenylalanine diet represents a substantial psychosocial burden, but alternative treatments have not been effective."

Tetrahydrobiopterin, a natural cofactor of aromatic aminio acid hydroxylases and nitric oxide synthase, is an established treatment in the rare cases of hyperphenylalanemia caused by defects in the biosynthesis of tetrahydrobiopterin. Because at least 98% of hyperphenylalanemic patients have mutations in the phenylalanine hydroxylase gene, accompanied by increased rather than decreased plasma concentrations of biopterin, tetrahydrobiopterin has not previously been considered as a possible treatment in these patients.

Of 38 children with phenylalanine hydroxylase deficiency, age range one day to 17 years, 10 (26%) had mild hyperphenylalanemia, 21 (55%) had mild PKU, and seven (1%) had classic PKU. Tetrahydrobiopterin significantly lowered blood phenylalanine levels in 27 of 31 patients (87%) with mild hyperphenylalanemia or mild PKU, but in none of the seven patients (2%) with classic PKU. Five children (13%) treated long-term with tetrahydrobiopterin were able to discontinue dietary restriction.

Genetic mapping revealed that seven mutations were classified as probably associated with tetrahydrobiopterin responsiveness, six mutations as potentially associated, and four as inconsistently associated with this phenotype. Those mutations linked to responsiveness were predominantly responsible for the catalytic domain of the protein rather than for cofactor binding.

"Tetrahydrobiopterin treatment provides an improvement in phenylalanine tolerance. The advantages of such treatment would include decreased stringency and easier management of diet," Margretta R. Seashore, MD, from Yale University in New Haven, Connecticut, writes in an accompanying perspective. "If treatment with tetrahydrobiopterin proves to have applicability in mild hyperphenylalanemia, this treatment might translate onto an improved quality of life for persons with mild PKU."

N Engl J Med. 2002;347(26):2122-2132,2094-2095

Reviewed by Gary D. Vogin, MD


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