Alkaptonuria is an autosomal recessive disease involving a deficiency of the enzyme homogentisate dioxygenase, which is involved in the tyrosine degradation pathway. The enzymatic deficiency results in high concentrations of homogentisic acid (HGA), which results in orthopedic and cardiac complications, among other symptoms. Nitisinone (NTBC) has been shown to effectively treat alkaptonuria by blocking the conversion of 4-hydroxyphenylpyruvate to HGA, but there have been concerns that using doses higher than about 2 mg/day could cause excessively high levels of tyrosine, resulting in crystal deposition and corneal pathology. We have enrolled seven patients in a study to determine whether higher doses of NTBC were effective at further reducing HGA levels while maintaining tyrosine at acceptable levels. Patients were given varying doses of NTBC (ranging from 2 to 8 mg/day) over the course of between 0.5 and 3.5 years. Urine HGA, plasma tyrosine levels, and plasma NTBC were then measured longitudinally at various doses. We found that tyrosine concentrations plateaued and did not reach significantly higher levels as NTBC doses were increased above 2 mg/day, while a significant drop in HGA continued from 2 to 4 mg/day, with no significant changes at higher doses. We also demonstrated using untargeted metabolomics that elevations in tyrosine from treatment resulted in proportional elevations in alternative tyrosine metabolic products, that of N-acetyltyrosine and γ-glutamyltyrosine.

Little is known about the influence of the right hemisphere (RH) on social and emotional development in children. In order to examine the effect of RH damage on behavioral function, the Personality Inventory for Children was administered to parents of 17 children who had suffered perinatal strokes and 23 control children. Children with focal brain lesions, regardless of hemisphere, had higher T scores (indicating greater abnormality) than controls on scales measuring social competence, emotional behavior, cognitive and academic development. Children with lesions involving the frontal lobe obtained higher T scores than did those with nonfrontal lesions or controls on scales related to cognitive function. The nonfrontal group had higher T scores than those with frontal lesions on measures of social competence and behavior. The data suggest that any focal brain lesion of early onset may predispose one to social and cognitive deficits. The site of the lesion within the hemisphere may be of importance in determining what difficulties the child may experience (i.e., frontal lobe lesions are more likely to result in cognitive deficits, whereas posterior lesions are more likely to be associated with social problems). These findings further suggest that brain localization for cognitive and social skills may be determined very early in development.

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