Perceptions and use of phenylbutyrate metabolite testing in urea cycle disorders: Results of a clinician survey and analysis of a centralized testing database.

The nitrogen scavengers sodium and glycerol phenylbutyrate (PB), approved for chronic treatment of urea cycle disorders (UCDs), undergo hepatic conversion to phenylacetate (PAA), which conjugates glutamine to form phenylacetylglutamine for urinary nitrogen excretion. Elevated PAA has been associated with reversible neurological toxicity, with symptoms similar to hyperammonemia. Plasma PB metabolite analysis can assess for toxicity and therapeutic drug levels. An online survey was undertaken to assess US clinician perceptions and use of the test in addition to an analysis of centralized US laboratory records. Survey responses from 52 clinicians were analyzed, including 58% who reported using plasma PB metabolite testing. Test users reported managing more UCD patients than nonusers. Users rated the test as "often helpful" for ruling out PAA toxicity (44%), informing PB dosing decisions (42%), and assessing adherence (28%). Test results were reported as most often unremarkable (61%) or suggestive of poor adherence (13%); 46% of users had never encountered results indicative of PAA toxicity. Analyses of laboratory records for 1668 plasma metabolite tests determined that only 5% of samples had plasma PAA-to-phenylacetylglutamine ratios associated with increased risk of PAA toxicity. Nearly half of surveyed clinicians were unsure of metabolite targets; those conducting ad hoc (versus regular) testing were significantly more likely to be unsure of targets. One-fifth of test users identified uncertainties, including questions about test validation, timing, and interpretation. Increased awareness of published PB metabolite data and further clinician education on test interpretation may help to inform the use of metabolite testing to optimize UCD care.

PHENOTYPIC VARIABILITY IN INDIVIDUALS WITH TYPE V OSTEOGENESIS IMPERFECTA WITH IDENTICAL IFITM5 MUTATIONS.

BACKGROUND: Osteogenesis imperfecta (OI) type V is a dominantly inherited skeletal dysplasia characterized by fractures and progressive deformity of long bones. In addition, patients often present with radial head dislocation, hyperplastic callus, and calcification of the forearm interosseous membrane. Recently, a specific mutation in the IFITM5 gene was found to be responsible for OI type V. This mutation, a C to T transition 14 nucleotides upstream from the endogenous start codon, creates a new start methionine that appears to be preferentially used by the translational machinery. However, the mechanism by which the lengthened protein results in a dominant type of OI is unknown. METHODS AND RESULTS: We report 7 ethnically diverse (African-American, Caucasian, Hispanic, and African) individuals with OI type V from 2 families and 2 sporadic cases. Exome sequencing failed to identify a causative mutation. Using Sanger sequencing, we found that all affected individuals in our cohort possess the c.-14 IFITM5 variant, further supporting the notion that OI type V is caused by a single, discrete mutation. Our patient cohort demonstrated inter-and intrafamilial phenotypic variability, including a father with classic OI type V whose daughter had a phenotype similar to OI type I. This clinical variability suggests that modifier genes influence the OI type V phenotype. We also confirm that the mutation creates an aberrant IFITM5 protein containing an additional 5 amino acids at the N-terminus. CONCLUSIONS: The variable clinical signs in these cases illustrate the significant variability of the OI type V phenotype caused by the c.-14 IFITM5 mutation. The affected individuals are more ethnically diverse than previously reported.