Purpose Despite implementation of newborn screening (NBS), outcomes in cobalamin C disease (cblC) remain poor. Therapy with hydroxycobalamin and betaine is widely used, but dietary recommendations vary among metabolic centers. We present a longitudinal analysis of the relationship between metabolic control, diet, and outcomes in a cohort of cblC patients. Methods We completed a retrospective analysis of 12 patients with cblC referred for abnormal NBS results and followed in our center between 1999 and 2015. Results Of the patients, 87.5% had intellectual disability and 75% had retinopathy; 16.7% had one episode of mild acidosis. However, no patients manifested major metabolic decompensation. Developmental outcomes correlated more closely with initial metabolic abnormalities than with long-term metabolic control. Increased intake of medical foods resulted in better control but also perturbations in the ratios of essential amino acids and lower z-scores for head circumference. We found no relationship between diet and cognitive outcomes. Conclusions Although dietary therapy for cblC patients improves metabolic control, few patients experience metabolic decompensation regardless of diet. Increased incomplete protein intake is not correlated with improvements in outcomes. Overall, outcomes are poor despite early initiation of therapy and regardless of the dietary strategy used.

Background and PurposePET scanning with fluorodeoxyglucose (FDG-PET) is a non-invasive method that measures regional glucose metabolic rate. Phenylalanine (Phe) and its metabolites appear to impair several aspects of brain energy metabolism. 1) To evaluate brain glucose metabolism with FDG-PET imaging in phenylketonuria (PKU) patients before and 4 months after sapropterin therapy; 2) to evaluate neurodevelopmental changes, blood Phe levels and dietary Phe tolerance before and after sapropterin therapy; 3) to generate pilot data to assess the feasibility of evaluating brain glucose metabolism with FDG-PET imaging and to explore potential trends resulting from the administration of sapropterin therapy.MethodsWe enrolled 5 subjects, ranged in age from 22 years to 51 years, with PKU. Subjects underwent FDG-PET brain imaging, blood tests for Phe and tyrosine levels, and neurocognitive evaluations before and 4 months after sapropterin therapy (20 mg/kg/day). All subjects' Phe and tyrosine levels were monitored once a week during the study. Subjects kept 3 day diet records that allow calculation of Phe intake.ResultsNone of the subjects responded to sapropterin therapy based on 30% decrease in blood Phe level. The data show that glucose metabolism appeared depressed in the cerebellum and left parietal cortex while it was increased in the frontal and anterior cingulate cortices in all five subjects. In response to sapropterin therapy, relative glucose metabolism showed significant increases in left Broca's and right superior lateral temporal cortices. Interestingly, there was corresponding enhanced performance in a phonemic fluency test performed during pre- and postneurocognitive evaluation.ConclusionsFurther studies with a larger sample size are needed to confirm the above changes in both sapropterin non-responsive and responsive PKU patients.