Anaplerotic therapy in propionic acidemia.

BACKGROUND: Propionic acidemia is a rare metabolic disorder caused by a deficiency of propionyl- CoA carboxylase, the enzyme converting propionyl-CoA to methylmalonyl-CoA that subsequently enters the citric acid cycle as succinyl-CoA. Patients with propionic acidemia cannot metabolize propionic acid, which combines with oxaloacetate to form methylcitric acid. This, with the defective supply of succinyl-CoA, may lead to a deficiency in citric acid cycle intermediates. PURPOSE: The objective of this study was to determine whether supplements with glutamine (400mg/kg per day), citrate (7.5mEq/kg per day), or ornithine α-ketoglutarate (400mg/kg per day) (anaplerotic agents that could fill up the citric acid cycle) would affect plasma levels of glutamine and ammonia, the urinary excretion of Krebs cycle intermediates, and the clinical outcome in 3 patients with propionic acidemia. METHODS: Each supplement was administered daily for four weeks with a two week washout period between supplements. The supplement that produced the most favorable changes was supplemented for 30 weeks following the initial study period and then for a 2 year extension. RESULTS: The urinary excretion of the Krebs cycle intermediates, α-ketoglutarate, succinate, and fumarate increased significantly compared to baseline during citrate supplementation, but not with the other two supplements. For this reason, citrate supplements were continued in the second part of the study. The urinary excretion of methylcitric acid and 3-hydroxypropionic acid did not change with any intervention. No significant changes in ammonia or glutamine levels were observed with any supplement. However, supplementation with any anaplerotic agents normalized the physiological buffering of ammonia by glutamate, with plasma glutamate and alanine levels significantly increasing, rather than decreasing with increasing ammonia levels. No significant side effects were observed with any therapy and safety labs (blood counts, chemistry and thyroid profile) remained unchanged. Motor and cognitive development was severely delayed before the trial and did not change significantly with therapy. Hospitalizations per year did not change during the trial period, but decreased significantly (p<0.05) in the 2years following the study (when citrate was continued) compared to the 2years before and during the study. CONCLUSIONS: These results indicate that citrate entered the Krebs cycle providing successful anaplerotic therapy by increasing levels of the downstream intermediates of the Krebs cycle: α-ketoglutarate, succinate and fumarate. Citrate supplements were safe and might have contributed to reduce hospitalizations in patients with propionic acidemia.

Randomized placebo-controlled study of lovastatin in children with neurofibromatosis type 1.

OBJECTIVE: To assess the efficacy of lovastatin on visuospatial learning and attention for treating cognitive and behavioral deficits in children with neurofibromatosis type 1 (NF1). METHODS: A multicenter, international, randomized, double-blind, placebo-controlled trial was conducted between July 2009 and May 2014 as part of the NF Clinical Trials Consortium. Children with NF1 aged 8-15 years were screened for visuospatial learning or attention deficits (n = 272); 146 children demonstrated deficits at baseline and were randomly assigned to lovastatin (n = 74; 40 mg/d) or placebo (n = 70). Treatment was administered once daily for 16 weeks. Primary outcomes were total errors on the Cambridge Neuropsychological Test Automated Battery Paired Associate Learning task (visuospatial learning) and the Score subtest from the Test of Everyday Attention for Children (sustained attention). Secondary outcomes measured executive function, attention, visuospatial skills, behavior, and quality of life. Primary analyses were performed on the intention-to-treat population. RESULTS: Lovastatin had no significant effect on primary outcomes after 16 weeks of treatment: visuospatial learning (Cohen d = -0.15, 95% confidence interval -0.47 to 0.18) or sustained attention (Cohen d = 0.19, 95% confidence interval -0.14 to 0.53). Lovastatin was well tolerated, with no increase in reported adverse events compared to placebo. CONCLUSIONS: Lovastatin administered once daily for 16 weeks did not improve visuospatial learning or attention in children with NF1 and is not recommended for amelioration of cognitive deficits in this population. CLINICALTRIALSGOV IDENTIFIER: This study was registered at ClinicalTrials.gov (NCT00853580) and Australian New Zealand Clinical Trials Registry (ACTRN12607000560493). CLASSIFICATION OF EVIDENCE: This study provides Class I evidence that for children with NF1, lovastatin does not improve visuospatial learning or attention deficits.

Correlation of age-specific phenylalanine levels with intellectual outcome in patients with phenylketonuria.

Patients with treated phenylketonuria (PKU) can have subtle deficits in intellect, academic skills, and executive functioning. This study evaluates the relationship between intellectual outcome and concentration/variation in blood phenylalanine (Phe) during specific developmental periods (0-6 years, 7-12 years, >12 years) in our patients with PKU. Verbal comprehension, perceptual reasoning, and processing speed were used as measures of intelligence. Data were collected from 55 patients receiving treatment at the University of Utah Metabolic Clinic. Yearly median Phe levels increased and mean number of blood Phe samples decreased as patients aged. Yearly median blood Phe from 0-6 and 7-12 years were inversely associated with perceptual reasoning abilities using linear regression. Additionally, increased blood Phe concentration negatively impacted specific areas of verbal comprehension abilities for those 0-6 years of age (p = 0.001). Variation of Phe levels around the mean (assessed as standard deviation) in each patient was associated with diagnostic (highest pretreatment) Phe levels and yearly median Phe levels (p < 0.001 for both), but did not significantly impact intelligence in our group of patients. Frequent blood Phe monitoring from 7-12 years significantly reduced the probability of yearly median Phe exceeding 360 µM (p = 0.005). Our data show that compliance with treatment in patients with PKU affects both the concentration and variation of blood Phe levels, and may have a greater impact on verbal comprehension and perceptual reasoning skills during the first 12 years of life when compared the influence beyond 12 years.