Sylvia Stockler-Ipsiroglu

Phenylketonuria (PKU) is a genetic metabolic disorder requiring life-long treatment to prevent severe neurocognitive disability. Despite early treatment, suboptimal neurobehavioral outcomes are common in individuals with PKU. The Canadian Inherited Metabolic Diseases Research Network (CIMDRN) presented an opportunity to investigate current approaches to care and associated outcomes in children with PKU and their parents. Four studies were conducted herein. The surveys of Canadian metabolic dietitians and physicians, described in Chapter 2, helped to understand current PKU management practices from the perspectives of healthcare providers. Data reflecting practices in metabolic treatment centres and associated outcomes were derived from the CIMDRN clinical longitudinal PKU database (Chapter 3). Finally, parent-reported child’s health and parental quality of life were analyzed in connection to the quality of metabolic control (Chapter 4). Providers’ surveys identified overall compliance with current PKU guidelines. Variation was found in case ascertainment, diagnostic workup (neonatal BH4 loading test), monitoring and follow up tests (neuropsychological assessments), treatment practices (sapropterin and large neutral amino acids, LNAA) and organization of care in metabolic centres. The mean phenylalanine (Phe) levels were within the recommended range of 120-360 µmol/L but increased (to 331±151 µmol/L) beyond 7 years of age for children with classic PKU. Among children with classic PKU, 32% were considered in good metabolic control by the 4th week of life. This increased to 55% by age 4-5 and declined to 28% at 8-9 years. Tiredness, lack of concentration, irritability and moodiness were reported as moderate symptoms in children. Parents reported considerable guilt due to non-adherence to the diet/supplements, their child’s anxiety, and practical impact of dietary protein restriction. Overall, healthcare providers follow the published guidelines in providing care for their patients. However, this work has identified variation in many areas of PKU nutritional and clinical management practices in Canadian metabolic centres, including diagnostic and follow up nutritional and clinical management practices. This variation has the potential to impact patients’ long-term health outcomes. The most variation was in areas of practice that were not strongly supported by empirical evidence. This knowledge will serve to further optimize health and quality of life outcomes in Canadian children with PKU.

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The ketone body D-3-hydroxybutyrate (3OHB) is an alternative energy substrate for the brain during hypoglycemia. The capacity and limitations of 3OHB to compensate for cerebral glucose depletion in developing brain is insufficiently understood. We studied the effect of 3OHB treatment in a newly developed infant rat model of insulin induced, sustained, and EEG-controlled hypoglycemia. Continuous treatment with 3OHB during hypoglycemia resulted in increased 3OHB plasma levels in hypoglycemic animals and delayed the onset of clinical coma and of EEG burst-suppression (burst-suppression coma). 3OHB treated animals did not survive after resuscitation with glucose, compared to 80% survival of untreated hypoglycemic pups. Cleaved-caspase-3 immunohistochemistry and double labelling studies demonstrated a 20-fold increase of apoptotic mature oligodendrocytes in white matter of 3OHB treated animals, indicating a limited protective effect of 3OHB treatment.In contrast to glucose, D-3-hydroxybutyrate is not an anaplerotic substrate. Anaplerosis plays in important role in cerebral glutamate glutamine metabolism. Combination of D-3-hydroxybutyrate with the anaplerotic substrate propionate could enhance its protective effect during hypoglycemia. We compared the effectiveness of treatment with a single dose D-3-hydroxybutyrate alone or combined with propionate at the time of EEG burst-suppression coma. Both treatments resulted in a reversion of EEG activity from burst suppression to continuity, but only combined treatment resulted in clincal improvement of the comatose state. 3OHB alone largely corrected pathometabolic changes of glutamate metabolism but not of glycolytic and pentose phosphate pathway intermediates or of long chain acylcarnitines. Combined treatment was not associated with biochemical corrections over and above those achieved by 3OHB alone for the metabolites measured. 3OHB treatment has a limited effectiveness on clinical and neuropathology outcome after hypoglycemia in infant rats. The limited effectiveness of 3OHB treatment may be related to its inability to support glycolysis with associated pentose phosphate pathway and anaplerotic activity. Combined treatment with propionate enhances 3OHB’s protective effect during hypoglycemic coma. Future protective treatment should be based on complementary metabolic substrates.

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