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Recommended reading – key published papers from 2018

Recommended reading – key published papers from 2018
  • Endocrinology and metabolism
  • Phenylketonuria (PKU)

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2018
PKU

A rich and diverse array of papers on PKU has been published during the year. The PKU Academy asked each of our contributing Scientific Committee Members, Professor Anita MacDonald (Birmingham, UK), Professor Nenad Blau (Heidelberg, Germany) and Professor Francjan van Spronsen (Groningen, The Netherlands) for a short list of the papers that have caught their eye during the year.

These are presented below, in no particular order: 


Aubi O, Knappskog PM, Martinez A. Early stage discovery and validation of pharmacological chaperones for the correction of protein misfolding diseases. Methods Mol Biol2019;1873:279-292. 

This paper describes a successful protocol for the discovery of pharmacological chaperones with potential for the therapeutic correction of phenylketonuria

Article available from: https://doi.org/10.1007/978-1-4939-8820-4_18


Rausell D, García-Blanco A, Correcher P, Vitoria I, Vento M, Cháfer-Pericás C. Newly validated biomarkers of brain damage may shed light into the role of oxidative stress in the pathophysiology of neurocognitive impairment in dietary restricted phenylketonuria patients. Pediatr Res2018 Oct 17. [Epub ahead of print] 

Increasingly, there is acceptance of the role of oxidative stress in PKU and hyperphenylalaninemia. This paper reports on validated brain-specific lipid peroxidation biomarkers and their relevance in the detection and monitoring of neurological damage in phenylketonuric patients.

Article available from: https://doi.org/10.1038/s41390-018-0202-x


Hofman DL, Champ CL, Lawton CL, Henderson M, Dye L. A systematic review of cognitive functioning in early treated adults with phenylketonuria. Orphanet J Rare Dis2018 Aug 30;13(1):150. 

This systematic review of 22 publications looked at adults who had successfully adhered to dietary management of phenylketonuria from early in life, and assessed the level of neurological impairment inherent in these individuals. Despite some inconsistencies and inter- and intra-study variability, the results most consistently showed patients with PKU have deficits in vigilance, working memory and motor skills.

Article available from:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6117942/


Mahan KC, Gandhi MA, Anand S. Pegvaliase: a novel treatment option for adults with phenylketonuria. Curr Med Res Opin2018 Oct 25:1-5. 


An overview of the mechanism of action, pharmacokinetic properties, clinical efficacy and the safety and tolerability profile of pegvaliase-pqpz (Palynziq), approved by the US Food and Drug Administration in May 2018 - the first enzyme substitution therapy for the treatment of PKU.

Article available from: https://doi.org/10.1080/03007995.2018.1528215


Isabella VM, Ha BN, Castillo MJ, Lubkowicz DJ, Rowe SE, Millet YA, Anderson CL, Li N, Fisher AB, West KA, Reeder PJ, Momin MM, Bergeron CG, Guilmain SE, Miller PF, Kurtz CB, Falb D. Development of a synthetic live bacterial therapeutic for the human metabolic disease phenylketonuria. Nat Biotechnol2018 Oct;36(9):857-864. 

Escherichia coli Nissle was engineered to express genes encoding Phe-metabolizing enzymes in response to anoxic conditions in the mammalian gut. When administered to a PKU mouse model, blood Phe concentrations were reduced by 38% compared with controls, independent of dietary protein intake. Results were similar in cynomolgus monkeys defining a strategy for the use of live bacterial therapeutics to treat metabolic disorders.

Article available from: https://www.nature.com/articles/nbt.4222


Gonzalez MJ, Polo MR, Ripolles P, Gassio R, Ormazabal A, Sierra C, Roura RC, Artuch R, Campistol J. White matter microstructural damage in early treated phenylketonuric patients. Orphanet J Rare Dis 2018;13:188.

MRI investigations in early-treated PKU patients, showing that despite early treatment, those with PKU had microstructural damage in the white matter. Despite this, no affectation in processing speed was observed in patients with good metabolic control.

Article available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6203973/


Villiger L, Grisch-Chan HM, Lindsay H, Ringnalda F, Pogliano CB, Allegri G, Fingerhut R, Haberle J, Matos J, Robinson MD, Thony B, Schwank G. Treatment of a metabolic liver disease by in vivo genome base editing in adult mice. Nat Med 2018;24:1519-1525.

Successful gene therapy (base-editing) for PKU mouse model

Article available from:https://www.nature.com/articles/s41591-018-0209-1


Muntau AC, du Moulin M, Feillet F. Diagnostic and therapeutic recommendations for the treatment of hyperphenylalaninemia in patients 0-4 years of age. Orphanet J Rare Dis 2018;13:173.

Experience-based, real-world guidance in an algorithmic format for the use of sapropterin dihydrochloride in newborns and small children

Article available from:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6162894/


Burton BK, Jones KB, Cederbaum S, Rohr F, Waisbren S, Irwin DE, Kim G, Lilienstein J, Alvarez I, Jurecki E, Levy H. Prevalence of comorbid conditions among adult patients diagnosed with phenylketonuria. Mol Genet Metab 2018 Nov;125(3):228-234.

This is a retrospective, case-controlled study of patients from United States insurance claims databases from 1998 to 2014, which looked at rates of comorbidity in patients with PKU.A total of 3691 patients with PKU and 18,455 matched, non-PKU controls were selected, average age was 35 years. Mean healthcare costs incurred by the patients with PKU were approximately 4 times that of the controls ($4141 vs $1283; P<0.0001). The highest adjusted PR were for renal insufficiency with hypertension and for being overweight.

Article available from: https://www.sciencedirect.com/science/article/pii/S1096719218303883


van Vliet D, van Wegberg AMJ, Ahring K, Bik-Multanowski M, Blau N, Bulut FD, Casas K, Didycz B, Djordjevic M, Federico A, Feillet F, Gizewska M, Gramer G, Hertecant JL, Hollak CEM, Jørgensen JV, Karall D, Landau Y, Leuzzi V, Mathisen P, Moseley K, Mungan NÖ, Nardecchia F, Õunap K, Powell KK, Ramachandran R, Rutsch F, Setoodeh A, Stojiljkovic M, Trefz FK, Usurelu N, Wilson C, van Karnebeek CD, Hanley WB, van Spronsen FJ. Can untreated PKU patients escape from intellectual disability? A systematic review. Orphanet J Rare Dis 2018 Aug 29;13(1):149.

Systematic review of 59 cases of patients with late-diagnosed PKU and favourable outcome. Patients had normal intellectual functioning but 19/59 had neurological, psychological, and/or behavioral symptoms.

Article available from:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6116368/


Brantley KD, Douglas TD, Singh RH. One-year follow-up of B vitamin and iron status in patients with phenylketonuria provided tetrahydrobiopterin (BH4). Orphanet J Rare Dis. 2018 Oct 30;13(1):192. 

Declining vitamin B12 status with BH4 treatment

Article available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6206913/


Huijbregts SCJ, Bosch AM, Simons QA, Jahja R, Brouwers MCGJ, De Sonneville LMJ, De Vries MC, Hofstede FC, Hollak CEM, Janssen MCH, Langendonk JG, Rubio-Gozalbo ME, Van der Meere JJ, Van der Ploeg AT, Van Spronsen FJ. The impact of metabolic control and tetrahydrobiopterin treatment on health related quality of life of patients with early-treated phenylketonuria: A PKU-COBESO study. Mol Genet Metab. 2018 Sep;125(1-2):96-103.

Beneficial effects of BH4 use limited to relief of practical burden of diet i.e. helping general mood and sociability, whereas metabolic control is more strongly related to basic physical and cognitive functioning.

Article available from: https://www.sciencedirect.com/science/article/pii/S1096719218302749


Couce ML, Sánchez-Pintos P, Vitoria I, De Castro MJ, Aldámiz-Echevarría L, Correcher P, Fernández-Marmiesse A, Roca I, Hermida A, Martínez-Olmos M, Leis R.  Carbohydrate status in patients with phenylketonuria. Orphanet J Rare Dis. 2018 Jun 27;13(1):103.

Patients with PKU are at risk of carbohydrate intolerance and insulin resistance. This is more evident in adult patients and those who are overweight, and may relate to their higher calorific intake from carbohydrates.

Article available from:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6020344/

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