Clinical trial NCT04879277: Study of Low-grade Systemic Inflammation in Adult Patients With Phenylketonuria
Official title: Etude de l'INflammation systémique de Bas GRade Chez Les Patients Adultes Atteints de PHénylcétonurie
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: NA
Conditions: Phenylketonuria
Keywords: Low grade inflammation
Cardiovascular
Phenylketonuria
Lead sponsor: University Hospital, Tours
Sponsor class: OTHER
First posted: 2021-05-10
Enrollment: 40
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: yes
Allocation: NON_RANDOMIZED
Intervention model: PARALLEL
Intervention model description: One group of healthy subject and one group of patient with phenylketonuria. Primary objective is to compare inflammation profile between the two groups through cytokine assay.
Primary purpose: SCREENING

Brief summary: Patient suffering from phenylketonuria have chronic hyperphenylalaninemia. Hyperphenylalaninemia is known to be toxic to central nervous system and cardiovascular system in particular through oxydative stress.

In this context, research of low grade systemic inflammation through cytokine assay appears legitimate.

The primary outcome of this study is to describe inflammation profile of patients with phenylketonuria.

Detailed description: Phenylketonuria (PKU) is a metabolic hereditary disease due to lack of activity of phenylalanine hydroxylase. This lack of activity whom origin is genetic, results in chronic hyperphenylalaninemia, toxic to central nervous system and cardiovascular system. Without treatment, PKU is responsible for mental retardation in children.

PKU is subject to systematic screening at birth and if diagnosis is confirmed a specific diet controlled in phenylalanine is prescribed for infant. This diet allows a neurodevelopment as closed as healthy infant. Despite this diet, neurological and systemic complications are more often reported at adult age. It is therefore recommended to follow patient regularly in order to search for those complications.

In a PKU murine model, it has been shown (cf references) that a low grade systematic inflammation exists and was reversible after dietetic treatment using glycomacropeptide (through a probiotic effect of this protein naturally phenylalanine free). Existence of this low grade systematic inflammation, evaluated by plasmatic cytokine screening (TNF alpha IL2, IL6, IL10, IFNgamma, IL1Alpha, IL1Beta and protein C reactive) has not been proven in humans to date.

Primary outcome of this study is to characterize this low grade systemic inflammation profile in patient with PKU.

Eligibility criteria: Inclusion Criteria (patient with PKU)

* Age \>/= 18 years old
* Phenylketonuria diagnosis
* Fasting condition
* Registered with a social security system
* Patient consent

Inclusion Criteria (healthy volunteer)

* Age \>/= 18 years old
* No metabolic condition
* Fasting condition
* Paired to patient with phenylketonuria already included according to age, sex and BMI class
* Registered with a social security system
* Volunteer consent

Exclusion Criteria, common to healthy volunteer and patient with phenylketonuria

* Pregnant and lactating women
* Subject to legal protection measures.
* Chronic or acute inflammatory disease
* Fever on inclusion
* Undergoing anti inflammatory treatment
* Surgery in the previous months
* Diabetes
* Included in other therapeutic trial

Primary outcomes:
measure: Plasma concentrations of pro-inflammatory cytokines
timeFrame: At the inclusion
measure: Plasma concentrations of CRP
timeFrame: At the inclusion
Secondary outcomes:
measure: Plasma concentrations of phenylalanine
timeFrame: At the inclusion
measure: Plasma concentrations of tyrosine
timeFrame: At the inclusion
Other outcomes:
Locations:
city: Tours
country: France
facility: Clinical investigation center, University Hospital, Tours
city: Tours
country: France
facility: Internal Medicine Service, University Hospital, Tours
Study officials:
affiliation: University Hospital, Tours
name: François MAILLOT, MD-PhD
role: STUDY_DIRECTOR
References:
citation: Solverson P, Murali SG, Brinkman AS, Nelson DW, Clayton MK, Yen CL, Ney DM. Glycomacropeptide, a low-phenylalanine protein isolated from cheese whey, supports growth and attenuates metabolic stress in the murine model of phenylketonuria. Am J Physiol Endocrinol Metab. 2012 Apr 1;302(7):E885-95. doi: 10.1152/ajpendo.00647.2011. Epub 2012 Jan 31.
citation: van Spronsen FJ, van Wegberg AM, Ahring K, Belanger-Quintana A, Blau N, Bosch AM, Burlina A, Campistol J, Feillet F, Gizewska M, Huijbregts SC, Kearney S, Leuzzi V, Maillot F, Muntau AC, Trefz FK, van Rijn M, Walter JH, MacDonald A. Key European guidelines for the diagnosis and management of patients with phenylketonuria. Lancet Diabetes Endocrinol. 2017 Sep;5(9):743-756. doi: 10.1016/S2213-8587(16)30320-5. Epub 2017 Jan 10.
citation: Boulet L, Besson G, Van Noolen L, Faure P; ECOPHEN Study Group; Maillot F, Corne C. Tryptophan metabolism in phenylketonuria: A French adult cohort study. J Inherit Metab Dis. 2020 Sep;43(5):944-951. doi: 10.1002/jimd.12250. Epub 2020 Jun 4.
citation: Stroup BM, Nair N, Murali SG, Broniowska K, Rohr F, Levy HL, Ney DM. Metabolomic Markers of Essential Fatty Acids, Carnitine, and Cholesterol Metabolism in Adults and Adolescents with Phenylketonuria. J Nutr. 2018 Feb 1;148(2):194-201. doi: 10.1093/jn/nxx039.
citation: Matalon R, Surendran S, McDonald JD, Okorodudu AO, Tyring SK, Michals-Matalon K, Harris P. Abnormal expression of genes associated with development and inflammation in the heart of mouse maternal phenylketonuria offspring. Int J Immunopathol Pharmacol. 2005 Jul-Sep;18(3):557-65. doi: 10.1177/039463200501800316.