Acute Nutritional Ketosis in GSD IIIa

Study Overview
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Brief Summary
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The investigators will study if acute nutritional ketosis in adult GSD IIIa patients can boost muscle mitochondrial function in vivo.

Detailed Description
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Glycogen Storage Disease type IIIa (GSD IIIa) is an inborn error of carbohydrate metabolism caused by impaired glycogen debranching enzyme (GDE) activity. The ageing GSD IIIa cohort shows that muscle involvement -despite dietary management- is a common disabling phenotype in adulthood. Currently, no specific therapy has been established for muscle problems in adult GSD IIIa patients. However, it could be hypothesized that nutritional ketosis (NK) will be highly beneficial to patients. Amongst others, ketone bodies could take on the role of primary energy source in exercising muscle. Recently, acute NK in exercise was studied in humans. NK was found to enhance muscle mitochondrial function in athletes. The investigators will study if acute NK in adult GSD IIIa patients can boost muscle mitochondrial function in vivo.

Official Title
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Acute Nutritional Ketosis and Exercise in Glycogen Storage Disease Type IIIa

Conditions
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Glycogen Storage Disease IIIA

Intervention / Treatment
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* Other: physical exercise


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: GSD III confirmed with enzyme assay and/or AGL mutation analysis and GSD IIIa further specified as deficient debranching enzyme activity in muscle or clinical and/or biochemical signs of cardiac and/or skeletal muscular involvement. Exclusion Criteria: contraindications for MRI studies (assessed by standardised questionnaire) inability to perform bicycle exercise. intercurrent illness which may influence exercise tolerance (anemia, musculoskeletal injury, or other undiagnosed illness under investigation). known coronary artery disease, positive history for angina or cardiomyopathy. insulin-dependent diabetes mellitus. loss of, or an inability to give informed consent. pregnancy or current breastfeeding. any other cause which in the opinion of the investigators, may affect the participant's ability to participate in the study

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 65 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Other
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Ketone-ester drink<br>Oral intake - physical exercise | Other: physical exercise<br>* In session II and III participants will perform an exercise test on a bicycle inside and outside the MR scanner.<br>|
| Active Comparator: Carbohydrate drink<br>Oral intake - physical exercise | Other: physical exercise<br>* In session II and III participants will perform an exercise test on a bicycle inside and outside the MR scanner.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Description of in vivo energy and proton balance during exercise in MR scanner with and without ketone ester drink: steady-state intramuscular levels of glycogen, Pi, PCr and pH and kinetic rate constant of metabolic recovery. |  | 10 minutes; during in-magnet exercise test of session II and III. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| time of individual desired workload | #minutes | through completion of the maximum exercise test (of approximately 12 minutes) during study session I. | 
| completion of supine bicycling bout at desired workload in scanner | (yes/no; if no, #minutes) | 10 min | 
| Muscle ultrasound density of the biceps, quadriceps, calf (gastrocnemius and/or soleus) and tibialis anterior muscles. | Will be performed during study session I by a neurologist. | Together with the muscle force examination this assessment will take 1.5 hour. | 
| Muscle force unilateral | Will be performed during study session I by a neurologist. | Together with the muscle ultrasound this assessment will take 1.5 hour. | 
| Subjective fatigue and muscle ache score | scale 0-10 | after each exercise bout and 24 hours after exercise | 
| International Physical Activity Questionnaire |  | This questionnaire will take 10 minutes to fill out. Participants will be asked to fill out the questionnaire one week before study session II and III | 
| Structural muscle parameters: fat infiltration. |  | During the in-magnet exercise test of 10 minutes during session II and III | 
| Change in blood glucose levels | #1 and #2 at baseline, #3 after 10 min, #4 after 15 minutes, #5 at the start of bicycle exercise test inside scanner, #6 after 10 minutes of in-magnet exercise and #7 three hours post-exercise inside scanner. | Up to 7 samples will be taken during the 25 minutes exercise test (session II and III). | 
| Blood ketones level (β-hydroxybutyrate, acetoacetate). | #1 and #2 at baseline, #3 after 10 min, #4 after 15 minutes, #5 at the start of bicycle exercise test inside scanner, #6 after 10 minutes of in-magnet exercise and #7 three hours post-exercise inside scanner. | Up to 7 samples will be taken during the 25 minutes exercise test (session II and III). | 
| Change of blood pH | #1 and #2 at baseline, #3 after 10 min, #4 after 15 minutes, #5 at the start of bicycle exercise test inside scanner, #6 after 10 minutes of in-magnet exercise and #7 three hours post-exercise inside scanner. | Up to 7 samples will be taken during the 25 minutes exercise test (session II and III). | 
| Blood levels of free fatty acids | #1 and #2 at baseline, #3 after 10 min, #4 after 15 minutes, #5 at the start of bicycle exercise test inside scanner, #6 after 10 minutes of in-magnet exercise and #7 three hours post-exercise inside scanner. | Up to 7 samples will be taken during the 25 minutes exercise test (session II and III). | 
| Blood levels of insulin | #1 and #2 at baseline, #3 after 10 min, #4 after 15 minutes, #5 at the start of bicycle exercise test inside scanner, #6 after 10 minutes of in-magnet exercise and #7 three hours post-exercise inside scanner. | Up to 7 samples will be taken during the 25 minutes exercise test (session II and III). | 
| Blood levels of creatine kinase | #1 and #2 at baseline, #3 after 10 min, #4 after 15 minutes, #5 at the start of bicycle exercise test inside scanner, #6 after 10 minutes of in-magnet exercise and #7 three hours post-exercise inside scanner. | Up to 7 samples will be taken during the 25 minutes exercise test (session II and III). | 
| Blood levels of ammonia | #1 and #2 at baseline, #3 after 10 min, #4 after 15 minutes, #5 at the start of bicycle exercise test inside scanner, #6 after 10 minutes of in-magnet exercise and #7 three hours post-exercise inside scanner. | Up to 7 samples will be taken during the 25 minutes exercise test (session II and III). | 
| Blood levels of NT-proBNP | #1 and #2 at baseline, #3 after 10 min, #4 after 15 minutes, #5 at the start of bicycle exercise test inside scanner, #6 after 10 minutes of in-magnet exercise and #7 three hours post-exercise inside scanner. | Up to 7 samples will be taken during the 25 minutes exercise test (session II and III). | 
| Blood levels of lactate | #1 and #2 at baseline, #3 after 10 min, #4 after 15 minutes, #5 at the start of bicycle exercise test inside scanner, #6 after 10 minutes of in-magnet exercise and #7 three hours post-exercise inside scanner. | Up to 7 samples will be taken during the 25 minutes exercise test (session II and III). | 
| Change of urine levels of myoglobin, ketones, tetraglucoside |  | Urine will be collected through study session II and III. A study session will take place from 8 am till 2 pm. | 
| optional: muscle metabolic profile (according to Cox et. al. 2016] of a muscle biopsy. | optional, on a patient-voluntary basis. If consent has been given a total of 4 muscle biopsies will be performed. | This procedure takes 30 minutes each time and will be performed prior to and immediately post-exercise during study session II and III. | 
| optional: individual phenotypic muscle properties (fiber type, mitochondrial density, capillary density | optional, on a patient-voluntary basis. If consent has been given a total of 4 muscle biopsies will be performed. | This procedure takes 30 minutes each time and will be performed prior to and immediately post-exercise during study session II and III. | 
| Individual physical performance during exercise; VO2 and VCO2 dynamics. |  | During session I; the maximum exercise test of approximately 12 minutes and during the exercise tests of 15 minutes outside the MR scanner at session II and III. | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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glycogen storage disease type IIIa, exercise, ketone esters, magnetic resonance spectroscopy