University of Groningen
Dietary lipids in glycogen storage disease type III
Rossi, Alessandro; Hoogeveen, Irene J; Bastek, Vanessa B; de Boer, Foekje; Montanari, Chiara; Meyer, Uta; Maiorana, Arianna; Bordugo, Andrea; Dianin, Alice; Campana, Carmen Published in:
Journal of Inherited Metabolic Disease DOI:
10.1002/jimd.12224
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Publication date: 2020
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Rossi, A., Hoogeveen, I. J., Bastek, V. B., de Boer, F., Montanari, C., Meyer, U., Maiorana, A., Bordugo, A., Dianin, A., Campana, C., Rigoldi, M., Kishnani, P. S., Pendyal, S., Strisciuglio, P., Gasperini, S., Parenti, G., Parini, R., Paci, S., Melis, D., & Derks, T. G. J. (2020). Dietary lipids in glycogen storage disease type III: a systematic literature study, case studies and future recommendations. Journal of Inherited Metabolic Disease, 43(4), 770-777. https://doi.org/10.1002/jimd.12224
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Dietary lipids in glycogen storage disease type III: a systematic literature
study, case studies and future recommendations
Alessandro Rossi, MD1*, Irene J. Hoogeveen, MD2*, Vanessa B. Bastek, BSc2, Foekje de Boer, RD2, Chiara Montanari, MD3, Uta Meyer, RD4, Arianna Maiorana, MD,PhD5, Andrea Bordugo, MD6, Alice Dianin, RD6, Carmen Campana, RD5, Miriam Rigoldi, MD7, Priya S Kishnani, MD⁸, Surekha Pendyal, RD⁸, Pietro Strisciuglio, MD¹, Serena Gasperini, MD9
, Giancarlo Parenti, MD1, Rossella Parini, MD9, Sabrina Paci, MD, PhD3, Daniela Melis, MD, PhD10, Terry G.J. Derks,
MD,PhD2
1
Department of Translational Medicine, Section of Pediatrics, University of Naples “Federico II”, Naples, Italy; 2Section of Metabolic Diseases, Beatrix Children‟s Hospital University Medical Center Groningen, University of Groningen, Groningen, The Netherlands; 3Department of Pediatrics, San Paolo Hospital, ASST Santi Paolo e Carlo, University of Milan, Milan, Italy;
4
Department of Pediatrics, Hannover Medical School, Hannover, Germany; 5Division of Metabolic Diseases, Department of Pediatric Specialties, Bambino Gesù Children's Hospital, Rome, Italy; 6Inherited Metabolic Diseases Unit, Department of Paediatrics, Regional Centre for Newborn Screening, Diagnosis and Treatment of Inherited Metabolic Diseases and Congenital Endocrine Diseases, Azienda Ospedaliera Universitaria Integrata, Verona, Italy; 7Rare Diseases Center, ASST Monza, San Gerardo Hospital, Monza, Italy; ⁸Division of Medical Genetics, Department of Pediatrics, Duke University Medical Center, Durham, North Carolina, USA ⁹Rare Metabolic Diseases Pediatric Center, Pediatric Clinic, Fondazione MBBM, San Gerardo Hospital, Monza, Italy. 10Department of Medicine, Surgery and Dentistry "Scuola Medica Salernitana", Section of Pediatrics, University of Salerno, Salerno, Italy
*Contributed equally
Number of figures and tables: one black and white table, three black and white figures.
Abbreviations: CK, creatine kinase; E-%, energy percentage of total caloric intake, GSD,
glycogen storage disease; IVSd, interventricular septum dimension; MCT, medium-chain triglycerides; TG, triglycerides.
Accepted
Article
This article has been accepted for publication and undergone full peer review but has not been through the copyediting, typesetting, pagination and proofreading process which may lead to differences between this version and the Version of Record. Please cite this article as doi: 10.1002/jimd.12224
Summary
1 2
Background 3
A potential role of dietary lipids in the management of hepatic glycogen storage diseases (GSD) 4
has been proposed, but no consensus on management guidelines exists. The aim of this study was 5
to describe current experiences with dietary lipid manipulations in hepatic GSD patients. 6
7
Methods 8
An international study was set up to identify published and unpublished cases describing hepatic 9
GSD patients with a dietary lipid manipulation. A literature search was performed according to 10
the Cochrane Collaboration methodology through PubMed and EMBASE (up to December 11
2018). All delegates who attended the dietetics session at the IGSD2017, Groningen were invited 12
to share unpublished cases. 13
14
Results 15
Due to multiple biases, only data on GSDIII were presented. A total of 28 cases with GSDIII and 16
a dietary lipid manipulation were identified. Main indications were cardiomyopathy and/or 17
myopathy. A high fat diet was the most common dietary lipid manipulation. A decline in creatine 18
kinase concentrations (n=19, p<0.001) and a decrease in cardiac hypertrophy in pediatric 19
GSDIIIa patients (n=7, p<0.01) were observed after the introduction with a high fat diet. 20
21
Conclusions 22
This study presents an international cohort of GSDIII patients with different dietary lipid 23
manipulations. High fat diet may be beneficial in pediatric GSDIIIa patients with cardiac 24
hypertrophy, but careful long-term monitoring for potential complications is warranted, such as 25
growth restriction, liver inflammation and hepatocellular carcinoma development. 26
27 28
Take home message
29
This international literature and retrospective international multi-center cohort study of dietary 30
lipid manipulations in hepatic GSD patients presents positive (cardio)myopathy related outcomes 31
observed after introduction with high fat diet in GSDIII patients and includes recommendations 32
for future monitoring and scientific studies. 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50
Accepted
Article
Details of the contributions of individual authors:
1
AR and IJH were involved in study design, data collection, data analysis and wrote the first and 2
final manuscript. VBB and IJH performed the literature search. TGJD initiated this project, was 3
involved in study design and critically reviewed the versions of the manuscript All other authors 4
contributed to data collection and revised the manuscript for important intellectual content. All 5
authors approved the final manuscript as submitted and agree to be accountable for all aspects of 6
the work. All authors confirm the absence of previous similar or simultaneous publications. 7 8 Corresponding Author: 9 Terry G.J. Derks, MD, PhD 10
University of Groningen, University Medical Centre Groningen 11
Beatrix Children‟s Hospital, Section of Metabolic Diseases 12
PO Box 30 001, 9700 RB Groningen, The Netherlands 13
e-mail: t.g.j.derks@umcg.nl; tel.: +31-50-3611036; fax: +31-50-3614233 14
15
Conflict of interest: Alessandro Rossi received a travel grant from Nestlè Vitaflo to present the
16
results of the study at the International GSD Conference in 2019 in Brazil. 17
Sources of financial support: This project was funded by Junior Scientific Masterclass by
18
University Medical Center Groningen (MD-PhD 15-16 grant to Irene J. Hoogeveen and dr. T.G.J. 19
Derks). The stay of Alessandro Rossi at University of Groningen was financially supported by 20
University of Naples “Federico II” and Compagnia di San Paolo, in the frame of Programme 21
STAR. 22
Ethics approval: not applicable.
23
Documentation Care and Use of Laboratory Animals (or comparable committee): not
24
applicable. 25
Keywords: glycogen storage diseases; high fat; medium-chain triglycerides; dietary intervention;
26
metabolic control. 27
Availability of data statement: The datasets generated for this study are available on request to
28
the corresponding author. 29
Acknowledgements: The authors would like to thank Margreet van Rijn, metabolic dietician
30
from Groningen who was involved in the initiation of this project. We also would like to 31
acknowledge Ellen Wagenaar who was responsible for the organization of the dietary networking 32
session at the IGSD2017. MR, SG and RP gratefully acknowledge Roberta Pretese, metabolic 33
dietician in Monza, who thoroughly followed all GSDIII patients of the center. 34 35 36 37 38 39 40 41 42
Accepted
Article
1
Introduction
2 3
Glycogen storage diseases (GSD) are inborn errors of glycogen synthesis or degradation. 4
Although a wide spectrum of clinical and biochemical presentation is observed, GSD are usually 5
classified into hepatic and muscle GSD. Primary manifestations of the hepatic GSD subtypes 0, I, 6
III, VI, IX and XI are fasting intolerance-associated hypoglycemia, hepatomegaly and failure to 7
thrive. In addition, GSDIII patients also show a myopathic phenotype with skeletal muscle 8
involvement and/or cardiomyopathy (Weinstein et al. 2018). 9
Management guidelines have been published for GSD subtypes Ia (Rake et al. 2002; 10
Kishnani et al. 2014), Ib (Visser et al. 2003), III (Kishnani et al. 2010), and VI and IX together 11
(Kishnani et al. 2019). Dietary management is the cornerstone of treatment for hepatic GSD 12
patients to maintain normoglycemia, prevent secondary metabolic derangements and long-term 13
complications. Strict dietary management and compliance has significantly improved the 14
outcomes for many GSD patients. Traditionally, dietary carbohydrates and protein have received 15
most interest, whereas lipids usually have been restricted. Several case reports have described 16
beneficial effects of dietary lipid manipulations in hepatic GSD patients, including (modified) 17
ketogenic diets and medium-chain triglyceride (MCT) enrichment (Das et al. 2010; Nagasaka et 18
al. 2007; Valayannopoulos et al. 2011; Brambilla et al. 2014; Mayorandan et al. 2014). However, 19
the role of dietary lipids as a third macronutrient in dietary management is still controversial 20
(Derks and van Rijn 2015). 21
The aim of this study was to describe current experiences with dietary lipid manipulations 22
in hepatic GSD patients. We performed a systematic literature study of all published cases 23
describing hepatic GSD patients after dietary lipid manipulation. Thereafter, an international, 24
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observational, retrospective study was performed to include unpublished cases. The subsequent 1
discussion provides recommendations for future patient care and research. 2
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Methods
1
2
Systematic literature study
3
Published cases were retrieved by a systematic literature search conducted according to the 4
Cochrane Collaboration methodology on the 31st of December 2018. PubMed and EMBASE 5
were searched using both MeSH terms and free text. A flowchart of the detailed search strategy 6
can be found in Supplementary File A. Initially, all hepatic GSD patients with a dietary lipid 7
manipulation were identified. However, the majority of cases describing GSD types I and VI 8
patients were published before the introduction of management guidelines and lacked important 9
clinical information (Levy et al. 1993; Cuttino et al. 1970; Cuttino, Summer, and Hill 1970; 10
Fernandes and Pikaar 1969). Therefore, these data were not included, and further data analysis 11
was solely focused on GSDIII. All reports about GSDIII patients receiving dietary lipid 12
manipulation were included. Inclusion criteria were GSDIII diagnosis based on biochemical or 13
molecular evaluation and English language. Exclusion criteria were no individual data 14
presentation and/or absence of follow-up data. Two independent reviewers (IJH, VBB) 15
performed title, abstract screening and subsequently full-text assessment. After selection of 16
eligible full-text papers and conference abstracts, case information was collected in a data table 17
specifically designed for the purpose of this study, including patient‟s age at start dietary 18
intervention, gender, GSDIII subtype, indication to start dietary intervention, specifications of 19
diet, duration of the intervention and follow-up, and outcome measures (laboratory results, 20
imaging tests and clinical picture). 21 22 Case studies 23
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Article
Unpublished cases were retrieved via the International GSD Conference 2017, organized in 1
Groningen, The Netherlands on June 15-17, 2017. All metabolic dieticians were invited to join a 2
networking session on the role of MCT in hepatic GSD. In October 2017, after the IGSD2017, all 3
delegates who had attended the networking session received an invitation by email to share 4
unpublished data of hepatic GSD patients with a dietary lipid manipulation. Data were collected 5
through the same table used for published cases. 6
7
Data synthesis and analysis
8
Data on macronutrients were presented as energy percentage (E-%) of total caloric intake, or if 9
otherwise noted in the legend. MCT supplementation was defined as regular GSD diet enriched 10
in MCT. MCT replacement was defined as long-chain triglycerides substituted with MCT. High 11
fat diet was defined as a diet in which lipids were the main macronutrient based on E-% values. 12
Ketogenic diets were also categorized as high fat even in the absence of E-% values. Standard 13
deviations of BMI were calculated using standard growth charts established by the CDC/2000. 14
Age specific outcomes were presented as Z-scores or in subgroups (i.e. child and adult). The 15
cutoff value for adulthood was set at 16 years of age. Laboratory parameters were presented as 16
range (minimum-maximum value) before and after the dietary intervention, respectively. For 17
each parameter, individual differences (Δ) were presented as percentage difference between mean 18
values before and after the dietary intervention, respectively. Concentrations were considered 19
increased when Δ > +10%, decreased when Δ < -10% and stable if Δ between -10% and +10%. 20
Z-scores were calculated for interventricular septum dimensions (IVSd) to normalize for the body 21
surface area. For Z-score calculation the regression equation by Pettersen was used (Pettersen et 22
al. 2008). The Haycock Formula was used for BSA calculation (Haycock et al. 1978). 23
24
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Statistical analysis
1
Data were analyzed using Prism 7 software (GraphPad Software, Inc. La Jolla California USA) 2
and Statistical Package for Social Sciences, version 23.0 (SPSS, IBM Corp., Armonk, New York, 3
USA). Differences in outcome measures before and after dietary lipid manipulation were 4
analyzed with a paired-t-test if data were normally distributed (assessed by the Shapiro–Wilk 5
test). Data were analyzed with Wilcoxon signed ranks test in case of non-normally distributed 6
data after log-transformation. Pearson‟s or Spearman‟s correlations tests were used to define 7
relationships between dietary parameters and changes in laboratory outcomes. Statistical 8
significance was defined as p < 0.05. 9 10 11 12 13 14 15 16 17 18 19 20 21
Accepted
Article
Results
1 2
Cases 3
Literature search revealed four full text articles and five conference abstracts describing 14 4
GSDIII patients (Supplementary File B), whereas 14 unpublished cases were collected from six 5
metabolic centers from three different countries (Supplementary File C). Therefore, a total of 28 6
cases with GSDIII and a dietary lipid manipulation were collected. 7
8
Patients features, indication to start the diet and compliance 9
Main features of GSDIII patients receiving a dietary lipid manipulation are presented in Table 1. 10
The main indication to start the dietary intervention were cardiomyopathy and/or myopathy. Four 11
patients (case 9, 19, 26, 27) did not follow the modified diet regimen regularly: either poor 12
compliance was reported, or the diet was discontinued several times. 13
14
Diet composition 15
Most common lipid manipulation was high fat diet (Table 1). Figure 1A presents the diet 16
composition before and after dietary intervention in GSDIII patients receiving a high fat diet. 17
Lipid intake ranged from 0.9 to 8.0 g/kg/day (2.9 - 8.0 g/kg/day in children, 0.9 - 2.7 g/kg/day in 18
adults) (Figure 1B). 19
Less common interventions included corn oil supplementation together with high fat diet (case 20
14) (Fernandes and Pikaar 1969), and MCT supplementation alone (cases 6, 7) (El-Gharbawy et 21
al. 2014) (Supplementary file B). 22
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Laboratory results 1
The changes in laboratory parameters in GSDIII patients receiving high fat diet are presented in 2
Figure 2 and Supplementary file D. 3
Creatine kinase (CK) concentrations were available in 73% (19/26) of GSDIII patients receiving 4
high fat diet (Figure 2A). Mean CK concentrations were lower after receiving high fat diet in 5
89% (17/19) of GSDIII patients (2070 U/L ± 1634 vs 1078 U/L ± 1148, p<0.001). One 6
previously unreported patient showed an increase in CK concentrations (case 25), however, CK 7
concentrations remained within the reference range (Soldin et al. 1999). Another patient showed 8
stable CK concentrations (case 26). No correlations between ΔCK and changes in macronutrients 9
were found. 10
Liver transaminases (AST/ALT) were documented in 58% (15/26) of GSDIII patients on a high 11
fat diet (Figure 2B-C). In adult GSDIII patients, ALT concentrations decreased in all cases (n=6); 12
AST concentrations decreased in 5 patients (83%) and were stable in the sixth patient. In 13
pediatric GSDIII patients, ALT concentrations increased in 4 patients (44%), decreased in 1 14
patient (11%) and were stable in 4 patients (44%); AST concentrations increased in 5 patients 15
(56%), decreased in 2 patients (22%) and were stable in 2 patients (22%). 16
17
Imaging and clinical outcomes 18
IVSd Z-scores decreased in pediatric GSDIII patients with a high fat diet (n=7, p<0.01; Figure 3), 19
but not in adult GSDIII patients (n=4, Supplementary File C). There were no correlations 20
between the change in IVSd Z-scores and changes in macronutrients. Data on muscle ultrasound 21
and muscle function tests were available in two adult GSDIIIa patients on a high fat diet with 22
MCT replacement (case 15,16). There was no effect on muscle density. Muscle strength as 23
Accepted
assessed with dynamometry improved only for case 15. Subjective improvements of exercise 1
tolerance and/or muscle strength were reported in 78% (14/18) of pediatric GSDIII patients and 2
50% (4/8) of adult GSDIII patients on high fat diet. 3
Among pediatric GSDIII patients receiving a high fat diet 18% (2/11) showed improved height 4
SDS, 64% (7/11) showed stable height SDS and 18% (2/11) showed decreased height SDS. All 5
pediatric patients showed normal BMI (60% stable, 40% normalized). BMI was stable in all adult 6 GSDIII patients. 7 8 Side effects 9
Side effects were reported in two patients. Hypoglycemia is an intrinsic symptom of hepatic GSD 10
and was reported in two GSDIII patients on a high fat diet. Specifically, one pediatric GSDIIIa 11
patient (case 18) reported isolated hypoglycemia three years after the start of a high fat diet, and 12
one pediatric GSDIIIa patient (case 19) presented with an isolated hypoglycemia one year before 13
and two years after starting with a high fat diet. 14
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Discussion
1 2
Complex carbohydrates and, for ketotic GSD patients, protein enrichment are the cornerstones of 3
dietary management in hepatic GSD. The role of lipids has not been systematically assessed and 4
the current guidelines do not provide clear indications for their use (Rake et al. 2002; Visser et al. 5
2003; Kishnani et al. 2010, 2014, 2019). This systematic literature study and retrospective 6
international multi-center cohort study presents that a high fat diet could be considered in 7
pediatric GSDIII patients with cardiomyopathy. The significant reduction in blood CK 8
concentrations and subjective improvement in muscle strength reported in GSDIII patients 9
necessitates further quantification of the effect of a high fat diet on muscle quality and function. 10
Also, liver function, morphology and growth should be carefully monitored under a high fat 11
regimen given the potential impact on underlying liver disease. 12
Before discussing the results, some methodological issues need to be addressed. The 13
analysis and interpretation of the data were hampered by large variation in age, dietary 14
intervention (e.g. lipid amount, high fat diet alone or together with lipid supplementation), 15
duration of intervention, and outcome parameters. Initially, this study was set up to describe all 16
hepatic GSD types. Most of the data on GSDI and GSDVI were limited and/or historical (Levy et 17
al. 1993; Cuttino et al. 1970; Cuttino, Summer, and Hill 1970; Nagasaka et al. 2007; Bernstein et 18
al. 2010; Das et al. 2010), whereas metabolic control has improved with increasing knowledge on 19
dietary management/glycemic control and the introduction of management guidelines, as 20
demonstrated for GSDIa patients (Dambska et al. 2017). Therefore, in this paper we only 21
included data from GSDIII patients. The published cases presented in this study (n=14) were 22
retrieved from case reports or small cohort studies (describing less than five patients); these data 23
were potentially affected by selection and publication bias. Also, the possible beneficial role of a 24
Accepted
more compliant dietary scheme during dietary intervention should be considered. Finally, 1
ascertainment bias extends to healthcare professionals attending a GSD conference. 2
The main indications to start with a dietary lipid manipulation in GSDIII patients were 3
cardiomyopathy, skeletal myopathy or a combination of both. Lipids became the main 4
macronutrient in GSDIII patients at the expense of carbohydrates. Interestingly, cardiac 5
hypertrophy, as quantified by IVSd Z-scores, decreased only in pediatric GSDIIIa patients. We 6
hypothesize that an early switch to high fat diet can reverse -or at least decrease- the cardiac 7
glycogen storage. Moreover, results showed decreased CK concentrations in 89% of GSDIII 8
patients in accordance with literature (Valayannopoulos et al. 2011; Brambilla et al. 2014; 9
Mayorandan et al. 2014), and improved subjective strength in most of the patients. Increased 10
blood CK concentrations reflect muscle damage which may partially be influenced by exercise. 11
Whether the beneficial effect of a high fat diet on CK concentrations is caused by a lower 12
carbohydrate intake -and thus less accumulation of abnormal glycogen in muscle tissue- or due to 13
the properties of fat to supply alternative energy substrate for muscle remains to be investigated. 14
Notably, most of the GSDIII patients included in the present study received a combination of a 15
high fat and high protein diet. Therefore, these changes in macronutrient composition could also 16
partly account for the beneficial effect on cardiomyopathy and CK concentrations. Nevertheless, 17
protein intake was comparable before and after intervention in GSDIII patients in the present 18
study (Figure1A). 19
The development of chronic liver disease is an important concern in ageing GSDIII 20
patients. Although the prevalence of hepatocellular carcinoma was low in the International Study 21
on GSDIII (Sentner et al. 2016), severe and progressive liver fibrosis has been described at early 22
ages (Halaby et al. 2019). Only one publication describing high fat diet in two GSDIIIa patients 23
documented data on liver transaminases (case 4,5; (Brambilla et al. 2014)) Interestingly, we 24
found that ALT concentrations increased in 44% (4/9) of pediatric GSDIII patients, but decreased 25
Accepted
in all adult GSDIII patients. After dietary lipid manipulation, the concomitant decrease in 1
carbohydrate intake would theoretically lead to less glycogen accumulation in the liver. It 2
remains speculative if these age-specific effects are part of the natural history or influenced by 3
dietary lipid manipulations. However, under these circumstances, careful monitoring and follow-4
up is warranted for liver complications such as hepatosteatosis, liver inflammation and 5
hepatocellular carcinoma (Mager et al. 2013). 6
Side effects were reported in two patients, consisting in isolated (and mostly mild) 7
hypoglycemia, an intrinsic symptom in GSD patients (Steunenberg et al. 2018). „Side effects‟ 8
was not a specific parameter in our data table, and therefore the side effects reported in this study 9
could be an underrepresentation. Previously mentioned concerns regarding MCT in GSD patients 10
are the unknown consequence towards the elongation of fatty acids or gluconeogenesis pathway 11
(Derks and van Rijn 2015). Increased triglycerides concentrations after introduction of MCT have 12
been reported in GSDIII patients (Goldberg 1993). However, in the present study, the majority of 13
GSDIII patients received a high fat diet rather than MCT supplementation or replacement. As 14
high fat diets have been associated with an increased risk of osteoporosis (Denova-Gutiérrez et al. 15
2018) combined with the reduced bone mineral density in GSDIII patients (Melis et al. 2016) the 16
long-term effect of dietary lipid manipulations on bone status should be carefully monitored. 17
Recommendations for future dietary intervention studies and follow-up of GSDIII 18
patients who start with a high fat diet are summarized in Supplementary File E. The present study 19
also provides insight in important outcome parameters when assessing the effect of a dietary 20
intervention in hepatic GSD patients. Several additional outcome measures are proposed 21
including muscle (Verbeek et al. 2016; Decostre et al. 2016; Tobaly et al. 2019), bone (Melis et 22
al. 2016), mitochondrial(Nagasaka et al. 2007; Rossi et al. 2018) and enzymatic (Paesold-Burda 23
et al. 2007) markers. Prospective, long-term follow-up studies are warranted to confirm efficacy 24
Accepted
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Ball, and Jason Yap. 2013. “A Meal High in Saturated Fat Evokes Postprandial Dyslipemia, 25
Hyperinsulinemia, and Altered Lipoprotein Expression in Obese Children with and without 26
Nonalcoholic Fatty Liver Disease.” Journal of Parenteral and Enteral Nutrition 37 (4): 27
517–28. https://doi.org/10.1177/0148607112467820. 28
Mayorandan, Sebene, Uta Meyer, Hans Hartmann, and Anibh Martin Das. 2014. “Glycogen 29
Storage Disease Type III: Modified Atkins Diet Improves Myopathy.” Orphanet Journal of 30
Rare Diseases 9: 196. https://doi.org/10.1186/s13023-014-0196-3. 31
Melis, D, A Rossi, R Pivonello, A Del Puente, C Pivonello, G Cangemi, M Negri, A Colao, G 32
Andria, and G Parenti. 2016. “Reduced Bone Mineral Density in Glycogen Storage Disease 33
Type III: Evidence for a Possible Connection between Metabolic Imbalance and Bone 34
Homeostasis.” Bone 86: 79–85. 35
Nagasaka, Hironori, Ken Ichi Hirano, Akira Ohtake, Takashi Miida, Tomozumi Takatani, Kei 36
Murayama, Tohru Yorifuji, et al. 2007. “Improvements of Hypertriglyceridemia and 37
Hyperlacticemia in Japanese Children with Glycogen Storage Disease Type Ia by Medium-38
Chain Triglyceride Milk.” European Journal of Pediatrics 166 (10): 1009–16. 39
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“Elevated Serum Biotinidase Activity in Hepatic Glycogen Storage Disorders - A 41
Convenient Biomarker.” Journal of Inherited Metabolic Disease 30: 896–902. 42
Accepted
Pettersen, Michael D, Wei Du, Mary Ellen Skeens, Richard A Humes, and Detroit Michigan. 1
2008. “Regression Equations for Calculation of Z Scores of Cardiac Structures in a Large 2
Cohort of Healthy Infants , Children , and Adolescents : An Echocardiographic Study.” 3
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Rake, Jan Peter, Gepke Visser, Philippe Labrune, James V Leonard, K Ullrich, and Smit. 2002. 5
“Guidelines for Management of Glycogen Storage Disease Type I – European Study on 6
Glycogen Storage Disease Type I ( ESGSD I ).” Eur J Pediatr 161: S112–19. 7
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Giovanna Gallo, Daniela Crisci, et al. 2018. “Insulin-Resistance in Glycogen Storage 9
Disease Type Ia: Linking Carbohydrates and Mitochondria?” Journal of Inherited Metabolic 10
Disease 41 (6): 985–95. 11
Sentner, Christiaan P., Irene J. Hoogeveen, David A. Weinstein, Ren?? Santer, Elaine Murphy, 12
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Diagnosis, Genotype, Management, Clinical Course and Outcome.” Journal of Inherited 14
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Cortisol.” Clinical Biochemistry 32 (1): 77–80. 18
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Foekje de Boer, Charlotte M.A. Lubout, Carolina F. de Souza, David A. Weinstein, and 20
Terry G.J. Derks. 2018. “Safety Issues Associated with Dietary Management in Patients 21
with Hepatic Glycogen Storage Disease.” Molecular Genetics and Metabolism 125: 79–85. 22
https://doi.org/10.1016/j.ymgme.2018.07.004. 23
Tobaly, David, Pascal Laforêt, Ariane Perry, Dalila Habes, Philippe Labrune, Valerie Decostre, 24
Marion Masingue, et al. 2019. “Whole‐Body Muscle MRI in Glycogen Storage Disease 25
Type III.” Muscle & Nerve 60 (1): 72–79. 26
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Cardiomyopathy in Glycogen Storage Disease Type III With D , L -3-Hydroxybutyrate , 29
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Johannes H. van der Hoeven, and Deborah A. Sival. 2016. “Muscle Ultrasound in Patients 32
with Glycogen Storage Disease Types I and III.” Ultrasound in Medicine & Biology 42: 33
133–42. https://doi.org/10.1016/j.ultrasmedbio.2015.08.013. 34
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Wendel, and Peter Smit. 2003. “Consensus Guidelines for Management of Glycogen 36
Storage Disease Type 1b - European Study on Glycogen Storage Disease Type 1.” 37
European Journal of Pediatrics 161: S120–23. 38
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“Inborn Errors of Metabolism with Hypoglycemia: Glycogen Storage Diseases and Inherited 40
Disorders of Gluconeogenesis.” Pediatric Clinics of North America 65 (2): 247–65. 41
42
Accepted
Figures and tables
1
Table 1. Features of published and unpublished cases with GSDIII and a dietary lipid
2 manipulation (n=28). 3 Cases, n Published 14 Unpublished 14 Total 28 Gender, n (%) Male 11 (39%) Female 15 (54%) Unknown 2 (7%) Age1, years Median [range] 7 [0-41] Indication, n (%) Hyperlipidemia 2 (7%)
Poor metabolic control 7 (25%)
Muscle involvement 19 (68%)
-Skeletal muscle weakness 3
-Cardiomyopathy 6
-Skeletal and cardiac muscle involvement
9
-Hypotonia 1
Intervention, n (%)
High fat diet 26* (93%)
MCT supplementation/replacement 6 (21%)
Atkins, ketogenic diet 5 (18%)
Corn oil supplementation 1 (4%)
Months of dietary intervention
Median [range] 18 [1-60]
Legend: 1, age at start dietary intervention; MCT, medium-chain triglycerides; *; four patients 4
received both MCT and a high fat diet (case 15, 16, 20, and 21), five patients received a 5
ketogenic diet which was also categorized as high fat diet (case 2, 8-11), one patient received a 6
high fat diet with corn oil substitution (case 14) (Fernandes and Pikaar 1969), and one GSDIII 7
patient received a high fat diet supplemented with D,L-3-hydroxybutyrate (case 12) 8
(Valayannopoulos et al. 2011). 9
Accepted
Figure 1. Dietary features of GSDIII patients.
1
Legend: A) Diet composition in GSDIII patients before (n=10) and after (n= 24) high fat diet, B) 2
Lipid intake in GSDIII patients receiving high fat diet (n= 18, patients on high fat diet also 3
receiving MCT supplementation were included). Data are presented as median [range]. CH, 4
carbohydrates. 5
Figure 2. Changes in laboratory parameters by dietary lipid manipulation in GSDIII.
6
Legend: 7
A) Relation between CK concentrations before intervention and change in CK concentration of 8
19 individual patients with GSDIII with high fat diet, including patients with combined high fat 9
diet and MCT supplementation (n=4). Spearman‟s rho correlation coefficient = -0.40, p > 0.05. 10
Grey square; GSDIII patient, black square; GSDIII patient receiving combined high fat diet and 11
MCT supplementation, white square; GSDIII patient showing CK concentrations within age-12
related reference values before and after dietary lipid manipulation1. 13
14
B) Measured blood ALT concentrations in GSDIII patients before (circle) and after (square) the 15
introduction of a high fat diet. 16
17
C) Measured blood AST concentrations in GSDIII patients before (circle) and after (square) the 18
introduction of a high fat diet. 19 20 1 , (Soldin et al. 1999). 21 22 23
Accepted
Article
Figure 3. Effect of high fat diet on interventricular septum dimension in pediatric GSDIIIa
1
patients (n=7).
2
Legend: Measurements are displayed as Z-scores. GSDIIIa subjects are noted with symbols 3
according to E-% of fat. Grey column represents range of normal Z-scores. 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20
Accepted
Article
Figure 1
Accepted
Figure 2
