University of Groningen Glycogen Storage Disease type IIIa Hoogeveen, Irene

Glycogen Storage Disease type IIIa

Hoogeveen, Irene

DOI:

10.33612/diss.130704555

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STORAGE DISEASES: A SYSTEMATIC

LITERATURE STUDY, CASE STUDIES AND

FUTURE RECOMMENDATIONS

Alessandro Rossi*, Irene J. Hoogeveen*, Vanessa B. Bastek, Foekje de Boer, Chiara Montanari,

Uta Meyer, Arianna Maiorana, Andrea Bordugo, Alice Dianin, Carmen Campana, Miriam Rigoldi,

Priya S Kishnani, Surekha Pendyal, Pietro Strisciuglio, Serena Gasperini, Giancarlo Parenti,

Rossella Parini, Sabrina Paci, Daniela Melis, Terry G.J. Derks

*Contributed equally.

A revised version of this chapter is accepted for publication in

Journal of Inherited Metabolic Disease: in press

4a

ABSTRACT

Background - A potential role of dietary lipids in the management of hepatic glycogen storage

disease (GSD) has been proposed, but no consensus on management guidelines exists. The

aim of this study was to describe current experiences with dietary lipid manipulations in hepatic

GSD patients.

Methods - An international study to identify published and unpublished cases describing hepatic

GSD patients with a dietary lipid manipulation. A literature search was performed according to the

Cochrane Collaboration methodology through PubMed and EMBASE (up to December 2018). All

delegates who attended the dietetics session at the IGSD2017, Groningen were invited to share

cases.

Results - 68 cases were collected, including GSDI (n=35), GSDIII (n=28), GSDVI (n=3) and GSDIX

(n=2). Main indications were hyperlipidemia in GSDI and cardiomyopathy and/or myopathy in

GSDIII. Most common interventions were medium-chain triglycerides (MCT) supplementation/

replacement in GSDI and high fat diet in GSDIII. 57% of the GSDI patients (but only 36% of children)

showed a decline in triglycerides concentrations after MCT administration. In GSDIII patients a

decline in creatine kinase concentrations (n=19, p<0.001) and a decrease in cardiac hypertrophy

in pediatric GSDIIIa patients (n=7, p<0.01) were observed after high fat diet.

Conclusions - This study presents an international cohort of hepatic GSD patients with different

dietary lipid manipulations. High fat diet may be beneficial in pediatric GSDIIIa patients with cardiac

hypertrophy, but careful long-term monitoring for potential complications is warranted, such

as growth restriction, liver inflammation and hepatocellular carcinoma development. The lipid

lowering effect of MCT in GSDI requires further investigation.

SYNOPSIS

This international literature and retrospective international multi-center cohort study of dietary

lipid manipulations in hepatic GSD patients presents positive (cardio)myopathy related outcomes

observed after introduction with high fat diet in GSDIII patients and includes recommendations

for future monitoring and scientific studies.

INTRODUCTION

Glycogen storage diseases (GSD) are inborn errors of glycogen synthesis or degradation. Although

a wide spectrum of clinical and biochemical presentation is observed, GSD are usually classified

into hepatic and muscle GSD. Primary manifestations of the hepatic GSD subtypes 0, I, III, VI, IX

and XI are fasting intolerance-associated hypoglycemia, hepatomegaly and failure to thrive. In

addition, GSDIII patients also show a myopathic phenotype with skeletal muscle involvement

and/or cardiomyopathy

1

_.

Management guidelines have been published for GSD subtypes Ia

2,3

_{, Ib}

4

_{, III}

5

_{and VI and IX}

together

6

_{. Dietary management is the cornerstone of treatment for hepatic GSD patients to maintain}

normoglycemia, prevent secondary metabolic derangements and long-term complications. Strict

dietary management and compliance has significantly improved the outcomes for many GSD

patients. Traditionally, dietary carbohydrates and protein have received most interest, whereas

lipids usually have been restricted. Several case reports have described beneficial effects of dietary

lipid manipulations in hepatic GSD patients, including (modified) ketogenic diets and medium-chain

triglyceride (MCT) enrichment

7–11

_{. However, the role of dietary lipids as a third macronutrient in}

dietary management is still controversial

12

_.

The aim of this study was to describe current experiences with dietary lipid manipulations in

hepatic GSD patients. We performed a systematic literature study of all published cases describing

hepatic GSD patients after dietary lipid manipulation. Thereafter, an international, observational,

retrospective study was performed to include unpublished cases. The subsequent discussion

provides recommendations for future patient care and research.

METHODS

Systematic literature study

Published cases were retrieved by a systematic literature search conducted according to the

Cochrane Collaboration methodology on the 31st of December 2018. PubMed and EMBASE

were searched using both MeSH terms and free text. A flowchart of the detailed search strategy

can be found in Supplementary File A. All reports about hepatic GSD patients receiving dietary

lipid manipulation were included. Inclusion criteria were GSD diagnosis based on biochemical or

molecular evaluation and English language. Exclusion criteria were no individual data presentation

and/or absence of follow-up data. Two independent reviewers (IJH, VBB) performed title, abstract

screening and subsequently full-text assessment. After selection of eligible full-text papers and

conference abstracts, case information was collected in a data table specifically designed for the

purpose of this study, including patient’s age at start dietary intervention, gender, GSD subtype,

indication to start dietary intervention, specifications of diet, duration of the intervention and

follow-up, and outcome measures (laboratory results, imaging tests and clinical picture).

Case studies

Unpublished cases were retrieved via the International GSD Conference 2017, organized in

Groningen, The Netherlands on June 15-17, 2017. All metabolic dieticians were invited to join

a networking session on the role of MCT in hepatic GSD. In October 2017, after the IGSD2017,

all delegates who had attended the networking session received an invitation by email to share

unpublished data of hepatic GSD patients with a dietary lipid manipulation. Data were collected

through the same table used for published cases.

Data synthesis and analysis

Data on macronutrients were presented as energy percentage (E-%) of total caloric intake, or if

otherwise noted in the legend. MCT supplementation was defined as regular GSD diet enriched

in MCT. MCT replacement was defined as long-chain triglycerides substituted with MCT. High

fat diet was defined as a diet in which lipids were the main macronutrient based on E-% values.

Ketogenic diets were also categorized as high fat even in the absence of E-% values. Standard

deviations of BMI were calculated using standard growth charts established by the CDC/2000.

Age specific outcomes were presented as Z-scores or in subgroups (i.e. child and adult). The

cutoff value for adulthood was set at 16 years of age. Laboratory parameters were presented as

range (minimum-maximum value) before and after the dietary intervention, respectively. For each

parameter, individual differences (Δ) were presented as percentage difference between mean values

before and after the dietary intervention, respectively. Concentrations were considered increased

when Δ > +10%, decreased when Δ < -10% and stable if Δ between -10% and +10%. Z-scores were

calculated for interventricular septum dimensions (IVSd) to normalize for the body surface area.

For Z-score calculation the regression equation by Pettersen was used

13

_{. The Haycock Formula}

was used for BSA calculation

14

_.

Statistical analysis

Data were analyzed using Prism 7 software (GraphPad Software, Inc. La Jolla California USA)

and SPSS, version 23.0 (IBM Corp., Armonk, New York, USA). Differences in outcome measures

before and after dietary lipid manipulation were analyzed with a paired-t-test if data was

normally distributed (assessed by the Shapiro–Wilk test). Non-normally distributed data was

log-transformed to induce normal distribution. Data were analyzed with Wilcoxon signed ranks

test in case of non-normally distributed data after log-transformation. Pearson’s or Spearman’s

correlations test were used to define relationships between dietary parameters and changes in

laboratory outcomes. Statistical significance was defined as p < 0.05.

RESULTS

Cases

Literature search revealed nine full-text articles and six conference abstracts describing 37

GSD patients (Supplementary File B), whereas 32 unpublished cases were collected from eight

metabolic centers from four different countries (Supplementary File C). Data from case 17 was

excluded from further data analysis, since case 17 and 18 likely represent the same patient

15,16

_.

Therefore, a total of 68 cases with hepatic GSD and a dietary lipid manipulation (35 GSDI, 28 GSDIII,

3 GSDVI, 2 GSDIX) were collected.

Patients features, indication to start the diet and diet duration

Main patients’ features are presented in Table 1. The main indication to start the dietary intervention

was hyperlipidemia in GSDI and muscle involvement in GSDIII. Eight patients (case 6, 29, 39, 47,

48, 58, 65, and 66) did not follow the modified diet regimen regularly: either poor compliance was

reported, or the diet was discontinued several times.

Diet composition

Most common lipid manipulations were MCT supplementation/replacement in GSDI and GSDIX,

high fat diet in GSDIII patients, and corn oil supplementation in GSDVI (Table 1). Figure 1A-B

presents the diet composition before and after dietary intervention in GSDI and GSDIII patients

receiving MCT supplementation/replacement and high fat diet, respectively. MCT intake in GSDI

patients ranged from 0.2 to 2.0 g/kg/day (0.4 - 2.0 g/kg/day in children, 0.2 - 0.5 g/kg/day in

adults) (Figure 1C); lipid intake in GSDIII patients 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 adults) (Figure 1D). Less common interventions included

omega-3FA supplementation (cases 42-44), corn oil supplementation (cases 19, 34-37)

17

_{, and}

MCT supplementation alone in GSDIII (cases 26,27)

18

_{and GSDIX (cases 68-69) (Supplementary}

files B-C).

GSDI

GSDIII

GSDVI

GSDIX

Cases, n

35

28

3

2

Published

19

14

3

-Unpublished

16

14

-

2

Gender, n (%)

Male

13 (37%)

11 (39%) 3 (100%)

2 (100%)

Female

10 (29%)

15 (54%)

-

-Unknown

12 (34%)

2 (7%)

-

-Age

1

_{, years}

Median [range]

7 [0-36]

7 [0-41]

2 [1-4]

7 [7-7]

Indication, n (%)

Hyperlipidemia

23 (66%)

2 (7%) 3 (100%)

-Poor metabolic control

12 (34%)

7 (25%)

-

2 (100%)

Muscle involvement

-

19 (68%)

-

--Skeletal muscle weakness

-

3

-

--Cardiomyopathy

-

6

-

--Skeletal and cardiac muscle involvement

-

9

-

--Hypotonia

-

1

-

-Intervention, n (%)

MCT supplementation/replacement

24 (69%)

6 (21%)

-

2 (100%)

High fat diet

- 26* (93%)

-

-Atkins, ketogenic diet

-

5 (18%)

-

-ω-3FA supplementation

10 (29%)

-

-

-Corn oil supplementation

1 (3%)

1 (4%) 3 (100%)

-Months of dietary intervention

Median [range]

8 [1-144]

18 [1-60]

1 [0.5-1] 53 [48-58]

Table 1. Features of published and unpublished cases with hepatic GSD and a dietary lipid manipulation (n=68).

Legend:

1

_{, age at start dietary intervention; available in 85% (58/68) of the cases; MCT, medium-chain}

triglycerides; ω-3FA, omega-3 fatty acids. *; four patients received both MCT and a high fat diet (case 54,55,59,

and 60), five patients received a ketogenic diet which was also categorized as high fat diet (case 22, 28-31),

one patient received a high fat diet with corn oil substitution (case 34)

17

_{, and one GSDIII patient received high}

fat diet supplemented with D,L-3-hydroxybutyrate (case 32)

8

_.

Figure 1. Dietary features of GSDI and GSDIII patients.

GSDI 0 20 40 60 80 100 CH LIPID PROTEIN E-% GSDIII 0 20 40 60 80 100 CH LIPID PROTEIN E-% Pre Post Children Adults 0.0 0.5 1.0 1.5 2.0 2.5 GSDI MC T in tak e (g/kg/day) Children Adults 0 2 4 6 8 10 GSDIII Lipi d in tak e (g/kg/day)

A

B

C

D

Legend: A) Diet composition in GSDI patients before (n=10) and after (n=21) MCT supplementation/

replacement. B) Diet composition in GSDIII patients before (n=10) and after (n= 24) high fat diet. C) MCT

intake in GSDI patients receiving MCT supplementation/replacement (n=15). D) Lipid intake in GSDIII patients

receiving high fat diet (n= 18, patients on high fat diet also receiving MCT supplementation were included).

Data are presented as median [range]. CH, carbohydrates.

Laboratory results

The changes in laboratory parameters in GSDI patients receiving MCT supplementation/replacement

and GSDIII patients receiving high fat diet are presented in Figure 2 and Supplementary file D.

Triglycerides (TG) concentrations were available in 21 out of 24 GSDI patients receiving MCT

supplementation/replacement. A decline in TG concentrations was found in 57% (12/21) of the

GSDI patients, specifically in all adult (4/4) and 36% (5/14) of pediatrics GSDI patients (age not

available in 3 patients). Pooled data showed a significant decline in TG concentrations after MCT

supplementation/replacement (9.7 mmol/L ± 9.4 vs 5.9 mmol/L ± 5.1, p<0.05). An inverse correlation

was found between TG concentrations before intervention and ΔTG (rho= -0.56, p< 0.01; Figure

2A). In 6 out of 14 children, TG concentrations increased after MCT supplementation/replacement.

Detectable ketones were reported in 75% (3/4) of GSDI patients (Supplementary File D). In three

GSDI patients acylcarnitine profile was determined; data showed an increase in acetylcarnitine and

butyrylcarnitine in two patients, and an increase in palmitoylcarnitine in one patient

9

_.

Creatine kinase (CK) concentrations were available in 73% (19/26) of GSDIII patients receiving

high fat diet (Figure 2B). Mean CK concentrations decreased in 89% (17/19) of GSDIII patients

receiving high fat diet (2070 U/L ± 1634 vs 1078 U/L ± 1148, p<0.001). One patient showed

an increase in CK concentrations (case 64), however, CK concentrations remained within the

reference range

19

_{. Another patient showed stable CK concentrations (case 65). No correlations}

between ΔCK and changes in macronutrients were found.

Liver transaminases (ALT/AST) were documented in 58% (15/26) of GSDIII patients on a high

fat diet (Figure 2C-D). In adult GSDIII patients, ALT concentrations decreased in all cases (n=6);

AST concentrations decreased in 5 patients (83%) and were stable in the sixth patient. In pediatric

GSDIII patients, ALT concentrations increased in 4 patients (44%), decreased in 1 patient (11%)

and were stable in 4 patients (44%); AST concentrations increased in 5 patients (56%), decreased

in 2 patients (22%) and were stable in 2 patients (22%).

Figure 2. Changes in laboratory outcomes by dietary lipid manipulation in GSDI and GSDIII.







                            



                          GSDIII -                



GSDIII -                 GSDIII GSDI

Legend: A) Relation between TG concentration before intervention and change in TG concentration of

21 individual patients with GSDI on MCT supplementation/replacement. Spearman’s rho correlation

coefficient = -0.60, p < 0.01. Grey circle; GSDI patient, triangle; GSDIb patient, open symbol; GSDI patient reaching

TG <6.0 mmol/L

2

_{after MCT supplementation/replacement. ** p < 0.01. B) Relation between CK concentrations}

before intervention and change in CK concentration of 19 individual patients with GSDIII with high fat diet,

including patients with combined high fat diet and MCT supplementation (n=4). Spearman’s rho correlation

coefficient = -0.40, p > 0.05. Grey square; GSDIII patient, black square; GSDIII patient receiving combined

Imaging and clinical outcomes

Longitudinal data on exact liver size (assessed with ultrasound) were available for three GSDI

patients receiving MCT supplementation/replacement: one adult GSDIa patient (stable liver size,

regression from 2 to 1 adenoma), one child with GSDIa (increased liver size, progression from 1

adenoma to 2 adenomas), one child with GSDIb (increased liver size, no adenoma).

Among GSDI patients receiving MCT supplementation/replacement, improved height SDS

was reported in 9/16 (56%) children. Among GSDI children, 50% showed stable (normal) BMI and

20% showed a beneficial change in BMI. Two adult GSDI patients showed improved BMI and one

adult patient had a stable (normal) BMI. One GSDI patient showed xanthomas disappearance

after MCT supplementation (case 17,18; considered as one patient)

15,16

_{. IVSd Z-scores decreased in}

pediatric GSDIII patients with a high fat diet (n=7, p<0.01; Figure 3), but not in adult GSDIII patients

(n=4, Supplementary file C). There were no correlations between the change in IVSd Z-scores and

changes in macronutrients. Data on muscle ultrasound and muscle function tests were available

in two adult GSDIIIa patients on a high fat diet with MCT replacement (case 54, 55). There was no

effect on muscle density. Muscle strength as assessed with dynamometry improved only for case

54. Subjective improvements of exercise tolerance and/or muscle strength were reported in 78%

(14/18) GSDIII children and 50% (4/8) GSDIII adult patients on high fat diet. Among pediatric GSDIII

patients receiving a high fat diet 18% (2/11) showed improved height SDS, 64% (7/11) showed

stable height SDS and 18% (2/11) showed decreased height SDS. All pediatric GSDIII patients

showed normal BMI (60% stable, 40% normalized). BMI was stable in all GSDIII adult patients.

Figure 3. Effect of high fat diet on interventricular septum dimension in pediatric GSDIIIa patients (n=7).

                         _{ - }  -   -     

Legend: Measurements are displayed as Z-scores. GSDIIIa subjects are noted with symbols according to E-%

of fat. Grey column represents range of normal Z-scores.

Side effects and concomitant medication

Side effects were reported in six patients. Hypoglycemia is a common symptom in GSD and

was reported in two GSDIa patients on MCT supplementation, and two GSDIII patients on a

high fat diet. Specifically, one pediatric GSDIa patient experienced hypoglycemia and ketonuria

during two episodes of severe gastroenteritis (case 5)

7

_{, one GSDIa adult presented with isolated}

hypoglycemia before and after MCT supplementation (case 47), one pediatric GSDIIIa patient (case

57) reported isolated hypoglycemia three years after the start of a high fat diet, and one pediatric

GSDIIIa patients (case 58) presented with an isolated hypoglycemia one year before and two years

after start of a high fat diet. Other reported side effects were gastro-intestinal symptoms in an

adult GSDIa patient (case 38) on MCT replacement and worsening of epistaxis in a GSDI patient

receiving omega 3-FA supplementation

20

_{. Four GSDI patients received fenofibrate treatment that}

was started before dietary intervention (case 7, 43, 45 and 51).

DISCUSSION

Complex carbohydrates and, for ketotic GSD patients, protein enrichment are the cornerstones

of dietary management in hepatic GSD. The role of lipids has not been systematically assessed

and the current guidelines do not provide clear indications for their use

2–6

_{. This is a systematic}

literature study and retrospective international multi-center cohort study presents that a high

fat diet could be considered in pediatric GSDIII patients with cardiomyopathy, but yet there is

insufficient data supporting dietary lipid intervention in remaining hepatic GSD patients and

indications. The significant reduction in blood CK concentrations and subjective improvement in

muscle strenght reported in GSDIII patients necessitates further quantification of the effect of a

high fat diet on muscle quality and function. Also liver function, morphology and growth should

be carefully monitored under a high fat diet given the potential impact on underlying liver disease.

Before discussing the results, some methodological issues need to be addressed. The analysis

and interpretation of the data were hampered by large variation in age, dietary intervention (e.g.

lipid amount, high fat diet alone or together with lipid supplementation), duration of intervention,

and outcome parameters. The published cases presented in this study (n=37) were retrieved from

case reports or small cohort studies (describing less than five patients); therefore, these data were

likely affected by selection and publication bias. Four (40%) of the full-text papers included in this

study were published before 1995

15–17,20

_{. No significant decline in TG concentrations was observed}

when case reports published before the introduction of international guidelines were excluded (8.3

mmol/L ± 6.7 vs 5.8 mmol/L ± 6.0, p=0.24). It is recognized that metabolic control has improved

with increasing knowledge on dietary management/glycemic control and the introduction of

management guidelines

21

_{. Also, the possible beneficial role of a more compliant dietary scheme}

during dietary intervention should be considered. Finally, ascertainment bias extends to healthcare

professionals attending a GSD conference.

Z-scores, decreased only in pediatric GSDIIIa patients. We hypothesize that an early switch to high

fat diet can reverse -or at least decrease- the cardiac glycogen storage. Moreover, results showed

decreased CK concentrations in 89% of GSDIII patients in accordance with literature

8,10,11

_{, and}

improved subjective strength in most patients. Increased blood CK concentrations reflect muscle

damage which may partially be influenced by exercise. Whether the beneficial effect of a high fat

diet on CK concentrations is caused by a lower carbohydrate intake -and thus less accumulation

of abnormal glycogen in muscle tissue- or due to the properties of fat to supply alternative energy

substrate for muscle remains to be investigated. Notably, most of the GSDIII patients included

in the present study received a combination of a high fat and high protein diet. Therefore, these

changes in macronutrient composition could also partly account for the beneficial effect on

cardiac hypertrophy and CK concentrations. Nevertheless, protein intake was comparable before

and after intervention in GSDIII patients in the present study (Figure1B).

The development of chronic liver disease is an important concern in ageing GSDIII patients.

Although the prevalence of hepatocellular carcinoma was low in the International Study on GSDIII

22

_,

severe and progressive liver fibrosis has been described at early ages

23

_{. Only one publication}

describing high fat diet in two GSDIIIa patients documented data on liver transaminases (case

24, 25)

10

_{. Interestingly, we found that ALT increased in 44% (4/9) of pediatric GSDIII patients, but}

decreased in all adult GSDIII patients. After dietary lipid manipulation, the concomitant decrease in

carbohydrate intake could theoretically lead to less glycogen accumulation in the liver. It remains

speculative if these age-specific effects are part of the natural history or influenced by dietary

lipid manipulations. However, under these circumstances, careful monitoring and follow-up is

warranted for liver complications such as hepatosteatosis, liver inflammation and hepatocellular

carcinoma

24

_.

The pathogenesis of hyperlipidemia in hepatic GSD is incompletely understood and likely

different between nonketotic and ketotic GSD types. Inhibition of mitochondrial carnitine

palmitoyltransferase 1 (CPT-1) by accumulated malonyl co-enzyme A is expected

12

_{and arrested}

very-low-density lipoprotein catabolism is demonstrated in GSDIa patients

25

_{. Theoretically, MCT}

could bypass the metabolic block of long-chain fatty acid oxidation (FAO) thereby supplying FAO

and providing an additional source of energy

26

_{. Variability in effect of MCT on TG concentrations}

among patients might be due to variable compliance, dietary scheme (e.g. MCT only at night), age,

severity of hyperlipidemia and concurring factors (e.g. apolipoprotein variants). In this respect, the

lipid lowering effect of MCT administration requires further mechanistic investigation.

Dietary lipid manipulation was started in childhood in 80% of the cases. This may suggest

that besides the importance of glycemic control, management of hepatic GSD patients is

increasingly focused on the correction of secondary metabolic disturbances and extrahepatic

manifestations. Hepatic adenomas with the risk of undergoing malignant transformation are

a great concern in ageing GSDI patients

27

_{. Hypertriglyceridemia is an important risk factor for}

adenomas

28

_{and improvement in TG concentrations is associated with regression of adenomas}

29

_.

In the present study, one GSDIa patient (case 51) developed a liver adenoma while receiving MCT

supplementation; in this patient MCT failed to decrease TG concentrations.

Side effects were reported in six patients, including gastrointestinal complaints and (mostly

mild) hypoglycemia, an intrinsic symptom in hepatic GSD patients

30

_{. ‘Side effects’ was not a}

specific parameter in our data table, and therefore the side effects reported in this study could be

an underrepresentation. Previous mentioned concerns regarding MCT in GSDI patients are the

unknown consequence towards the elongation of fatty acids or gluconeogenesis

12

_{. Increased TG}

concentrations after MCT supplementation have been reported in GSDIII patients

31

_{. However, in}

the present study, the majority of GSDIII patients received a high fat diet rather than MCT. As high

fat diets have been associated with an increased risk of osteoporosis

32

_{combined with the reduced}

bone mineral density in GSDIII patients

33

_{the long-term effect of dietary lipid manipulations on}

bone status should be carefully monitored.

Recommendations for future dietary intervention studies and follow-up of GSDIII patients

who start with a high fat diet are summarized in Supplementary File E. The present study

provides insight in useful and missing outcome parameters when assessing the effect of a

dietary intervention in hepatic GSD patients. Several additional outcome measures are proposed

including muscle

34–36

_{, bone}

33

_{, mitochondrial}

9,37

_{and enzymatic}

38

_{markers. Prospective, long-term}

follow-up studies are warranted to confirm efficacy and safety of dietary lipid manipulations in

the international GSDIII and further hepatic GSD cohort.

FUNDING

This project was funded by Junior Scientific Masterclass by University Medical Center Groningen

(MD-PhD 15-16 grant to Irene J. Hoogeveen and dr. T.G.J. Derks). The stay of Alessandro Rossi

at University of Groningen was financially supported by University of Naples “Federico II” and

Compagnia di San Paolo, in the frame of Programme STAR.

ACKNOWLEDGMENTS

The authors would like to thank Margreet van Rijn, metabolic dietician from Groningen who was

involved in the initiation of this project. We also would like to acknowledge Ellen Wagenaar who

was responsible for the organization of the dietary networking session at the IGSD2017. MR, SG

and RP gratefully acknowledge Roberta Pretese, metabolic dietician in Monza, who thoroughly

followed all GSDIII patients of the center.

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Patients with Glycogen Storage Disease Type I. JIMD Rep. 2014;18:23-31.

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SUPPLEMENTARY MATERIAL

Supplementary File A. PRISMA flowchart of search strategy.

Supplementary File B: Table published cases.

Supplementary File C: Table unpublished cases.

Supplementary File D: Individual laboratory outcomes of metabolic control for all GSDI and

GSDIII patients.

Supplementary File E: Recommendations for clinical follow-up of dietary lipid manipulations in

patients with glycogen storage diseases type III.

Supplementary File A. Prisma fl owchart of search strategy. PubMed and Embase were searched using both

MeSH terms and free text: a. PubMed search: ‘(“Glycogen Storage Disease”[Mesh] OR glycogen storage[tiab]

OR glycogenos*[tiab]) AND (“Ketogenic Diet”[Mesh] OR “Diet, Carbohydrate-Restricted”[Mesh] OR ((fat[tiab]

OR fatty*[tiab] OR oil*[tiab] OR atkins[tiab] OR ketogen*[tiab]) AND (diet[tiab] OR diets[tiab] OR dietary[tiab] OR

dieting[tiab])) OR “triheptanoin” [Supplementary Concept] OR “Triglycerides”[Mesh] OR “Dietary Fats”[Mesh] OR

“Fish Oils”[Mesh] OR medium chain triglycerid*[tiab] OR MCT[tiab] OR triheptanoin*[tiab] OR omega-3-fatty

acid*[tiab] OR fi sh oil*[tiab]) NOT ((“Animals”[Mesh] NOT “Humans”[Mesh]) OR animal*[ti] OR rat[ti] OR rats[ti]

OR mouse[ti] OR mice[ti] ); b. Embase search: (‘glycogen storage disease’/exp OR (‘glycogen storage’ OR

gly-cogenos*):ab,ti) AND (‘ketogenic diet’/exp OR ‘low carbohydrate diet’/exp OR ((fat OR fatty* OR oil* OR atkins

OR ketogen*) AND (diet OR diets OR dietary OR dieting)):ab,ti OR ‘triheptanoin’/exp OR ‘triacylglycerol’/exp OR

‘fat intake’/de OR ‘fi sh oil’/exp OR (‘medium chain triglycerid*’ OR MCT OR triheptanoin* OR ‘omega-3-fatty

acid*’ OR ‘fi sh oil*’):ab,ti) NOT ((( ‘animal’/exp OR ‘nonhuman’/exp) NOT ‘human’/exp) OR (animal* OR rat OR

rats OR mouse OR mice):ti). The search was conducted on the 31th of December 2018. The PubMed search

revealed 179 articles whereas the Embase search resulted in 388 articles. After the duplicate check a total of

455 articles could be included for the search strategy. *From this case missing data in the published report

were collected during the retrospective study part; this case was therefore included as unpublished case (case

60) in Supplementary File C.

P

P

LEM

ENT

A

RY

F

ILE

B

tie nt r Re fe re nc e A ge a t s ta rt (y ea rs ), gen de r (M /F ) a nd G SD ty pe In di ca tio n t o s ta rt the d ie tar y int er ve nt ion Di et ar y i nt er ve nt io n a nd D ie t c ompo si tio n D ur at io n o f int er ve nt ion (m on th s) O ut co m e p ar am et er s: la bo rat or y r es ul ts (g lu co se /lac ta te /K et on es/ Ac Ac /B O HB /T C/ TG / H D L/ LD L: m m ol /L , in su lin : m U /L , u ric a ci d: m g/ dL , A ST / AL T/ C K : U /L ,F FA : µ m ol /L , T nT / N T-pr oB N P: n g/ L, M b: µ m ol /L ) O ut co m e p ar am et er s: di ag no st ic imag in g Ou tc om e par am et er s C lin ic al p ic tu re : W ei ght : k g, H ei ght : C m , B M I: k g/ m 2 Be rn st ei n e t a l, J In he rit M et ab D is . 20 10 AB ST R ACT n/a n/a Ia H yp er tr ig ly ce rid em ia M CT s up pl em en ta tio n 10 g M CT /d ay n/a Gl uc ose : n /a La ct at e, i ns ul in , u ric a ci d, ke to ne s, T C : n /a TG : - 7 3% O th er : n /a n/a n/a Be rn st ei n e t a l, J In he rit M et ab D is . 20 10 AB ST R ACT n/a n/a Ia H yp er tr ig ly ce rid em ia M CT s up pl em en ta tio n 10 g M CT /d ay n/a Gl uc ose : n /a La ct at e, i ns ul in , u ric a ci d, ke to ne s, T C : n /a TG : - 6 9% O th er : n /a n/a n/a Be rn st ei n e t a l, J In he rit M et ab D is . 20 10 AB ST R ACT n/a n/a Ia H yp er tr ig ly ce rid em ia M CT s up pl em en ta tio n 20 g M CT /d ay n/a Gl uc ose : n /a La ct at e, i ns ul in , u ric a ci d, ke to ne s, T C : n /a TG : - 3 2% O th er : n /a n/a n/a D as e t a l, A nn N ut r M et ab . 2 01 0 31 F Ia Po or m et ab ol ic c on tro l M CT s up pl em en ta tio n 16 50 K ca l/d ay , 6 5% ca rb oh yd ra te s, 2 1% l ip id s (2 5% M CT , 1 0 g /d ay , 1 4% pr ote in s 37 Gl uc ose : n /a La ct ate : n on -s ig ni fic an t de cr ea se b ut r ea ch ed n or m al val ue s In sul in : n /a U ric a cid : s ig ni fic an t d ec re as e Ke to ne s, T C : n /a TG : n on -s ig ni fic an t d ec re as e O th er : n /a n/a n/a D as e t a l, A nn N ut r M et ab . 2 01 0 1. 6 _{M Ia} Po or m et ab ol ic c on tro l M CT s up pl em en ta tio n 10 50 K ca l/d ay , 6 6% ca rb oh yd ra te s, 2 6% l ip id s (4 5% M CT , 1 3 g /d ay ), 8 % pr ote in s 32 Gl uc ose : n /a ( m or e s ta bl e gl uc ose v al ue s) La ct ate : n on -s ig ni fic an t de cr ea se b ut r ea ch ed n or m al val ue s In sul in : n /a U ric a cid : s ig ni fic an t d ec re as e Ke to ne s, T C : n /a TG : s ig ni fic an t d ec re as e O th er : n /a n/a Im pro ve d g ro w th (in cr ea se d b od y he igh t) D ur in g M CT su pp le m en ta tio n 2 e pi so de s of s ev er e ga st ro en te rit is as so ci at ed w ith hy po gl yc em ia a nd ke to nu ria

on

tin

ued.

4a

Re fe re nc e A ge a t s ta rt (y ea rs ), gen de r (M /F ) a nd G SD ty pe In di ca tio n t o s ta rt the d ie tar y int er ve nt ion Di et ar y i nt er ve nt io n a nd D ie t c ompo si tio n D ur at io n o f int er ve nt ion (m on th s) O ut co m e p ar am et er s: la bo rat or y r es ul ts (g lu co se /lac ta te /K et on es/ Ac Ac /B O HB /T C/ TG / H D L/ LD L: m m ol /L , in su lin : m U /L , u ric a ci d: m g/ dL , A ST / AL T/ C K : U /L ,F FA : µ m ol /L , T nT / N T-pr oB N P: n g/ L, M b: µ m ol /L ) O ut co m e p ar am et er s: di ag no st ic imag in g Ou tc om e par am et er s C lin ic al p ic tu re : W ei ght : k g, H ei ght : C m , B M I: k g/ m 2 D as e t a l, A nn N ut r M et ab . 2 01 0 6.5 F Ib Po or m et ab ol ic c on tro l M CT s up pl em en ta tio n 85 0 K ca l/d ay , 6 3% ca rb ohy dr at es , 2 7% l ip id s (2 0% M CT , 5 g /d ay ), 1 0% pr ote in s 40 8 m on th s on d ie t, t he n di sc on tinu ed fo r 7 m on th s, t he n re sum ed Gl uc ose : n /a ( m or e s ta bl e gl uc ose v al ue s) La ct ate : n on -s ig ni fic an t de cr ea se b ut r ea ch ed n or m al val ue s In sul in : n /a U ric a ci d: s ig ni fic an t d ec re as e Ke to ne s, T C : n /a TG : s ig ni fic an t i nc re as e O th er : n /a U po n M CT di sc on tin ua tio n: 10 0% i nc re as e in l ac ta te , 4 0% i nc re as e i n T G an d 4 0% i nc re as e i n u ric a ci d. La ct at e, T G a nd u ric a ci d l ev el s fe ll a ga in w he n M CT r es um ed n/a Im pr ov em en t of gr ow th ( in cr ea se d bo dy h ei ght ) N ag as ak a e t a l, E ur J P ed ia tr. 2 00 7 13 M Ia H yp er tr ig ly ce rid em ia M CT rep lac em en t U C C S r ep la ce d w ith ca rb oh yd ra te r ic h M CT m ilk 23 50 K ca l/d ay , 6 5% ca rb oh yd ra te s (g alac tose an d f ru ct os e l im ite d t o 5% ), 2 0-25 % l ip id s, 1 0-15 % pr ote in 3 Gl uc ose : n o s ig ni fic an t di ff er en ce (n or ma l) La ct ate : s ig ni fic an t d ec re as e In sul in : n /a ; s ig ni fic an t i nc re as e in i ns ul in /g lu co se r at io U ric a cid : n /a Ke to ne s: s ig ni fic an t i nc re as e TC : n o s ig ni fic an t d iff er en ce (h ig h) TG : s ig ni fic an t d ec re as e O th er : H D L: s ig ni fic ant in cr ea se ; F FA : s ig ni fic an t in cr ea se ; T ot al c ar ni tin e: si gn ifi ca nt d ec re as e; A C s: si gn ifi ca nt i nc re as e Ac et oa cet yl ca rni tin e a nd bu ty ry lc ar ni tin e a cc ou nt ed f or th e m os t of t he i nc re as ed A C s. n/a n/a

Pa tie nt numbe r Re fe re nc e A ge a t s ta rt (y ea rs ), gen de r (M /F ) a nd G SD ty pe In di ca tio n t o s ta rt the d ie tar y int er ve nt ion Di et ar y i nt er ve nt io n a nd D ie t c ompo si tio n D ur at io n o f int er ve nt ion (m on th s) O ut co m e p ar am et er s: la bo rat or y r es ul ts (g lu co se /lac ta te /K et on es/ Ac Ac /B O HB /T C/ TG / H D L/ LD L: m m ol /L , in su lin : m U /L , u ric a ci d: m g/ dL , A ST / AL T/ C K : U /L ,F FA : µ m ol /L , T nT / N T-pr oB N P: n g/ L, M b: µ m ol /L ) O ut co m e p ar am et er s: di ag no st ic imag in g Ou tc om e par am et er s C lin ic al p ic tu re : W ei ght : k g, H ei ght C m , B M I: k g/ m 2 8 N ag as ak a e t a l, E ur J P ed ia tr. 2 00 7 0.5 n/a Ia H yp er tr ig ly ce rid em ia M CT r ep la ce m en t C ar bo hy dr at e-ric h, lip id -po or m ilk r ep la ce d w ith ca rb ohy dr at e-ric h M CT m ilk . 10 0 K ca l/g /d ay , 6 5% ca rb oh yd ra te s (g alac tose an d f ru ct os e l im ite d t o 5% ), 2 0-25 % l ip id s, 1 0-15 % pr ote in s 1 Gl uc ose : s ig ni fic an t i nc re as e (no rm al iz at io n) La ct ate : s ig ni fic an t d ec re as e In sul in : n /a ; s ig ni fic an t i nc re as e in i ns ul in /g lu co se r at io U ric a cid : n /a Ke to ne s: s ig ni fic an t i nc re as e TC : s ig ni fic an t d ec re as e TG : s ig ni fic an t d ec re as e O th er : H D L: s ig ni fic ant in cr ea se ; F FA : s ig ni fic an t in cr ea se ; T ot al c ar ni tin e: si gn ifi ca nt d ec re as e; A C s: si gn ifi ca nt i nc re as e Ac et oa cet yl ca rni tin e a nd bu ty ry lc ar ni tin e a cc ou nt ed f or th e m os t of t he i nc re as ed A C s. n/a n/a 9 N ag as ak a e t a l, E ur J P ed ia tr. 2 00 7 0.6 n/a Ia H yp er tr ig ly ce rid em ia M CT rep lac em en t C ar bo hy dr at e-ric h, lip id -po or m ilk r ep la ce d w ith ca rb oh yd ra te -r ic h M CT m ilk 10 0 K ca l/g /d ay , 6 5% ca rb oh yd ra te s (g alac tose an d f ru ct os e l im ite d t o 5% ), 2 0-25 % l ip id s, 1 0-15 % pr ote in s 2 Gl uc ose : s ig ni fic an t i nc re as e (no rm al iz at io n) La ct ate : s ig ni fic an t d ec re as e In sul in : n /a ; s ig ni fic an t i nc re as e in i ns ul in /g lu co se r at io U ric a cid : n /a Ke to ne s: s ig ni fic an t i nc re as e TC : s ig ni fic an t d ec re as e TG : s ig ni fic an t d ec re as e O th er : H D L: s ig ni fic ant in cr ea se ; F FA : n o s ig ni fic an t di ff er en ce ; T ot al c ar ni tin e: si gn ifi ca nt d ec re as e; A C s: si gn ifi ca nt i nc re as e Ac et oa cet yl ca rni tin e a nd bu ty ry lc ar ni tin e a cc ou nt ed f or th e m os t of t he i nc re as ed A C s. n/a n/a

C

on

tin

ued.

4a

Re fe re nc e A ge a t s ta rt (y ea rs ), gen de r (M /F ) a nd G SD ty pe In di ca tio n t o s ta rt the d ie tar y int er ve nt ion Di et ar y i nt er ve nt io n a nd D ie t c ompo si tio n D ur at io n o f int er ve nt ion (m on th s) O ut co m e p ar am et er s: la bo rat or y r es ul ts (g lu co se /lac ta te /K et on es/ Ac Ac /B O HB /T C/ TG / H D L/ LD L: m m ol /L , in su lin : m U /L , u ric a ci d: m g/ dL , A ST / AL T/ C K : U /L ,F FA : µ m ol /L , T nT / N T-pr oB N P: n g/ L, M b: µ m ol /L ) O ut co m e p ar am et er s: di ag no st ic imag in g Ou tc om e par am et er s C lin ic al p ic tu re : W ei ght : k g, H ei ght : C m , B M I: k g/ m 2 Le vy e t a l, A m J C lin N ut r. 1 99 3 10 -2 7 n/a I H yp er lip id em ia Fi sh o il s up pl em ent at io n D ie t e nr ic he d i n ω -3 FA . 10 g ω -3 FA /1 .7 3m 2/d ay . 3 Gl uc ose : n o s ig ni fic ant di ff er en ce (n or ma l) La ct ate : n o s ig ni fic an t dif fe re nc e (h ig h) In sul in : n /a U ric a ci d: n o s ig ni fic an t dif fe re nc e (h ig h) Ke to ne s: n /a TC : n on -s ig ni fic ant d ec re as e TG : s ig ni fic ant d ec re as e O th er : L D L; s ig ni fic an t de cr ea se : H D L, a po A1 : si gn ifi ca nt i nc re as e; a po B: n on -si gn ifi ca nt d ec re as e In cr ea se d H D L/ LD L a nd H D L/ TC rat io s. Re du ce d T G e nr ic hm en t of VL D L, I D L, H D L; r ed uc ed V LD L, ID L, L D L s iz e. In cr ea se d l ip op ro te in l ip as e ac tivi ty . Im pr ov em en ts i n l ip op ro te in co m po si tio n d is ap pe ar ed up on d is co nt in ua tio n of ω -3 FA su ppl em en ta tio n n/a n/a No s ig ni fic an t si de ef fe ct s ( 1 pa tie nt w or se n ep is ta xis ) Cu tt in o e t a l A rc h D er m at ol . 1 97 0 7 M Ia Sk in x an th om as H yp er lip id em ia M CT rep lac em en t LC T r ep la ce d w ith M CT 14 00 K ca l/d ay , 4 5% ca rb oh yd ra te s, 4 0% l ip id s, 15 % p ro te in s 2.1 7 Gl uc ose : n o s ig ni fic an t di ff er en ce (n or ma l) La ct at e, i ns ul in , u ric a ci d: n /a Ke to ne s: s lig ht i nc re as e TC : n /a TG : -82 % O th er : n /a n/a Xa nt ho m as co m pl ete ly di sap pe ar ed D ec re as ed liv er si ze

Pa tie nt numbe r Re fe re nc e A ge a t s ta rt (y ea rs ), gen de r (M /F ) a nd G SD ty pe In di ca tio n t o s ta rt the d ie tar y int er ve nt ion Di et ar y i nt er ve nt io n a nd D ie t c ompo si tio n D ur at io n o f int er ve nt ion (m on th s) O ut co m e p ar am et er s: la bo rat or y r es ul ts (g lu co se /lac ta te /K et on es/ Ac Ac /B O HB /T C/ TG / H D L/ LD L: m m ol /L , in su lin : m U /L , u ric a ci d: m g/ dL , A ST / AL T/ C K : U /L ,F FA : µ m ol /L , T nT / N T-pr oB N P: n g/ L, M b: µ m ol /L ) O ut co m e p ar am et er s: di ag no st ic imag in g Ou tc om e par am et er s C lin ic al p ic tu re : W ei ght : k g, H ei ght C m , B M I: k g/ m 2 10 -1 6 Le vy e t a l, A m J C lin N ut r. 1 99 3 10 -2 7 n/a I H yp er lip id em ia Fi sh o il s up pl em ent at io n D ie t e nr ic he d i n ω -3 FA . 10 g ω -3 FA /1 .7 3m 2/d ay . 3 Gl uc ose : n o s ig ni fic an t di ff er en ce (n or ma l) La ct ate : n o s ig ni fic an t dif fe re nc e (h ig h) In sul in : n /a U ric a ci d: n o s ig ni fic an t dif fe re nc e (h ig h) Ke to ne s: n /a TC : n on -s ig ni fic ant d ec re as e TG : s ig ni fic ant d ec re as e O th er : L D L; s ig ni fic an t de cr ea se : H D L, a po A1 : si gn ifi ca nt i nc re as e; a po B: n on -si gn ifi ca nt d ec re as e In cr ea se d H D L/ LD L a nd H D L/ TC rat io s. Re du ce d T G e nr ic hm en t of VL D L, I D L, H D L; r ed uc ed V LD L, ID L, L D L s iz e. In cr ea se d l ip op ro te in l ip as e ac tivi ty . Im pr ov em en ts i n l ip op ro te in co m po si tio n d is ap pe ar ed up on d is co nt in ua tio n of ω -3 FA su ppl em en ta tio n n/a n/a No s ig ni fic an t si de ef fe ct s ( 1 pa tie nt w or se n ep is ta xis ) 17 Cu tt in o e t a l A rc h D er m at ol . 1 97 0 7 M Ia Sk in x an th om as H yp er lip id em ia M CT rep lac em en t LC T r ep la ce d w ith M CT 14 00 K ca l/d ay , 4 5% ca rb oh yd ra te s, 4 0% l ip id s, 15 % p ro te in s 2.1 7 Gl uc ose : n o s ig ni fic an t di ff er en ce (n or ma l) La ct at e, i ns ul in , u ric a ci d: n /a Ke to ne s: s lig ht i nc re as e TC : n /a TG : -82 % O th er : n /a n/a Xa nt ho m as co m pl ete ly di sap pe ar ed D ec re as ed liv er si ze

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Pa tie nt numbe r Re fe re nc e A ge a t s ta rt (y ea rs ), gen de r (M /F ) a nd G SD ty pe In di ca tio n t o s ta rt the d ie tar y int er ve nt ion Di et ar y i nt er ve nt io n a nd D ie t c ompo si tio n D ur at io n o f int er ve nt ion (m on th s) O ut co m e p ar am et er s: la bo rat or y r es ul ts (g lu co se /lac ta te /K et on es/ Ac Ac /B O HB /T C/ TG / H D L/ LD L: m m ol /L , in su lin : m U /L , u ric a ci d: m g/ dL , A ST / AL T/ C K : U /L ,F FA : µ m ol /L , T nT / N T-pr oB N P: n g/ L, M b: µ m ol /L ) O ut co m e p ar am et er s: di ag no st ic imag in g Ou tc om e par am et er s C lin ic al p ic tu re : W ei ght : k g, H ei ght C m , B M I: k g/ m 2 18 Cu tt in o e t a l, Pe di at ric s. 1 97 0 7 M Ia Sk in x an th om as H yp er lip id em ia M CT rep lac em en t LC T r ep la ce d w ith M CT , lo w c ar bo hy dr at e i nt ak e. 5 di et p er io ds 1 . 1 40 0 K ca l/ da y, 4 5% c ar bo hy dr at es , 40 % l ip id s a s L CT , 1 5% pr ote in s 2. 1 00 0 K ca l/d ay , 7 5% ca rb ohy dr at es , 1 5% l ip id s as L CT , 1 0% p ro te in s 3. 1 60 0 K ca l/d ay , 4 5% ca rb ohy dr at es , 4 0% l ip id s as M CT , 1 5% p ro te in s 4. 1 60 0 K ca l/d ay , 3 5% ca rb ohy dr at es , 4 5% l ip id s as M CT , 2 0% p ro te in s 5. 1 30 0 K ca l/d ay , 3 5% ca rb ohy dr at es , 4 5% l ip id s as M CT , 2 0% p ro te in s 2.6 7 Per io d 1: 0. 13 Per io d 2: 0. 37 Pe rio d 3 : 1 .5 Pe rio d 4 : 0 .17 Pe rio d 5 : 0 .5 Gl uc ose : n /a La ct at e, i ns ul in , u ric a ci d: n /a Ke to ne s: s lig ht i nc re as e TC : -40 % TG : -80 % O th er : n /a Se ru m l ip id s i nc re as ed u po n re in st itu tio n of r eg ul ar di et a nd fe ll a ga in w he n M CT r es um ed n/a Xa nt ho m as co m pl ete ly di sap pe ar ed D ec re as ed liv er si ze 19 Fe rn an de s e t Pik aar , Am J Cl in N ut r. 19 69 4 M Ia H yp er lip id em ia C or n o il s up pl em en ta tio n 3 d ie t p er io ds . B et w ee n tw o p er io ds o f h ig h ca rb oh yd ra te /lo w f at d ie t, th e c hi ld w as f ed a d ie t w ith c al or ie s o ut of c or n o il 1. 6 7% c ar bo hy dr at es , 1 4% lip id s c or n o il, 1 9% p ro te in s 2. 4 7% c ar bo hy dr at es , 3 4% lip id s c or n o il, 1 9% p ro te in s 3. 6 7% c ar bo hy dr at es , 1 4% lip id s c or n o il, 1 9% p ro te in s 3.5 Perio d 1 : 0 .5 Pe rio d 2 : 1 .5 Pe rio d 5 : 1 .5 G lu co se , L ac ta te , in su lin : n /a U ric a ci d, k et on es : n /a TC : n o s ig ni fic an t d iff er en ce (h ig h) TG : n /a O th er : P ho sp ho lip id s: n o si gn ifi ca nt d iff er en ce ( hi gh ); FF A: n o s ig ni fic an t d iff er en ce (h ig h) n/a n/a

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Re fe re nc e A ge a t s ta rt (y ea rs ), gen de r (M /F ) a nd G SD ty pe In di ca tio n t o s ta rt the d ie tar y int er ve nt ion Di et ar y i nt er ve nt io n a nd D ie t c ompo si tio n D ur at io n o f int er ve nt ion (m on th s) O ut co m e p ar am et er s: la bo rat or y r es ul ts (g lu co se /lac ta te /K et on es/ Ac Ac /B O HB /T C/ TG / H D L/ LD L: m m ol /L , in su lin : m U /L , u ric a ci d: m g/ dL , A ST / AL T/ C K : U /L ,F FA : µ m ol /L , T nT / N T-pr oB N P: n g/ L, M b: µ m ol /L ) O ut co m e p ar am et er s: di ag no st ic imag in g Ou tc om e par am et er s C lin ic al p ic tu re : W ei ght : k g, H ei ght : C m , B M I: k g/ m 2 Fe rn an de s e t Pik aar , Am J Cl in N ut r. 19 69 1 F Ia H yp er lip id em ia M CT s up pl em en ta tio n 3 d ie t p er io ds 1. 42 % c ar bo hy dr at es , 4 0% lip id s c or n o il, 1 8% p ro te in s 2. 42 % c ar bo hy dr at es , 4 0% lip id s M CT , 1 8% p ro te in s 3. 5 0% c ar bo hy dr at es , 28 % l ip id s m ix ed f at , 2 2% pr ote in s 3. 25 Pe rio d 1 : 1 .7 5 Pe rio d 2 : 1 Pe rio d 5 : 0 .5 G lu co se , L ac ta te , in su lin : n /a U ric a ci d, k et on es : n /a TC : s ig ni fic an t i nc re as e TG : n /a O th er : P ho sp ho lip id s, F FA : si gn ifi ca nt i nc re as e n/a n/a W hi te e t a l, J I nh er it M et ab D is . 20 18 AB ST R ACT 0.4 2 F IIIa H ig h g lu co se d em an d, se iz ur e H ig h-fa t, h ig h p ro te in d ie t 20 % c ar bo hy dr at es , 6 0% lip id s, 2 0% p ro te in 7 Gl uc ose : > 2. 8 m m ol /L Ke to ne s: 0 .5 - 2 .4 m m ol /L In su lin , T C , T G , C K : n /a O th er : n /a C ar di ac U S: hy pe rt ro ph ic ca rd io m yo pat hy fu lly re so lv ed . In cr ea se d f as tin g tole ra nc e. G ro se lj e t a l, J I nb or n E rr or s M et ab S cr ee n 2 01 7 AB ST R ACT 12 F IIIa Sev er e h yp er tro ph ic ca rd io m yo pat hy , hep at om eg aly , m yo pa th y. Ket og eni c d iet . K et og eni c ra tio s of m ea ls w er e f ro m 2. 5: 1 t o 4 :1. 2% c ar bo hy dr at es , 8 7% lip id s, 1 1% p ro te in 18 Gl uc ose : n o hy po gl yc em ia Ke to ne s, i ns ul in , T C , T G , C K : n/a Oth er : li pi d l ev el s i m pr ov ed si gni fic an tly . Li ve r U S: s ig ni fic ant im pr ov em en t of hep at om eg aly C ar di ac M RI : no rm al iz at io n of l ef t ve nt ric ul ar p ar am et er s an d m as s ( fr om 7 0 g t o 3 5 g ), w ith ou t re si du al o ut flo w ob st ruc tio n. Ex er tio n d ys pn ea di sap pe ar ed . C ap ac ity fo r o xy ge n co ns um pt io n alm os t d ou bl ed Ku m ru e t a l, J I nh er it M et ab D is . 20 16 AB ST R ACT 6 M IIIa H yp er tro ph ic ca rd io m yo pat hy Fat ig ue H ig h-fa t, h ig h p ro te in d ie t. 30 % c ar bo hy dr at es , 5 0% lip id s, 20 % p ro tein . 18 Gl uc ose , k et on es , in su lin , T C, TG : n /a C K : f ro m 1 62 8 t o 1 12 5 O th er : n /a C ar di ac U S: lef t ve nt ric ul ar o ut flo w gr ad ie nt r ed uc ed f ro m 35 t o 2 0 m m H g; I VS th ic kn es s r ed uc ed fr om 2 1 t o 1 0 m m ; po st er io r w al l th ic kn es s r ed uc ed fr om 1 8 t o 1 1 m m Fa tig ue re so lv ed

Pa tie nt numbe r Re fe re nc e A ge a t s ta rt (y ea rs ), gen de r (M /F ) a nd G SD ty pe In di ca tio n t o s ta rt the d ie tar y int er ve nt ion Di et ar y i nt er ve nt io n a nd D ie t c ompo si tio n D ur at io n o f int er ve nt ion (m on th s) O ut co m e p ar am et er s: la bo rat or y r es ul ts (g lu co se /lac ta te /K et on es/ Ac Ac /B O HB /T C/ TG / H D L/ LD L: m m ol /L , in su lin : m U /L , u ric a ci d: m g/ dL , A ST / AL T/ C K : U /L ,F FA : µ m ol /L , T nT / N T-pr oB N P: n g/ L, M b: µ m ol /L ) O ut co m e p ar am et er s: di ag no st ic imag in g Ou tc om e par am et er s C lin ic al p ic tu re : W ei ght : k g, H ei ght C m , B M I: k g/ m 2 24 Br am bi lla e t a l,J In he rit M et ab D is . Re p. 2 01 4 7 F IIIa Se ve re ca rd io m yo pat hy , m us cl e w ea kn es s H ig h-fa t h ig h p ro te in d ie t 11 20 K ca l/d ay , 1 5% ca rb ohy dr at es , 5 9% l ip id s, 26 % p ro te in s U C C S p ro gr es si ve ly w ith dr aw n Po ly un sat ur at ed fat ty ac id s p re fe rr ed O nl y e xt ra -v irg in o liv e o il as re lis h Ad di tio na l p ro te in p ow der s to i nc re as e p ro te in i nt ak e 12 Gl uc ose , la ct at e: n o s ig ni fic an t di ff er en ce (n or ma l) In sul in : n /a Ke to ne s: n /a TC , T G : n o s ig ni fic an t di ff er en ce (n or ma l) C K : s ig ni fic an t d ec re as e O th er : N T-pr oB N P, M b, A LT : si gn ifi ca nt d ec re as e; A ST : sl ig ht de cr ea se ; T nT : n o si gn ifi ca nt d iff er en ce ( no rm al ) C ar di ac U S: I VS th ic kn es s, p os te rio r w al l t hi ck ne ss an d o ut flo w tra ct o bs tr ucti on si gn ifi ca nt ly re du ce d In cr ea se d st re ng th a nd re du ce d e xe rt io n dy sp ne a. N o s ig ni fic an t im pa ct o n g ro w th (n or m al ) a nd l iv er si ze ( in cr ea se d) 25 Br am bi lla e t a l,J In he rit M et ab D is . Re p. 2 01 4 5 M IIIa Se ve re ca rd io m yo pat hy , m us cl e w ea kn es s H ig h-fa t h ig h p ro te in d ie t 10 50 K ca l/d ay , 1 5% ca rb ohy dr at es , 6 0% l ip id s, 25 % p ro te in s U C C S p ro gr es si ve ly w ith dr aw n Po ly un sat ur at ed fat ty ac id s p re fe rr ed O nl y e xt ra -v irg in o liv e o il as re lis h Ad di tio na l p ro te in p ow der s to i nc re as e p ro te in i nt ak e 12 Gl uc ose , la ct at e: n o s ig ni fic an t di ff er en ce (n or ma l) In sul in : n /a Ke to ne s: n /a TC : n o s ig ni fic an t d iff er en ce (n or ma l) TG : s lig ht i nc re as e C K : s ig ni fic an t d ec re as e O th er : N T-pr oB N P, M yo gl ob in , AL T, A ST : s ig ni fic ant d ec re as e; Tn T: n o s ig ni fic an t d iff er en ce (n or ma l) C ar di ac U S: IV S th ic kn es s, p os te rio r w al l t hi ck ne ss an d o ut flo w tra ct o bs tr ucti on si gn ifi ca nt ly re du ce d In cr ea se d str en gth N o s ig ni fic an t im pa ct o n g ro w th (n or m al ) a nd l iv er si ze ( in cr ea se d) 26 El -G ha rb aw y e t a l, M ol G en et M et ab . 20 14 AB ST R ACT 3.5 n/a IIIa Po or m et ab ol ic c on tro l M CT s up pl em en ta tio n U C C S p ro gr es si ve ly w ith dr aw n 1 Gl uc ose , in su lin , T C, T G : n o sig ni fic an t dif fe re nc e Ke to ne s: n o e vi de nc e o f k et os is C K : s ig ni fic an t d ec re as e O th er : A LT , A ST : m od es t de cr ea se n/a Im pro ve d e ne rg y lev el s

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Re fe re nc e A ge a t s ta rt (y ea rs ), gen de r (M /F ) a nd G SD ty pe In di ca tio n t o s ta rt the d ie tar y int er ve nt ion Di et ar y i nt er ve nt io n a nd D ie t c ompo si tio n D ur at io n o f int er ve nt ion (m on th s) O ut co m e p ar am et er s: la bo rat or y r es ul ts (g lu co se /lac ta te /K et on es/ Ac Ac /B O HB /T C/ TG / H D L/ LD L: m m ol /L , in su lin : m U /L , u ric a ci d: m g/ dL , A ST / AL T/ C K : U /L ,F FA : µ m ol /L , T nT / N T-pr oB N P: n g/ L, M b: µ m ol /L ) O ut co m e p ar am et er s: di ag no st ic imag in g Ou tc om e par am et er s C lin ic al p ic tu re : W ei ght : k g, H ei ght : C m , B M I: k g/ m 2 El -G ha rb aw y e t a l, M ol G en et M et ab . 20 14 AB ST R ACT 2 n/a IIIa Po or m et ab ol ic c on tro l M CT s up pl em en ta tio n U C C S p ro gr es si ve ly w ith dr aw n 1 Gl uc ose , in su lin , T C, T G : n o sig ni fic an t dif fe re nc e Ke to ne s: n o e vi de nc e o f k et os is C K : s ig ni fic an t d ec re as e O th er : A LT , A ST : m od es t de cr ea se n/a Im pro ve d e ne rg y lev el s M ayo ra nd an et a l, O rp ha ne t J Ra re D is . 2 01 4 9 M IIIa Se ve re ca rd io m yo pat hy , m us cl e w ea kn es s H ig h-fa t h ig h p ro te in d ie t U C C S p ro gr es si ve ly w ith dr aw n M od ifi ed A tk in s d ie t 0. 4 g /K g/ da y ca rb oh yd ra te s, 8 g /K g/ da y lip id s, 7 g /K g/ da y p ro te in s 32 G lu co se , in sul in : n /a ; oc ca sio na l h yp og ly ce m ia du rin g t he fi rs t we ek s Ke to ne s: i nc re as ed TC : n /a TG : s lig ht i nc re as e C K : s ig ni fic an t d ec re as e O th er : N T-pr oB N P: s ig ni fic an t de cr ea se ; L D L: n o s ig ni fic an t di ff er en ce (n or ma l) C ar di ac U S: I VS th ic kn es s a nd l ef t ve nt ric ul ar o ut flo w tra ct -g ra di en t si gn ifi ca nt ly re du ce d In cr ea se d st am in a N o s ig ni fic an t im pa ct o n g ro w th (n or ma l) M ayo ra nd an et a l, O rp ha ne t J Ra re D is . 20 14 11 M IIIa ca rd io m yo pat hy , m us cl e w ea kn es s, ch es t p ai n, n au se a af te r ex er ci se H ig h-fa t h ig h p ro te in d ie t U C C S p ro gr es si ve ly w ith dr aw n M od ifi ed A tk in s d ie t 0. 5 g /K g/ da y ca rb ohy dr at es , 6 g /K g/ da y lip id s, 5 g /K g/ da y l ip id s 3 Dis co nt in ue d fo r s ev er al m ont hs , t he n re sum ed G lu co se , in sul in : n /a Ke to ne s: i nc re as ed TC : n /a TG : n o s ig ni fic an t d iff er en ce (n or ma l) C K : s ig ni fic an t d ec re as e O th er : L D L: n o s ig ni fic an t di ff er en ce (n or ma l) In cr ea se i n C K l ev el s a nd lo st k et os is u po n d ie t di sc on tin ua tio n. C K l ev el s fe ll a ga in a nd k et os is w as re -e st ab lis he d w he n t he d ie t re sum ed C ar di ac U S: H yp er tro ph ic ca rd io m yo pat hy di sap pe ar ed Ch es t p ai n, na us ea a nd w ea kn es s di sap pe ar ed In cr ea se d st am in a Ch es t p ai n an d w ea kn es s re ap pe ar ed up on d ie t dis co nt in ua tio n an d r ev er te d ag ai n w he n t he die t w as re sum ed M ey er e t a l, J I nh er it M et ab D is . 20 13 A BS TR AC T 9 M IIIa Po or m et ab ol ic c on tro l H ig h-fa t h ig h p ro te in d ie t At ki ns d iet 12 G lu co se , in sul in : n /a Ke to ne s, T C , T G : n /a C K : s ig ni fic an tly d ec re as ed C ar di ac f un ct io n st ab ilis ed Im pr ov ed p hy sic al str en gth

Pa tie nt numbe r Re fe re nc e A ge a t s ta rt (y ea rs ), gen de r (M /F ) a nd G SD ty pe In di ca tio n t o s ta rt the d ie tar y int er ve nt ion Di et ar y i nt er ve nt io n a nd D ie t c ompo si tio n D ur at io n o f int er ve nt ion (m on th s) O ut co m e p ar am et er s: la bo rat or y r es ul ts (g lu co se /lac ta te /K et on es/ Ac Ac /B O HB /T C/ TG / H D L/ LD L: m m ol /L , in su lin : m U /L , u ric a ci d: m g/ dL , A ST / AL T/ C K : U /L ,F FA : µ m ol /L , T nT / N T-pr oB N P: n g/ L, M b: µ m ol /L ) O ut co m e p ar am et er s: di ag no st ic imag in g Ou tc om e par am et er s C lin ic al p ic tu re : W ei ght : k g, H ei ght C m , B M I: k g/ m 2 31 M ey er e t a l, J I nh er it M et ab D is . 20 13 A BS TR AC T 11 M IIIa Po or m et ab ol ic c on tro l H ig h-fa t h ig h p ro te in d ie t At ki ns d iet 12 G lu co se , in sul in : n /a Ke to ne s, T C , T G : n /a C K : s ig ni fic an tly d ec re as ed In cr ea se i n C K l ev el s u po n di et d is co nt in ua tio n; C K l ev el s fe ll a ga in w he n t he d ie t w as re sum ed C ar di ac f un ct io n st ab ilis ed Im pr ov ed p hy sic str en gth Ch es t p ai n a nd re du ce d p hy si ca st re ng th u po n d ie dis co nt in ua tio n 32 Va la ya nn op ou lo s e t al , P ed ia tr R es . 20 11 0.1 7 M III Se ve re ca rd io m yo pat hy H ig h-fa t h ig h p ro te in d ie t 20 % c ar bo hy dr at es , 6 5% lip id s, 1 5% p ro te in s + B H B (4 00 -8 00 m g/K g/ da y) 24 G lu co se , in sul in : s ig ni fic an t de cr ea se (n or ma l) Ke to ne s: s ig ni fic an t i nc re as e TC : n o s ig ni fic an t d iff er en ce (n or ma l) TG : n o s ig ni fic an t d iff er en ce (el ev at ed ) C K : s ig ni fic an t d ec re as e O th er : F FA : s ig ni fic ant in cr ea se ; A ST , A LT : n o si gn ifi ca nt d iff er en ce ( el ev at ed ) C ar di ac U S: I VS th ic kn es s s ig ni fic ant ly de cr ea sed N or m al m us cl e to ne a nd s tre ng th gr ow th a nd dev el op m en t Li ve r s iz e in cr ea se d w ith in t he fi rs t 6 m ont hs a nd t he n re m ain ed s tab le D ie t a nd B H B tre at m en t w el l t ol er at ed ; no f ur th er hy po gl yc em ia 33 Fe rn an de s e t Pik aar , Am J Cl in N ut r. 19 69 1 F III H yp er lip id em ia H ig h f at l ow c ar bo hy dr at e di et Pe rio d 1 . 3 9% ca rb ohy dr at es , 5 0% l ip id s (3 2% co rn oi l, 1 8% m ilk fa t), 11 % p ro te in s Pe rio d 2 . 3 9% ca rb ohy dr at es , 5 0% l ip id s (3 2% ol iv e o il, 1 8% m ilk f at ), 11 % p ro te in s Pe rio d 3 . 3 9% ca rb ohy dr at es , 5 0% l ip id s (3 2% c oc on ut o il, 1 8% m ilk fa t), 1 1% p ro te in s Pe rio d 4 . 3 9% ca rb ohy dr at es , 5 0% l ip id s (M CT ) , 1 1% p ro te in s 5 Perio d 1 : 1 .5 Pe rio d 2 : 0 .7 5 Pe rio d 3 : 1 .2 5 Pe rio d 4 : 1 .5 G lu co se , in su lin , k et on es , T G , C K : n /a Pe rio d 1 .T C n o s ig ni fic an t di ff er en ce ( hi gh ) F FA : si gn ifi ca nt d ec re as e Pe rio d 2 . T C , F FA : n o sig ni fic an t dif fe re nc e Pe rio d 3 . T C n o s ig ni fic an t dif fe re nc e, F FA : h ig h flu ct ua tio n Pe rio d 4 . T C , F FA : s ig ni fic an t in cr ea se n/a n/a

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