University of Groningen
Glycogen storage disease type I Rake, Jan Peter
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clinical, biochemical and genetic aspects, and implications for treatment and follow-up.
(management of glycogen storage disease type I)
Jan Peter Rake
All rights reserved. No part of this book may be reproduced or transmitted in any form or by any means without written permission of the author and the publisher holding the copyright of the published articles.
ISBN: 90-367-1851-1 (printed version) ISBN: 90-367-1852-X (electronic version)
Photograph on cover: van Creveld, girl with glycogen storage disease at the beach of Zandvoort
Page design: P. van der Sijde, Groningen, The Netherlands Printed by: Ponsen & Looijen B.V., Wageningen, The Netherlands
Glycogen Storage Disease type I:
clinical, biochemical and genetic aspects, and implications for
treatment and follow-up.
(management of glycogen storage disease type I)
Proefschrift
ter verkrijging van het doctoraat in de Medische Wetenschappen aan de Rijksuniversiteit Groningen
op gezag van de
Rector Magnificus, dr. F. Zwarts, in het openbaar te verdedigen op
woensdag 8 oktober 2003 om 16.00 uur
door
Jan Peter Rake
geboren op 21 augustus 1968te Groningen
Co-promotor: Dr. G.P.A. Smit
Beoordelingscommissie: Prof. dr. R.O.B. Gans Prof. dr. F. Kuipers Prof. dr. K. Ullrich
J.H.A. Rake
‘Toutes les expériences s’enchaînent naturellement pour établir que le sucre, véritable produit d’une sécrétion intérieure, à laquelle j’ai donné le nom de glycogénie, prend naissance dans le foie aux dépens des éléments du sang et indépendamment de l’alimentation féculente et sucrée ….’
Claude Bernard, 24-03-1855, Vingt-cinquième leçon: ‘Sur la glycogénie animale’
Storage Disease type I
5.1 Is Glycogen Storage Disease type 1a associated 127 with atherosclerosis?
Eur J Pediatr 2002;161:s62-s64
5.2 Are dyslipidaemia and microalbuminuria in a 133 dolescents with Glycogen Storage Disease
type Ia associated with cardiovascular disease?
(submitted)
5.3 Increased lipogenesis and resistance of 143
lipoproteins to oxidative modification in two
patients with with Glycogen Storage Disease type Ia.
J Pediatr 2002;140:256-260
Chapter 6 Guidelines for the management of Glycogen 157 Storage Disease type I
6.1 Guidelines for management of Glycogen Storage 159 Disease type I - European Study on Glycogen
Storage Disease Type I (ESGSD I).
Eur J Pediatr 2002;161:s112-s119
6.2 Consensus guidelines for management of 173
Glycogen storage Disease type Ib - European
Study on Glycogen Storage Disease Type I (ESGSD I).
Eur J Pediatr 2002;160:s120-s123
Chapter 7 Summary, conclusions, discussion and 185 future perspectives
Chapter 8 Samenvatting en discussie voor de niet-medicus 229
Dankwoord 252
Curriculum vitae 255
Abbreviations 8 Chapter 1 Glycogen Storage Disease type I: introduction 9
and outline thesis
Chapter 2 Long-term management and outcome of 27 patients with Glycogen Storage Disease type I
2.1 Glycogen Storage Disease type I: diagnosis, 29 management, clinical course, and outcome.
Results of the European study on Glycogen Storage Disease type I (ESGSD I).
Eur J Pediatr 2002;161:s20-s34
2.2 Glycogen Storage Disease type I: long-term 53 outcome of patients born before 1975.
Results of the European study on Glycogen Storage Disease type I (ESGSD I).
(submitted)
Chapter 3 DNA-based diagnosis in Glycogen Storage 75 Disease type Ia
3.1 Glycogen Storage Disease type Ia: four novel 77 mutations (175delGG, R170X, G266V and V338F)
identified.
Hum Mutation 1999;13:173 (online citation:
Human Mutation, Mutation in Brief #220 (1998)
3.2 Identification of a novel mutation (867delA) in the 85 glucose-6-phosphatase gene in two siblings with
Glycogen Storage Disease type Ia with different phenotypes.
Hum Mutation 2000;15:381 (online citation:
Human Mutation, Mutation in Brief #304 (1999)
3.3 Glycogen Storage Disease type Ia: recent 89
experience with mutation analysis, a summary of mutations reported in literature, and a newly developed diagnostic flowchart.
Eur J Pediatr 2000;159:322-330
Chapter 4 Osteopenia in Glycogen Storage Disease type I 105 Bone mineral density in children, adolescents and
adults with Glycogen Storage Disease type Ia:
a cross-sectional and longitudinal study.
J Inher Metab Dis 2003;26 (in press)
ACE angiotensin converting enzyme
BMC bone mineral content
BMD bone mineral density
BMDareal areal bone mineral density in g/cm2
BMDbone age areal bone mineral density corrected for delayed bone maturation in g/cm2
BMDvol volumetric bone mineral density in g/cm3
BMI body mass index
CD Crohn’s disease
CNGDF continuous nocturnal gastric drip feeding CVS chorionic villus samples
DXA dual energy X-ray absorptiometry E/A ratio early filling velocity / atrial filling velocity
ER endoplasmic reticulum
ERPF effective renal plasma flow
ESGSD I European study on glycogen storage disease type I
FMs frequent meals
G6P glucose-6-phosphate
G6Pase glucose-6-phosphatase
G6PC glucose-6-phosphatse gene
G6PT glucose-6-phosphate translocase gene GCSF granulocyte colony stimulating factor GFR glomerular filtration rate
GLUT glucose transporter
GSD(s) glycogen storage disease(s) HDL high density lipoprotein
IBD inflammatory bowel disease
IDDM insulin dependent diabetes mellitus
IMT intima-media thickness
ISGSD I international study on glycogen storage disease type I
KT kidney transplantation
LDL low density lipoprotein
LT liver transplantation
LVM(I) left ventricular mass (index)
MD metabolic derangement
MIDA mass isotopomer distribution analysis MUFA monounsaturated fatty acids
PET positron emission tomography
PCOs polycystic ovaries
PCR polymerase chain reaction
PLR partial liver resection PUFA polyunsaturated fatty acids
RRT renal replacement therapy
RWT relative wall thickness
SDS standard deviation score
SFA saturated fatty acids
SSCP single strand conformational polymorphism
UCCS uncooked (corn) starch
UK United Kingdom
USA United States of America
VLDL very low density lipoprotein
XO xanthine oxidase
introduction and outline thesis Chapter 1
The Glycogen Storage Diseases
Glycogen is a giant molecule in which glucose is stored. It was discovered, isolated and characterised both chemically and physiologically in the mid 19th century by Claude Bernard6. Glycogen is a polysaccharide with a molecular weight varying from a few million to well over several hundred million. It has a spherical form and consists of D-glucose residues which are joined in straight chains by α1-4 linkages. The straight chains are branched at intervals of 4 to 10 residues with α1-6 linkages (Figure 1.1)65.
Figure 1.1 The glycogen molecule with enlargement of the structure at a branch point (adapted from Harper’s Review of Biochemistry)
Although almost all cells of the human body are capable of storing at least some glycogen, especially muscle and liver cells store large amounts.
Muscle cells can store up to 1 to 3 per cent of their weight as glycogen, whereas liver cells can store up to 5 to 8 percent glycogen. The role of glycogen in muscle is to provide substrates for the generation of ATP for muscle contraction, whereas glucose derived from glycogen in liver is mainly used to maintain normal blood glucose concentration during fasting16.
Glycogen storage diseases (GSDs) are inherited disorders that affect glycogen metabolism. Synthesis and degradation of glycogen are catalysed by enzymes that are (in)activated by hormones (Figure 1.2)28. Nowadays, defects in virtually all proteins involved in this synthesis or degradation of glycogen and its regulation have been found to cause some type of GSD16.
GSDs that affect glycogen degradation in liver cause hepatomegaly as a consequence of glycogen storage and (features of) hypoglycaemia. GSDs that affect glycogen degradation in muscle cause muscle cramps, exercise intolerance, susceptibility to fatigue, progressive weakness and other features of (cardio)myopathy. An overview of GSDs affecting the liver is given in Table 1.1.
Historical background Glycogen Storage Disease type I
The first clinical description of a patient with GSD was given by van Creveld, a Dutch pediatrician. At a meeting of the Dutch Society for Pediatrics in 1928, he gave a lecture titled ‘Over een bijzondere stoornis in de koolhydraatstofwisseling in den kinderleeftijd’ (‘an unusual disturbance of carbohydrate metabolism in childhood’)22,75. In retrospect this patient had GSD III. The first report of a patient with GSD I is attributed to von Gierke, a German pathologist. ‘Hepatonephromegalia glykogenia’ was the title of his description of a autopsy, performed at the cemetery, of a girl with enlargement of the liver and kidneys due to deposition of massive amounts of glycogen30. Biochemical tests on liver material of this patient performed by Schoenheimer, a German chemist, revealed that the glycogen was exclusively composed of glucose residues and could be degraded by minced normal liver61. Von Gierke and Schoenheimer concluded that in their patient a glycogen–degrading substance was missing. In 1952, Cori and Cori21 demonstrated that absence of glucose-6-phosphatase (G6Pase) activity was the enzymatic defect Figure 1.2 Liver glycogen metabolism and its enzymes
Table 1.1 Classification of Glycogen Storage Diseases affecting the liver (adapted from36 and28) TypeSynonymSubtypesdefective enzyme / transportertissuechromosome(main) symptoms Ivon GierkeIaglucose-6-phosphataseL, K17q21HM, GR, HG, LA, HL I-non-aglucose-6-phosphate translocase (Ib)L, K, NG11q23as Ia, + or – NP, I, IBD phosphate translocase (Ic)L, K, NG11q23, ?as Ia, + or – NP, I, IBD IIICori / ForbesIIIadebranching enzyme (transferase + glucosidase)L, M1p21HM, GR, HG, HT, (C)MP IIIbdebranching enzyme (transferase + glucosidase)L1p21HM, GR, HG IIIddebranching enzyme (transferase)L, M1p21as IIIa IVAndersenbranching enzymeL, (M)3p12HM, C, (HT, (C)MP) VIHersphosphorylaseL14q21-22HM, GR, (HG), HL IXIXa - XLG Iphosphorylase-b-kinaseL, E, LCXp22HM, GR, (HG), HL IXa - XLG IIphosphorylase-b-kinaseLXp22HM, GR, (HG), HL IXaphosphorylase-b-kinaseL?HM, GR, (HG), HL IXbphosphorylase-b-kinaseL, M16q12-13?HM, GR, (HG), HT, MP XIFanconi-BickelGLUT 2L, K, I3q26HM, GR, HG, RPTD, OP 0glycogen synthaseL12p12GR, HG GSDs are caused by enzyme defects of glycogen degradation. Classification is usually still done by type number, which reflects the historical sequence of elucidation of the underlying defect. GSD-0 is grouped under the GSDs as it shares many clinical and metabolic abnormalities with other (liver-related) GSDs. The GSDs affecting merely (heart) muscle (GSD II, m. Pompe, acid α-glucosidase; GSD V, m. McArdle, myophosphorylase deficiency; GSD VII, m. Tarui, phosphofructokinase deficiency; GSD IXc, myophosphorylase-b-kinase deficiency; phosphoglucomutase deficiency; phosphoglycerate-kinase deficiency; phosphoglycerate-mutase deficiency; lactate-dehydrogenase deficiency) are not included in this table. Abbreviations: GSD glycogen storage disease; XLG x-linked glycogenosis; GLUT glucose transporter; L liver; K kidney; NG neutrophil granulocyte; M muscle; E erythrocyte; LC leucocyte; I intestine; HM hepatomegaly; GR growth retardation; HG hypoglycaemia; LA lactic acidosis; HL hyperlipidaemia; NP neutropenia; I recurrent infections; IBD inflammatory bowel disease; HT hypotonia; (C)MP (cardio)myopathy; RPTD renal proximal tubular dysfunction; OP osteopenia
responsible for the disease. This made GSD I the first ever metabolic disorder in which an enzyme defect was identified.
In the late 50’s, patients were described having the same clinical and biochemical abnormalities as ‘classic’ GSD I but having normal G6Pase activity in frozen liver tissue51. In 1968, Senior and Loridan63 proposed the term GSD Ib for this specific subtype. In the late 70’s, it was demonstrated that these patients had deficient G6Pase activity in fresh (unfrozen) liver tissue53.
The glucose-6-phosphatase enzyme system and genetics
Among the enzymes involved in glycogen synthesis and breakdown, G6Pase is unique since its active hydrolysing site is situated inside the lumen of the endoplasmic reticulum (ER), whereas the other enzymes involved in glycogen metabolism are in the cytoplasm56. This means that the substrate, glucose-6-phosphate (G6P), and the products, glucose and phosphate, must cross the ER membrane. In 1975, Arion3 postulated a model for the function of the G6Pase system. In this transport-model, the G6Pase system consists of a catalytic subunit, G6Pase, situated on the luminal surface of the ER, and at least one membrane transporter (Figure 1.3)4,80. Despite the fact that a lot of progress has been made, the controversy about the exact working mechanism of the G6Pase system still remains: the number of proteins, stoichiometry of each of these proteins, exact topology and whether these proteins form a complex are still unanswered questions16.
Figure 1.3 The glucose-6-phosphatase complex
Untill recently, four different types of GSD I were distinguished based on kinetic enzyme studies in hepatic microsomal preparations54. Deficient G6Pase activity in intact and disrupted microsomes indicate a defect in the catalytic unit, the actual G6Pase, and is called GSD Ia. Deficient G6Pase activity in intact microsomes and (sub)normal G6Pase activity in disrupted microsomes indicate a defect of the transporter proteins. Using different substrates a further differentiation was made between GSD Ib, GSD Ic and GSD Id. GSD Ib is caused by defects of the G6P transporter, which transports G6P from the cytoplasm to the inside of the ER53,40. GSD Ic is caused by defects of the putative phosphate/pyrophosphate transporter, which transports phosphate from inside ER back to the cytoplasm55. The suggestion was made that there might also be a GSD Id, attributed to defects of glucose transporter (GLUT) 7, a protein which transports glucose from inside ER to the cytoplasm.
However, this observation has been withdrawn8, and so far, no patient with GSD Id has been really described75.
In 1993 the gene encoding the catalytic unit of the G6Pase complex was identified. It is located in band q21 of chromosome 17. It consists of 5 exons and has a genomic length of 12.5 kb. It encodes a protein of 357 amino acids with a calculated molecular mass of 35-40 kD45,46,64. More recently also the gene encoding the G6P transporter has been identified. It is located in band q23 of chromosome 11. It consists of 9 exons2,29. Patients diagnosed by enzyme studies as GSD Ib, Ic and the putative Id, all had mutations in this G6P translocase gene70,71. Furthermore, in GSD Ib and GSD Ic identical mutations were found. This is consistent with the clinical findings as GSD I can be divided in two clinical phenotypes: GSD Ia patients have ‘classical’
findings as listed below, whilst those with ‘GSD I non-a’ (GSD Ib and Ic) may have recurrent bacterial infections and inflammatory bowel disease (IBD) associated with neutropenia and neutrophil dysfunction in addition73,74. However, recently a GSD Ic patient without mutations in the G6P transporter gene was described suggesting the existence of a distinct GSD Ic locus50. Furthermore, some GSD Ia patients who are homozygous for the G188R mutation, a missense mutation which most likely also disturbs a correct splicing of the G6Pase mRNA17, have neutropenia and neutrophil dysfunction81. In this thesis the term GSD Ib includes patients in whom GSD Ic had been diagnosed formerly.
Metabolic derangements in Glycogen Storage Disease type I
Hypoglycaemia, hyperlactacidaemia, hyperlipidaemia and hyperuricaemia are the most characteristic metabolic derangements of GSD I28.
Hypoglycaemia occurs during fasting as soon as exogenous sources of
glucose are exhausted, since deficiency of G6Pase activity in the liver blocks the final step in both the glycogenolytic and gluconeogenetic pathway.
Although both pathways of endogenous glucose production are blocked, evidence exists that GSD I patients are capable of some endogenous glucose production19,37. The mechanism behind this endogenous glucose production is still unclear.
Hyperlactacidaemia is a consequence of excess of G6P which can not be hydrolysed to glucose. G6P is further metabolised following the glycolytic pathway, generating ultimately pyruvate and lactate16. Lactate may serve as alternate fuel for the brain when the blood glucose concentration drops, hereby protecting patients against cerebral symptoms25. However, hyper- lactacidaemia may be associated with the development of long-term complications. Metabolic substrates as galactose, fructose and glycerol need the G6P-pathway in the liver to be metabolised to glucose. Therefore, in GSD I, ingestion of sucrose and lactose results in hyperlactacidaemia with only little rise in blood glucose24.
Hyperlipidaemia is thought to be a result of both increased synthesis of lipids from excess acetyl-CoA and decreased serum lipid clearance35,48,49,62
. Excess of pyruvate and lactate is converted into acetyl-coenzyme A (CoA), which is further converted to malonyl-CoA, an intermediate of fatty acid synthesis. Furthermore, malonyl-CoA inhibits mitochondrial β-oxidation which results in reduced ketone production23,28. Elevated serum triglycerides predominate; cholesterol and phospholipids are less elevated.
Hyperuricaemia is a result of both increased hepatic production and decreased renal clearance of uric acid16. Increased production is caused by increased degradation of adenine nucleotides to uric acid, associated with decreased intrahepatic phosphate concentration and ATP depletion33. Decreased renal clearance is caused by competitive inhibition of the excretion of uric acid by lactate18.
Clinical findings and long-term complications in Glycogen Storage Disease type I
Untreated patients display short stature, a rounded ‘doll face’, protruding abdomen (marked hepatomegaly), truncal obesity, and wasted muscles (Figure 1.4).
Hypoglycaemia may occur frequently, especially in childhood. Trivial events (short delay of a meal or a lower carbohydrate intake as consequence of an intercurrent illness) may elicit hypoglycaemia28. Symptoms of hypoglycaemia (paleness, sweating, abnormal behaviour, decreased consciousness, coma, convulsions) are usually accompanied by hyperventilation, a symptom of
lactic acidosis. Long-term cerebral function seems to be normal if hypo- glycaemic damage is prevented. Other symptoms directly related to metabolic derangements are skin xanthomas, which are positively correlated with the degree of hyperlipidaemia, and gout, which is associated with hyperuricaemia but rarely develops before puberty16. Patients bruise easily, and epistaxis is common as a result of impaired platelet function20. Furthermore, they may suffer from episodes of chronic diarrhoea52,77, the mechanism still being unresolved. Patients with GSD Ib may have neutropenia and neutrophil dysfunction that predispose to frequent infections and IBD74.
Marked hepatomegaly in GSD I is caused by storage of glycogen and fat.
Except for glucose homeostasis, liver functions are normal and cirrhosis does not develop28. In the second decade of life, patients may develop liver adenomas39,44, which have the potential to transform into carcinomas7.
In most patients, the kidneys are moderately enlarged. ‘Silent’ glomerular hyperfiltration may be observed already in prepubertal patients5,59. Microalbuminuria and subsequently proteinuria may develop, proceeding to hypertension and eventually end-stage renal disease12,14,42. Also renal proximal Figure 1.4 Italian boy with
glycogen storage disease type Ia
and distal tubular functions may be impaired, especially in metabolically poorly controlled patients13,60.
Other complications that may develop are anaemia, osteopenia, ovarian cysts, pancreatitis and pulmonary hypertension28.
The prevalence, severity and pathogenesis of most of the complications are still unknown, as is their association with metabolic control. Also the management of most of the complications is an open question.
Dietary treatment in Glycogen Storage Disease type I
The aim of treatment is to prevent hypoglycaemia in order to suppress secondary metabolic derangements as much as possible28. Maintaining normoglycaemia will reduce the morbidity (and mortality) associated with the disease16. Initially, treatment consisted of frequent carbohydrate-enriched meals during day and night. In 1974 continuous nocturnal gastric drip feeding (CNGDF) via a nasogastric tube was introduced9,32 allowing the patient and parents to sleep during the night. In 1983 uncooked (corn) starch (UCCS), from which glucose is much more slowly released than from cooked starch, was introduced10,11. Both CNGDF and UCCS have been proven to be able to maintain normoglycemia during night with equally favourable (short-term) results15,27,34,66,82,83,84
. UCCS during daytime is used to prolong the fasting period. As the diet is restricted, dietary supplements of multivitamins and calcium may be required16.
The collaborative European Study on Glycogen Storage Disease type I GSD I has an estimated frequency among newborns of one in 100.00016. Thus, no single metabolic centre has experience with large series of patients.
To share experience and knowledge, the collaborative European study on GSD I (ESGSD I) was initiated in 1996. Objectives of this study-group were to evaluate the management, clinical course and long-term outcome in both paediatric and adult patients with GSD I, to study the (long-term) complications, to develop therapeutic strategies and to develop guidelines for (long-term) management and follow-up. A management team consisting of GPA Smit (chairman) and J Fernandes (Groningen, The Netherlands), Ph Labrune (Clamart, France), JV Leonard (London, United Kingdom) and K Ullrich (Hamburg, Germany) was formed to supervise the ESGSD I. Twenty- five colleagues from 16 metabolic centres from 12 countries participated: D Skladal (Innsbruck, Austria); E Sokal (Brussels, Belgium); J Zeman (Prague, Czech Republic); Ph Labrune (Clamart, France); P Bührdel (Leipzig), K Ullrich (Münster/Hamburg), G Däublin, U Wendel (Düsseldorf, Germany); P Lee, JV Leonard (London), G Mieli-Vergani (London, Great Britain); L Szönyi
(Budapest, Hungary); P Gandullia, R Gatti, M di Rocco (Genoa), D Melis, G Andria (Naples, Italy); S Moses (Beersheva, Israel); J Taybert, E Pronicka (Warsaw, Poland); JP Rake, GPA Smit, G Visser (Groningen, The Netherlands);
H Özen, N Kocak (Ankara, Turkey). The department of Metabolic Diseases of the ‘Beatrix Kinderkliniek’, University Hospital Groningen, The Netherlands served as the co-ordinating centre and hosted the central database. The ESGSD I was executed by Jan Peter Rake and Gepke Visser.
Parts of the thesis ‘Glycogen Storage Disease type Ib: clinical and biochemical aspects and implications for treatment’ by Gepke Visser75 and parts of this thesis are based on data obtained in the ESGSD I. The thesis of Gepke Visser describes the incidence, severity and course of neutropenia, neutrophil dysfunction, infections and IBD in GSD Ib74 and the benefits and hazards of G-CSF treatment in these patients76. In vitro studies to gain more insight in neutrophil dysfunction in GSD Ib are also included72,79. Furthermore, it describes in vivo studies performed to investigate intestinal (dys)function in both GSD Ia and GSD Ib patients77. Finally, it provides guidelines for follow-up and treatment of the specific GSD Ib complications78. These consensus guidelines are also incorporated in chapter 7 of this thesis.
Outline of this thesis
GSD I represents a rare disease. In literature there is a relative paucity of data on outcome of this disease, and all these reports15,26,57,67,68,84
, except one69, focus on small groups of patients under 18 years. The first aim of the ESGSD I was to increase knowledge of diagnosis, management, (natural) clinical course, and (long-term) outcome in GSD I. Therefore, data on these aspects obtained from the ESGSD I were elaborated. Results are described in chapter 2.1 ‘Glycogen Storage Disease type I: diagnosis, management, clinical course, and outcome. Results of the European study on Glycogen Storage Disease type I (ESGSD I)’. Outcome of (adult) GSD I patients born before 1975 were studied in more detail. Results are described in chapter 2.2 ‘Glycogen Storage Disease type I: long-term outcome of patients born before 1975. Results of the European study on Glycogen Storage Disease type I (ESGSD I)’.
In 1993 the gene encoding the G6Pase catalytic unit was identified45,64. We started to perform DNA-based diagnosis in GSD Ia using a modification of a method described previously by others45,47. Mutations were identified by direct sequencing of PCR-amplified fragments showing an aberrant single strand conformation polymorphism (SSCP) migration pattern. Firstly, it was studied if this procedure is a reliable and save method allowing DNA-based
diagnosis in GSD Ia instead of enzyme assays in liver tissue obtained by biopsy and prenatal DNA-based diagnosis. Furthermore, a genotype- phenotype correlation was studied since it may be helpful in adjusting dietary and pharmacological strategies. A final study question was whether among our (North-Western) European GSD I population other (novel) mutations exist compared to mutations described in literature among other GSD I populations. Identified novel mutations are described in chapter 3.1
‘Glycogen Storage Disease type Ia: four novel mutations (175delGG, R170X, G266V and V338F) identified’ and chapter 3.2 ‘Identification of a novel mutation (867delA) in the glucose-6-phosphatase gene in two siblings with Glycogen Storage Disease type Ia with different phenotypes’. The other above mentioned study-questions are answered in chapter 3.3 ‘Glycogen Storage Disease type Ia: recent experience with mutation analysis, a summary of mutations reported in literature, and a newly developed diagnostic flowchart’.
Although abnormal bone formation and bone mineralisation in GSD I was already demonstrated more than 30 years ago58 and the occurrence of pathological fractures is a known complication in the ageing patients nowadays69, so far, only one study concerning bone mineralisation in GSD I has been published43. It showed reduced bone mineral content in the studied prepubertal patients. We investigated bone mineralisation in GSD I using dual energy X-ray absorptiometry. Results are described in chapter 4 ‘Bone mineral density in children, adolescents and adults with Glycogen Storage Disease type Ia: a cross-sectional and longitudinal study’.
Data about the development of (premature) atherosclerosis in (young) adult GSD I patients are very scarce41,69. However, in familial hyper- cholesterolaemia or familial combined hyperlipidaemia, a comparable degree of hyperlipidaemia is associated with cardiovascular morbidity and mortality at early age31,38. We performed non-invasive vascular measurements to study if GSD Ia is associated with premature atherosclerosis. Condensed results are described in chapter 5.1 ‘Is Glycogen Storage Disease type Ia associated with atherosclerosis?’ and more extended results are presented in chapter 5.2 ‘Are dyslipidaemia and microalbuminuria in adolescents with Glycogen Storage Disease type Ia associated with cardiovascular disease?.
Hyperlipidaemia is a very well known metabolic derangement in GSD I.
However, the exact pathogenesis is still not fully clarified. It is thought to be a result of both increased synthesis of lipids from excess of acetyl-CoA and lactate, and decreased serum lipid clearance1,35,48,49,62
. In vivo stable-isotopes studies were performed to investigate lipid synthesis in more detail.
Furthermore in vitro studies were performed to unravel the protective factor(s) against the development of premature atherosclerosis in GSD Ia. Results are described in chapter 5.3 ‘Increased lipogenesis and resistance of lipoproteins to oxidative modification in two patients with Glycogen Storage Disease type Ia’.
Life-expectancy in GSD I has improved considerably. However, its relative rarity implies that experience with long-term management and follow-up at each referral medical centre is limited. Furthermore, there is a large variation in long-term management and follow-up. One of the main objectives of the ESGSD I was to develop guidelines for long-term management and follow- up. These guidelines are based on the data of the ESGSD I, discussions with the members of the ESGSD I and participants of a international symposium
‘Glycogen Storage Disease type I and II: recent developments, management and outcome’ (Fulda, Germany; 22-25th November 2000) and on data from literature. The guidelines are described and discussed in chapter 6.1
‘Guidelines for management of Glycogen Storage Disease type I - European Study on Glycogen Storage Disease type I (ESGSD I)’ and chapter 6.2
‘Consensus guidelines for management of Glycogen Storage Disease type Ib - European Study on Glycogen Storage Disease type I (ESGSD I)’.
Finally, in chapter 7 (English) and chapter 8 (Dutch), a summary and conclusions along with a discussion and future perspectives are prersented.
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of patients with
Glycogen Storage Disease type I
2.1 Glycogen Storage Disease type I: diagnosis, clinical course, management and outcome.
Results of the European study on Glycogen Storage Disease type I (ESGSD I).
2.2 Glycogen Storage Disease type I: long-term outcome of patients born before 1975.
Results of the European study on Glycogen Storage Disease type I (ESGSD I).
Chapter 2
2.1 Glycogen Storage Disease type I: diagnosis, management, clinical course and outcome. Results of the European study on Glycogen Storage Disease type I (ESGSD I).
Jan Peter Rake Gepke Visser Philippe Labrune James V. Leonard Kurt Ullrich G. Peter A Smit
Eur J Pediatr 2002;161:s20-s34
On behalf of the members of the ESGSD I:
Austria Dr D Skladal, Innsbruck; Belgium Dr E Sokal, Brussels; Czech Republic Dr J Zeman, Prague; France Prof Ph Labrune, Clamart; Germany Prof P Bührdel, Leipzig; Prof K Ullrich, Münster (Hamburg); Dr G Däublin, Prof U Wendel, Düsseldorf; Great Britain Dr P Lee, Prof JV Leonard, London; Prof G Mieli-Vergani, London; Hungary Dr L Szönyi, Budapest; Italy Dr P Gandullia, Prof R Gatti, Dr M di Rocco, Genoa; Dr D Melis, Prof G Andria, Naples; Israel Prof S Moses, Beersheva;
Poland Dr J Taybert, Prof E Pronicka, Warsaw; The Netherlands Dr JP Rake, Dr GPA Smit, Dr G Visser, Groningen; Turkey Dr H Özen, Dr N Kocak, Ankara
Summary
Glycogen storage disease type I (GSD I) is a relatively rare metabolic disease and therefore no metabolic centre has experience of large series of patients. To document outcome, to develop guidelines about (long-term) management and follow-up, and to develop therapeutic strategies the collaborative European Study on GSD I (ESGSD I) was initiated.
This chapter is an descriptive analysis of data obtained from the retrospective part of the ESGSD I. Included were 231 GSD type Ia and 57 GSD type Ib patients. Median age of data collection was 10.4 years (range 0.4 - 45.4 years) for Ia and 7.1 years (0.4 - 30.6 years) for Ib patients. Data on dietary treatment, pharmacological treatment, and outcome including mental development, hyperlipidaemia and its complications, hyperuricaemia and its complications, bleeding tendency, anaemia, osteopenia, hepatomegaly, liver adenomas and carcinomas, progressive renal disease, height and adult height, pubertal development and bone maturation, school type, employment, and pregnancies are presented. Data on neutropenia, neutrophil dysfunction, infections, inflammatory bowel disease, and the use of granulocyte colony- stimulating factor are presented elsewhere90,91.
In conclusion, there is a wide variation in methods of dietary and pharmacological treatment of GSD I. Intensive dietary treatment will improve, but not correct completely, clinical and biochemical status and fewer GSD I patients will die as a direct consequence of acute metabolic derangement.
With ageing, more complications will develop of which progressive renal disease and the complications related to liver adenomas are likely to be two major causes of morbidity and mortality.
Introduction
Glycogen storage disease type I (GSD I, McKusick 232200) is an autosomal recessive inborn error of carbohydrate metabolism caused by defects of the glucose-6-phosphatase (G6Pase) complex. G6Pase plays a central role in both glycogenolysis and gluconeogenesis, hydrolysing glucose-6-phosphate (G6P) to glucose. Deficiency of G6Pase activity in liver, kidney and intestine results in accumulation of glycogen in these organs. As a result of inadequate glucose production patients have severe fasting hypoglycaemia with secondary biochemical abnormalities: hyperlactacidaemia, hyperuricaemia and hyper- lipidaemia. Untreated patients have a protruding abdomen because of marked hepatomegaly (storage of glycogen and fat), short stature, truncal obesity, a rounded doll face, wasted muscles, and bleeding tendency due to impaired platelet function16,26.
Based on the most plausible molecular model, G6Pase is a multicomponent complex consisting of a catalytic subunit, situated on the luminal side of the endoplasmic reticulum, and one or more membrane transporters4,5,95. Deficient activity of the catalytic unit of G6Pase is called GSD Ia. In 1993 the gene encoding this unit was identified in band q21 of chromosome 17 and a steadily growing list of mutations has been reported59,72,82. Defects of the putative transporter(s) were named GSD Ib, GSD Ic and GSD Id. Molecular genetic studies have shown that patients diagnosed by enzyme studies as GSD Ib, Ic and the putative Id, all had mutations in the G6P translocase gene identified in band q23 of chromosome 113,31,89. This is consistent with the clinical findings as GSD I can be divided in two clinical phenotypes: GSD Ia patients have
‘classical’ findings as listed above, whilst those with ‘GSD I non-a’ have in addition recurrent bacterial infections and inflammatory bowel disease (IBD) associated with neutropenia and neutrophil dysfunction90. Recently, however, a GSD Ic patient without mutations in the G6P transporter gene was described suggesting the existence of a distinct GSD Ic locus63. In the present study, the term GSD Ib is used for ‘GSD I non-a’ patients and includes patients formerly diagnosed as GSD Ib, GSD Ic and GSD Id.
The aim of treatment is to prevent hypoglycaemia and suppress secondary metabolic derangements as much as possible. Methods to achieve this are frequent meals (FMs), continuous nocturnal gastric drip feeding (CNGDF) and the administration of uncooked cornstarch (UCCS). If hypoglycaemia can be prevented, the clinical and biochemical abnormalities in most patients will improve24. However in older patients numerous complications may still develop16,26,86.
GSD I has an estimated frequency among newborns of one in 100.00016. Thus no single metabolic centre has experience of large series of patients.
Furthermore, in literature there is a relative paucity of data on outcome, and all these reports15,24,70,84,85,103, except one86, focus on patients under 18 years.
To study the management, clinical course and long-term outcome in both paediatric and adult patients with GSD I, the collaborative European Study on GSD I (ESGSD I) was initiated in 1996. Other objectives of this study- group were to develop therapeutic strategies and to develop guidelines about (long-term) treatment and follow-up.
This chapter is a descriptive analysis of data concerning diagnosis, management, clinical course, and outcome of a large cohort of paediatric and adult GSD I patients obtained from the retrospective part of the ESGSD I. More detailed outcome data of adult GSD I patients is presented in chapter 2.2.
Patients and methods
Patients were identified from hospital records of 16 metabolic centres, in 12 European countries. Patients treated in the centres including patients who had died since 1960 were enlisted. Patients were coded by initials and date of birth to check for duplication. Retrospective case records forms were discussed in a multicenter meeting and filled in by either the treating physician or by one of the investigators (JPR).
The diagnosis of GSD Ia was made either by enzyme studies that showed the combination of deficient G6Pase activity in intact and/or disrupted microsomes and/or by mutation analysis of the G6Pase gene. The diagnosis of GSD Ib was made either by enzyme studies that showed the combination of deficient G6Pase activity in intact microsomes and (sub)normal G6Pase activity in disrupted microsomes and/or by mutation analysis of the G6P transporter gene.
Most of the results are descriptive. Results are expressed as mean (± standard deviation) or as median (minimum - maximum), except otherwise stated. Differences in the number of affected individuals between two subgroups of patients (2x2 contingency table) were analysed using the Fisher exact test (including calculating an odds ratio with 95% confidence interval).
Differences in variables with a normal distribution between two subgroups of patients were analysed using unpaired two tailed t-tests. A p value < 0.05 was considered to be significant in all instances.
Results general results
Retrospective case records were obtained from 301 patients. A further 23 ‘patients’ were mentioned in case record forms of siblings, but not included
because the data were incomplete. Of the 301 patients, another 13 were excluded because they did not meet the diagnostic criteria. Thus, 288 patients were included: of whom 231 had GSD Ia and 57 had GSD Ib. There were 20 families with two affected children and two with three. In 28% of the patients, the parents were consanguineous. Demographic characteristics are shown in Table 2.1.1. The patients were born between 1943 and 1996 (Figure 2.1.1).
Median age when the data were collected was 10.4 years (range 0.4 - 45.4 years) for Ia and 7.1 years (range 0.4 - 30.6 years) for Ib patients.
Table 2.1.1 Characteristics of 288 included GSD I patients
GSD Ia GSD Ib Total
male - female (n) 134 / 97 30 / 27 164 / 124
percentages (58% / 42%) (53% / 47%) (57% / 43%)
race or ethnic group (n)
Asian 3 5 8
Caucasian 131 33 164
Caucasian - Mediterranean 92 13 105
Negroid 0 0 0
mixed 5 6 11
original country of residence (n)
France 10 0 10
Germany 54 13 67
Israel 9 4 13
Italy 39 7 46
Poland 10 9 19
Netherlands 17 0 17
Turkey 43 3 46
United Kingdom 25 17 42
other 24 4 28
pregnancy, delivery, additional diseases
Complications of pregnancy and/or delivery were reported infrequently and these did not differ from normal pregnancies and deliveries. Prematurity (gestational age < 37 weeks) was observed in 3%, low birth weight (≤ 2500 g) in 10% and very low birth weight (≤ 1500 g) in 1%.
Congenital heart anomalies were observed in 9 (3%) patients (four ventricular septal defect, two atrial septal defect, one patent foramen ovale, one patent ductus arteriosus and atrial septal defect, and one congenital mitral insufficiency). The prevalence of other congenital disorders did not differ from the normal population.
Figure 2.1.1 ESGSD I cohort: year of birth
Figure 2.1.2 Prevalence of the presenting symptoms metabolic derangement (MD), hepatomegaly (H), growt retardation (GR) among GSD Ia an Ib patients presenting at different ages
presenting signs and symptoms
GSD Ia patients presented at a median age of 6 months (range day 1 - 12 years), GSD Ib patients at a median age of 4 months (range day 1 - 4 years). 80% of the Ia patients and 90% of the Ib patients presented before the age of 1 year.
The dominant presenting features were protruded abdomen (in 83% of the patients), symptoms of acute metabolic derangement (71%), failure to thrive/growth retardation (25%), recurrent infections (3% in GSD Ia; 41%
in GSD Ib patients), muscular hypotonia (13%) and delayed psychomotor development (7%). The numbers and percentages of GSD Ia and Ib patients presenting in different age groups and the prevalence of symptoms of metabolic derangement, hepatomegaly and growth retardation among these age groups are shown in Figure 2.1.2.
dietary treatment at present
Dietary treatment during the day and night among different age groups is shown in Figure 2.1.3 and 2.1.4. Six patients are not included in these figures: two patients died before dietary treatment was introduced and in four patients details of dietary treatment were not known. During the daytime, 21% of the patients used FMs only and 70% used FMs and UCCS (1 - 5 times a day) in addition. Overnight, 41% of the patients were on CNGDF (in the majority a glucose-polymer solution, in the minority a complete formula solution) and 45% used UCCS (1 - 3 times a night). In 9% of the patients it was mentioned that dietary compliance was low. Lactose was restricted in 62% of the patients. The use of multi-vitamins supplements was reported in 40%. Furthermore, the use of vitamin B2, vitamin B6, folic acid, vitamin D, and/or vitamin E in different combinations was reported in a minority of patients. (Sodium)bicarbonate treatment was reported in 12% of the patients.
Figure 2.1.3 Dietary treatment during day at latest follow-up
Figure 2.1.4 Dietary treatment during night at latest follow-up
history of dietary treatment
Eight patients had no dietary treatment at all during life. In almost all other patients, FMs during both day and night were started immediately after (the suspicion of) diagnosis. Median age of starting UCCS during daytime
was 2.9 years (range 1 month - 25 years). Median age of starting CNGDF was 1.3 years (range 1 month - 19.5 years) and of starting UCCS overnight 3.2 years (range 2 months - 25 years).
A total of 38 patients had used CNGDF of whom 34 switched to UCCS overnight (median age 13.1 years, range 0.9 - 22.0 years), two to FMs (0.5 and 4.0 years) and two patients had no specific dietary treatment after discontinuation (17.8 and 18.5 years). A total of 18 patients had taken UCCS overnight of whom 11 switched to CNGDF (median age 4.1 years, range 0.9 - 11.5 years) and seven patients had no specific dietary treatment after discontinuation (median age 12.8 years, range 7.0 - 22.0 years).
Three patients discontinued the use of UCCS because of intestinal complaints. Furthermore, three patients had been treated with total parental feeding for a period.
Table 2.1.2 Details of deceased GSD I patients year of year of age at cause of death
birth death death
1943 Ia 1989 46 years sepsis after 2nd renal transplantation 1965 Ib 1966 < 1 year metabolic derangement
1966 Ia 1977 11 years acute renal insufficiency with respiratory insufficiency
1967 Ib 1985 17 years car accident
1969 Ia 1985 16 years unknown (probably vitamin B1 deficiency with heart failure)
1974 Ia 1978 4 years severe epistaxis complicated by aspiration pneumonia
1975 Ib 1978 3 years metabolic derangement (failure of gastric drip pump)
1975 Ia 1994 18 years end-stage heart failure by pulmonary hypertension
(Osler-Weber-Rendu syndrome)
1976 Ia 1980 4 years metabolic derangement
1977 Ia 1979 3 years metabolic derangement
1981 Ib 1989 8 years metabolic derangement
1984 Ia 1988 4 years gastroenteritis, metabolic derangement 1984 Ib 1985 < 1 year metabolic derangement
1985 Ia 1992 7 years metabolic derangement (connec tion failure nasogastric tube)
1988 Ib 1995 7 years sepsis with multi organ failure
1993 Ia 1994 1 year metabolic derangement
deceased patients
Of the included patients, nine GSD Ia and seven GSD Ib patients had died. Details of these patients are summarised in Table 2.1.2. Furthermore, 17 of the 23 ‘patients’ mentioned in the case records of siblings, had died.
Most of them died because of a direct consequence of GSD I, mainly acute metabolic derangement (Table 2.1.3).
year of year of cause of year of year of cause of
birth death death birth death death
1966 Ia 1967 metabolic derangement 1967 Ia 1967 metabolic derangement 1969 Ia 1969 metabolic derangement 1973 Ib 1973 metabolic derangement 1975 Ia 1981 necrotising pancreatitis 1976 Ia 1984 metabolic derangement
<1977 Ia <1977 metabolic derangement <1977 Ia <1978 metabolic derangement
<1979 Ib <1979 metabolic derangement <1986 Ia <1987 metabolic derangement
<1987 Ia ? unknown 1988 Ia 1988 metabolic derangement
<1990 Ib ? unknown <1992 Ia <1992 metabolic derangement
? Ia ? metabolic derangement ? Ia ? unknown
? Ia ? traffic accident
Table 2.1.3 Details of deceased ‘GSD I patients’, not included in the ESGSD I
metabolic derangement, comas, admissions, mental development, epilepsy After starting dietary treatment, coma as consequence of metabolic derangement was reported in 34% of the GSD Ia and in 40% of the GSD Ib patients. The number of episodes varied from one (in 19% of the patients), two to four (11%), to five or more (5%).
After starting dietary treatment, metabolic derangement necessitating admission was reported in 55% of the GSD Ia and in 65% of the GSD Ib patients. The number of admissions varied from one to five (in 29% of the patients), six to ten (13%) to more than ten (15%). Metabolic derangements presented with convulsions in 65%, with severe sweating and paleness in 15% and were ‘asymptomatic’ in 16%. Metabolic derangements were mainly caused by infections (31%), vomiting and/or diarrhoea (21%), a combination of infection and gastrointestinal complaints (30%), and dietary errors (13%).
Mental development was low (IQ < 65) in 3% and borderline (IQ 65 - 85) in 18% of the patients. Of the patients who had experienced coma, 32% had a low or borderline mental development. Of the patients who had never experienced coma 16% had a low or borderline mental development (p<0.01;
odds ratio 2.43 (95% 1.37 - 4.30). The use of anti-epileptics because of non-hypoglycaemic epilepsy was reported in 6% of the patients.
