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Glycogen storage disease type I: diagnosis, management, clinical course and outcome. Results of the European Study on Glycogen Storage Disease Type I (ESGSD I)

Glycogen storage disease type I: diagnosis, management, clinical course and outcome. Results of the European Study on Glycogen Storage Disease Type I (ESGSD I)
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  ORIGINAL PAPER Jan Peter Rake  Æ  Gepke Visser  Æ  Philippe LabruneJames V. Leonard  Æ  Kurt Ullrich  Æ  G. Peter A. Smit Glycogen storage disease type I: diagnosis, management, clinicalcourse and outcome. Results of the European Study on Glycogen Storage Disease Type I (ESGSD I) Published online: 22 August 2002   Springer-Verlag 2002 Abstract  Glycogen storage disease type I (GSD I) is arelatively rare metabolic disease and therefore, no meta-bolic centre has experience of large numbers of patients.Todocumentoutcome,todevelopguidelinesabout(long-term) management and follow-up, and to develop thera-peutic strategies, the collaborative European Study onGSD I (ESGSD I) was initiated. This paper is an de-scriptive analysis of data obtained from the retrospectivepart of the ESGSD I. Included were 231 GSD Ia and 57GSD Ib patients. Median age of data collection was 10.4years(range0.4–45.4 years)forIaand7.1years(0.4–30.6years) for Ib patients. Data on dietary treatment, phar-macological treatment, and outcome including mentaldevelopment, hyperlipidaemia and its complications,hyperuricaemiaanditscomplications,bleedingtendency,anaemia, osteopenia, hepatomegaly, liver adenomas andcarcinomas, progressive renal disease, height and adultheight, 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 granulocytecolony-stimulating factor are presented elsewhere (Visseretal.2000,J Pediatr137:187–191;Visseretal.2002,EurJPediatr DOI 10.1007/s00431-002-1010-0).  Conclusion: there is still wide variation in methods of dietary andpharmacological treatment of glycogen storage diseasetype I. Intensive dietary treatment will improve, but notcorrect completely, clinical and biochemical status andfewer patients will die as a direct consequence of acutemetabolic derangement. With ageing, more and morecomplications will develop of which progressive renaldisease and the complications related to liver adenomasare likely to be two major causes of morbidity and mor-tality. Keywords  Cinical course  Æ  Collaborative EuropeanRetrospective Registry Study  Æ  Dietary andpharmacological treatment  Æ  Glycogen storage diseasetype I  Æ  Outcome Abbreviations  BMI   body mass index  Æ  CNGDF   contin-uous nocturnal gastric drip feeding  Æ  ESGSD I   Europe-an Study on Glycogen Storage Disease Type I  Æ FM   frequent meals  Æ  GSD  glycogen storage disease  Æ G6P   glucose-6-phosphate  Æ  G6Pase  glucose-6-phospha-tase  Æ  IBD  inflammatory bowel disease  Æ  LT   livertransplantation  Æ  MD  metabolic derangement  PCOs polycystic ovaries  Æ  SDS   standard deviation score  Æ UCCS   uncooked corn starch  Æ  XO  xanthine oxidase Introduction Glycogen storage disease type I (GSD I, McKusick232200) is an autosomal recessive inborn error of carbo-hydrate metabolism caused by defects of the glucose-6-phosphatase (G6Pase) complex. G6Pase plays a central Eur J Pediatr (2002) 161: S20–S34DOI 10.1007/s00431-002-0999-4On behalf of the participating members of the ESGSD I. Membersof the ESGSD I are: Austria (W Endres, D Skladal, Innsbruck),Belgium (E Sokal, Brussels), Czech Republic (J Zeman, Prague),France (P Labrune, Clamart), Germany (P Bu ¨hrdel, Leipzig,K Ullrich, Hamburg, G Da ¨ublin, U Wendel, Du ¨sseldorf), GreatBritain (P Lee, JV Leonard, G Mieli-Vergani, London), Hungary(L Szo ¨nyi, Budapest), Italy (P Gandullia, R Gatti, M di Rocco,Genoa, D Melis, G Andria, Naples), Israel (S Moses, Beersheva),Poland (J Taybert, E Pronicka, Warsaw), The Netherlands(JP Rake, GPA Smit, G Visser, Groningen), Turkey (H O ¨ zen,N Kocak, Ankara)J.P. Rake ( & )  Æ  G. Visser  Æ  G.P.A. SmitDepartment of Paediatrics, Beatrix Children’s Hospital,University Hospital Groningen, PO Box 30.001,9700 RB Groningen, The NetherlandsE-mail: rakejp@cs.comTel.: +31-50-3614147Fax: +31-50-3614235P. LabruneHospital Antoine-Be ´cle `re, Clamart, FranceJ.V. LeonardInstitute of Child Health, Great Ormond Street Hospital,London, UKK. UllrichDepartment of Paediatrics, University Hospital,Hamburg, Germany  role in both glycogenolysis and gluconeogenesis, hydro-lysing glucose-6-phosphate (G6P) to glucose. Deficiencyof G6Pase activity in liver, kidney and intestine results inaccumulation of glycogen in these organs. As a result of inadequate glucose production, patients have severefasting hypoglycaemia with secondary biochemical ab-normalities: hyperlactacidaemia, hyperuricaemia andhyperlipidaemia. Untreated patients have a protrudingabdomen because of marked hepatomegaly (storage of glycogen and fat), short stature, truncal obesity, arounded doll-like face, wasted muscles, and bleedingtendency due to impaired platelet function [12, 21].Based on the mostplausible molecularmodel,G6Paseis a multicomponent complex consisting of a catalyticsubunit, situated on the luminal side of the endoplasmicreticulum, and one or more membrane transporters [4, 5,83]. Deficient activity of the catalytic unit of G6Pase iscalled GSD Ia. In 1993 the gene encoding this unit wasidentified in band q21 of chromosome 17 and a steadilygrowing list of mutations has been reported [54, 65, 72].Defects of the putative transporter(s) were named GSDIb, GSD Ic and GSD Id. Molecular genetic studies haveshownthatpatientsdiagnosedbyenzymestudiesasGSDIb, Ic and the putative Id, all had mutations in the G6Ptranslocasegeneidentifiedinbandq23ofchromosome11[3, 29, 79]. This is consistent with the clinical findings asGSD I can be divided into two clinical phenotypes: GSDIa patients have ‘classical’ findings as listed above, whilstthose with ‘GSD I non-a’ have in addition recurrentbacterial infections and inflammatory bowel disease(IBD) associated with neutropenia and neutrophil dys-function [80]. Recently, however, a GSD Ic patient with-out mutations in the G6P transporter gene was describedsuggestingtheexistenceofadistinctGSDIclocus[57].Inthepresentstudy,thetermGSDIbisusedfor‘GSDInon-a’ patients and includes patients formerly diagnosed asGSD Ib, GSD Ic and GSD Id.The aim of treatment is to prevent hypoglycaemiaand suppress secondary metabolic derangements asmuch as possible. Methods to achieve this are frequentmeals (FM), continuous nocturnal gastric drip feeding(CNGDF) and the administration of uncooked corn-starch (UCCS). If hypoglycaemia can be prevented, theclinical and biochemical abnormalities in most patientswill improve [23]. However in older patients numerouscomplications may still develop [12, 21, 76].GSD I has an estimated frequency among newbornsof 1 in 100,000 [12]. Thus no single metabolic centre hasexperience of large series of patients. Furthermore, inthe literature there is a relative paucity of data aboutoutcome, and all these reports [16, 23, 63, 73, 75, 87],except one [76], focus on patients under 18 years. Tostudy the management, clinical course and long-termoutcome in both paediatric and adult patients with GSDI, the collaborative European Study on GSD I (ESGSDI) was initiated in 1996. Other objectives of this study-group were to develop therapeutic strategies and todevelop guidelines about (long-term) management andfollow-up.This paper is a descriptive analysis of data concerningdiagnosis, management, clinical course, and outcome of a large cohort of paediatric and adult GSD I patientsobtained from the retrospective part of the ESGSD I.More detailed outcome data of GSD I patients bornbefore 1975 and a comparison of outcome data betweendifferent (dietary) treatment strategies will be publishedelsewhere. Patients and methods Patients were identified from hospital records of 16 metaboliccentres, in 12 European countries. Patients treated in the centresincluding patients who had died since 1960 were enlisted. Patientswere coded by initials and date of birth to check for duplication.Retrospective case records forms were discussed in a multicentremeeting and completed by either the treating physician or by one of the investigators (JPR).The diagnosis of GSD Ia was made either by enzyme studiesthat showed the combination of deficient G6Pase activity in intactand/or disrupted microsomes and/or by mutation analysis of the G6Pase  gene. The diagnosis of GSD Ib was made either by enzymestudies that showed the combination of deficient G6Pase activity inintact microsomes and (sub)normal G6Pase activity in disruptedmicrosomes and/or by mutation analysis of the G6P transportergene.Most of the results are descriptive. Results are expressed asmean (± standard deviation) or as median (minimum – maxi-mum), except otherwise stated. Differences in the number of affected individuals between two subgroups of patients (2 · 2 con-tingency table) were analysed using the Fisher exact test (includingcalculating an odds ratio with 95% confidence interval). Differ-ences in variables with a normal distribution between two sub-groups 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 resultsRetrospective case records were obtained from 301 pa-tients. A further 23 ‘patients’ were mentioned in caserecord forms of siblings, but not included because thedata were incomplete. Of the 301 patients, another 13were excluded because they did not meet the diagnosticcriteria. Thus, 288 patients were included, of whom 231had GSD Ia and 57 had GSD Ib. There were 20 familieswith two affected children and two with three. In 28% of the patients, the parents were consanguineous. Demo-graphic characteristics are shown in Table 1. Thepatients were born between 1943 and 1996 (Fig. 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.Pregnancy, delivery, additional diseasesComplications of pregnancy and/or delivery were re-ported infrequently and these did not differ from normalpregnancies and deliveries. Prematurity (gestational age<37 weeks) was observed in 3%, low birth weight S21  ( £  2500 g) in10% andvery low birth weight( £  1500 g)in1%.Congenital heart anomalies were observed in nine(3%) patients (four with ventricular septal defect, twowith atrial septal defect, one patent foramen ovale, onepatent ductus arteriosus and atrial septal defect, onecongenital mitral insufficiency). The prevalence of othercongenital disorders did not differ from the normalpopulation.Presenting signs and symptomsGSD Ia patients presented at a median age of 6 months(day 1–12 years), GSD Ib patients at a median age of 4months (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 ab-domen (in 83% of the patients), symptoms of acute met-abolic derangement (71%), failure to thrive/growthretardation (25%), recurrent infections (3% in GSD Ia;41%inGSDIbpatients),muscularhypotonia(13%)anddelayed psychomotor development (7%). The numbersand percentages of GSD Ia and Ib patients presenting indifferent age groups and the prevalence of symptoms of metabolic derangement, hepatomegaly and growth re-tardation among these age groups are shown in Fig. 2.Dietary treatment at presentDietary treatment during the day and night among dif-ferent age groups is shown in Fig. 3 and Fig. 4. Sixpatients are not included in these figures: two patientsdied before dietary treatment was introduced and in fourpatients, details of the dietary treatment were notknown. During the daytime, 21% of the patients usedFM only and 70% used FM and UCCS (1–5 times aday) in addition. Overnight, 41% of the patients were onCNGDF (in the majority a glucose-polymer solution, inthe minority a complete formula solution) and 45% usedUCCS (1–3 times a night). In 9% of the patients it wasmentioned that dietary compliance was low. Lactose wasrestricted in 62% of the patients. The use of multi-vitamins supplements was reported in 40%. Further-more, the use of vitamin B2, vitamin B6, folic acid,vitamin D, and/or vitamin E in different combinationswas reported in a minority of patients. (Sodium) bicar-bonate treatment was reported in 12% of the patients.History of dietary treatmentEight patients had no dietary treatment at all during life.In almost all other patients, FM during both day andnight were started immediately after (the suspicion of)diagnosis. Median age of starting UCCS during thedaytime was 2.9 years (range 1 month–25 years). Median Table 1.  Characteristics of 288 included GSD I patientsGSD Ia ( n ) GSD Ib ( n ) Total ( n )Male/female 134/97 30/27 164/124Percentage (%) (58/42) (53/47) (57/43)Race or ethnic groupAsian 3 5 8Caucasian 131 33 164Caucasian– Mediterranean92 13 105Negroid 0 0 0Mixed 5 6 11Original country of residenceFrance 10 0 10Germany 54 13 67Israel 9 4 13Italy 39 7 46Poland 10 9 19Netherlands 17 0 17Turkey 43 3 46United Kingdom 25 17 42Other 24 4 28 Fig. 1.  ESGSD I cohort: yearof birthS22  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 34switched to UCCS overnight (median age 13.1 years,range 0.9–22.0 years), two to FM (0.5 and 4.0 years) andtwo had no specific dietary treatment after discontinu-ation (17.8 and 18.5 years). Eighteen patients had takenUCCS overnight; 11 patients switched to CNGDF(median age 4.1 years (range 0.9–11.5 years) and sevenhad no specific dietary treatment after discontinuation(median age 12.8 years, range 7.0–22.0 years). Three Fig. 2.  Prevalence of thepresenting symptoms metabolicderangement ( MD ), hepato-megaly ( H  ) and growth retar-dation ( GR ) among GSD Iaand Ib patients presenting atdifferent ages Fig. 3.  Dietary treatment during day at latest follow-up  Fig. 4.  Dietary treatment during night at latest follow-upS23  patients discontinued the use of UCCS because of in-testinal complaints. Three patients had been treated withtotal parental feeding.Deceased patientsOf the included patients, nine GSD Ia and seven GSD Ibpatients had died. Details of these patients are sum-marised in Table 2. Furthermore, 17 of the 23 ‘patients’mentioned in the case records of siblings, had died. Mostof them died because of a direct consequence of GSD I,mainly acute metabolic derangement (Table 3).Metabolic derangement, comas, admissions,mental development, epilepsyAfter starting dietary treatment, coma as a consequenceof metabolic derangement was reported in 34% of theGSD Ia and in 40% of the GSD Ib patients. The numberof episodes varied from one (in 19% of the patients), twoto four (11%), to five or more (5%). After starting di-etary treatment, metabolic derangement necessitatingadmission was reported in 55% of the GSD Ia and in65% of the GSD Ib patients. The number of admissionsvaried from one to five (in 29% of the patients), six toten (13%) to more than ten (15%). These metabolicderangements presented with convulsions in 65%, withsevere sweating and paleness in 15% and were ‘asymp-tomatic’ in 16%. Metabolic derangements were mainlycaused by infections (31%), vomiting and/or diarrhoea(21%), a combination of infection and gastrointestinalcomplaints (30%), and dietary errors (13%).Mental development was low (IQ <65) in 3% andborderline (IQ 65–85) in 18% of the patients. Of thepatients who had experienced coma, 32% had a low orborderline mental development; whereas of the patientswho had never experienced coma, 16% had a low orborderline mental development ( P  <0.01; odds ratio2.43 (95%CI 1.37–4.30). The use of anti-epileptics be-cause of non-hypoglycaemic epilepsy was reported in6% of the patients.Hyperlipidaemia and complicationsMean serum cholesterol and triglyceride concentrationsin different age groups are summarised in Table 4.Complications due to hyperlipidaemia were reportedinfrequently. Pancreatitis was reported in three patients,and cholelithiasis in two patients. One 46-year-old Table 2.  Details of deceased GSD I patientsYear of birth GSD Year of death Age at death (years) Cause of death1943 Ia 1989 46 Sepsis after 2nd renal transplantation1965 Ib 1966 <1 MD1966 Ia 1977 11 Acute renal insufficiency with respiratory insufficiency1967 Ib 1985 17 Car accident1969 Ia 1985 16 Unknown (probably vitamin B1 deficiency with heart failure)1974 Ia 1978 4 Severe epistaxis complicated by aspiration pneumoniaand respiratory insufficiency1975 Ib 1978 3 MD (failure of gastric drip pump)1975 Ia 1994 18 End-stage heart failure caused by pulmonaryhypertension (Osler-Weber-Rendu syndrome)1976 Ia 1980 4 MD1977 Ia 1979 3 MD1981 Ib 1989 8 MD1984 Ia 1988 4 Gastroenteritis, MD1984 Ib 1985 <1 MD1985 Ia 1992 7 MD (connection failure nasogastric tube)1988 Ib 1995 7 Sepsis with multi-organ failure1993 Ia 1994 1 MDMD metabolic derangement Table 3.  Details of deceased ‘GSD I patients’, not included in the ESGSD IYear of birth GSD Year of death Cause of death Year of birth GSD Year of death Cause of death1966 Ia 1967 MD 1967 Ia 1967 MD1969 Ia 1969 MD 1973 Ib 1973 MD1975 Ia 1981 Pancreatitis 1976 Ia 1984 MD<1977 Ia <1977 MD <1977 Ia <1978 MD<1979 Ib <1979 MD <1986 Ia <1987 MD<1987 Ia ? Unknown 1988 Ia 1988 MD<1990 Ib ? Unknown <1992 Ia <1992 MD? Ia ? MD ? Ia ? Unknown? Ia ? Traffic accidentS24
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