Glycogen storage disease type III: diagnosis, genotype, management, clinical course and outcome.

Glycogen storage disease type III (GSDIII) is a rare disorder of glycogenolysis due to AGL gene mutations, causing glycogen debranching enzyme deficiency and storage of limited dextrin. Patients with GSDIIIa show involvement of liver and cardiac/skeletal muscle, whereas GSDIIIb patients display only liver symptoms and signs. The International Study on Glycogen Storage Disease (ISGSDIII) is a descriptive retrospective, international, multi-centre cohort study of diagnosis, genotype, management, clinical course and outcome of 175 patients from 147 families (86 % GSDIIIa; 14 % GSDIIIb), with follow-up into adulthood in 91 patients. In total 58 AGL mutations (non-missense mutations were overrepresented and 21 novel mutations were observed) were identified in 76 families. GSDIII patients first presented before the age of 1.5 years, hepatomegaly was the most common presenting clinical sign. Dietary management was very diverse and included frequent meals, uncooked cornstarch and continuous gastric drip feeding. Chronic complications involved the liver (hepatic cirrhosis, adenoma(s), and/or hepatocellular carcinoma in 11 %), heart (cardiac involvement and cardiomyopathy, in 58 % and 15 %, respectively, generally presenting in early childhood), and muscle (pain in 34 %). Type 2 diabetes mellitus was diagnosed in eight out of 91 adult patients (9 %). In adult patients no significant correlation was detected between (non-) missense AGL genotypes and hepatic, cardiac or muscular complications. This study demonstrates heterogeneity in a large cohort of ageing GSDIII patients. An international GSD patient registry is warranted to prospectively define the clinical course, heterogeneity and the effect of different dietary interventions in patients with GSDIII.

Muscle Ultrasound in Patients with Glycogen Storage Disease Types I and III.

In glycogen storage diseases (GSDs), improved longevity has resulted in the need for neuromuscular surveillance. In 12 children and 14 adults with the "hepatic" (GSD-I) and "myopathic" (GSD-III) phenotypes, we cross-sectionally assessed muscle ultrasound density (MUD) and muscle force. Children with both "hepatic" and "myopathic" GSD phenotypes had elevated MUD values (MUD Z-scores: GSD-I > 2.5 SD vs. GSD-III > 1 SD, p < 0.05) and muscle weakness (GSD-I muscle force; p < 0.05) of myopathic distribution. In "hepatic" GSD-I adults, MUD stabilized (GSD-I adults vs. GSD-I children, not significant), concurring with moderate muscle weakness (GSD-I adults vs. healthy matched pairs, p < 0.05). In "myopathic" GSD-III adults, MUD increased with age (MUD-GSD III vs. age: r = 0.71-0.83, GSD-III adults > GSD-III children, p < 0.05), concurring with pronounced muscle weakness (GSD-III adults vs. GSD-I adults, p < 0.05) of myopathic distribution. Children with "hepatic" and "myopathic" GSD phenotypes were both found to have myopathy. Myopathy stabilizes in "hepatic" GSD-I adults, whereas it progresses in "myopathic" GSD-III adults. Muscle ultrasonography provides an excellent, non-invasive tool for neuromuscular surveillance per GSD phenotype.

Pain: a prevalent feature in patients with mucopolysaccharidosis. Results of a cross-sectional national survey.

BACKGROUND: While clinical observations suggest that many patients with mucopolysaccharidosis (MPS) experience chronic pain, few studies have assessed its extent and impact. We therefore investigated its prevalence in patients with all types of MPS in the Netherlands. We also examined the association between pain and health related quality of life (HRQoL) and other clinical variables. METHODS: We conducted a nationwide MPS survey that used questionnaires on MPS and disease-related symptoms (MPS-specific questionnaire), developmental level (Vineland Screener 0-6 years), quality of life (PedsQl and SF-36), and disability (Childhood Health Assessment Questionnaire). Depending on their age and developmental level, patients or their parents were asked to assess pain by keeping a pain diary for five consecutive days: either the Non-communicating Children's Pain Checklist - Revised (3-18 years intellectually disabled and children <8 years), the VAS-score (> 18 years), or the Faces Pain Scale - Revised (8-18 years). RESULTS: Eighty-nine MPS patients were invited, 55 of whom agreed to participate (response rate 62 %; median age 10.9 years, range 2.9-47.2 years). They covered a wide spectrum in all age groups, ranging from no pain to severe pain. Forty percent scored above the cut-off value for pain. Most reported pain sites were the back and hips. While the MPS III group experienced the highest frequency of pain (52.9 %), 50 % of patients with an intellectual disability seemed to experience pain, versus 30 % of patients with a normal intelligence. MPS patients scored much lower (i.e., more pain) than a random sample of the Dutch population on the bodily pain domain of the SF-36 scale and the PedsQl. CONCLUSION: With or without intellectual disabilities, many MPS patients experience pain. We recommend that standardized pain assessments are included in the regular follow-up program of patients with MPS.

Dietary management in glycogen storage disease type III: what is the evidence?

In childhood, GSD type III causes relatively severe fasting intolerance, classically associated with ketotic hypoglycaemia. During follow up, history of (documented) hypoglycaemia, clinical parameters (growth, liver size, motor development, neuromuscular parameters), laboratory parameters (glucose, lactate, ALAT, cholesterol, triglycerides, creatine kinase and ketones) and cardiac parameters all need to be integrated in order to titrate dietary management, for which age-dependent requirements need to be taken into account. Evidence from case studies and small cohort studies in both children and adults with GSD III demonstrate that prevention of hypoglycaemia and maintenance of euglycemia is not sufficient to prevent complications. Moreover, over-treatment with carbohydrates may even be harmful. The ageing cohort of GSD III patients, including the non-traditional clinical presentations in adulthood, raises ‬‬‬new questions.

In vitro digestion of starches in a dynamic gastrointestinal model: an innovative study to optimize dietary management of patients with hepatic glycogen storage diseases.

Uncooked cornstarch (UCCS) is a widely used treatment strategy for patients with hepatic glycogen storage disease (GSD). It has been observed that GSD-patients display different metabolic responses to different cornstarches. The objective was to characterize starch fractions and analyze the digestion of different starches in a dynamic gastrointestinal in vitro model. The following brands of UCCS were studied: Argo and Great Value from the United States of America; Brazilian Maizena Duryea and Yoki from Brazil; Dutch Maizena Duryea from the Netherlands. Glycosade, a modified starch, and sweet polvilho, a Brazilian starch extracted from cassava, were also studied. The starch fractions were analyzed by glycemic TNO index method and digestion analyses were determined by the TIM-1 system, a dynamic, computer-controlled, in vitro gastrointestinal model, which simulates the stomach and small intestine. The final digested amounts were between 84 and 86% for the UCCS and Glycosade, but was 75.5% for sweet povilho. At 180 min of the experiment, an important time-point for GSD patients, the digested amount of the starches corresponded to 67.9-71.5 for the UCCS and Glycosade, while it was 55.5% for sweet povilho. In an experiment with a mixture of sweet polvilho and Brazilian Maizena Duryea, a final digested amount of 78.4% was found, while the value at 180 min was 61.7%. Sweet polvilho seems to have a slower and extended release of glucose and looks like an interesting product to be further studied as it might lead to extended normoglycemia in GSD-patients.

Targeted deletion of kidney glucose-6 phosphatase leads to nephropathy.

Renal failure is a major complication that arises with aging in glycogen storage disease type 1a and type 1b patients. In the kidneys, glucose-6 phosphatase catalytic subunit (encoded by G6pc) deficiency leads to the accumulation of glycogen, an effect resulting in marked nephromegaly and progressive glomerular hyperperfusion and hyperfiltration preceding the development of microalbuminuria and proteinuria. To better understand the end-stage nephropathy in glycogen storage disease type 1a, we generated a novel kidney-specific G6pc knockout (K-G6pc(-/-)) mouse, which exhibited normal life expectancy. After 6 months, K-G6pc(-/-) mice showed glycogen overload leading to nephromegaly and tubular dilation. Moreover, renal accumulation of lipids due to activation of de novo lipogenesis was observed. This led to the activation of the renin-angiotensin system and the development of epithelial-mesenchymal transition process and podocyte injury by transforming growth factor ß1 signaling. The K-G6pc(-/-) mice developed microalbuminuria caused by the impairment of the glomerular filtration barrier. Thus, renal G6pc deficiency alone is sufficient to induce the development of the early-onset nephropathy observed in glycogen storage disease type 1a, independent of the liver disease. The K-G6pc(-/-) mouse model is a unique tool to decipher the molecular mechanisms underlying renal failure and to evaluate potential therapeutic strategies.

Experimental evidence for protein oxidative damage and altered antioxidant defense in patients with medium-chain acyl-CoA dehydrogenase deficiency.

The objective of this study was to test whether macromolecule oxidative damage and altered enzymatic antioxidative defenses occur in patients with medium-chain acyl coenzyme A dehydrogenase (MCAD) deficiency. We performed a cross-sectional observational study of in vivo parameters of lipid and protein oxidative damage and antioxidant defenses in asymptomatic, nonstressed, MCAD-deficient patients and healthy controls. Patients were subdivided into three groups based on therapy: patients without prescribed supplementation, patients with carnitine supplementation, and patients with carnitine plus riboflavin supplementation. Compared with healthy controls, nonsupplemented MCAD-deficient patients and patients receiving carnitine supplementation displayed decreased plasma sulfhydryl content (indicating protein oxidative damage). Increased erythrocyte superoxide dismutase (SOD) activity in patients receiving carnitine supplementation probably reflects a compensatory mechanism for scavenging reactive species formation. The combination of carnitine plus riboflavin was not associated with oxidative damage. These are the first indications that MCAD-deficient patients experience protein oxidative damage and that combined supplementation of carnitine and riboflavin may prevent these biochemical alterations. Results suggest involvement of free radicals in the pathophysiology of MCAD deficiency. The underlying mechanisms behind the increased SOD activity upon carnitine supplementation need to be determined. Further studies are necessary to determine the clinical relevance of oxidative stress, including the possibility of antioxidant therapy.

A new coding system for metabolic disorders demonstrates gaps in the international disease classifications ICD-10 and SNOMED-CT, which can be barriers to genotype-phenotype data sharing.

Data sharing is essential for a better understanding of genetic disorders. Good phenotype coding plays a key role in this process. Unfortunately, the two most widely used coding systems in medicine, ICD-10 and SNOMED-CT, lack information necessary for the detailed classification and annotation of rare and genetic disorders. This prevents the optimal registration of such patients in databases and thus data-sharing efforts. To improve care and to facilitate research for patients with metabolic disorders, we developed a new coding system for metabolic diseases with a dedicated group of clinical specialists. Next, we compared the resulting codes with those in ICD and SNOMED-CT. No matches were found in 76% of cases in ICD-10 and in 54% in SNOMED-CT. We conclude that there are sizable gaps in the SNOMED-CT and ICD coding systems for metabolic disorders. There may be similar gaps for other classes of rare and genetic disorders. We have demonstrated that expert groups can help in addressing such coding issues. Our coding system has been made available to the ICD and SNOMED-CT organizations as well as to the Orphanet and HPO organizations for further public application and updates will be published online (www.ddrmd.nl and www.cineas.org).

In vitro and in vivo consequences of variant medium-chain acyl-CoA dehydrogenase genotypes.

BACKGROUND: Medium-chain acyl-CoA dehydrogenase (MCAD) deficiency is the most common inherited disorder of the mitochondrial fatty acid oxidation, caused by mutations in the ACADM gene. Since the introduction of neonatal screening for MCAD deficiency, a subgroup of newborns have been identified with variant ACADM genotypes that had never been identified before in clinically ascertained patients. In vitro residual MCAD enzyme activity has been found to facilitate risk-stratification. In this study we integrated results of in vitro (residual MCAD enzyme activities) and in vivo (clinical fasting tolerance tests, and phenylpropionic acid loading tests) tests in this subgroup of newborns, defining the consequences of variant ACADM genotypes. METHODS: Enzyme analyses were performed in leukocytes with: hexanoyl-CoA (C6-CoA) +/- butyryl-CoA (C4-CoA), and phenylpropionyl-CoA (PP-CoA). In vitro studies were performed in 9 subjects with variant ACADM genotypes, in vivo functional tests in 6 of these subjects. RESULTS: Enzyme analyses with C6-CoA, C6-CoA + C4-CoA, and PP-CoA identified significantly higher residual MCAD enzyme activities in subjects with variant ACADM genotypes when compared to patients with classical ACADM genotypes.After prolonged fasting (range 15-18.5 hours) no hypoglycaemia was observed. Increasing concentrations of free fatty acids indicated lipolysis, and ketone body concentrations were sufficient for blood glucose concentrations in 5 out of 6 subjects. Phenylpropionic acid loading clearly demonstrated in vivo residual MCAD enzyme activity in all studied subjects. CONCLUSIONS: Subjects with variant ACADM genotypes and residual MCAD enzyme activities >10% display residual MCAD enzyme activities in vitro and in vivo. Our findings support the hypothesis that the guidelines on maximal duration of fasting might be abandoned in subjects with residual MCAD enzyme activities >10% under normal conditions. An emergency regimen and parental instructions remain necessary in all subjects with MCAD deficiency, regardless of residual MCAD enzyme activity.

Mutation Analysis in Glycogen Storage Disease Type III Patients in the Netherlands: Novel Genotype-Phenotype Relationships and Five Novel Mutations in the AGL Gene.

Glycogen Storage Disease type III (GSD III) is an autosomal recessive disorder in which a mutation in the AGL gene causes deficiency of the glycogen debranching enzyme. In childhood, it is characterized by hepatomegaly, keto-hypoglycemic episodes after short periods of fasting, and hyperlipidemia. In adulthood, myopathy, cardiomyopathy, and liver cirrhosis are the main complications. To determine the genotype of the GSD III patients (n = 14) diagnosed and treated in our center, mutation analysis was performed by either denaturing gradient gel electrophoresis or full gene sequencing. We developed, validated and applied both methods, and in all patients a mutation was identified on both alleles. Five novel pathogenic mutations were identified in seven patients, including four missense mutations (c.643G>A, p.Asp215Asn; c.655A>G, p.Asn219Asp; c.1027C>T, p.Arg343Trp; c.1877A>G, p.His626Arg) and one frameshift mutation (c.3911delA, p.Asn1304fs). The c.643G>A, p.Asp215Asn mutation is related with type IIIa, as this mutation was found homozygously in two type IIIa patients. In addition to five novel mutations, we present new genotype-phenotype relationships for c.2039G>A, p.Trp680X; c.753_756delCAGA, p.Asp251fs; and the intron 32 c.4260-12A>G splice site mutation. The p.Trp680X mutation was found homozygously in four patients, presenting a mild IIIa phenotype with mild skeletal myopathy, elevated CK values, and no cardiomyopathy. The p.Asp251fs mutation was found homozygously in one patient presenting with a severe IIIa phenotype, with skeletal myopathy, and severe symptomatic cardiomyopathy. The c.4260-12A>G mutation was found heterozygously, together with the p.Arg343Trp mutation in a severe IIIb patient who developed liver cirrhosis and hepatocellular carcinoma, necessitating an orthotopic liver transplantation.

Molecular characterization of hepatocellular adenomas developed in patients with glycogen storage disease type I.

BACKGROUND & AIMS: Hepatocellular adenomas (HCA) are benign liver tumors mainly related to oral contraception and classified into 4 molecular subgroups: inflammatory (IHCA), HNF1A-inactivated (H-HCA), ß-catenin-activated (bHCA) or unclassified (UHCA). Glycogen storage disease type I (GSD) is a rare hereditary metabolic disease that predisposes to HCA development. The aim of our study was to characterize the molecular profile of GSD-associated HCA. METHODS: We characterized a series of 25 HCAs developed in 15 patients with GSD by gene expression and DNA sequence of HNF1A, CTNNB1, IL6ST, GNAS, and STAT3 genes. Moreover, we searched for glycolysis, gluconeogenesis, and fatty acid synthesis alterations in GSD non-tumor livers and compared our results to those observed in a series of sporadic H-HCA and various non-GSD liver samples. RESULTS: GSD adenomas were classified as IHCA (52%) mutated for IL6ST or GNAS, bHCA (28%) or UHCA (20%). In contrast, no HNF1A inactivation was observed, showing a different molecular subtype distribution in GSD-associated HCA from that observed in sporadic HCA (p = 0.0008). In non-tumor GSD liver samples, we identified glycolysis and fatty acid synthesis activation with gluconeogenesis repression. Interestingly, this gene expression profile was similar to that observed in sporadic H-HCA. CONCLUSIONS: Our study showed a particular molecular profile in GSD-related HCA characterized by a lack of HNF1A inactivation. This exclusion could be explained by similar metabolic defects observed with HNF1A inactivation and glucose-6-phosphatase deficiency. Inversely, the high frequency of ß-catenin mutations could be related to the increased frequency of malignant transformation in hepatocellular carcinoma.

A novel defect of peroxisome division due to a homozygous non-sense mutation in the PEX11ß gene.

BACKGROUND: Peroxisomes are organelles that proliferate continuously and play an indispensable role in human metabolism. Consequently, peroxisomal gene defects can cause multiple, often severe disorders, including the peroxisome biogenesis disorders. Currently, 13 different PEX proteins have been implicated in various stages of peroxisome assembly and protein import. Defects in any of these proteins result in a peroxisome biogenesis disorder. The authors present here a novel genetic defect specifically affecting the division of peroxisomes. METHODS: The authors have studied biochemical and microscopical peroxisomal parameters in cultured patient fibroblasts, sequenced candidate PEX genes and determined the consequence of the identified PEX11ß gene defect on peroxisome biogenesis in patient fibroblasts at different temperatures. RESULTS: The patient presented with congenital cataracts, mild intellectual disability, progressive hearing loss, sensory nerve involvement, gastrointestinal problems and recurrent migraine-like episodes. Although microscopical investigations of patient fibroblasts indicated a clear defect in peroxisome division, all biochemical parameters commonly used for diagnosing peroxisomal disorders were normal. After excluding mutations in all PEX genes previously implicated in peroxisome biogenesis disorders, it was found that the defect was caused by a homozygous non-sense mutation in the PEX11ß gene. The peroxisome division defect was exacerbated when the patient's fibroblasts were cultured at 40°C, which correlated with a marked decrease in the expression of PEX11γ. CONCLUSIONS: This novel isolated defect in peroxisome division expands the clinical and genetic spectrum of peroxisomal disorders and indicates that peroxisomal defects exist, which cannot be diagnosed by standard laboratory investigations.

Risk stratification by residual enzyme activity after newborn screening for medium-chain acyl-CoA dehyrogenase deficiency: data from a cohort study.

BACKGROUND: Since the introduction of medium-chain acyl coenzyme A dehydrogenase (MCAD) deficiency in population newborn bloodspot screening (NBS) programs, subjects have been identified with variant ACADM (gene encoding MCAD enzyme) genotypes that have never been identified in clinically ascertained patients. It could be hypothesised that residual MCAD enzyme activity can contribute in risk stratification of subjects with variant ACADM genotypes. METHODS: We performed a retrospective cohort study of all patients identified upon population NBS for MCAD deficiency in the Netherlands between 2007-2010. Clinical, molecular, and enzymatic data were integrated. RESULTS: Eighty-four patients from 76 families were identified. Twenty-two percent of the subjects had a variant ACADM genotype. In patients with classical ACADM genotypes, residual MCAD enzyme activity was significantly lower (median 0%, range 0-8%) when compared to subjects with variant ACADM genotypes (range 0-63%; 4 cases with 0%, remainder 20-63%). Patients with (fatal) neonatal presentations before diagnosis displayed residual MCAD enzyme activities <1%. After diagnosis and initiation of treatment, residual MCAD enzyme activities <10% were associated with an increased risk of hypoglycaemia and carnitine supplementation. The prevalence of MCAD deficiency upon screening was 1/8,750 (95% CI 1/7,210-1/11,130). CONCLUSIONS: Determination of residual MCAD enzyme activity improves our understanding of variant ACADM genotypes and may contribute to risk stratification. Subjects with variant ACADM genotypes and residual MCAD enzyme activities <10% should be considered to have the same risks as patients with classical ACADM genotypes. Parental instructions and an emergency regimen will remain principles of the treatment in any type of MCAD deficiency, as the effect of intercurrent illness on residual MCAD enzyme activity remains uncertain. There are, however, arguments in favour of abandoning the general advice to avoid prolonged fasting in subjects with variant ACADM genotypes and >10% residual MCAD enzyme activity.

Heart Failure Due to Severe Hypertrophic Cardiomyopathy Reversed by Low Calorie, High Protein Dietary Adjustments in a Glycogen Storage Disease Type IIIa Patient.

In glycogen storage disease type III (GSD III), deficiency of the debranching enzyme causes storage of an intermediate glycogen molecule (limit dextrin) in the affected tissues. In subtype IIIa hepatic tissue, skeletal- and cardiac muscle tissue is affected, while in subtype IIIb only hepatic tissue is affected. Cardiac storage of limit dextrin causes a form of cardiomyopathy, which resembles primary hypertrophic cardiomyopathy on cardiac ultrasound. We present a 32-year-old GSD IIIa patient with severe left ventricular hypertrophy (LVH) first diagnosed at the age of 8 years. LVH remained stable and symptomless until the patient presented at age 25 years with increasing dyspnea, fatigue, obesity, and NYHA (New York Heart Association) functional classification two out of four. Dyspnea, fatigue, and obesity progressed, and at age 28 years she was severely symptomatic with NYHA classification 3+ out of 4. On echocardiogram and electrocardiogram, the LVH had progressed as well. Initially, she was rejected for cardiac transplantation because of severe obesity. Therefore, a 900 cal, high protein diet providing 37% of total energy was prescribed during 4 months on which 10 kg weight loss was achieved. However, her symptoms as well as the electrocardiographic and echocardiographic LVH indices had improved dramatically - ultimately deferring cardiac transplantation. Thereafter, the caloric intake was increased to 1,370 cal per day, and the high protein intake was continued providing 43% of total energy. After 3 years of follow-up, the patient remains satisfied with reasonable exercise tolerance and minor symptoms in daily life.

Survival, but not maturation, is affected in neutrophil progenitors from GSD-1b patients.

Glycogen storage disease type 1b (GSD 1b) is caused by mutations in the Glucose-6-phosphate transporter and is characterized by impaired glucose homeostasis. In addition, GSD-1b is associated with chronic neutropenia resulting in recurrent infections and inflammatory bowel disease. It is unclear whether the neutropenia is solely due to enhanced apoptosis of mature neutrophils or whether aberrant neutrophil development may also contribute. Here we demonstrate that hematopoietic progenitors from GSD-1b patients are not impaired in their capacity to develop into mature neutrophils. However, optimal survival of neutrophil progenitors from GSD-1b patients requires high glucose levels (> 200 mg dl(-1)), suggesting that even under normoglycemic conditions these cells are more prone to apoptosis. Furthermore, analysis of cytokine levels in peripheral blood suggests an inflammatory state with an inverse correlation between the level of inflammation and the number of neutrophils. Finally, in some patients, with low numbers of peripheral blood neutrophils, high numbers of neutrophils were observed in the intestine. Together, these results suggest that the neutropenia observed in GSD-1b patients is not caused by impaired maturation, but may be caused by both increased levels of apoptosis and egress of neutrophils from the blood to the inflamed tissues.

Glycogen storage disease type III diagnosis and management guidelines.

PURPOSE: Glycogen storage disease type III is a rare disease of variable clinical severity affecting primarily the liver, heart, and skeletal muscle. It is caused by deficient activity of glycogen debranching enzyme, which is a key enzyme in glycogen degradation. Glycogen storage disease type III manifests a wide clinical spectrum. Individuals with glycogen storage disease type III present with hepatomegaly, hypoglycemia, hyperlipidemia, and growth retardation. Those with type IIIa have symptoms related to liver disease and progressive muscle (cardiac and skeletal) involvement that varies in age of onset, rate of disease progression, and severity. Those with type IIIb primarily have symptoms related to liver disease. This guideline for the management of glycogen storage disease type III was developed as an educational resource for health care providers to facilitate prompt and accurate diagnosis and appropriate management of patients. METHODS: An international group of experts in various aspects of glycogen storage disease type III met to review the evidence base from the scientific literature and provided their expert opinions. Consensus was developed in each area of diagnosis, treatment, and management. RESULTS: This management guideline specifically addresses evaluation and diagnosis across multiple organ systems (cardiovascular, gastrointestinal/nutrition, hepatic, musculoskeletal, and neuromuscular) involved in glycogen storage disease type III. Conditions to consider in a differential diagnosis stemming from presenting features and diagnostic algorithms are discussed. Aspects of diagnostic evaluation and nutritional and medical management, including care coordination, genetic counseling, hepatic transplantation, and prenatal diagnosis, are addressed. CONCLUSIONS: A guideline that will facilitate the accurate diagnosis and appropriate management of individuals with glycogen storage disease type III was developed. This guideline will help health care providers recognize patients with all forms of glycogen storage disease type III, expedite diagnosis, and minimize stress and negative sequelae from delayed diagnosis and inappropriate management. It will also help identify gaps in scientific knowledge that exist today and suggest future studies.

Renal function in glycogen storage disease type I, natural course, and renopreservative effects of ACE inhibition.

BACKGROUND AND OBJECTIVES: Renal failure is a major complication in glycogen storage disease type I (GSD I). We studied the natural course of renal function in GSD I patients. We studied differences between patients in optimal and nonoptimal metabolic control and possible renoprotective effects of angiotensin converting enzyme inhibition. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: Thirty-nine GSD I patients that visited our clinic were studied. GFR and effective renal plasma flow (ERPF) were measured by means of I(125) iothalamate and I(131) hippuran clearance and corrected for body surface area. Microalbuminuria was defined as >2.5 mg albumin/mmol creatinine and proteinuria as >0.2 g protein per liter. Optimal metabolic control was present when blood glucoses were >3.5 mmol/L, urine lactate/creatinine ratios <0.06 mmol/mmol, triglycerides <6.0 mmol/L, and uric acid concentrations <450 micromol/L. RESULTS: Quadratic regression analysis showed a biphasic pattern in the course of GFR and ERPF related to age. Microalbuminuria was observed significantly less frequently in the patients with optimal metabolic control compared with the patients with nonoptimal metabolic control. A significant decrease in GFR was observed after starting ACE inhibition. CONCLUSIONS: This study describes a biphasic pattern of the natural course of GFR and ERPF in GSD I patients, followed by the development of microalbuminuria and proteinuria. Optimal metabolic control has a renoprotective effect on the development of microalbuminuria and proteinuria in GSD I patients. Treatment with ACE inhibitors significantly decreases the GFR, especially in GSD I patients with glomerular hyperfiltration.