Type I glycogen storage disease with vasoconstrictive pulmonary hypertension

Summary A case of glycogen storage disease (GSD) type I with vasoconstrictive pulmonary hypertension is described.     

Intestinal function in glycogen storage disease type I

Glycogen storage disease type I (GSD I) (McKusick 232200) is caused by inherited defects of the glucose-6-phosphatase complex. Patients with GSD Ia as well as patients with GSD Ib may suffer from intermittent diarrhoea, which seems to worsen with age. The cause of this diarrhoea is unknown. This study describes the results of investigations of intestinal functions and morphology in patients with GSD Ia and GSD Ib, which were performed to detect a common cause for chronic diarrhoea in GSD I. The following were investigated: faecal fat excretion, faecal ₁-antitrypsin and faecal chymotrypsin, expiratory H₂ concentrations, persorption of cornstarch in urine and colonic biopsies. With the investigations presented in this study, no common cause for diarrhoea in GSD I was found. In GSD Ib loss of mucosal barrier function due to inflammation, documented by increased faecal ₁-antitrypsin excretion (3.5–9.6mg/g dry faeces) and inflammation in the colonic biopsies, seems to be the main cause. The inflammation is most likely related to disturbed neutrophil function, which is often found in GSD Ib. Whether another cause is involved in GSD Ia and in GSD Ib, related to the disturbed function of glucose-6-phosphatase in the enterocyte, remains to be investigated.     

Hepatocellular carcinoma in type I glycogen storage disease

Patients suffering from Type I glycogen storage disease frequently develop hepatic tumors. Some of these were classified as carcinoma, with the majority of tumors representing benign adenomata. However, no evidence exists of malignant transformation of adenomata in these patients. Here, we describe the occurrence of a hepatocellular carcinoma in the adenomata-bearing liver of the elder of two sisters suffering from Type I glycogen storage disease at the age of 20 years, 6 years after the diagnosis had been made. Surprisingly, alpha-fetoprotein levels were normal throughout the entire course of this patient, whereas the younger sister had elevated levels despite the absence of malignant lesions. Thus, the clinical significance of alpha-fetoprotein remains unclear in both cases. Nocturnal feeding, although performed continuously over the 6 years after the diagnosis, had obviously failed to prevent the development of hepatic tumors in both patients.     

Endogenous glucose production in type I glycogen storage disease

The adaptive mechanisms that protect some patients with Type I glycogen storage disease from fasting hypoglycemia were examined in two young adults. Both maintained low normal fasting plasma glucose concentrations even during 3 day fasts; blood lactate concentrations increased during the first 12 hr and then decreased to normal during the second and third days. Acute hyperglycemic responses to glucagon nearly doubled after three days of starvation when compared with responses following 12 hr fasts. Enhanced glucagon-induced hyperglycemic changes also were observed following the administration of alcohol or glucocorticoids. However, fructose infusions failed to demonstrate hyperglycemic responses after a 3 day fast, alcohol or glucocorticoids. The present studies demonstrate endogenous glucose production in our patients despite an absence of the enzyme glucose-6-phosphatase. These findings could explain why some patients with Type I glycogen storage disease are protected from fasting hypoglycemia.     

Mutation spectrum of type I glycogen storage disease in Hungary

Summary We performed mutation analysis in 12 Hungarian type I glycogen storage disease (GSD I) patients in order to determine the mutation spectrum. All patients were clinically classified as GSD Ia. Nine patients carried biallelic G6PC mutations (p.Q27fsX35, p.D38V, p.W70X, p.K76N, p.W77R, p.R83C, p.E110Q, p.G222R), with E110Q reported only in Hungary. However, three patients displayed two common G6PT1 (SLC37A4) mutations (p.L348fsX400, p.C183R) which were originally described in association with GSD Inon-a. Review of the literature and our data show that G6PT1 mutations are not associated with neutropenia and related clinical findings in approximately 10% of these cases. Homozygosity for the truncating G6PT1 mutation p.L348fsX400 can be observed with and without neutropenia, indicating that one or more modifiers of the action of G6PT1 exist. Our data are suitable to provide DNA-based and thus noninvasive confirmation of diagnosis in Hungarian patients with this disorder.     

Pulmonary hypertension due to glycogen storage disease type II (Pompe's disease): a case report

A rare case of pulmonary hypertension due to glycogen storage disease type II (Pompe's disease) was reported. An 18-year-old girl was admitted to Kawasaki Medical School Hospital because of cyanosis, dyspnea on exertion and amenorrhea. She was 149 cm in height and 29 kg in body weight. Clinical examination revealed that pulmonary artery pulse and right ventricular heave were palpable over the precordium. On auscultation, an accentuated pulmonic second heart sound, pulmonic ejection sound and diastolic decrescendo murmur (Levine III/VI) were heard in the second intercostal space at the right sternal border. Her skeletal muscles, especially her intercostal muscles were generally weak and atrophic. Her electrocardiogram showed a pulmonary P-wave and right ventricular hypertrophy. The chest X-ray revealed right ventricular enlargement and a dilated pulmonary trunk. On echocardiography, the right ventricle and the main pulmonary artery were dilated, and a systolic notch of the pulmonary valve was found. Swan-Ganz catheterization disclosed that pulmonary artery pressure, right ventricular pressure and mean pulmonary capillary wedge pressure were 76/35 (50) mmHg, 76/12 mmHg and 10 mmHg, respectively. Respiratory function tests showed severe restrictive ventilatory impairment with hypercapnea and hypoxemia. On biopsy of the left quadriceps femoris muscle, the most striking finding was numerous intracytoplasmic vacuoles. The small vacuoles were stained with PAS and acid phosphatase. Electron microscopy showed massive glycogen accumulation in the sarcoplasm and membrane bound vacuoles (glycogenosome). Alpha-1, 4-glucosidase activity in the peripheral lymphocytes was definitely decreased. Her pulmonary hypertension resulted from respiratory muscular atrophy and alveolar hypoventilation caused by Pompe's disease.     

Clinical evaluation of a portable lactate meter in type I glycogen storage disease

Summary High lactate concentrations occur in type I glycogen storage disease (GSD) whenever glycogenolysis occurs. Not only does hyperlactataemia cause acute clinical deterioration, but chronic lactate elevations have also been associated with many of the long-term complications in GSD. A portable finger-stick blood lactate meter has recently been marketed as a training tool for high-performance athletes, but it has not been tested as a clinical diagnostic tool. This study was performed to assess the accuracy of the portable lactate meter in subjects with GSD I who are predisposed to high lactate concentrations. A total of 166 intravenous and 39 capillary samples from 13 subjects were tested concomitantly on three different lactate meters. The meter readings were compared with the lactate concentration determined by the laboratory gold-standard enzymatic colorimetric assay. Almost no inter-meter variability was found. The lactate meter values had outstanding correlation with the laboratory lactate determination, although the meters were found to run 0.5 mmol/L higher than the laboratory assay. The meter deviation was independent of lactate concentration. More variability was noted with finger-stick capillary lactate determinations, but monitoring of trends with capillary samples should prove valuable as a method for determining long-term control or acute deterioration. The portable lactate meter is a highly accurate tool for monitoring lactate concentrations, and should prove valuable for monitoring metabolic control in patients with GSD type I and other disorders associated with hyperlactataemia.     

Dietary dilemmas in the management of glycogen storage disease type I

Over the last 50 years, understanding the biochemical bases of glycogen storage disease type I has led to vastly improved survival and health outcomes but the management still centres around an extremely intensive dietary regimen. Patients’ metabolic profiles are really determined by the whole of the diet and it can be very difficult to adjust therapy accordingly. In an iso-energetic diet with reference total energy intake, high carbohydrate intake could compromise other macro- and micro-nutrients; if carbohydrates are not restricted then total energy intake is excessive. The quality of the macronutrient such as the glycemic index of carbohydrate, the type of sugar and the proportion of medium–chain triglyceride and essential fatty acids also has a bearing on an individual’s long-term metabolic control with potential clinical correlates. These factors as well as the different requirements between individuals and within individuals as they get older mean that the management of glycogen storage disease type I is particularly fraught. Regular clinical and dietary review is imperative as patients grow, ensuring adequate but not excessive low glycaemic index carbohydrate intake, appropriate dynamic biochemical profiles and suitable age appropriate eating patterns. Without diligent management, and education that empowers the patient, these individuals can struggle in adult life.     

Metabolic control and renal dysfunction in type I glycogen storage disease

This study was undertaken to determine the effect on renal function of continuous glucose therapy from early childhood. Twenty-three subjects, median age 13.9 years, range 5.9-26.9 years, with type I glycogen storage disease (GSDI) treated with continuous glucose therapy from a median age of 1.3 years, range 0.1-12.9 years, had 24 h monitoring of metabolites and glucoregulatory hormones on their home feeding regimen to assess metabolic control at approximately yearly intervals for a median duration of 8 years. During the most recent evaluation, 24 h urinary albumin excretion rate (AER), kidney size, and creatinine clearance (Ccr) were measured.CCr was unrelated to age and was increased (>2.33 ml/s per 1.73 m2) in 10/23 (43%). Mean kidney length exceeded 2SD in 16/23 (70%). AER was normal in all five subjects < 10 years and was increased (> 10 µg/min) in 8/23 (35%), all > 10 years of age. AER was significantly greater in subject of similar age who started continuous glucose therapy later in childhood and was significantly higher in subjects with lower mean 24 h plasma glucose concentrations and higher mean 24 h blood lactate concentrations, both at the time of assessment of renal function and over the preceding 5 years.GSDI subjects with persistently elevated concentrations of blood lactate, serum lipids and uric acid are at increased risk of nephropathy. Optimal dietary therapy instituted early in life may delay, prevent, or slow the progression of renal disease.     

Continuous glucose monitoring in children with glycogen storage disease type I

Glycogen storage disease type I (GSD I) is characterized by impaired production of glucose from glycogenolysis and gluconeogenesis resulting in severe fasting hypoglycaemia. The aim of the present study was to examine the efficacy of a continuous subcutaneous glucose monitoring system (CGMS MiniMed), to determine the magnitude and significance of hypoglycaemia in GSD I and to evaluate the efficacy of its dietary treatment. Four children with GSD I were studied over a 72-h period. Results indicated that the values recorded with continuous subcutaneous glucose monitoring were highly correlated with paired blood glucose values measured by glucometer. Significant periods of asymptomatic hypoglycaemia were noted, especially during night-time. The study suggests that repeated continuous subcutaneous glucose monitoring may serve as a useful tool for the assessment of the long-term management of GSD I patients.     

Cardiomyopathy of glycogen storage disease type III

Summary To identify the severity of cardiac involvement in glycogen storage disease type III (GSDIII), and its relation to skeletal muscle involvement and age, 23 patients were studied. The median age was 10 years. Echocardiography, electrocardiography, and creatine phosphokinase (CK) levels were used to assess cardiac and skeletal muscle involvement. Septal and left ventricular posterior wall measurements were compared with normal data. Shortening fraction was derived from left ventricular cavity dimensions. In some patients the echocardiogram resembled that of hypertrophic cardiomyopathy. Thirteen of 20 electrocardiograms (ECG) were abnormal. Eleven patients had septal and/or posterior wall thickness >95% confidence limits (CL). Despite this, cardiac symptoms were uncommon. The CK levels were not directly associated with cardiac abnormalities. Older patients (>20 years) had more abnormal measurements of posterior wall thickness than did younger ones (<20 years). This finding, albeit in a cross-sectional series, suggests progressive myocardial involvement with age despite the absence of symptoms.     

Effect of ramipril in a patient with glycogen storage disease type I and nephrotic-range proteinuria

We studied the effect of ramipril on urinary protein excretion and arterial pressure in a 27-year-old patient with GSD Ia and heavy proteinuria (2–3 g/24 h). Ramipril therapy resulted in an important reduction of proteinuria (0.3–0.5 g/24 h): no changes were observed in arterial pressure and renal function during the 12-month follow-up. We conclude that treatment with ramipril can be employed effectively and safely in GSD Ia patients with nephrotic-range proteinuria.