Safety issues associated with dietary management in patients with hepatic glycogen storage disease.

INTRODUCTION: Hepatic glycogen storage diseases (GSDs) are a group of inherited disorders of carbohydrate metabolism for which dietary management is the cornerstone. Safety and acute complications associated with dietary management have been poorly documented. We hypothesized that safety issues and complications associated with dietary management are prevalent amongst patients with these ultra-rare disorders. METHODS: A questionnaire was developed consisting of 40 questions and was distributed via eight GSD patient organizations from multiple countries. Respondents were (caregivers of) patients with self-reported hepatic GSD. RESULTS: 249 GSD patients from 26 countries responded with a median age of 14.8 years (range: 0.5-66.1). Although management was considered safe by 71% of patients, 51% reported at least one acute complication associated with dietary management, with a total number of 425 reported complications. Most frequently reported causes were: not waking up by an alarm clock (n = 70), forgetting a meal (n = 57) and infections (n = 43). Most frequently reported complications were: hypoglycemia (n = 112), hospital admissions (n = 79) and drowsiness (n = 74). Most complications occurred before the age of 12 years (82%; 637/774 total number of reported events) and during night time (63%; 340/536). Only 61% (152/249) of the GSD patients reported using a written emergency protocol. CONCLUSIONS: Safety issues and complications associated with dietary management are prevalently reported by (caregivers of) 249 GSD patients. A discrepancy has been observed between the patient's perspective on safety of dietary management and occurrence of complications as a result of dietary management.

Role of continuous glucose monitoring in the management of glycogen storage disorders.

Management of liver glycogen storage diseases (GSDs) primarily involves maintaining normoglycemia through dietary modifications and regular glucose monitoring. Self-monitoring of blood glucose is typically done 3-6 times per day, and may not sufficiently capture periods of asymptomatic hypoglycemia, particularly during sleep. Continuous glucose monitoring systems (CGMS) provide 24-h continuous glucose data and have been used effectively in diabetes mellitus to monitor metabolic control and optimize treatment. This is a relatively new approach in GSDs with only a handful of studies exploring this modality. In this study we used Dexcom CGMS to study the glycemic profile of 14 pediatric and six adult patients with GSD I, III, and IX. A total of 176 days of CGMS data were available. The CGMS was found to be a reliable tool in monitoring glucose levels and trends at all times of the day with good concordance with finger-stick glucose values. This study revealed that in addition to overnight hypoglycemia, CGMS can uncover previously undetected, subclinical, low glucose levels during daytime hours. Additionally, the CGMS detected daytime and overnight hyperglycemia, an often overlooked concern in liver GSDs. The CGMS with concurrent dietary adjustments made by a metabolic dietitian improved metabolic parameters and stabilized blood glucose levels. The CGMS was found to be a safe, effective, and reliable method for optimizing treatment in patients with GSD I, III, and IX.

Multiple phenotypes in phosphoglucomutase 1 deficiency.

BACKGROUND: Congenital disorders of glycosylation are genetic syndromes that result in impaired glycoprotein production. We evaluated patients who had a novel recessive disorder of glycosylation, with a range of clinical manifestations that included hepatopathy, bifid uvula, malignant hyperthermia, hypogonadotropic hypogonadism, growth retardation, hypoglycemia, myopathy, dilated cardiomyopathy, and cardiac arrest. METHODS: Homozygosity mapping followed by whole-exome sequencing was used to identify a mutation in the gene for phosphoglucomutase 1 (PGM1) in two siblings. Sequencing identified additional mutations in 15 other families. Phosphoglucomutase 1 enzyme activity was assayed on cell extracts. Analyses of glycosylation efficiency and quantitative studies of sugar metabolites were performed. Galactose supplementation in fibroblast cultures and dietary supplementation in the patients were studied to determine the effect on glycosylation. RESULTS: Phosphoglucomutase 1 enzyme activity was markedly diminished in all patients. Mass spectrometry of transferrin showed a loss of complete N-glycans and the presence of truncated glycans lacking galactose. Fibroblasts supplemented with galactose showed restoration of protein glycosylation and no evidence of glycogen accumulation. Dietary supplementation with galactose in six patients resulted in changes suggestive of clinical improvement. A new screening test showed good discrimination between patients and controls. CONCLUSIONS: Phosphoglucomutase 1 deficiency, previously identified as a glycogenosis, is also a congenital disorder of glycosylation. Supplementation with galactose leads to biochemical improvement in indexes of glycosylation in cells and patients, and supplementation with complex carbohydrates stabilizes blood glucose. A new screening test has been developed but has not yet been validated. (Funded by the Netherlands Organization for Scientific Research and others.).

Aggressive therapy improves cirrhosis in glycogen storage disease type IX.

Glycogen storage disease type IX (GSD IX) is described as a benign condition that often does not require treatment. Most patients with the disease are thought to outgrow the childhood manifestations, which include hepatomegaly, poor growth, and ketosis with or without hypoglycemia. Long term complications including fibrosis and cirrhosis have seldom been reported in the most common subtype, GSD IXα. We present two cases of children with GSD IXα who had fibrosis at the time of diagnosis in addition to the commonly reported disease manifestations. Structured therapy with frequent doses of uncooked cornstarch and protein supplementation was initiated, and both children responded with improved growth velocity, increased energy, decreased hepatomegaly and improved well-being. Additionally, radiographic features of fibrosis improved. We propose that GSD IXα is not a benign condition. Even in patients with a less severe presentation, consideration of a structured treatment regimen to improve quality of life appears warranted.

Dietary Management of the Glycogen Storage Diseases: Evolution of Treatment and Ongoing Controversies.

The hepatic glycogen storage diseases (GSDs) are a group of disorders where abnormal storage or release of glycogen leads to potentially life-threatening hypoglycemia and metabolic disturbances. Dietary interventions have markedly improved the outcome for these disorders, from a previously fatal condition to one where people can do well with proper care. This article chronicles the evolution of dietary management and treatment of the hepatic GSDs (types 0, I, III, VI, IX, and XI). We examine historic and current approaches for preventing hypoglycemia associated with GSDs. There is a lack of consensus on the optimal dietary management of GSDs despite decades of research, and the ongoing controversies are discussed.

Nutritional therapy for glycogen storage diseases.

Glycogen storage diseases (GSDs) are a group of inherited disorders characterized by enzyme defects that affect the glycogen synthesis and degradation cycle, classified according to the enzyme deficiency and the affected tissue. The understanding of GSD has increased in recent decades, and nutritional management of some GSDs has allowed better control of hypoglycemia and metabolic complications. However, growth failure and liver, renal, and other complications are frequent problems in the long-term outcome. Hypoglycemia is the main biochemical consequence of GSD type I and some of the other GSDs. The basis of dietary therapy is nutritional manipulation to prevent hypoglycemia and improve metabolic dysfunction, with the use of continuous nocturnal intragastric feeding or cornstarch therapy at night and foods rich in starches with low concentrations of galactose and fructose during the day and to prevent hypoglycemia during the night.

Intact transferrin and total plasma glycoprofiling for diagnosis and therapy monitoring in phosphoglucomutase-I deficiency.

Phosphoglucomutase 1 (PGM1) deficiency results in a mixed phenotype of a Glycogen Storage Disorder and a Congenital Disorder of Glycosylation (CDG). Screening for abnormal glycosylation has identified more than 40 patients, manifesting with a broad clinical and biochemical spectrum which complicates diagnosis. Together with the availability of D-galactose as dietary therapy, there is an urgent need for specific glycomarkers for early diagnosis and treatment monitoring. We performed glycomics profiling by high-resolution QTOF mass spectrometry in a series of 19 PGM1-CDG patients, covering a broad range of biochemical and clinical severity. Bioinformatics and statistical analysis were used to select glycomarkers for diagnostics and define glycan-indexes for treatment monitoring. Using 3 transferrin glycobiomarkers, all PGM1-CDG patients were diagnosed with 100% specificity and sensitivity. Total plasma glycoprofiling showed an increase in high mannose glycans and fucosylation, while global galactosylation and sialylation were severely decreased. For treatment monitoring, we defined 3 glycan-indexes, reflecting normal glycosylation, a lack of complete glycans (LOCGI) and of galactose residues (LOGI). These indexes showed improved glycosylation upon D-galactose treatment with a fast and near-normalization of the galactose index (LOGI) in 6 out of 8 patients and a slower normalization of the LOCGI in all patients. Total plasma glycoprofiling showed improvement of the global high mannose glycans, fucosylation, sialylation, and galactosylation status on D-galactose treatment. Our study indicates specific glycomarkers for diagnosis of mildly and severely affected PGM1-CDG patients, and to monitor the glycan-specific effects of D-galactose therapy.

A novel starch for the treatment of glycogen storage diseases.

OBJECTIVE: To determine whether a new starch offers better short-term metabolic control than uncooked cornstarch in patients with glycogen storage diseases (GSDs). STUDY DESIGN: A short-term double-blind cross-over pilot study comparing uncooked physically modified cornstarch (WMHM20) with uncooked cornstarch in patients with GSD types Ia, Ib and III. Twenty-one patients (ages 3-47, 9 female) were given 2 g/kg cornstarch or WMHM20 mixed in water. Blood glucose, lactate and insulin, and breath hydrogen and (13)CO2 enrichment were measured, at baseline and after each load. The hourly biochemical evaluations terminated when blood glucose was < or = 3.0 mmol/L, when the study period had lasted 10 h or when the patient wished to end the test. The alternative starch was administered under similar trial conditions a median of 10 days later. RESULTS: The median starch load duration was 9 h for WMHM20 versus 7 h for cornstarch. Glucose decreased more slowly (p = 0.05) and lactate was suppressed faster (p = 0.17) for WMHM20 compared with cornstarch. Peak hydrogen excretion was increased (p = 0.05) when cornstarch was taken. CONCLUSION: These data indicate longer duration of euglycaemia and better short-term metabolic control in the majority of GSD patients with WMHM20 compared to cornstarch.

Complex carbohydrates in the dietary management of patients with glycogenosis caused by glucose-6-phosphatase deficiency.

Carbohydrates with digestion characteristics between those of lente uncooked starches and rapidly digestible oligosaccharides were administered in a dose of 1.5 g/kg body weight to five patients with glycogenosis from glucose-6-phosphatase deficiency. Postprandial duration of normoglycemia and concentrations of blood insulin and lactate were determined. Uncooked barley groats in water, or incorporated in a meal turned out to behave as lente carbohydrates. Uncooked couscous in water, couscous incorporated in a meal, and partially cooked macaroni given as a meal behaved as semilente carbohydrates as compared with uncooked cornstarch and glucose. The in vitro determination of the digestibility index along with the in vivo tolerance test enables us to choose and incorporate semilente carbohydrates in the day-time treatment of patients.

Nutrition therapy for hepatic glycogen storage diseases.

Hepatic glycogen storage diseases (GSD) are a group of rare genetic disorders in which glycogen cannot be metabolized to glucose in the liver because of one of a number of possible enzyme deficiencies along the glycogenolytic pathway. Patients with GSD are usually diagnosed in infancy or early childhood with hypoglycemia, hepatomegaly, poor physical growth, and a deranged biochemical profile. Dietary therapies have been devised to use the available alternative metabolic pathways to compensate for disturbed glycogenolysis in GSD I (glucose-6-phosphatase deficiency), GSD III (debrancher enzyme deficiency), GSD VI (phosphorylase deficiency, which is less common), GSD IX (phosphorylase kinase deficiency), and GSD IV (brancher enzyme deficiency). In GSD I, glucose-6-phosphate cannot be dephosphorylated to free glucose. Managing this condition entails overnight continuous gastric high-carbohydrate feedings; frequent daytime feedings with energy distributed as 65% carbohydrate, 10% to 15% protein, and 25% fat; and supplements of uncooked cornstarch. In GSD III, though glycogenolysis is impeded, gluconeogenesis is enhanced to help maintain endogenous glucose production. In contrast to treatment for GSD I, advocated treatment for GSD III comprises frequent high-protein feedings during the day and a high-protein snack at night; energy is distributed as 45% carbohydrate, 25% protein, and 30% fat. Patients with GSD IV, VI, and IX have benefited from high-protein diets similar to that recommended for patients with GSD III.

McArdle's syndrome: the reaction to a fat-rich diet.

The effect of a diet enriched with fats on the muscle performance of a patient with McArdle's syndrome was studied. The tolerance to physical activity was studied during exercise (ergometric examination) and by sustained abduction to 90 degrees of the deltoid muscle, both after a three-day period on a normal diet and after a three-day period on a fat-rich diet. After the first period a woody spasm of the deltoid muscle was found which lasted several days. After a period on fat-rich diet the patient's physical fitness was increased and the recovery period after the acute load was shorter. Moreover, no induration of the deltoid muscle was observed after the sustained abduction to 90 degrees. It is argued that maximal strength is not improved by a fat-rich diet but tolerance to submaximal loads is increased by such treatment and recovery from non-lactate-produced muscle discomfort is hastened.

Nutrition in children affected by inherited metabolic diseases.

Diet-therapy represents an elective approach to the treatment of several inborn errors of metabolism. According to the type of disease, dietary intervention can be addressed to three different goals: a) dietary restriction (global or partial) of one or more nutritional components become "toxic" because of the occurring enzymatic defect; b) supplementation with a given defective nutritional component; c) elimination through the use of diet and drugs of the accumulated "toxic" compounds. These interventions are aimed at overtaking the metabolic block and to avoid the accumulation of intermediate "toxic" substrates. The efficacy of the therapy should then be evaluated by means of a thorough biochemical and clinical follow-up (including anthropometric and psychomotor development parameters). In particular, nutritional indexes should be constantly monitored in order to support the dietary therapy, discover and correct any possible nutritional deficiency secondary to the "by exclusion dietary regimen". To elucidate these general principles, we discuss in detail some hereditary diseases of amino acid (phenylketonuria) and carbohydrate (glycogen storage disease and galactosemia) metabolism that, being responsive to the nutritional intervention, can be considered reliable examples of all the problems linked to diagnosis, acute and long-term therapy and follow-up of these diseases.

Dietary management of inborn errors of metabolism.

Inborn errors of metabolism are individually rare but are an important cause of mortality and morbidity in infants and children. Dietary therapy is the mainstay of treatment in phenylketonuria, maple syrup urine disease, homocystinuria, galactosemia and glycogen storage disease (Type I/III). Some disorders like urea cycle disorders and organic acidurias require dietary modification in addition to other modalities. Certain basic principles of dietary management should be clearly understood for proper management of these disorders. Commercially available diets are very expensive and modification in routine Indian diet may be tried based on content of different nutrients but the desirable fine control is not achieved.

Ketogenic diet in neuromuscular and neurodegenerative diseases.

An increasing number of data demonstrate the utility of ketogenic diets in a variety of metabolic diseases as obesity, metabolic syndrome, and diabetes. In regard to neurological disorders, ketogenic diet is recognized as an effective treatment for pharmacoresistant epilepsy but emerging data suggests that ketogenic diet could be also useful in amyotrophic lateral sclerosis, Alzheimer, Parkinson's disease, and some mitochondriopathies. Although these diseases have different pathogenesis and features, there are some common mechanisms that could explain the effects of ketogenic diets. These mechanisms are to provide an efficient source of energy for the treatment of certain types of neurodegenerative diseases characterized by focal brain hypometabolism; to decrease the oxidative damage associated with various kinds of metabolic stress; to increase the mitochondrial biogenesis pathways; and to take advantage of the capacity of ketones to bypass the defect in complex I activity implicated in some neurological diseases. These mechanisms will be discussed in this review.