Dietary considerations for glycogen storage disease -
It is passed from parent to child in an autosomal recessive pattern. This means that both parents must pass the same defective gene for the child to develop a disorder. When a parent has an autosomal recessive trait, they don't have symptoms and usually don't know they have it. Defects in the glycogen synthase 1 GYS 1 gene cause muscle GSD 0, while defects in the glycogen synthase 2 GYS 2 gene cause the version of the disorder that affects the liver.
Only a healthcare provider can deliver an accurate diagnosis of GSD 0. The diagnosis involves a physical examination, a history of symptoms, and the laboratory tests needed to identify the disorder. Laboratory tests usually involve an evaluation of the following substance levels to identify whether they reflect levels that are unique to this disease:.
Patients who have a suspected case of GSD 0 are usually admitted for inpatient monitoring after fasting. A glucagon challenge test, which measures the amount of glucagon in the blood, may also be recommended.
A liver biopsy can accurately diagnose this disease. However, molecular genetic testing to identify abnormal genes can often prevent the need for an invasive procedure.
This type of testing can also specify carriers and a prenatal diagnosis. Exome sequencing , a type of genetic testing that identifies changes in your genes, can also diagnose GSD 0. Though there is no proven medical treatment or cure for GSD 0, dietary therapy can manage the disorder.
This involves a diet organized to avoid low blood sugar by avoiding fasting. It is also designed to provide enough calories and protein for normal growth and development. Frequent meals and snacks throughout the day can help maintain normal blood sugar levels.
Eating a diet high in protein may help offset common symptoms of cramping, fatigue, and lethargy. Uncooked cornstarch can prevent overnight hypoglycemia during sleep because it delivers a "slow release" type of glucose.
The recommended diet involves avoiding highly processed carbohydrates that prevent the changing of excess glucose into lactate, or lactic acid. GSD 0 usually involves a good prognosis for normal growth, intellectual development, and average lifespan.
Early diagnosis and treatment with dietary management can prevent hypoglycemic episodes and support this prognosis. Short-term symptoms of liver GSD 0 can improve when food is consumed. However, in cases in which symptoms remain undiagnosed for years, the disease may lead to growth failure and developmental delay.
Muscle GSD 0 can interfere with the heart's ability to pump blood effectively. This increases the risk of cardiac arrest and sudden death after physical activity for children and adolescents with this version of the disease. Patient education for the affected person, their parents, and sibling s can help those involved understand how to better manage the disease, as well as their risk of inheriting or passing it on to their children.
Managing this disease usually involves lifelong monitoring and working with a team of specialists that may include the following healthcare professionals:. GSD 0 hinders the body's power to produce, use, and store glycogen.
People with this disease have a deficiency of the glycogen synthase enzyme GSY in either their liver or muscles.
The disease is passed from parent to child. Though other glycogen storage disorders result in too much glycogen, this type causes slightly lower than normal levels in the liver or muscles.
When levels of this enzyme are low, the body can't supply glucose to the rest of the body and support normal function. This lifetime disease is often found in older infants or young children based on whether the liver or muscles are affected.
Hypoglycemia, or low blood sugar, is a common first symptom. This disease has no cure but can be controlled with the right diet. The key to getting the best outcomes is to find the disease early. This can allow the affected child to start a diet that prevents bouts of low blood sugar before it affects normal growth and development.
Though it can be challenging to follow the diet necessary to manage this condition, doing so increases your chances of achieving the best possible outcomes.
Having a multidisciplinary healthcare team can help ensure that you're doing all you can to live a normal life. This and other glucose storage diseases are passed from parents to their children. If your parents or a sibling has one of these diseases, it's important that you learn about your risk of passing it on to your children so you make the best decisions for your life.
GSD 0 is a very rare disease that is inherited in families. Fewer than 30 people with the liver type and fewer than 10 people with the muscle type are included in scientific literature.
Muscle GSD 0 can cause deadly symptoms without management. This type of the disease can cause irregular heart rhythms, increasing the risk of cardiac arrest after moderate activity for children and adolescents. People with GSD 0 can usually live a normal life.
Early diagnosis and the introduction of a high-protein diet to avoid low blood sugar can help support normal growth and development. Working with a nutritionist can help you understand how your diet can affect your health. Ross KM, Ferrecchia IA, Dahlberg KR, Dambska M, Ryan PT, Weinstein DA.
Dietary management of the glycogen storage diseases: evolution of treatment and ongoing controversies. Adv Nutr. NORD - National Organization for Rare Disorders, Inc. NIH GARD information: glycogen storage disease type 0, liver. Association for Glycogen Storage Disease. Type 0 glycogen storage disease.
Arko JJ, Debeljak M, Tansek MZ, Battelino T, Groselj U. A patient with glycogen storage disease type 0 and a novel sequence variant in GYS2 : a case report and literature review. J Int Med Res. doi: Glycogen storage disease type 0. Glycogen-storage disease type 0 GSD-0 glycogen synthetase deficiency clinical presentation.
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Development of severe anemia during the course of the disease warrants further evaluation for hepatic adenomas and inflammatory bowel disease in GSD-Ia and GSD-Ib, respectively. Patients diagnosed with GSD-Ia or GSD-Ib may experience intermittent diarrhea which seems to deteriorate with age[ 43 ].
However, the cause of diarrhea remains unknown. Intolerance to UCCS and inflammatory bowel disease are possible causes of diarrhea in this population. Inflammatory bowel disease is a well characterized feature in individuals with GSD-Ib. Neutropenia and impaired neutrophil function are the underlying causes of inflammatory bowel disease in GSD-Ib[ 44 ].
However, inflammatory bowel disease was also recently reported in adult patients with GSD-Ia as a new, long-term complication of the disease[ 45 ].
The prevalence of symptomatic inflammatory bowel disease in adults with GSD-Ia also seems to be higher than the general population[ 45 ]. The authors speculated that inflammatory bowel disease in GSD-Ia may be caused by chronic UCCS therapy, which could be altering the microbiota of the gastrointestinal tract leading to inflammation.
More recently, very early onset inflammatory bowel disease was reported in a child with GSD-Ia at the age of 42 mo[ 46 ]. A notable finding among the majority of patients with this condition during childhood is growth retardation, while short stature is commonly observed in affected adults[ 5 , 47 , 48 ].
Cognitive delay and epilepsy due to repeated or severe hypoglycemic events may occur[ 31 ]. Hyperlipidemia may cause xanthomas, pancreatitis, and cholelithiasis[ 30 , 49 ]. Acute pancreatitis may develop secondary to very high serum triglycerides in GSD-I and necessitate plasmapheresis[ 50 ].
Systemic metabolic perturbations and glycogen deposition in the kidneys result in glomerular and proximal and distal renal tubular injury. Renal manifestations may occur in childhood but often are not noticed without proper diagnostic work-up.
The prevalence of renal involvement tends to rise as patients age[ 51 ]. Glomerular hyperfiltration, whose underlying mechanism is not yet fully understood, is typically the initial manifestation of renal involvement.
Possible etiologies have been suggested including activation of the renin-angiotensin system, persistent oxidative stress, profibrotic cytokines such as transforming growth factor-β, and changes in energy reserves of renal tubular epithelial cells[ 52 - 54 ].
Glomerular hyperfiltration then progresses to microalbuminuria, proteinuria, glomerular scarring and interstitial fibrosis, and end-stage renal disease in adult patients[ 48 , 55 ].
This may increase the risk of urinary tract infections causing further renal parenchymal damage. Hypertension and hematuria are other findings[ 55 , 56 ].
Systemic hypertension may develop early in childhood but is seen more often in adults with GSD-I[ 58 ]. Renal cysts have also been described in individuals with GSD-I[ 59 ]. Gout can develop due to persistent hyperuricemia as gouty attacks, gouty tophi, and kidney stones.
In GSD-Ia patients, various types of liver lesions, including hepatic adenoma, hepatocellular carcinoma, hepatoblastoma, focal fatty infiltration, focal fatty sparing, peliosis hepatis, and focal nodular hyperplasia have been reported, with hepatic adenomas being the most prevalent among them[ 37 ].
The median age of adenoma presentation is 15 years[ 30 ]. Although the prevalence of hepatic adenomas increases with age in GSD-I, they may be seen in younger children[ 60 ].
Inadequate metabolic control appears to play a central role in hepatic adenoma formation. The degree of hyperlipidemia is associated with development of hepatic adenomas[ 61 ]. However, the pathophysiological mechanisms are yet to be fully understood and factors other than metabolic control may also be responsible for adenoma formation.
Chromosomal and genetic alterations may also play a role in hepatocellular carcinoma associated with GSD-I[ 63 ]. Hepatic adenomas have the potential to transform into hepatocellular carcinoma over an extended period, with reports of malignant transformation occurring as long as 28 years after initial diagnosis[ 64 , 65 ].
A rapid increase in size or number of adenomas is associated with an increased risk of adenoma to hepatocellular carcinoma transformation and should be evaluated carefully. The link between GSD-I and risk for cardiovascular disease is controversial.
Although GSD-Ia patients have elevated levels of triglycerides, very low density lipoprotein and low density lipoprotein, the occurrence of endothelial vascular dysfunction and atherosclerosis is uncommon.
It has been suggested that the increased serum levels of apoE may offset the elevated risk of atherosclerosis associated with dyslipidemia[ 66 ].
In addition, an increase in serum levels of antioxidative factors may contribute as a protective mechanism[ 67 , 68 ]. There are conflicting data regarding whether patients with GSD-I are at increased risk for atherosclerosis[ 69 , 70 ]. Pulmonary hypertension is a rare long-term complication of GSD-I with few cases reported.
Patients with a concomitant predisposing condition for pulmonary arterial hypertension are at increased risk[ 37 ]. The main neurological impact of GSD is related to hypoglycemia.
Patients with GSD-I may suffer from brain damage, which may be caused by recurrent severe hypoglycemia[ 71 ]. Studies have found a significant correlation between the frequency of hospital admissions for hypoglycemia and abnormalities in both performance ability tests and brainstem auditory evoked potentials.
In addition, electroencephalography abnormalities were found to be correlated with dietary compliance. Brain imaging abnormalities were more frequent among GSD-I patients with early symptom onset, frequent and longer hospital admissions, and poor metabolic control including elevated levels of uric acid, lactate, and triglyceride[ 32 , 72 ].
Some females may have polycystic ovaries and irregular menstrual cycles with normal fertility[ 73 ]. Women with GSD-Ia may have pregnancies and deliveries without complications[ 74 ]. In consideration of the risk of development of hepatic adenomas in GSD-I patients, estrogen-containing contraceptives should be avoided whenever possible[ 75 ].
In addition to hypoglycemia, the most prominent laboratory abnormalities observed in patients with GSD-I include lactic acidosis, hyperlipidemia especially hypertriglyceridemia but also hypercholesterolemia , and hyperuricemia Figure 1.
Mild elevation in transaminase levels is usually detected[ 30 ]. Ultrasonographic examination may reveal enlarged kidneys in affected patients of all ages.
Serum biotinidase activity is increased in GSD-Ia patients[ 76 - 79 ]. Biotinidase activity was reported to be positively correlated with hypertriglyceridemia in subjects with GSD-I while severe fibrosis and cirrhosis were related to reduced enzyme activity[ 80 ].
There may also be hypercalciuria[ 5 ]. There is little or no increase in blood glucose concentration in response to administration of glucagon and this may even lead to worsening of the metabolic acidosis.
Histopathological examination of the liver in patients with GSD-Ia typically reveals a mosaic pattern with pale-staining and swollen hepatocytes. Other observed features include steatosis and nuclear hyperglycogenation.
Periodic acid-Schiff PAS -positive and diastase sensitive glycogen is evenly dispersed throughout the cytoplasm. Glycogen accumulation may be within the normal range or exhibit only a mild increase. While fibrosis is not as prominent in GSD-I as in GSD types III, IV, and VI, it may still be present in some affected individuals[ 5 , 81 - 83 ].
GSD-Ia is usually suspected based on a set of clinical e. The definitive diagnosis is confirmed by a mutation analysis or a liver biopsy and an enzyme assay. If a liver biopsy is performed, diagnosis can be confirmed by measuring G6Pase enzyme activity on a liver biopsy specimen; however, it should be kept in mind that measurement of G6Pase enzyme activity will not detect GSD-Ib.
When the specific mutation in the index case is known, prenatal diagnosis via chorionic villus sampling can be performed for GSD-I[ 84 ].
The mainstay of treatment is to prevent hypoglycemia by avoiding prolonged fasting[ 85 ]. Continuously providing a dietary supply of glucose during the day and night by frequent feedings, frequent ingestion of UCCS or nocturnal enteral tube feeding are possible feeding strategies.
Infants and children should be fed frequently, not allowing fasting periods longer than h. In adolescents and adults, fasting more than h should be avoided.
Small, frequent meals with balanced macronutrient content and use of UCCS are recommended. Continuous intragastric feeding through a nasogastric or gastrostomy tube can be used overnight allowing the patients to sleep through the night[ 37 ].
UCCS can be introduced as early as mo of age. For the administration of UCCS in GSD-I patients, the recommended dose is Digestion of UCCS is slow, enabling a sustained release of glucose, thereby achieving a more stable glycemic profile over an extended duration, in contrast to other carbohydrate sources.
The administration of UCCS has been shown to achieve adequate glycemia for a median duration of 4. Glycosade ® , a modified, waxy maize extended-release cornstarch, is available as a single-dose overnight treatment[ 87 ]. In GSD-I, intake of fructose and galactose, which cannot be metabolized to glucose via G6P, further contributes to the metabolic derangement.
Lactose galactose and glucose , fructose and sucrose fructose and glucose should be restricted in all age groups. Restricting the intake of fruits, vegetables, juices, and dairy products renders the diet inadequate.
Micronutrients, vitamins, and minerals should be supplemented to avoid nutritional deficiencies. Effective dietary management is essential to minimize the metabolic derangement associated with GSD-I and to reduce the development of long-term complications[ 37 , 85 ].
However, caution must be exercised to avoid overtreatment. Overtreatment with UCCS has many consequences including obesity, increased glycogen storage in the liver, worsening lactic acidosis, increased gastrointestinal disturbances, hyperinsulinemia, and insulin resistance[ 88 ].
If there is anemia, the causes must be evaluated e. In the case of severe anemia, hepatic adenomas in GSD-Ia and enterocolitis in GSD-Ib should be investigated[ 42 ]. Angiotensin converting enzyme inhibitors or angiotensin receptor blockers should be used to delay the progression of renal damage[ 53 , 89 - 91 ].
If serum triglyceride levels remain high despite optimizing dietary treatment, the administration of lipid-lowering drugs, such as 3-hydroxymethylglutaryl-coenzyme A reductase inhibitors and fibrates, may be necessary to decrease the risk of atherosclerosis, cholelithiasis, and pancreatitis.
For adults with persistently elevated cholesterol levels, statins may be considered as a treatment option[ 85 ]. The positive effect of medium-chain triglycerides on lowering serum cholesterol and triglyceride levels has been reported[ 92 , 93 ].
Recommendations regarding perioperative management of patients with GSD-I are available[ 37 , 94 ]. Close monitoring of blood glucose, electrolytes, and lactate levels is crucial during the peri-operative period. The administration of Ringer lactate solution should be avoided in GSD-I patients, as it may exacerbate lactic acidosis and worsen metabolic decompensation[ 37 ].
Bleeding time must be normalized before elective surgical interventions by h continuous gastric drip feeding for one week or by intravenous glucose infusion over 24 to 48 h[ 85 ].
In , after realizing that in vitro G6Pase activity was normal despite glucose not being released from G6P in vivo , a second subtype of GSD-I was identified[ 95 ].
In , it was elucidated that a transport system specific to G6P exists and is responsible for transporting G6P from the cytoplasm to the endoplasmic reticulum[ 96 ]. The responsible gene, SLC37A4 the solute carrier family 37 member 4 , has been cloned and located on chromosome 11q23[ 97 , 98 ].
GSD-Ib is characterized by distinctive features such as recurrent infections, neutropenia, and neutrophil dysfunction, in addition to the clinical symptoms and findings observed in GSD-Ia.
While not all GSD-Ib patients have neutropenia and neutrophil dysfunction, these conditions are common and predispose patients to severe infections and inflammatory bowel disease[ 44 ]. Patients with GSD-Ib may have normal neutrophil counts in the first year of life.
G6PT gene, unlike G6Pase , is also expressed in hematopoietic progenitor cells, which may be responsible for neutropenia and recurrent infections in GSD-Ib[ 99 ].
The neutrophil dysfunction in GSD-Ib includes both impaired motility and respiratory burst[ , ]. Impaired glucose transport across the cell membrane of polymorphonuclear leukocytes may be responsible for neutrophil dysfunction in GSD-Ib.
Microsomal transport of G6P has a potential role in the antioxidant protection of neutrophils. Dysfunction of this transporter due to genetic defects in G6PT may impair cellular functions and induce apoptosis, contributing to the neutrophil dysfunction seen in GSD-Ib[ ].
Some individuals with GSD-Ib do not develop neutropenia. It has been suggested that this could be due to residual transporter activity of some G6PT mutations[ ]. Young children with GSD-Ib may experience frequent otitis, gingivitis, periodontal disease, dental caries, and skin abscesses.
Oral and genital ulcerations and intestinal mucosal ulcers may occur[ 43 , ]. Individuals with GSD-Ib may experience recurrent episodes of diarrhea. The underlying cause of this symptom appears to be inflammation of the intestinal mucosa, as evidenced by elevated fecal α1-antitrypsin excretion and colonic inflammation in colonoscopic biopsies[ 44 ].
There is no established association between the specific genetic mutations causing GSD-Ib and the occurrence of neutropenia, bacterial infections, and other systemic complications in affected individuals[ ]. Patients with GSD-Ib may require liver transplantation.
Although hypoglycemia, lactic acidosis and dyslipidemia improve after liver transplantation, neutropenia generally continues to be present as it is primarily attributable to an intrinsic defect in the neutrophils[ - ].
Another characteristic clinical finding of GSD-Ib is the occurrence of Crohn disease-like colitis[ , ].
Accompanying findings and symptoms include fever, diarrhea, and perioral and anal ulcers. Interestingly, the severity of the primary disorder does not appear to be correlated with the occurrence or severity of intestinal symptoms[ , ].
Manifestations of inflammatory bowel disease may improve with granulocyte colony-stimulating factor G-CSF treatment[ ].
Enteral nutrition with a polymeric formula enriched in the anti-inflammatory cytokine transforming growth factor-β is recommended as a first-line treatment of digestive complications in GSD-Ib[ ].
Inflammatory bowel disease may require treatment with anti-inflammatory and immunosuppressive medications[ ]. Successful treatment of inflammatory bowel disease with biologics including infliximab and adalimumab in GSD-Ib patients refractory to conventional treatment has been reported[ , ].
GSD-Ib is characterized by an increased risk for developing autoimmune disorders like thyroid autoimmunity and myasthenia gravis[ ]. GSD-Ib patients have a higher likelihood of developing thyroid autoimmunity and hypothyroidism, while GSD-Ia patients show little indication of thyroid pathologies[ , ].
Based on the slightly elevated levels of thyrotropin, even in patients with overt hypothyroidism, it could be postulated that there is concomitant damage occurring at the hypothalamus or pituitary gland[ ].
Recently, predisposition to autoimmunity in GSD-Ib patients was linked with a profound defect in conventional T cells and regulatory T cells caused by defective engagement of glycolysis in T cells due to G6PT deficiency[ ]. Although a rare outcome of GSD-Ib, patients may develop terminal kidney disease, which may necessitate kidney transplantation[ ].
Nutritional management of GSD-Ib is similar to that of GSD-Ia. Neutropenic patients with GSD-Ib should be treated with G-CSF. G-CSF therapy may normalize the number of neutrophils and restore myeloid functions[ - ].
The implementation of a combined therapeutic approach including both dietary management and G-CSF treatment improves the prognosis of patients by significantly mitigating metabolic and myeloid abnormalities.
G-CSF administration is associated with not only an elevation of peripheral neutrophil counts, but also a reduction in the incidence of febrile episodes and infections, as well as improvement in enterocolitis in patients with GSD-Ib[ ].
In conjunction with other therapies aminosalicylates, mesalamine, and corticosteroids , G-CSF ameliorates inflammatory bowel disease symptoms[ ]. To prevent complications such as splenomegaly, hypersplenism, hepatomegaly, and bone pain, it is recommended that the lowest effective dose of G-CSF is used.
Caution must be exercised regarding the development of splenomegaly and myeloid malignancy[ , ]. Vitamin E has been reported to be effective in reducing the frequency of infections and improving neutropenia[ ]. Liver transplantation is the ultimate therapy for hepatic metabolic disease related to GSD-I.
There is no possibility of the recurrence of GSD-I within the allograft. Recently, an unusual post-transplant finding of two siblings with persistent hyperuricemia requiring allopurinol treatment has been reported[ ]. Moreover, chronic renal failure is a well-known complication that may arise as a consequence of liver transplantation in individuals with GSD-Ia, and progression to renal failure within a few years of transplantation was reported[ ].
It is uncertain whether post-transplantation renal failure is related to disease progression, toxicity from immunosuppressants used after liver transplantation, a secondary reaction to poor metabolic control, or a combination of these factors. Renal transplantation in GSD-I, on the other hand, corrects only renal abnormalities[ ].
Conflicting results have been reported in different studies regarding whether catch-up growth is achieved or not following liver transplantation in children with GSD-I[ , ].
Despite improved survival and growth, long-term complications of GSD-I like progressive renal failure and development of hepatic adenomas do not respond completely to dietary treatment.
Although liver transplantation corrects metabolic derangement and improves the quality of life of these patients, it is not without complications[ ]. These findings suggest that novel therapeutic approaches with higher success and lower complication rates are warranted.
A recent advance in the treatment of neutropenia and neutrophil dysfunction in individuals with GSD-Ib is repurposing empagliflozin, a sodium-glucose co-transporter-2 SGLT2 inhibitor that is approved to treat type 2 diabetes in adults, to improve neutrophil number and function.
A study conducted by Veiga-Da-Cunha et al [ ] revealed the crucial function of glucosephosphate transporter in neutrophils, which clarifies the pathophysiology of neutropenia in GSD-Ib patients.
In addition to G6P, G6PT transports the G6P structural analog 1,5-anhydroglucitolphosphate 1,5AG6P. Neutrophils lacking G6PT activity cannot transport 1,5AG6P from the cytosol into the endoplasmic reticulum, where it is normally dephosphorylated by G6PC3, a phosphatase in the membrane of the endoplasmic reticulum.
Cytosolic accumulation of 1,5AG6P inhibits glucose phosphorylation by hexokinases that catalyzes the first step of glycolysis. As glycolysis is the sole energy source for mature neutrophils, depletion of intracellular G6P leads to a deficit in energy production which in turn results in neutrophil dysfunction and subsequent apoptosis.
Empagliflozin inhibits renal SGLT2 leading to increased urinary excretion of 1,5AG. This leads to a reduction in the concentration of 1,5AG in the blood, thereby decreasing the cellular accumulation of toxic 1,5AG6P in neutrophils[ ]. Following the first report of successful repurposing of empagliflozin to treat neutropenia and neutrophil dysfunction in 4 patients with GSD-Ib, several case reports and case series have shown beneficial effects of this treatment approach on neutrophil number and function, inflammatory bowel disease, recurrent infections[ - ], oral and urogenital mucosal lesions, skin abscesses, anemia, wound healing, and dose reduction or even cessation of G-CSF therapy in GSD-Ib patients[ - ].
Despite a favorable safety profile in patients with GSD-Ib, there is a risk of hypoglycemia with SGLT2 inhibitors. A low dose at treatment initiation with careful titration to optimal dosing is recommended[ ].
Growing evidence suggests that empagliflozin is a candidate for first-line treatment of neutropenia and neutrophil dysfunction related symptoms in GSD-Ib patients. Another promising novel therapeutic strategy is gene therapy by using recombinant adeno-associated virus vectors.
The use of a viral vector to administer G6Pase and hepatocyte transplantation are being investigated as potential treatments for GSD-I. Various animal models have shown an increase in hepatic G6Pase and G6PT activity, as well as improvements in metabolic parameters[ - ].
Multiple approaches have been explored for the integration of the G6Pase transgene into the host genome[ , ]. The successful correction of metabolic imbalances in animal models through gene therapy shows promising potential for future applications of gene therapy in humans.
Glycogen debrancher enzyme has two independent catalytic activities; alpha-glucanotransferase and amylo-1,6-glucosidase, with the two catalytic sites being separated on the same polypeptide.
Both catalytic activities are required for complete debranching enzyme activity[ ]. Deficient activity of these catalytic sites results in accumulation of glycogen with short outer chains, previously defined as limit-dextrins.
Deficiency in glycogen debranching enzyme due to biallelic pathogenic variants in the AGL gene results in the harmful accumulation of abnormal glycogen in hepatocytes. The AGL gene was mapped to the chromosomal locus 1p21, and its nucleotide sequence was determined, revealing the existence of multiple tissue-specific isoforms[ , ].
GSD-III is inherited in an autosomal recessive manner. Certain populations have an increased prevalence due to a founder effect. The highest known GSD-III prevalence occurs in Inuit population in Nunavik about , c.
There is currently limited evidence supporting a correlation between disease severity and pathogenic variants in the AGL gene, except for specific exon 3 variants c.
It was suggested that in muscle isoforms of the AGL gene, alternative exon or translation initiation may not require exon 3, thereby resulting in normal enzyme activity in the muscle tissues of patients with GSD-IIIb who harbor an exon 3 deletion[ , ].
Recent evidence suggests that the presence of frameshift, nonsense, and splice site variants may lead to severe phenotypes. Differences in tissue expression of the deficient enzyme is responsible for the phenotypic variability observed in GSD-III patients[ ].
GSD-III is characterized by heterogeneous involvement of the liver, skeletal muscle, and cardiac muscle, leading to variable clinical presentations. Various subtypes are defined by the extent of tissue involvement. Two major subtypes of GSD-III have been identified.
In a limited number of cases, it has been demonstrated that there is a selective loss of either glucosidase activity resulting in muscle involvement, referred to as GSD-IIIc or transferase activity resulting in both muscle and liver involvement, referred to as GSD-IIId [ , ].
Hepatomegaly, ketotic hypoglycemia, growth retardation and dyslipidemia hypertriglyceridemia are the dominant features of hepatic involvement in infancy and childhood. As gluconeogenesis is intact in GSD-III, fasting hypoglycemia tends to be milder than that seen in GSD-I.
During infancy, serum hepatic transaminases are markedly elevated. Uric acid and lactate concentrations are relatively normal[ ]. Symptoms and laboratory findings related with liver involvement often improve with age and usually disappear after puberty[ , ]. However, liver disease can also be progressive resulting in liver fibrosis, cirrhosis, hepatic failure, and end-stage liver disease[ , ].
Hepatic fibrosis may occur as early as 1 year of age[ ]. Overt liver cirrhosis is not common and occurs rarely[ , ]. Hepatocellular carcinoma can develop as a long-term complication of liver cirrhosis, rather than transformation of an adenoma to carcinoma, as seen in GSD-I[ , ].
Children with failure to thrive often catch-up in height in adulthood with optimized, individualized dietary management. Muscle symptoms associated with GSD-III can manifest concurrently with liver disease or long after hepatic disorders or even after the resolution of hepatic symptoms during childhood.
Nonetheless, a normal CK level does not entirely exclude the possibility of an underlying muscular disease[ , ]. The median age of onset of CK elevation was reported to be 10 years[ ]. Although muscle involvement becomes clinically more obvious later in life, mild muscle weakness on physical examination, motor developmental delay delayed sitting, delayed standing upright, delayed onset of walking , exercise intolerance, and hypotonia were reported in the majority of pediatric patients with GSD-III[ - ].
Muscle weakness and wasting may slowly progress and become severe by the third or fourth decade of life[ , ]. In a subset of adult patients with GSD-III, muscle symptoms can present in the absence of any clinical or previous evidence of liver dysfunction[ , ].
Muscle weakness, although minimal during childhood, is slowly progressive in nature and may become the predominant feature with significant permanent muscle weakness in adults with type IIIa disease[ ]. Although myopathy generally progresses slowly and is not severely debilitating, some patients may have severe muscle involvement leading to loss of ambulation[ ].
Myopathy can be proximal, distal, or more generalized. Exercise intolerance with muscle fatigue, cramps and pain are evident in more than half of patients[ , , ]. Bulbar or respiratory dysfunctions are rarely seen in GSD-III patients while no clinical involvement of facial or ocular muscles has been described in the literature[ ].
Cardiac involvement in GSD-III is variable. Cardiac involvement is present in most patients, with varying degrees of severity ranging from ventricular hypertrophy detected on electrocardiography to clinically apparent cardiomegaly[ ]. Mogahed et al [ ] reported that cardiac muscle involvement is less common and mostly subclinical in the pediatric age group.
Sudden death has occasionally been reported[ ]. Patients with GSD-III may exhibit facial abnormalities such as indistinct philtral pillars, bow-shaped lips with a thin vermillion border, a depressed nasal bridge and a broad upturned nasal tip, and deep-set eyes, particularly in younger patients[ ].
Some individuals with GSD-III may have an increased risk of developing osteoporosis with reduced bone mineral density which, in part, may be due to suboptimal nutrition, the effects of metabolic abnormalities and muscle weakness[ 41 , , ].
Bone fractures due to osteopenia and osteoporosis were reported in patients with GSD-III[ ]. Polycystic ovary disease has been reported in women with GSD-III with no significant effect on fertility[ ]. Type 2 diabetes may occur during the course of the disease in adulthood[ ].
Michon et al [ ] reported global cognitive impairment in adult GSD-III patients as an underlying cause of psychological and attention deficits seen in this patient group.
Liver histology shows uniform distension of hepatocytes secondary to glycogen accumulation. There is often septal formation, periportal and reticular fibrosis, fine microsteatosis, and less frequently, micronodular cirrhosis without inflammation or interface hepatitis.
Skeletal muscle shows subsarcolemmal glycogen accumulation[ 12 ]. The diagnosis of GSD-III is made by identification of biallelic AGL pathogenic variants on molecular genetic testing.
If the diagnosis cannot be established by genetic analysis, demonstrating enzyme deficiency in peripheral leukocytes or erythrocytes, cultured skin fibroblasts or in the liver or muscle tissue samples is necessary.
A practice guideline was published by the American College of Medical Genetics and Genomics in providing recommendations on the diagnosis and management of the complications of GSD-III[ ].
The mainstay of GSD-III treatment is dietary intervention, which aims to maintain normal blood glucose levels while balancing macronutrient and total caloric intake. This is achieved by the avoidance of fasting, frequent meals enriched in complex carbohydrates and use of UCCS.
Continuous enteral feeding may be needed in some cases. Sucrose, fructose, and lactose are not contraindicated unlike GSD-I. UCCS can be used as early as the first year of life to prevent hypoglycemia.
As an alternative, Glycosade ® , an extended-release cornstarch, can also be used[ 87 ]. Caution must be exercised to avoid overtreating with cornstarch or carbohydrates, which may lead to excessive storage of glycogen in the liver and weight gain.
In patients with myopathy, along with managing hypoglycemia, a high-protein diet is recommended as it prevents muscle protein breakdown during glucose deprivation, thereby preserving skeletal and cardiac muscle[ ].
A ketogenic diet alone or in combination with high protein and ketone bodies was also shown to ameliorate cardiomyopathy[ , ]. It has been shown that a high-fat, low-calorie and high-protein diet can reduce cardiomyopathy in individuals with GSD-III[ , ]. The beneficial effects on cardiac or skeletal muscle function of these ketogenic or high-fat diets are possibly related to the increased ketone bodies or fats as fuel sources, or reduced glycogen accumulation through decreased carbohydrate intake.
Whether long-term muscular, cardiac, or even liver complications can be prevented by these dietary approaches warrants further studies[ ]. Liver transplantation corrects all liver related biochemical abnormalities but does not correct myopathy or cardiomyopathy[ , , ].
Detailed information about surveillance recommendations on hepatic, metabolic, musculoskeletal, cardiac, nutritional, and endocrine aspects of the disease can be found elsewhere[ ]. Gene therapy and gene-based therapeutic approaches are in development. Branching of the chains is essential to pack a very large number of glycosyl units into a relatively soluble spherical molecule.
Without GBE, abnormal glycogen with fewer branching points and longer outer chains resembling an amylopectin-like structure polyglucosan accumulates in various tissues including hepatocytes and myocytes[ ].
The mapping of the GBE1 gene to chromosome 3p Notably, mutations in the same gene are also responsible for adult polyglucosan body disease.
GSD-IV accounts for only 0. This rare disorder has a prevalence of to [ ]. GSD-IV exhibits significant clinical heterogeneity and phenotypic variability, partly due to variations in tissue involvement, which may be influenced by the presence of tissue-specific isozymes[ , ].
The liver is the primary organ affected, with the classical hepatic form appearing normal at birth but progressing rapidly to cirrhosis in early life, leading to liver failure and death between 3 to 5 years of age[ ]. Besides the complications of progressive cirrhosis including portal hypertension, ascites and esophageal varices, the development of hepatocellular carcinoma was also reported[ ].
In rare cases, the hepatic disease in GSD-IV may not progress or progress slowly[ ]. Patients with the non-progressive hepatic form may present with hepatosplenomegaly and mildly elevated liver transaminases, and experience normal growth.
Liver size and transaminase levels may return to normal[ ]. Patients with the non-progressive hepatic form usually survive into adulthood. GSD-IV can present with multiple system involvement, with the enzyme deficiency in both liver and muscle[ ].
This form of the disease can manifest as peripheral myopathy with or without cardiomyopathy, neuropathy, and liver cirrhosis.
Onset of the disease can be from the neonatal period to adulthood[ ]. The neuromuscular presentation can be divided into four groups based on age at onset[ ]. In the perinatal fetal form, which can lead to hydrops fetalis and polyhydramnios, arthrogryposis develops due to akinesia[ ].
Detection of cervical cystic hygroma during pregnancy may indicate the disease[ ]. Prenatal diagnosis can be performed by determining enzyme activity in cultured amniocytes or chorionic villi samples.
Genetic studies can complement uncertain enzyme activity studies, such as equivocal results in prenatal fetal samples and in patients with higher levels of residual enzyme activity that overlap heterozygote levels[ ].
Mortality is unavoidable in the neonatal period. Liver cirrhosis or liver failure has not been reported. Severe hypotonia, hyporeflexia, cardiomyopathy, depressed respiration, and neuronal involvement are features of the congenital form of the disease[ , - ].
Liver disease is not severe, and the child dies in early infancy due to other reasons. The childhood neuromuscular form may start at any age with either myopathy or cardiomyopathy[ , ].
Presenting symptoms mainly include exercise intolerance, exertional dyspnea, and congestive heart failure in advanced stages. The disease can be confined to muscular tissue and serum CK level can be within the normal range. In the adult form, there is isolated myopathy or a multisystemic disease called adult polyglucosan body disease.
Onset of symptoms can occur at any age during adulthood, usually after the age of 50, and may exhibit a resemblance to muscular dystrophies. Symptomatology includes progressive gait difficulty and proximal muscle weakness, which is more pronounced in the arms as compared to the legs.
Both upper and lower motor neurons are affected in the disorder. The disease may manifest as pyramidal tetraparesis, peripheral neuropathy, early onset of neurogenic bladder, extrapyramidal symptoms, seizures, and cognitive dysfunction leading to dementia[ ].
The diagnosis can be established by enzyme activity assay in erythrocytes[ ]. Amylopectin-like inclusions are detected through ultrastructural examination of the central nervous system and skeletal muscle.
These inclusions are intensely PAS-positive and diastase-resistant, both in neurons and muscular fibers[ ]. Magnetic resonance imaging shows white matter abnormalities[ ]. Liver biopsy can be diagnostic in patients with hepatic involvement[ ].
The histopathological evaluation of the liver reveals abnormal hepatocellular glycogen deposits in the form of PAS-positive, diastase-resistant inclusions.
Ultrastructural examination with electron microscopy reveals accumulation of fibrillar aggregations that are typical of amylopectin. Typically, enzyme deficiency can be documented through diagnostic assays performed on hepatocytes, leukocytes, erythrocytes, and fibroblasts.
However, patients with cardioskeletal myopathy may exhibit normal leukocyte enzyme activity[ ]. The diagnosis of GSD-IV can be confirmed through histopathological examination, detection of enzyme deficiency, and mutation analysis of the GBE1 gene. Genetic confirmation is recommended whenever possible in patients with suspected GSD-IV to provide more data for genotype-phenotype correlations in this extremely rare disease.
The genotype-phenotype correlation remains unclear for GSD-IV and the same genetic defect may cause different clinical presentations in unrelated patients[ ]. Mutation analysis can also provide crucial diagnostic information in cases with equivocal results of biochemical analyses[ ].
Mutations with significant preservation of enzyme activity may be related with milder e. Hypoglycemia has traditionally been considered a late manifestation and generally develops due to hepatocellular dysfunction caused by progressive cirrhosis.
At this stage of the disease, the biochemical profile of the patients is representative of what is observed in other causes of liver cirrhosis. No specific dietary and pharmacological treatments are available for GSD-IV. There is a lack of established guidelines based on either evidence or expert consensus for the dietary management of GSD-IV.
Improvement in clinical, anthropometric, and laboratory parameters was reported with a high-protein and low-carbohydrate diet[ , ]. Derks et al [ ] recently reported improved clinical and biochemical outcomes after dietary interventions including a late evening meal, continuous nocturnal intragastric drip feeding, restriction of mono- and disaccharides, the addition of UCCS, and protein enrichment in patients with GSD-IV.
Individual dietary plans should also aim to avoid hyperglycemia to minimize glycogen accumulation in the liver.
At present, there is no effective therapeutic approach other than liver transplantation for GSD-IV patients who are affected by progressive liver disease. However, anecdotal reports indicate that liver transplantation may not alter the extrahepatic progression of GSD-IV[ ].
The presence of extrahepatic involvement, especially amylopectin storage in the myocardium, may lead to fatal complications following liver transplantation[ - ]. Careful assessment of cardiac function even in the absence of clinical decompensation or consideration of combined liver-heart transplantation is warranted for patients with GSD-IV[ ].
Liver transplantation may provide beneficial effects not only for patients with liver disease but also for those affected by muscular involvement in GSD-IV[ , , ].
This may be explained by systemic microchimerism donor cells presenting in various tissues of the liver recipient after liver allotransplantation and amelioration of pancellular enzyme deficiencies resulting in a decrease in amylopectin in other organ systems[ 12 ].
It has been suggested that the donor cells can transfer enzyme to the native enzyme-deficient cells[ ]. In recent years, animal studies have been conducted to prevent glycogen and polyglucosan body accumulation in GSD-IV patients, and GYS inhibitor guaiacol and DG11 are promising in this regard[ , ].
The molecular target of DG11 is the lysosomal membrane protein lysosome-associated membrane protein 1 LAMP1 , which enhances autolysosomal degradation of glycogen and lysosomal acidification.
In the adult polyglucosan body disease mouse model, DG11 reduced polyglucosan and glycogen in brain, liver, heart, and peripheral nerve[ ]. GSD-VI was first reported by Hers[ ] in three patients with hepatomegaly, mild hypoglycemia, an increased glycogen content and deficient activity of glycogen phosphorylase in the liver in GSD-VI is a rare autosomal recessive genetic disease caused by deficiency of hepatic glycogen phosphorylase.
At least three human glycogen phosphorylases exist including muscle, liver, and brain isoforms[ ]. In response to hypoglycemia, liver glycogen phosphorylase catalyzes the cleavage of glucosyl units from glycogen which results in the release of glucosephosphate.
The glucosephosphate is subsequently converted to glucosephosphate. The PYGL gene is currently the only known genetic locus associated with the development of GSD-VI and was mapped to chromosome 14qq22 in [ ]. Incidence of the disease is estimated to be and believed to be underestimated due to nonspecific and variable phenotypes, and a paucity of cases confirmed by genetic testing[ ].
GSD-VI is more prevalent among the Mennonite community, with a prevalence of 1 in , representing the only known population at higher risk for the disease[ ]. GSD-VI is a disorder with broad clinical heterogeneity[ ]. Infants with liver phosphorylase deficiency mainly present with hepatomegaly and growth retardation.
The condition typically has a benign course, and symptoms tend to improve as the child grows[ ]. Hepatomegaly usually normalizes by the second decade of life[ ]. The child shows mild to moderate ketotic hypoglycemia related to prolonged fasting, illness, or stressful conditions[ ].
As gluconeogenesis is intact in GSD-VI, hypoglycemia is usually mild. Despite gross hepatomegaly, the patient may be largely asymptomatic without hypoglycemia. However, there is a range of clinical severity in GSD-VI, with some patients experiencing severe and potentially life-threatening hypoglycemia.
There is generally mild ketosis, growth retardation, abdominal distension due to marked hepatomegaly and mildly elevated levels of serum transaminases, triglycerides, and cholesterol. However, in patients with high residual enzyme activity, biochemical investigations may be normal[ , ].
Hypertriglyceridemia may persist despite treatment[ ]. A few patients showing mild muscular hypotonia, muscle weakness or developmental impairment were observed, but otherwise, no neurological symptoms were reported in the literature[ ]. Sleep difficulties and overnight irritability are common[ ].
In contrast to GSD-I, serum levels of lactic acid and uric acid are generally within the normal range[ 15 ]. However, in a recent clinical study including 56 GSD-VI patients, hyperuricemia was reported as a complication in adolescent and adult patients with GSD-VI, which indicates the need for long-term monitoring of uric acid in older GSD-VI patients[ ].
CK concentration is usually normal. In some patients, severe and recurrent hypoglycemia, pronounced hepatomegaly, and postprandial lactic acidosis have been reported[ ]. Recently, children with GSD-VI have been reported to present with only ketotic hypoglycemia as the sole manifestation of the disease, without the characteristic hepatomegaly[ ].
Mild cardiopathy has also been described for GSD-VI[ ]. The clinical picture of GSD-VI virtually overlaps with phosphorylase kinase PHK deficiency GSD-IX and the differential diagnosis includes other forms of GSDs associated with hepatomegaly and hypoglycemia, especially GSD-I and GSD-III[ ].
It is not possible to distinguish between GSD-VI and GSD-IX based on clinical or laboratory findings alone[ ]. Mutation analysis is the suggested method for the diagnosis of GSD-VI. A liver biopsy is not recommended to establish the diagnosis to avoid an invasive procedure.
Excessive glycogen accumulation with structurally normal glycogen in the liver biopsy is consistent with GSD-VI. Fibrosis, mild steatosis, lobular inflammatory activity and periportal copper binding protein staining have also been reported in GSD-VI patients. Although it is possible to document glycogen phosphorylase deficiency in frozen liver biopsy tissue or blood cells including leukocytes and erythrocytes, normal in vitro residual enzyme activity may be seen and prevents establishment of a definitive diagnosis by an enzyme assay alone in some patients[ , ].
In GSD-VI, nutrition therapy aims to improve metabolic control and prevent primary manifestations such as hypoglycemia, ketosis, and hepatomegaly, as well as secondary complications including delayed puberty, short stature, and cirrhosis.
The aim of the therapeutic approach is to achieve euglycemia and normoketosis by administration of the appropriate doses of cornstarch.
An extended-release corn starch derived from waxy maize, marketed as Glycosade ® , has been found to have a positive impact in delaying overnight hypoglycemia in children over 5 years of age and adults[ 87 ]. Some individuals with GSD-VI may not require any treatment.
GSD-VI usually has a benign disease course. However, focal nodular hyperplasia, fibrosis, cirrhosis, and a degeneration to hepatocellular carcinoma have been reported in some patients[ - ].
Cirrhosis has been reported in patients as young as preschool age, even within the second year of life[ ]. Based on these findings, aggressive treatment of GSD-VI has recently been suggested to maintain optimal metabolic control and prevent long-term complications[ ].
Long-term monitoring of hepatic function is also recommended[ ]. Glucagon and epinephrine play a critical role in the regulation of glycogenolysis by activation of adenylate cyclase which leads to an increase in the cytosolic concentration of cyclic adenosine monophosphate cAMP.
The increased level of cAMP activates cAMP-dependent protein kinase which activates PHK. PHK is a heterotetramer composed of 4 different subunits α, β, γ, and δ. Each subunit is encoded by different genes that are located on different chromosomes and differentially expressed in a variety of tissues[ ].
α and β subunits have regulatory functions, the γ subunit contains the catalytic site, and δ is a calmodulin protein[ ]. PHK has a wide tissue distribution with multiple tissue-specific isoforms.
The α subunit has two isoforms, a muscle isoform, and a liver isoform, which are encoded by two different genes PHKA1 and PHKA2 , respectively on the X chromosome[ ]. The genetic loci of other subunits are mapped to autosomal chromosomes.
The γ subunit also has muscle and liver isoforms, each of which is encoded by a distinct gene PHKG1 and PHKG2 , respectively. There is only one gene encoding the β-subunit PHKB. However, PHKB is expressed in both muscle and liver[ , ]. Liver PHK deficiency liver GSD-IX can be classified according to the involved gene, the X-linked form GSD-IXa, X-linked glycogenosis and autosomal recessive forms GSD-IXb and GSD-IXc.
GSD-IXa PHKA2 -related GSD-IX is caused by pathogenic variants in the PHKA2 gene on X chromosome. GSD-IXb PHKB -related GSD-IX and GSD-IXc PHKG2 -related GSD-IX are inherited in an autosomal recessive manner and caused by mutations in PHKB and PHKG2 genes, respectively Table 1.
GSD-IXa is further classified into subtypes XLG-I formerly GSD-VIII with no enzyme activity in liver or erythrocytes, and XLG-II with no enzyme activity in liver, but normal activity in erythrocytes[ , ].
GSD-IX is one of the most common forms of GSDs. The frequency of liver PHK deficiency was estimated to be [ 15 ]. On the X chromosome, there are two enzyme loci; one for the alpha subunit of muscle PHK, and one for the alpha subunit of liver PHK.
In , the liver PHK gene was located to Xp GSD-IXa is more common in males due to the X-linked inheritance pattern. Female carriers may become symptomatic due to X chromosome inactivation[ ]. Hepatomegaly, growth retardation, delayed motor development, mild hypotonia, significantly elevated serum transaminase levels, hyperlipidemia, fasting hyperketosis, and hypoglycemia are the main symptoms and findings[ - ].
Rarely described clinical features include splenomegaly, liver cirrhosis, doll-like facies, osteoporosis, neurologic involvement, high serum lactate levels, metabolic acidosis, and renal tubular acidosis[ ]. With increasing age, there is a gradual resolution of both clinical symptoms and laboratory abnormalities.
Although puberty may be delayed, eventual attainment of normal height and complete sexual development is still possible[ ]. Most adult patients are asymptomatic[ ].
Unusual presentations including asymptomatic hepatomegaly and isolated ketotic hypoglycemia without hepatomegaly have been reported in affected male children underscoring the importance of screening for GSD-IXa in male patients who are suspected of having GSD with atypical features[ , ].
More severe phenotypes including severe recurrent hypoglycemia and liver cirrhosis have also been reported[ , , ]. Recent findings suggest that GSD-IXa is not a benign condition as is often reported in the literature and patients may have fibrosis even at the time of diagnosis[ ].
GSD-IXc is caused by autosomal recessive mutations in the PHKG2 gene. The genetic locus of the liver form was located to 16p The presence of PHKG2 mutations has been linked to more severe clinical and biochemical abnormalities, such as an elevated risk for liver fibrosis and cirrhosis[ - ].
Liver cirrhosis can develop in infancy[ ]. Cirrhosis related esophageal varices and splenomegaly, liver adenomas, renal tubulopathy and significant hypocalcemia were other reported clinical findings[ ]. Patients with this condition commonly present with severe hypoglycemia requiring overnight feeding, show very low PHK activity in the liver, and exhibit highly elevated serum transaminase levels.
A wide range of clinical symptoms can be observed, including hypoglycemia during fasting, hepatomegaly, elevated levels of transaminases, hepatic fibrosis, cirrhosis, muscle weakness, hypotonia, delayed motor development, growth retardation, and fatigue[ ].
The genetic cause of GSD-IXb is attributed to mutations in the PHKB gene, which is located on 16qq13 and encodes the beta subunit of PHK[ ].
The main features of the disease include marked hepatomegaly, increased glycogen content in both liver and muscle, and the development of hypoglycemic symptoms after physical activity or several hours of fasting[ ].
Patients with liver fibrosis, adenoma-like mass, mild cardiopathy and interventricular septal hypertrophy were reported[ ]. The muscle symptoms are generally mild or absent, affecting virtually only the liver. Distinction between GSD-IXb and individuals with pathogenic variants in PHKA2 or PHKG2 cannot be carried out based on clinical findings alone.
Genetic analysis is the preferred first-line diagnostic test in suspected patients. An approach using next-generation sequencing panels is advised due to the involvement of multiple genes. Liver biopsy can be a valuable diagnostic tool for confirming the diagnosis in cases where there are variants of unknown significance.
Histopathological assessment of liver involvement is superior to biochemical parameters[ ]. It is important to keep in mind that PHK enzyme activity can be normal in blood cells and even in liver tissue of affected patients.
On the other hand, a reduction in PHK enzyme activity can also occur secondary to other metabolic defects such as pathogenic variants in GLUT2 in Fanconi-Bickel syndrome FBS , PRKAG2 cardiomyopathy syndrome, or mitochondrial complex 1 deficiency[ ]. In patients with GSD-IX, close monitoring of long-term liver and cardiac complications is recommended[ ].
Aggressive structured dietary treatment with UCCS and relatively high protein intake was associated with considerable improvement in growth velocity, energy, biochemical abnormalities, hepatomegaly, and overall well-being of patients with GSD-IX. Radiographic features of fibrosis were also reported to be improved with early and aggressive dietary management[ ].
General nutritional recommendations for GSD-IX are similar to those for GSD-VI and have recently been published[ ]. The primary defect in FBS is deficiency of glucose transporter 2 GLUT2 , a monosaccharide carrier that is responsible for the transport of both glucose and galactose across the membranes in hepatocytes, pancreatic β-cells, enterocytes, and renal tubular cells.
Utilization of both glucose and galactose is impaired in FBS[ ]. Hepatorenal glycogen accumulation and proximal renal tubular dysfunction are the characteristic features of this rare disease[ , ]. FBS follows an autosomal recessive inheritance pattern. The responsible gene, GLUT2 gene solute carrier family 2 member 2, SLC2A2 , was localized to 3q Infants with FBS typically present between the ages of 3 to 10 mo.
In addition to hepatorenal glycogen accumulation and proximal renal tubular dysfunction, FBS is characterized by fasting hypoglycemia, postprandial hyperglycemia and hypergalactosemia, rickets and marked growth retardation. Patients have entirely normal mental development.
In older patients, dwarfism is the most notable finding. Puberty is significantly delayed, with other remarkable observations including a distended abdomen caused by hepatomegaly, deposition of fat on the abdomen and shoulders, and a moon-shaped face[ ].
Some patients may not exhibit hepatomegaly during the early stages of the disease[ , ]. Hyperlipidemia and hypercholesterolemia are prominent and may cause acute pancreatitis. The development of generalized osteopenia occurs early and may result in fractures.
Hypophosphatemic rickets and osteoporosis are characteristics of the disease that emerge later in life[ ]. Tubular nephropathy is characterized by excessive glucosuria, moderate hyperphosphaturia along with persistent hypophosphatemia, hyperuricemia, hyperaminoaciduria, and intermittent albuminuria, collectively referred to as renal Fanconi syndrome[ , ].
Hypercalciuria is also evident. Due to increased renal losses, there is a frequent tendency towards hyponatremia and hypokalemia.
Polyuria may develop due to high urinary osmotic load[ ]. Progression to renal failure is not the case. Nephrocalcinosis was also reported in one third of the patients in a recent retrospective study[ ]. There may be mild metabolic hyperchloremic acidosis with normal anion gap due to renal loss of bicarbonate[ ].
Cataracts, a frequently documented consequence of hypergalactosemia, are only present in a small number of patients[ ]. Laboratory findings include fasting hypoglycemia and ketonuria, hyperglycemia and hypergala ctosemia in the postabsorptive state, hypercholesterolemia, hyperlipidemia, moderately elevated alkaline phosphatase, mildly elevated transaminases, normal hepatic synthetic function, hypophosphatemia, hyperaminoaciduria, glucosuria, galactosuria, proteinuria, normal activity of enzymes involved in galactose and glycogen metabolism, normal fructose metabolism, and normal endocrinologic results[ ].
FBS patients develop different patterns of dysglycemia, ranging from fasting hypoglycemia, postprandial hyperglycemia, glucose intolerance, to transient neonatal diabetes to gestational diabetes and frank diabetes mellitus[ ].
The exact molecular mechanisms underlying the occurrence of dysglycemia in individuals with FBS are not yet fully understood. Impaired renal glucose reabsorption, as well as the accumulation of glucose within the hepatocytes, which stimulates glycogen synthesis and inhibits gluconeogenesis and glycogenolysis, result in fasting ketotic hypoglycemia and hepatic glycogen deposition.
Postprandial findings of hyperglycemia and hypergalactosemia are caused by impaired hepatic uptake and diminished insulin response[ ]. Glycated hemoglobin A1c is usually within the normal range due to recurrent hypoglycemia episodes[ ].
Accumulation of glycogen and free glucose in renal tubular cells leads to general impairment in proximal renal tubular function. Histological evaluation of liver biopsy indicates an excessive buildup of glycogen along with steatosis. Due to the presence of galactose intolerance, newborn screening for galactosemia can sometimes identify patients with FBS[ ].
The diagnosis is ultimately confirmed by genetic analysis of SLC2A2 gene. The management of symptoms involves measures to stabilize glucose homeostasis and compensate for the renal loss of water and various solutes.
Patients typically require replacement of water, electrolytes, and vitamin D, while also restricting galactose intake and adhering to a diabetes mellitus-like diet.
Frequent small meals with adequate caloric intake and administration of UCCS are important components of symptomatic treatment. In cases of renal tubular acidosis, it may be required to administer alkali to maintain acid-base balance.
Catch-up growth was reported to be induced by UCCS[ ]. Continuous nocturnal gastric drip feeding may be indicated in some cases with growth failure[ ]. With these measures, the prognosis is good. However, a recent retrospective study reported poor outcome despite adequate metabolic management emphasizing the importance of early genetic diagnosis and facilitating prompt nutritional interventions[ ].
Pompe disease is a typical example of a lysosomal storage disease. The clinical manifestations of Pompe disease are variable, predominantly due to the varying amounts of residual acid alpha-glucosidase GAA activity linked with distinct mutations in the causative gene GAA.
GAA gene is mapped to chromosome 17q Enzyme deficiency results in intra-lysosomal storage of glycogen especially in skeletal and cardiac muscles.
There is no genotype-phenotype correlation, but DD genotype in the angiotensin converting enzyme gene and XX genotype in the alpha actinin 3 gene are significantly associated with an earlier age of onset of the disease[ ].
There are mainly two types of GSD-II according to age of onset: Infantile-onset and late-onset Pompe disease. Patients with disease onset before the age of 12 mo without cardiomyopathy and all patients with disease onset after 12 mo of age are included in the late-onset form[ ].
The combined frequency of infantile onset and late onset GSD-II varies between and depending on ethnicity and geographic region. In the infantile-onset form, cardiomyopathy and muscular hypotonia are the cardinal features and patients die around 1 year of age.
Patients also have feeding difficulties, macroglossia, failure to thrive, hearing impairment and respiratory distress due to muscle weakness. The liver is rarely enlarged unless there is heart failure. Hypoglycemia and acidosis do not occur[ ]. In the late-onset form, involvement of skeletal muscles dominates the clinical picture, and cardiac involvement is generally clinically insignificant depending on the age of onset.
Glycogen accumulation in vascular smooth muscle may cause the formation and subsequent rupture of an aneurysm[ ].
Both severe infantile and asymptomatic adult forms of the disease were observed in two generations of the same family[ ]. Although women with GSD-II do not have an increased risk of pregnancy or delivery complications, pregnancy may worsen muscle weakness and respiratory complications[ ].
As a rule, there is an inverse correlation between the age at disease onset and the severity of clinical manifestations with the level of residual enzyme activity[ ]. Laboratory testing reveals nonspecific elevations in CK, aldolase, aminotransferases, and lactate dehydrogenase.
Elevated urinary tetrasaccharide is highly sensitive but not specific. To establish the final diagnosis, the measurement of enzyme activity in skin fibroblasts or muscle tissue or the demonstration of the responsible mutation is required[ ]. Although it is not curative, ERT has changed the course of Pompe disease since its first use in [ ].
Alglucosidase alfa, a lysosomal glycogen-specific recombinant enzyme, was approved by the European Medicines Agency EMA in in the European Union and by the Food and Drug Administration FDA in in the United States.
pdf ; accessed on November 5, Based on data from later studies, treatment initiation was shifted to the neonatal period.
A new formulation of GAA enzyme, avalglucosidase alfa, improves the delivery of the enzyme to target cells and has 15 times higher cellular uptake when compared with alglucosidase alfa.
The FDA and EMA approved avalglucosidase in and in , respectively, for the treatment of patients who are one year of age and older with late-onset Pompe disease[ ]. Ongoing studies show that avalglucosidase is generally well tolerated in patients with infantile-onset Pompe disease[ ].
Criteria for starting and stopping ERT in adult patients with GSD-II are similar in different countries. While a confirmed diagnosis and being symptomatic are general criteria for starting ERT, patient wish, severe infusion associated reactions, noncompliance with treatment, and lack of effect are criteria for stopping ERT[ ].
Another way to increase the effectiveness of ERT is to use antibodies as an intracellular delivery vehicle. The 3E10 anti-nuclear antibody, that penetrates cells and localizes to the cell nucleus, has been used for this purpose.
VAL is a fusion protein consisting of 3E10 antibody and GAA complex. The presence of 3E10 increases the delivery of GAA to both lysosomal and extra-lysosomal storage of glycogen within cells[ ]. The earlier ERT is started, the better its effectiveness. Therefore, it is recommended that ERT is started before irreversible clinical symptoms begin.
This concept has led to the development of screening programs for Pompe disease[ ]. Recently, it has been shown that in utero alglucosidase alfa treatment, which was started at 24 wk 5 d of gestation and given 6 times at 2-wk intervals through the umbilical vein, was successful[ ].
Although antibodies against the enzyme may develop, a recent study showed that the development of antibodies did not affect the clinical course[ ]. Whether additional treatments such as oral supplementation of L-alanine is beneficial is being investigated[ ].
As an alternative to ERT, studies on gene therapy have also commenced[ ]. Although Danon disease was previously classified as a variant of GSD-II with normal alpha-glucosidase activity, it is still controversial whether it is a real GSD.
A lysosomal structural protein, LAMP2, is deficient in Danon disease.
The overall considderations GSD incidence is 1 case per live stodage. There are Dietary considerations for glycogen storage disease 20 types Antioxidant-related disorders GSD including the subtypes. This heterogeneous Dietary considerations for glycogen storage disease of Ditary diseases represents inborn errors of carbohydrate metabolism and are classified based on the deficient enzyme and affected tissues. GSDs primarily affect liver or muscle or both as glycogen is particularly abundant in these tissues. Although GSDs share similar clinical features to some extent, there is a wide spectrum of clinical phenotypes. A: GSD1 stands for Disrase Storage Diabetic neuropathy in the toes Type 1, also known as von Gierkes disease or diseasee deficiency. Dierary patients with this disorder, a specific liver Spicy cayenne pepper is shorage missing or not working properly. This makes it difficult to maintain normal blood sugar glucose levels between meals. A: GSD1 is a genetic disorder. Both parents have to be carriers of this disease in order to pass it onto their children. GSD1 has been found in almost every culture around the world and affects approximately 1 in everypeople.Dietary considerations for glycogen storage disease -
Patient Information. Historical Perspective. Differentiating Glycogen storage disease type I from other Diseases. Epidemiology and Demographics. Risk Factors. Natural History, Complications and Prognosis. Diagnostic Study of Choice. History and Symptoms. Physical Examination.
Laboratory Findings. X Ray. Other Imaging Findings. Other Diagnostic Studies. Primary Prevention. Secondary Prevention. Cost-Effectiveness of Therapy. Future or Investigational Therapies.
Case 1. Most recent articles. Most cited articles. Review articles. CME Programs. Powerpoint slides. Ongoing Trials at Clinical Trials. US National Guidelines Clearinghouse. NICE Guidance. FDA on Glycogen storage disease type I medical therapy. CDC on Glycogen storage disease type I medical therapy.
Glycogen storage disease type I medical therapy in the news. Blogs on Glycogen storage disease type I medical therapy. Directions to Hospitals Treating Glycogen storage disease type I. Risk calculators and risk factors for Glycogen storage disease type I medical therapy. Editor-In-Chief: C. Michael Gibson, M.
The medical management of glycogen storage disease type 1 GSD type 1 is divided into nutritional therapy and pharmacologic management of systemic complications.
The primary concern in infants and young children with GSD type 1 is hypoglycemia. Small frequent feeds high in complex carbohydrates preferably those high in fiber are administered at regular intervals throughout 24 hours for the prevention of hypoglycemia.
Sucrose fructose and glucose and lactose galactose and glucose may be limited or avoided. Solid food is introduced at the time of 4 - 6 months. Infant cereals are started followed by vegetables and then by meat.
Other treatment strategies are directed towards management of hypocitraturia , hypercalcemia , proteinuria , platelet dysfunction , and neutropenia.
Template:WH Template:WS. gov US National Guidelines Clearinghouse NICE Guidance FDA on Glycogen storage disease type I medical therapy CDC on Glycogen storage disease type I medical therapy Glycogen storage disease type I medical therapy in the news Blogs on Glycogen storage disease type I medical therapy Directions to Hospitals Treating Glycogen storage disease type I Risk calculators and risk factors for Glycogen storage disease type I medical therapy Editor-In-Chief: C.
Medical Therapy The medical management of glycogen storage disease type 1 GSD type 1 is divided into nutritional therapy and pharmacologic management of systemic complications.
So, the first line treatment for GSD type 1 is the prevention of hypoglycemia. Small frequent feeds high in complex carbohydrates preferably those high in fiber are distributed evenly throughout 24 hours for the prevention of hypoglycemia. A metabolic dietician should be consulted once a case of GSD type 1 is diagnosed.
Good metabolic control help to prevent complications in patients with GSD type 1. Infants 1. Note 2 : A G-tube may not be a good option in patients of GSD type 1b with neutropenia as it increases the risk of recurrent infections at the surgical site. Granulocyte colony-stimulating factor G-CSF or Neupogen should be administered before placing a G-tube if the child has neutropenia.
Note 4 : Feeding regimen are decided on a case by case basis. Note 7 : It is advisable to use safety precautions such as bed-wetting devices to detect formula spilling onto the bed , infusion pump alarms, safety adapters, connectors, and tape for tubing to detect pump failure and occluded or disconnected tubing.
These events may lead to hypoglycemia , seizures , and even death. Note 2 : Fruits, juice, and other sucrose -containing, fructose -containing, and lactose -containing foods are limited or avoided.
A: The liver in glucosephosphatase deficiency will never be normal in size. The liver in debrancher deficiency does get smaller following puberty.
This is also the case of phosphorylase-b-kinase deficiency, but not well established. Q: Will my child outgrow glycogen storage disease? A: One never outgrows glycogen storage disease.
This is a genetic defect which is permanently encoded in the genetic makeup of the person. Q: Is research being done for a cure?
A: YES. There is a great deal of work being done in the glycogen storage diseases. Several of the key enzymes have been purified, and in some the gene has been isolated and characterized. The rapid advances in molecular genetics will impact the area of glycogen storage disease quite positively.
Q: How many patients are there? A: Glycogen storage disease occurs in about one of 50, to , births. That means that there are several thousand such persons in the United States.
Some patients might die before diagnosis with severe infantile forms. Some milder forms might go unrecognized. The Association for Glycogen Storage Disease - AGSD - was established in in order to create an organization which would be a focus for parents of and individuals with glycogen storage disease GSD to communicate, share their successes and concerns, share useful findings, provide support, create an awareness of this condition for the public, and to stimulate research in the various forms of glycogen storage diseases.
This website provides basic information about the glycogen storage diseases. The information is intended to be of use to people affected by one of the glycogen storage diseases, their families, and other interested parties.
Some forms of GSD cause little in the way of illness, while others are life threatening. Included in this site is a description of the general symptoms, associated problems, current treatment, and long-term outcome for the most commonly diagnosed glycogen storage diseases.
It does not do justice to the difficulty patients and their families' experience, and their deep desire for improved forms of treatment or ultimately total correction.
Association for Glycogen Storage Disease. info agsdus. Log in. Remember me. Forgot password. All About AGSD AGSD Governance. Scientific Advisory Board. Research Grants. What is GSD? Type II. Type III. Type IV. Type VI. Type VII. Type IX.
Other GSDs. Join us Member benefits. Get Involved Donate. GSD Awareness Week. Home What is GSD? Frequently Asked Questions about GSDs Q: Does the liver release any stored glycogen as a waste into the system? About the association. Association for Glycogen Storage Disease Flammang Dr.
Life-expectancy in glycogen storage disease type I GSD Glycogdn Dietary considerations for glycogen storage disease improved High-fiber diet. Its relative rarity Turmeric for immune support that considerahions metabolic centre consideratoons experience consixerations Dietary considerations for glycogen storage disease series of patients and experience with long-term management and follow-up at each centre is limited. There is wide variation in methods of dietary and pharmacological treatment. Conclusion : In this paper guidelines for the management of GSD I are presented. This is a preview of subscription content, log in via an institution to check access. Rent this article via DeepDyve. Institutional subscriptions.
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