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Genetic counseling for glycogen storage disease

Genetic counseling for glycogen storage disease

Dlsease characterization of fog storage disease type III. Genetic counseling for glycogen storage disease PubMed Google Scholar Bao Glycofen, Yang BZ, Dawson TL Jr, Chen Storabe. Penultimate drafts of these guidelines were shared with an external review group cuonseling of Salvatore DeMauro, Allergy relief through yoga and meditation, William Rhead, MD, Lane Rutledge, MD, Mark Tarnopolsky, MD, PhD, Joseph Wolfsdorf, MB, BCh, and Yuan-Tsong Chen, MD, PhD. CAS PubMed Google Scholar Lee P, Burch M, Leonard JV. Growth hormone therapy has been associated with adenoma growth and complications in GSD I, and use in any individual with GSD must be only when there is a documented growth hormone deficiency. Glycogen is a form of sugar glucose that is stored in the liver and muscles.

Genetic counseling for glycogen storage disease -

Their suggestions were considered by the working group, and changes were made as considered appropriate. This guideline is directed at a wide range of providers.

Type III GSD has variable symptoms depending on the severity and tissues and organs involved. The most common alternative diagnosis in the differential is GSD type Ia. Features common to both disorders are hepatomegaly, hyperlipidemia, and hypoglycemia. However, some key differences between GSD I and III help differentiate these two disorders.

Individuals with GSD I typically present earlier in the first few months of life with severe fasting hypoglycemia 3 to 4 hours after a feed.

In individuals with GSD III, hypoglycemia is usually not as severe as in GSD I because of intact gluconeogenesis and the ability to metabolize peripheral branches of glycogen via phosphorylase.

Nonetheless, there are cases of GSD III whose clinical onset is similar to that of GSD I. Ultrasound imaging of the liver at baseline is similar in GSD I and GSD III, but the presence of nephromegaly in GSD type I can be a clue to the diagnosis. Blood lactate concentrations rise rapidly in GSD type I as soon as hypoglycemia develops, whereas hyperketonemia with fasting is suggestive of GSD III.

Although transaminase elevation and hepatomegaly are common to many primary hepatic diseases and other metabolic disorders, hypoglycemia is uncommon until the development of end-stage liver disease ESLD for most disorders except GSDs.

The extent of the hypoglycemia, transaminase elevation, and hyperlipidemia are usually more severe in GSD III; however, severely affected individuals with GSD VI and GSD IX are being increasingly recognized. GSD type IV does not have hypoglycemia or ketone abnormalities until reaching end stage, and liver dysfunction is usually more pronounced in GSD IV.

Muscle involvement and elevated CK concentrations can occur in GSD IIIa, some hepatic forms of GSD IX, McArdle disease, and late onset GSD II Pompe disease but with clinical and pathophysiologic differences.

Muscle weakness in late onset Pompe disease is primarily truncal and proximal, affecting lower more than upper limbs; diaphragm weakness is common and may be the presenting symptom; and hepatomegaly or hypoglycemia are absent.

Respiratory distress caused by involvement of the diaphragm is highly suggestive of Pompe disease and can be a key distinguishing feature not only from GSD III but also from other neuromuscular disorders. Individuals with McArdle disease may have significantly elevated CK levels together with exercise-induced muscle cramps and are prone to develop rhabdomyolysis.

These features help to distinguish it from GSD III. Myopathic motor unit potentials along with the presence of spontaneous activity on EMG may suggest a myositis, but this pattern is often seen with glycogen storage disorders, such as Pompe disease and GSD III. Rarely, a severe infantile cardiomyopathy can occur in GSD III, 23 which can be difficult to distinguish from Pompe disease and Danon disease.

In these primary cardiac disorders, hypoglycemia is not present. There may be hepatomegaly caused by cardiac failure. A rare variant of phosphorylase kinase deficiency caused by mutations in the PRKAG2 gene can also present with severe infantile hypertrophic cardiomyopathy.

Other metabolic disorders such as Gaucher disease and Niemann-Pick disease may, initially, be confused with GSD because of the presence of hepatomegaly. In these storage disorders, however, splenomegaly is massive and helps in the differential diagnosis. In GSD III, the administration of glucagon 2 hours after a carbohydrate-rich meal provokes a normal increase in blood glucose BG , whereas, after an overnight fast, glucagon typically provokes no change in BG level.

Critical blood samples drawn at the time of hypoglycemia are useful in evaluation of the various metabolic and endocrine causes Table 2. The coexistence of hepatomegaly and hypoglycemia should prompt a workup that includes measurement of BG, lactate, uric acid, and hepatic profile including liver function studies, CK, plasma total and free carnitine, acylcarnitine profile, urinalysis, and urine organic acids.

When the diagnosis is unclear, measurement of insulin, growth hormone, cortisol, free fatty acids, beta-hydroxybutyrate, and acetoacetate levels may also be needed. In addition, the results of newborn screening should be checked because fatty acid oxidation disorders and galactosemia are included both in the differential diagnosis and standard newborn screening panels.

At the time of hypoglycemia, beta-hydroxybutyrate concentration will be elevated, which is in contrast to the hypoketosis characteristic of fatty acid oxidation disorders and hyperinsulinism. A more detailed workup of the individual who presents with hypoglycemia and hepatomegaly can be found in Scriver's Online Metabolic and Molecular Bases of Inherited Disease.

Electromyograms and nerve conduction studies are generally both abnormal showing evidence of myopathy small, short duration motor units and a mixed pattern of myopathy and neuropathy. Biopsies should lead to a definitive diagnosis in most cases but are critically dependent on the site of the biopsy and correct processing of the tissue.

Usually 30—40 mg of tissue or four cores of liver tissue are required for all the studies necessary to make a definitive diagnosis.

In the United States, reliable enzymatic analysis is only available on frozen muscle and liver biopsy samples. Liver histology in those with GSD III can help differentiate it from other liver GSDs. Histopathologic findings of the liver in GSD I include distention of the liver cells by glycogen and fat with uniform glycogen distribution.

Lipid vacuoles are large and frequent. Lipid vacuoles are less frequent in GSD III than in GSD I. The presence of fibrosis, ranging from minimal periportal fibrosis to micronodular cirrhosis, is noted in GSD III and not in GSD I. With thorough noninvasive routine laboratory testing, it is often possible to arrive at a presumptive diagnosis of GSD III without a biopsy.

However, definitive testing for GSD IIIa via either molecular genetic or enzymatic testing is necessary. GDE is an unusual protein because of its two independent catalytic activities; 1,4-alpha-d-glucan 4-alpha-d-glycosyltransferase and AGD, with separate active sites on a single polypeptide chain.

Clinical assays measure overall GDE activity in the affected tissue samples. The glycogen content is markedly increased in GSD III as high as 3 to 5 times the normal levels , and the accumulated glycogen appears structurally abnormal shorter outer branches; indicated by decreased GP to glucose ratio as compared with normal controls.

This is an important distinguishing feature for GSD III compared with other GSDs II, IV, V, VI, and IX where glycogen content may be elevated but glycogen structure is normal. The pattern of GDE deficiency in different tissues determines the specific subtype of GSD III. Individuals with GSD IIIa have deficient enzyme activity in both liver and muscle, whereas those with GSD IIIb have enzyme deficiency limited to the liver.

Thus, for a definitive diagnosis of GSD III, muscle biopsy is usually necessary to distinguish GSD IIIa from IIIb, although the finding of mutations specific to GSD IIIb can help in this regard see below. Some rare cases of GSD IIIc isolated glucosidase deficiency and IIId isolated transferase deficiency where there is a selective loss of only one of the two GDE activities have also been reported.

The molecular basis of tissue-specific GDE activity in individuals with the various subtypes of GSD III is also poorly understood. GDE deficiency has also been demonstrated in blood cells and skin fibroblasts, but these assays are not clinically available in the United States.

Western blot analysis has also been used to prove the absence of GDE protein in erythrocytes, leukocytes, lymphoblastoid cells, and skin biopsy samples for cultured skin fibroblasts from individuals with GSD III.

Prenatal diagnosis based on measurement of enzyme activity in cultured chorionic villus cells or amniocytes is possible but not clinically available. Prenatal diagnosis has also been performed by immunoblot.

GSD IIIa and IIIb are allelic disorders. Mutation testing can help confirm the diagnosis and provide information to predict GSD III subtype, carrier testing, and prenatal or preimplantation genetic diagnosis. Mutations causing GSD IIIa are scattered throughout the AGL gene and are associated with considerable allelic heterogeneity.

All mutation types, including missense, nonsense, splice site, small frame shift deletions and insertions, and large gene deletions and duplications, have been described in the AGL gene. Most mutations are specific to individual families although there are some common mutations associated with specific ethnic backgrounds.

RX RX 5. Unlike GSD IIIa, which is associated with allelic heterogeneity, two mutations in exon 3—c. Gln6HisfsX20 , formerly described as c. Gln6X —are specifically associated with the GSD IIIb phenotype. However, the mechanism by which these mutations result in retained muscle GDE activity is unknown.

However, failure to identify an exon 3 mutation in an individual without myopathic symptoms at the time of presentation does not confirm the diagnosis of GSD IIIa.

Other than the association between the two exon 3 mutations and GSD IIIb, no strong genotype-phenotype correlations exist for GSD type III. Previous reports suggest that some mutations are associated with a severe phenotype including c.

Considering the large size of the AGL gene 35 exons and 33 coding exons and the marked genetic heterogeneity observed a mutation screening strategy has been suggested. If the individual has muscle involvement, screening for ethnic group specific mutations may be appropriate.

Full AGL gene sequencing which is clinically available should be performed if targeted mutation analysis fails to reach a diagnosis. GSD III disease is a multisystem disorder best managed by a multidisciplinary team led by an experienced physician.

This might include a cardiologist, neuromuscular specialist, gastroenterologist, physical therapist, occupational therapist, genetic counselor, and a metabolic dietitian. All specialists involved in the care of an individual with GSD III should have an understanding of the disease, its broad and protean manifestations, and its challenges, including the psychologic and emotional impact of this disease on patients and families.

There should be a team member with experience in GSD III e. Glycogen deposition in cardiac muscle has been recognized since 70 ; however, the amount of glycogen was thought to be insignificant and to have little clinical effect, especially when compared with the cardiac hypertrophy with heart failure and death observed in individuals with infantile Pompe disease GSD II.

An early case report in by Miller et al. Another case report in described a young woman with GSD III who developed symptomatic congestive heart failure during pregnancy and also had cardiac hypertrophy with glycogen deposition documented by heart biopsy. The report in first suggested that serial echocardiograms might be able to identify individuals with GSD III who have cardiac involvement and are at risk of symptomatic congestive heart failure.

Individuals with GSD III do not develop valvular disease such as semilunar or atrioventricular valve regurgitation, but left ventricular hypertrophy LVH seems to be common in GSD III, although only a small fraction of individuals with GSD III actually develop cardiomyopathy symptomatic ventricular hypertrophy.

No correlation with myopathy or CK activity has been noted. Endomyocardial biopsy specimens show glycogen deposition but no myocyte disarray, which contrasts with the histologic hallmark of myocyte disarray seen in hypertrophic cardiomyopathy because of sarcomeric mutations, despite the similar appearance of hypertrophy on echo imaging.

More sophisticated echo measurements such as LV mass, as have been studied in Pompe disease, 78 may better define the increase in LV thickness. Given that diastolic dysfunction is often the first functional abnormality in hypertrophic cardiomyopathy, it usually precedes any systolic dysfunction.

There is one case report 79 that notes echo parameters suggesting LV diastolic dysfunction in the face of preserved systolic function with normal ejection fraction. Furthermore, longitudinal follow-up of GSD III patients with respect to cardiac involvement has not been reported; however, in this journal, a recent study is included with longitudinal follow-up and LV mass and wall thickness measurements.

Limited data are available regarding heart rhythm abnormalities in GSD III. Only a few series have reported electrocardiography ECG findings and, in most cases, these have shown cardiac hypertrophy. The infant who died suddenly at the age of 4 months with marked ventricular hypertrophy may have died from an arrhythmia.

Vertilus et al. in this issue of Genetics in Medicine also note a few patients who died suddenly, thought to be likely because of arrhythmia. Other than ECG findings suggestive of ventricular hypertrophy, specific rhythm disturbances on ECG appear to be uncommon.

Given the known LVH and these case reports, there is the potential for serious arrhythmia. Thus, vascular dysfunction with early atherosclerosis or early coronary artery disease could occur in individuals with GSD III.

There are limited data to date regarding this clinical question. A report by Hershkovitz et al. They found normal lipid profiles and vascular endothelial function, 82 suggesting that there is no strong association of GSD III with hyperlipidemia or with functional measure of vascular reactivity.

More studies are needed to confirm these observations. Based on currently available data regarding cardiovascular involvement in GSD III, several recommendations for evaluation and management can be made. Because ventricular hypertrophy, sometimes associated with cardiomyopathy and clinical symptoms, is well documented in GSD III, routine evaluation of rhythm by ECG and for ventricular hypertrophy by echocardiogram is recommended.

Echocardiograms should measure wall thickness and ventricular mass. Echo measurement of systolic function such as shortening fraction and ejection fraction should be performed periodically, but measures of diastolic function are useful as well because diastolic dysfunction may precede overt systolic dysfunction and could indicate the need to begin closer follow-up for potential cardiovascular symptoms.

For individuals with GSD IIIa, serial echocardiograms are recommended beginning at the time of diagnosis and repeated every 12—24 months until there is an abnormality by echo or clinical symptoms suggestive of poor ventricular function or arrhythmia.

For individuals with GSD IIIb, a baseline echo at the time of diagnosis and then every 5 years seems to be a reasonable screening strategy to monitor cardiac status. Although current knowledge is that individuals with GSD IIIb do not develop cardiac involvement, long-term follow-up of these individuals has not been done, and there are some with GSD IIIb in whom LV mass is at upper limits of normal.

Although potential heart rhythm abnormalities have not been accurately quantified, it seems that arrhythmia can develop in a subset of individuals with GSDIII. It seems prudent to perform serial lead ECGs every other year in individuals with GSD IIIa to examine the heart rhythm.

Additional electrophysiologic monitoring is indicated for individuals with clinical symptoms such as palpitations, for individuals in whom an ECG abnormality develops, or for individuals who develop moderate or more severe ventricular hypertrophy by serial echo imaging.

As a general rule, no exercise restrictions are recommended for individuals with GSD III. The type of GSD III IIIa or IIIb , the age at diagnosis, and the individual's symptoms will determine the best dietary treatment options.

The initial focus of the diet for the infant and young child with either GSD IIIa or IIIb is to prevent hypoglycemia. Small, frequent feedings and the avoidance of fasting are generally agreed on as the first step. There is still controversy regarding the distribution of calories from carbohydrates, protein, and fat.

The onset of myopathy GSD IIIa only occurs at an earlier age than was once thought; therefore, the importance of protein in the younger child's diet should not be overshadowed by a singular focus on carbohydrates.

The child with myopathy and growth failure should be started on a high protein diet. Additional protein may also offset excessive glycogen storage. Because gluconeogenesis is intact in GSD III, sucrose, fructose, and lactose are not restricted as they are for individuals with GSD I.

However, simple sugars are discouraged in favor of a diet that is higher in complex carbohydrates and protein and to reduce glycogen storage. In general, the dietary recommendations for fat follow the usual guidelines for children. The use of medium chain triglycerides MCTs in GSD III as an alternative source of energy and its effect on triglyceride levels warrants further investigation.

There are reports of an increase in triglycerides levels with MCTs. Reduced bone mineral density has been reported in GSD III.

Therefore, calcium and vitamin D intake must be assessed as part of the overall nutrition evaluation. Periodic laboratory evaluation of these levels may also be beneficial.

Because all food groups are allowed on the diet for GSD IIIa and IIIb, vitamin and mineral supplements are only prescribed based on individual need. CS can be introduced early; however, in infants aged younger than 12 months, CS may not be tolerated as the necessary digestive enzyme, amylase, may not be fully functional before this age.

Inability to digest CS causes gas, bloating, and diarrhea. A gradual introduction of CS may help reduce some of these side effects. In some instances, pancrelipase has been used with CS to aid digestion and lessen side effects. Pancrelipase is a combination of three enzymes proteins : lipase, protease, and amylase.

These enzymes are normally produced by the pancreas and are important in the digestion of fats, proteins, and sugars. In many cases, the CS requirements in GSD III may be less than the amounts required for preventing hypoglycemia in GSD I. For these two reasons, we recommend starting with a lower dose of CS and increase it as needed, rather than treating the child with too much CS.

Both dietary overtreatment and undertreatment can be problematic in GSD III. These two issues will be discussed in a later section. One gram of CS per kilogram of body weight may be sufficient to maintain normal levels of BG for 4 hours or longer in GSD III. Initially, BG must be monitored hourly to determine if the dose of CS is adequate.

Once the CS dose has been established, the frequency of BG monitoring is decreased. BG should be monitored during illness, when changes are made to the diet or schedule, to establish exercise routines, and randomly to detect asymptomatic hypoglycemia. In some cases of GSD IIIa or IIIb, hypoglycemia may be as severe as in GSD I and may require similar amounts of CS.

In these cases, 1. Repeated reports from individuals with GSD III indicate Argo brand www. com CS is preferred for its taste and palatability, stability, and effectiveness. CS can be mixed in any beverage; preferably, the CS should be mixed in milk or added to yogurt to provide a source of protein and fat.

In many cases, if the CS is not maintaining the child's BG at desirable levels adding more protein instead of more CS may correct the problem. In severe cases, especially in infancy, when it is hard to maintain normal BG levels, continuous overnight enteral feedings may be required.

The type of formula chosen for the overnight enteral feeds in GSD III does not need to be sucrose, fructose, or galactose free as it would for the treatment of GSD I. A child older than the age of 1 year who still requires overnight enteral feedings may benefit from a higher protein formula such as those used for the treatment of diabetes.

It is imperative that the child eats or takes CS as soon as the feeding pump is turned off to avoid developing hypoglycemia. As mentioned above, providing too much CS can be problematic.

Providing too much CS, too much formula, or excessively large meals can lead to excess glycogen storage in the liver and muscle and also to insulin resistance. In general, overtreating can also lead to excess weight gain, which negatively impacts the child in many ways, both psychologically and medically.

There is also a concern about undertreatment in GSD III. Some children, as well as adults, with GSD III are unable to feel the symptoms of hypoglycemia.

Hyperketosis has been reported in patients with GSD III. It is possible that in the setting of moderate to large ketosis in GSD III as a result of increased fatty acid oxidation and upregulated neoglucogenesis, 41 BG levels may be normal.

The role of ketone monitoring in this setting as a marker of metabolic control requires further systematic investigation. Monitoring of BG should be over a 1- to 2-day period periodically and especially during times of growth, or intercurrent illness. The ideal times to monitor the BG depend on the individual's schedule, but in general, BG should be checked before meals, before doses of CS, before bed, and first thing in the morning.

As noted above, any time there is a change in schedule, such as with a new school year, starting dance lessons, or adding after-school sports, BG monitoring is imperative. Long-term monitoring of growth is important. Tracking height-for-age, weight-for-age, weight-for-height, body mass index, and head circumference for age on standard growth charts allows any change in trends to be detected.

If a change in growth parameters is noted and does not appear related to inadequate nutritional intake, then the patient should be referred to either an endocrinologist or gastroenterologist, depending on the available evidence regarding the changes in growth.

Growth hormone therapy has been associated with adenoma growth and complications in GSD I, and use in any individual with GSD must be only when there is a documented growth hormone deficiency.

In such a situation, the individual should be monitored closely for the appearance or increased size of adenomas and also for hypertriglyceridemia.

As with all metabolic disorders, other important issues related to feeding should not be overlooked. These include psychosocial issues and exercise.

All children have a need for structure and guidance with their diet, but this is especially true for children with special diets. Early establishment of healthy dietary habits consistent with GSD III guidelines will improve the likelihood of long-term dietary compliance.

Teaching children about their GSD III diet and its importance in ways that are age appropriate will help them gain independence and take ownership of their dietary needs as they grow older. When consistently providing this structure, it is also important to maintain as much normalcy about the diet as possible, so that the child does not feel isolated or adopt a negative view of the diet.

Choices within the framework of the diet will allow the children to feel that they have some control. Offering more choices in other areas of their life will also give the child a sense of control.

Exercise is especially important for individuals with GSD IIIa. Manifestations of GSD IIIa, including myopathy, low bone mineral density, and hypoglycemia, are impacted by exercise and diet. Exercise in GSD IIIa is covered more thoroughly in the sections on Exercise and Physical therapy.

The emphasis of the diet for the adult with GSD IIIa is on a higher percentage of protein. Carbohydrates may be limited, but preference should be given to complex carbohydrates, as opposed to simple sugars.

Again, there are no diet restrictions with regards to specific types of sugars. Simple sugars should be avoided as they result in sudden rise and fall of BG. However, most of these recommendations refer to infants and children. There are two case reports regarding the use of a high protein diet in adults with GSD IIIa.

Dagli et al. outlined the course of a patient who was followed up for more than 2 decades. A dramatic improvement in his cardiomyopathy was observed, suggesting that a high protein diet without overtreating with CS can reverse and possibly prevent cardiomyopathy.

For the adult with GSD IIIb, there is no special dietary treatment. The potential for hypoglycemia with severe stress still exits, but in general, a regular, well-balanced diet is sufficient. The liver is involved in a variety of ways in GSD III.

Hepatomegaly occurs in childhood, and ALT and AST are typically elevated, consistent with hepatocellular injury. Serum activities of AST and ALT are markedly elevated in the first decade of life but tend to decrease significantly thereafter. Liver histology demonstrates distension of hepatocytes by glycogen and periportal septal fibrosis early in the disease process, perhaps related to the accumulation of abnormally short-branched glycogen.

Liver disease is reported as improving with age; however, as the life expectancy of individuals with GSD III improves, the long-term hepatic manifestations of the disease are being better recognized.

There are several publications of patients with cirrhosis 18 and some who progressed to ESLD. The estimated prevalence of cirrhosis among individuals with GSD III is based chiefly on results of laboratory testing, e. It is not known whether glycogen deposition and accompanying fibrosis is greater in individuals with type IIIa or IIIb disease since there are reports of liver cirrhosis in both.

In a study of 16 patients with GSD III age range 14—24 years , 4 developed adenomas age range 10— Alpha fetoprotein and chorionic embryonic antigen levels remain normal and do not predict the presence of hepatocellular adenomas or malignant transformation. Although the histologic abnormalities in individuals with GSD III may be striking, the only detectable biochemical abnormality for many years is elevation of the serum AST and ALT concentrations.

The levels are typically between two to three times the upper limit of the normal range and are accompanied by normal synthetic function: serum albumin, PT, and bilirubin concentrations. To what extent the increase in transaminase concentrations is associated with symptoms such as fatigue is less clear.

The individual's clinical course, particularly if myopathy is present, will be dictated by those features rather than by the effects of liver injury.

Liver imaging is routinely performed in individuals with GSD III. With increasing age, computed tomography or magnetic resonance imaging scanning using intravenous contrast should be considered to look for evidence of liver cirrhosis nodular hepatic contour and manifestations of portal venous hypertension such as splenomegaly , presence of adenomas, and evidence of HCC.

Although individuals with GSD III may develop histologic evidence of cirrhosis, so long as their synthetic function remains normal or well preserved, liver transplantation LT is not necessary. In the United States, and increasingly in other countries, priority for LT is governed by the individual's model for ESLD MELD score.

This score is calculated using a logarithmic assessment of three objective and reproducible variables, namely total serum bilirubin and creatinine concentrations, and the international normalized ratio.

The score may range from as low as 6 to a high capped at In contrast to the Child's score, which formed the basis of assessment of disease severity and, therefore, organ allocation until , the MELD score represents a continuous assessment of liver disease severity.

The primary function of the MELD score is to estimate an individual's mortality risk from liver disease and its complications during the next 90 days: the higher the score the greater the risk of death.

A MELD score of 15—17 is significant in that this is the point at which the mortality risk associated with liver disease and its complications is equivalent to the 1-year mortality associated with complications arising from LT. It has been suggested that individuals with GSD III and advanced liver disease should be considered for liver transplant.

LT does not correct the skeletal or cardiac manifestations of GSD III. As individuals with GSD III continue to have a better quality of life and live longer, it is possible that the incidence both of ESLD and HCC will also increase, thereby resulting in greater demands on liver transplant services.

Clinical manifestations in GSD III, as described earlier, are heterogeneous, ranging from asymptomatic to significant proximal and distal weakness and atrophy. In childhood, muscle symptoms are reported as usually absent or mild. In a series of 16 patients aged 3—22 years, detailed neuromuscular evaluation revealed one patient with severe weakness, four with slight involvement, and 11 who were asymptomatic or minimally affected.

Gross motor symptoms presenting in early childhood may improve or resolve somewhat with the potential for reemergence of proximal and distal weakness in adult, exacerbated by distal atrophy suggesting underlying neuropathy. Anterior pelvic tilt and increased width of base of support may be related to postures assumed to accommodate increased abdominal girth from hepatomegaly and may lead to biomechanical disadvantage in the use of abdominal muscles and hip extensors and abductors.

Increased abdominal girth when young may alter postural development. Weakness, whether primary and related to debrancher enzyme deficiency or secondary to altered biomechanics or both, seems to affect trunk and proximal muscles abdominal muscles, hip extensors, and abductors and distal muscles, with decreased grip strength and decreased ability to jump and hop.

Significant weakness attributable to debrancher deficiency most often is recognized in adult life. Although these cases may be termed distal myopathy, peripheral neuropathy due to debrancher deficiency may contribute to this pattern of weakness. It appears that these findings may become more evident with increasing age and that the median nerve may be preferentially involved.

Clinical heterogeneity is paralleled by genetic heterogeneity, 28 , 55 and even among individuals with the same mutation, the range of muscle symptoms has varied from minimal to severe for reasons that are unclear. Muscle glycogen is a crucial fuel for anaerobic metabolism to support maximal effort and is broken down by myophosphorylase and muscle debranching enzyme.

Despite the fact that muscle glycogen is crucial for normal muscle energy metabolism, dynamic symptoms of exercise intolerance are not recognized in GSD III. In addition to anaerobic metabolism, muscle glycogen is also necessary for normal muscle oxidative metabolism.

It provides a substrate for oxidative phosphorylation in the transition from rest to exercise. In fact, glycogen is a critical oxidative substrate to support maximal rates of oxidative phosphorylation.

Limited aerobic capacity or reduced endurance have not been identified as characteristic features of GSD IIIa. This may relate to a protective effect of retained capacity to metabolize glucosyl residues accessible to myophosphorylase.

It may also be attributable to a protective effect of weakness that limits exercise or to a lack of appropriate testing of affected individuals. Furthermore, impaired aerobic capacity or reduced endurance is notoriously difficult to assess without quantitative exercise testing and appropriate controls.

The associated restriction in hepatic glucose production in GSD III, by limiting the normal increase in muscle utilization of BG during sustained exercise, also would be expected to limit sustained exercise and could potentially provoke hypoglycemia.

The fact that neither have been described may relate to increased abundance of alternative oxidative fuels free fatty acids and ketone bodies , to enhanced capacity for gluconeogenesis and fatty acid oxidation, 41 or to a lack of appropriate and rigorous testing.

A lack of information limits the ability to provide firm recommendations regarding regular exercise in GSD III. Nevertheless, the benefits of exercise training in muscle phosphorylase deficiency GSD V suggest that aerobic conditioning may be beneficial also in GSD III.

The vulnerability of other disorders of muscle glycogenolysis and glycolysis to injury triggered by maximal effort suggests that such exercise be approached with caution in GSD III. Musculoskeletal assessment is recommended with respect to potential alterations in alignment described earlier hypermobility, increased width of base of support, anterior pelvic tilt, genu valgum and recurvatum, hindfoot valgus, and forefoot varus.

Intervention with custom-molded foot orthoses may improve distal alignment at feet and ankles and secondarily decrease genu valgum, leading to improved weight-bearing alignment for protection of the musculoskeletal system over time.

Taller orthotic intervention with ankle foot orthoses may be recommended for more severe malalignment, instability, or distal weakness in adults. Direct and functional assessment of strength and endurance is recommended for monitoring status over time and guiding individualized exercise programs as described above.

Standardized gross and fine motor testing in children is recommended to assess function relative to age-level peers, to identify specific individual areas of impairment and decreased function, and to optimize participation. Functional adaptation and appropriate provision of adaptive equipment may address fine motor issues compromised by distal weakness cutting, writing, keyboard use, and opening jars.

This may include adaptations for participation, such as driving modification if grasp or upper extremity strength and function are compromised or if lower extremity involvement necessitates use of hand controls, and may include mobility devices if needed because of decreased strength or endurance.

Avoidance of contact sports in the presence of hepatomegaly may be advised in children. Median nerve damage may occur at the wrist in adults because of compression from glycogen deposition in the nerve within the limited space of the carpal tunnel.

Appropriate precautions in individuals with cardiac involvement have been described in the Cardiology section. General medical care should be individualized as disease manifestations vary.

During childhood, routine immunizations should be given on the recommended schedule. Any immunizations that may prevent illness such as influenza leading to hypoglycemia should be offered, because these may avoid an illness and the risk of hypoglycemia. Hepatitis B immunizations should be given.

Hepatitis C status should be monitored in individuals with risk factors for hepatitis C. Hepatitis B or C infection may potentiate the risk for liver tumors in individuals with GSD III.

Beta-blockade is often prescribed in individuals with hypertrophic cardiomyopathy with ventricular outflow tract obstruction. Beta-blockers should be used with great caution in individuals with GSD III because of their potential to mask the symptoms of hypoglycemia, and other medications should be considered before using a beta-blocker.

There is little available information regarding the use of over-the-counter medications and concomitant hypoglycemia in individuals with GSD III. Although there are no reports in the literature of drugs precipitating hypoglycemia in children with GSD III, drugs known to cause hypoglycemia should be avoided.

The most important agents causing hypoglycemia are insulin and insulin secretogogues the sulfonylureas. Parents of children with hypoglycemia should be educated on the importance of monitoring during intercurrent illnesses that may involve prolonged fasting.

Medic-Alert bracelets and emergency letters from the managing physician are helpful and should be provided. Hypoglycemic events in adults with GSD III are relatively uncommon; however, caution should be used with drugs causing potential hypoglycemia, particularly in cases of impaired liver function.

Alcohol may predispose individuals to hypoglycemia. Caution should be used when prescribing hormonal birth control; estrogen is known to contribute to both benign and malignant hepatocellular tumors. Females with GSD III are known to have polycystic ovaries from a young age, 31 on rare occasions, individuals can develop hirsutism, irregular menstrual cycles, and other features of polycystic ovarian syndrome.

Fertility is not thought to be reduced. Any woman with GSD III who chooses to pursue pregnancy runs some risks and requires careful follow-up by a high risk obstetrician.

Ideally, individuals with GSD III will consult with their health care team and maintain optimal metabolic control before conception.

The primary goal during pregnancy is to maintain normoglycemia. The appropriate diet during pregnancy is unique to each individual.

Adequate amount of protein is necessary to provide an alternate source of glucose via gluconeogenesis. It is extremely important to maintain euglycemia throughout pregnancy and to avoid upregulation of counter-regulatory hormones this would result in lipolysis and ketosis, with risk of fetal demise.

Complications of GSD III in reproductive-age women include hepatic adenomas, osteoporosis, and exacerbation of liver symptoms. Hepatic adenomas may increase in size caused by the hormonal changes of pregnancy. Radiology imaging should be performed before pregnancy and after delivery to monitor this risk.

Physical therapy assessment may be helpful regarding altered biomechanics and musculoskeletal management. Management may benefit from a planned delivery via induction in a tertiary care facility. At the time of delivery, important precautions include the use of an intravenous glucose infusion to prevent hypoglycemia ; usually, D10 is preferred.

Coordination of care with a high-risk obstetrical group and the metabolic team are essential. Prior arrangements for labor, delivery, and postpartum recovery should include a dextrose infusion until the mother can resume eating and is able to maintain normoglycemia.

Children with GSD IIIa should be monitored for hypoglycemia during any surgical procedure. The duration of allowable preoperative fasting should be based on the individual's usual dietary history.

Hepatic enlargement may impact anesthetic care because of its effect on diaphragmatic excursion. Hepatic involvement in GSD III causes elevation of hepatic enzymes with generally normal synthetic function; however, because some individuals develop progressive cirrhosis, coagulation function should be assessed before surgery.

In cases of cirrhosis, anesthetic agents with known negative effects on the liver should be avoided. There may be an increased sensitivity to the nondepolarizing agents. Agents such as succinylcholine should not be used in individuals with myopathy given their potential for rhabdomyolysis.

Careful perioperative monitoring is recommended given the possibility of respiratory and metabolic complications during surgery and anesthesia. The Web site provides descriptions of the various types of GSD and a listserve, a mechanism for people with all forms of GSD to connect via the Internet.

The AGSD also holds a medical conference each year for individuals with GSD and their families. In the United States, the Muscular Dystrophy Association MDA also supports individuals with GSD III.

Because of the muscular manifestations of GSD III, certain equipment and services may be available at free or at reduced cost via a participating MDA clinic. Similar to other inborn errors of metabolism, genetic counseling should be offered to all parents of children with GSD III and to adults affected with the condition.

In counseling families with GSD III, at least a three-generation pedigree from the consult and or proband should be obtained. GSD III is an autosomal recessive condition. Alternatively, a gastrostomy tube G-tube can be placed to deliver food directly to the stomach overnight.

A medicine to lower uric acid in the blood and decrease the risk for gout may be prescribed. Your provider may also prescribe medicines to treat kidney disease, high lipids, and to increase the cells that fight infection. People with von Gierke disease cannot properly break down fruit or milk sugar.

It is best to avoid these products. More information and support for people with von Gierke disease and their families can be found at:. Association for Glycogen Storage Disease -- www. With treatment, growth, puberty, and quality of life have improved for people with von Gierke disease.

Those who are identified and carefully treated at a young age can live into adulthood. Contact your provider if you have a family history of glycogen storage disease or early infant death due to low blood sugar.

Couples who wish to have a baby may seek genetic counseling and testing to determine their risk for passing on von Gierke disease.

Bonnardeaux A, Bichet DG. Inherited disorders of the renal tubule. In: Yu ASL, Chertow GM, Luyckx VA, Marsden PA, Taal MW, Skorecki K, eds. Brenner and Rector's The Kidney. Philadelphia, PA: Elsevier; chap Kishnani PS, Chen Y-T.

Defects in metabolism of carbohydrates. In: Kliegman RM, St. Geme JW, Blum NJ, Shah SS, Tasker RC, Wilson KM, eds. Nelson Textbook of Pediatrics. Litwack G. September 19, Lauren Woods - Schools of Medicine and Dental Medicine.

The clinical trial originally set out to simply test the safety and dosage of the gene therapy for three patients with GSD Type Ia. The dramatic improvement in their lives was unexpected. The rare and deadly genetic liver disorder, GSD type Ia, affects children from infancy through adulthood, causing dangerously low blood sugar levels and constant dependence on glucose consumption in the form of cornstarch every few hours for survival.

If a cornstarch dose is missed, the disease can lead to seizures and even death. One year after patient Jerrod Watts first received the GSD vaccine during a minute infusion, he is completely off of cornstarch. In addition to totally stopping daily cornstarch consumption, Watts has experienced normal regulation of his blood glucose levels, weight loss, increased muscle strength, and marked improvement in his energy.

Missed cornstarch doses no longer are resulting in hypoglycemia, which previously could have been life threatening. The clinical trial, conducted in conjunction with the biopharmaceutical company Ultragenyx , originally set out to simply test the safety and dosage of the gene therapy for three patients with GSD Type Ia.

The gene therapy works by delivering a new copy of a gene to the liver via a naturally occurring virus. They can now go through the night without any treatment and they wake up clinically well.

The xounseling of this review is Indoor cycling workouts development of coubseling therapy for glycogen storage diseases GSDs. Diseade results Genetic counseling for glycogen storage disease the eisease of forr enzymes Genetic counseling for glycogen storage disease in the storage and retrieval of glucose in the body. Ror, GSDs gpycogen be divided into types that affect liver or muscle or both tissues. For example, glucosephosphatase G6Pase deficiency in GSD type Ia GSD Ia affects primarily the liver and kidney, while acid α-glucosidase GAA deficiency in GSD II causes primarily muscle disease. The lack of specific therapy for the GSDs has driven efforts to develop new therapies for these conditions. Gene therapy needs to replace deficient enzymes in target tissues, which has guided the planning of gene therapy experiments. Gene therapy with adeno-associated virus AAV vectors has demonstrated appropriate tropism for target tissues, including the liver, heart and skeletal muscle in animal models for GSD. Genetic counseling for glycogen storage disease

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