Anesthetic complications in patients with inborn errors of metabolism undergoing non-cardiac surgery. Rev Colomb Anestesiol. E-mail address martaberrio gmail. Introduction: Inborn errors of metabolism are alterations in one or more steps in a metabolic pathway. They are associated with multisystem complications and have a high impact on the quality of life of patients.

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NCBI Bookshelf. In infancy and early childhood, liver involvement presents as ketotic hypoglycemia, hepatomegaly, hyperlipidemia, and elevated hepatic transaminases. In adolescence and adulthood, liver disease becomes less prominent. Its clinical significance ranges from asymptomatic in the majority to severe cardiac dysfunction, congestive heart failure, and rarely sudden death.

Skeletal myopathy manifesting as weakness is not usually evident in childhood, but slowly progresses, typically becoming prominent in the third to fourth decade. The serum CK may not be elevated at the time of the diagnostic work up, but the absence of lactic acidosis and markedly elevated aspartate aminotransferase AST and alanine aminotransferase ALT concentrations may provide clues to the diagnosis.

Measurement of fasting serum concentration of glucose after glucagon administration can be used to support the diagnosis; glucagon administration should not cause the glucose concentration to rise following a prolonged fast, but should do so after a fast of two hours or less. The diagnosis is established by identification of biallelic pathogenic variants in AGL.

Treatment of manifestations: A high-protein diet and frequent feeds every hours to maintain euglycemia is the mainstay of management in infancy.

Fructose and galactose can be used; special formulas are not required. Liver transplantation may exacerbate myopathy and cardiomyopathy. Prevention of secondary complications: Special precautions for persons undergoing surgery to avoid hypoglycemia. Surveillance: To identify periods of suboptimal metabolic control, blood glucose should be measured between 2 AM and 4 AM or urine ketones should be measured upon awakening at least several times per month.

Annual: measurement of height and weight; liver ultrasound examination; laboratory studies LFTs, CK, lipid profile ; and echocardiogram. A bone density determination is recommended after growth is complete. Use with caution: hormonal contraceptives and statins for control of hyperlipidemia. Evaluation of relatives at risk: Diagnosis of at-risk sibs at birth allows for early dietary intervention to prevent hypoglycemia.

Pregnancy management : Increased monitoring and support during pregnancy of women with GSD III because of increasing glucose needs during the course of pregnancy. Carrier testing for at-risk family members and prenatal testing and preimplantation genetic testing for pregnancies at increased risk are possible if the pathogenic variants have been identified in the family.

Myopathy presenting as weakness progresses slowly and becomes prominent in the third to fourth decade of life [ Lucchiari et al ]. Hypertrophic cardiomyopathy develops in the majority of people with GSD IIIa usually during childhood and in rare cases as early as the first year of life ; skeletal myopathy is absent or minimal.

Its clinical significance varies as most affected individuals are asymptomatic [ Lee et al ]; however, severe cardiac dysfunction, congestive heart failure, and rarely sudden death have been reported.

However, non-ketotic hypoglycemia has been reported [ Seigel et al ]. Ketone concentrations of 0. Identification of biallelic AGL pathogenic variants on molecular genetic testing is the next step in confirming the diagnosis:. If molecular genetic testing cannot establish a diagnosis, analysis of debranching enzyme activity in either liver or muscle can be considered see Analysis of debranching enzyme activity. View in own window. See Table A. Genes and Databases for chromosome locus and protein.

See Molecular Genetics for information on allelic variants detected in this gene. Sequence analysis detects variants that are benign, likely benign, of uncertain significance , likely pathogenic, or pathogenic.

For issues to consider in interpretation of sequence analysis results, click here. Goldstein et al [] , Sentner et al []. Methods used may include quantitative PCR , long-range PCR, multiplex ligation-dependent probe amplification MLPA , and a gene -targeted microarray designed to detect single- exon deletions or duplications. Exon deletion s or complex rearrangements have been reported [ Endo et al , Goldstein et al , Lu et al ].

Analysis of debranching enzyme activity. The debranching enzyme is a single polypeptide with two catalytic sites, amylo-1,6-glucosidase EC 3. However, if molecular genetic testing is inconclusive, debranching enzyme activity can be measured in either liver or muscle biopsy specimens and compared to controls.

Note: 1 Analysis of debranching enzyme activity in white blood cells is not available in the United States. Liver disease. The spectrum of presentation may include severe hypoglycemia as seen in GSD I or asymptomatic hepatomegaly. Liver disease is progressive, resulting in liver fibrosis and in some cases cirrhosis and hepatocellular carcinoma [ Siciliano et al , Cosme et al , Demo et al , Lucchiari et al ].

Liver histology shows prominent distension of hepatocytes by glycogen; fibrous septa and periportal fibrosis are frequently present. Elevated prothrombin time and low serum concentration of albumin are noted in those with GSD III who develop cirrhosis [ Demo et al ]. However, the true prevalence is thought to be less; more recently Sentner et al [] showed a prevalence of 6.

The relationship between metabolic control and formation of adenomas has not been elucidated. In contrast, in GSD I hepatocellular carcinoma develops in existing adenomas. Myopathy is absent or minimal in childhood and progresses slowly, becoming prominent in the third to fourth decade of life. Proximal muscles are primarily affected but involvement of distal muscles including the calves, peroneal muscles [ Lucchiari et al ], and hands is also seen.

Altered perfusion [ Wary et al ] and nerve dysfunction may contribute to exercise intolerance and muscle weakness [ Hobson-Webb et al ], respectively. Cardiomyopathy with an echocardiographic appearance of hypertrophic cardiomyopathy occurs in the majority of individuals with GSD IIIa. Cardiomyopathy usually appears during childhood; however, rarely it has been documented in the first year of life.

Its clinical significance is uncertain as most affected individuals are asymptomatic; however, severe cardiac dysfunction, congestive heart failure, and sudden death have occasionally been reported.

Growth may be compromised by poor metabolic control. Catch-up growth may be observed with the establishment of good metabolic control. Mundy et al [] suggested that the cause of the osteoporosis is probably multifactorial with muscle weakness, abnormal metabolic environment, and suboptimal nutrition playing roles in pathogenesis. Melis et al [] also hypothesized a multifactorial causation due to metabolic imbalance stemming from chronic hyperlipidemia and reduced serum levels of IGF-1, insulin, and osteocalcin.

There is a clear genotype - phenotype correlation with at least two pathogenic variants in exon 3 c. It is unclear, however, what mechanism enables individuals with pathogenic variants in exon 3 to retain debranching enzyme activity in muscle tissue. A possible explanation was proposed by Goldstein et al [] in which the exon 3 pathogenic variant is bypassed using a downstream start codon, thus creating a fully functioning isoform without the exon 3 pathogenic variants.

No genotype-phenotype correlations between other AGL pathogenic variants and disease severity have been reported. Heterogeneity even within a given family has been noted [ Lucchiari et al ]. GB Forbes. Certain populations have high prevalence as the result of a founder effect , including:. No phenotypes other than those discussed in this GeneReview are known to be associated with pathogenic variants in AGL. However, some important differences may help distinguish the two. Phosphorylase kinase is responsible for activation of hepatic glycogen phosphorylase that cleaves the terminal glucose moieties from the glycogen chain.

Affected individuals present with ketotic hypoglycemia and hepatomegaly. GSD IX, caused by mutation of genes encoding phosphorylase kinase, can be inherited in an X-linked or autosomal recessive manner. In infancy, feeds every three to four hours are recommended. Toward the end of the first year of life, cornstarch is tolerated and can be used to prevent hypoglycemia.

The doses can be titrated based on the results of glucose and ketone monitoring. A high-protein diet prevents breakdown of endogenous muscle protein in times of glucose need and preserves skeletal and cardiac muscles. Periods of suboptimal metabolic control can be identified by measuring blood glucose and blood ketone several times per month. Existing skeletal and cardiac myopathies can be improved with high-protein diet and avoidance of excessive carbohydrate intake [ Slonim et al , Slonim et al , Dagli et al , Valayannopoulos et al , Sentner et al ].

Titration of protein and cornstarch in the diet is the primary treatment for elevated cholesterol and triglyceride concentrations, which usually result from suboptimal metabolic control.

Emergency protocol. An emergency protocol to avoid dangerous hypoglycemia should be established. Serum concentrations of electrolytes, glucose, and ketones should be monitored. Efforts should be made to correct ketosis as it can induce vomiting and worsen the catabolic state. Liver transplantation. Also, modern treatment strategies and good metabolic control can prevent major complications. When euglycemia is maintained and ketosis is avoided, hepatomegaly regresses and other abnormal laboratory values e.

Myopathy and cardiomyopathy may be partially avoided by good dietary control. Consumption of fructose or sucrose prior to exercise may improve exercise tolerance, but does not completely prevent exercise-induced damage [ Preisler et al ].

Glucose and ketone monitoring should continue overnight and during the procedure. IV dextrose infusion should not be stopped abruptly as dangerous hypoglycemia can occur from a hyperinsulinemic state.

IV fluids need to be tapered slowly once optimal oral intake has been established and tolerated. Good metabolic control leads to improved muscle strength and decreased ketosis. Bone mineralization is adversely affected in acidic environments. In contrast, improved muscle condition and strength increase bone mineralization. Supplementation with vitamin D and calcium is also recommended to augment bone mineralization.

To identify periods of suboptimal metabolic control, blood glucose should be measured between 2 AM and 4 AM or urine ketones should be measured upon awakening at least several times per month. Diagnosis of at-risk sibs at birth allows for early dietary intervention to prevent development of hypoglycemia associated with GSD III.

See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes. The metabolic requirements will gradually increase throughout the second and third trimesters, and close monitoring of both glucose and ketones is critical to ensure optimal metabolic control.

In the third trimester and close to term, it is imperative to maintain ketones within normal levels as ketosis can precipitate uterine contractions and preterm labor. During labor and in the postnatal period, intravenous glucose supplementation must be available at all times to prevent hypoglycemic episodes. Search ClinicalTrials.


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Alternative titles; symbols. Other entities represented in this entry:. Glycogen storage disease III is an autosomal recessive metabolic disorder caused by deficiency of the glycogen debrancher enzyme and associated with an accumulation of abnormal glycogen with short outer chains. These subtypes have been explained by differences in tissue expression of the deficient enzyme Endo et al. In rare cases, selective loss of only 1 of the 2 debranching activities, glucosidase or transferase, results in type IIIc or IIId, respectively. Van Hoof and Hers, ; Ding et al.


Only comments seeking to improve the quality and accuracy of information on the Orphanet website are accepted. For all other comments, please send your remarks via contact us. Only comments written in English can be processed. Glycogen debranching enzyme GDE deficiency, or glycogen storage disease type 3 GSD 3 , is a form of glycogen storage disease characterized by severe muscle weakness and hepatopathy.


NCBI Bookshelf. In infancy and early childhood, liver involvement presents as ketotic hypoglycemia, hepatomegaly, hyperlipidemia, and elevated hepatic transaminases. In adolescence and adulthood, liver disease becomes less prominent. Its clinical significance ranges from asymptomatic in the majority to severe cardiac dysfunction, congestive heart failure, and rarely sudden death.

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