GLUCOGENOSIS TIPO 1B PDF
Las glucogenosis son enfermedades hereditarias del metabolismo del glucógeno. Se reconocen más de 12 tipos y afectan principalmente al hígado y al músculo, by Glycogen storage disease 1b: Speculation on the role of autoimmunity. Tratamiento continuo con factores estimulantes de colonias (G-CSF) de la neutropenia asociada a la glucogenosis tipo IbTreatment with granulocyte colony . A glycogen storage disease (GSD) is the result of an enzyme defect. These enzymes normally catalyze reactions that ultimately convert.
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University of Washington, Seattle; April 19, ; Last Update: Glycogen storage disease type I GSDI is characterized by accumulation of glycogen and fat in the liver and kidneys, resulting in hepatomegaly and renomegaly.
Affected children typically have doll-like faces with fat cheeks, relatively thin extremities, short stature, and protuberant abdomen. Xanthoma and diarrhea may be present. Impaired platelet function tiop lead to a bleeding tendency with frequent epistaxis.
Untreated GSDIb is associated with impaired neutrophil and monocyte function as well as chronic neutropenia after the first few years of life, all of which result in recurrent bacterial infections and oral and intestinal mucosal ulcers. Long-term complications of untreated GSDI include growth retardation resulting in short stature, osteoporosis, delayed puberty, gout, renal disease, pulmonary hypertension, hepatic adenomas with potential for malignant transformation, polycystic ovaries, pancreatitis, and changes in brain function.
Normal growth and puberty is expected in treated children. Most affected individuals live into adulthood. Deficient hepatic enzyme activity glucosephosphatase catalytic activity or glucosephosphate exchanger SLC37A4 activity from a liver biopsy specimen establishes the diagnosis if molecular genetic testing is inconclusive.
Medical nutritional therapy to maintain normal blood glucose levels, prevent hypoglycemia, glucogenoss provide optimal nutrition for growth and development; allopurinol glucogenossis prevent gout when dietary therapy fails to completely normalize blood uric acid concentration; lipid-lowering medications for elevated lipid levels despite good metabolic control; citrate supplementation to help prevent development of urinary calculi or ameliorate nephrocalcinosis; angiotensin-converting enzyme ACE glucogenlsis to treat microalbuminuria; kidney transplantation for end-stage renal disease ESRD ; surgery or other interventions such as percutaneous ethanol injections and radiofrequency ablation for hepatic adenomas; liver transplantation for those individuals refractory to medical treatment; and treatment with human granulocyte colony-stimulating factor G-CSF for recurrent infections.
Prevention of secondary complications: Improve hyperuricemia and hyperlipidemia and maintain normal renal function to prevent development of renal disease; maintain lipid levels within the normal range to prevent atherosclerosis and pancreatitis. Diet should be low in fructose and sucrose; galactose and lactose intake should be limited to one serving per day; combined oral contraception should be avoided in women, particularly those with adenomas.
Evaluation of relatives at risk: GSDI is inherited in an autosomal recessive manner. Heterozygotes carriers are asymptomatic. Carrier testing for at-risk family members and prenatal diagnosis for pregnancies at increased risk are possible glucogenosid both pathogenic variants have been identified in an affected family member.
The lack of either Tipoo catalytic activity or glucosephosphate exchanger SLC37A4 transporter 1n in the liver leads to inadequate conversion of glucosephosphate into glucose through normal glycogenolysis and gluconeogenesis pathways, resulting in severe hypoglycemia and many other signs and symptoms of the GSDI disorders. Guidelines for diagnosis and management glucogneosis been published by the American College of Medical Genetics and Genomics [ Kishnani et al ] full text.
GSDI should be suspected in individuals with the following clinical, laboratory, and histopathologic features. Distention of the liver cells by glycogen and fat; PAS positive and diastase sensitive glycogen that is uniformly distributed within the cytoplasm; normal or only modestly increased glycogen as compared with that seen in other liver GSDs especially GSDIII and GSDIX ; and large and numerous lipid vacuoles.
Fibrosis and cirrhosis do not occur in GSDI. As liver biopsy is invasive, it should only be done when a diagnosis cannot be made using molecular genetic testing see Establishing the Diagnosis. Liver tissue may be obtained at the same time as another surgery e. Molecular testing approaches can include serial single- gene testing, targeted analysis for pathogenic variantsuse of a multigene paneland more comprehensive genomic testing:. A sample of mg of snap-frozen liver obtained by percutaneous or open biopsy should be shipped on dry ice via overnight delivery to the clinical diagnostic laboratory.
Because of its relatively high sensitivitymolecular genetic testing is increasingly the preferred confirmatory test when weighed against the need for liver biopsy to determine the level of enzyme activity. However, liver biopsy can additionally be used to obtain histology and electronic micrographic information, which along with enzyme analysis can be used to further investigate pathology associated with variants of uncertain significance VOUS found on genetic testing.
View in own window. 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 significancelikely pathogenic, or pathogenic. For issues to consider in interpretation of sequence analysis results, click here.
Methods that may be used include: The frequency of multi exon deletions is unknown; very few have been reported in either of these genes [ Janecke et alWang et al ].
The clinical manifestations of glycogen storage disease type I GSDI are growth retardation leading to short stature tiipo accumulation of glycogen and fat in liver and kidneys resulting in hepatomegaly and renomegaly, respectively [ Kishnani et al ]. Hypoglycemia and lactic acidosis can develop after a short fast hours. Untreated children typically have doll-like faces with fat cheeks, relatively thin extremities, short stature, and protuberant abdomen caused by massive hepatomegaly.
The spleen is of normal size. Impaired platelet function can lead to glicogenosis bleeding tendency, making epistaxis a frequent problem.
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In addition to the above findings, untreated GSDIb is associated with chronic neutropenia and impaired neutrophil and monocyte function. Neutropenia is noted typically after the first few years of life, resulting in recurrent bacterial infections and oral and intestinal mucosal ulcers [ Visser et alVisser et al a ].
Oral manifestations such as ulcers, gingivitis, periodontal disease, bleeding diathesis, dental caries, and delayed dental maturation and eruption have been reported in a few affected individuals [ Mortellaro et al ].
In the past, many individuals with GSDI who were untreated died at a young age and the prognosis was guarded in survivors. However, early diagnosis and treatment have improved prognosis.
Normal growth and puberty may be expected in treated children, and most affected individuals live into adulthood. However, it is not known if all long-term secondary complications can be avoided by good metabolic control.
Some individuals treated early develop hepatic adenoma and proteinuria in adulthood. Two case reports suggested that individuals with GSDIa who are homozygous for the c. Of 19 Japanese adults who were homozygous for c. A study of 40 individuals who were homozygous for this pathogenic variant found that c. Individuals with GSDIa who are homozygous for the pathogenic variant c.
This phenotype was not observed in an individual who was compound heterozygous for this pathogenic variant [ Eminoglu et al ]. G6Pase is a multicomponent enzyme complex often referred to as the G6Pase system.
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Hence, the classification of GSDI into four subtypes no longer exists. Edgar von Gierke, who first described the disease in In Ashkenazi Jews the estimated carrier frequency of the most common pathogenic variant p. The increased frequency of some pathogenic variants in different ethnic groups e. With age, however, clinical findings and biochemical work up can differentiate between the two disorders.
To establish the extent of disease and needs in an individual diagnosed with glycogen storage disease type I GSDIthe following evaluations are recommended:. Guidelines for management have been published by the American College of Medical Genetics [ Kishnani et al ] full text. Treatment includes care by a metabolic team familiar with the medical issues associated with long-term management of persons with Hlucogenosis.
At a minimum, such a team should include the following:. Allopurinol, a xanthine oxidase inhibitor, is used to prevent gout when dietary therapy fails to completely normalize blood uric acid concentration, especially after puberty. Citrate supplementation may help prevent or ameliorate nephrocalcinosis and the development of urinary calculi. Angiotensin-converting enzyme ACE inhibitors such as captopril are used tilo treat microalbuminuria, an early indicator of renal dysfunction.
Hepatic adenomas can be treated with surgery or other interventions including percutaneous ethanol injections and radiofrequency ablation. Human granulocyte colony-stimulating factor G-CSF can be used to treat recurrent infections:.
Improve hyperuricemia and hyperlipidemia and maintain normal renal function to prevent the development of renal disease. Follow GSDI guidelines published recently through a group of experts in the field [ Kishnani et al ]. Annual ultrasound examination of the kidneys glucogenois nephrocalcinosis should be initiated after the first decade of life. For those individuals treated with G-CSF serial blood counts should be performed approximately every three months to assess response to treatment and, although the risk of acute myeloid leukemia AML is low, to evaluate for the presence of myeloblasts glucogenozis the blood.
Any imaging performed for liver surveillance e. Due to potential negative effects of sex hormones on hepatic adenomas, combined oral contraception must be avoided in women with GSDI, especially those with adenomas [ Tiipo et alAustin et al ].
Evaluation of sibs of a proband as early as possible allows for prompt diagnosis and treatment with much-improved outcome. See Genetic Tippo for issues related to testing of at-risk relatives for goucogenosis counseling purposes. Although successful pregnancies have been reported in women with GSDI, certain precautions should be taken:. Metabolic control should be followed closely throughout the pregnancy. Because carbohydrate requirements may increase with pregnancy, glucose levels should be monitored closely and treated accordingly glucofenosis Martens et alDagli et alYamamoto et alFerrecchia et al ].
Abdominal ultrasound should be performed every six to 12 weeks. Sechi et al  reported an increase in the size of pre-existent adenomas and the development of new adenomas during pregnancy and recommended monitoring by imaging before, during, and after pregnancy. Renal function should be followed closely, as this may worsen during pregnancy [ Martens et alDagli et alYamamoto et al ].
Glucose infusion during labor has been used [ Martens et alDagli et alFerrecchia et al ]. Platelet count, hemoglobin, and clotting studies should be performed because of the potential for increased bleeding at delivery [ Lewis et al ].
Current dietary treatment prevents hypoglycemia and greatly improves the life expectancy of individuals with GSDI. However, long-term complications — including progressive renal failure and development of hepatic adenomas that progress to hepatocellular carcinoma HCC — still occur. The development of new therapies for GSDI has focused on correcting the glucogenoosis cause of glucogenoiss disorders and avoiding long-term complications.
Pilot studies of hepatocyte transplantation have shown that donor cells persist. Glucogeosis, further studies are needed to investigate the long-term efficacy of this approach [ Lee et alRibes-Koninckx et al ]. However, transgene expression decreased over time, indicating that repeated administration may be necessary for long-term treatment in humans. Strategies to integrate the G6Pase transgene into the genome are being investigated, with promising results [ Landau et al ].
Correction of renal G6Pase deficiency by gene glcuogenosis has been less well studied, and the most efficient methods tipoo transducing kidney cells tupo to be investigated [ Chou et al ]. Identification of AAV serotypes that effectively transduce all affected tissue types including liver, kidney, and hematopoietic stem cells would be beneficial [ Chou et al ].
Genetic counseling is the process of providing individuals and families with information on the nature, inheritance, and implications of genetic disorders to help them make informed medical and personal decisions. The following section deals with genetic risk assessment and the use of family history and genetic testing to clarify genetic status for family members. This section is not meant to address all personal, cultural, or ethical issues that individuals may face or to substitute for consultation with a genetics professional.
Offspring of a proband.