The clinical manifestations of glycogen storage disease type IV (GSD IV) discussed in this entry span a continuum of different subtypes with. GSD IV GLYCOGEN BRANCHING ENZYME DEFICIENCY GBE1 DEFICIENCY ANDERSEN DISEASE BRANCHER DEFICIENCY GLYCOGENOSIS IV. Spanish Synonyms of “enfermedad por almacenamiento de glucógeno-tipo IV”: EAG tipo IV, enfermedad de Andersen, glucogenosis tipo IV.
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University of Washington, Glucogneosis The clinical manifestations of glycogen storage disease type IV GSD IV discussed in this entry span a continuum of different subtypes with variable ages of onset, severity, and clinical features.
Clinical findings vary extensively both within gluclgenosis between families. The diagnosis is suspected based on the clinical presentation and the finding of abnormally branched glycogen accumulation in muscle or liver tissue.
Management should involve a multidisciplinary team including specialists in hepatology, neurology, nutrition, medical or biochemical genetics, and child development.
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Liver transplantation is the only treatment option for individuals with the progressive hepatic subtype of GSD IV who develop liver failure; however, the risk for morbidity and mortality is high, glucpgenosis part because of the extrahepatic manifestations of GSD type IV, especially cardiomyopathy.
Those with cardiomyopathy warrant care by a cardiologist. Heart transplant may be an option in patients with severe cardiac involvement. Prevention of secondary complications: Prevent nutritional deficiencies e. No clinical guidelines for surveillance are available.
The following evaluations are suggested with frequency varying according to disease severity: If cardiomyopathy was not observed on baseline screening echocardiogram at the time of initial diagnosis, repeat echocardiograms every three months during infancy, every six months during early childhood, and annually thereafter.
Evaluation of relatives at risk: If the GBE1 pathogenic variants have been identified in an affected family member, test at-risk relatives to allow early diagnosis and management of disease manifestations.
GSD IV is inherited in an autosomal recessive manner. Although affected sibs are expected to manifest the same subtype of GSD IV, the age of onset and presentation may differ.
Carrier testing for at-risk family members and prenatal and prenatal diagnosis for pregnancies at increased risk are possible based on molecular testing if the pathogenic variants in hipo family have been identified. If the pathogenic variants have not been identified, glycogen branching enzyme GBE testing on cultured amniocytes can be performed for prenatal diagnosis.
The diagnosis of glycogen storage disease type IV GSD IV is suspected based on the clinical presentation and the finding of abnormally branched glycogen accumulation in muscle or liver tissue. GSD IV can manifest as several different subtypes, with variable ages of onset, severity, and clinical features, including the following:.
Although subtypes have been recognized, the GSD IV phenotype is a continuum that ranges from mild to severe [ Burrow et al ]. Thus, categorizing an g,ucogenosis or family into one specific ov may be difficult. Liver enzymes are typically elevated in the hepatic subtypes.
Hypoalbuminemia and prolonged partial thromboplastin time PTT and prothrombin time PT are also observed with progressive deterioration of liver function due to the accumulation of abnormally branched glycogen.
The liver is typically enlarged with signs of fibrosis or cirrhosis. Glycogen branching enzyme GBE activity is most commonly assayed in cultured skin fibroblasts, but may also be assayed in muscle or liver tissue. Histopathology of affected tissues, such as the liver, heart, or muscle, is very helpful in making an accurate diagnosis of GSD IV. GBE1 is the only gene in which pathogenic variants are known to cause glycogen storage disease type IV.
View in own window. Genes and Databases for chromosome locus and protein.
See Molecular Genetics for information on allelic variants. The ability of the test method used to detect a variant that is present in the indicated 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. Of 37 affected individuals, 28 had biallelic pathogenic variants and six had one identifiable pathogenic variantimplying that the second causative variant was not identified.
Of 37 affected individuals, three were homozygous for exon or multiexon deletions and four were compound heterozygous for one exon or multiexon deletion and one sequence variant detectable by sequence analysis [ Li et alMagoulas et al ].
Carrier testing for at-risk relatives requires prior identification of the pathogenic variants in the family, the preferred method of carrier detection. Prenatal diagnosis and preimplantation genetic diagnosis PGD for at-risk pregnancies require prior identification of the pathogenic variants in the family. If the pathogenic variants have not been identified, GBE activity can be measured in cultured amniocytes.
Within this continuum several different subtypes with variable age of onset, severity, and clinical features have been recognized. Although prognosis tends to depend on the subtype of GSD IV, clinical findings vary extensively both within and between families.
The fatal perinatal neuromuscular subtypethe most severe subtype, presents in utero with fetal akinesia deformation sequence FADS with decreased fetal movements, polyhydramnios, and fetal hydrops. Newborns may have arthrogryposis, severe hypotonia, and muscular atrophy, often resembling infants with the severe forms of spinal muscular atrophy [ Janecke et alTay et al ]. Death usually occurs in the neonatal period frequently due to cardiopulmonary compromise.
Li et al  recently reported two unrelated infants with this subtype of GSD IV who were also small for gestational age. Both died between ages two and three months. The hepatic subtypethe most common presentation of GSD IV, can be classified as progressive classic or non-progressive. In the progressive hepatic subtype children may appear normal at birth, but then rapidly deteriorate in the first few months of life with failure to thrive, hepatomegaly, and elevated liver enzymes.
This stage is typically followed by progressive liver dysfunction and cirrhosis with hypoalbuminemia, prolonged partial thromboplastin time PTT and prothrombin time PTportal hypertension, ascites, and esophageal varices. Muscle tone, often normal at the time of diagnosis, progresses to generalized hypotonia within the first one to two years of life [ Magoulas et al ]. Dilated cardiomyopathy and progressive cardiac failure, reported to occur following orthotopic liver transplantation, have resulted in death [ Sokal et alRosenthal et al ].
In the less common non-progressive hepatic subtype, presentation can be in childhood with hepatomegaly, liver dysfunction, myopathy, and hypotonia. They also may not show cardiac, skeletal muscle, or neurologic involvement. Liver enzymes are usually abnormal in childhood at the time of presentation, but subsequently may return to and remain normal [ McConkie-Rosell et al ]. Individuals typically present in the second decade and may have mild to severe myopathy and dilated cardiomyopathy. The natural history is variable: APBD is typically the result of homozygous or compound heterozygous pathogenc missense variants Table 2.
Despite these generalizations, considerable overlap exists both between and within the subtypes of GSD IV [ Li et al ]. Penetrance for GSD IV is complete in those with biallelic pathogenic variants but shows extensive clinical variability between families and may show age-related progression of symptoms over time.
APBD is characterized by adult-onset progressive neurogenic bladder, gait difficulties i. Affected individuals are either homozygous or compound heterozygous for a pathogenc missense variant in GBE1 including p. ArgHisand p. ArgGln [ Lossos et alZiemssen et alKlein et al ]. Inheritance is autosomal recessive. Differential diagnoses for the perinatal and congenital neuromuscular subtypes of GSD IV include spinal muscular atrophyPompe diseaseZellweger syndromeand congenital disorders of glycosylation.
Differential diagnoses for the classic hepatic subtype of GSD IV include other glycogen storage disorders e.
Differential diagnoses for the childhood neuromuscular subtype of GSD IV include muscular dystrophies e. To establish the extent of disease and needs of an individual diagnosed with glycogen storage disease type IV GSD IVthe following evaluations are recommended:.
Liver transplantation is the only treatment option for individuals with the progressive hepatic subtype of GSD IV who develop liver failure.
Of the 18 individuals with GSD IV who have received a liver transplant to date, two required a second liver transplant and six died: Selecting appropriate candidates for liver transplantation can be complex. Factors such as glycogen branching enzyme GBE activity may not be the best predictor of outcome since the level of GBE activity in different tissues can vary by disease subtype and severity.
For those with cardiomyopathy, care by a cardiologist is warranted. Individuals with severe cardiomyopathy secondary to glycogenosis may be candidates for cardiac transplantation [ Ewert et al ]; however, consideration of potential contraindications to cardiac transplantation, including myopathy, liver failure, and cachexia, is essential before pursuing this treatment option. Bleeding due to coagulopathy can occur especially with surgical procedures; therefore, it is recommended that a coagulation profile be assessed before surgical procedures and fresh frozen plasma be given preoperatively as needed.
The following evaluations are suggested with frequency varying according to the severity of the condition:. If cardiomyopathy was not observed on the baseline screening echocardiogram at the time of initial diagnosis, repeat echocardiograms are recommended every three months during infancy, every six months during early childhood, and annually thereafter.
If the GBE1 pathogenic variants have been identified in an affected family member, at-risk relatives can be tested so that those with the pathogenic variants can be evaluated for involvement of the liver, skeletal muscle, and heart to allow early diagnosis and management of disease manifestations.
See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes. There may not be clinical trials for this disorder. 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.
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Offspring of a proband. The offspring of an individual with glycogen storage disease type IV are obligate heterozygotes carriers for a pathogenic variant in GBE1. Carrier testing for at-risk family members is possible tip the pathogenic variants in the family have been identified. Analysis of glycogen branching enzyme GBE activity alone is not sufficient to determine carrier status since enzyme activity in carriers may be within the normal range.
See Management, Evaluation of Relatives at Risk for information on evaluating at-risk relatives for the purpose of early diagnosis and treatment.
DNA banking is the storage of DNA typically extracted from white blood cells for possible future use. Because it is likely that testing methodology and our understanding of genes, allelic variants, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals.
Once the pathogenic variants glcogenosis been identified in an affected family member, prenatal testing for a glucogenosus at increased risk and preimplantation genetic diagnosis are possible. Gestational age is expressed as menstrual weeks calculated either from the first day of the last normal menstrual period or by ultrasound measurements.
GeneReviews is not responsible for the information provided by other organizations. For information on selection criteria, click here. Data are compiled from the following standard references: GBE1 comprises 16 exons. For a detailed summary of gene and protein information, see Table AGene. Of the 40 GBE1 pathogenic variants, 16 are missensesix nonsensefive splice-site, seven frameshift, and six exon or multiexon deletions [ Li et alMagoulas et al ].