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 and between families.
- The fatal perinatal neuromuscular subtype presents in utero with fetal akinesia deformation sequence (FADS) with decreased fetal movements, polyhydramnios, and fetal hydrops. Death usually occurs in the neonatal period.
- The congenital neuromuscular subtype presents in the newborn period with profound hypotonia, respiratory distress, and dilated cardiomyopathy. Death usually occurs in early infancy.
- Infants with the classic (progressive) hepatic subtype may appear normal at birth, but rapidly develop failure to thrive; hepatomegaly, liver dysfunction, and progressive liver cirrhosis; hypotonia; and cardiomyopathy. Without liver transplantation, death from liver failure usually occurs by age five years.
- Children with the non-progressive hepatic subtype tend to present with hepatomegaly, liver dysfunction, myopathy, and hypotonia; however, they are likely to survive without progression of the liver disease and may not show cardiac, skeletal muscle, or neurologic involvement.
- The childhood neuromuscular subtype is rare and the course is variable, ranging from onset in the second decade with a mild disease course to a more severe, progressive course resulting in death in the third decade.
The diagnosis is suspected based on the clinical presentation and the finding of abnormally branched glycogen accumulation in muscle or liver tissue. The diagnosis is confirmed by the demonstration of glycogen branching enzyme (GBE) deficiency in liver, muscle, or skin fibroblasts, and/or the identification of biallelic pathogenic variants in GBE1, the only gene in which pathogenic variants are known to cause GSD IV.
Treatment of manifestations: Management should involve a multidisciplinary team including specialists in hepatology, neurology, nutrition, medical or biochemical genetics, and child development. 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, in part because of the extrahepatic manifestations of GSD type IV, especially cardiomyopathy. Children with skeletal myopathy and/or hypotonia warrant developmental evaluation and physical therapy as needed. 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.g., of fat-soluble vitamins) by ensuring adequate dietary intake; prevent perioperative bleeding by assessment of a coagulation profile and use of fresh frozen plasma as needed.
Surveillance: No clinical guidelines for surveillance are available. The following evaluations are suggested (with frequency varying according to disease severity): liver function tests including liver transaminases, albumin, and coagulation profile (PT and PTT); abdominal ultrasound examination; echocardiogram; neurologic assessment; nutritional assessment. 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. Each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. 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 the 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. The diagnosis is confirmed by the demonstration of glycogen branching enzyme (GBE) deficiency in liver, muscle, or skin fibroblasts [Brown & Brown 1983], and/or the identification of biallelic pathogenic variants in GBE1.
GSD IV can manifest as several different subtypes, with variable ages of onset, severity, and clinical features, including the following:
- Fatal perinatal neuromuscular subtype. Decreased fetal movements, polyhydramnios, and fetal hydrops that may be detected prenatally; arthrogryposis, severe hypotonia, muscle atrophy at birth, early neonatal death
- Congenital neuromuscular subtype. Profound neonatal hypotonia at birth, respiratory failure, dilated cardiomyopathy, early infantile death
- Classic (progressive) hepatic subtype. Failure to thrive, hepatomegaly, liver dysfunction, progressive liver cirrhosis with portal hypertension, ascites, and esophageal varices, hypotonia, and cardiomyopathy; death typically by age five years from liver failure
- Non-progressive hepatic subtype. Liver dysfunction, myopathy, and hypotonia in childhood
- Childhood neuromuscular subtype. Chronic, progressive myopathy, with dilated cardiomyopathy in some
Although subtypes have been recognized, the GSD IV phenotype is a continuum that ranges from mild to severe [Burrow et al 2006]. Thus, categorizing an individual or family into one specific subtype may be difficult.
Liver function tests. 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. Note: These abnormalities are not specific for or diagnostic of GSD IV.
Abdominal ultrasound examination. The liver is typically enlarged with signs of fibrosis or cirrhosis. Note: Hepatomegaly is not specific or diagnostic for GSD IV nor does its absence rule out the diagnosis of GSD IV.
Glycogen branching enzyme (GBE) activity is most commonly assayed in cultured skin fibroblasts, but may also be assayed in muscle or liver tissue. All individuals with GSD IV have reduced GBE activity.
Histopathology of affected tissues, such as the liver, heart, or muscle, is very helpful in making an accurate diagnosis of GSD IV.
- In general, hepatocytes are markedly enlarged and contain periodic acid-Schiff (PAS)-positive and diastase-resistant inclusions, features characteristic of the abnormally branched glycogen found in GSD IV. Widespread infiltrates of foamy histiocytes with intra-cytoplasmic deposits within the reticuloendothelial system (RES) have been reported [Magoulas et al 2012]. Interstitial fibrosis with wide fibrous septa and distorted hepatic architecture are observed [Moses & Parvari 2002].
- Electron microscopy may demonstrate fine fibrillary aggregates of electron-dense amylopectin-like material within the cytoplasm of hepatocytes.
Molecular Genetic Testing
Gene. GBE1 is the only gene in which pathogenic variants are known to cause glycogen storage disease type IV.
To confirm/establish the diagnosis in a proband
- If a liver biopsy, obtained as a part of the workup for hepatomegaly and abnormal liver function studies, shows PAS-positive and partially diastase-resistant deposits (i.e., abnormally branched glycogen) within the hepatocyte cytoplasm, additional recommended studies are typically glycogen branching enzyme (GBE) assay and/or GBE1 molecular genetic testing.
- If GSD IV is suspected based on clinical findings and liver biopsy cannot be performed, additional recommended studies are typically GBE assay on fibroblast or muscle tissue, and/or GBE1 molecular genetic testing.
Carrier testing for at-risk relatives requires prior identification of the pathogenic variants in the family, the preferred method of carrier detection.
Note: (1) Analysis of GBE activity alone is not sufficient to determine carrier status since enzyme activity in carriers may be within the normal range. (2) Carriers are heterozygotes for this autosomal recessive disorder and are not at risk of developing the disorder.
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.
The clinical manifestations of glycogen storage disease type IV (GSD IV) span a continuum from mild to severe [Burrow et al 2006]. 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 subtype, the 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 al 2004, Tay et al 2004]. Death usually occurs in the neonatal period frequently due to cardiopulmonary compromise.
The congenital neuromuscular subtype presents in the newborn period with profound hypotonia, respiratory distress, dilated cardiomyopathy, and death in early infancy typically due to cardiopulmonary compromise [Moses & Parvari 2002]. 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 subtype, the 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 (PT), portal 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 2012]. Without liver transplantation, death from liver failure usually occurs by age five years [Chen 2001, Moses & Parvari 2002]. Dilated cardiomyopathy and progressive cardiac failure, reported to occur following orthotopic liver transplantation, have resulted in death [Sokal et al 1992, Rosenthal et al 1995].
In the less common non-progressive hepatic subtype, presentation can be in childhood with hepatomegaly, liver dysfunction, myopathy, and hypotonia. These individuals tend to survive without evidence of progression of the liver disease [Moses & Parvari 2002]. 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 1996].
The childhood neuromuscular subtype of GSD IV is rare [Reusche et al 1992, Schröder et al 1993]. Individuals typically present in the second decade and may have mild to severe myopathy and dilated cardiomyopathy. The natural history is variable: some individuals have a mild disease course throughout life while others have a more severe, progressive course resulting in death in the third decade.
Genotype-phenotype correlations between phenotypes associated with biallelic GBE1 pathogenic variants (various subtypes of GSD IV and APBD; see Genetically Related Disorders) remain unclear, but are emerging [Bao et al 1996, Ziemssen et al 2000, Nambu et al 2003, Bruno et al 2004, Janecke et al 2004, Assereto et al 2007, Magoulas et al 2012].
APBD is typically the result of homozygous or compound heterozygous pathogenc missense variants (Table 2).
In GSD IV, generally:
- Individuals with the perinatal and congenital subtypes tend to have two null variants, including nonsense, frameshift, and splice site variants leading to premature truncation of the protein likely resulting in complete absence of glycogen branching enzyme (GBE) activity;
- Individuals with the classic hepatic subtype tend to be compound heterozygotes for a null and a missense variant.
Despite these generalizations, considerable overlap exists both between and within the subtypes of GSD IV [Li et al 2010].
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.
Glycogen storage disease type IV is rare, accounting for approximately 3% of the glycogen storage diseases [Chen 2001] for an overall incidence of approximately 1:600,000-1:800,000.
To date, 37 individuals with molecularly confirmed GSD IV have been reported [Bao et al 1996, Bruno et al 1999, Nambu et al 2003, Bruno et al 2004, Janecke et al 2004, Tay et al 2004, L'Herminé-Coulomb et al 2005, Akman et al 2006, Burrow et al 2006, Shin 2006, Assereto et al 2007, Nolte et al 2008, Raju et al 2008, Lamperti et al 2009, Li et al 2010, Li et al 2012, Magoulas et al 2012].
Genetically Related (Allelic) Disorders
Adult-onset polyglucosan body disease (APBD) is the only other phenotype known to be associated with mutation of GBE1 (see Adult Polyglucosan Body Disease). APBD is characterized by adult-onset progressive neurogenic bladder, gait difficulties (i.e., spasticity and weakness) from mixed upper and lower motor neuron involvement, sensory loss predominantly in the distal lower extremities, and mild cognitive difficulties (often executive dysfunction). In APBD GBE activity is reduced or normal. Affected individuals are either homozygous or compound heterozygous for a pathogenc missense variant in GBE1 including p.Tyr329Ser, p.Arg515His, and p.Arg524Gln [Lossos et al 1998, Ziemssen et al 2000, Klein et al 2004]. Inheritance is autosomal recessive.
Differential diagnoses for the classic hepatic subtype of GSD IV include other glycogen storage disorders (e.g., GSD III) and mitochondrial DNA depletion syndromes (e.g., MPV17-related hepatocerebral mitochondrial DNA depletion syndrome, DGUOK-related mitochondrial DNA depletion syndrome, hepatocerebral form).
Evaluations Following Initial Diagnosis
To establish the extent of disease and needs of an individual diagnosed with glycogen storage disease type IV (GSD IV), the following evaluations are recommended:
- Liver function studies including albumin, transaminases, and coagulation profile
- Abdominal ultrasound examination to assess liver size and texture
- Referral to a cardiologist for baseline echocardiogram and electrocardiogram (ECG) to assess for cardiomyopathy
- Neurodevelopmental evaluation
- Neurologic consultation and comprehensive neurologic examination with a baseline assessment of skeletal muscle involvement that can be used to monitor disease progression
- Medical or biochemical genetics consultation
Treatment of Manifestations
Management should involve a multidisciplinary team including specialists in hepatology, neurology, nutrition, medical or biochemical genetics, and child development.
Hepatic manifestations. 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: four from sepsis, one from hepatic artery thrombosis, and one from cardiomyopathy. The prognosis in persons with GSD IV who undergo liver transplantation is poor because of the significant risk for morbidity and mortality, which is in part attributed to the extrahepatic manifestations of GSD type IV, especially cardiomyopathy [Davis & Weinstein 2008, Magoulas et al 2012].
Selecting appropriate candidates for liver transplantation can be complex. Histologic, molecular, or clinical predictors of disease progression are likely to be useful in stratifying patients prior to liver transplantation [Davis & Weinstein 2008]. 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.
Neurologic manifestations. Children with skeletal myopathy and/or hypotonia who experience motor developmental delay warrant developmental evaluation and physical therapy as needed.
Cardiac manifestations. 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 1999]; however, consideration of potential contraindications to cardiac transplantation, including myopathy, liver failure, and cachexia, is essential before pursuing this treatment option.
Prevention of Secondary Complications
Nutritional deficiencies (e.g., of fat-soluble vitamins) can be prevented by ensuring adequate dietary intake based on frequent assessments by and recommendations of a dietitian experienced in managing children with liver disease.
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.
No clinical guidelines for surveillance are available.
The following evaluations are suggested with frequency varying according to the severity of the condition:
- Liver function tests including liver transaminases, albumin, and coagulation profile (PT and PTT)
- Abdominal ultrasound examination
- Neurologic assessment
- Nutritional assessment
Note: 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.
Evaluation of Relatives at Risk
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.
Therapies Under Investigation
Search ClinicalTrials.gov for access to information on clinical studies for a wide range of diseases and conditions. Note: 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. —ED.
Mode of Inheritance
Glycogen storage disease type IV (GSD IV) is inherited in an autosomal recessive manner.
Risk to Family Members
Parents of a proband
- The parents of an affected child are obligate heterozygotes (i.e., carriers of one mutant allele).
- Heterozygotes (carriers) are asymptomatic.
Sibs of a proband
- At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. Although affected sibs are expected to manifest the same subtype of GSD IV, the age of onset and presentation may differ.
- Once an at-risk sib is known to be unaffected, the risk of his/her being a carrier is 2/3.
- Heterozygotes (carriers) are asymptomatic.
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.
Other family members. Each sib of the proband’s parents is at a 50% risk of being a carrier.
Molecular genetic testing. Molecular genetic testing is the preferred method for determining an individual’s carrier status. Carrier testing for at-risk family members is possible if the pathogenic variants in the family have been identified.
Biochemical genetic testing. 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.
Related Genetic Counseling Issues
See Management, Evaluation of Relatives at Risk for information on evaluating at-risk relatives for the purpose of early diagnosis and treatment.
- The optimal time for determination of genetic risk, clarification of carrier status, and discussion of the availability of prenatal testing is before pregnancy.
- It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers.
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.
Molecular genetic testing. If the pathogenic variants have been identified in the family, prenatal testing for pregnancies at increased risk may be available from a clinical laboratory offering either testing of the gene of interest or custom testing.
Biochemical genetic testing. Prenatal testing is possible by analysis of glycogen branching enzyme (GBE) activity in amniocytes or cultured chorionic villi obtained by amniocentesis usually performed at approximately 15 to 18 weeks’ gestation or chorionic villus sampling (CVS) at approximately ten to 12 weeks’ gestation.
Note: Gestational age is expressed as menstrual weeks calculated either from the first day of the last normal menstrual period or by ultrasound measurements.
Preimplantation genetic diagnosis (PGD) may be an option for some families in which the pathogenic variants have been identified.
GeneReviews staff has selected the following disease-specific and/or umbrella support organizations and/or registries for the benefit of individuals with this disorder and their families. GeneReviews is not responsible for the information provided by other organizations. For information on selection criteria, click here.
- Association for Glycogen Storage Disease (AGSD)PO Box 896Durant IA 52747Phone: 563-514-4022Email: firstname.lastname@example.org
- Children Living with Inherited Metabolic Diseases (CLIMB)United KingdomPhone: 0800-652-3181Email: email@example.com
Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED.
Gene structure. GBE1 comprises 16 exons. For a detailed summary of gene and protein information, see Table A, Gene.
Pathogenic allelic variants. To date, 40 GBE1 pathogenic variants have been identified in individuals with GSD IV or adult-onset polyglucosan body disease (APBD). See Genetically Related Disorders, Table 2, and Table 3 (pdf).
Seven of the 40 pathogenic variants are located in exon 12, previously reported as a potential mutation hotspot [Moses & Parvari 2002].
Of the 40 pathogenic variants identified, 29 are within the catalytic domain of the enzyme. Twelve of the 16 missense variants have occurred in the enzyme catalytic domain, indicating that such variants disturb the enzymatic activity of the protein [Magoulas et al 2012].
See Table 3 (pdf) for a complete list of GBE1 pathogenic variants identified to date.
Normal gene product. Glycogen branching enzyme (GBE), a 702-amino acid protein, catalyzes the transfer of alpha-1,4-linked glucosyl units from the outer end of a glycogen chain to an alpha-1,6 position on the same or a neighboring glycogen chain. Branching of the chains is essential to increase the solubility of the glycogen molecule and, consequently, reduce the osmotic pressure within cells [Thon et al 1993]. The GBE protein contains two highly conserved domains at the N- and C-terminals with sequences similar to isoamylase (glycoside hydrolase) and alpha-amylase, respectively. These two domains flank the alpha-amylase catalytic domain that encompasses the central portion of the enzyme [Moses & Parvari 2002].
Abnormal gene product. The underlying molecular defects in GBE1 lead to the production of little or no functional GBE, resulting in abnormally formed glycogen (with fewer branch points and longer unbranched outer chains) with an amylopectin-like structure that accumulates in various tissues, most commonly the liver, heart, muscle, brain, spinal cord, peripheral nerve, and skin [Thon et al 1993, Chen 2001, Moses & Parvari 2002]. It has been postulated that alteration in the glycogen branching structure that makes it less soluble may result in a foreign body reaction that leads to the tissue injury and dysfunction observed in GSD IV [Howell 1991]; however, the specific pathologic mechanisms remain unknown.
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- 3 January 2013 (me) Review posted live
- 17 September 2012 (aeh) Original submission
Texas Children’s Hospital
King Fahad Medical City – Children’s Hospital
King Saud bin Abdulaziz University for Health Sciences
Riyadh, Saudi Arabia
Initial Posting: January 3, 2013.
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University of Washington, Seattle, Seattle (WA)
Magoulas PL, El-Hattab AW. Glycogen Storage Disease Type IV. 2013 Jan 3. In: Pagon RA, Adam MP, Ardinger HH, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2017.