Glycogen Storage Disease (GSD) and Disorders of Glucose Metabolism Panel

The Glycogen Storage Diseases (GSDs) are a group of inherited metabolic disorders that result from a defect in any one of several enzymes required for either glycogen synthesis or glycogen degradation. Broadly speaking, the GSDs can be divided into hepatic or myopathic forms. Patients with hepatic GSDs typically present with hypoglycemia and often with hepatomegaly, whereas those with myopathic forms of GSDs can present with exercise intolerance, muscle pain, rhabdomyolysis and/or muscle weakness. Some of the myopathic forms of GSD can present with cardiomyopathy as well. When performed, liver or muscle biopsies may reveal an accumulation of glycogen or abnormally structured glycogen, dependent upon the specific enzymatic defect. Additional long-term complications are common in many of the GSDs. The severity of the GSDs range from those that are fatal in infancy if untreated to mild disorders with a normal lifespan. While some forms of GSD affect a single tissue type (for example, skeletal muscle in McArdle disease), other GSDs affect multiple systems.

Defects in a number of genes that encode proteins involved in glucose or fructose metabolism can result in a clinical picture similar to that of some of the GSDs, and are therefore included in this sequencing panel.

Defects in the following genes are associated primarily with a hepatic clinical presentation:

GYS2 (GSD 0, liver type); G6PC1/G6PC (GSD Ia, von Gierke Disease); SLC37A4 (GSD Ib); PYGL (GSD VI, Hers Disease); PHKA2 (GSD IXa); PHKG2 (GSD IXc); SLC2A2 (GSD XI*, Fanconi-Bickel Disease); ALDOB (Hereditary Fructose Intolerance); FBP1 (fructose-1,6-bisphosphatase deficiency); SLC16A1 (MCT1 Deficiency); EPM2A** (progressive myoclonic epilepsy 2A); NHLRC1** (progressive myoclonic epilepsy 2B)

Defects in the following genes are associated primarily with a myopathic clinical presentation (may include cardiac defects):

GYS1 (GSD 0, muscle type); GAA (GSD II, Pompe Disease); PYGM (GSD V, McArdle Disease); PFKM (GSD VII, Tarui Disease); PHKA1 (GSD IXd); PGAM2 (GSD X); LDHA (GSD XI*); ENO3 (GSD XIII); GYG1 (GSD XV); LAMP2 (Pseudoglycogenosis II, Danon Disease); PRKAG3 (altered glycogen and triglyceride levels in muscle)

Defects in the following genes are associated with both a hepatic and/or a myopathic clinical presentation (may include cardiac defects):

AGL (GSD III, Cori Disease); GBE1 (GSD IV, Andersen Disease, Adult Polyglucosan Body Disease); PHKB (GSD IXb); ALDOA (GSD XII); PGM1 (GSD XIV); PRKAG2 (GSD of the heart, congenital); PC (Pyruvate Carboxylase Deficiency); PCK1 (PEP Carboxykinase Deficiency, cytosolic); PCK2 (PEP Carboxykinase Deficiency, mitochondrial); RBCK1 (polyglucosan body myopathy 1 with or without immunodeficiency)

* Defects in both the GLUT2 transporter and lactate dehydrogenase have been named GSD XI, although these are distinct disorders.

** The EPM2A and NHLRC1 genes are primarily associated with progressive myoclonic epilepsy, although hepatic failure can occur. In both disorders, intracellular polyglucosan bodies can be found in various tissues.

Many of the glycogen storage diseases are reviewed individually in GeneReviews. In addition, comprehensive reviews of the hepatic forms of GSD (Wolfsdorf and Weinstein 2003. PubMed ID: 12618563; Burda and Hochuli 2015. PubMed ID: 26001652) as well as the myopathic forms of GSD (DiMauro and Spiegel 2011. PubMed ID: 22106711; Scalco et al. 2015. PubMed ID: 25929793) are available. Additional comprehensive reviews of all glycogen storage diseases are also available (Hicks et al. 2011. PubMed ID: 21910565; Kilimann and Oldfors 2015. PubMed ID: 25376534; Adeva-Andany et al. 2016. PubMed ID: 27051594; Cenacchi et al. 2019. PubMed ID: 31363843). The GSDs have traditionally been diagnosed using a combination of clinical symptoms, biochemical results, and pathology findings. Within the last decade, DNA sequence variant analysis has become the primary method for diagnosing the glycogen storage diseases.

The estimated disease incidence for all forms of glycogen storage disease in the United States is approximately 1 in 20,000 to 1 in 43,000 births (Ozen. 2007. PubMed ID: 17552001). These disorders are found in all ethnic groups, but founder pathogenic variants may put certain populations at higher risk (for example, GSD Type III in the Faroe Islands and GSD Type VI in the U.S. Mennonite community) (Santer et al. 2001. PubMed ID: 11378828; Chang et al. 1998. PubMed ID: 9536091).

Obtaining an accurate molecular diagnosis may help in determining the patient’s prognosis, planning for the best treatment and/or management of symptoms, and allow for reproductive planning.

Although the majority of disorders tested for in this sequencing panel show autosomal recessive inheritance, a few exceptions do exist. Two forms of GSD Type IX (due to pathogenic variants in PHKA1 and PHKA2) as well as pseudoglycogenosis II (Danon Disease, caused by pathogenic variants in LAMP2) show X-linked recessive inheritance. Female carriers of PHKA2 pathogenic variants may or may not be affected, depending on the pattern of X-chromosome inactivation. To date, no symptomatic females with PHKA1 variants have been reported (Herbert et al. 2018. PubMed ID: 21634085). Female carriers of LAMP2 variants tend to be more mildly affected than males (Cenacchi et al. 2019. PubMed ID: 31363843). MCT1 deficiency (due to pathogenic variants in SLC16A1) appears to be inherited in both an autosomal recessive and autosomal dominant manner, with patients with two variants being more severely affected (van Hasselt et al. 2014. PubMed ID: 25390740). Glycogen storage disease of the heart (due to pathogenic variants in PRKAG2) is inherited in an autosomal dominant manner.

All manner of single nucleotide and small sequence variants (missense, nonsense, splicing, small deletions, small insertions or duplications, and small indels) have been reported in the genes in this panel. Larger copy number variants (particularly deletions) have also been reported in a number of the genes in this panel (AGL, EPM2A, FBP1, G6PC1, GAA, GBE1, LAMP2, PC, PHKA2, PHKB, PYGL, PYGM, and SLC37A4). To our knowledge, de novo variants are not a common cause of disease for the genes in this panel.

See individual gene summaries for more information about molecular biology of gene products and spectra of pathogenic variants.

Due to the genetic heterogeneity of the disorders tested in this panel, the clinical sensitivity of this specific grouping of genes is difficult to estimate. To our knowledge, only two studies have been published in which multiple genes known to cause a glycogen storage disease were sequenced via NextGen sequencing. In the first study (Wang et al. 2013. PubMed ID: 22899091), 16 genes were examined. The authors reported a confirmed molecular diagnosis in 11 of 17 patients (~65%) that were suspected to have a GSD. In the second study (Vega et al. 2016. PubMed ID: 26913919), 19 out of 43 patients (~44%) were found to harbor pathogenic variants in genes included in our sequencing panel, and 4 in non-GSD genes which are not included in our panel. Of note, our panel contains several genes that were not reported by either Wang (2013) or Vega 2016): EPM2A, FBP1, LAMP2, NHLRC1, PC, PCK1, PCK2, PRKAG2, PRKAG3, RBCK1, and SLC16A1.

The sensitivity of this panel will vary based on the clinical phenotype of the patient. Analytical sensitivity of this test is expected to be high as the majority of pathogenic variants reported in the genes in the panel are detectable via direct sequencing.

This test is performed using Next-Gen sequencing with additional Sanger sequencing as necessary.

This panel typically provides 99.9% coverage of all coding exons of the genes plus 10 bases of flanking noncoding DNA in all available transcripts along with other non-coding regions in which pathogenic variants have been identified at PreventionGenetics or reported elsewhere. We define coverage as ≥20X NGS reads or Sanger sequencing. PGnome panels typically provide slightly increased coverage over the PGxome equivalent. PGnome sequencing panels have the added benefit of additional analysis and reporting of deep intronic regions (where applicable).

Dependent on the sequencing backbone selected for this testing, discounted reflex testing to any other similar backbone-based test is available (i.e., PGxome panel to whole PGxome; PGnome panel to whole PGnome).