© American College of Medical Genetics and Genomics ACMG PRACTICE RESOURCE Diagnosis and management of glycogen storage diseases type VI and IX: a clinical practice resource of the American College of Medical Genetics and Genomics (ACMG) A full list of authors and affiliations appears at the end of the paper. Disclaimer This practice resource is designed primarily as an educational resource for medical geneticists and other clinicians to help them provide quality medical services. Adherence to this practice resource is completely voluntary and does not necessarily assure a successful medical outcome. This practice resource should not be considered inclusive of all proper procedures and tests or exclusive of other procedures and tests that are reasonably directed to obtaining the same results. In determining the propriety of any specific procedure or test, the clinician should apply his or her own professional judgment to the specific clinical circumstances presented by the individual patient or specimen. Clinicians are encouraged to document the reasons for the use of a particular procedure or test, whether or not it is in conformance with this practice resource. Clinicians also are advised to take notice of the date this practice resource was adopted, and to consider other medical and scientific information that becomes available after that date. It also would be prudent to consider whether intellectual property interests may restrict the performance of certain tests and other procedures. Purpose: Glycogen storage disease (GSD) types VI and IX are rare Results: This management guideline specifically addresses evalua- diseases of variable clinical severity affecting primarily the liver. tion and diagnosis across multiple organ systems involved in GSDs GSD VI is caused by deficient activity of hepatic glycogen PYGL VI and IX. Conditions to consider in a differential diagnosis phosphorylase, an enzyme encoded by the gene. GSD IX is stemming from presenting features and diagnostic algorithms are caused by deficient activity of phosphorylase kinase (PhK), the discussed. Aspects of diagnostic evaluation and nutritional and enzyme subunits of which are encoded by various genes: ɑ (PHKA1, PHKA2 β PHKB ɣ PHKG1 PHKG2 δ CALM1 CALM2 medical management, including care coordination, genetic counsel- ), ( ), ( , ), and ( , , ing, and prenatal diagnosis are addressed. CALM3). Glycogen storage disease types VI and IX have a wide spectrum of clinical manifestations and often cannot be distin- Conclusion: A guideline that will facilitate the accurate diagnosis guished from each other, or from other liver GSDs, on clinical and optimal management of patients with GSDs VI and IX was presentation alone. Individuals with GSDs VI and IX can present developed. This guideline will help health-care providers recognize with hepatomegaly with elevated serum transaminases, ketotic patients with GSDs VI and IX, expedite diagnosis, and minimize hypoglycemia, hyperlipidemia, and poor growth. This guideline for adverse sequelae from delayed diagnosis and inappropriate the management of GSDs VI and IX was developed as an management. It will also help identify gaps in scientific knowledge educational resource for health-care providers to facilitate prompt that exist today and suggest future studies. and accurate diagnosis and appropriate management of patients. Genetics in Medicine Methods: A national group of experts in various aspects of GSDs VI (2019) https://doi.org/10.1038/s41436-018-0364-2 and IX met to review the limited evidence base from the scientific literature and provided their expert opinions. Consensus was Keywords: glycogen storage diseases; glycogen storage disease developed in each area of diagnosis, treatment, and management. type VI; glycogen storage disease type IX; diagnostic guidelines; Evidence bases for these rare disorders are largely based on expert management guidelines opinion, particularly when targeted therapeutics that have to clear the US Food and Drug Administration (FDA) remain unavailable. PURPOSE present in other tissues. Glycogen is a polymer made up of This guideline is intended as an educational resource. It highly branched chains of glucose molecules. In the liver, highlights current practices and therapeutic approaches to the glycogen acts as a glucose reserve for maintenance of blood diagnosis and management of the multiple complications of glucose levels, especially in the fasting state. A low blood glycogen storage disease (GSD) types VI and IX. glucose level activates a series of enzymatic reactions that break down liver glycogen into glucose. The regulation of GENERAL BACKGROUND glycogen breakdown involves activation of adenylate cyclase Overview by the hormones glucagon and epinephrine, which increases Glycogen is the main storage form of carbohydrate in the cytosolic level of cAMP. The increased level of cAMP humans. It is most abundant in liver and muscle but is also activates cAMP-dependent protein kinase which, in turn, Correspondence: Michael S. Watson ([email protected]) The Board of Directors of the American College of Medical Genetics and Genomics approved this clinical practice resource on 27 August 2018. Submitted 24 September 2018; accepted: 15 October 2018 GENETICS in MEDICINE | Volume 0 | Number 0 | Month 1 ACMG PRACTICE RESOURCE KISHNANI et al activates phosphorylase kinase (PhK). PhK activates the next different genes: PHKG1 (OMIM *172470) in muscle and enzyme in the cascade, phosphorylase. Phosphorylase cata- PHKG2 (OMIM *172471) in liver. There is only one gene lyzes the sequential cleavage of the terminal units from the encoding the β-subunit, PHKB (OMIM *172490), but it is glycogen chains, liberating glucose-1-phosphate, which is then differentially spliced in different tissues including muscle, converted to glucose-6-phosphate.1 liver, and brain.13,14 The δ-subunit of PhK, calmodulin, is At least three human glycogen phosphorylases exist, each of encoded by three different genes—CALM1 (OMIM *114180), which is preferentially expressed in a different tissue; muscle, CALM2 (OMIM *114182), and CALM3 (OMIM *114183)— liver, and brain isoforms have been identified.1,2 GSD VI which are ubiquitously expressed and involved in other (OMIM 232700) is the result of a deficiency of liver glycogen cellular processes as well. Pathogenic variants in the PHKA2, phosphorylase, which is encoded by the PYGL (OMIM PHKB, and PHKG2 genes have been identified in patients *613741) gene located on chromosome 14q21-q22.3 PYGL is with liver GSD IX. the only gene known to be associated with GSD VI. Deficiency of muscle glycogen phosphorylase causes GSD V History (OMIM 232600),4 also known as McArdle disease, and will Glycogen storage disease type VI (Hers disease) (OMIM not be discussed here. 232700) (GSD VI) was reported by Henry-Gery Hers in Glycogen storage disease type IX, liver form, (OMIM 1959.15 Hers described three patients with hepatomegaly, mild 306000) (GSD IX) is often clinically indistinguishable from hypoglycemia, an increased glycogen content and deficient GSD VI. It results from deficiency of liver phosphorylase activity of glycogen phosphorylase in the liver. kinase (PhK). Isolated muscle PhK deficiency that is caused The first reported patient with liver PhK deficiency was by pathogenic variants in PHKA1 and has also been known as described by Hug et al. in 1966.16 The patient was a female – GSD IXd, has also been described5 11 but will not be discussed and the disorder was believed to be inherited in an autosomal 1234567890():,; in further detail here. PhK is a protein kinase that recessive manner. Later in the 1960s, patients with X-linked phosphorylates the inactive form of glycogen phosphorylase, inheritance of hepatic PhK deficiency were described.17 In phosphorylase b, to produce the active form, phosphorylase a. some early publications, these patients were described as PhK is a heterotetramer composed of four copies each of α, β, having a subtype of GSD VI, because they had low γ, and δ subunits.12 The γ subunit contains the catalytic site. phosphorylase activity in addition to PhK deficiency.18,19 Its activity is regulated by the phosphorylation state of the The term GSD IX, first designated by Hug et al.,20 was regulatory α and β subunits, and by the δ subunit ultimately used to describe patients with primary PhK (calmodulin) via calcium levels.12 PhK has a wide tissue deficiency, regardless of the inheritance pattern. distribution with multiple tissue-specific isoforms generated by the expression and differential splicing of the various PhK Nomenclature subunit genes12 (Tables 1 and 2). The α-subunit is encoded by In older literature, GSD VI has sometimes been referred to as the PHKA1 (OMIM *311870) gene in muscle and by the type VIII and IX, and GSD IX has been called GSD VIa and PHKA2 (OMIM *300798) gene in liver. There are also muscle VIII.21 To standardize the nomenclature in this guideline and liver isoforms of the γ-subunit, each also encoded by paper, GSD VI will be used here to describe liver glycogen phosphorylase deficiency, and GSD IX will refer to PhK Table 1 Phosphorylase kinase (PhK) subunit genes known to deficiency. PhK deficiency can be divided into two main types cause PhK deficiency in which symptoms primarily affect liver or muscle. Liver PhK Gene PhK Location Inheritance Tissue/organ deficiency (liver GSD IX) can be further subclassified subunit primarily affected according to the gene involved. PHKA2-related GSD IX is PHKA2 PHKA1 α Xq13.1 X-linked Muscle caused by changes