Glycogen storage disease type IX: High variability in clinical phenotype

Beauchamp, Nicholas; Dalton, Ann; Ramaswami, Uma; Niinikoski, Harri; Mention, Karine; Kenny, Patricio; Kolho, Kaija‐Leena; Raiman, Julian; Walter, John H.; Treacy, Eileen P.; Tanner, Stuart; Sharrard, Mark

doi:10.1016/j.ymgme.2007.06.007

Cited by 106 publications

(93 citation statements)

References 46 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Therefore, GSD IXa has been described as a benign form since often does not need treatment. However, genetic variants in PHKA2 are associated with a broad phenotypic spectrum [7] and even cases of cirrhosis have been described. The first reported case was a white 18 months old boy who had micronodular liver cirrhosis and presented the mutation p.Arg298Pro [5].…”

Section: Introductionmentioning

confidence: 99%

A new variant in PHKA2 is associated with glycogen storage disease type IXa

Rodríguez-Jiménez

Santos‐Simarro

Campos-Barros

et al. 2017

Molecular Genetics and Metabolism Reports

View full text Add to dashboard Cite

Glucogenosis type IX is caused by pathogenic variants of the PHKA2 gene. Herein, we report a patient with clinical symptoms compatible with Glycogen Storage Disease type IXa. PYGL, PHKA1, PHKA2, PHKB and PHKG2 genes were analyzed by Next Generation Sequencing (NGS). We identified the previously undescribed hemizygous missense variant NM_000292.2(PHKA2):c.1963G > A, p.(Glu655Lys) in PHKA2 exon 18. In silico analyses showed two possible pathogenic consequences: it affects a highly conserved amino acid and disrupts the exon 18 canonical splice donor site. The variant was found as a “de novo” event.

show abstract

Section: Introductionmentioning

confidence: 99%

A new variant in PHKA2 is associated with glycogen storage disease type IXa

Rodríguez-Jiménez

Santos‐Simarro

Campos-Barros

et al. 2017

Molecular Genetics and Metabolism Reports

View full text Add to dashboard Cite

show abstract

“…Although mutations in PHKG2 or other subunits of the PhK complex have not been reported to cause neutropenia, mutations in either of two other enzymes of glycogen metabolism (glucose-6-phosphatase-b and the glucose-6-phosphate transporter) cause congenital neutropenia (14)(15)(16). PhK is expressed ubiquitously, including in leukocytes (14)(15)(16)(17)(18)(19)(20)(21), and the mutant PHKG2 likely explains the transient neutropenia that occurred twice when the patient's glycemic control was extremely poor. The hemizygous R309Q mutation in PHKG2 destabilizes the PhK enzyme complex and inhibits the activity of the entire enzyme complex in a dominant-negative mechanism (Fig.…”

Section: Resultsmentioning

confidence: 99%

Discovery of a Genetic Metabolic Cause for Mauriac Syndrome in Type 1 Diabetes

et al. 2016

View full text Add to dashboard Cite

A mechanistic cause for Mauriac syndrome, a syndrome of growth failure and delayed puberty associated with massive liver enlargement from glycogen deposition in children with poorly controlled type 1 diabetes, is unknown. We discovered a mutation in the catalytic subunit of liver glycogen phosphorylase kinase in a patient with Mauriac syndrome whose liver extended into his pelvis. Glycogen phosphorylase kinase activates glycogen phosphorylase, the enzyme that catalyzes the first step in glycogen breakdown. We show that the mutant subunit acts in a dominant manner to completely inhibit glycogen phosphorylase kinase enzyme activity and that this interferes with glycogenolysis causing increased levels of glycogen in human liver cells. It is known that even normal blood glucose levels physiologically inhibit glycogen phosphorylase to diminish glucose release from the liver when glycogenolysis is not needed. The patient’s mother possessed the same mutant glycogen phosphorylase kinase subunit, but did not have diabetes or hepatomegaly. His father had childhood type 1 diabetes in poor glycemic control, but lacked the mutation and had neither hepatomegaly nor growth failure. This case proves that the effect of a mutant enzyme of glycogen metabolism can combine with hyperglycemia to directly hyperinhibit glycogen phosphorylase, in turn blocking glycogenolysis causing the massive liver in Mauriac disease.

show abstract

“…This variation is especially observed in GSD VI; hepatic phosphorylase deficiency, encoded by the PYGL gene (OMIM #232700), and GSD (Beauchamp et al 2007b). The hypoglycemia in GSD IX patients included those with mutations in the PHKG2 gene, which is in line with Bali et al, who reported fasting hypoglycemia in all five patients with PHKG2 mutations (Bali et al 2014).…”

Section: Discussionmentioning

confidence: 99%

Normoglycemic Ketonemia as Biochemical Presentation in Ketotic Glycogen Storage Disease

et al. 2015

View full text Add to dashboard Cite

Background: According to the textbooks, the ketotic glycogen storage disease (GSD) types 0, III, VI, IX, and XI are associated with fasting ketotic hypoglycemia and considered milder as gluconeogenesis is intact.Methods: A retrospective cohort study of biochemical profiles from supervised clinical fasting studies is performed in ketotic GSD patients in our metabolic center. For data analysis, hypoglycemia was defined as plasma glucose concentration <2.6 mmol/L. Total KB was defined as the sum of blood acetoacetate and b-hydroxybutyrate concentrations. If the product of glucose and KB concentrations was greater than 10, a ketolysis defect was suspected.Results: Data could be collected from 13 fasting studies in 12 patients with GSD III (n ¼ 4), GSD VI (n ¼ 3), and GSD IX (n ¼ 5). Six patients remained normoglycemic with median glucose concentration of 3.9 mmol/L (range, 2.8-4.6 mmol/L) and median total KB concentration of 1.9 mmol/L (range, 0.6-5

show abstract

Glycogen storage disease type IX: High variability in clinical phenotype

Cited by 106 publications

References 46 publications

A new variant in PHKA2 is associated with glycogen storage disease type IXa

A new variant in PHKA2 is associated with glycogen storage disease type IXa

Discovery of a Genetic Metabolic Cause for Mauriac Syndrome in Type 1 Diabetes

Normoglycemic Ketonemia as Biochemical Presentation in Ketotic Glycogen Storage Disease

Contact Info

Product

Resources

About