Abstract
Glycogen storage disease (GSD) type IX is a rare disease of variable clinical severity affecting primarily the liver tissue. Individuals with liver phosphorylase b kinase (PhK) deficiency (GSD IX) can present with hepatomegaly with elevated serum transaminases, ketotic hypoglycemia, hyperlipidemia, and poor growth with considerable variation in clinical severity. PhK is a cAMP-dependent protein kinase that phosphorylates the inactive form of glycogen phosphorylase, phosphorylase b, to produce the active form, phosphorylase a. PhK is a heterotetramer; the alpha 2 subunit in the liver is encoded by the X-linked PHKA2 gene. About 75% of individuals with liver PhK deficiency have mutations in the PHKA2 gene; this condition is also known as X-linked glycogenosis (XLG). Here we report the variability in clinical severity and laboratory findings in 12 male patients from 10 different families with X-linked liver PhK deficiency caused by mutations in PHKA2. We found that there is variability in the severity of clinical features, including hypoglycemia and growth. We also report additional PHKA2 variants that were identified in 24 patients suspected to have liver PhK deficiency. The basis of the clinical variation in GSDIX due to X-linked PHKA2 gene mutations is currently not well understood. Creating systematic registries, and collecting longitudinal data may help in better understanding of this rare, but common, glycogen storage disorder.
Synopsis: Liver phosphorylase b kinase (PhK) deficiency caused due to mutations in X-linked PHKA2 is highly variable.
“Deeksha S. Bali” and “Jennifer L. Goldstein” contributed equally.
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Acknowledgments
We would like to thank the patients and families who participated in this research study and the healthcare providers who helped in providing clinical information and samples including Dr. Mary-Alice Abbott; Dr. Avihu Boneh; Dr. Dwight Koeberl, MD, PhD; Dr. Nicola Longo; Dr. William Rhead; Dr. Jesus Rodriguez; Dr. Charles Stanley; Jan Sullivan, RN, MS; Rena Vanzo, MS; and Amy White, MS. We are grateful to the Association for Glycogen Storage Diseases, USA, and the YT and Alice Chen Pediatric Genetics and Genomics Center at Duke for funding this research.
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Communicated by: Francois Feillet, MD, PhD
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Supplementary Table 1
PHKA2 variants predicted to be pathogenic and likely pathogenic, based on the American College of Medical Genetics and Genomics criteria, identified in our study cohort (Patients 1–12) and from analysis of a further 24 families (DOCX 18 kb)
Supplementary Table 2
PHKA2 variants of unknown clinical significance (VOUS), based on the American College of Medical Genetics Criteria, identified in our study cohort (Patients 1–12) and from analysis of a further 24 families (DOCX 16 kb)
Supplementary Table 3
PHKA2 variants predicted to be likely benign or benign, based on the American College of Medical Genetics Criteria, identified in our study cohort (Patients 1–12) and from analysis of a further 24 families (DOCX 16 kb)
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Bali, D.S. et al. (2017). Clinical and Molecular Variability in Patients with PHKA2 Variants and Liver Phosphorylase b Kinase Deficiency. In: Morava, E., Baumgartner, M., Patterson, M., Rahman, S., Zschocke, J., Peters, V. (eds) JIMD Reports, Volume 37. JIMD Reports, vol 37. Springer, Berlin, Heidelberg. https://doi.org/10.1007/8904_2017_8
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DOI: https://doi.org/10.1007/8904_2017_8
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