1. PHKA2 variants expand the phenotype of phosphorylase B kinase deficiency to include patients with ketotic hypoglycemia only
- Author
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Anja Lisbeth Frederiksen, Diva D. De León, Matthew Lines, Henrik Thybo Christesen, Anne Benner, Yazeid Alhaidan, Klaus Brusgaard, and Rebecca Sparkes
- Subjects
0301 basic medicine ,Male ,Propionic Acidemia ,next‐generation sequencing ,030105 genetics & heredity ,ketotic hypoglycemia ,Missense mutation ,Glycogen storage disease ,whole-exome sequencing ,Idiopathic Ketotic Hypoglycemia ,Child ,Genetics (clinical) ,Exome sequencing ,High-Throughput Nucleotide Sequencing ,Pedigree ,Phenotype ,Child, Preschool ,Female ,Original Article ,whole‐exome sequencing ,medicine.symptom ,Hepatomegaly ,Adult ,medicine.medical_specialty ,Adolescent ,Phosphorylase Kinase ,Mutation, Missense ,inborn errors of metabolism ,Short stature ,Asymptomatic ,Diagnosis, Differential ,03 medical and health sciences ,Young Adult ,glycogen storage disease ,Internal medicine ,Exome Sequencing ,Genetics ,medicine ,Humans ,business.industry ,Original Articles ,medicine.disease ,Ketotic hypoglycemia ,Hypoglycemia ,030104 developmental biology ,Endocrinology ,next-generation sequencing ,business ,Asymptomatic carrier - Abstract
Idiopathic ketotic hypoglycemia (IKH) is a diagnosis of exclusion with glycogen storage diseases (GSDs) as a differential diagnosis. GSD IXa presents with ketotic hypoglycemia (KH), hepatomegaly, and growth retardation due to PHKA2 variants. In our multicenter study, 12 children from eight families were diagnosed or suspected of IKH. Whole‐exome sequencing or targeted next‐generation sequencing panels were performed. We identified two known and three novel (likely) pathogenic PHKA2 variants, such as p.(Pro869Arg), p.(Pro498Leu), p.(Arg2Gly), p.(Arg860Trp), and p.(Val135Leu), respectively. Erythrocyte phosphorylase kinase activity in three patients with the novel variants p.(Arg2Gly) and p.(Arg860Trp) were 15%–20% of mean normal. One patient had short stature and intermittent mildly elevated aspartate aminotransferase, but no hepatomegaly. Family testing identified two asymptomatic children and 18 adult family members with one of the PHKA2 variants, of which 10 had KH symptoms in childhood and 8 had mild symptoms in adulthood. Our study expands the classical GSD IXa phenotype of PHKA2 missense variants to a continuum from seemingly asymptomatic carriers, over KH‐only with phosphorylase B kinase deficiency, to more or less complete classical GSD IXa. In contrast to typical IKH, which is confined to young children, KH may persist into adulthood in the KH‐only phenotype of PHKA2.
- Published
- 2021
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