LAUSR

Unexplained cardiac hypertrophy is most commonly associated with hypertrophic cardiomyopathy, the number one monogenic cardiovascular disorder. Echocardiography-based epidemiological studies have shown a disease prevalence of 1 per 500 individuals, but a prevalence of 1 per 200 is estimated by clinical and genetic data including family members [1]. Hypertrophic cardiomyopathy is inherited in an autosomal dominant pattern, associated with mutations in the contractile components of the sarcomere or Z disk. A small subset with unexplained hypertrophy, however, have mutations in genes not related to the sarcomere. One of these is PRKAG2, which encodes the gamma2 subunit of the adenosine monophosphate activated protein kinase (AMPK) [2]. In contrast to hypertrophic cardiomyopathy, which is not characteristically a progressive disorder, PRKAG2 cardiomyopathy patients manifest progressive symptoms around the second decade of life. It is crucial to correctly differentiate those disorders because their management and prognosis are diverse. In this issue of EBioMedicine Dan Hu and colleagues report on the identification, clinical manifestation and structural mechanisms of mutations in AMPK associated cardiac glycogen storage disease. They investigated 885 patients with unexplained hypertrophy and found 25 carriers (2.8%) from 12 independent families harboring 5 different variants of PRKAG2 gene mutations. The reported incidence could be twice as high (»5%), if the 22 family members who died from cardiac disease had been included in the study population [3]. A growing body of evidence suggests that AMPK plays a role in normal renal physiology and pathogenesis of hypertension and kidney disease [4]. Hypertension has been systematically reported in patients with PRKAG2 mutations [5]. Hu et al. reported acute glomerulonephritis in one PRKAG2 mutation carrier who evolved to endstage kidney disease at 26 years of age. Giudici et al. reported a 36-