PRKAG2 syndrome is a progressive glycogen storage disease. It had been considered a part of HCM for several decades until 2001 when autosomal dominant inherited mutations in the PRKAG2 gene were first observed to be responsible for this syndrome [6]. PRKAG2 gene encodes the γ2 regulatory subunit of AMPK, enhancing glucose and lipids metabolism [9]. This rare disease is characterized by LVH, ventricular preexcitation, diverse arrhythmia, advanced heart failure, and sudden cardiac death. Almost 10% of PRKAG2 cases suffered from sudden death; more than 30% required pacemaker implantation [10]. Although PRKAG2 syndrome comprises less than one percent of unexplained LVH, the differential diagnosis is crucial because of its distinct natural history, poor prognosis, and active treatment strategies.

Echocardiography is a noninvasive, widely available, and first-line technique to identify and quantify LVH [11]. This study collected the parameters of conventional two-dimensional echocardiography, Doppler ultrasound, and 3D STE. We aimed to compare PRKA2G syndrome with healthy volunteers and sarcomeric HCM.

In literature, MWT of PRAKG2 syndrome is from 20 to 21 mm, which is similar to our measurements of 21.89 ± 6.45 mm [10, 12]. The RWT of PRKAG2 syndrome in this study was 0.48 ± 0.15, which reached the definition of concentric hypertrophy pattern (RWT > 0.42) [13]. These findings confirmed the concentric LVH pattern of PRKAG2 syndrome. However, we also observed asymmetric septal hypertrophy in our PRKAG2 patients (LVWa = 1.42 ± 0.52). This may reflect the diversity of PRKAG2 syndrome. Larger size studies are needed to find the exact ratio of hypertrophy patterns.

We evaluated LV diastolic function using parameters of Doppler echocardiography parameters (E, A, e’, E/e’). Most parameters indicated PRKAG2 LV diastolic dysfunction similar to sarcomeric HCM.

General HCM patients had worse GLS compared with healthy individuals [14]. Recently, STE has been reported to be a non-Doppler-oriented and angle-independent technique that helped detect different causes of LVH [15,16,17]. However, few articles focused on the STE parameters in PRKAG2 syndrome because of the low prevalence.

Interestingly, we observed preserved GLS and GCS in our PRKAG2 patients compared with healthy volunteers (GLS -18.92 ± 4.98 vs. -21.45 ± 3.73%, P = 0.083; GCS -29.27 ± 9.06 vs. -31.17 ± 6.93%, P = 0.481). However, in a recent study using STE, the GLS and GCS strains of PRKAG2 syndrome decreased as -13 ± 4.8% and -16.1 ± 4.4%, respectively [12]. Healthy controls were not involved in that study. Different echocardiographic systems, software, operators, and pathophysiological heterogeneity might contribute to the discrepancy. In our study, LVEF and EF from 3D STE also evidenced the uncompromised PRKAG2 LV systolic function.

To distinguish PRKAG2 syndrome from HCM, we combined HR and GLS for ROC curve analysis. For the best cut-off value (0.114), the sensitivity and the specificity were 69% and 100%, respectively. The progression of gene sequencing provides opportunities to identify patients with PRKAG2 syndrome from HCM patients. However, gene sequencing is limited by clinical availability and economic factors. Clinically, the suspicion is based on “red flags”, which traditionally include young age, unexplained LVH, bradycardia, ventricular preexcitation, and high-grade conduction disease [1]. LVH has been reported as the most common clinical phenotype of PRKAG2 syndrome [2]. Only one-third of PRKAG2 patients demonstrate preexcitation [10]. For PRKAG2 patients whose phenocopies mimic HCM, preserved GLS may also be used as “red flags”. The AUC for HR was 0.828 (95% CI, 0.646—1); the best cut-off value’s sensitivity and specificity (57 bpm) were 86.7% and 77.8%, respectively. When GLS was incorporated, the specificity increased to 100%, with the sensitivity decreasing to 69%. ECG examination has the potential for screening PRKAG2 syndrome. 3D STE can also be performed for more evidence of PRKAG2 syndrome.

Limitations

The studied population is a sample of PRKAG2 syndrome with LVH. However, some PRKAG2 patients do not present LVH. The 3D STE characteristics of those patients are not investigated in this study. Another limitation is that the number of PRKAG patients enrolled was small and all the patients were from the same hospital.

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