A 16-year-old boy with a history of intellectual disability and pathological myopia presented with worsening shortness of breath and swelling of feet of 2 months duration. On examination, he had a regular heart rate of 66 beats per minute, blood pressure of 90/60 mm Hg, jugular venous distension, S3 gallop, and bibasilar rales. Neurological examination revealed symmetric proximal myopathy. A 12-lead ECG obtained at admission is shown in Figure 1. An echocardiogram showed concentric left ventricular hypertrophy (LVH) and severe impairment of the left ventricular ejection fraction (30%). He had elevated natriuretic peptide levels and raised transaminases and required intravenous diuretics for initial heart failure stabilization.

Figure 1. Twelve-lead ECG obtained at emission.

What is the interpretation of the ECG and what is the underlying pathology in our patient?

Please turn the page to read the diagnosis.

The ECG (Figure 1) shows normal sinus rhythm with a heart rate of 68 beats per minute. Manifest preexcitation is noticeable with a short PR interval and initial slurring of the QRS upstroke (delta wave). Also noticeable is the presence of left atrial enlargement as seen in the deep and splayed latter half of the p wave in V₁. Last, the wide and fragmented QRS is also remarkable. It is difficult to comment on LVH on an ECG with manifest preexcitation. The presence of preexcitation in a background of LVH may be seen in Danon disease, PRKAG2 mutation cardiomyopathy, Fabry disease, Pompe disease, and mitochondrial disorders. Cardiac magnetic resonance and genetic testing are required to identify the correct diagnosis.

In view of the constellation of neuromuscular and cardiac features, a provisional diagnosis of Danon disease was made. Cardiac magnetic resonance revealed massive LVH along with diffuse late gadolinium enhancement (Figure 2). Laboratory parameters revealed elevated muscle creatine phosphokinase levels and spontaneous fibrillatory activity on electromyography, after which the patient underwent a muscle biopsy that was suggestive of a vacuolar myopathy. Subsequent genetic analysis confirmed the diagnosis of Danon disease, with a pathogenic mutation in exon 5 of LAMP2 (lysosome-associated membrane protein 2) gene (c.733C>T; p.Gln245Ter). He was treated aggressively with anti–heart failure measures and discharged from the hospital, but subsequently died 1 month later due to Covid-19–related complications while awaiting heart transplantation.

Figure 2. Demonstration of massive left ventricular hypertrophy along with diffuse late gadolinium enhancement. Apical 2-chamber echocardiogram: massive left ventricular hypertrophy (left). Extensive late gadolinium enhancement on magnetic resonance image (MRI; right).

The presence of preexcitation on a background of LVH points to a diagnosis of hypertrophic cardiomyopathy phenocopy (storage or metabolic diseases) like Danon disease, PRKAG2 mutation, Fabry disease, or mitochondrial disorders.¹ Danon disease is an X-linked disorder resulting from mutations in the LAMP-2 gene leading to disruption of cellular autophagy process. Affected patients clinically manifest a characteristic triad of cardiomyopathy, skeletal myopathy, and intellectual disability. Males have an earlier onset of symptoms (average age at onset, 12 years), more severe presentation along with death at a younger age (average, 19 years). The majority of patients have a cardiomyopathy phenotype mimicking hypertrophic cardiomyopathy. The clinical course from hypertrophic cardiomyopathy phenotype with preserved ejection fraction to end-stage heart failure can be very rapid (a few months), and sudden deaths due to fatal ventricular arrhythmias are also described.² Cardiac conduction disorders and atrial and ventricular arrhythmias are common in Danon disease. In particular, preexcitation and Wolff-Parkinson-White syndrome occur in up to 70% cases. Such patients with LVH and preexcitation may have multiple and high-risk accessory pathways and thus not a benign entity, unlike isolated Wolff-Parkinson-White syndrome.³

Thus, careful interpretation of ECG may provide important clues to the underlying cause of heart failure. In this case, the presence of preexcitation pointed to an underlying storage or metabolic disorder; however, further differentiation between these clues on the 12-lead ECG is difficult. Some clues exist like QTc prolongation in Leber optic neuropathy and fasciculoventricular bypass tracts or typical atrial flutter in PRKAG2 mutation. Clinical correlation with associated noncardiac features and genetic testing is usually necessary.

The presence of preexcitation on ECG in a patient with left ventricular hypertrophy points to an underlying storage or metabolic disorder.

Danon disease is characterized by a triad of cardiomyopathy, skeletal myopathy, and intellectual disability.

The 12-lead ECG provides important clues to the underlying pathogenesis of heart failure.

None.

Disclosures None.

For Sources of Funding and Disclosures, see page 1616.

Circulation is available at www.ahajournals.org/journal/circ

一名16岁男孩，有智力障碍和病理性近视病史，出现呼吸急促和脚部肿胀加重2个月。检查时，患者心率正常，每分钟 66 次，血压 90/60 mm Hg，颈静脉怒张，S3 奔马律，双底罗音。神经系统检查发现对称性近端肌病。入院时获得的 12 导联心电图如图 1 所示。超声心动图显示左心室向心肥厚 (LVH) 和左心室射血分数严重受损 (30%)。他的利钠肽水平升高，转氨酶升高，需要静脉注射利尿剂来稳定最初的心力衰竭。

图 1. 发射时获得的十二导联心电图。
图 1. 发射时获得的十二导联心电图。

心电图的解释是什么以及我们患者的潜在病理是什么？

请翻页阅读诊断书。

心电图（图 1）显示正常窦性心律，心率为每分钟 68 次。明显的预激在短 PR 间期和 QRS 上冲（δ 波）初始模糊时很明显。同样值得注意的是左心房扩大的存在，如 V ₁中 p 波的深部和张开的后半部分所见。最后，宽且碎片化的 QRS 波也很引人注目。很难根据具有明显预激的心电图来评价 LVH。 LVH 背景中预激的存在可见于 Danon 病、PRKAG2 突变心肌病、法布里病、庞贝病和线粒体疾病。需要进行心脏磁共振和基因检测才能做出正确的诊断。

鉴于神经肌肉和心脏的一系列特征，初步诊断为达农病。心脏磁共振显示大量 LVH 以及弥漫性晚期钆增强（图 2）。实验室参数显示肌肉肌酸磷酸激酶水平升高，肌电图显示自发性颤动活动，之后患者接受了肌肉活检，提示患有空泡肌病。随后的基因分析证实了Danon病的诊断，LAMP2（溶酶体相关膜蛋白2）基因的外显子5发生致病性突变（c.733C>T；p.Gln245Ter）。他接受了积极的抗心力衰竭治疗并出院，但1个月后在等待心脏移植期间因Covid-19相关并发症死亡。

图 2. 左心室大量肥大以及弥漫性晚期钆增强的表现。心尖二腔超声心动图：左心室大量肥厚（左）。磁共振图像上广泛的晚期钆增强（MRI；右）。
图 2. 左心室大量肥大以及弥漫性晚期钆增强的表现。心尖二腔超声心动图：左心室大量肥厚（左）。磁共振图像上广泛的晚期钆增强（MRI；右）。

LVH 背景上存在预激表明诊断为肥厚型心肌病表型（储存或代谢疾病），如 Danon 病、PRKAG2 突变、法布里病或线粒体疾病。¹ Danon 病是一种 X 连锁疾病，由 LAMP-2 基因突变导致细胞自噬过程破坏所致。受影响的患者在临床上表现出心肌病、骨骼肌病和智力障碍的特征性三联征。男性症状出现较早（平均发病年龄为 12 岁），症状较严重，死亡年龄较年轻（平均 19 岁）。大多数患者具有模仿肥厚型心肌病的心肌病表型。从射血分数保留的肥厚型心肌病表型到终末期心力衰竭的临床病程可能非常快（几个月），并且还描述了由于致命性室性心律失常导致的突然死亡。²心脏传导障碍以及房性和室性心律失常在 Danon 病中很常见。特别是预激和沃尔夫-帕金森-怀特综合征的发生率高达 70%。与孤立性沃尔夫-帕金森-怀特综合征不同，此类患有 LVH 和预激的患者可能有多个高风险的旁路，因此不是良性实体。³

因此，仔细解释心电图可能为心力衰竭的根本原因提供重要线索。在这种情况下，预激的存在表明存在潜在的储存或代谢紊乱；然而，在 12 导联心电图上进一步区分这些线索很困难。存在一些线索，例如 Leber 视神经病变和束室旁路中的 QTc 延长或 PRKAG2 突变中的典型心房扑动。与相关非心脏特征和基因检测的临床相关性通常是必要的。

左心室肥厚患者心电图出现预激表明存在潜在的储存或代谢紊乱。

Danon 病的特点是心肌病、骨骼肌病和智力障碍三联征。

12 导联心电图为心力衰竭的潜在发病机制提供了重要线索。

没有任何。

披露无。 披露 无。

有关资金来源和披露信息，请参阅第 1616 页。

流通量可在 www.ahajournals.org/journal/circ 上获取