Author + information
- Amir Toib, MD* (, )
- Dorothy K. Grange, MD,
- Beth A. Kozel, MD, PhD,
- Gregory A. Ewald, MD,
- Frances V. White, MD and
- Charles E. Canter, MD
- ↵*Department of Pediatrics, Campus Box 8116-NWT, One Children's Place, St. Louis, Missouri 63110
To the Editor:
Male patients with Danon disease usually present in adolescence with left ventricular hypertrophy (LVH) and a Wolff-Parkinson-White (WPW) pre-excitation pattern on electrocardiogram (ECG). The typical course involves deterioration to severe ventricular dysfunction with end-stage heart failure or sudden cardiac death. Histopathology of cardiac and skeletal muscle tissue displays vacuolar myopathy and lysosomal glycogen accumulation (1–3).
Characterization of the disease in female patients has been thus far limited. We present 3 families in which an initial diagnosis of Danon disease in a male proband revealed affected female family members who previously presented with a cardiomyopathy as having a dilated cardiomyopathy (DCM) phenotype. Some female members had been previously diagnosed with peri-partum cardiomyopathy (PPCM). The use of ECG frequently did not demonstrate pre-excitation, and heterogeneous histopathological findings were observed in the cardiac explant in those female patients who had undergone heart transplantation.
The clinical data of 3 families with Danon disease were analyzed. Patients were evaluated by history, physical examination, ECG, echocardiography, lysosomal-associated membrane protein 2 (LAMP-2) genetic analysis, and histopathological analysis. In this study a DCM phenotype was defined as an echocardiographically derived left ventricular ejection fraction (LVEF) <45% with normal LV wall thicknesses and an echocardiographic left ventricular end-diastolic dimension (LVEDD) ≥2 SDs above the normal mean for body surface area in patients <18 years of age (5) and >56 mm for patients >18 years of age (6). We defined LVH as an echocardiographically derived LV posterior and/or septal wall thickness >2 SDs above the normal mean for body surface area in patients <18 years of age (5) or >15 mm in patients >18 years of age (4), associated with a nondilated chamber.
Probands 1, 2, and 3 (Figs. 1Ato 1C, P1, P2, P3, respectively) presented at ages 15 years, 17 years, and 20 months with a WPW pattern on their ECGs and LVH (LV diastolic posterior wall thicknesses of 18, 15, and 14 mm, respectively, on echocardiogram. These wall thicknesses were all >4 SDs above the normal mean for body surface area). Cardiac biopsy revealed myocyte hypertrophy with extensive cytoplasmic vacuolization (a representative histology of proband 1 is shown in Fig. 1D). The use of LAMP-2gene sequencing revealed 2 distinct, previously reported, mutations in probands 1 and 2. A nucleotide G293A transition in exon 3 of the LAMP-2gene was identified in proband 3. The later is a novel mutation that has not been previously reported but is predicted to be pathogenic.
Male patients 4 and 5 (Fig. 1B II-6 and 1C III-5, respectively) are maternal uncles of probands 2 and 3, who died suddenly at 17 and 20 years of age, respectively. The presumed cause of their death per autopsy (no further information available) was hypertrophic cardiomyopathy (HCM).
Mothers of probands 1 and 2 (Fig. 1A II-2 and 1B II-3, respectively) presented in early adulthood (ages 24 and 34 years, respectively) with heart failure. Proband 1's mother developed heart failure at the end of her first pregnancy. She was diagnosed with presumed PPCM (LV enlargement with severely decreased systolic function, estimated EF 20% to 25%). Her clinical status improved shortly after delivery but worsened in a subsequent pregnancy, progressing to severe heart failure and ultimately leading to heart transplantation. The mother of proband 2 was diagnosed with DCM (LVEDD of 66 mm, EF <25%). She deteriorated rapidly, requiring heart transplantation at 19 months after presentation. Neither ECG demonstrated a WPW pattern. Histopathology of both explants showed marked myocyte hypertrophy and extensive interstitial fibrosis. Cytoplasmic vacuolization was present but was heterogeneous in distribution (a representative histology of proband 1's mother is shown in Fig. 1E). LAMP-2gene sequencing of proband 1's mother revealed a LAMP-2mutation identical to her son's mutation.
The mother of proband 3 (Fig. 1C, III-3) was diagnosed with presumed HCM at age 14 years (diastolic interventricular septal wall thickness of 15 mm, >9 SDs above the normal mean for body surface area) when a screening echocardiogram was performed because of sudden cardiac death in her maternal half-brother. She has been treated with propanolol for occasional palpitations but has demonstrated neither heart failure nor a WPW pattern on her ECG.
Proband 3's maternal grandmother (Fig. 1C, II-2) died suddenly during pregnancy at the age of 28 and was diagnosed as PPCM (no further information available). Proband 1's half sister (Fig. 1A, III-1) presented with a DCM phenotype (borderline LVEDD of 54 mm, LVEF of 42%), on a screening echocardiogram at the age of 20. An ECG did not demonstrate a WPW pattern. She developed rapidly progressive heart failure requiring heart transplantation at 13 months after her initial diagnosis. Explant histopathology was similar to that of her mother. LAMP-2gene sequencing revealed the same LAMP-2mutation that her mother and brother carry. Testing of her maternal grandmother (Fig. 1A, I-1) was negative, signifying a de novo mutation in her mother.
Proband 2's maternal aunt (Fig. 1B, II-7) was diagnosed with WPW and underwent ablation. She has no other known cardiac abnormalities. Proband 2's maternal grandmother (Fig. 1B, I-1) died of a cardiac cause (further history is unavailable) at the age of 65 years.
We describe 3 families demonstrating heterogeneous clinical phenotypes in female members with LAMP-2mutations. This heterogeneity may be attributed to a variable genotype-phenotype relationship of different mutations. The phenotypic difference between male and female subjects with Danon cardiomyopathy is presumably the gene dosage difference (2,3). Severe female cases can be attributed to X chromosome inactivation of nonmutated chromosome (unfavorable lyonization), leaving only mutated LAMP-2protein (1). Random variable X inactivation may account for the differences in phenotypic severity between female members in the same family. A possible caveat is that other untested genetic influences could also have affected the phenotypic expression of the LAMP-2mutations. The potential for de novo mutations in the LAMP-2gene, as demonstrated in proband 1's family, indicates that Danon cardiomyopathy should be considered even in the absence of a positive family history.
The histopathology of the heart explants of all female family members in this study was characterized by extensive fibrosis, with prominent myocyte vacuolization in the areas of fibrosis. This “end-stage” pathology overlaps and may mask the characteristic vacuolar changes of Danon disease. These findings may be similar to HCM patients who develop a “burned-out” pathology (7,8).
Peri-partum cardiomyopathy is defined as the development of congestive heart failure with a DCM phenotype of unidentified cause, leading to a decreased LVEF (<45%) in the last month of pregnancy or within 5 months after delivery (9). Two female members in these families demonstrate a situation in which Danon cardiomyopathy presented for the first time in the peri-partum period. Thus, these results suggest that some cases of PPCM may be LAMP-2mutations presenting with a DCM phenotype, either as a coincidence or as the result of the physiologic alterations of pregnancy, triggering the clinical expression of the cardiomyopathy. The absence of pre-excitation in 6 of the 7 female subjects in our study suggests that ECG would not be a reliable screening tool for the presence of Danon cardiomyopathy. These cases emphasize the importance of a detailed family history in the evaluation of young woman presenting with a DCM phenotype in the peri-partum period and consideration of testing for LAMP-2mutations in this patient population.
Please note: Dr. Grange was a consultant to BioMarin Pharmaceutical Inc. Dr. Grange also received research funding for a PKU project from the same company.
- American College of Cardiology Foundation