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Familial hypertrophic obstructive cardiomyopathy with the GLA E66Q mutation and zebra body.

Oikawa M, Sakamoto N, Kobayashi A, Suzuki S, Yoshihisa A, Yamaki T, Nakazato K, Suzuki H, Saitoh S, Kiko Y, Nakano H, Hayashi T, Kimura A, Takeishi Y - BMC Cardiovasc Disord (2016)

Bottom Line: Although the enzymatic activity of GLA was within normal range, the c. 196G>C nucleotide change, which lead to the E66Q mutation of GLA gene, was detected.However, immunostaining showed few deposition of globotriaosylceramide in left ventricular myocardium, and gene mutations in the disease genes for hypertrophic cardiomyopathy (HCM), MYBPC3 and MYH6, were detected.Although the pathogenicity of the E66Q mutation cannot be ruled out, hypertrophic obstructive cardiomyopathy (HOCM) was more reasonable to explain the pathophysiology in the case.

View Article: PubMed Central - PubMed

Affiliation: Department of Cardiology and Hematology, Fukushima Medical University, 1 Hikarigaoka, Fukushima, 960-1295, Japan. moikawa@fmu.ac.jp.

ABSTRACT

Background: Fabry disease is caused by mutations in the α-galactosidase A (GLA) gene, which is located in X-chromosome coding for the lysosomal enzyme of GLA. Among many gene mutations, E66Q mutation is under discussion for its pathogenicity because there is no clinical report showing pathological evidence of Fabry disease with E66Q mutation.

Case presentation: A 65-year-old Japanese female was referred to our hospital for chest discomfort on effort. Transthoracic echocardiography showed severe left ventricular (LV) hypertrophy with LV outflow obstruction. Maximum LV outflow pressure gradient was 87 mmHg, and Valsalva maneuver increased the pressure gradient up to 98 mmHg. According to medical interview, one of her younger sister and a nephew died suddenly at age 42 and 36, respectively. Another younger sister also presented LV hypertrophy with outflow obstruction. Maximum LV outflow pressure gradient was 100 mmHg, and the E66Q mutation was detected similar to the case. Endomyocardial biopsy specimens presented vacuolation of cardiomyocytes, in which zebra bodies were detected by electron microscopic examination. Although the enzymatic activity of GLA was within normal range, the c. 196G>C nucleotide change, which lead to the E66Q mutation of GLA gene, was detected. We initially diagnosed her as cardiac Fabry disease based on the findings of zebra body. However, immunostaining showed few deposition of globotriaosylceramide in left ventricular myocardium, and gene mutations in the disease genes for hypertrophic cardiomyopathy (HCM), MYBPC3 and MYH6, were detected. Although the pathogenicity of the E66Q mutation cannot be ruled out, hypertrophic obstructive cardiomyopathy (HOCM) was more reasonable to explain the pathophysiology in the case.

Conclusions: This is the confusable case of HOCM with Fabry disease with the GLA E66Q mutation. We have to take into consideration the possibility that some patients with the E66Q mutation may have similar histological findings of Fabry disease, and should be examed the possibility for harboring gene mutations associated with HCM.

No MeSH data available.


Related in: MedlinePlus

Immunostaining of myocardium against Gb3. a Immunostaining of myocardium in typical Fabry disease’s case. Brown staining indicates Gb3 accumulation. Bar, 50 μm. b Immunostaining of myocardium in the present case. Bar, 50 μm
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Fig4: Immunostaining of myocardium against Gb3. a Immunostaining of myocardium in typical Fabry disease’s case. Brown staining indicates Gb3 accumulation. Bar, 50 μm. b Immunostaining of myocardium in the present case. Bar, 50 μm

Mentions: A 65-year-old female was referred to our hospital with chest discomfort on effort. On auscultation, a grade III/VI systolic murmur at the 4th left intercostal space was detected. Her blood pressure was 122/66 mmHg. A chest X-ray showed cardiomegaly (cardiothoracic ratio; 0.55) without pulmonary congestion, and an electrocardiogram showed regular sinus rhythm, poor R wave progression in leads V1 to V4, an inverted T wave, and left ventricular (LV) high voltage (SV1 + RV5 = 6.52 mV). She presented no angiokeratoma on her skin, and had no history of acroparesthesia. A medical interview revealed that her father, one of her younger sisters, and a nephew died suddenly at age 58, 42, and 36, respectively (Fig. 1). Another younger sister also presented with LV hypertrophy with outflow obstruction. Transthoracic echocardiography showed diffuse LV hypertrophy with more than 20 mm wall thickness and hyper contraction with LV outflow obstruction. The maximum LV outflow pressure gradient was 87 mmHg, and Valsalva maneuver increased the pressure gradient up to 98 mmHg (Fig. 2a-c). Moderate mitral valve regurgitation was detected due to systolic anterior motion of the anterior mitral leaflet. Laboratory data displayed preserved renal function and no proteinuria. Cardiac catheterization revealed a systolic pressure gradient between mid LV and outflow tract by 82 mmHg, and biopsy specimens presented vacuolation of cardiomyocytes, which were stained by periodic acid-Schiff (PAS) stain (Fig. 3a and b). Zebra bodies were detected by electron microscopic examination in the cells with vacuolation (Fig. 3c and d). Zebra body is a specific finding of Fabry disease, but is also found in other lysosome diseases, such as Niemann-Pick disease, Landing’s disease, Sandhoff’s disease, and mucopolysaccharidosis. The patient had no clinical findings consistent with those diseases. Cationic amphiphilic drugs, including gentamycin, hydroxychloroquine, and amiodarone, are capable of inducing phospholipidosis, leading to deposition of zebra bodies in various cells [4–6], but she had not taken any of these drugs. Although the enzymatic activity of leukocyte GLA was within normal range (62 nmol/mg/h), we initially diagnosed the case with cardiac Fabry disease with the E66Q mutation based on the histological findings. But because the distribution and the density of zebra body were much less than typical cases of Fabry disease, we added the immunostaining against Gb3 in the specimen of LV myocardium. As compared to a case of typical Fabry disease (Fig. 4a), there was few deposition of Gb3, even in vacuolated cells (Fig. 4b). We also analyzed plasma levels of Gb3, but it was within normal range (2.8 μg/ml). In contrast, when we analyzed the case for mutations in the disease genes for HCM [7, 8], it was revealed that the patient carried heterozygous mutations of MYBPC3 (Gly1009Val) and MYH6 (Ser624del). Although both mutations were novel, they were not found in the public sequence databases including dbSNP [9], 1000 genomes [10], and Human Genetic Variation database [11]. In addition, the MYBPC3 mutation was predicted to be a disease-causing mutation by three different in silico studies; predicted to be disease-causing by Mutation Taster [12], probably damaging (score 1.000) by PolyPhen-2 [13], and damaging (score 0) by SIFT [14]. As for the MYH6 mutation, one amino acid at 624th position in the head domain was deleted, which might be deleterious for the function of α-myosin heavy chain. However, because MYH6 is mainly expressed in the atrial muscles and not in the ventricular muscles in human adult hearts, pathological role of the MYH6 mutation in cardiac hypertrophy in this case might be less significant than the MYBPC3 mutation. From these observations, HOCM was more reasonable to explain the pathophysiology in the case, although the disease modifying effect of the E66Q mutation cannot be ruled out.Fig. 1


Familial hypertrophic obstructive cardiomyopathy with the GLA E66Q mutation and zebra body.

Oikawa M, Sakamoto N, Kobayashi A, Suzuki S, Yoshihisa A, Yamaki T, Nakazato K, Suzuki H, Saitoh S, Kiko Y, Nakano H, Hayashi T, Kimura A, Takeishi Y - BMC Cardiovasc Disord (2016)

Immunostaining of myocardium against Gb3. a Immunostaining of myocardium in typical Fabry disease’s case. Brown staining indicates Gb3 accumulation. Bar, 50 μm. b Immunostaining of myocardium in the present case. Bar, 50 μm
© Copyright Policy - OpenAccess
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC4862085&req=5

Fig4: Immunostaining of myocardium against Gb3. a Immunostaining of myocardium in typical Fabry disease’s case. Brown staining indicates Gb3 accumulation. Bar, 50 μm. b Immunostaining of myocardium in the present case. Bar, 50 μm
Mentions: A 65-year-old female was referred to our hospital with chest discomfort on effort. On auscultation, a grade III/VI systolic murmur at the 4th left intercostal space was detected. Her blood pressure was 122/66 mmHg. A chest X-ray showed cardiomegaly (cardiothoracic ratio; 0.55) without pulmonary congestion, and an electrocardiogram showed regular sinus rhythm, poor R wave progression in leads V1 to V4, an inverted T wave, and left ventricular (LV) high voltage (SV1 + RV5 = 6.52 mV). She presented no angiokeratoma on her skin, and had no history of acroparesthesia. A medical interview revealed that her father, one of her younger sisters, and a nephew died suddenly at age 58, 42, and 36, respectively (Fig. 1). Another younger sister also presented with LV hypertrophy with outflow obstruction. Transthoracic echocardiography showed diffuse LV hypertrophy with more than 20 mm wall thickness and hyper contraction with LV outflow obstruction. The maximum LV outflow pressure gradient was 87 mmHg, and Valsalva maneuver increased the pressure gradient up to 98 mmHg (Fig. 2a-c). Moderate mitral valve regurgitation was detected due to systolic anterior motion of the anterior mitral leaflet. Laboratory data displayed preserved renal function and no proteinuria. Cardiac catheterization revealed a systolic pressure gradient between mid LV and outflow tract by 82 mmHg, and biopsy specimens presented vacuolation of cardiomyocytes, which were stained by periodic acid-Schiff (PAS) stain (Fig. 3a and b). Zebra bodies were detected by electron microscopic examination in the cells with vacuolation (Fig. 3c and d). Zebra body is a specific finding of Fabry disease, but is also found in other lysosome diseases, such as Niemann-Pick disease, Landing’s disease, Sandhoff’s disease, and mucopolysaccharidosis. The patient had no clinical findings consistent with those diseases. Cationic amphiphilic drugs, including gentamycin, hydroxychloroquine, and amiodarone, are capable of inducing phospholipidosis, leading to deposition of zebra bodies in various cells [4–6], but she had not taken any of these drugs. Although the enzymatic activity of leukocyte GLA was within normal range (62 nmol/mg/h), we initially diagnosed the case with cardiac Fabry disease with the E66Q mutation based on the histological findings. But because the distribution and the density of zebra body were much less than typical cases of Fabry disease, we added the immunostaining against Gb3 in the specimen of LV myocardium. As compared to a case of typical Fabry disease (Fig. 4a), there was few deposition of Gb3, even in vacuolated cells (Fig. 4b). We also analyzed plasma levels of Gb3, but it was within normal range (2.8 μg/ml). In contrast, when we analyzed the case for mutations in the disease genes for HCM [7, 8], it was revealed that the patient carried heterozygous mutations of MYBPC3 (Gly1009Val) and MYH6 (Ser624del). Although both mutations were novel, they were not found in the public sequence databases including dbSNP [9], 1000 genomes [10], and Human Genetic Variation database [11]. In addition, the MYBPC3 mutation was predicted to be a disease-causing mutation by three different in silico studies; predicted to be disease-causing by Mutation Taster [12], probably damaging (score 1.000) by PolyPhen-2 [13], and damaging (score 0) by SIFT [14]. As for the MYH6 mutation, one amino acid at 624th position in the head domain was deleted, which might be deleterious for the function of α-myosin heavy chain. However, because MYH6 is mainly expressed in the atrial muscles and not in the ventricular muscles in human adult hearts, pathological role of the MYH6 mutation in cardiac hypertrophy in this case might be less significant than the MYBPC3 mutation. From these observations, HOCM was more reasonable to explain the pathophysiology in the case, although the disease modifying effect of the E66Q mutation cannot be ruled out.Fig. 1

Bottom Line: Although the enzymatic activity of GLA was within normal range, the c. 196G>C nucleotide change, which lead to the E66Q mutation of GLA gene, was detected.However, immunostaining showed few deposition of globotriaosylceramide in left ventricular myocardium, and gene mutations in the disease genes for hypertrophic cardiomyopathy (HCM), MYBPC3 and MYH6, were detected.Although the pathogenicity of the E66Q mutation cannot be ruled out, hypertrophic obstructive cardiomyopathy (HOCM) was more reasonable to explain the pathophysiology in the case.

View Article: PubMed Central - PubMed

Affiliation: Department of Cardiology and Hematology, Fukushima Medical University, 1 Hikarigaoka, Fukushima, 960-1295, Japan. moikawa@fmu.ac.jp.

ABSTRACT

Background: Fabry disease is caused by mutations in the α-galactosidase A (GLA) gene, which is located in X-chromosome coding for the lysosomal enzyme of GLA. Among many gene mutations, E66Q mutation is under discussion for its pathogenicity because there is no clinical report showing pathological evidence of Fabry disease with E66Q mutation.

Case presentation: A 65-year-old Japanese female was referred to our hospital for chest discomfort on effort. Transthoracic echocardiography showed severe left ventricular (LV) hypertrophy with LV outflow obstruction. Maximum LV outflow pressure gradient was 87 mmHg, and Valsalva maneuver increased the pressure gradient up to 98 mmHg. According to medical interview, one of her younger sister and a nephew died suddenly at age 42 and 36, respectively. Another younger sister also presented LV hypertrophy with outflow obstruction. Maximum LV outflow pressure gradient was 100 mmHg, and the E66Q mutation was detected similar to the case. Endomyocardial biopsy specimens presented vacuolation of cardiomyocytes, in which zebra bodies were detected by electron microscopic examination. Although the enzymatic activity of GLA was within normal range, the c. 196G>C nucleotide change, which lead to the E66Q mutation of GLA gene, was detected. We initially diagnosed her as cardiac Fabry disease based on the findings of zebra body. However, immunostaining showed few deposition of globotriaosylceramide in left ventricular myocardium, and gene mutations in the disease genes for hypertrophic cardiomyopathy (HCM), MYBPC3 and MYH6, were detected. Although the pathogenicity of the E66Q mutation cannot be ruled out, hypertrophic obstructive cardiomyopathy (HOCM) was more reasonable to explain the pathophysiology in the case.

Conclusions: This is the confusable case of HOCM with Fabry disease with the GLA E66Q mutation. We have to take into consideration the possibility that some patients with the E66Q mutation may have similar histological findings of Fabry disease, and should be examed the possibility for harboring gene mutations associated with HCM.

No MeSH data available.


Related in: MedlinePlus