Correspondence
Atypical Infantile‑onset Pompe Disease with Hypertrophic Cardiomyopathy Jun‑Jun Quan1, Ling‑Juan Liu1, Tie‑Wei Lyu1, Xu‑Pei Huang2, Jie Tian1 1
Department of Cardiology, Children’s Hospital of Chongqing Medical University, Ministry of Education Key Laboratory of Child Development and Disorders, China International Science and Technology Cooperation Base of Child Development and Critical Disorders, Chongqing Key Laboratory of Pediatrics, Chongqing 400014, China 2 Department of Biomedical Science, Charlie E. Schmidt College of Medicine, Florida Atlantic University, Boca Raton, Florida 33431, USA
To the Editor: Pompe disease, a rare autosomal recessive disorder due to alpha‑1,4‑glucosidase (GAA) activity deficiency caused by its gene mutation, can cause an excessive lysosomal glycogen storage in muscular tissues. Pompe disease has two major clinical forms: infantile‑onset and adult‑onset forms. Without treatment, most infantile‑onset patients die from respiratory and cardiac failure within the 1st year of life.[1,2] A small percentage of infantile‑onset patients, known as an atypical infantile form,[1] present abnormalities in the 1st year and reveal a slower progression with less severe or an absence of cardiomyopathy. For this form, it is not easy to make a differential diagnosis with idiopathic hypertrophic cardiomyopathy. Here, we report a case of atypical infantile‑onset Pompe disease from a Chinese family based on genetic and enzyme activity analyses. A 5‑month‑old girl was admitted to hospital with oliguria for 10 days. Family history did not reveal any consanguinity. No family history of hypertrophic cardiomyopathy or sudden death was presented. Laboratory studies showed alanine aminotransferase (ALT) level of 121.2 U/L, aspartate aminotransferase (AST) level of 180.3 U/L, and lactate dehydrogenase (LDH) level of 630.8 U/L. Echocardiogram revealed hypertrophic cardiomyopathy with left ventricular posterior wall (LVPW) thickness of 9 mm and interventricular septum (IVS) thickness of 9 mm. A diagnosis of hypertrophic cardiomyopathy was made at that time, and the patient was given diuretic and supportive treatments. After 7 days, the patient’s situation was improved and she was discharged from the hospital. One year later, the patient was admitted again to the hospital with gross motor delay. Neurological examination revealed weak limb muscles with Medical Research Council score of 4/5. Laboratory tests demonstrated ALT level of 190.0 U/L, AST level of 319.3 U/L, LDH level of 576.1 U/L, creatine kinase level of 980.0 U/L, and brain natriuretic peptide level of 291.26 pg/ ml. Echocardiogram revealed left ventricular dilation (diameter of 27 mm in systole and 36 mm in diastole), LVPW thickness of 9 mm and IVS thickness of 12 mm [Figure 1a]. Reduced systolic and diastolic functions with an ejection fraction of Access this article online Quick Response Code:
Website: www.cmj.org
DOI: 10.4103/0366-6999.215340
Chinese Medical Journal ¦ October 5, 2017 ¦ Volume 130 ¦ Issue 19
51% and delayed isovolumetric relaxation time (IVRT) of 102 ms were determined, respectively. Cardiac magnetic resonance imaging confirmed a significant increase of the left ventricular wall thickness and IVS thickness. Abdominal ultrasonography detected that medium hepatomegaly with the liver edge below the right rib of 3.7 cm. Electromyogram of the quadriceps femoris muscles was normal. Based on the clinical observations, the patient and her families were recommended to take genetic tests to find out the cause of the disorder. The results of next generation sequencing revealed a homozygous mutation at c.2015G>A (p. R672Q) in exon 14 of GAA gene [Figure 1b], which causes an abnormal splicing and an amino acid change from arginine to glutamine. All of the proband’s parents and grandfathers carried this mutation. The subsequent blood GAA enzyme activity was 1.51 μmol·L−1·h−1 at pH 3.8, significantly lower compared to the normal range. The diagnosis of Pompe disease was finally established based on genetic and biochemical analyses. It was first reported in 1998 that the mutation was associated with the reduced GAA activities,[3] however, it has never been reported in the mainland of China. A child from two heterozygous parents has a 25% probability to become homozygous. In this case, the clinical manifestations, laboratory analysis, imaging findings, genetic tests, and enzyme activity detections are consistent with atypical infantile‑onset Pompe disease. At the early stage of the disorder, it is difficult to distinguish cardiomegaly due to Pompe disease from idiopathic hypertrophic cardiomyopathy without GAA enzyme activity tests or genetic analysis. In pediatric patients, in the setting of undetermined left ventricular hypertrophy or cardiac dysfunction, Pompe disease should be taken into consideration in the diagnostic algorithm and the determination of the etiology.[4] Furthermore, early GAA genetic Address for correspondence: Prof. Jie Tian, Department of Cardiology, Children’s Hospital of Chongqing Medical University, No. 136 Zhongshan Er Road, Yuzhong District, Chongqing 400014, China E‑Mail: [email protected] This is an open access article distributed under the terms of the Creative Commons Attribution‑NonCommercial‑ShareAlike 3.0 License, which allows others to remix, tweak, and build upon the work non‑commercially, as long as the author is credited and the new creations are licensed under the identical terms. © 2017 Chinese Medical Journal ¦ Produced by Wolters Kluwer ‑ Medknow
Received: 26‑06‑2017 Edited by: Peng Lyu How to cite this article: Quan JJ, Liu LJ, Lyu TW, Huang XP, Tian J. Atypical Infantile-onset Pompe Disease with Hypertrophic Cardiomyopathy. Chin Med J 2017;130:2393-4. 2393
a
b
Figure 1: Echocardiogram observation and pedigree analysis of the Pompe disease case. (a) Echocardiogram demonstrated increased thicknesses of the left ventricular posterior wall and interventricular septum (white arrows). (b) Pedigree analysis revealed the patient carrying a homozygous mutation at c.2015G>A (p.R672Q) in GAA gene inherited from her parents. LA: Left atrium; RA: Right atrium; LV: Left ventricle; RV: Right ventricle; GAA: Alpha‑1,4‑glucosidase. tests and enzyme biochemical analysis are important for the diagnosis of the disease and genetic advising for patients and their families.
Declaration of patient consent
The authors certify that they have obtained all appropriate patient consent forms. In the form, the patient/patient’s guardians have given consent for their images and other clinical information to be reported in the journal. The patient/patient’s guardians understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.
Financial support and sponsorship Nil.
Conflicts of interest
There are no conflicts of interest.
2394
References 1. Bhengu L, Davidson A, du Toit P, Els C, Gerntholtz T, Govendrageloo K, et al. Diagnosis and management of Pompe disease. S Afr Med J 2014;104:273‑4. doi: 10.7196/SAMJ.7386. 2. Tarnopolsky M, Katzberg H, Petrof BJ, Sirrs S, Sarnat HB, Myers K, et al. Pompe disease: Diagnosis and management. Evidence‑Based Guidelines from a Canadian Expert Panel. Can J Neurol Sci 2016;43:472‑85. doi: 10.1017/cjn.2016.37. 3. Colan SD, Lipshultz SE, Lowe AM, Sleeper LA, Messere J, Cox GF, et al. Epidemiology and cause‑specific outcome of hypertrophic cardiomyopathy in children: Findings from the pediatric cardiomyopathy registry. Circulation 2007;115:773‑81. doi: 10.1161/ CIRCULATIONAHA.106.621185. 4. Huie ML, Tsujino S, Sklower Brooks S, Engel A, Elias E, Bonthron DT, et al. Glycogen storage disease type II: Identification of four novel missense mutations (D645N, G648S, R672W, R672Q) and two insertions/deletions in the acid alpha‑glucosidase locus of patients of differing phenotype. Biochem Biophys Res Commun 1998;244:921‑7. doi: 10.1006/bbrc.1998.8255.
Chinese Medical Journal ¦ October 5, 2017 ¦ Volume 130 ¦ Issue 19
Atypical Infantile‑onset Pompe Disease with Hypertrophic Cardiomyopathy Jun‑Jun Quan1, Ling‑Juan Liu1, Tie‑Wei Lyu1, Xu‑Pei Huang2, Jie Tian1 1
Department of Cardiology, Children’s Hospital of Chongqing Medical University, Ministry of Education Key Laboratory of Child Development and Disorders, China International Science and Technology Cooperation Base of Child Development and Critical Disorders, Chongqing Key Laboratory of Pediatrics, Chongqing 400014, China 2 Department of Biomedical Science, Charlie E. Schmidt College of Medicine, Florida Atlantic University, Boca Raton, Florida 33431, USA
To the Editor: Pompe disease, a rare autosomal recessive disorder due to alpha‑1,4‑glucosidase (GAA) activity deficiency caused by its gene mutation, can cause an excessive lysosomal glycogen storage in muscular tissues. Pompe disease has two major clinical forms: infantile‑onset and adult‑onset forms. Without treatment, most infantile‑onset patients die from respiratory and cardiac failure within the 1st year of life.[1,2] A small percentage of infantile‑onset patients, known as an atypical infantile form,[1] present abnormalities in the 1st year and reveal a slower progression with less severe or an absence of cardiomyopathy. For this form, it is not easy to make a differential diagnosis with idiopathic hypertrophic cardiomyopathy. Here, we report a case of atypical infantile‑onset Pompe disease from a Chinese family based on genetic and enzyme activity analyses. A 5‑month‑old girl was admitted to hospital with oliguria for 10 days. Family history did not reveal any consanguinity. No family history of hypertrophic cardiomyopathy or sudden death was presented. Laboratory studies showed alanine aminotransferase (ALT) level of 121.2 U/L, aspartate aminotransferase (AST) level of 180.3 U/L, and lactate dehydrogenase (LDH) level of 630.8 U/L. Echocardiogram revealed hypertrophic cardiomyopathy with left ventricular posterior wall (LVPW) thickness of 9 mm and interventricular septum (IVS) thickness of 9 mm. A diagnosis of hypertrophic cardiomyopathy was made at that time, and the patient was given diuretic and supportive treatments. After 7 days, the patient’s situation was improved and she was discharged from the hospital. One year later, the patient was admitted again to the hospital with gross motor delay. Neurological examination revealed weak limb muscles with Medical Research Council score of 4/5. Laboratory tests demonstrated ALT level of 190.0 U/L, AST level of 319.3 U/L, LDH level of 576.1 U/L, creatine kinase level of 980.0 U/L, and brain natriuretic peptide level of 291.26 pg/ ml. Echocardiogram revealed left ventricular dilation (diameter of 27 mm in systole and 36 mm in diastole), LVPW thickness of 9 mm and IVS thickness of 12 mm [Figure 1a]. Reduced systolic and diastolic functions with an ejection fraction of Access this article online Quick Response Code:
Website: www.cmj.org
DOI: 10.4103/0366-6999.215340
Chinese Medical Journal ¦ October 5, 2017 ¦ Volume 130 ¦ Issue 19
51% and delayed isovolumetric relaxation time (IVRT) of 102 ms were determined, respectively. Cardiac magnetic resonance imaging confirmed a significant increase of the left ventricular wall thickness and IVS thickness. Abdominal ultrasonography detected that medium hepatomegaly with the liver edge below the right rib of 3.7 cm. Electromyogram of the quadriceps femoris muscles was normal. Based on the clinical observations, the patient and her families were recommended to take genetic tests to find out the cause of the disorder. The results of next generation sequencing revealed a homozygous mutation at c.2015G>A (p. R672Q) in exon 14 of GAA gene [Figure 1b], which causes an abnormal splicing and an amino acid change from arginine to glutamine. All of the proband’s parents and grandfathers carried this mutation. The subsequent blood GAA enzyme activity was 1.51 μmol·L−1·h−1 at pH 3.8, significantly lower compared to the normal range. The diagnosis of Pompe disease was finally established based on genetic and biochemical analyses. It was first reported in 1998 that the mutation was associated with the reduced GAA activities,[3] however, it has never been reported in the mainland of China. A child from two heterozygous parents has a 25% probability to become homozygous. In this case, the clinical manifestations, laboratory analysis, imaging findings, genetic tests, and enzyme activity detections are consistent with atypical infantile‑onset Pompe disease. At the early stage of the disorder, it is difficult to distinguish cardiomegaly due to Pompe disease from idiopathic hypertrophic cardiomyopathy without GAA enzyme activity tests or genetic analysis. In pediatric patients, in the setting of undetermined left ventricular hypertrophy or cardiac dysfunction, Pompe disease should be taken into consideration in the diagnostic algorithm and the determination of the etiology.[4] Furthermore, early GAA genetic Address for correspondence: Prof. Jie Tian, Department of Cardiology, Children’s Hospital of Chongqing Medical University, No. 136 Zhongshan Er Road, Yuzhong District, Chongqing 400014, China E‑Mail: [email protected] This is an open access article distributed under the terms of the Creative Commons Attribution‑NonCommercial‑ShareAlike 3.0 License, which allows others to remix, tweak, and build upon the work non‑commercially, as long as the author is credited and the new creations are licensed under the identical terms. © 2017 Chinese Medical Journal ¦ Produced by Wolters Kluwer ‑ Medknow
Received: 26‑06‑2017 Edited by: Peng Lyu How to cite this article: Quan JJ, Liu LJ, Lyu TW, Huang XP, Tian J. Atypical Infantile-onset Pompe Disease with Hypertrophic Cardiomyopathy. Chin Med J 2017;130:2393-4. 2393
a
b
Figure 1: Echocardiogram observation and pedigree analysis of the Pompe disease case. (a) Echocardiogram demonstrated increased thicknesses of the left ventricular posterior wall and interventricular septum (white arrows). (b) Pedigree analysis revealed the patient carrying a homozygous mutation at c.2015G>A (p.R672Q) in GAA gene inherited from her parents. LA: Left atrium; RA: Right atrium; LV: Left ventricle; RV: Right ventricle; GAA: Alpha‑1,4‑glucosidase. tests and enzyme biochemical analysis are important for the diagnosis of the disease and genetic advising for patients and their families.
Declaration of patient consent
The authors certify that they have obtained all appropriate patient consent forms. In the form, the patient/patient’s guardians have given consent for their images and other clinical information to be reported in the journal. The patient/patient’s guardians understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.
Financial support and sponsorship Nil.
Conflicts of interest
There are no conflicts of interest.
2394
References 1. Bhengu L, Davidson A, du Toit P, Els C, Gerntholtz T, Govendrageloo K, et al. Diagnosis and management of Pompe disease. S Afr Med J 2014;104:273‑4. doi: 10.7196/SAMJ.7386. 2. Tarnopolsky M, Katzberg H, Petrof BJ, Sirrs S, Sarnat HB, Myers K, et al. Pompe disease: Diagnosis and management. Evidence‑Based Guidelines from a Canadian Expert Panel. Can J Neurol Sci 2016;43:472‑85. doi: 10.1017/cjn.2016.37. 3. Colan SD, Lipshultz SE, Lowe AM, Sleeper LA, Messere J, Cox GF, et al. Epidemiology and cause‑specific outcome of hypertrophic cardiomyopathy in children: Findings from the pediatric cardiomyopathy registry. Circulation 2007;115:773‑81. doi: 10.1161/ CIRCULATIONAHA.106.621185. 4. Huie ML, Tsujino S, Sklower Brooks S, Engel A, Elias E, Bonthron DT, et al. Glycogen storage disease type II: Identification of four novel missense mutations (D645N, G648S, R672W, R672Q) and two insertions/deletions in the acid alpha‑glucosidase locus of patients of differing phenotype. Biochem Biophys Res Commun 1998;244:921‑7. doi: 10.1006/bbrc.1998.8255.
Chinese Medical Journal ¦ October 5, 2017 ¦ Volume 130 ¦ Issue 19
