Glycogen storage disease type III (GSD-III) is an autosomal recessive inherited metabolic disorder caused by a deficiency in the glycogen debranching enzyme (amylo-1,6-glucosidase).1 The disease is characterized by hepatomegaly, fasting hypoglycemia, growth retardation, and progressive myopathy.1 It can also cause cardiomyopathy.1–5 We report a rare case of GSD-III with metabolic cardiomyopathy mimicking obstructive hypertrophic cardiomyopathy, a sarcomere-protein gene disorder.
A 20-year-old female with GSD has been followed up for 13 years in our hospital. The patient was admitted to our hospital for hepatosplenomegaly, hypoglycemia and growth retardation thirteen years ago, at her 7 years of age. Physical examination found hepatomegaly with the liver palpable 19 cm below costal margin and 14 cm below xyphoid and splenomegaly with spleen palpable 4 cm below costal margin. A grade 2 systolic murmur was heard at the apex. Epinephrine stimulating test demonstrated blood glucose of 4.2 mmol/L after injection of epinephrine while fasting blood glucose (FBG) was 2.8 mmol/L. Postprandial epinephrine stimulating test showed blood glucose of 6.9 mmol/L one hour after meal while blood glucose was 12.7 mmol/L after using epinephrine. GSD type III was diagnosed.
Laboratory findings showed alanine aminotransferase (ALT) 367 U/L, aspartate aminotransferase (AST) 334 U/L, total bilirubin (TBil) 59.9 μmol/L, direct bilirubin (DBil) 35.9 μmol/L, alkaline phosphatase (ALP) 443 U/L, γ-glutamyl transpeptidase (γ-GT) 369 U/L, fasting blood glucose 2.2 mmol/L, cholesterol 17.3 mmol/L, triglycerin 10.0 mmol/L, high density lipoprotein cholesterol (HDL-C) 0.9 mmol/L, apolipoprotein A1 (ApoA1) 95 mg/dl, apolipoprotein B (ApoB) 88 mg/dl, lactic acid 3.3 mmol/L and creatine phosphokinase (CK) 227 U/L. Electrocardiography (Figure 1A) showed evidence of left ventricular hypertrophy and myocardial damage (inverted T waves in leads II, aVF, V1 to V3) while echocardiography was normal.
The patient received treatment of a high-protein diet and corn starch that was increased gradually from 120 g/d to 200 g/d. Two years later, the liver function, lipid profile improved notablely and fasting blood glucose stably varied between normal range of 3.6 to 5.3 mmol/L. The size of liver was rebounded little by little. She was followed up every one to three years in the outpatient department. Seven years ago, at the age of 13, it was found that she had bulging of precordium and degree four systolic murmur at the apex. Echocardiogram was examined again and it demonstrated extreme hypertrophy of left ventricle, mild hypertrophy of right ventricle,enlarged left atrium and small pericardial effusion. The echocardiogram also revealed systolic anterior motion of anterior mitral leaflet, abnormal high flow velocity both in left ventriluar outflow tract (LVOT) and middle of the left ventricle (LV), with values of 3.1 m/s and 4.4 m/s respectively. Chest X-ray showed cardiac enlargement in round shapes. Abnormality of electrocardiogram became more marked compared with that at 7 years of age, showing giant inverted T waves in leads II, III, aVF, V1-6 (Figure 1B). Blood troponin I was 1.71 ng/ml, a little higher than normal. Creatine kinase and CK-BM were 208 U/L and 15.5 ng/ml, respectively. GSD-related cardiomyopathy was diagnosed.
Angiotensin converting enzyme inhibitor (ACEI) and β blocker (perindopril 2 mg/d, metoprolol 50 mg/d) was prescribed. The gene analysis performed at the age of 15 confirmed the diagnosis of GSD type III. Echocardiogram examinations were repeated and demonstrated the same results of high flow velocity in middle LV chamber and LVOT, resembling hypertrophic cardiomyopathy. During the next three years, she felt slight fatigue on activity and LVOT obstruction did not alleviate in echocardiographic studies. Then verapamil substituted for ACE inhibitor and β blocker for one year. One year later when she was 19 years old, an unexpected result was found in the echocardiographic study which indicated that the posterior left ventricular wall thickness decreased and obstruction of LVOT disappeared with the flow velocity of 1.9 m/s and LV ejection fraction of 59%. She was found in good health and normal mental development with height of 165 cm and body weight of 66 kg. The heart function was NYHA II. The laboratory findings were much more improved than those at her young age. The laboratory parameters were as follows: ALT 37 U/L, AST 54 U/L, TBil 41.0 μmol/L, DBil 12.0 μmol/L, ALP 83 U/L, γ-GT 28 U/L, cholesterol 3.9 mmol/L, triglycerin 2.2 mmol/L, low density lipoprotein cholesterol (LDL-C) 2.0 mmol/L, HDL-C 1.5 mmol/L, ApoA1 148 mg/dl, ApoB 59 mg/dl, lactic acid 2.3 mmol/L. However another one year later, she had three onsets of acute left heart failure and the echocardiogram showed hypokinesia and thinning of some segments of the left ventricular wall with low ejection fraction (Figure 2) consistent with dilated cardiomyopathy or resembling the dilated phase of hypertrophic cardiomyopathy (HCM). Verapamil was discontinued immediately and the therapy of ACEI and β blocker according to the guideline of chronic systolic heart failure was performed. Table 1 shows the results of the series of echocardiographic studies.
The clinical features of the present case are: (1) The evidence of abnormal electrocardiography occurred early at the age of seven while echocardiogram was normal; (2) The marked hypertrophy of left ventricle occurred within six years, from 7 to 13 years of age while the liver function dramatically improved; (3) LVOT was obstructive and the obstruction of LVOT was relieved by verapamil.
Cardiac involvement most commonly occurs in GSD types II (Pompe disease), III, and IV.1 Cardiomyopathy has been described in approximately 30% of children with GSD-III. Fifty percent of patients with GSD-III had septal and/or posterior wall thickness, however cardiac symptoms were uncommon. Of 23 cross-sectional patients with GSD type IIIa, 12 had increased left ventricular mass, 11 had increased wall thickness.2
GSD-III-associated cardiomyopathy usually appears during childhood, but rarely has been documented in the first year of life. In general, cardiomyopathy in GSD-III is apparent only after 30 years of age. Its clinical significance ranges from asymptomatic in the majority to severe cardiac dysfunction, congestive heart failure, and rarely sudden death. Ventricular hypertrophy in GSD-III is usually morphologically concentric on echocardiography. An enlarged left ventricle with low contractility, resembling the dilated phase of HCM, is considered to be one of distinctive findings in GSD-III.3 Disproportionate septal hypertrophy is common in HCM and also can be found in other cardiomyopathy such as Fabry's disease and amyloidosis. The echocardiographic finding in the present patient reveals disproportionate septal hypertrophy can also exist in GSD. So the feature of disproportionate septal hypertrophy that is an echocardiographic appearance of HCM does not always point to the diagnosis of HCM. Metabolic cardiomyopathy caused by mutations in genes has been reported to mimic HCM.4 To distinguish GSD-III from HCM, the main clinical features are the presence of hypoglycemia and hepatomegaly.1
GSD-III causes cardiomyopathy not due to myocyte disarray and fibrosis in HCM but an intracellular accumulation of glycogen in the myocardium. The prominent hypertrophy of left ventricle and normal contractility leads to obstruction of LVOT and high velocities in the middle of left ventricle mimicking the features of echocardiographic imagings in obstructive hypertrophic cardiomyopathy. On one hand, the abnormal electrocardiographic findings in this patient became more marked during the several years follow-up. On the other hand, the electrocardiographic change was several years earlier than that of cardiac structure revealed by echocardiography, suggesting not only electrocardiography but also a series of echocardiogram are needed in the follow-up for patient with GSD-III.
Beta-blockers and calcium-channel blockers have traditionally been administered to treat HCM. Because the haemodynamics by cardiomyopathy in this patient was similar to that of HCM, β-blocker or non-dihydropyridines calcium-channel blockers should be considered. However metoprolol did not alleviate the obstruction in this patient probably because of perindopril. Perindopril as an ACEI is a vasodilator that may aggravate the obstruction of LVOT. ACEI is the cornerstone for treatment of systolic heart failure and can ameliorate the abnormal remodeling, but its useful effect in hypertrophic cardiomyopathy needs further study. Verapamil was useful in the present case indicating the beneficial effect of non-dihydropyridines in GSD-induced cardiomyopathy with obstruction of LVOT. However the cardiomyopathy is progressive in this patient, developing to chronic sysytolic heart failure.
It was reported that enzyme replacement therapy (ERT) caused rapid regression of ventricular hypertrophy in most of the treated patients with GSD type II while systolic ventricular function was preserved, suggesting rapid reversal of excessive glycogen storage in cardiac muscle cells.5 In the present case the treatment of corn starch improved hypoglycemia, liver function, her overall growth and development, and reduced liver size, but did not reverse the hypertrophy of left ventricle, indicating cardiac accumulation of glycogen continued in spite of using corn starch. It is unclear whether ERT can regress ventricular hypertrophy in GSD-III.
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