Infantile Hypertrophic Cardiomyopathy of Glycogenosis Type IX: Isolated Cardiac Phosphorylase Kinase Deficiency

Regalado, Jacinto; Rodríguez, Maria M.; Ferrer, Pedro L.

doi:10.1007/s002469900471

Cited by 24 publications

(14 citation statements)

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“…A classification is presented in List 1 based on groupings of familial, syndromic, neuromuscular, and metabolic (storage disease and mitochondrial disorders). Other classification schemes are commonly used, including division into primary and secondary forms, where the primary form is a familial disorder (“familial hypertrophic cardiomyopathy”, FHC) typically devoid of findings outside of the heart, and the secondary forms include diseases such as Friedreich ataxia 2 where ventricular hypertrophy is common but is not the dominant clinical manifestation and others, such as glycogenosis Type IX 3, in which a systemic disorder has primarily or exclusively cardiac manifestations.…”

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confidence: 99%

Hypertrophic Cardiomyopathy in Childhood

Colan

2010

Heart Failure Clinics

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Keywordscardiomyopathy; hypertrophic cardiomyopathy; sudden death; pediatrics; children; infants Hypertrophic cardiomyopathy (HCM) is defined as the presence of a hypertrophied, nondilated ventricle in the absence of another disease that creates a hemodynamic disturbance that is capable of producing the existent magnitude of wall thickening (eg, hypertension, aortic valve stenosis, catecholamine secreting tumors, hyperthyroidism, etc). HCM accounts for 42% of childhood cardiomyopathy and has an incidence of 0.47/100,000 children 1 and represents a heterogeneous group of disorders with a diversity that is more apparent in childhood than at any other age. It is possible to further subdivide these diseases based on a number of characteristics. A classification is presented in List 1 based on groupings of familial, syndromic, neuromuscular, and metabolic (storage disease and mitochondrial disorders). Other classification schemes are commonly used, including division into primary and secondary forms, where the primary form is a familial disorder ("familial hypertrophic cardiomyopathy", FHC) typically devoid of findings outside of the heart, and the secondary forms include diseases such as Friedreich ataxia 2 where ventricular hypertrophy is common but is not the dominant clinical manifestation and others, such as glycogenosis Type IX 3 , in which a systemic disorder has primarily or exclusively cardiac manifestations.Most of the available information for HCM derives from studies in adult populations, and the implication of these observations for pediatric populations is often uncertain. The purpose of this review is not to attempt to review the vast body of literature that has accumulated about HCM but rather to summarize key findings and to discuss their implications for diagnosis and management of children with HCM. Epidemiology and SurvivalThe Pediatric Cardiomyopathy Registry is a multicenter observational study of pediatric cardiomyopathies initiated in 1995 that in 2003 reported the sex, age, and race-specific incidence of the several forms of cardiomyopathy based on 2 geographically diverse sections of the United States 1 . Of note, the incidence of HCM was found to be 69% more common in males, occurred at 10 times the rate in subjects under age 1, and was significantly more common in blacks than in whites or Hispanics. Subsequently, the distribution of etiologies and the etiology-specific survival in 849 children, the largest series to date, was reported 4 . Overall, Corresponding author for proof and reprints: Steven D. Colan, M.D., Department of Cardiology, Children's Hospital, 300 Longwood Avenue, Boston, MA 02115, (617) 355-7893, (617) 739-6282 (fax), colan@alum.mit.edu (email). Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable fo...

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Hypertrophic Cardiomyopathy in Childhood

Colan

2010

Heart Failure Clinics

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“…The only other glycogenosis causing massive and rapidly fatal cardiomegaly in infants is a variant of phosphorylase b kinase (PHK) deficiency, which has been reported only in a handful of patients (2)(3)(4)(5)(6)(7). In these cases, and contrary to what happens in GSD II, glycogen does not accumulate within lysosomes but is free in the cytoplasm of cardiomyocytes, and the disease seems to be restricted to the heart.…”

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Fatal Infantile Cardiac Glycogenosis with Phosphorylase Kinase Deficiency and a Mutation in the γ2-Subunit of AMP-Activated Protein Kinase

et al. 2007

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A 10-wk-old infant girl with severe hypertrophy of the septal and atrial walls by cardiac ultrasound, developed progressive ventricular wall thickening and died of aspiration pneumonia at 5 mo of age. Postmortem examination revealed ventricular hypertrophy and massive atrial wall thickening due to glycogen accumulation. A skeletal muscle biopsy showed increased free glycogen and decreased activity of phosphorylase b kinase (PHK). The report of a pathogenic mutation (R531Q) in the gene (PRKAG2) encoding the ␥2 subunit of AMP-activated protein kinase (AMPK) in three infants with congenital hypertrophic cardiomyopathy, glycogen storage, and "pseudo PHK deficiency" prompted us to screen this gene in our patient. We found a novel (R384T) heterozygous mutation in PRKAG2, affecting an arginine residue in the N-terminal AMPbinding domain. Like R531Q, this mutation reduces the binding of AMP and ATP to the isolated nucleotide-binding domains, and prevents activation of the heterotrimer by metabolic stress in intact cells. The mutation was not found in DNA from the patient's father, the only available parent, and is likely to have arisen de novo. Our studies confirm that mutations in PRKAG2 can cause fatal infantile cardiomyopathy, often associated with apparent PHK deficiency. T he most common cause of cardiac glycogenosis in infancy is Pompe disease (glycogen storage disease type II, GSD II), due to deficiency of the lysosomal enzyme acid ␣-1,4-glucosidase (1). The only other glycogenosis causing massive and rapidly fatal cardiomegaly in infants is a variant of phosphorylase b kinase (PHK) deficiency, which has been reported only in a handful of patients (2-7). In these cases, and contrary to what happens in GSD II, glycogen does not accumulate within lysosomes but is free in the cytoplasm of cardiomyocytes, and the disease seems to be restricted to the heart. The molecular basis of this disorder has been a puzzle until recently because none of the several isozymes of PHK is heart-specific or predominantly expressed in the heart (8). The riddle was solved when, in three unrelated sporadic patients, Burwinkel et al. (9) found an identical heterozygous pathogenic mutation (R531Q) in the gene encoding the ␥2-subunit of AMP-activated protein kinase (PRKAG2). This finding prompted us to revisit an infant with fatal infantile cardiac glycogenosis and PHK deficiency that we had briefly described in 1998. We found a novel heterozygous mutation in PRKAG2, thus confirming the seemingly paradoxical association between an enzyme defect and a mutation in an unrelated gene. PATIENTS AND METHODSPatient. This baby girl was born at term by caesarian section (due to fetal bradycardia) to nonconsanguineous parents without any family history of cardiac disease or fetal loss. A cardiac ultrasound at 10 wk of age showed severe hypertrophy of both septal (1.52 cm) and atrial (1 cm) walls (Fig. 1, A and B). Left ventricular ejection fraction was 81%, and peak instantaneous left ventricular outflow gradient was 75 mm Hg. Electrocard...

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“…Recently, the role of Epo in vasoproliferative processes and its direct interaction with endothelial cells has been emphasized in human endothelial cell-line studies (3). Moreover, the proliferative effect of rHuEpo on endothelial cells has recently been observed by Leung, who reported the development of strawberry haemangiomas in a preterm neonate, multiple and very small, shortly after starting rHuEpo (4). We report on three additional cases of unrelated verylow-birthweight infants, who were treated from 2 wk of age with rHuEpo (900 IU kg À1 wk À1 intravenously), oral elemental iron supplementation (2 mg Kg À1 die À1 ), folates (0.2 mg die À1 ) and Vit E (40 IU die À1 ).…”

Section: Recombinant Human Erythropoietin Might Induce Strawberry Haementioning

confidence: 99%

“…PBK-deficiency syndromes involving liver and muscle are usually benign. In contrast, all patients with cardiac PBK deficiency reported to date were boys or girls who succumbed to progressive hypertrophic cardiomyopathy between 6 wk and 5 mo of age (1)(2)(3)(4). Their clinical course resembled infantile forms of lysosomal glycogen storage disease (5).…”

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confidence: 99%