Glycogen Storage Disease Of Heart, Lethal Congenital

A number sign (#) is used with this entry because of evidence that lethal congenital glycogen storage disease of the heart is caused by heterozygous mutation in the gene encoding the noncatalytic gamma-2 subunit of AMP-activated protein kinase (PRKAG2; 602743) on chromosome 7q36.

Clinical Features

Mizuta et al. (1984) and Eishi et al. (1985) described a seemingly unique case of glycogenosis, apparently confined to the heart, with deficient activity of cardiac phosphorylase kinase. The patient, a Japanese male, was found in the neonatal period to have hypoglycemia and general cyanosis; he died of heart failure at the age of 5 months. An apparently identical case was described by Servidei et al. (1988).

Servidei et al. (1988) suggested that this disorder is a third variety of phosphorylase kinase deficiency, inherited as an autosomal recessive, that affects muscle alone; symptoms consist of exercise intolerance with myalgia and cramps, and probably with myoglobinuria in some. An X-linked form of phosphorylase kinase deficiency (306000) is characterized by hepatomegaly and a tendency to develop hypoglycemia with fasting; muscle is not affected, but the enzyme defect is expressed in erythrocytes. In an autosomal recessive form of the disorder (261750), both liver and muscle are affected; there is hepatomegaly, stunted growth, and, in some patients, hypotonia and mild weakness.

Elleder et al. (1993) reported the case of a male infant who was noted to have heart murmur, mild cardiomegaly, and failure to thrive at the age of 3 weeks and was found to have severe glycogenosis restricted to heart muscle. Rapidly progressive hypertrophic cardiomyopathy caused death at the age of 47 days.

Regalado et al. (1999) described 2 patients with fatal infantile cardiomyopathy. The first patient was a female born to a Latino mother with dermatomyositis who had been treated with cortisone during pregnancy. A sonogram at 17.5 weeks was unremarkable, but one done 2 days before delivery revealed thickened cardiac walls and large kidneys. Fetal echocardiogram showed severe 4-chamber hypertrophic nonobstructive cardiomyopathy with sinus bradycardia, prompting a cesarean section delivery. The baby was noted at birth to have hepatomegaly, bilateral renomegaly, macroglossia, and some facial dysmorphism. Electrocardiogram showed wide QRS, short PR interval, inverted T waves, and ST elevation. Electromyogram showed a diffuse myogenic degenerative process. Echocardiogram showed severe biventricular hypertrophy, obstruction of the right ventricular outflow tract, and decreased systolic flow. The infant died at 2.75 months of age. On postmortem examination, the myocardium had a mesh-like appearance and showed increased glycogen and reduced phosphorylase kinase. The kidneys were enlarged, but there was no hepatomegaly. Histologic and histochemical analysis showed no abnormal glycogen deposition in skeletal muscle, tongue, kidneys, or liver. The second patient was a Caucasian male who presented at birth with a regular sinus rhythm without murmur, micrognathia, and macroglossia. At 10 days, an echocardiogram showed septal hypertrophy without outflow tract obstruction. At 5 weeks, an echocardiogram showed increased biventricular hypertrophy, and a skeletal biopsy showed nonspecific atrophy. The patient died at 2 months of age. Postmortem examination revealed severe cardiac hypertrophy and renomegaly, but no hepatomegaly. Histologic and histochemical findings were the same as those in the female patient.

Burwinkel et al. (2005) described 5 sporadic, unrelated patients with fatal congenital nonlysosomal cardiac glycogenosis and noted the similarities between these patients and those previously described with so-called phosphorylase kinase deficiency of the heart. All but 1 had extreme cardiomegaly, onset of cardiac or respiratory distress in the neonatal period, and death at 3 weeks to 5 months of age. Burwinkel et al. (2005) also observed low to absent phosphorylase kinase enzyme activity in their patients' heart autopsy specimens, but sequence analysis in 4 of their patients revealed no mutations in the 8 genes encoding phosphorylase kinase subunits or in the 2 genes encoding the muscle and brain forms of glycogen phosphorylase. Burwinkel et al. (2005) suggested that the low phosphorylase kinase activity in autopsy specimens from their patients and perhaps in the previously reported cases is likely to be secondary or artifactual in nature.

Molecular Genetics

In 3 of 5 patients with fatal congenital nonlysosomal cardiac glycogenosis, Burwinkel et al. (2005) identified heterozygosity for an R531Q mutation in the PRKAG2 gene (602743.0007). Burwinkel et al. (2005) noted that this severe phenotype characterized by fetal onset, extreme cardiomegaly, and death in infancy extended the clinical spectrum of PRKAG2 mutations, which had previously been shown to cause familial hypertrophic cardiomyopathy with Wolff-Parkinson-White syndrome (600858). Patients with the R531Q mutation died of hemodynamic and respiratory failure secondary to hypertrophic nonobstructive cardiomyopathy, but also had Wolff-Parkinson-White-like conduction anomalies.

In a female infant with severe cardiac hypertrophy due to glycogen accumulation, in whom Pompe disease (232300) had been excluded and who died at 5 months of age while awaiting heart transplantation, Akman et al. (2007) identified heterozygosity for a missense mutation in the PRKAG2 gene (R384T; 602743.0012). Postmortem examination showed marked ventricular hypertrophy; there was greatly increased glycogen content in the myocardium and, to a lesser extent, in skeletal muscle. Biochemical assays in postmortem myocardium showed an 8-fold increase in glycogen concentration and undetectable phosphorylase kinase activity.