Sudden Cardiac Failure, Infantile

A number sign (#) is used with this entry because of evidence that infantile sudden cardiac failure (SCFI) is caused by homozygous or compound heterozygous mutation in the PPA2 gene (609988) on chromosome 4q24.

Clinical Features

Guimier et al. (2016) reported 7 children in 3 unrelated families who had sudden and unexpected fatal cardiac arrest between 4 and 20 months of age. In the first family, 4 of 5 children were affected, and in the second family, 2 of 2 children. Growth parameters and psychomotor milestones were normal, and no arrhythmias were ever recorded before death. A febrile illness or infection (e.g., gastroenteritis, otitis media) preceded the episode of acute and severe bradycardia/asystole by days or weeks. The mother and a maternal uncle in the first family had been diagnosed with Brugada syndrome (see 601144); however, flecainide testing was negative in the 2 children in whom it was performed. In the third family the proband presented with hypotonia, feeding difficulties, and failure to thrive at 3 months of age. Myopathy was suspected, and muscle biopsy showed variable-sized fibers, lipid accumulation, and nemaline rods. One month later, she was diagnosed with hypertrophic cardiomyopathy with heart failure, and died in the intensive care unit of cardiac arrest at age 4 months. Heart muscle histology, performed in 6 of the 7 children, showed features of myocarditis with polymorphic and nonspecific inflammatory infiltrates, necrosis, and/or fibrosis of variable severity. In addition, fat deposits were observed in the heart, skeletal muscle, and kidney of 1 of the affected children in the second family, and lipid accumulation was also noted in heart muscle of the proband from the third family.

Kennedy et al. (2016) described 6 children from 3 unrelated families who all presented with classic mitochondrial disease symptoms and died within the first 2 years of life from cardiac failure. In 5 affected children from consanguineous Sri Lankan and Pakistani families, the clinical presentation involved lactic acidosis, seizures, hypotonia, and cardiac dysrhythmia within the first months of life. Myocyte loss, disarray, or fibrosis was present in all individuals. Respiratory chain function varied from normal to moderate reduction in complex I and IV activities in cardiac tissue and was normal in fibroblasts and skeletal muscle tissue. In the third family, the Irish proband presented with seizures at age 10 months and developed dilated cardiomyopathy and multiorgan failure at age 1 year. All affected individuals died from cardiac failure after sudden deterioration. Three of the 6 children had viral infections just prior to their final heart failure, and 2 others had vomiting and loose stools but viral infection was not confirmed.

Inheritance

The transmission pattern of infantile sudden cardiac failure in the families reported by Guimier et al. (2016) and Kennedy et al. (2016) was consistent with autosomal recessive inheritance.

Molecular Genetics

By whole-exome sequencing in affected individuals from 3 families with infantile sudden cardiac failure, Guimier et al. (2016) identified compound heterozygosity for missense mutations in the PPA2 gene (609988.0001-609988.0005) that segregated with disease.

From large exome datasets of individuals suspected of a disorder in mitochondrial energy metabolism, Kennedy et al. (2016) identified 6 affected children from 3 unrelated families with homozygous or compound heterozygous missense mutations in the PPA2 gene (609988.0003 and 609988.0006-609988.0007). The parents were each heterozygous for 1 of the mutations in the 2 families for which parental DNA was available. Five affected children from 2 of the families were homozygous for a P167L mutation (609988.0007), which showed only 5 to 10% residual activity compared to wildtype on pyrophosphatase activity assay. Kennedy et al. (2016) noted that in such cases of severe PPA2 dysfunction, ATP depletion has an acute effect, with lactic acidosis and cardiomyopathy occurring prior to the development of chronic damage. The authors suggested that this could lead to acute symptoms in the presence of secondary triggers, such as a viral stressor, which might have been responsible for adversely affecting mitochondrial metabolism in these families.