Pediatric Forms of Inherited Cardiomyopathies

All phenotypes of cardiomyopathy presenting in childhood can occur as a genetic disorder. Unlike adult disease, pediatric cardiomyopathies, particularly those presenting in the first year of life, have an increased likelihood of being mitochondrial or metabolic-based. Evaluation of these young children must include studies aimed at determining whether mitochondrial dysfunction or metabolic derangement is central to the underlying basis of the cardiac disorder. In the case of mitochondrial disease, mitochondrial DNA (mtDNA) mutations inherited from the mother (maternal inheritance) or autosomal recessive inheritance underlie these disorders. Metabolic defects most commonly are inherited as autosomal recessive traits.

In the remaining cases of inherited cardiomyopathies of childhood, the same inheritance patterns as seen in adulthood are expected.

HCM of Childhood. Young children with left ventricular hypertrophy (LVH) may have an underlying mitochondrial or metabolic disease, while others have early clinical expression of HCM due to a sarcomere gene mutation. For instance, the deadly infiltrative lysosomal storage disorder, Pompe disease, or the benign infant of a diabetic mother form of LVH may appear to be similar by echocardiography. In addition, syndromes such as Noonan syndrome, overgrowth disorders such as Beckwith-Wiedeman syndrome or Sotos syndrome, or children with chromosomal disorders may present with LVH. A subgroup of these young children with LVH, however, has the typical "adult form" of disease caused by mutations in genes encoding sarcomere proteins.36 Children can inherit these mutations or the gene defects can arise de novo and cause sporadic disease.

Children with HCM from mutations in sarcomeric genes typically demonstrate the classical clinical phenotypic features of HCM seen in adults. Phenotypic heterogeneity is common in children with familial forms of disease, both in clinical expression and outcome. For these reasons, the clinical follow-up of children with HCM tends to differ from that outlined for adults. Children younger than 1 year of age with HCM are usually seen frequently, commonly every 3 months. Siblings without clinical features of disease are followed yearly in most cases until reaching puberty. At that time, follow-up is every 1-2 years depending on their specific clinical, echocardiographic and electrocardiographic features. In cases where HCM presents in older children, the siblings are usually seen every 3 years unless a defect is identified.

DCM of Childhood. Inherited forms of DCM in childhood appear to exist in approximately 50% of affected subjects presenting by 18 years of age. Like HCM, mitochondrial and metabolic disease, as well as chromosomal defects and dysmorphic syndromes may be responsible for a substantial subgroup of cases. In the remaining inherited forms, autosomal and X-linked inheritance is most common. A substantial subgroup of children has associated skeletal myopathy, and some of these will also have conduction system disease. In inherited cases, similar to that described for HCM, onset of clinical features is age-dependent. In families with earlier onset of symptoms, follow-up of at-risk relatives should begin earlier. Relatives, particularly siblings, also follow a similar pattern as those outlined for relatives of HCM patients.

RCM of Childhood. Restrictive cardiomyopathy in childhood is an uncommon but serious form of cardiomyopathy. Inherited forms are infrequent, but when they occur appear to be associated with defective sarcomeric genes or mutations in desmin. Associated skeletal myopathy is common. In children with RCM, autosomal dominant inheritance predominates. Family evaluation for siblings tends to be approximately every 3 years unless a defect is identified.

LVNC of Childhood. Left ventricular noncompaction is seen during all ages of childhood from birth onward. Mitochondrial, metabolic, syndromic, chromosomal, and neuromuscular abnormalities are common. In addition, autosomal dominant inheritance is notable. LVNC is subdivided into dilated, hypertrophic, and hypertrophic/dilated forms, isolated LVNC without other abnormalities of size, thickness or function, and LVNC associated with congenital heart disease. Family members are followed every 3 years unless a defect is identified.