Researchers from University of Washington, Seattle, WA, and Washington University, St Louis, MO propose a genetic and biologic classification of infantile spasms. Infantile spasms are of 2 main groups: those with known or unknown predisposing genotypes. Genes associated with lissencephaly are strongly associated with infantile spasms, as high as 80%, whereas 40% of patients with tuberous sclerosis complex may manifest infantile spasms. Inborn errors of metabolism associated with infantile spasms include the aminoacidopathies phenylketonuria, and nonketotic hyperglycinemia, the organic acidemias methylmalonic acidemia, propionic acidemia, and maple syrup urine disease, and Menkes kinky hair disorder of copper metabolism. Mitochondrial disorders are infrequently associated with infantile spasms.

Five chromosomal syndromes comprise predisposing genotypes for infantile spasms, including Miller-Dieker, Down and Williams syndromes. Infrequent associations occur with Smith-Lemli-Opitz, Sotos syndrome, and neurofibromatosis type 1. Unknown predisposing genotypes are suspected in some patients with a global developmental disorder and nonspecific cranial imaging malformations. Aicardi syndrome is an example of a developmental disorder of unknown genotype with unifying phenotype and prominent association with infantile spasms. It affects only females, suggesting a gene located on the X chromosome.

Infantile spasms associated with hypoxic-ischemic encephalopathy or infection may exhibit imaging patterns such as atrophy, calcifications and white matter intensities, suggesting an overlap with predisposing genotypes. Hypoxia or infection could represent a “second hit” in a population made vulnerable to spasms by an undiscovered predisposing genotype. A prospective study of prevalence of infantile spasms in patients with perinatal hypoxia or meningitis is needed to investigate this hypothesis. Children with patterns of extrinsic injury are prime candidates for further study of possible genetic mutations. [1]

COMMENT. The authors propose a primary biologic link between infantile spasms and autism, emphasizing connections between infantile spasms and phenotypes other than intractable epilepsy, including tuberous sclerosis. West's son James, the first patient reported with the syndrome, exhibited symptoms compatible with autism, as described by Langdon-Down (of Down's syndrome) who treated the child in later life [2]. Patients with infantile spasms show mutations to several genes, and all forms of infantile spasms may be symptomatic. The symptomatic, cryptogenic, and idiopathic classification system of epilepsy syndromes should be replaced, as recommended by the ILAE [3]. This review is considered a first step toward a genetic and biological classification of infantile spasms.