Clinical Characteristics

Main clinical features are epilepsy (e.g. infantile spasms, focal, generalized, mixed, nocturnal seizures), microcephaly, early-onset cataracts, feeding difficulties, failure to thrive, stereotypic hand movements, and delayed brain myelination. Almost all families report cyclical episodes of extreme irritability and inconsolability. Most have profound developmental impairment such that walking and speech are absent or greatly impaired. Hypotonia, sleep disorders, breath-holding spells, and repetitive or choreiform movements, hand flapping, or Rett-like hand automatisms were present in the majority of individuals. Individuals tend to have a broad nasal tip but are otherwise nondysmorphic.

NACC1 variants other than the recurring c.892C>T (p.Arg298Trp) variant may be associated with a less specific phenotype including developmental delay, intellectual disability, and/or autism (de Ligt et al. 2012; Iossifov et al. 2014; Gilissen et al. 2014).