Brain imaging
The severity of lissencephaly and subcortical band heterotopia varies from complete or nearly complete agyria (grades 1 and 2), to mixed agyria–pachygyria (grade 3), to pachygyria only (grade 4), to mixed pachygyria–subcortical band heterotopia (grade 5), and finally to subcortical band heterotopia only (grade 6). Both LIS and SBH may have anterior or posterior predominant distribution. Thus, the gradient of LIS and SBH can be anterior equal to posterior (a = p), anterior more severe than posterior (a > p), or posterior more severe than anterior (p > a). In LIS1/PAFAH1B1-related lissencephaly, the cerebral gyri are absent or abnormally broad and the cerebral cortex is abnormally thick (12-20 mm; normal: 3-4 mm). In LIS1/PAFAH1B1-related SBH, the subcortical heterotopic bands are restricted to the parietal and occipital lobes.
Clinical features
Children with the most common types of LIS1/PAFAH1B1-related lissencephaly typically appear normal as newborns, although a few have a history of polyhydramnios, apnoea, hypotonia, poor feeding, and mildly elevated newborn bilirubin levels that may reflect poor swallowing. Most affected children come to medical attention due to neurological deficits in the first months of life. The major medical problems encountered are ongoing feeding problems and epilepsy of many different types that is often intractable.
For children with the most severe forms of classic LIS, the mortality rate can reach 50% by 10 years, but lifespan may be near to normal for the milder forms of pachygyria and SBH. Patients with severe LIS have early developmental delay, early diffuse hypotonia, later spastic quadriplegia, and eventual severe or profound intellectual disability. Seizures occur in over 90% of children with LIS, with onset before 6 months in about 75%. Between 35% and 85% of children with classic LIS develop infantile spasms, often without hypsarrhythmia. Most children with LIS will subsequently continue to have epileptic spasms in association with other seizure types. The EEG shows diffuse, high-amplitude, fast rhythms, which are considered to be highly specific for this malformation.
Patients with PAFAH1B1/LIS1 related SBH have normal facial appearance, epilepsy, and intellectual disability. In general individuals with SBH live into adult life.
Miller–Dieker syndrome (MDS) is characterised by severe four-layered lissencephaly with diffuse agyria and no clear gradient, typical facial appearance and other birth defects (e.g., heart malformations).