Band Heterotopia

A number sign (#) is used with this entry because of evidence that band heterotopia (BH) is caused by homozygous or compound heterozygous mutation in the EML1 gene (602033) on chromosome 14q32.

Clinical Features

Kielar et al. (2014) reported a French family in which 3 brothers had severe developmental delay with intellectual disability. Two of the boys had refractory epilepsy, whereas the third boy had no history of seizures by age 8 years. More variable features included hypotonia, mild spasticity, sleep disturbances, and behavioral problems. Kielar et al. (2014) also reported an unrelated boy, born of consanguineous Moroccan parents, with macrocephaly, congenital hydrocephalus, severe psychomotor delay, and seizures. A later pregnancy in the family was terminated because of hydrocephalus shown by ultrasound. All patients had enlarged head circumference (+2.5 SD). Brain imaging showed periventricular and ribbon-like subcortical heterotopia with polymicrogyria and agenesis of the corpus callosum. The heterotopia was most obvious in the frontal regions.

Shaheen et al. (2017) reported a consanguineous Saudi family (family 22) in which 4 individuals had hydrocephalus. Two of the affected individuals were deceased. Detailed clinical information was only available for the proband, who was a 2-year-old girl with congenital hydrocephalus, profound global developmental delay, and intractable epilepsy. Brain imaging showed band heterotopia, extensive polymicrogyria, agenesis of the corpus callosum, dilated lateral ventricles, and compressed cerebellum with herniated cerebellar tonsils.

Inheritance

The transmission pattern of band heterotopia in the families reported by Kielar et al. (2014) was consistent with autosomal recessive inheritance.

Molecular Genetics

In 4 patients from 2 unrelated families with band heterotopia, Kielar et al. (2014) identified compound heterozygous or homozygous mutations in the EML1 gene (602033.0001-602033.0003). The mutations in 1 family were found by direct sequencing of the EML1 gene, whereas the mutation in the other family was found by a combination of homozygosity mapping and exome sequencing. The mutations segregated with the disorder in both families.

In a girl, born of consanguineous Saudi parents (family 22), with BH and congenital hydrocephalus, Shaheen et al. (2017) identified a homozygous nonsense mutation in the EML1 gene (R523X; 602033.0004). The mutation, which was found by a combination of homozygosity mapping and exome sequencing, was confirmed by Sanger sequencing. The mutation segregated with the disorder in the family. There were 3 additional similarly affected family members, 2 of whom were deceased, but DNA was not available from those patients. Functional studies of the variant and studies of patient cells were not performed, but the variant was predicted to result in a complete loss of function manifest as a severe phenotype. The patient was part of a genetic study of 27 consanguineous Saudi families with congenital hydrocephalus.

Animal Model

The spontaneous mouse mutant 'HeCo' has seizures and subtle learning deficits associated with heterotopic neurons in the brain white matter. Kielar et al. (2014) determined that the HeCo mutant resulted from truncation of the Eml1 gene. Examination of HeCo mice showed that by E17, both early- and late-born neurons formed the heterotopia, and radial glial cells were disorganized compared to controls. Postnatally, the late-born neurons failed to reach cortical layers and formed a column between the heterotopia and cortex, but the mutant neurons did not show migration abnormalities. In HeCo brains, the early-born neuronal progenitor cells showed altered distribution and were misplaced: they were present outside the ventricular zones and continued to proliferate longer than wildtype cells. In wildtype murine and ferret embryos, Eml1 was expressed in cortical neuronal progenitors of the ventricular zone and postmitotic neurons of the cortical plate. In neurons, punctate Eml1 appeared to be distributed throughout the cell, aligning with microtubules and spindles during cell division, and prominent in perinuclear regions and growth cones. The findings were consistent with a role for Eml1 in different types of neuronal progenitors, as well as in postmitotic neurons, during cortical development. Kielar et al. (2014) concluded that ectopic progenitors represent the primary defect leading to neuronal heterotopia.