Polymicrogyria, Bilateral Temporooccipital

A number sign (#) is used with this entry because of evidence that bilateral temporooccipital polymicrogyria (BTOP) is caused by homozygous mutation in the FIG4 gene (609390) on chromosome 6q21. One such family has been reported.

Clinical Features

Ouled Amar Ben Cheikh et al. (2009) reported a large consanguineous Moroccan family in which 6 individuals had a seizure disorder. Two affected individuals died from status epilepticus at age 6 months and 28 years, respectively. Seizure onset ranged from birth to 24 years, but all had a homogeneous phenotype consisting of complex partial seizures with visual hallucinations and secondary generalization. Variable seizure features also included salivation, constriction of the larynx, auditory buzzing, epigastric sensations, and automatisms, suggesting temporal lobe involvement. Three of 4 patients examined in detail had psychiatric abnormalities with severe behavior problems and aggression: 2 were diagnosed with a schizophrenic-type psychotic disorder. Brain MRI performed in 3 patients showed bilateral occipital polymicrogyria and enlarged ventricles. In a follow-up of the family reported by Ouled Amar Ben Cheikh et al. (2009), Baulac et al. (2014) noted that 2 patients had committed suicide and another had died of a seizure. Reevaluation of brain imaging showed temporooccipital polymicrogyria. One patient was diagnosed with an axonal sensorimotor neuropathy, but electrophysiologic studies were normal.

Inheritance

The transmission pattern of temporooccipital polymicrogyria in the family reported by Ouled Amar Ben Cheikh et al. (2009) was consistent with autosomal recessive inheritance.

Mapping

By genomewide linkage analysis of a consanguineous Moroccan family with bilateral occipital polymicrogyria, followed by haplotype analysis, Ouled Amar Ben Cheikh et al. (2009) identified a 14-Mb candidate region on chromosome 6q16.3-q22.1 between markers D6S283 and rs720446 (maximum multipoint lod score of 3.02 at D6S1594-D6S261). Sequence analysis excluded mutations in 6 candidate genes within the interval, including GRIK2 (138244), NR2E1 (603849), and GPR6 (600553).

Molecular Genetics

In affected members of the Moroccan family with temporooccipital polymicrogyria reported by Ouled Amar Ben Cheikh et al. (2009), Baulac et al. (2014) identified a homozygous missense mutation in the FIG4 gene (D783V; 609390.0016). The mutation was found by whole-exome sequencing. Functional expression studies indicated that the mutation caused a partial loss of function. Examination of Fig4-null mice showed postmigration abnormalities in several brain regions, consistent with mechanisms underlying polymicrogyria in humans.