Polymicrogyria, Bilateral Perisylvian, X-Linked

Description

Polymicrogyria (PMG) is a malformation of cortical development in which the brain surface is irregular and the normal gyral pattern replaced by multiple small, partly fused gyri separated by shallow sulci. Microscopic examination shows a simplified 4-layered or unlayered cortex. Several patterns of PMG, including bilateral frontal, bilateral perisylvian, and bilateral mesial occipital PMG, have been described on the basis of their topographic distribution. All but the perisylvian form appear to be rare. Bilateral perisylvian PMG (BPP) often results in a typical clinical syndrome that is manifested by mild mental retardation, epilepsy, and pseudobulbar palsy, which causes difficulties with expressive speech and feeding (Kuzniecky et al., 1993).

PMG may be a feature of other conditions as well (see, e.g., 300643).

Clinical Features

Kuzniecky et al. (1993) studied 31 patients with a congenital neurologic syndrome characterized by pseudobulbar palsy, cognitive deficits, and bilateral perisylvian abnormalities on imaging studies. All patients had diplegia of the facial, pharyngeal, and masticatory muscles, of variable severity. Some patients had slight dysarthria, while others were unable to speak. Mental retardation, ranging from mild to severe, was present in 85% of patients. Epilepsy was present in 27 (87%) and commonly consisted of atypical absence, atonic/tonic, tonic-clonic seizures, and, less frequently, partial attacks. Seizures were poorly controlled in 55%. Magnetic resonance imaging (MRI) showed bilateral perisylvian cortical malformations consistent with polymicrogyria, confirmed at necropsy. Improvement in the seizures accompanied the division of the corpus callosum in several patients. There was no instance of parental consanguinity. Epilepsy was present in the sib of 1 patient. In 2 families the syndrome occurred in more than 1 person; in 1 family monozygotic male twins were both affected (Graff-Radford et al. (1986)), and in another family a brother and sister were affected and a deceased maternal uncle was probably affected. Present in all patients and considered essential criteria were oropharyngoglossal dysfunction, dysarthria, and bilateral perisylvian malformations on imaging.

Hattori et al. (1996) reported the first case in a Japanese child, a 9-year-old boy. He had oropharyngoglossal dysfunction and severe dysarthria. MRI of the brain disclosed bilateral perisylvian malformations suggesting polymicrogyria. He also showed mental retardation, epilepsy, and poor motor skills. The clinical manifestations of pseudobulbar palsy, congenital facio-pharyngo-glosso-masticatory diplegia represented developmental Foix-Chavany-Marie syndrome, or bilateral anterior opercular syndrome, resulting from bilateral opercular lesions.

Jansen and Andermann (2005) reviewed the clinical and radiologic features as well as the genetics of the various forms of polymicrogyria.

Brandao-Almeida et al. (2008) reported the clinical features of 31 patients with CBPS, including 22 patients from 6 families. Fourteen patients had bilateral involvement of the sylvian fissure cortex, whereas 15 had bilateral posterior perisylvian polymicrogyria. One patient had normal imaging, but had dyslexia and fathered 2 children with dyslexia and PMG. Six patients with diffuse PMG had generalized tonic-clonic seizures, and 17 patients, including 13 with diffuse PMG, had pseudobulbar signs. Twenty-five patients had delayed language development, 10 with dyslexia. Most patients did not have global cognitive deficits. Inheritance patterns in familial cases were heterogeneous. Adverse prenatal events were associated with nonfamilial cases.

Clark and Neville (2008) noted that there is significant phenotypic overlap between PMG and Worster-Drought syndrome (185480) and that the disorders may be part of a phenotypic spectrum.

Pathogenesis

Nongenetic causes of PMG are recognized, including intrauterine cytomegalovirus infection (Barkovich and Lindan, 1994) and placental perfusion failure often related to twinning (Baker et al., 1996). In addition, a severe and unlayered form of PMG is a prominent feature of Zellweger syndrome (see 214100).

Inheritance

Familial recurrence of PMG in a pattern consistent with X-linked inheritance was reported by Borgatti et al. (1999) and Guerreiro et al. (2000). In some families, only males have PMG, whereas, in others, individuals of both sexes are affected but with more severe expression in males. Further support for an X-linked locus for PMG came from a study group of 220 patients with PMG referenced by Villard et al. (2002) in which 60% were males and in which males were generally more severely affected than females.

Mapping

Villard et al. (2002) investigated 5 families containing a total of 12 severely affected males and 1 mildly affected female. They demonstrated linkage to a region at the distal end of Xq between marker DXS8103 and Xqter, i.e., in the Xq28 region.

Genetic Heterogeneity

Santos et al. (2008) reported a family in which 8 members, including 5 males and 3 females, had bilateral polymicrogyria inherited in an X-linked dominant pattern. Overall, the males showed a more severe pattern of brain involvement both on MRI scan and in clinical phenotype compared to the females. Linkage analysis yielded a maximum 2-point lod score of 2.06 at markers DXS1205 and DXS1227 on chromosome Xq27.2-q27.3. Multipoint lod scores delineated a 13-cM candidate region between markers DXS1205 and DXS8043. All 8 patients with MRI findings had the affected haplotype, but neurologic and language evaluations were variable. In addition, 1 asymptomatic individual carried at least part of the affected haplotype, suggesting incomplete penetrance. Santos et al. (2008) noted that this candidate locus was centromeric to and did not overlap with that reported by Villard et al. (2002), suggesting genetic heterogeneity.