Bilateral perisylvian polymicrogyria in three generations

Patients and methods.

The family pedigree is shown in figure 1. The proband is Patient IV-1. All 9 living family members were examined clinically. Brain MRI, cognitive testing, and EEG recordings were performed in the 6 patients with abnormal neurologic examination results, mental retardation, or seizures and in the one clinically healthy offspring (Subject IV-3).

• Download figure
• Open in new tab
• Download powerpoint

Figure 1. Family pedigree. No reliable clinical data could be obtained for Subject II-1, who died at age 18 years, or Subject II-2, who died at 2 years 3 months.

MRI was performed with 0.5- or 1.5-Tesla apparatus. Conventional spin-echo T2*-, proton density-, and T1*-weighted images were obtained in the axial plane with 5-mm–thick sections. A whole-brain magnetization prepared rapid acquisition gradient-echo acquisition was also performed with a 165-mm sagittal slab, 128 partitions, and 1.3-mm partition thickness. Axial and coronal reconstruction was obtained from the original acquisition volume.

Cognitive testing was done with the Wechsler intelligence scales for adults and children in 5 of the 6 affected patients and in Subject IV-3, but could not be done for Patient II-3, who had become severely aphasic after experiencing a stroke at age 52.

Results.

Clinical and EEG findings are summarized in the table. All patients had dysarthria and nasal speech. Tongue movements were restricted, with limited protrusion and lateral movements. The degree of impairment was mild in the 5 affected women and was severe and accompanied by prominent drooling in the proband. Three of the 5 women had partial epilepsy, the onset having occurred in childhood in 2 and at age 52, after a stroke, in one. In all 3 patients, antiepileptic drugs achieved complete seizure control. The proband had intractable partial and generalized seizures beginning in the first year of life.

MRI of the proband (Patient IV-1, figure 2A) showed bilaterally abnormal and asymmetric sylvian fissures. The right sylvian fissure extended posteriorly up to the top of the right hemisphere, where a large part of the parietal cortex was thickened and showed irregular infoldings, consistent with polymicrogyria. The cortical gyri and sulci of the inferomesial aspect of the left occipital lobe were also irregular and small. The left sylvian fissure was particularly deep, but the cortical thickening was limited to its posterior part. The right occipital lobe was smaller than the left.

• Download figure
• Open in new tab
• Download powerpoint

Figure 2. Coronal (A) and axial (B) T1*-weighted images of the proband (Patient IV-1) (A) and of his mother (Patient III-2) (B). (B) MRI of Patient III-2 showing, as in all other affected women, bilateral irregular thickening of the gray matter in the border or in the depth of the sylvian fissure, or both, with areas of infolding and reduction of the underlying white matter. (A) More extensive abnormality in the proband, also involving the cortical pattern of the right parietal and temporal lobes. The whole right hemisphere is smaller than the left.

MRI findings in the sister, mother (figure 2B), grandmother, and aunts showed that these family members shared remarkably similar structural abnormalities involving the perisylvian cortex bilaterally. The sylvian fissures, especially in their more posterior part, were deeply infolded, with thickening of the cortex, and were separated from the ventricular walls by a thin layer of white matter.

Discussion.

BPPMG is a well-recognized syndrome with varying anatomic and clinical severity.1 The family described here includes 6 members of 3 consecutive generations. The 5 affected women had homogeneous anatomic and clinical findings, with low average intelligence to mild mental retardation, mild pseudobulbar paresis, and dysarthria in all subjects and epilepsy in 3. Conversely, clinical and anatomic impairment were much more severe in the only male individual affected.

This family demonstrates unequivocal evidence for a genetic transmission of the syndrome. The analysis of the pedigree makes an autosomal recessive pattern extremely unlikely. Similarly, anticipation phenomena do not appear to be present, given the homogeneity of the clinical and MRI findings in the affected women over 3 generations. Among the other possible patterns of genetic transmission, this pedigree is compatible with an autosomal dominant mode of inheritance with variable expressivity, with the inheritance of a paternally imprinted gene, or with a mitochondrial disorder. Nevertheless, the severity of the features shown by the affected boy in comparison with the affected women, and the transmission of the disorder through women, suggest that transmission of an X-linked dominant trait is plausible. This mode of inheritance was previously reported for malformations of cortical development. Mutations in the doublecortin gene,5 mapping to the long arm of the X chromosome, cause classic lissencephaly in affected boys, whereas heterozygous women belonging to the same families show subcortical laminar heterotopia.

BPPMG has previously been reported to occur in more than one person in the same family. Affected monozygotic male twins were described by Graff-Radford et al,8 and occurrence in a brother and sister was reported by Kuzniecky et al.1 There have been no reported instances of parental consanguinity, and no clearcut sex predominance has been identified. An X-linked recessive pattern of inheritance has been hypothesized in the family described by Yoshimura et al,4 in which, however, BPPMG was one expression of a wide range of structural abnormalities. Moreover, in that family women were asymptomatic, except for one, who appeared to have inherited the mutation from her affected father.

Localized polymicrogyria could result from abnormalities of regionally expressed developmental genes. An attractive candidate is EMX2, a homeotic gene located on chromosome 10q26. This gene is mutated in some patients with schizencephaly,9 a usually sporadic brain malformation in which unlayered polymicrogyria covers clefts in the brain. Nevertheless, the search for EMX2 mutations in patients with BPPMG has been unsuccessful (E. Boncinelli and R. Guerrini, unpublished data, 1998).

BPPMG has also been observed at MRI in children born from monochorionic biamniotic twin pregnancies that were complicated by twin-to-twin transfusion syndrome with death of the co-twin between the 10th and 18th weeks of gestation.6,7 In such cases the malformation could have resulted from ischemic injury secondary to hemodynamic changes induced by death of the co-twin.

Neuropathologic studies conducted in 4 sporadic BPPMG cases have shown 4-layered polymicrogyria in 31,3 and unlayered polymicrogyria in one.2 Four-laynered polymicrogyria is believed to result from fetal injury, possibly caused by perfusion failure.10 Unlayered polymicrogyria is thought either to result from early exogenous insults (13th to 18th week of gestation) or to be genetically determined.10

Etiologic and histopathologic differences suggest that the syndrome of BPPMG is not a single entity but rather encompasses different malformations with the same topography, that only in some cases is it genetically determined, and that different genetic mechanisms may be responsible.

The family reported herein, along with the other cases showing a familial recurrence of the syndrome, raises the question of the existence of multiple genes whose mutations can lead to BPPMG. At present, the complex heterogeneity underlying the etiology of this disorder precludes the assessment of a precise recurrence risk. Nevertheless, the evidence for familial cases should be taken into account for genetic counseling issues.