Pachygyria With Mental Retardation, Seizures, And Arachnoid Cysts

Description

This autosomal recessive neurodevelopmental disorder is characterized by pachygyria, mental retardation, seizures, and diffuse localization of arachnoid cysts. It most likely represents a neuronal migration disorder within the lissencephaly spectrum (summary by Guzel et al., 2007).

Clinical Features

Kuzniecky (1994) described 2 brothers, born of healthy, unrelated parents, with a profound static encephalopathy characterized by moderate impairment of intelligence, motor and developmental delay, and atypical absence, atonic, and generalized tonic-clonic seizures with onset at age 5 years. The head circumference was normal, as was the remainder of the neurologic examination. Chromosomal analysis was reportedly normal. Brain MRI demonstrated a distinctive pattern of enlargement of the parietal cortex to 10 to 12 mm. On the strength of this MRI finding, the authors speculated that this may be pachygyria, but histologic evidence was not available to distinguish this from polymicrogyria, which usually has cortical thickness on the order of 5 to 7 mm. Polymicrogyria is seen in the congenital bilateral perisylvian syndrome (300388) described by Kuzniecky et al. (1993). Kuzniecky (1994) distinguished the disorder in the 2 brothers from several other neuronal migration disorders, such as the double cortex syndrome (Palmini et al., 1991; see 600348 and 300067). Kuzniecky (1994) did not describe the sloping forehead associated with Norman-Roberts lissencephaly (257320) or features associated with Neu-Laxova lissencephaly (256520).

Guzel et al. (2007) reported a consanguineous Turkish family (NG-8) in which 3 of 7 sibs had pachygyria, mental retardation, seizures, and arachnoid cysts. The affected brother had all of the features except for seizures; onset of seizures in the sisters occurred at ages 19 and 10 years, respectively. The 2 affected sisters also had multiple enlarged perivascular spaces in the white matter of the centrum semiovale, a finding commonly seen in lissencephaly. However, Guzel et al. (2007) analyzed 3 genes known to cause lissencephaly, PAFAH1B1 (601545), 14-3-3-epsilon (YWHAE; 605066), and DCX (300121), and did not find any mutations in this family. Guzel et al. (2007) concluded that the disorder resulted from a neuronal migration defect, leading to structural problems and the formation of arachnoid cysts.

Inheritance

Consanguinity in the family reported by Guzel et al. (2007) suggested autosomal recessive inheritance.

Mapping

By genomewide linkage analysis of the consanguineous Turkish family NG-8 reported by Guzel et al. (2007), Bilguvar et al. (2009) found evidence suggestive of linkage to chromosome 11p15 with a lod score of 2.5, which was the maximum theoretical lod score attainable in this family. The approximately 20-cM interval was defined centromerically by rs953115.