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  • Updated 05.07.2020
  • Released 09.01.1998
  • Expires For CME 05.07.2023

Subcortical laminar heterotopia

Introduction

This article includes discussion of subcortical laminar heterotopia, band heterotopia, diffuse cortical dysplasia, double cortex syndrome, and laminar heterotopia. The foregoing terms may include synonyms, similar disorders, variations in usage, and abbreviations.

Overview

Subcortical laminar heterotopia, or double cortex, is a genetic condition that occurs chiefly, although not exclusively, in females. Imaging shows a thickened band of subcortical white matter that consists microscopically of 2 layers of gray matter—an outer normal layer and an inner layer of heterotopic neurons—located subcortically in white matter. Developmental delay and seizures are early complications, as is intellectual disability; visual, perceptual, and fine motor deficits; or even spastic quadriparesis. Doublecortin (DCX), a gene involved in the growth of neuronal processes, neuronal migration, and possibly the regulation of cell adhesion, is mutated in a large proportion of patients with subcortical laminar heterotopia. The large number of patients with doublecortin deficiency is female because it is an X-linked dominant trait. However, cases of subcortical laminar heterotopia not associated with doublecortin mutations occur in both sexes.

Key points

• Subcortical laminar heterotopia (double cortex) is a genetic condition that occurs chiefly, although not exclusively, in females.

• X-linked dominant cases arise from mutations in the doublecortin gene (DCX); cases not associated with this mutation affect both sexes.

• In the disorder, 2 layers of gray matter are found within a thick band of subcortical white matter and are visible by MRI.

• Patients may exhibit developmental delay; seizures; visual, perceptual, and fine motor deficits; and spastic quadriparesis.

Historical note and terminology

Subcortical band (or laminar) heterotopia has become a clinically defined disorder largely because of the widespread use of MRI in the diagnosis of idiopathic epilepsy. Although the disease was first described in the late 1800s by Matell in a postmortem specimen from a 25-year-old, mildly retarded epileptic woman (61), and subsequently by other pathologists (45), it was only first described radiologically in 1989 (07). Since that time, over 10 cases have been identified. Palmini and colleagues presented the first clinical series of subcortical band heterotopia patients. The series identified marked female sex predominance in subcortical band heterotopia and suggested that genetic factors may be playing a role in the etiology of subcortical band heterotopia (72). Barkovich and colleagues presented a collection of 27 subcortical band heterotopia patients in 1994 and observed a correlation between the severity of the radiographic abnormalities and the degree of clinical symptoms (06). Subcortical band heterotopia was proposed to be a milder form of lissencephaly or pachygyria by Friede (30), but it was Pinard who presented the first pedigrees in which affected males displayed lissencephaly and affected females displayed subcortical band heterotopia (77).

The identification of these 2 families suggested that a gene locus for lissencephaly was present on the X chromosome and that this X-linked form of lissencephaly and subcortical band heterotopia was allelic (ie, due to mutations in the same gene). Because subcortical band heterotopia and the X-linked form of lissencephaly are allelic, pedigrees that display both diseases are referred to as displaying subcortical band heterotopia or X-linked form of lissencephaly (SBH/XLIS). The inheritance pattern in these 2 pedigrees suggested that subcortical band heterotopia or X-linked form of lissencephaly follows an X-linked dominant pattern of inheritance, with males hemizygous for the X-linked mutation displaying lissencephaly and females heterozygous for the X-linked mutation displaying subcortical band heterotopia. Using these 2 pedigrees and several others, subcortical band heterotopia or X-linked form of lissencephaly mapped to a 15 cM region in Xq22-Xq24 (20; 84) and subsequently located at Xq22.3-q23 (63). The gene responsible for subcortical band heterotopia or X-linked form of lissencephaly was cloned by analyzing a balanced X-chromosomal translocation from a patient with the X-linked form of lissencephaly (19; 34) and named doublecortin. Several mutations have since been identified in doublecortin (48).

Animal models have shown great potential in the understanding of neuronal migration defects. Species differences are recognized (82). Doublecortin mutations in mice, for example, do not alter cortical neuronal migration or result in subcortical band heterotopia; RNA interference of doublecortin in rats in utero does produce the disorder. Overexpression of LIS1 is responsible for the development of lissencephaly and other neuronal migration abnormalities. In mice, it is associated with smaller brain size, increased apoptosis, and distorted cellular architecture (10). Prenatal x-ray irradiation also interferes with neuronal migration and laminar formation in the rat cerebral cortex (56).

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