Double Cortex Syndrome

What is Double Cortex Syndrome?

The cerebral cortex, serving as the highest center that regulates or controls sensory and motor activities, is composed of about 14 billion neurons with multiple types. The abnormality of these neuronal components can cause structural or functional dysplasia of the cortical. Double cortex syndrome, also known as subcortical band heterotopia, is a neuronal migration disorder characterized by a band of gray matter formed between the ventricular surface and the cortical mantle, as well as the separated cortical plates. It is an X-linked genetic disease that mainly affects female individuals, although few males have been reported. Double cortex syndrome patients usually manifest frequent epilepsy and varying degrees of intellectual impairment.

Fig.1 Double cortex syndrome related to DCX mutations. (Bahi-Buisson, 2013)

Pathogenesis of Double Cortex Syndrome

As a neuronal migration disorder, double cortex syndrome is usually caused by improper neural migration in the embryonic stage. Neuron subsets that are supposed to locate in the cerebral cortex cannot migrate to the correct position due to gene mutations, forming band-like clusters under the cerebral cortex and leading to cortical malformation. Currently, double cortex syndrome has been reported to be closely associated with mutations in genes of DCX, PAFAH1B1, TUBA1A, and some other tubulin genes.

Fig.2 Illustration of a coronal section from a brain with double cortex syndrome. (LoTurco, 2013)

Role of Critical Proteins in Double Cortex Syndrome

Doublecortin (DCX). DCX, also known as neuronal migration protein doublecortin or lissencephalin-X, is a microtubule-binding protein that is primarily expressed by neuronal precursor cells and immature neurons in embryonic or mammalian cortical regions. It is necessary for neuronal dispersion and cortex lamination during cerebral cortex development. Additionally, DCX also is an important biomarker for neurogenesis. DCX mutations have been detected in about 80% of the double cortex syndrome females.
Platelet-activating factor acetylhydrolase IB subunit alpha (PAFAH1B1). PAFAH1B1, also known as Lis1, is a non-catalytic subunit of the platelet-activating factor acetylhydrolase. PAFAH1B1 plays an essential role in the proliferation of neuronal precursors and the migration of newly formed neurons from the ventricular/subventricular zone toward the cortical plate during brain development. And it also regulates the function of the motor protein Dynein, which is a key protein in nucleokinesis.
Tubulin alpha-1A chain (TUBA1A). Tubulin proteins (tubulin alpha and tubulin beta) are the major constituents of microtubules, a central part of the eukaryotic cytoskeleton. TUBA1A mutation could result in the disability of the formation of microtubule tubulin heterodimer, thereby affecting microtubule-related cellular processes. TUBA1A mutation is the main cause of Type 3 Lissencephaly and double cortex syndrome.