The brain is the result of many thousands of years of evolution of our species. It is one of the most complex natural phenomena we know, and the essence of what makes us human. Although it is no stranger to the umbrella of scientific knowledge, new questions about its functioning are raised every day.

Its appearance is also very striking. In the part visible to the outside, it is composed of a group of convolutions (protrusions with similar shapes and locations for almost all people) and grooves (cracks or gaps that are located between the turns), which serve for the correct location of anatomical sections.

The adoption of its particular form occurs throughout the process of gestation, and is linked to the way genes act on our prenatal development. Genetic alterations, or maternal exposure to certain pathogens and toxins, can compromise such a delicate biological balance.

In this article, one of these clinical circumstances, the pachygiria , will be discussed in particular, which implies a situation of great severity and risk for the continuity of life. Its most essential characteristics, its causes and frequent symptoms will be addressed here.

What is pachygiria?

Pachygiria is a congenital and serious malformation, which affects the organization of neurons and the structure of the brain . It is characterized by the presence of barely pronounced cerebral gyres, as well as by the thinning of the cortex, which alters the overall structure of the organ (few apparent elevations on its surface, the gyres being thicker and wider than those observed in the average population). This neuropathology, which has multiple consequences for those who suffer it, would be included in the nosological category of cortical dysgenesis.

Specifically, the pachygiria belongs to the family of lysencephalias , between agyria (total absence of convolutions) and subcortical band heterotopia (presence of a “layer” of gray substance in the area between the walls of the lateral ventricles and the cortex itself), according to the classification of Dobyns. Such structural involvement is usually predominantly posterior, although it occasionally spreads to the front of the brain and compromises a wide range of cognitive functions.

In fact, it is a severe health condition, with very high mortality rates in the first years (it affects 1/90,000 people in its severe forms, although there is no information about it in the mild forms). It is also associated with the presence of physical and mental symptoms of enormous importance, which compromise daily autonomy and/or pose a real danger to survival. The most notable are muscular hypotonia, ataxia or epileptiform seizures (resistant to medical treatment and of very early onset), as well as severe intellectual disability and general developmental delay.

The diagnosis is usually carried out by means of two very different, but also complementary strategies: the clinical exploration of the signs/symptoms and the use of structural neuroimaging techniques such as magnetic resonance imaging .

This last procedure is very useful, since it allows obtaining detailed images of the grooves/cissures and the convolutions, which makes the clinical certification of this pathology much easier (especially if we consider that many of its symptoms can be confused with other more common problems). The absence of dysmorphia (facial alterations typical of chromosomal abnormalities) could hinder its early detection.

What are the symptoms of pachygiria?

Pachygiria has three basic symptoms: seizures, severe developmental disturbance, and intellectual disability. This triad can be easily detected from the fourth/fifth month of life, and usually warrants consultation with the paediatrician. Although the overall prognosis is unclear (since these symptoms are resistant to pharmacological intervention or directly untreatable), early care can minimize or prevent the occurrence of more serious complications (such as infectious processes, which are common in these patients).

1. Epileptic seizures

Pachygiria is one of the diseases that cause childhood epileptic seizures, which can be a serious risk to life. Its establishment is early, since a high percentage of subjects experience them within the time range between the fourth and seventh month after birth (exceptionally after 18 months). It usually consists of sudden onset seizures, both in flexion (abdominal torsion in which the body adopts a position similar to that of a “closed razor”) and in extension (arms and legs stretched out in the form of a “cross”). Until the expansion of functional neuroimaging technologies, these epilepsies were considered cryptogenic (of unknown origin).

Developmental delay

Delayed motor development, as well as language use, is a common feature in people diagnosed with pachygiria. It is usually very frequent that the basic verbal catalogue is not acquired in order to fully construct communicative acts, or that laxity is evident in the arms and legs.

Many of these infants are unable to maintain an upright, standing position without the support/help of others. A significant percentage also show a sign that will predict the problems cited: microcephaly , or what is the same, a reduction in the expected growth of the cranial perimeter.

3. Intellectual disability

People with pachygiria have a severe intellectual disability, seeing altered practically all the cognitive functions and the potential to develop full personal autonomy.

Such difficulty would respond to the abnormal migration of neurons (which will be detailed below) and becomes more evident when the child has to deal with all the demands of school or other contexts requiring social and/or motor skills. The identification of such a situation is key, because the deployment of an adequate program of curricular adaptation and therapeutic pedagogy will depend on it.

What are the causes of pachygiria?

Pachygiria is caused by an abnormal migration of neurons during pregnancy . This process extends between the seventh and twentieth week, and is fundamental for the system to acquire correct functionality from birth.

It is a peculiar “journey” that the nerve cells undertake to relocate themselves in such a way as to make possible the characteristic cognition of the human being, and which requires their deambulation from the ventricles to the external cerebral cortex (travelling enormous distances in proportion to their size). This phenomenon does not occur in a continuous way, but is presented as intermittent “spurts”.

Although the general purpose is to form six differentiated layers of tissue , prepared to host the unfathomable complexity of the mind, in this case only four would be formed (and also subject to many structural problems). This laminar disposition motivates the agenesis of the convolutions and/or the furrows, being a result of the deficient organization of the brain. The observation of this abnormality, thanks to the optical or electronic microscopes, shows an anatomopathology that we proceed to point out (for each of its four layers).

The first layer (molecular or plexiform), which is the outermost layer of our cerebral cortex, would not show aberrations of any kind . The neurons in this region would have an identical shape and location to those in a brain without problems. However, in the second region there are already some important differences: the number of cells is clearly lower and they are disorganized, coexisting with neurons from layers II, V and VI of the normal brain. This quantitative/qualitative alteration impacts on the general appearance of the organ (since it forms the true cortex of the organ).

The third layer is also very different from the six-layer cortex. Here the neurons are poorly organized and distributed as large columns, resulting in a tissue of low density or thickness. There is also some evidence of lamellar necrosis , which is responsible for hindering proper cell migration. Finally, the fourth layer would also look thin, but built with white substance invaded by a myriad of heterotopic neurons (located in different spaces than they should occupy).

In addition to deficiencies in neuron migration, which is the common etiological basis for all lysencephalias, multiple environmental and genetic risk factors are known. In the following lines we proceed to describe them in detail.

1. Exposure to substances and/or viral infections

Pachygiria usually appears in the fourth month of gestation, after the neural migration stage. Although it is a problem that tends to occur sporadically (perhaps influenced by genetic factors), it is known that exposure to certain chemicals is closely related to the probability of suffering from it .

The most common are ethanol (ethyl alcohol), methylmercury (resulting from the activity of the industry that uses acetaldehyde; such as paper, plastics, paints, rubber or leather) and retinoic acid (a metabolite of vitamin A); but also radiation exposure could play a key role.

Infections with cytomegalovirus (throughout pregnancy) have been associated with both pachygiria and other serious alterations in neuronal migration. When an individual comes into contact with this particular pathogen it is usually retained for life, but acute episodes during pregnancy can be very dangerous. The problem is that it tends not to be too invasive (asymptomatic) in those who are healthy, so it is recommended that diagnostic tests are carried out if contact with an infected person in the acute phase is believed.

2. Genetic alterations

A succession of alterations in the genome have been described that are related to an accentuated risk of pachygiria. The most common is the one involving chromosomes 17 and X , which are the most frequently detected when a cause at this level is filiated (which is not always possible). In other cases, a mutation in the Reelin gene (essential for neural migration) has been found on chromosome 7

Although the general purpose is to form six differentiated layers of tissue , prepared to host the unfathomable complexity of the mind, in this case only four would be formed (and also subject to many structural problems). This laminar disposition motivates the agenesis of the convolutions and/or the furrows, being a result of the deficient organization of the brain.
The observation of this abnormality, thanks to the optical or electronic microscopes, shows an anatomopathology that we proceed to point out (for each of its four layers).

The first layer (molecular or plexiform), which is the outermost layer of our cerebral cortex, would not show aberrations of any kind .
The neurons in this region would have an identical shape and location to those in a brain without problems.
However, in the second region there are already some important differences: the number of cells is clearly lower and they are disorganized, coexisting with neurons from layers II, V and VI of the normal brain. This quantitative/qualitative alteration impacts on the general appearance of the organ (since it forms the true cortex of the organ).

The third layer is also very different from the six-layer cortex.
Here the neurons are poorly organized and distributed as large columns, resulting in a tissue of low density or thickness. There is also some evidence of lamellar necrosis , which is responsible for hindering proper cell migration. Finally, the fourth layer would also look thin, but built with white substance invaded by a myriad of heterotopic neurons (located in different spaces than they should occupy).

In addition to deficiencies in neuron migration, which is the common etiological basis for all lysencephalias, multiple environmental and genetic risk factors are known.