The term lissencephaly means “smooth brain” and is used to refer to a neurological disorder in which there is insufficient development of the grooves and cerebral convolutions (Mota et al., 2005).
This type of pathology is a congenital malformation product of a neuronal migration disorder (Hernández et al., 2007), that is, in the process that nerve cells follow from the place of origin to their final location in the cortex brain during the embryonic period (Cleveland Clinic, 2016).
The clinical course of lissencephaly may include generalized growth retardation, muscle spasms, seizures, severe psychomotor retardation, facial abnormalities, among others (Cleveland Clinic, 2016).
In addition, this type of neuronal migration disorder is often associated with other medical conditions such as Miller-Dieker syndrome and Walker-Warburg syndrome (Cleveland Clinic, 2016).
Currently there is no curative treatment for lissencephaly. The prognosis for those affected by this pathology varies considerably between different cases, depending on the degree of brain malformation: some will not survive at 10 years of age, while others may show a serious delay of development and growth and others almost normal physical and cognitive development (National Institute of Neurological Disorders and Stroke, 2015).
Characteristics of lissencephaly
Lissencephaly is a genetic brain malformation characterized by the absence of normal convolutions in the cerebral cortex (Cortical Foundation, 2012).
The cerebral convolutions or turns are each of the folds existing on the outer surface of the brain, separated from each other by a series of grooves called fissures or cerebral fissures. (Wordreference, 2005).
Specifically, lissencephaly can manifest itself with different degrees of involvement, characterized by the absence (agiria) or reduction (paquya) of cerebral convolutions (Palacios Marqués et al., 2011).
The agiria, refers to the absence of folds in the brain surface and is often used as a synonym for “complete lissencephaly”, while the pachyria or presence of few thicker folds, is used as a synonym for “incomplete lisecenphaly” (Mota et al. al., 2005).
Thus, lissencephaly results from a disorder of brain development (Palacios Marqués et al., 2011) product of a group of anomalies in neuronal migration (Mota et al., 2005).
When the nervous system is being formed and developed during the prenatal stage, the neurons must travel from the layers or primitive areas to the cerebral cortex (Hernández et al., 2007),
During embryonic growth, newly formed cells that are later to become specialized nerve cells must miter from the surface of the brain to a preprogrammed final location. This migration is carried out in successive moments from the seventh week of gestation to the twentieth (National Organization for Rare Disorders, 2015):
There are several mechanisms by which the neurons reach their final location: some reach their location through displacement along the glial cells while others reach through chemical attraction mechanisms.
The ultimate goal of this displacement is to form a laminar structure of 6 layers in the cerebral cortex, essential for the correct functioning and development of cognitive functions (Hernández et al., 2007).
When an interruption of this process takes place and a lisecenphaly develops, the cerebral cortex presents an abnormally thick structure of 4 badly organized layers (Hernández et al., 2007).
Therefore, at the anatomical level, the lissencephaly can be defined by the presence of agiria or paquya and even the formation of a double cortex (Heterotopia) (Mota et al., 2005).
Lissencephaly is a group of rare brain malformations (Hernández et al., 2007).
Although there are no statistical data on the prevalence of milder forms of lissencephaly, the classical form has a frequency of 11.7 per million newborn children (Hernández et al., 2007).
The absence of recent data is mainly due to the sporadic occurrence of this pathology, as to the fact that a large part of the cases remained undiagnosed due to the absence of technical doctors (National Organization for Rare Disorders, 2015).
However, currently the use of advanced neuroimaging techniques in neurological evaluations has allowed an accurate recognition of this pathology and therefore an increase in the cases diagnosed (National Organization for Rare Disorders, 2015).
Characteristic signs and symptoms
Lissencephaly is a neurological disorder that is characterized by producing a completely smooth or partial brain surface and therefore a shortage of the development of brain turns and grooves (Lo Nigro et al., 1997, Jhons Hopkins University, 2016).
Classical forms are associated with the presence of an abnormally thick cerebral cortex composed of 4 primitive layers, a mixture of agiria and pachyria, neuronal heterotopia, dilated and dysmorphic cerebral ventricles, and in many cases, with hypoplasia of the corpus callosum (Lo Nigro et al. ., 1997; Jhons Hopkins University, 2016).
In addition to these characteristic anatomical findings, affected individuals may also exhibit other associated brain malformations, such as microcephaly (National Organization for Rare Disorders, 2015).
All structural alterations will produce a wide range of symptoms and medical signs (National Organization for Rare Disorders, 2015):
- Intellectual deficit
- Generalized growth retardation.
- Deficit in motor skills.
- Craniofacial malformations.
- Muscle tone decreased (hypotonia) or increased (hypertonia).
Types of lissencephaly
There is a wide variety of classifications of lissencephaly depending on the pathological, genetic and anatomical findings (Hernández et al., 2007).
Despite this, one of the most common classifications is that which refers to type I and type II of lissencephaly:
- Lissencephaly type I or type Bielchowsky : e s sporadic type in which the bark has certain organization, although it is formed by fewer layers than usual, generally four layers (Palomero-Domíngez et al . , 1998).
- Type II lissencephaly : characterized by a destructured cerebral cortex in which no layer (polyrogyric) can develop that develops with severe muscle disturbances, neurological dysfunction, hydrocephalus and encephalocele (Palomero-Domíngez et al., 1998).
In addition to this, there are other classifications based on the associated malformations and the etiological cause. Based on these criteria, lissencephaly can be classified into (Orphanet Encyclopedia, 2004):
- Classical lissencephaly (Type I) : includes cases of lissencephaly due to a mutation of the LIS1 gene (Isolated liencephaly type 1 and Mieller-Deker syndrome); lissencephaly due to a mutation of the DCX gene; isolated type 1 lissencephaly without known genetic defects.
- Lysencephaly linked to the X chromosome with agenesis of the corpus callosum.
- Lissencephaly with cerebellar hypoplasia .
- Microlisencefalia .
- Lisencephaly type II : includes the syndromes of Walker-Warburg, Fukuyama, among others.
The investigations that have tried to find the specific causes of lissencephaly indicate that there may be genetic and non- genetic etiological factors : intrauterine infection; cerebral ischemia or deficient oxygen supply to the brain during fetal development; alteration or absence of a region of chromosome 17; autosomal recessive linked X chromosome transmission (National Organization for Rare Disorders, 2015).
The causes of this pathology are heterogeneous, approximately 76% of the diagnosed cases present primary genetic alterations, while the rest of the cases present some association with another series of environmental factors (maternal exposure to retinoic acid, ethanol, radiation or infectious processes , 2007).
It is generally considered that lissencephaly is a fundamentally genetic pathology associated with different alterations in some of the following genes: LIS1, 14-3-3, DCX, REELIN and ARX (Nall, 2014).
On the other hand, scientific evidence suggests that in isolated cases of lissencephaly, this pathology can result from the presence of mutations in at least two different genes (National Organization for Rare Disorders, 2015):
- LIS1 , located on the short arm (p) of chromosome 17. It is a gene that regulates the production of a protein ( platelet activating factor acetylhydrolase factor) that plays an important role in the development of the outer layer of the brain.
- XLIS , located on the long arm (q) of the X chromosome. According to specialists, this gene is responsible for regulating a protein (doublecortin -DCX-) that is essential for the neuronal migration process to develop efficiently.
In the case of the LIS1 gene, such mutations may occur sporadically at random or may result from the chromosomal rearrangements of one of the progenitors. On the other hand, in the case of the XLIS gene, mutations can also occur randomly in the absence of family history and in other cases it appears as an inherited condition linked to the X chromosome (National Organization for Rare Disorders, 2015).
Medical pathologies associated with lissencephaly
Lysencephaly, in addition to presenting in isolation showing the structural alterations and clinical symptoms characteristic of this pathology, may appear associated with other genetic diseases (Nall, 2014):
- Miller-Dieker syndrome : this pathology results from a mutation in a gene located on chromosome 17p13. At the cynic level, it is characterized by the presentation of classical lissencephaly, facial anomalies, severe developmental disorder, epilepsy or feeding problems (Orphanet, 2005).
- Walker-Warburg syndrome : this pathology is a congenital form of muscular dystrophy that is associated with the presence of cerebral and colar anomalies . Clinically, Walker-Warburg syndrome is characterized by the presence of type II lysecephaly, hydrocephalus, hypoplasia of the brainstem and cerebellum, generalized muscular hypotonia, absence or poor psychomotor development, ocular involvement and convulsive episodes (Orphanet, 2011). .
The lissencephaly can be diagnosed before birth, approximately at the end of the second trimester, since it is from that moment when the cerebral convolutions are visible in ultrasounds (Palacios Marqués et al., 2011).
The techniques of unsound that are routinely used in the sanitary controls of pregnancy, may indicate the presence of alterations and brain abnormalities, however, should be complemented with other diagnostic techniques (Cortical Foundation, 2012).
When there is a suspected ultrasonography of lissencephaly, other types of secondary examinations should be used, such as magnetic resonance imaging or genetic studies to detect possible alterations (Palacios Marqués et al., 2011).
In addition to this diagnostic procedure, when there is a compatible family history or history of lissencephaly, it is possible to perform other tests such as amniocentesis (extraction of amniotic fluid that surrounds the fetus) and chorionic villus sampling (extraction of a sample of tissue from an area of the placenta) to identify the presence of genetic alterations (National Organization for Rare Disorders, 2015).
Despite this, it is more common for the diagnosis of lissencephaly to be performed after birth through the use of computed tomography or magnetic resonance (Cortical Foundation, 2012).
There is no curative intervention for lissencephaly, it is a pathology that can not be reversed (Nall, 2014).
The treatments used are aimed at improving the associated symptomatology and secondary medical complications. For example, the use of gastrostomy to replace feeding difficulties, surgical bypass to drain possible hydrocephalus or the use of antiepileptic drugs to control possible seizure episodes (Nall, 2014).
Therefore, the usual treatment for lissencephaly is directed towards the specific symptoms that appear in each case and requires the coordinated effort of a broad team of specialists: pediatricians, neurologists, etc. (National Organization for Rare Disorders, 2015).
Prognosis of people affected by lissencephaly
The medical prognosis of an individual suffering from lissencephaly depends fundamentally on its severity (Nall, 2014).
In the most severe cases of lissencephaly, the affected person may not be able to develop physical and cognitive skills beyond those of a child between the ages of three and five months (Nall, 2014).
In general, children with a serious condition have a life expectancy of approximately 10 years. The most common causes of death are aspiration or drowning with food or liquids, respiratory pathologies or convulsions (Nall, 2014).
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On the other hand, there are cases of children with mild lissencephaly who may experience a normalized development, more adjusted to their age group, sex and school level (Nall, 2014).