Lissencephaly of the brain

Among organic cerebral pathologies, such a congenital anomaly in the development of the brain as lissencephaly stands out, the essence of which lies in the almost smooth surface of the cortex of its hemispheres - with an insufficient number of convolutions and grooves. [1]

In the complete absence of convolutions, agiria is determined, and the presence of several wide flat convolutions is called pachigiria. These defects, like some other reduction deformities of the brain, in the ICD-10 have the code Q04.3.

Epidemiology

According to statistics on rare diseases, there are 1-1.2 cases of lissencephaly per 100 thousand newborns. [2], [3]

According to some reports, up to 25-30% of cases of classic lissencephaly are observed in children with Miller-Dicker syndrome; almost 85% of patients show point mutations and deletions of the LIS1 and DCX genes. [4]

Genetic studies of 17 genes associated with lissencephaly showed that the LIS1 mutation or deletion accounts for 40% of patients and 23% are associated with the DCX mutation, followed by TUBA1A (5%) and DYNC1H1 (3%). [5]

Causes lissencephaly

All known reasons for the formation of the cerebral cortex (cortex cerebri) almost or completely without convolutions and grooves that increase the "working area" of the human brain and provide the "performance" of the central nervous system are associated with disorders of its perinatal development. That is, lissencephaly develops in the fetus. [6]

Failure in the formation of layers of the cerebral cortex of the fetal brain with lissencephaly is the result of abnormal migration of the neurons that form it or the premature stop of this process. 

This process, most important for cerebrocortical histogenesis, occurs in several stages from 7 to 18 weeks of gestation. And, given its increased sensitivity to genetic mutations, as well as various negative physical, chemical and biological influences, any deviation from the norm can lead to incorrect localization of neurons with the possible formation of a thickened layer of gray matter of the cortex without a characteristic structure. [7]

In some cases, lissencephaly in children is associated with Miller-Dicker, Walker-Warburg, or Norman-Roberts syndromes.

Read also -  Malformations of the brain

Risk factors

In addition to mutations of some genes, risk factors for having a child with such a severe defect include oxygen starvation (hypoxia) of the fetus; insufficient supply of the brain with blood (hypoperfusion); acute disturbance of cerebral circulation in the form of perinatal stroke; pathology of the placenta; viral infections of a pregnant woman (including TORCH); [8]problems with general metabolism and thyroid function; smoking, alcohol, psychotropic and narcotic substances; the use of a number of drugs; increased background radiation. [9]

Pathogenesis

Not all cases of lissencephaly have a pathogenesis due to chromosomal abnormalities and gene mutations. But some genes are known that encode proteins that play an important role in the correct movement of neuroblasts and neurons along the cells of the radial glia - for the formation of the cerebral cortex. And mutations of these genes lead to this pathology. [10]

In particular, these are sporadic mutations (without heredity) of the LIS1 gene on chromosome 17, which regulates the cytoplasmic motor protein of microtubules dynein, as well as the DCX gene on the X chromosome, which encodes the doublecortin protein (lissencephalin-X). [11]In the first case, experts define classic lissencephaly (type I), in the second - X-linked. [12]

When the FLN1 gene, which encodes the phosphoprotein filamin 1, is deleted, the process of directed migration of neurons may not start at all, leading to a complete absence of convolutions (agiria). [13]

Mutations in the CDK5 gene, which encodes a kinase enzyme, a catalyst for intracellular metabolism, regulates the cell cycle in neurons of the central nervous system and ensures their normal migration during the prenatal formation of brain structures.

Abnormal changes in the RELN gene on chromosome 7, causing defects in the gyrus of the cerebral hemispheres in Norman-Roberts syndrome, lead to a lack of extracellular glycoprotein reelin, which is necessary for the regulation of migration and positioning of nerve stem cells during the development of cortex cerebri. [14],  [15], [16]

The ARX gene encodes a homeobox protein unrelated to aristalens, which is a transcription factor that plays an important role in the forebrain and other tissues. [17]Children with the ARX mutation have other symptoms such as missing parts of the brain (agenesis of the corpus callosum), abnormal genitals, and severe epilepsy. [18], [19]

Several genes have been linked to lissencephaly. These genes are VLDLR, ACTB, ACTG1, TUBG1, KIF5C, KIF2A, and CDK5.[20]

Cytomegalovirus (CMV) is associated with the development of lissencephaly due to decreased blood supply to the fetal brain. The severity of CMV infection depends on the length of the pregnancy. Early infection is more likely to cause lissencephaly as neuronal migration occurs early in pregnancy.[21]

In addition, the mechanism of occurrence of this anomaly includes an incomplete or later arrest of the movement of neurons from the periventricular generative zone to the cerebral cortex. And in such cases, either incomplete lissencephaly or pachigiria develops, in which several wide grooves and convolutions are formed (but most of them are absent).

Symptoms lissencephaly

The first signs of this pathology (in the absence of the previously named syndromes) may appear not immediately after birth, but after one and a half to two months. And most often such clinical symptoms of lissencephaly are observed, such as:

• muscle hypotension, often combined with spastic paralysis;
• convulsions and generalized tonic-clonic seizures (in the form of opisthotonus);
• profound mental retardation and growth retardation;
• violation of neurological and motor functions.

Swallowing problems make it difficult to feed the infant. [22]

A high degree of neuromotor disorders is often manifested by tetraplegia - paralysis of all limbs. Deformation of hands, fingers or toes is possible.

In Norman-Roberts syndrome with type I lissencephaly, craniofacial abnormalities are noted: severe microcephaly, low forehead slope and a protruding wide nose bridge, wide-set eyes (hyperterlorism), underdevelopment of the jaws (micrognathia). [23]

Miller-Dicker syndrome may also have an abnormally small head size with a wide, high forehead and short nose, depressions in the temples (bitemporal depressions), and low-set, deformed ears.

Severe lissencephaly syndrome is characterized by microcephaly, decreased size of the eyeballs (microphthalmia) in combination with retinal dysplasia, obstructive hydrocephalus, and absence or hypoplasia of the corpus callosum. 

Complications and consequences

Among the complications of this anomaly, experts call impaired swallowing function (dysphagia) and gastroesophageal reflux; refractory (uncontrolled) epilepsy; frequent upper respiratory tract infections; pneumonia (including chronic aspiration).

Infants with lissencephaly may have congenital cardiac problems of an organic nature in the form of an atrial septal defect or complex heart defect with cyanosis (Fallot's tetralogy). [24]

The consequences of postnatal developmental failure are in most cases fatal within 24 months after birth.

Diagnostics lissencephaly

Diagnosis begins with a physical examination of the baby, parental history, and history of pregnancy and childbirth.

During gestation, fetal extracellular DNA tests, amniocentesis, or chorionic villus sampling may be required. [25]For more information, see -  Prenatal Diagnosis of Congenital Diseases

Instrumental diagnostics are used to visualize brain structures and assess their functions:

• computed tomography of the brain ;
• magnetic resonance imaging (MRI) of the brain ;
• electroencephalogram (EEG). [26]

During pregnancy, lissencephaly on ultrasound of the fetus after 20-21 weeks can be suspected in the absence of parieto-occipital and spur furrows and anomalies of the sylvian groove of the brain.

Differential diagnosis

Differential diagnostics with other syndromes of congenital cerebral defects is carried out.

There are over 20 types of lissencephaly, most of which fall into 2 main categories: classic lissencephaly (type 1) and cobblestone lissencephaly (type 2). Each category has similar clinical manifestations, but different genetic mutations.[27]

Examination of the brain for type I lysencephaly shows the cerebral cortex with four layers instead of six as in normal patients, whereas in type 2 lysencephaly the cerebral cortex is disorganized and appears lumpy or nodular due to the complete displacement of the cerebral cortex in clusters. Cortical neurons separated by gliomesenchymal tissue. The patients also had muscle and eye abnormalities. 

1. Classic lissencephaly (type 1):
   • LIS1: Isolated lisencephaly and Miller-Dicker syndrome (lissencephaly associated with facial dysmorphism). [28]
   • LISX1: DCX gene mutation. Compared to lissencephaly caused by LIS1 mutations, DCX shows a six-layered cortex instead of four.
   • Isolated lissencephaly without other known genetic defects
2. Lissencephaly paving stones (type 2):
   • Walker-Warburg Syndrome
   • Fukuyama Syndrome
   • Disease of muscles, eyes and brain
3. Other types cannot be placed in one of the above two groups:
   • LIS2: Norman-Roberts syndrome, similar to type I lysencephaly or Miller-Dicker syndrome, but without deletion of the 17th chromosome.
   • LIS3
   • LISX2

Microlisencephaly: This is a combination of the absence of a normal cortex fold and an abnormally small head. Babies with normal lissencephaly at birth have a normal head size. Children with reduced head size at birth are usually diagnosed with microlysencephaly.

It is also important to distinguish between lysencephaly and polymicrogyria, which are different malformations of the brain.

Treatment lissencephaly

Lissencephaly refers to incurable organic defects, therefore only supportive and symptomatic treatment is possible. [29]

First of all, this is the use of anticonvulsants and antiepileptic drugs, as well as the installation of a gastrostomy tube in the stomach (if the child is not able to swallow on his own). Massage is helpful.

With severe hydrocephalus, cerebrospinal fluid is removed.

Prevention

Experts recommend that future parents seek genetic counseling, and pregnant women - timely register with obstetricians and gynecologists and undergo all routine examinations.

Forecast

For children with lissencephaly, the prognosis depends on its degree, but most often the child's mental development does not exceed the level of four to five months. And all children with such a diagnosis suffer from severe psychomotor disorders and intractable epilepsy. [30]

According to the NINDS (American National Institute of Neurological Diseases and Stroke), the maximum life expectancy for lissencephaly is about 10 years.