Lissencephaly is a group of genetically determined brain development abnormalities characterized by partial or complete underdevelopment of the convolutions and furrows of the cerebral cortex, as well as a violation of its ultrastructure. The severity and combinations of symptoms of this condition differ in different forms of the disease, the most common are seizures, deep mental retardation, swallowing disorders and muscle hypotension. Diagnosis can be performed by ultrasound techniques (including prenatal), computer and magnetic resonance imaging, for the most common forms it is possible to determine by molecular genetic analysis. There is no specific treatment, symptomatic and supportive therapy is used.
Lissencephaly is a group of severe brain development abnormalities that are accompanied by underdevelopment of the cerebral cortex with the formation of pachygyria (the presence of only a few convolutions and furrows) or agyria (complete absence of cortical folding). This pathology can act as an independent genetic disease or enter into the symptom complex of other syndromes – for example, Miller-Dicker, Fukuyama and Walker-Warburg. The mechanism of inheritance of various types of lissencephaly can be autosomal recessive, autosomal dominant (in this case, spontaneous or germinative mutations most often occur) and linked to the X chromosome. Due to the variety of inheritance mechanisms, the sexual distribution of the disorder is not the same in various forms of pathology. Lissencephaly is a fairly rare genetic abnormality of brain development, so the occurrence is determined only for the most common first group of disorders – it is 11.7 cases per 1,000,000 newborns. For the remaining groups of lissencephaly, the occurrence has not been established, including because in many cases a fetus with such a pathology is not carried, and pregnancy is spontaneously interrupted in the first trimester even before the presence of a defect is determined.
The main common cause of all types of lissencephaly is a violation of the migration of precursor cells of neurons (neuroblasts) from the anterior parts of the neural tube to the future cortex of the large hemispheres. As a result, instead of a complex folded structure, which has six layers in its composition, a smooth bark is formed or has many times fewer furrows, consisting of 2-4 layers (depending on the form of the disease). Since the cerebral cortex in humans is responsible for cognitive functions, it contains a huge number of nerve centers and extensive associative zones, lissencephaly leads to severe disorders. In addition, with some types of mutations that cause this condition, it is possible to develop abnormalities of other organs and tissues, which further aggravates the patient’s condition.
The most common types of lissencephaly are caused by defects in the PAFAH1B1 gene, also known as LIS1 and located on the 17th chromosome. Many geneticists note that for the occurrence of pronounced underdevelopment of the cerebral cortex and Miller-Dicker syndrome, not point mutations in LIS1 are necessary, but large deletions with the capture of hundreds of pairs of nitrogenous bases. Often, the surrounding genes are also damaged, which causes a variety of phenotypic manifestations of this type of lissencephaly. The LIS1 gene encodes an intracellular subunit of a structurally complex enzyme that takes an active part in neuroblast migration. Defects in the structure of this subunit lead to a violation of this process and the development of this disease.
Another form of lissencephaly is caused by a mutation of the DCX gene localized on the X chromosome, so the inheritance of this type of pathology is linked to gender. The protein obtained as a result of the expression of this gene is involved in the formation of a special type of microtubules, which are produced only by neuroblasts and are necessary for them to form connections between cells. Violations in the structure of DCX lead to the synthesis of a defective protein, which provokes lissencephaly. Another relatively studied variant of this condition, also linked to the X chromosome, is caused by mutations of the ARX gene, which is a transcription factor for other genes. It controls the development of the cerebral cortex, pancreas and genitals, which is why ARX defects are manifested by numerous defects of these organs, including lissencephaly.
Another common variant of lissencephaly is a form of the disease caused by a mutation of the RELN gene located on the 7th chromosome. Defects in this gene lead to the so-called Norman-Roberts syndrome, which, among other things, is accompanied by a pronounced violation of the folding of the cerebral cortex. The RELN gene encodes the sequence of the glycoprotein rilin, which takes an active part in the formation of nervous tissue, and also controls the formation of new dendrites and the functioning of long-term memory in adults. It was possible to identify another gene that leads to the development of lissencephaly – TUBA1A, which is localized on the 12th chromosome. It encodes a certain component of the cytoskeleton of neurons, its defect leads to the inferiority of neuroblasts, which disrupts the process of their migration in the embryonic period.
To date, more than twenty variants of lissencephaly have been identified. These variants are caused by various mutations, have differences in the phenotypic manifestations of the disease, different inheritance mechanisms and severity of symptoms. For a long time, the varieties of pathology could not be successfully classified due to a significant variety of genetic defects and insufficient data on key genes leading to the development of some forms of the disease. Only in 2003, it was possible to create a classification of lissencephaly that is quite acceptable from the point of view of modern genetics and neurology, which takes into account the main nuances of this condition. Experts divide all forms of lissencephaly into five classes:
- Class 1, often referred to as classical lissencephaly. It includes forms of the disease caused by mutations of the LIS1 gene (isolated type and Miller-Dicker syndrome), as well as a sex-linked variety caused by the DCX mutation. In addition, some types of lissencephaly with unclear genetic causes are often included in this class. A feature of the group is a violation of the folding of the cerebral cortex with minimal manifestation of other anomalies of the central nervous system.
- Class 2 – Currently consists of only one type of lissencephaly, which is caused by defects in the ARX gene. The disease is linked to the X chromosome, in addition to malformations of the cortex, patients often show the absence of a corpus callosum, thermoregulation disorders, pronounced abnormalities of the genitals and pancreas.
- Class 3 – includes varieties of lissencephaly in combination with hypoplasia or complete underdevelopment of the cerebellum, the most typical mutation for this class are defects of the RELN gene. It can be registered as an isolated variant of pathology or as part of Norman-Roberts syndrome.
- Class 4, is often called microlissencephaly, since a violation of the formation of the cerebral cortex is accompanied by severe microcephaly. Some forms of this disease have been reliably associated with mutations of the TUBA1A gene.
- Class 5 or cobblestone lissencephaly, which include Fukuyama and Walker-Warburg syndromes. The latter correlates with defects in the genes POMT1, POMT2, FKRP and some others, all of them are located on the 9th chromosome.
This classification is criticized by some researchers due to the presence of a large number of “white spots” in the form of the inclusion of forms of lissencephaly with uncertain key genes. However, at present it is this division that is considered the most generally accepted in the scientific world. The classification is adjusted as the condition is further studied.
The main manifestations of lissencephaly are muscle weakness, detected already at birth, frequent swallowing and sucking disorders, convulsive seizures, severe lag in physical and mental development. The severity of certain manifestations of the disease depends on the presence of malformations of both the brain and other organs and systems, as well as on the degree of underdevelopment of the cortex. The most severe forms of pathology are observed in the presence of complete agyria. Sometimes patients with lissencephaly can live to adolescence and even adulthood, deep underdevelopment of the central nervous system persists throughout life. Some patients live their lives on the verge of a vegetative state. The fatal outcome in lissencephaly occurs due to complications caused by defects in other organs and systems, as well as due to secondary pneumonia, cardiovascular and other anomalies.
Diagnosis and treatment
With regard to lissencephaly, prenatal diagnosis is possible using ultrasound research methods, while increasing the resolution of ultrasound equipment contributes to the earlier detection of the disease. The development of disorders in the structure of the cerebral cortex occurs at the 14th-20th week of gestation, currently, during this period, pathology can be determined and the question of termination of pregnancy can be raised. After the birth of a child with suspected lissencephaly, the diagnosis is confirmed by CT and MRI. Molecular genetic diagnostics is highly accurate, but it is only available for those forms of the disease for which the key genes are known. There is no specific treatment for lissencephaly, anticonvulsants, nootropics and other means are used to reduce the severity of symptoms. In the presence of other malformations, their correction is performed for medical reasons.
Prognosis and prevention
The prognosis of almost any form of lissencephaly is extremely unfavorable, most patients die in early childhood from complications and other malformations. Some mild cases of this condition with partial or focal underdevelopment of the cerebral cortex have been described, but not all specialists are inclined to classify such types of pathology as lissencephaly. Prevention is possible only within the framework of prenatal diagnosis. In the presence of such diseases in the genus, it makes sense to conduct a genetic analysis for the carriage of genes of autosomal recessive types of pathology. If the fetus is found to have brain formation disorders corresponding to lissencephaly, the question of termination of pregnancy is raised.