Lissencephaly (, meaning 'smooth brain') is a set of rare brain disorders whereby the whole or parts of the surface of the brain are smooth. It is caused by defective neuronal migration during the 12th to 24th weeks of gestation, resulting in a lack of development of brain folds (gyri) and grooves (sulci). It is a form of cephalic disorder. Terms such as agyria (no gyri) and pachygyria (broad gyri) are used to describe the appearance of the surface of the brain. Children with lissencephaly generally have significant developmental delays, but these vary greatly from child to child depending on the degree of brain malformation and seizure control. Life expectancy can be shortened, generally due to respiratory problems.
Signs and symptoms
Affected children display severe psychomotor impairment, failure to thrive, seizures, and muscle spasticity or hypotonia. Other symptoms of the disorder may include unusual facial appearance, difficulty swallowing, and anomalies of the hands, fingers, or toes. Symptoms of lissencephaly are detected via ultrasound at about twenty-three weeks of gestation and require confirmation via prenatal MRI. It is characterized by absence or reduction of the sulci and gyri of the cerebral surface and a thickened cortex. There are anatomical symptoms that differ across the two main types of lissencephaly, Classical (Type I) and Cobblestone (Type 2). In classical lissencephaly, the cerebral cortex becomes thickened and has only four identifiable layers rather than the usual six. Cobblestone lissencephaly is named after the pebbled or cobblestone appearance of the cortical surface. This uneven cortical surface is due to incomplete organogenesis which leads to no distinguishable layers in the cerebral cortex. Cobblestone lissencephaly shows a reduction and abnormalities in the grey matter of the cerebral cortex.
Causes Causes of lissencephaly can include viral infections of the uterus or the fetus during the first trimester, or insufficient blood supply to the fetal brain early in pregnancy. There are also a number of genetic causes of lissencephaly, including mutation of the reelin gene (on chromosome 7), as well as other genes on the X chromosome and on chromosome 17. Genetic counseling is usually offered if there is a risk of lissencephaly, coupled with genetic testing.
Neuronal migration Folding of the cerebral cortex is important in the development of overall brain function and cognitive abilities. Neuronal migration is the process by which neurons migrate to the final position in the brain during the development of the nervous system. This development of the nervous system occurs between 12 and 16 weeks of gestation. The neurons are created at the ventricular zone. The neurons then extend along the radial glia to reach the cortical zone. It is the disruption of the radial and tangential migration that causes reduced or absent gyri that is known as lissencephaly. The lack of gyri causing a smooth appearance of the cerebral cortex is due to abnormal neuronal migration in the developmental stages of the nervous system. The cause of lissencephaly has been linked to both genetic and non-genetic factors. Three main types of lissencephaly have been identified, and although all types display similar symptoms, the pathogenesis of each type varies. The genes associated with lissencephaly are still being discovered; however, due to advances in genetics, individual genes are being identified as the cause of lissencephaly. Mutations in LIS1, DCX (doublecortin), ARX (aristaless related homeobox), RELN have all been identified to cause lissencephaly. Viral infections can also cause lissencephaly. The known genetic and viral causes are listed below:
LIS1 LIS1 (also known as PAFAH1B1) is the most widely studied. LIS1 is located on chromosome 17p13.3. LIS1 is integral in regulating the motor protein dynein which plays an important role in the movement of neuronal nuclei along microtubules. The mutation or deletion involving LIS1 is associated with both Isolated Lissencephaly syndrome and Miller–Dieker syndrome. Miller-Dieker syndrome, however, has additional deletions of adjacent genes on chromosome 17 causing facial and other congenital abnormalities and defects. This mutation full or deletion of chromosome 17p13.3 leads to inadequate neuronal migration due to LIS1 encoding for an enzyme that interacts with the microtubule protein dynein. LIS1 mutation or deletion is not inherited from a parent and thus recurrence is unlikely. A Chinese family with an autosomal dominant inheritance pattern and a mutation in this gene has been reported.
DCX DCX or doublecortin encodes for the doublecortin protein which is similar to LIS1 as it encodes a microtubule associated protein that is related to microtubule function and transport in developing neuronal processes. DCX mutation causes the disorganisation of neocortical layering in the cerebral cortex leading to a reduced folding. DCX is localised to the X chromosome and thus this mutation may be inherited however it still can appear randomly. As it is an X chromosome linked abnormality males who inherit the gene are more likely to be severely affected. Females who inherit the DCX mutation have a more mild version of the syndrome.
ARX The ARX gene encodes for the aristaless related homeobox genes which are active in the early embryonic development to control formation of many tissues and structure. ARX is involved in the development of the embryonic forebrain, migration and communication of neurons as well as migration and proliferation of interneurons. As ARX is expressed in the ganglionic eminences and the neocortical ventricular zone it can affect both radial and tangential migration. Similar to DCX, ARX is an X chromosome linked gene and is linked with other symptoms such as absence of portions of the brain, abnormal genitalia and severe epilepsy.
RELN Reelin (RELN) is an extracellular matrix glycoproteins that is secreted to help with the regulation of neuronal migration. Lack of RELN in mice has shown deficiencies in migrating neurons. In reported cases, lissencephaly caused by RELN deficiency has been more severe in anterior brain regions with a very small cerebellum.
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