Diagnosis: Lissencephaly type I

Lissencephaly type 1 (agyria), also known as classical lissencephaly, is a malformation of the brain that may occur as an isolated abnormality (isolated lissencephaly sequence [ILS]) or in association with certain syndromes (e.g., Miller–Dieker syndrome). This condition is characterized by agyria or pachygyria, meaning absence or incomplete development of brain gyrification or convolution, resulting in the brain surface appearing unusually smooth.

If an underlying syndrome is present, additional symptoms and physical findings may exist. Various causes of isolated lissencephaly are possible, including viral infections, insufficient blood supply to the brain during development, or certain genetic factors. Changes (mutations) in several genes are involved in isolated lissencephaly, including LIS1, RELN, TUBA1A, NDE1, KATNB1, CDK5, ARX, and DCX. Among these, gene mutations in LIS1 and DCX have been most extensively studied.

Diagnosis

Lissencephaly may result from various non-genetic (external) and genetic factors. These factors may include intrauterine infection, prenatal brain hypoxia (insufficient oxygenated blood supply to the brain during fetal development), and/or various gene mutations.

Several gene mutations have been implicated in isolated lissencephaly. One of the best studied examples is LIS1 (also known as PAFAH1B1). Mutations in this gene are responsible for lissencephaly type 1. The LIS1 gene is located on chromosome 17p13.3. This gene encodes the isoform 1B of platelet-activating factor acetylhydrolase, which interacts with microtubule-associated proteins such as dynein and dynactin. This interaction is essential for proper neuronal migration during fetal brain development; disruption of this interaction results in lissencephaly. Most children with isolated lissencephaly sequence have mutations or deletions involving only the LIS1 gene, whereas infants with Miller–Dieker syndrome are usually found to have mutations in the LIS1 gene along with additional deletions of adjacent genes on chromosome 17, resulting in features of type 1 lissencephaly and other craniofacial abnormalities. Such chromosomal changes occur randomly and are observed only in the affected child, without evidence of alterations in either parent. Importantly, this genetic form of lissencephaly does not typically recur in families, and therefore the risk of having another affected child is extremely low.

Among the genes involved in lissencephaly, DCX and ARX are notable because they are located on the X chromosome. This genetic form of lissencephaly may be observed in more than one child within a family, as the mutation may be present in the DNA of a healthy mother. Lissencephaly caused by DCX and ARX mutations is referred to as X‑linked lissencephaly types 1 and 2 (XLIS1–2 or LISX1–2). Because males have only one X chromosome, those who inherit the disease gene are more likely to express the full spectrum of abnormalities associated with the disorder and are therefore usually more severely affected. Females who inherit the mutation may have a more variable presentation and may be more mildly affected or even asymptomatic.

The DCX gene encodes the protein doublecortin, which binds to microtubules to regulate neuronal migration. X-linked mutations may occur randomly or be inherited. The ARX gene encodes a homeobox protein. In addition to classical lissencephaly features, children with ARX mutations may also have absence of parts of the brain (hydranencephaly), abnormal genitalia, severe epilepsy, and other abnormalities.

Other gene mutations associated with lissencephaly, such as RELN (causing Norman–Roberts syndrome), follow an autosomal recessive inheritance pattern. Recessive genetic disorders occur when an individual inherits two copies of an abnormal gene for the same trait, one from each parent. If an individual inherits one normal gene and one gene for the disorder, that person will be a carrier but will usually not show symptoms. The risk for two carrier parents to have an affected child is 25% in each pregnancy. The risk of having a child who is a carrier like the parents is 50% in each pregnancy. The chance that a child will inherit normal genes from both parents is 25%. The risk is the same for males and females.

In addition to LIS1, RELN, DCX, and ARX, mutations in other genes such as TUBA1A, NDE1, KATNB1, and CDK5 have also been found to cause lissencephaly. These genes share molecular functions with LIS1 and DCX, acting as part of the cellular dynein and dynactin apparatus required for neuronal migration during fetal brain development.

Emerging evidence suggests that both genetic changes and non-genetic causes lead to lissencephaly due to impaired migration of neurons in the outer region of the brain during fetal development. The cerebral cortex, which is responsible for conscious movement and thinking, normally consists of several deep gyri and sulci formed by folding of the cortex. During embryonic growth, newly formed cells that later develop into specialized nerve cells normally migrate to the surface of the brain (neuronal migration), resulting in the formation of multiple cellular layers. In lissencephaly type 1, however, these cells fail to migrate properly, leading to neuronal dysmigration and the development of an insufficient number of cortical layers, with absence or incomplete formation of gyri.

The overall incidence of lissencephaly is rare, estimated at approximately 1.2 per 100,000 live births.

Lissencephaly type 1 may be diagnosed through thorough clinical examination, brain imaging methods including cranial ultrasound (in newborns through the anterior fontanelle), computed tomography (CT of the brain), and/or magnetic resonance imaging (MRI of the brain), as well as genetic testing such as chromosomal analysis and/or specific gene mutation analysis. During CT scanning, a computer and X-rays are used to create images showing cross-sectional views of brain structures. In MRI, magnetic fields and radio waves generate cross-sectional images of the brain. Additional diagnostic methods may include electroencephalography (EEG). During EEG, electrical impulses of the brain are recorded. Brain malformations, including lissencephaly, are often associated with abnormal brain electrical activity and/or seizures. An abnormal EEG pattern may guide and support the diagnosis of lissencephaly. Finally, DNA analysis can detect specific deletions or mutations in genes associated with lissencephaly. Commercial genetic testing for known causes of lissencephaly is now available, and the number of genes included in these tests continues to increase with ongoing research.

Treatment

Therapy is directed toward the specific symptoms present in each individual. Treatment may require the coordinated efforts of a team of specialists. Pediatricians, neurologists, and other healthcare professionals may need to systematically and comprehensively plan the treatment of a child with lissencephaly.

Rehabilitation is recommended for delayed psychomotor development, speech therapy for feeding difficulties or problems with nutrition, and methods aimed at stimulating the intellectual development of the child (supportive therapies such as animal-assisted therapy, occupational therapy, special education sessions, etc.). Correction of visual and hearing impairments is performed as needed.

Therapy for individuals with lissencephaly type 1 is symptomatic and supportive. Treatment may include measures to improve nutritional intake in infants with feeding difficulties and administration of anticonvulsant medications to prevent or reduce seizures (antiepileptic drugs).

Genetic counseling is recommended for families of children with lissencephaly.

Lissencephaly type I

General

Diagnosis

Treatment

Do you want to see more?