NORD gratefully acknowledges Dillon Chen, MD, and Joseph G. Gleeson, MD, Rady Children’s Hospital, and University of California San Diego, for assistance in the preparation of this report.
Lissencephaly type 1, also known as classic lissencephaly, is a brain malformation that may occur as an isolated abnormality (isolated lissencephaly sequence [ILS]) or in association with certain syndromes (e.g., Miller-Dieker syndrome). The condition is characterized by agyria or pachygyria, which means absence or incomplete development, respectively, of the brain gyri or convolution, causing the brain’s surface to appear unusually smooth.
Infants with classical lissencephaly may have a head that is smaller than would be expected (microcephalic). Additional abnormalities may include seizures, profound intellectual disability, feeding difficulties, growth retardation, and impaired motor abilities. If an underlying syndrome is present, there may be additional symptoms and physical findings.
There may be various possible causes of isolated lissencephaly, including viral infections, insufficient blood flow to the brain during development, or certain genetic factors. Changes (mutations) in several genes have been implicated in isolated lissencephaly: LIS1, RELN, TUBA1A, NDE1, KATNB1, CDK5, ARX and DCX. Of these, LIS1 and DCX gene mutations have been most studied.
Newborns with lissencephaly type 1 who have no underlying syndrome are said to have isolated lissencephaly sequence (ILS). In addition to lissencephaly, those with the condition may have other associated brain malformations, such as absence or underdevelopment of the corpus callosum, which is the thick band of nerve fibers that join and carry messages between the brain’s two cerebral hemispheres. Affected infants often also have microcephaly, seizures, and severe or profound intellectual disability. In addition, those with the condition may have a normal facial appearance or subtle facial changes, such as a relatively small jaw (micrognathia) or a slight indentation of the temples (bitemporal hollowing). Additional symptoms and findings may include feeding difficulties, growth failure, abnormally diminished muscle tone (hypotonia) early in life, and increased muscle tone (hypertonia) later during infancy, and impaired motor abilities.
Lissencephaly type 1 also occurs in association with genetic syndromes, including Miller-Dieker syndrome and Norman-Roberts syndrome. In addition to signs and symptoms of classical lissencephaly, infants with Miller-Dieker syndrome may also malformations including microcephaly with a broad, high forehead; bitemporal hollowing; a relatively wide face; micrognathia; a long, thin upper lip; a short nose with upturned nostrils; low-set, malformed ears; polydactyly; abnormal palmar creases; cataracts and/or malformations of the heart, kidneys and/or other organs.
Norman-Roberts syndrome is also characterized by lissencephaly type 1 features with certain craniofacial abnormalities, such as a low, sloping forehead; abnormal prominence of the back portion of the head; a broad, prominent nasal bridge; and widely set eyes (ocular hyperterlorism).
Lissencephaly may be due to various non-genetic and genetic factors. Such factors may include intrauterine infection, insufficient supply of oxygenated blood to the brain (ischemia) during fetal development, and/or different gene mutations.
Several gene mutations have been implicated in isolated lissencephaly. One of the best-studied examples is LIS1 or PAFAH1B1. Mutations in this gene are responsible for lissencephaly type 1. LIS1 gene is localized on chromosome 17p13.3. The gene encodes for platelet-activating factor acetylhydrolase isoform 1B that interacts with microtubule associated proteins: dynein and dynactin. This interaction is critical for proper neuronal migration during fetal brain development; disruption of this interaction results in lissencephaly. Most infants with isolated lissencephaly sequence show mutations or deletions of just the LIS1 gene, whereas infants with Miller-Dieker syndrome are mostly found to have mutations in the LIS1 gene but also have additional deletions of adjacent genes on chromosome 17, thus resulting in lissencephaly type 1 features and other craniofacial abnormalities. Such chromosomal alterations occur randomly and are observed in the child only, without evidence of alteration in either parent. Importantly, this genetic form of lissencephaly does not recur in families, and so the risk of another child with this condition is extremely low.
Of the genes that have been implicated in lissencephaly, DCX and ARX genes are notable because they are localized on the X chromosome. This genetic form of lissencephaly can be observed in more than one child per family, because the mutation can be present in the DNA of a healthy mother. Lissencephaly caused by DCX and ARX is referred to as X-linked lissencephaly type 1 and 2, respectively (XLIS 1-2 or LISX 1-2). Because males only have one X chromosome, males who inherit the disease gene are more likely to manifest the full spectrum of abnormalities associated with the disorder and therefore are usually more severely affected. Females who inherit this gene mutation may have a more variable presentation and be more mildly affected than the males, or can be healthy without symptoms.
The DCX gene encodes for the doublecortin protein. Doublecortin associates with microtubules to regulate neuronal migration. X-linked mutations may appear randomly or can be inherited. The ARX gene encodes for the aristaless-related homeobox protein. In addition to classic lissencephaly features, infants with a ARX mutation may also have absence of portions of the brain (hydranencephaly), abnormal genitalia, severe epilepsy and other abnormalities.
Other gene mutations that have been associated with lissencephaly, such as RELN, which causes Norman-Roberts syndrome, have 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 disease, the person will be a carrier for the disease but usually will not show symptoms. The risk for two carrier parents to both pass the altered gene and have an affected child is 25% with each pregnancy. The risk to have a child who is a carrier like the parents is 50% with each pregnancy. The chance for a child to receive 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 have also been found to cause lissencephaly. They include: TUBA1A, NDE1, KATNB1, and CDK5. These genes share molecular function with LIS1 and DCX, working as part of the cellular machinery of dynein and dynactin required for neuronal migration during fetal brain development.
Emerging evidence suggests that genetic alterations and non-genetic causes result in lissencephaly due to impaired neuronal migration of the outer region of the brain during fetal development. The cerebral cortex, which is responsible for conscious movement and thought, normally consists of several deep gyri and sulci (grooves), which are formed by “in-folding” of the cerebral cortex. During embryonic growth, newly formed cells that will later develop into specialized nerve cells normally migrate to the brain’s surface (neuronal migration), resulting in the formation of several cellular layers. However, in cases of lissencephaly type 1, the cells fail to migrate to their destined locations resulting in neuronal dysmigration, and the cerebral cortex develops an insufficient number of cellular layers, with absence or incomplete development of gyri.
The overall incidence of lissencephaly is rare and estimated around 1.2/100,000 births.
When the suspicion is high for lissencephaly type 1 because of family history and/or prenatal ultrasound screening, it is possible that the condition may be confirmed by specialized testing during pregnancy, such as cell-free fetal DNA, amniocentesis or chorionic villus sampling (CVS).
Lissencephaly type 1 may be diagnosed thorough clinical evaluation, brain imaging studies, including computerized tomography (CT) scanning and/or magnetic resonance imaging (MRI) and genetic testing like chromosomal analysis and/or specific gene mutational analysis. During CT scanning, a computer and x-rays are used to create a film showing cross-sectional images of the brain’s tissue structure. With MRI, a magnetic field and radio waves create cross-sectional images of the brain. Another test that can aid in the diagnosis is electroencephalogram (EEG). During an EEG, the brain’s electrical impulses are recorded. Brain malformations, including lissencephaly, are often associated with abnormal brain electrical impulses and/or seizures. An abnormal EEG pattern may prompt further brain imaging and lead to the diagnosis of lissencephaly. Lastly, DNA analysis may detect certain deletions/mutations in genes linked to lissencephaly. Commercially available gene testing for known genetic causes of lissencephaly is now available. The number of genes included in these tests continues to expand with additional research.
The treatment of lissencephaly type 1 is directed toward the specific symptoms that are apparent in each individual. Treatment may require the coordinated efforts of a team of specialists. Pediatricians, neurologists, and other health care professionals may need to systematically and comprehensively plan an affected child’s treatment.
Therapies for individuals with lissencephaly type 1 are symptomatic and supportive. Treatment may include measures to improve the intake of nutrients in infants with feeding difficulties; the administration of anticonvulsant drugs to help prevent, reduce, or control seizures; and/or other measures.
Genetic counseling is recommended for families of affected children.
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Dr. William Dobyns of the University of Washington and Dr. Joseph Gleeson at the University of California, San Diego are conducting genetic research on lissencephaly and related brain malformations.
For more information about the lissencephaly project and related research, contact:
William B. Dobyns, MD
University of Washington
E-mail: [email protected]
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