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Gene (#OMIM):PAFAH1B1 / LIS1 (*601545)
Classical lissencephaly and subcortical band heterotopia (the agyria-pachygyria-band spectrum) and lissencephaly with cerebellar hypoplasia
Lissencephaly (LIS), derived from the Greek words “lissos” meaning smooth and “enkephalos” which means brain, is a neuronal migration disorder characterized by absent (agyria) or decreased (pachygyria) convolutions, producing a smooth cerebral surface. Several different types of LIS have been recognized. The most common type, known as classical LIS or type 1 LIS, features a very thick 10–20 mm cortex (vs. the normal 4 mm) and no other major brain malformations. Subcortical band heterotopia (SBH) is a related disorder in which there are bilateral bands of grey matter found interposed in the white matter between the cortex and the lateral ventricles.
Two major genes have been associated with classical LIS and SBH. The LIS1 gene on chromosome 17p13.3 is responsible for the autosomal form of LIS, while the doublecortin gene (DCX or XLIS) is X-linked. Although mutations in either gene can result in either LIS or SBH, most cases of classical LIS are due to deletions or mutations of LIS1, whereas most cases of SBH are due to mutations of DCX. LIS1 mutations result in more severe LIS in the posterior brain regions (p>a gradient), whereas DCX mutations result in more severe LIS in the anterior brain regions (a>p gradient). Patients with missense mutations generally have less severe malformations and may, accordingly, present with milder motor and cognitive impairment. Severe truncating mutations cause severe LIS, while milder mutations, usually missense mutations, cause pachygyria and rare cases of SBH. Mosaic mutations of LIS1 also cause SBH in the posterior brain.
The SBH phenotype is classically caused by DCX mutations. Women with DCX mutations have anteriorly predominant band/pachygyria. However, rare carrier women harbouring missense mutations with normal brain MRI, due to either favourable X-inactivation skewing or to mutations with mild functional consequences, have been described. Genomic deletions of the DCX gene have been identified in females with sporadic SBH and in males with X-linked lissencephaly. Maternal germline or mosaic DCX mutations may occur in about 10% of cases of either SBH or XLIS. Hemizygous males with DCX mutations have classical LIS but rare boys with missense DCX mutations with an anteriorly predominant SBH have also been described.
Recently, it has been demonstrated that mutationS in the TUBA1A (TUBA3) gene were identified in patients with LIS. The clinical and anatomic spectrum of severity TUBA1A-related LIS appears to be wide.
Classical LIS is rare with a prevalence of about 12 per million births. Patients with sever LIS have early developmental delay, early diffuse hypotonia, later spastic quadriplegia and eventual severe or profound mental retardation. Some children with lissencephaly have lived more than 20 years, although anecdotal experience suggests that the lifespan is less than 10 years in most patients. Patients with less severe cortical malformations have moderate mental and motor impairment and may have a normal life span expectancy. Seizures occur in over 90% of children, with onset before 6 months in about 75%.
The main clinical manifestations of SBH are mental retardation and epilepsy. Epilepsy is present in almost all patients and is intractable in about 65%. About 50% of epilepsy patients have focal seizures and the remaining 50% have generalized epilepsy, often within the spectrum of Lennox-Gastaut syndrome. Depth electrode studies have demonstrated that epileptiform activity can originate directly from the heterotopic neurons with nearly constant simultaneous involvment of the ‘true’ cortex. Callosotomy has been associated with worthwhile improvement in drop attacks in a few patients. Epilepsy surgery for focal seizures yields poor results.
Our laboratory has contributed to better define the clinical, anatomic and molecular features of lissencephaly and SBH. We have characterized mutations in the LIS1 and DCX genes and established phenotype-genotype correlations in a large series of patients. We are continuing to enrol patients/families with lissencephaly or SBH to continue these studies and establish the yield of new diagnostic methods.
If you have a child who you think may have this condition and you would like us to review the diagnosis or provide genetic testing please contact us at firstname.lastname@example.org.