The Experts below are selected from a list of 321 Experts worldwide ranked by ideXlab platform

Richard J Leventer - One of the best experts on this subject based on the ideXlab platform.

  • listen carefully lis1 and dcx mlpa in Lissencephaly and subcortical band heterotopia
    European Journal of Human Genetics, 2009
    Co-Authors: Martin B Delatycki, Richard J Leventer
    Abstract:

    Malformations of the brain are a common cause of morbidity in the community. With an estimated 100 billion neuronal cells that migrate to their final destinations, and subsequent formation of one quadrillion (1 000 000 000 000 000) synapses during pre- and postnatal development, it is not surprising that the process of cortical development can be disrupted by genetic and environmental factors. Common outcomes from such brain malformations include severe intellectual disability, cerebral palsy and epilepsy. Much has been learnt over recent years about the genetic causes of neuronal migration disorders and other brain malformations. In Lissencephaly, there is a thickened cortex and a paucity of gyration ranging from absent gyri (agyria) to less severe forms with widened gyri (pachygyria). Subcortical band heterotopia, or ‘double cortex', is manifest by bilateral bands of grey matter in the white matter between the lateral ventricles and the cerebral cortex. Both Lissencephaly and subcortical band heterotopia are disorders of neuronal migration, with many neurons failing to reach their intended destination in the cortical mantle. A major advance in the understanding of these disorders occurred with the discovery of the LIS1 gene in 1993 and the DCX gene in 1998.1, 2, 3 Mutations involving the LIS1 gene, located at 17p13.3, generally cause Lissencephaly, more severe in the posterior than in the anterior part of the brain. Lissencephaly generally has severe manifestations including severe intellectual disability and intractable epilepsy. Mutations involving DCX on the X chromosome at Xq22.3 can result in severe Lissencephaly usually in male individuals and generally more severe anteriorly than posteriorly. The same mutations may also result in subcortical band heterotopia, and this is usually in female individuals. Subcortical band heterotopia usually results in seizures with or without intellectual impairment and rarely can be asymptomatic.4 Mutations in either LIS1 or DCX account for approximately 80% of cases of typical Lissencephaly and subcortical band heterotopia. Mutations in a number of other genes including ARX, RELN and TUBA1A account for a small percentage of the remaining cases of Lissencephaly, leaving 10–20% of patients without a genetic diagnosis. On page XXX of this issue, Haverfield and colleagues present data from MLPA testing of LIS1 and DCX in 83 individuals with Lissencephaly of varying severity or subcortical band heterotopia, in an attempt to improve the yield of making a genetic diagnosis in otherwise typical forms of these conditions. These individuals earlier had sequencing of LIS1 and DCX and FISH studies for large microdeletions involving LIS1, with no mutations being found. The investigators found that in 52 individuals with Lissencephaly, suggestive of LIS1 involvement (more severe posteriorly than anteriorly), there were 12 deletions and six duplications of LIS1. In 31 individuals with brain abnormalities suggestive of DCX involvement (more severe anteriorly than posteriorly), three deletions were identified in DCX. Of the 18 deletions and duplications in LIS1, alterations varied from deletion or duplication of a single exon to deletions involving the entire coding region of LIS1. Notably, this whole gene deletion was not identifiable by FISH using commercially available probes. It is worth noting that no deletions or duplications in LIS1 were found in individuals with the most severe Lissencephaly (grade 1 or 2), or in individuals with subcortical band heterotopia with a gradient of severity greater posteriorly than anteriorly. The three DCX deletions were found in female individuals with subcortical band heterotopia. No DCX deletions were found in individuals with more severe Lissencephaly, or in male individuals with subcortical band heterotopia. The results of the study of Haverfield and colleagues add important knowledge to the field. Before this study, about 75% of individuals with Lissencephaly were known to have mutations in LIS1 or DCX, and around 85% of individuals with subcortical band heterotopia were known to have mutations in DCX. The findings of this study mean that these figures are increased to around 85 and 90%, respectively. The authors recommend that in individuals with isolated Lissencephaly sequence, MLPA of LIS1 and DCX should be the first step as it will identify intragenic deletions and duplications as well as larger microdeletions. If normal, this should be followed by sequencing of LIS1 or DCX, depending on the pattern of malformation. By contrast, the authors recommend that where subcortical band heterotopia is present, DCX sequencing should be the first-line investigation as deletions and duplications are far less common. These new findings mean that around 10% of additional individuals with isolated Lissencephaly sequence and 5% of additional individuals with subcortical band heterotopia will now be able to have the cause of their brain malformation diagnosed. This has very important implications for these individuals and their families. Female individuals identified with DCX mutations that result in subcortical band heterotopia have a 50% risk that their sons will have Lissencephaly and significant morbidity. Therefore, the identification of an intragenic deletion or duplication in DCX means that individuals can have appropriate genetic counselling and can avail themselves of prenatal testing or preimplantation diagnosis should they choose. If an individual is found to have a deletion or duplication involving LIS1, then families can be reassured that the risk of similar problems in subsequent children is very low and that prenatal testing or preimplantation diagnosis is available to identify the unlikely possibility of gonadal mosaicism resulting in a recurrence. Using current techniques, approximately 10% of patients with typical forms of Lissencephaly and subcortical band heterotopia remain without a genetic diagnosis. This rate is significantly higher for those with atypical forms such as subcortical band heterotopia in male individuals and Lissencephaly with unusual severity gradients or abnormalities of other brain structures such as the corpus callosum or cerebellum. No doubt there are other genes to be found for these conditions, so we will continue to listen carefully to this interesting and expanding area of neurogenetics▪

  • Lissencephaly type I.
    Handbook of clinical neurology, 2008
    Co-Authors: Richard J Leventer
    Abstract:

    Publisher Summary Classical or type I Lissencephaly are a group of cortical malformations with the common features of cortical thickening and a reduction in gyration. Classical Lissencephaly is primarily a disorder of neuroblast migration and is the first of the human cortical malformations for which the genetic basis, and subsequently the molecular mechanism, was identified. Classical Lissencephaly is, however, a somewhat heterogeneous group, containing subtypes with variable pathological, imaging, and clinical features and differing etiologies and genetic bases. This chapter describes the features of the main subtypes of classical Lissencephaly in humans, emphasizing the features that are of greatest importance to a practicing clinician, including the clinical and imaging characteristics and the known genetic causes. Lissencephaly is primarily a disorder of migration of neuroblasts in the developing brain, although some forms may also involve abnormal neuroblast proliferation and neuronal organization. The recent elucidation of the genetic basis of the majority of these Lissencephaly syndromes has allowed clinicians to provide accurate prognostic and genetic counseling to affected families. In addition, these rare disorders have provided molecular geneticists and developmental neurobiologists with a unique opportunity to gain insight into the normal processes required for cortical development in humans and other species.

  • topical review genotype phenotype correlation in Lissencephaly and subcortical band heterotopia the key questions answered
    Journal of Child Neurology, 2004
    Co-Authors: Richard J Leventer
    Abstract:

    Lissencephaly and subcortical band heterotopia are closely related cortical malformations and are true disorders of neuronal migration. The genetic basis of approximately 70% of classic Lissencephaly and 80% of typical subcortical band heterotopia is known. Most are due to abnormalities within the LIS1 or DCX genes, with abnormalities ranging from single basepair substitutions to contiguous gene deletions. Understanding the genetic basis of these disorders has led to the elucidation of the molecular and developmental mechanisms that are adversely affected. There is a robust correlation between many of the clinical aspects of Lissencephaly or subcortical band heterotopia and the type and location of mutations in the affected gene. Using this knowledge, the clinician can predict with some accuracy which gene is likely to be affected based on the clinical and imaging features. This review answers some of the key questions regarding the genotype-phenotype correlation for Lissencephaly and subcortical band het...

  • Magnetic resonance imaging features of Lissencephaly in 2 Lhasa Apsos.
    Veterinary radiology & ultrasound : the official journal of the American College of Veterinary Radiology and the International Veterinary Radiology As, 2002
    Co-Authors: Miyoko Saito, Richard J Leventer, Nicholas J.h. Sharp, Gregg D. Kortz, Alexander De Lahunta, Mikihiko Tokuriki, Donald E. Thrall
    Abstract:

    Two Lhasa Apsos were diagnosed with Lissencephaly based on MR imaging and clinical findings. Histologic confirmation of the diagnosis was obtained in one dog. The MR imaging appearance of the brain in 2 Lhasa Apsos with Lissencephaly was of a smooth cerebral surface and a thick neocortex with an absence of the corona radiata. This correlated very well with the histopathologic findings in the dog. Our findings, together with the histopathologic features reported previously, are most consistent with Lhasa Apsos having the canine equivalent of human classical Lissencephaly. MR is the imaging modality of choice for antemortem diagnosis of canine Lissencephaly.

  • The location and type of mutation predict malformation severity in isolated Lissencephaly caused by abnormalities within the LIS1 gene
    Human molecular genetics, 2000
    Co-Authors: Carlos Cardoso, Julie Kuc, Melissa B Ramocki, Stephanie K Mewborn, L. Dudlicek, Naomichi Matsumoto, Patti L. Mills, Richard J Leventer, Lorraine F. May, Soma Das
    Abstract:

    Lissencephaly is a cortical malformation secondary to impaired neuronal migration resulting in mental retardation, epilepsy and motor impairment. It shows a severity spectrum from agyria with a severely thickened cortex to posterior band heterotopia only. The LIS1 gene on 17p13.3 encodes a 45 kDa protein named PAFAH1B1 containing seven WD40 repeats. This protein is required for optimal neuronal migration by two proposed mechanisms: as a microtubule-associated protein and as one subunit of the enzyme platelet-activating factor acetylhydrolase. Approximately 65% of patients with isolated Lissencephaly sequence (ILS) show intragenic mutations or deletions of the LIS1 gene. We analyzed 29 non-deletion ILS patients carrying a mutation of LIS1 and we report 15 novel mutations. Patients with missense mutations had a milder Lissencephaly grade compared with those with mutations leading to a shortened or truncated protein (P = 0.022). Early truncation/deletion mutations in the putative microtubule-binding domain resulted in a more severe Lissencephaly than later truncation/deletion mutations (P < 0.001). Our results suggest that the Lissencephaly severity in ILS caused by LIS1 mutations may be predicted by the type and location of the mutation. Using a spectrum of ILS patients, we confirm the importance of specific WD40 repeats and a putative microtubule-binding domain for PAFAH1B1 function. We suggest that the small number of missense mutations identified may be due to underdiagnosis of milder phenotypes and hypothesize that the greater Lissencephaly severity seen in Miller-Dieker syndrome may be secondary to the loss of another cortical development gene in the deletion of 17p13.3.

William B. Dobyns - One of the best experts on this subject based on the ideXlab platform.

  • Bi-allelic Loss of Human APC2, Encoding Adenomatous Polyposis Coli Protein 2, Leads to Lissencephaly, Subcortical Heterotopia, and Global Developmental Delay
    American journal of human genetics, 2019
    Co-Authors: Sangmoon Lee, Nataliya Donato, Dillon Y. Chen, Maha S. Zaki, Reza Maroofian, Henry Houlden, Dalia Abdin, Heba Morsy, Ghayda Mirzaa, William B. Dobyns
    Abstract:

    Lissencephaly is a severe brain malformation in which failure of neuronal migration results in agyria or pachygyria and in which the brain surface appears unusually smooth. It is often associated with microcephaly, profound intellectual disability, epilepsy, and impaired motor abilities. Twenty-two genes are associated with Lissencephaly, accounting for approximately 80% of disease. Here we report on 12 individuals with a unique form of Lissencephaly; these individuals come from eight unrelated families and have bi-allelic mutations in APC2, encoding adenomatous polyposis coli protein 2. Brain imaging studies demonstrate extensive posterior predominant Lissencephaly, similar to PAFAH1B1-associated Lissencephaly, as well as co-occurrence of subcortical heterotopia posterior to the caudate nuclei, "ribbon-like" heterotopia in the posterior frontal region, and dysplastic in-folding of the mesial occipital cortex. The established role of APC2 in integrating the actin and microtubule cytoskeletons to mediate cellular morphological changes suggests shared function with other Lissencephaly-encoded cytoskeletal proteins such as α-N-catenin (CTNNA2) and platelet-activating factor acetylhydrolase 1b regulatory subunit 1 (PAFAH1B1, also known as LIS1). Our findings identify APC2 as a radiographically distinguishable recessive form of Lissencephaly.

  • Genotypically defined lissencephalies show distinct pathologies.
    Journal of neuropathology and experimental neurology, 2005
    Co-Authors: Mark S. Forman, William B. Dobyns, Waney Squier, Jeffrey A. Golden
    Abstract:

    Lissencephaly is traditionally divided into 2 distinct pathologic forms: classic (type I) and cobblestone (type II). To date, mutations in 4 genes, LIS1, DCX, RELN, and ARX, have been associated with distinct type I Lissencephaly syndromes. Each of these genes has been shown to play a role in normal cell migration, consistent with the presumed pathogenesis of type I Lissencephaly. Based on these data, we hypothesized that all forms of radiographically defined type I Lissencephaly independent of genotype would be pathologically similar. To test this hypothesis, we examined brains from 16 patients, including 15 lissencephalic patients and one patient with subcortical band heterotopia. Of these 16 patients, 6 had LIS1 deletions, 2 had DCX mutations, and 2 had ARX mutations. In addition, 6 patients had no defined genetic defect, although the patient with subcortical band heterotopia exhibited the same pattern of malformation expected with an XLIS mutation. In all cases, the cortex was thickened; however, the topographic distribution of the cortical pathology varied, ranging from frontal- to occipital-biased pathology to diffuse involvement of the neocortex. Although brains with LIS1 deletions exhibited the classic 4-layer lissencephalic architecture, patients with DCX and ARX mutations each had unique cytoarchitectural findings distinct from LIS1. Furthermore, 2 of the 5 patients with no known genetic defect showed a fourth type of histopathology characterized by a 2-layered cortex. Interestingly, the 2 brains with the fourth type of Lissencephaly showed profound brainstem and cerebellar abnormalities. In summary, we identified at least 4 distinct histopathologic subtypes of Lissencephaly that stratify with the underlying genetic defect. Based on these data, a new classification for Lissencephaly is proposed that incorporates both pathologic and genetic findings.

  • x linked Lissencephaly with abnormal genitalia as a tangential migration disorder causing intractable epilepsy proposal for a new term interneuronopathy
    Journal of Child Neurology, 2004
    Co-Authors: Mitsuhiro Kato, William B. Dobyns
    Abstract:

    X-linked Lissencephaly with abnormal genitalia is the first human disorder in which deficient tangential migration in the brain has been demonstrated. Male patients with X-linked Lissencephaly with abnormal genitalia show intractable seizures, especially clonic convulsions or myoclonus from the first day of life, but neither infantile spasms nor hypsarrhythmia on electroencephalograms so far. Brain magnetic resonance imaging shows anterior pachygyria and posterior agyria with a mildly thick cortex, agenesis of the corpus callosum, and dysplastic basal ganglia. ARX, a paired-class homeobox gene with four polyalanine sequences, is a responsible gene for X-linked Lissencephaly with abnormal genitalia. The brain of Arx knockout mice shows aberrant tangential migration and differentiation of γ-aminobutyric acid (GABA)ergic interneurons. In human X-linked Lissencephaly with abnormal genitalia, a neuropathologic study has suggested a loss of interneurons. Meanwhile, polyalanine expansion of ARX causes symptomati...

  • Familial Lissencephaly with cleft palate and severe cerebellar hypoplasia
    American journal of medical genetics, 1999
    Co-Authors: Berit Kerner, Jeffrey A. Golden, John M. Graham, Samuel H. Pepkowitz, William B. Dobyns
    Abstract:

    Lissencephaly is a brain malformation characterized by absence of gyral formation, resulting in a smooth brain surface. Histologic study shows severe anomalies of cerebral cortical development. Several Lissencephaly syndromes have been described. Here we report a familial syndrome of Lissencephaly, cleft palate, diffuse agyria, and severe cerebellar hypoplasia. Microscopic examination of the abnormally thick cerebral cortex showed absence of cortical layering, with preservation of the pia-glial barrier. This is the first report of recurrent Lissencephaly with cleft palate and severe cerebellar hypoplasia in which these unique neuropathology findings are described. Autosomal recessive inheritance is suggested by recurrence in sibs within the same family, but germ cell mosaicism for a dominant mutation is not excluded.

  • X-linked Lissencephaly with absent corpus callosum and ambiguous genitalia.
    American journal of medical genetics, 1999
    Co-Authors: William B. Dobyns, Elizabeth Berry-kravis, Nancy J. Havernick, Kenton R. Holden, David Viskochil
    Abstract:

    Lissencephaly has been described in over 10 distinct malformation syndromes. Recently, we have recognized 5 children from four unrelated families with an almost identical disorder comprising Lissencephaly with a posterior-to-anterior gradient and only moderate increase in thickness of the cortex, absent corpus callosum, neonatal-onset epilepsy, hypothalamic dysfunction including deficient temperature regulation, and ambiguous genitalia in genotypic males. Our observation of 5 affected males in one of these families is consistent with an X-linked pattern of inheritance. However, it differs in many regards from the X-linked form of isolated Lissencephaly sequence that is associated with mutations of the XLIS (DCX) gene. Therefore, we propose that this disorder comprises a new X-linked malformation syndrome, which we refer to as X-linked Lissencephaly with ambiguous genitalia (XLA-G).

Olivier Dulac - One of the best experts on this subject based on the ideXlab platform.

David H Ledbetter - One of the best experts on this subject based on the ideXlab platform.

  • Differences in the gyral pattern distinguish chromosome 17–linked and X-linked Lissencephaly
    Neurology, 1999
    Co-Authors: William B. Dobyns, Naomichi Matsumoto, David H Ledbetter, Christopher A. Walsh, Chip Truwit, M E Ross, Daniela T Pilz, Joseph G Gleeson, A. J. Barkovich
    Abstract:

    Background: Classical Lissencephaly or “smooth brain” is a human brain malformation that consists of diffuse agyria and pachygyria. Two genes associated with classical Lissencephaly have recently been cloned— LIS1 from chromosome 17p13.3 and XLIS (also called DCX ) from Xq22.3-q23. Objective: We performed genotype-phenotype analysis in children with Lissencephaly associated with mutations of different genes. Methods: We compared the phenotype, especially brain imaging studies, in a series of 48 children with Lissencephaly, including 12 with Miller-Dieker syndrome (MDS), which is associated with large deletions of LIS1 and other genes in the region, 24 with isolated Lissencephaly sequence caused by smaller LIS1 deletions or mutations, and 12 with isolated Lissencephaly sequence caused by XLIS mutations. Results: We found consistent differences in the gyral patterns, with the malformation more severe posteriorly in individuals with LIS1 mutations and more severe anteriorly in individuals with XLIS mutations. Thus, mutations of LIS1 are associated with a posterior-to-anterior gradient of Lissencephaly, whereas mutations of XLIS are associated with an anterior-to-posterior gradient. We also confirmed differences in severity between MDS and ILS17. Hypoplasia of the cerebellar vermis proved to be more common with XLIS mutations. Conclusion: It is often possible to predict the gene mutation from careful review of brain imaging studies.

  • differences in the gyral pattern distinguish chromosome 17 linked and x linked Lissencephaly
    Neurology, 1999
    Co-Authors: William B. Dobyns, Naomichi Matsumoto, David H Ledbetter, Christopher A. Walsh, Chip Truwit, M E Ross, Daniela T Pilz, Joseph G Gleeson
    Abstract:

    Background: Classical Lissencephaly or “smooth brain” is a human brain malformation that consists of diffuse agyria and pachygyria. Two genes associated with classical Lissencephaly have recently been cloned— LIS1 from chromosome 17p13.3 and XLIS (also called DCX ) from Xq22.3-q23. Objective: We performed genotype-phenotype analysis in children with Lissencephaly associated with mutations of different genes. Methods: We compared the phenotype, especially brain imaging studies, in a series of 48 children with Lissencephaly, including 12 with Miller-Dieker syndrome (MDS), which is associated with large deletions of LIS1 and other genes in the region, 24 with isolated Lissencephaly sequence caused by smaller LIS1 deletions or mutations, and 12 with isolated Lissencephaly sequence caused by XLIS mutations. Results: We found consistent differences in the gyral patterns, with the malformation more severe posteriorly in individuals with LIS1 mutations and more severe anteriorly in individuals with XLIS mutations. Thus, mutations of LIS1 are associated with a posterior-to-anterior gradient of Lissencephaly, whereas mutations of XLIS are associated with an anterior-to-posterior gradient. We also confirmed differences in severity between MDS and ILS17. Hypoplasia of the cerebellar vermis proved to be more common with XLIS mutations. Conclusion: It is often possible to predict the gene mutation from careful review of brain imaging studies.

  • Classical Lissencephaly syndromes: does the face reflect the brain?
    Journal of Medical Genetics, 1998
    Co-Authors: Judith E Allanson, David H Ledbetter
    Abstract:

    Both Miller-Dieker syndrome and isolated Lissencephaly sequence are associated with classical Lissencephaly. Both have been shown to be associated with deletions and mutations in LIS1 on 17p. Traditionally, the two disorders have been distinguished by the presence of a characteristic facial appearance in Miller-Dieker syndrome. The forehead is tall and prominent and may have vertical furrowing. There is narrowing at the temples. Eyes are widely spaced with upward slanting fissures. The nose is very short with anteverted nares. The upper lip is long, wide, and thick. The ears may have minor flattening of the helices. By contrast, these features are not seen in isolated Lissencephaly sequence. We have measured five children with Miller-Dieker syndrome (MDS) and 25 children and adolescents with isolated Lissencephaly sequence (ILS). Z score (standard deviation score) pattern profiles have been formulated and compared. Patients with ILS at all ages show reduced head circumference, a round head, and a wide and flat face with a broad nose and widely spaced eyes. The most unexpected finding is the similarity of pattern profiles of ILS and MDS in the age group 6 months to 4 years. Correlation coefficient is 0.812 (p

  • a revision of the Lissencephaly and miller dieker syndrome critical regions in chromosome 17p13 3
    Human Molecular Genetics, 1997
    Co-Authors: Samuel S Chong, Anna V Roschke, Svetlana Pack, Romeo Carrozzo, Ann C M Smith, Akira Tanigami, David H Ledbetter
    Abstract:

    : Miller-Dieker syndrome (MDS) is a multiple malformation syndrome characterized by classical Lissencephaly and a characteristic facies. It is associated with visible or submicroscopic deletions within chromosome band 17p13.3. Lissencephaly without facial dysmorphism has also been observed and is referred to as isolated Lissencephaly sequence (ILS). Apparently partial and non-overlapping deletions of the 5' or 3' end of a candidate gene LIS1 in one ILS and one MDS patient had suggested that MDS was a single gene disorder, and that LIS1 spans in excess of 400 kb. However, the originally presumed 5' end of LIS1 was found to belong to the 14-33 epsilon gene residing more distally on 17p13.3. We have now isolated the correct 5' end of LIS1, constructed a approximately 500 kb genomic contig encompassing LIS1, and estimated its gene to be approximately 80 kg. Fluorescence in situ hybridization analysis of an ILS patient with a de novo balanced translocation, as well as analysis of several other key MDS and ILS deletion patients, localizes the Lissencephaly critical region within the LIS1 gene. Therefore, LIS1 remains the strongest candidate gene for the Lissencephaly phenotype in ILS and MDS. Our analyses also suggest that additional genes distal to LIS1 may be responsible for the facial dysmorphology and other abnormalities seen in MDS but not in ILS patients, supporting our original concept MDS as a contiguous gene deletion syndrome.

  • Lissencephaly: A Human Brain Malformation Associated With Deletion of the LIS1 Gene Located at Chromosome 17p13
    JAMA, 1993
    Co-Authors: William B. Dobyns, Romeo Carrozzo, Orly Reiner, David H Ledbetter
    Abstract:

    Objective. —We review the clinical phenotype, pathological changes, and results of cytogenetic and molecular genetic studies in 90 probands with Lissencephaly (smooth brain) with emphasis on patients with the classical form (type I). We also describe the recent discovery of the Lissencephaly gene ( LIS1 ), deletions of which have been implicated as the cause of this disorder in many patients. Data Sources. —We have performed clinical, cytogenetic, and molecular genetic studies of 25 probands with Miller-Dieker syndrome and 65 probands with isolated Lissencephaly sequence (ILS). We have further subdivided patients with ILS into those with classical Lissencephaly and those with Lissencephaly variants. Study Selection. —We consider primarily our own published and unpublished data, but include references to studies of other series of patients with Lissencephaly. Data Synthesis. —Visible cytogenetic deletions of 17p13.3 were detected in 14 of 25 Miller-Dieker syndrome probands, and either visible cytogenetic or submicroscopic deletions in 23 (92%) of 25. Submicroscopic deletions were detected in eight of 45 patients with all types of ILS. If only ILS patients with the classical form are considered, we detected deletions in eight (38%) of 21. Conclusions. —Deletions of the Lissencephaly critical region in chromosome 17p13.3, including LIS1 , appear to be the most frequent cause of classical Lissencephaly. Molecular cytogenetic studies, particularly fluorescence in situ hybridization, should be performed in all such patients. LIS1 shows homology to genes involved in signal transduction, which may be its function in development of the telencephalon. Other genetic causes of classical Lissencephaly and genetic and nongenetic causes of other types of Lissencephaly exist and are under study. ( JAMA . 1993;270:2838-2842)

Jacques Motte - One of the best experts on this subject based on the ideXlab platform.

  • dominant x linked subcortical laminar heterotopia and Lissencephaly syndrome xsclh lis evidence for the occurrence of mutation in males and mapping of a potential locus in xq22
    Journal of Medical Genetics, 1997
    Co-Authors: Des V Portes, Jacques Motte, J M Pinard, D Smadja, Odile Boespflugtanguy, M L Moutard, Isabelle Desguerre, Pierre Billuart, Alain Carrie, T Bienvenu
    Abstract:

    X linked subcortical laminar heterotopia and Lissencephaly syndrome (XSCLH/ LIS) is an intriguing disorder of cortical development, which causes classical Lissencephaly with severe mental retardation and epilepsy in hemizygous males, and subcortical laminar heterotopia (SCLH) associated with milder mental retardation and epilepsy in heterozygous females. Here we report an exclusion mapping study carried out in three unrelated previously described families in which males are affected with Lissencephaly and females with SCLH, using 38 microsatellite markers evenly distributed on the X chromosome. Most of the X chromosome was excluded and potential intervals of assignment in Xq22.3-q23 or in Xq27 are reported. Although the number of informative meioses did not allow a decision between these two loci, it is worth noting that the former interval is compatible with the mapping of a breakpoint involved in a de novo X;autosomal balanced translocation 46,XX,t(X;2)(q22;p25) previously described in a female with classical Lissencephaly. In addition, haplotype inheritance in two families showed a grandpaternal origin of the mutation and suggested in one family the presence of mosaicism in germline cells of normal transmitting males.

  • Subcortical laminar heterotopia and Lissencephaly in two families: a single X linked dominant gene.
    Journal of Neurology Neurosurgery and Psychiatry, 1994
    Co-Authors: Jean-marc Pinard, R. Brian, Eva Andermann, Jacques Motte, Catherine Chiron, Olivier Dulac
    Abstract:

    Neuronal migration disorders can now be recognised by MRI. This paper reports two families in which the mothers had subcortical laminar heterotopia and four of their children had either similar heterotopia (two girls) or severe pachygyria or Lissencephaly (two boys). Laminar heterotopia was more evident on MRI T2 weighted images. The patients had mild to severe epilepsy and mental retardation depending on the extent of cortical abnormalities. In these families, subcortical laminar heterotopia, pachygyria, and Lissencephaly seem to share the same X linked or autosomal dominant gene. No chromosomal abnormalities, especially of chromosome 17, could be identified. For appropriate genetic counselling of the family of a child with Lissencephaly or subcortical laminar heterotopia, MRI should be performed in parents or siblings with mental retardation or epilepsy.