The location of DCX mutations predicts malformation severity in X-linked lissencephaly
ABSTRACT Lissencephaly spectrum (LIS) is one of the most severe neuronal migration disorders that ranges from agyria/pachygyria to subcortical band heterotopia. Approximately 80% of patients with the LIS spectrum carry mutations in either the LIS1 or DCX (doublecortin) genes which have an opposite gradient of severity. The aim of the study was to evaluate in detail the phenotype of DCX-associated lissencephaly and to look for genotype-phenotype correlations. Of the 180 male patients with DCX-related lissencephaly, 33 males (24 familial cases and nine cases with de novo mutations) were found with hemizygous DCX mutations and were clinically and genetically assessed here. DCX mutation analysis revealed that the majority of mutations were missense (79.2%), clustered in the two evolutionary conserved domains, N-DC and C-DC, of DCX. The most prominent radiological phenotype was an anteriorly predominant pachygyria or agyria (54.5%) although DCX-associated lissencephaly encompasses a complete range of LIS grades. The severity of neurological impairment was in accordance with the degree of agyria with severe cognitive impairment in all patients, inability to walk independently in over half and refractory epilepsy in more than a third. For genotype-phenotype correlations, patients were divided in two groups according to the location of DCX missense mutations. Patients with mutations in the C-DC domain tended to have a less severe lissencephaly (grade 4-5 in 58.3%) compared with those in the N-DC domain (grade 4-5 in 36.3%) although, in this dataset, this was not statistically significant (p = 0.12). Our evaluation suggests a putative correlation between phenotype and genotype. These data provide further clues to deepen our understanding of the function of the DCX protein and may give new insights into the molecular mechanisms that could influence the consequence of the mutation in the N-DC versus the C-DC domain of DCX.
- SourceAvailable from: Séverine M Sigoillot
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- "Seizures in SBH patients appear within the first decade of life, and often evolve to multifocal and refractory epilepsy. In addition to these symptoms, delayed motor development as well as hypotonia can be observed   , suggesting deficits in the neuromuscular system. "
ABSTRACT: Mutations in the microtubule-associated protein doublecortin (DCX) cause type I (X-linked or XLIS) lissencephaly in hemizygous males and subcortical band heterotopia (SBH) in females, with defects in neuron migration during development affecting cortical lamination. We found that besides its well-established expression in migrating neurons of the brain, doublecortin (Dcx in mice) is also expressed in motor neurons and skeletal muscle in embryonic neuromuscular junctions (NMJs), raising the possibility of a role in synaptogenesis. Studies with whole-mount preparations of embryonic mouse diaphragm revealed that loss of Dcx leads to abnormal presynaptic arborization and a significantly increased incidence of short axonal extensions beyond innervated acetylcholine receptor (AChR) clusters in the developing NMJ. This phenotype, albeit relatively mild, suggests that Dcx contributes to a stop/stabilizing signal at the synapse, which normally limits further axonal growth following establishment of synaptic contact with the postsynaptic element. Importantly, we also identified abnormal and denervated NMJs in a muscle biopsy from a 16-year-old female patient with SBH, showing both profound presynaptic and postsynaptic morphological defects. Overall, these combined results point to a critical role of doublecortin in the formation of the NMJ. Copyright © 2015 Elsevier B.V. All rights reserved.Neuromuscular Disorders 02/2015; 25(6). DOI:10.1016/j.nmd.2015.01.012 · 3.13 Impact Factor
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- "When this protein is absent, or mutated in mouse, migration is disorganized (Corbo et al., 2002; Kappeler et al., 2006) and retarded (Friocourt et al., 2007). DCX mutations in human produce a disorganized, unfolded cortex, with band heterotopia, where some neurons remain in cortical white matter and do not reach the cortex (Kerjan & Gleeson, 2007; Leger et al., 2008; Jaglin & Chelly, 2009). Two approaches have been used to explore how abnormal lamination due to DCX mutations produces an epileptic phenotype. "
ABSTRACT: We report data on the neuronal form, synaptic connectivity, neuronal excitability and epileptiform population activities generated by the hippocampus of animals with an inactivated doublecortin gene. The protein product of this gene affects neuronal migration during development. Human doublecortin (DCX) mutations are associated with lissencephaly, subcortical band heterotopia, and syndromes of intellectual disability and epilepsy. In Dcx(-/Y) mice, CA3 hippocampal pyramidal cells are abnormally laminated. The lamination defect was quantified by measuring the extent of the double, dispersed or single pyramidal cell layer in the CA3 region of Dcx(-/Y) mice. We investigated how this abnormal lamination affected two groups of synapses that normally innervate defined regions of the CA3 pyramidal cell membrane. Numbers of parvalbumin (PV)-containing interneurons, which contact peri-somatic sites, were not reduced in Dcx(-/Y) animals. Pyramidal cells in double, dispersed or single layers received PV-containing terminals. Excitatory mossy fibres which normally target proximal CA3 pyramidal cell apical dendrites apparently contact CA3 cells of both layers in Dcx(-/Y) animals but sometimes on basilar rather than apical dendrites. The dendritic form of pyramidal cells in Dcx(-/Y) animals was altered and pyramidal cells of both layers were more excitable than their counterparts in wild-type animals. Unitary inhibitory field events occurred at higher frequency in Dcx(-/Y) animals. These differences may contribute to a susceptibility to epileptiform activity: a modest increase in excitability induced both interictal and ictal-like discharges more effectively in tissue from Dcx(-/Y) mice than from wild-type animals.European Journal of Neuroscience 01/2012; 35(2):244-56. DOI:10.1111/j.1460-9568.2011.07962.x · 3.67 Impact Factor
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- "Most male patients harboring mutations in the N-doublecortin or C-doublecortin domains have severe lissencephaly, profound cognitive impairment, and symptomatic generalized epilepsy (Leger et al., 2008). Male patients with missense mutations involving the first 46 amino acid residues, such as the p.E2K mutation observed in our patients, or the p.D9N mutation identified in four patients in another study (Leger et al., 2008), have anteriorly predominant pachygyria , rather than LIS, less severe cognitive impairment, and intractable generalized seizures. Although mutations in DCX are likely to be a rare cause of LGS, this family highlights the importance of neuroimaging in previously diagnosed cases in which imaging studies may have been inadequate. "
ABSTRACT: Lennox-Gastaut syndrome (LGS) has numerous causes,but only rarely has familial recurrence been observed. We studied a family in which three male members had severe epilepsy and intellectual disability. The proband had seizure onset at 7 years of age with atonic, myoclonic, atypical absence, and tonic seizures with slow spike-wave on electroencephalography (EEG). One living sibling had a similar clinical pattern. One deceased sibling was known to have had seizures with intellectual disability. Neuroimaging revealed anterior predominant pachygyria. DNA sequencing of the gene doublecortin (DCX) on the X chromosome revealed a novel missense mutation in the two living affected male siblings. The occurrence of three affected male family members with proven or suspected LGS in this family was puzzling and only solved by a combination of magnetic resonance (MR) and molecular genetics evaluations. This finding provided essential information for genetic counseling.Epilepsia 09/2010; 51(9):1902-5. DOI:10.1111/j.1528-1167.2010.02694.x · 4.58 Impact Factor