Mutations in the HECT domain of NEDD4L lead to AKT-mTOR pathway deregulation and cause periventricular nodular heterotopia.

Neurodevelopmental disorders with periventricular nodular heterotopia (PNH) are etiologically heterogeneous, and their genetic causes remain in many cases unknown. Here we show that missense mutations in NEDD4L mapping to the HECT domain of the encoded E3 ubiquitin ligase lead to PNH associated with toe syndactyly, cleft palate and neurodevelopmental delay. Cellular and expression data showed sensitivity of PNH-associated mutants to proteasome degradation. Moreover, an in utero electroporation approach showed that PNH-related mutants and excess wild-type NEDD4L affect neurogenesis, neuronal positioning and terminal translocation. Further investigations, including rapamycin-based experiments, found differential deregulation of pathways involved. Excess wild-type NEDD4L leads to disruption of Dab1 and mTORC1 pathways, while PNH-related mutations are associated with deregulation of mTORC1 and AKT activities. Altogether, these data provide insights into the critical role of NEDD4L in the regulation of mTOR pathways and their contributions in cortical development.

Identification of Multiple Gene Mutations Accounts for a new Genetic Architecture of Primary Ovarian Insufficiency.

CONTEXT: Idiopathic primary ovarian insufficiency (POI) is a major cause of amenorrhea and infertility. POI affects 1% of women before age 40 years, and several genetic causes have been reported. To date, POI has been considered a monogenic disorder. OBJECTIVE: The aim of this study was to identify novel gene variations and to investigate if individuals with POI harbor mutation in multiple loci. PATIENTS AND METHODS: One hundred well-phenotyped POI patients were systematically screened for variants in 19 known POI loci (and potential candidate genes) using next-generation sequencing. RESULTS: At least one rare protein-altering gene variant was identified in 19 patients, including missense mutations in new candidate genes, namely SMC1ß and REC8 (involved in the cohesin complex) and LHX8, a gene encoding a transcription factor. Novel or recurrent deleterious mutations were also detected in the known POI candidate genes NOBOX, FOXL2, SOHLH1, FIGLA, GDF9, BMP15, and GALT. Seven patients harbor mutations in two loci, and this digenicity seems to influence the age of symptom onset. CONCLUSIONS: Genetic anomalies in women with POI are more frequent than previously believed. Digenic findings in several cases suggest that POI is not a purely monogenic disorder and points to a role of digenicity. The genotype-phenotype correlations in some kindreds suggest that a synergistic effect of several mutations may underlie the POI phenotype.

Mosaic parental germline mutations causing recurrent forms of malformations of cortical development.

To unravel missing genetic causes underlying monogenic disorders with recurrence in sibling, we explored the hypothesis of parental germline mosaic mutations in familial forms of malformation of cortical development (MCD). Interestingly, four families with parental germline variants, out of 18, were identified by whole-exome sequencing (WES), including a variant in a new candidate gene, syntaxin 7. In view of this high frequency, revision of diagnostic strategies and reoccurrence risk should be considered not only for the recurrent forms, but also for the sporadic cases of MCD.

Abnormal sodium current properties contribute to cardiac electrical and contractile dysfunction in a mouse model of myotonic dystrophy type 1.

Myotonic dystrophy type 1 (DM1) is the most common neuromuscular disorder and is associated with cardiac conduction defects. However, the mechanisms of cardiac arrhythmias in DM1 are unknown. We tested the hypothesis that abnormalities in the cardiac sodium current (INa) are involved, and used a transgenic mouse model reproducing the expression of triplet expansion observed in DM1 (DMSXL mouse). The injection of the class-I antiarrhythmic agent flecainide induced prominent conduction abnormalities and significantly lowered the radial tissular velocities and strain rate in DMSXL mice compared to WT. These abnormalities were more pronounced in 8-month-old mice than in 3-month-old mice. Ventricular action potentials recorded by standard glass microelectrode technique exhibited a lower maximum upstroke velocity [dV/dt](max) in DMSXL. This decreased [dV/dt](max) was associated with a 1.7 fold faster inactivation of INa in DMSXL myocytes measured by the whole-cell patch-clamp technique. Finally in the DMSXL mouse, no mutation in the Scn5a gene was detected and neither cardiac fibrosis nor abnormalities of expression of the sodium channel protein were observed. Therefore, alterations in the sodium current markedly contributed to electrical conduction block in DM1. This result should guide pharmaceutical and clinical research toward better therapy for the cardiac arrhythmias associated with DM1.

New NOBOX mutations identified in a large cohort of women with primary ovarian insufficiency decrease KIT-L expression.

CONTEXT: Primary ovarian insufficiency (POI) is a major cause of anovulation and infertility in women. This disease affects 1% of women before 40 years, and several genetic causes have been reported. OBJECTIVE: The aim of the study was to evaluate the prevalence of NOBOX mutations in a new large cohort of women with POI and to characterize these variants and identify a NOBOX novel target gene. PATIENTS AND METHODS: A total of 213 unrelated patients with POI were screened for NOBOX mutations, and luciferase reporter assays were performed for the mutations identified. RESULTS: We reported 3 novel and 2 recurrent heterozygous missense NOBOX rare variants found in 12 patients but not in 724 alleles from ethnic-matched individual women with occurrence of menopause at a normal age. Their functional impact had been tested on the classic growth differentiation factor-9 (GDF9) promoter and on KIT-L, a new NOBOX target gene. The p.Gly91Thr, p.Gly111Arg, p.Arg117Trp, p.Lys371Thr, and p.Pro619Leu mutations were deleterious for protein function. CONCLUSIONS: In our series, 5.6% of the patients with POI displayed heterozygous NOBOX mutations. We demonstrate that KIT-L could be now a direct NOBOX target. These findings replicate the high prevalence of the association between the NOBOX rare variants and POI.

Mutations in tubulin genes are frequent causes of various foetal malformations of cortical development including microlissencephaly.

Complex cortical malformations associated with mutations in tubulin genes are commonly referred to as "Tubulinopathies". To further characterize the mutation frequency and phenotypes associated with tubulin mutations, we studied a cohort of 60 foetal cases. Twenty-six tubulin mutations were identified, of which TUBA1A mutations were the most prevalent (19 cases), followed by TUBB2B (6 cases) and TUBB3 (one case). Three subtypes clearly emerged. The most frequent (n = 13) was microlissencephaly with corpus callosum agenesis, severely hypoplastic brainstem and cerebellum. The cortical plate was either absent (6/13), with a 2-3 layered pattern (5/13) or less frequently thickened (2/13), often associated with neuroglial overmigration (4/13). All cases had voluminous germinal zones and ganglionic eminences. The second subtype was lissencephaly (n = 7), either classical (4/7) or associated with cerebellar hypoplasia (3/7) with corpus callosum agenesis (6/7). All foetuses with lissencephaly and cerebellar hypoplasia carried distinct TUBA1A mutations, while those with classical lissencephaly harbored recurrent mutations in TUBA1A (3 cases) or TUBB2B (1 case). The third group was polymicrogyria-like cortical dysplasia (n = 6), consisting of asymmetric multifocal or generalized polymicrogyria with inconstant corpus callosum agenesis (4/6) and hypoplastic brainstem and cerebellum (3/6). Polymicrogyria was either unlayered or 4-layered with neuronal heterotopias (5/6) and occasional focal neuroglial overmigration (2/6). Three had TUBA1A mutations and 3 TUBB2B mutations. Foetal TUBA1A tubulinopathies most often consist in microlissencephaly or classical lissencephaly with corpus callosum agenesis, but polymicrogyria may also occur. Conversely, TUBB2B mutations are responsible for either polymicrogyria (4/6) or microlissencephaly (2/6).

The wide spectrum of tubulinopathies: what are the key features for the diagnosis?

Complex cortical malformations associated with mutations in tubulin genes: TUBA1A, TUBA8, TUBB2B, TUBB3, TUBB5 and TUBG1 commonly referred to as tubulinopathies, are a heterogeneous group of conditions with a wide spectrum of clinical severity. Among the 106 patients selected as having complex cortical malformations, 45 were found to carry mutations in TUBA1A (42.5%), 18 in TUBB2B (16.9%), 11 in TUBB3 (10.4%), three in TUBB5 (2.8%), and three in TUBG1 (2.8%). No mutations were identified in TUBA8. Systematic review of patients' neuroimaging and neuropathological data allowed us to distinguish at least five cortical malformation syndromes: (i) microlissencephaly (n = 12); (ii) lissencephaly (n = 19); (iii) central pachygyria and polymicrogyria-like cortical dysplasia (n = 24); (iv) generalized polymicrogyria-like cortical dysplasia (n = 6); and (v) a 'simplified' gyral pattern with area of focal polymicrogyria (n = 19). Dysmorphic basal ganglia are the hallmark of tubulinopathies (found in 75% of cases) and are present in 100% of central pachygyria and polymicrogyria-like cortical dysplasia and simplified gyral malformation syndromes. Tubulinopathies are also characterized by a high prevalence of corpus callosum agenesis (32/80; 40%), and mild to severe cerebellar hypoplasia and dysplasia (63/80; 78.7%). Foetal cases (n = 25) represent the severe end of the spectrum and show specific abnormalities that provide insights into the underlying pathophysiology. The overall complexity of tubulinopathies reflects the pleiotropic effects of tubulins and their specific spatio-temporal profiles of expression. In line with previous reports, this large cohort further clarifies overlapping phenotypes between tubulinopathies and although current structural data do not allow prediction of mutation-related phenotypes, within each mutated gene there is an associated predominant pattern of cortical dysgenesis allowing some phenotype-genotype correlation. The core phenotype of TUBA1A and TUBG1 tubulinopathies are lissencephalies and microlissencephalies, whereas TUBB2B tubulinopathies show in the majority, centrally predominant polymicrogyria-like cortical dysplasia. By contrast, TUBB3 and TUBB5 mutations cause milder malformations with focal or multifocal polymicrogyria-like cortical dysplasia with abnormal and simplified gyral pattern.

Brugada syndrome and abnormal splicing of SCN5A in myotonic dystrophy type 1.

BACKGROUND: In patients with myotonic dystrophy type 1 (DM1), the mechanisms underlying sudden cardiac death, which occurs in up to 1/3 of patients, are unclear. AIMS: To study the potential role of Brugada syndrome in ventricular tachyarrhythmias and sudden death in DM1 patients. METHODS: We screened 914 adult patients included in the DM1 Heart Registry during 2000-2009 for the presence of type 1 Brugada pattern on electrocardiogram (ECG). We also performed direct sequencing of SCN5A in patients with Brugada pattern. Further, we analysed SCN5A splicing on ventricular myocardial specimens harvested during cardiac transplantation in a 45-year-old patient with DM1 and three controls with inherited dilated cardiomyopathy. RESULTS: A type 1 Brugada pattern was present on the ECG of seven of 914 patients (0.8%), including five with a history of sustained ventricular tachyarrhythmia or sudden death, who fulfilled the criteria for Brugada syndrome. SCN5A sequencing was normal in all patients. Ventricular myocardial specimen analysis displayed abnormal splicing of SCN5A exon 6, characterized by over-expression of the 'neonatal' isoform, called exon 6A, in the patient with DM1, but not from the controls. CONCLUSION: Our findings suggest a potential implication of Brugada syndrome in sudden death in DM1, which may be related to missplicing of SCN5A. Our findings provide a new insight into the pathophysiology of heart disease in DM1.

New insights into genotype-phenotype correlations for the doublecortin-related lissencephaly spectrum.

X-linked isolated lissencephaly sequence and subcortical band heterotopia are allelic human disorders associated with mutations of doublecortin (DCX), giving both familial and sporadic forms. DCX encodes a microtubule-associated protein involved in neuronal migration during brain development. Structural data show that mutations can fall either in surface residues, likely to impair partner interactions, or in buried residues, likely to impair protein stability. Despite the progress in understanding the molecular basis of these disorders, the prognosis value of the location and impact of individual DCX mutations has largely remained unclear. To clarify this point, we investigated a cohort of 180 patients who were referred with the agyria-pachygyria subcortical band heterotopia spectrum. DCX mutations were identified in 136 individuals. Analysis of the parents' DNA revealed the de novo occurrence of DCX mutations in 76 cases [62 of 70 females screened (88.5%) and 14 of 60 males screened (23%)], whereas in the remaining cases, mutations were inherited from asymptomatic (n = 14) or symptomatic mothers (n = 11). This represents 100% of families screened. Female patients with DCX mutation demonstrated three degrees of clinical-radiological severity: a severe form with a thick band (n = 54), a milder form (n = 24) with either an anterior thin or an intermediate thickness band and asymptomatic carrier females (n = 14) with normal magnetic resonance imaging results. A higher proportion of nonsense and frameshift mutations were identified in patients with de novo mutations. An analysis of predicted effects of missense mutations showed that those destabilizing the structure of the protein were often associated with more severe phenotypes. We identified several severe- and mild-effect mutations affecting surface residues and observed that the substituted amino acid is also critical in determining severity. Recurrent mutations representing 34.5% of all DCX mutations often lead to similar phenotypes, for example, either severe in sporadic subcortical band heterotopia owing to Arg186 mutations or milder in familial cases owing to Arg196 mutations. Taken as a whole, these observations demonstrate that DCX-related disorders are clinically heterogeneous, with severe sporadic and milder familial subcortical band heterotopia, each associated with specific DCX mutations. There is a clear influence of the individual mutated residue and the substituted amino acid in determining phenotype severity.

Custom oligonucleotide array-based CGH: a reliable diagnostic tool for detection of exonic copy-number changes in multiple targeted genes.

The frequency of disease-related large rearrangements (referred to as copy-number mutations, CNMs) varies among genes, and search for these mutations has an important place in diagnostic strategies. In recent years, CGH method using custom-designed high-density oligonucleotide-based arrays allowed the development of a powerful tool for detection of alterations at the level of exons and made it possible to provide flexibility through the possibility of modeling chips. The aim of our study was to test custom-designed oligonucleotide CGH array in a diagnostic laboratory setting that analyses several genes involved in various genetic diseases, and to compare it with conventional strategies. To this end, we designed a 12-plex CGH array (135k; 135 000 probes/subarray) (Roche Nimblegen) with exonic and intronic oligonucleotide probes covering 26 genes routinely analyzed in the laboratory. We tested control samples with known CNMs and patients for whom genetic causes underlying their disorders were unknown. The contribution of this technique is undeniable. Indeed, it appeared reproducible, reliable and sensitive enough to detect heterozygous single-exon deletions or duplications, complex rearrangements and somatic mosaicism. In addition, it improves reliability of CNM detection and allows determination of boundaries precisely enough to direct targeted sequencing of breakpoints. All of these points, associated with the possibility of a simultaneous analysis of several genes and scalability 'homemade' make it a valuable tool as a new diagnostic approach of CNMs.

Expanding the spectrum of TUBA1A-related cortical dysgenesis to Polymicrogyria.

De novo mutations in the TUBA1A gene are responsible for a wide spectrum of neuronal migration disorders, ranging from lissencephaly to perisylvian pachygyria. Recently, one family with polymicrogyria (PMG) and mutation in TUBA1A was reported. Hence, the purpose of our study was to determine the frequency of TUBA1A mutations in patients with PMG and better define clinical and imaging characteristics for TUBA1A-related PMG. We collected 95 sporadic patients with non-syndromic bilateral PMG, including 54 with perisylvian PMG and 30 PMG with additional brain abnormalities. Mutation analysis of the TUBA1A gene was performed by sequencing of PCR fragments corresponding to TUBA1A-coding sequences. Three de novo missense TUBA1A mutations were identified in three unrelated patients with PMG representing 3.1% of PMG and 10% of PMGs with complex cerebral malformations. These patients had bilateral perisylvian asymmetrical PMG with dysmorphic basal ganglia cerebellar vermian dysplasia and pontine hypoplasia. These mutations (p.Tyr161His; p.Val235Leu; p.Arg390Cys) appear distributed throughout the primary structure of the alpha-tubulin polypeptide, but their localization within the tertiary structure suggests that PMG-related mutations are likely to impact microtubule dynamics, stability and/or local interactions with partner proteins. These findings broaden the phenotypic spectrum associated with TUBA1A mutations to PMG and further emphasize that additional brain abnormalities, that is, dysmorphic basal ganglia, hypoplastic pons and cerebellar dysplasia are key features for the diagnosis of TUBA1A-related PMG.

Mosaic DCX deletion causes subcortical band heterotopia in males.

Subcortical band heterotopia (SBH) is a neuronal migration disorder usually described in females carrying heterozygous mutations in the X-linked doublecortin (DCX) gene. Hemizygous DCX mutations in males result in lissencephaly. Recently, exonic deletions of DCX resulting in a severer form of agyria have been reported. Nevertheless, rare male patients with SBH have been described with somatic mosaicism of point mutations. Here, we identified a somatic mosaicism for a deletion of exon 4 in the DCX gene in a male patient with SBH detected prenatally. This finding points to the possible implication of mosaic deletions in the DCX gene in unexplained forms of SBH and may allow for detection of SBH prenatally.

Focal polymicrogyria are associated with submicroscopic chromosomal rearrangements detected by CGH microarray analysis.

Polymicrogyria is a relatively common cortical malformation characterized by multiple small gyri with abnormal cortical lamination. The pathophysiological bases are heterogeneous and include extrinsic factors and genetic causes. Recent data has emphasized the high prevalence of chromosomal rearrangements in bilateral and mainly perisylvian polymicrogyria in the context of multiple congenital abnormalities. We present here two cases of rare submicroscopic abnormalities ascertained by array-comparative genome hybridization screening of 18 patients with polymicrogyria. The first patient is an 11 year-old female with developmental delay, behavioural disturbance, postnatal microcephaly, focal seizures and temporo-occipital polymicrogyria. She presented a 7.2 Mb terminal deletion in the 6q27 region. The second patient is a 3 year-old boy with psychomotor retardation, spastic diplegia and right temporal polymicrogyria who presented a 3 Mb duplication in the 22q11.2 region. These two patients exhibited focal temporal or occipital polymicrogyria without additional brain malformations or multiple congenital abnormalities. This data suggest that patients with polymicrogyria, even focal and/or unilateral and isolated forms, should be screened for submicroscopic chromosomal rearrangements using array-CGH.

GPR56-related bilateral frontoparietal polymicrogyria: further evidence for an overlap with the cobblestone complex.

GPR56 mutations cause an autosomal recessive polymicrogyria syndrome that has distinctive radiological features combining bilateral frontoparietal polymicrogyria, white matter abnormalities and cerebellar hypoplasia. Recent investigations of a GPR56 knockout mouse model suggest that bilateral bifrontoparietal polymicrogyria shares some features of the cobblestone brain malformation and demonstrate that loss of GPR56 leads to a dysregulation of the maintenance of the pial basement membrane integrity in the forebrain and the rostral cerebellum. In light of these findings and other data in the literature, this study aimed to refine the clinical features with the first description of a foetopathological case and to define the range of cobblestone-like features in GPR56 bilateral bifrontoparietal polymicrogyria in a sample of 14 patients. We identified homozygous GPR56 mutations in 14 patients from eight consanguineous families with typical bilateral bifrontoparietal polymicrogyria and in one foetal case, out of 30 patients with bifrontoparietal polymicrogyria referred for molecular screening. The foetal case, which was terminated at 35 weeks of gestation in view of suspicion of Walker Warburg syndrome, showed a cobblestone-like lissencephaly with a succession of normal, polymicrogyric and 'cobblestone-like' cortex with ectopic neuronal overmigration, agenesis of the cerebellar vermis and hypoplastic cerebellar hemispheres with additional neuronal overmigration in the pons and the cerebellar cortex. The 14 patients with GPR56 mutations (median 8.25 years, range 1.5-33 years) were phenotypically homogeneous with a distinctive clinical course characterized by pseudomyopathic behaviour at onset that subsequently evolved into severe mental and motor retardation. Generalized seizures (12/14) occurred later with onset ranging from 2.5 to 10 years with consistent electroencephalogram findings of predominantly anterior bursts of low amplitude α-like activity. Neuroimaging demonstrated a common phenotype with bilateral frontoparietally predominant polymicrogyria (13/13), cerebellar dysplasia with cysts mainly affecting the superior vermis (11/13) and patchy to diffuse myelination abnormalities (13/13). Additionally, the white matter abnormalities showed a peculiar evolution from severe hypomyelination at 4 months to patchy lesions later in childhood. Taken as a whole, these observations collectively demonstrate that GPR56 bilateral bifrontoparietal polymicrogyria combines all the features of a cobblestone-like lissencephaly and also suggest that GRP56-related defects produce a phenotypic continuum ranging from bilateral bifrontoparietal polymicrogyria to cobblestone-like lissencephaly.

Evidence for tangential migration disturbances in human lissencephaly resulting from a defect in LIS1, DCX and ARX genes.

During corticogenesis, neurons adopt different migration pathways to reach their final position. The precursors of pyramidal neurons migrate radially, whereas most of the GABA-containing interneurons are generated in the ventral telencephalon and migrate tangentially into the neocortex. Then, they use a radial migration mode to establish themselves in an inside-out manner in the neocortex, similarly to pyramidal neurons. In humans, the most severe defects in radial migration result in lissencephaly. Lately, a few studies suggested that lissencephaly was also associated with tangential neuronal migration deficits. In the present report, we investigated potential anomalies of this migration mode in three agyric/pachygyric syndromes due to defects in the LIS1, DCX and ARX genes. Immunohistochemistry was performed on paraffin-embedded supra- and infratentorial structures using calretinin, calbindin and parvalbumin antisera. The results were compared with age-matched control brain tissue. In the Miller-Dieker syndrome, GABAergic neurons were found both in upper layers of the cortex and in heterotopic positions in the intermediate zone and in ganglionic eminences. In the DCX mutant brain, few interneurons were dispersed in the cortical plate, with a massive accumulation in the intermediate zone and subventricular zone as well as in the ganglionic eminences. In the ARX-mutated brain, the cortical plate contained almost exclusively pyramidal cells and was devoid of interneurons. The ganglionic eminences and basal ganglia were poorly cellular, suggesting an interneuron production and/or differentiation defect. These data argue for different mechanisms of telencephalic tangential migration impairment in these three agyric/pachygyric syndromes.

CDKL5 and ARX mutations are not responsible for early onset severe myoclonic epilepsy in infancy.

BACKGROUND: Severe myoclonic epilepsy of infancy (SMEI) or Dravet syndrome (DS) is a distinctive epilepsy syndrome often associated with de novo mutations in the SCN1A gene. However, 25-30% patients with SMEI/DS are negative for SCN1A mutation screening, suggesting that other molecular mechanisms may account for these disorders. Given the overlapping and heterogeneous clinical features of CDKL5- and ARX-related epilepsies and SMEI/DS, we postulated that CDKL5 mutations in females and ARX mutations gene in males may be associated with early onset seizures forms of SMEI/DS. METHODS: Twenty-eight patients with early onset SMEI/DS before 6 months negative for SCN1A mutational screening were selected and screened for mutations in the ARX gene in males (n=14) or the CDKL5 gene in females (n=14). RESULTS: No mutations in either gene were found except one intronic variation of uncertain pathogenicity in the CDKL5 gene. All patients started seizures at mean age of 3.48 months. Thirteen patients had familial history of epilepsy or febrile seizures. Patients evolved toward refractory epilepsy with generalized tonic clonic seizures (18/28) and myoclonia (23/28) and severe neurological impairment with autistic features (13/28), ataxia (14/28) and spasticity (5/28). No patient ever exhibited infantile spasms, dystonia, or Rett-like features. INTERPRETATIONS: Our results illustrate that mutation screening of ARX and CDKL5 is not effective in patients selected on the basis of clinical signs associated to early onset SMEI/DS. In addition, they might reflect that other phenotypic features associated with CDKL5 mutations (Rett-like features, infantile spasm) or ARX mutations (dystonia, spasticity) are more distinctive.

LIS1-related isolated lissencephaly: spectrum of mutations and relationships with malformation severity.

OBJECTIVE: With the largest data set of patients with LIS1-related lissencephaly, the major cause of posteriorly predominant lissencephaly related to either LIS1 mutation or intragenic deletion, described so far, we aimed to refine the spectrum of neurological and radiological features and to assess relationships with the genotype. DESIGN: Retrospective study. Subjects A total of 63 patients with posteriorly predominant lissencephaly. INTERVENTIONS: Of the 63 patients, 40 were found to carry either LIS1 point mutations (77.5%) or small genomic deletions (20%), and 1 carried a somatic nonsense mutation. On the basis of the severity of neuromotor impairment, epilepsy, and radiological findings, correlations with the location and type of mutation were examined. RESULTS: Most patients with LIS1 mutations demonstrated posterior agyria (grade 3a, 55.3%) with thin corpus callosum (50%) and prominent perivascular spaces (67.4%). By contrast, patients without LIS1 mutations tended to have less severe lissencephaly (grade 4a, 41.6%) and no additional brain abnormalities. The degree of neuromotor impairment was in accordance with the severity of lissencephaly, with a high incidence of tetraplegia (61.1%). Conversely, the severity of epilepsy was not determined with the same reliability because 82.9% had early onset of seizures and 48.7% had seizures more often than daily. In addition, neither the mutation type nor the location of the mutation were found to predict the severity of LIS1-related lissencephaly. CONCLUSION: Our results confirm the homogeneity profile of patients with LIS1-related lissencephaly who demonstrate in a large proportion Dobyns lissencephaly grade 3a, and the absence of correlation with LIS1 mutations.