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Polymicrogyria (PMG) is a clinically heterogeneous malformation of cortical development, characterized by a loss of the normal gyral pattern that is replaced by many small and infolded gyri separated by shallow sulci that are partly fused in their depths. Causes of PMG are heterogeneous and include acquired and genetic causes. There are more than 100 syndromes possibly associated with PMG but mutations in specific genes such as SRPX2, GPR56, TUBB2B, TUBB3, NHEJ1, TUBA1A, TUBA8, and WDR62 have been reported only in a minority of patients.

Cobblestone lissencephaly represents a peculiar brain malformation with characteristic radiological anomalies, defined as cortical dysplasia combined with dysmyelination, dysplastic cerebellum with cysts and brainstem hypoplasia. Cortical dysplasia results from neuroglial overmigration into the arachnoid space, forming an extracortical layer, responsible for agyria and/or 'cobblestone' brain surface and ventricular enlargement. The underlying mechanism is a disruption of the glia limitans, the outermost layer of the brain. Cobblestone lissencephaly is pathognomonic of a continuum of autosomal recessive diseases with cerebral, ocular and muscular deficits, Walker-Warburg syndrome, muscle-eye-brain and Fukuyama muscular dystrophy. Mutations in POMT1, POMT2, POMGNT1, LARGE, FKTN and FKRP genes attributed these diseases to α-dystroglycanopathies. However, studies have not been able to identify causal mutations in the majority of patients and to establish a clear phenotype/genotype correlation. Therefore, we decided to perform a detailed neuropathological survey and molecular screenings in 65 foetal cases selected on the basis of histopathological criteria. After sequencing the six genes of α-dystroglycanopathies, a causal mutation was observed in 66% of cases. On the basis of a ratio of severity, three subtypes clearly emerged. The most severe, which we called cobblestone lissencephaly A, was linked to mutations in POMT1 (34%), POMT2 (8%) and FKRP (1.5%). The least severe, cobblestone lissencephaly C, was linked to POMGNT1 mutations (18%). An intermediary type, cobblestone lissencephaly B, was linked to LARGE mutations (4.5%) identified for the first time in foetuses. We conclude that cobblestone lissencephaly encompasses three distinct subtypes of cortical malformations with different degrees of neuroglial ectopia into the arachnoid space and cortical plate disorganization regardless of gestational age. In the cerebellum, histopathological changes support the novel hypothesis that abnormal lamination arises from a deficiency in granule cells. Our studies demonstrate the positive impact of histoneuropathology on the identification of α-dystroglycanopathies found in 66% of cases, while with neuroimaging criteria and biological values, mutations are found in 32-50% of patients. Interestingly, our morphological classification was central in the orientation of genetic screening of POMT1, POMT2, POMGNT1, LARGE and FKRP. Despite intensive research, one-third of our cases remained unexplained; suggesting that other genes and/or pathways may be involved. This material offers a rich resource for studies on the affected neurodevelopmental processes of cobblestone lissencephaly and on the identification of other responsible gene(s)/pathway(s).

Objective: To determine the prevalence and the timing of pregnancy termination relative to the type of central nervous system (CNS) malformations. Design Retrospective cohort study., Setting: Multidisciplinary centre for prenatal diagnosis in the Languedoc-Roussillon region, France., Population: A cohort of 481 pregnancy terminations performed between 2005 and 2009., Methods: Detailed post-termination fetal and neuropathological analyses were carried out to identify the CNS malformations. Then, the prevalence and timing of pregnancy termination were assessed relative to the identified malformations., Results: About one-third of pregnancy terminations (143/481) were performed for severe CNS malformations. Up to 24 weeks of gestation (WG), pregnancy terminations (56.6%) were carried out mainly for defects occurring during the two major first steps of CNS development (neurulation and differentiation of cerebral vesicles). After 24 WG, pregnancy terminations (43.3%) were mainly performed for corpus callosum agenesis (16/17), vermian agenesis (10/12) and gyral anomalies (13/15). For hindbrain malformations and gyral anomalies, there was a significant relationship between the timing of pregnancy termination and the presence of a severe ventriculomegaly at prenatal diagnosis (p=0.002 and p=0.02, respectively)., Conclusion: By classifying CNS malformations according to the neuropathological analysis, the authors show that the timing and prevalence of pregnancy termination are distributed in a manner that is consistent with what is currently known on the development of brain. They are also influenced by the French prenatal screening policy and the variable expressivity of the brain malformations and associated lesions.

Cerebral proliferative glomeruloid vasculopathy (PGV) is a severe disorder of brain angiogenesis, resulting in abnormally thickened and aberrant perforating vessels, forming glomeruloids with inclusion-bearing endothelial cells. This peculiar vascular malformation was delineated by Fowler in 1972 as a stereotyped lethal fetal phenotype associating hydranencephaly-hydrocephaly with limb deformities, called Fowler syndrome (FS) or "proliferative vasculopathy and hydranencephaly-hydrocephaly" or "encephaloclastic proliferative vasculopathy" (OMIM#225790). In PGV, the disruptive impact of vascular malformation on the developing central nervous system (CNS) is now well admitted. However, molecular mechanisms of abnormal angiogenesis involving the CNS vasculature exclusively remain unknown, as no genes have been localized nor identified to date. We observed the pathognomonic FS vascular malformation in 16 fetuses, born to eight families, four consanguineous and four non-consanguineous. A diffuse form of PGV affecting the entire CNS and resulting in classical FS in 14 cases, can be contrasted to two cases with focal forms, confined to restricted territories of the CNS. Interestingly in PGV, immunohistological response to a marker of pericytes (SMA, Smooth in PGV Muscle Actin), was drastically reduced as compared to a match control. Our studies has expanded the description of FS to additional phenotypes, that could be called Fowler-like syndromes and suggest that the pathogenesis of PGV may be related to abnormal pericyte-dependent remodelling of the CNS vasculature, during CNS angiogenesis. Gene identification will determine the molecular basis of PGV and will help to know whether the Fowler-like phenotypes are due to the same underlying molecular mechanisms.

Meckel syndrome (MKS) is a rare autosomal recessive lethal condition characterized by central nervous system malformations, polydactyly, multicystic kidney dysplasia, and ductal changes of the liver. Three loci have been mapped (MKS1-MKS3), and two genes have been identified (MKS1/FLJ20345 and MKS3/TMEM67), whereas the gene at the MKS2 locus remains unknown. To identify new MKS loci, a genomewide linkage scan was performed using 10-cM-resolution microsatellite markers in eight families. The highest heterogeneity LOD score was obtained for chromosome 12, in an interval containing CEP290, a gene recently identified as causative of Joubert syndrome (JS) and isolated Leber congenital amaurosis. In view of our recent findings of allelism, at the MKS3 locus, between these two disorders, CEP290 was considered a candidate, and homozygous or compound heterozygous truncating mutations were identified in four families. Sequencing of additional cases identified CEP290 mutations in two fetuses with MKS and in four families presenting a cerebro-reno-digital syndrome, with a phenotype overlapping MKS and JS, further demonstrating that MKS and JS can be variable expressions of the same ciliopathy. These data identify a fourth locus for MKS (MKS4) and the CEP290 gene as responsible for MKS.

Objective: We describe the analysis of an apparently balanced inherited reciprocal translocation in a fetus presenting with multiple congenital abnormalities, characterize the structural chromosome rearrangement, and report an unexpected additional imbalance to the inherited rearrangement., Methods: DNA microarray was used to screen for genomic imbalance in subtelomeric and interstitial critical regions. High-resolution comparative genomic hybridization was used to screen for genomic imbalance at a genome-wide level. Fluorescence in situ hybridization using whole-chromosome painting and specific probes was used to characterize the inherited translocation, and the size of the de novoadditional deletion., Results: An unexpected additional deletion was found in 7qter on derivative 10 of the inherited maternal reciprocal translocation t(7;10)(q11.23; p14)., Conclusions: We show the usefulness of genome-wide and specific molecular cytogenetic techniques to explore apparently balanced rearrangements., (Copyright (c) 2007 S. Karger AG, Basel.)

A third type of lissencephaly that does not fufil diagnostic criteria of type I ("classical") and type II ("cobblestone") lissencephaly was described by our group as a new entity identified as OMIM 601160. This lethal familial syndrome comprises micrencephaly/lissencephaly and a spectrum of abnormalities lined to a severe fetal akinesia deformation sequence. Neuropathological findings suggest severe neurodegeneration leading to a marked neuronal dropout of the entire central nervous system and atrophy. Similar neuropathological findings have been described in the Neu-Laxova syndrome (NLS), an apparently different lethal malformation syndrome. Neuropathological similarities between OMIM 601160 and NLS raise the question of clinicopathological variability and genetic heterogeneity of type III lissencephaly. To answer this question, we compared our clinicopathological findings in a series of fetuses with OMIM 601160 to pathological data reported in NLS. In the study, 5 unrelated families with 7 affected fetuses were included. Interestingly, we found striking clinicopathological similarities between OMIM 601160 and NLS, which may represent a variability of a single neurodegenerative disease with early prenatal onset. Molecular studies in multiplex families defined through detailed clinicopathological screening are needed to clarify the distinction, if any, between these two entities.

In type I or classical lissencephaly, two genetic causes, namely the LIS1 gene mapping at 17p13.3 and the DCX (doublecortin on X) gene mapping at Xq22.3 are involved. These are considered to act during corticogenesis on radial migratory pathways. The prevailing view is that heterozygous mutations in the LIS1 gene and hemizygous mutations in the DCX gene produce similar histological pattern. The present detailed neuropathological study in two unrelated fetuses with respectively a mutation in the LIS1 and the DCX genes do not confirm this view. In LIS1 mutation, the cortical ribbon displays a characteristic inverted organization, also called "four layered cortex" while in DCX mutation, the cortex displays a roughly ordered "six layered" lamination. Our hypothesis is that mutations of the LIS1 and DCX genes, may not affect the same neuronal arrangement in the neocortex. Because the pathology of proven XLIS is rarely documented, further detailed neuropathological analysis in other cases identified through molecular study would be of a great help in the recognition of neuronal population involved in these migrational disorders and their underlying molecular mechanism., (Copyright 2003 Wiley-Liss, Inc.)

Introduction: Fetal brain evaluation implies a perfect knowledge of the timing and characteristics of the developing nervous system during gestation., Discussion: The first half of gestation corresponds to the neurulation, differentiation of primary cerebral vesicles, and neuronogenesis. The second half is characterized by the tremendous growth of the cerebral hemispheres and the settlement of gyral formation, while the ventricular system undergoes gradual narrowing. Gyral formation follows an invariable temporospatial schedule and is a good marker of fetal maturation. At the histological level, the fetal cortex displays transient developmental features, a superficial granular layer, and cells of Cajal-Retzius, which disappear at term. Neuroblasts formation has usually ceased by the 16th week of gestation, while neuronal migration continues until the extinction of the germinal layer. At this time, the remnant of the germinal layer constitutes, between the thalami and the caudate nucleus, an eminence of tightly packed cells, called the ganglionic eminence or germinal zone. They disappear by the age of 1 year.

Introduction: The sophistication of prenatal brain imaging (US, MRI) has awakened interest in fetal neuropathology and changed the concept of brain malformations, defined until recently through descriptive terms and considered as senseless accidents of development. Usually, most CNS malformations are documented from a clinical and radiological point of view. However, only a detailed neuropathological study permits their exact phenotype to be established, which is instrumental for a precise diagnosis and cause analysis., Discussion: After pregnancy termination for fetal malformations (or prenatal death) full autopsy and frozen tissue storage for DNA analysis are mandatory. The delay between death and autopsy should be limited because of the rapid autolysis of brain tissue. Detailed neuropathological and cause analysis have made it clear that each brain malformation is phenotypically "unique" and causally heterogeneous. Molecular studies have shown that mutations in different genes involved in a signaling pathway may result in a similar malformation. In addition, signaling pathways may be a possible target of toxic agents, which will mimic the genetic causes of malformations. These findings have raised growing interest in the early patterning of the developing nervous system in humans and its molecular controlling pathways. Consequently, brain malformations are now evaluated with special regard to their mechanism and cause analysis, considering fetal, maternal, and placental pathology. The predictive value of this multidisciplinary approach is now well demonstrated and has led, in some conditions, to gene identification, which is crucial for genetic counseling. It permits a prenatal molecular diagnosis as early as the 10-12th gestational week on chorionic villus sampling.

A 4-base pair deletion in the neuronal serine protease neurotrypsin gene was associated with autosomal recessive nonsyndromic mental retardation (MR). In situ hybridization experiments on human fetal brains showed that neurotrypsin was highly expressed in brain structures involved in learning and memory. Immuno-electron microscopy on adult human brain sections revealed that neurotrypsin is located in presynaptic nerve endings, particularly over the presynaptic membrane lining the synaptic cleft. These findings suggest that neurotrypsin-mediated proteolysis is required for normal synaptic function and suggest potential insights into the pathophysiological bases of mental retardation.

We report on two new cases of syndromic lissencephaly in two consanguineous sibs, with skeletal abnormality, born to young, healthy, second cousin parents with healthy children. In Case 1, fetal ultrasound screening at 32 weeks of gestation showed microcephaly, skin infiltration and equinovarus feet. MRI disclosed cerebral agyria, hypoplastic cerebral mantle and posterior agenesis of the corpus callosum. The propositus, a boy, died soon after birth at term. In Case 2, fetal ultrasound study performed at 16 weeks of gestation disclosed skin infiltration. MRI at 22 weeks of gestation showed microcephaly with agenesis of corpus callosum and cerebellar hypoplasia. Pregnancy was terminated at 22 weeks of gestation. The fetus had normal 46, XY karyotype and similar anomalies found in the index case, with cranio-facial edema and arthrogryposis. X-ray films showed epiphyseal stippling of cervical vertebrae, feet and sacrum. Metacarpal bones were shortened with hypoplastic distal phalanges. Neuropathological findings were concordant with the pattern described in type III lissencephaly: an agyric brain with hypoplastic brain stem and cerebellum, severe neuronal loss of the cortical plate, matrix zone, basal ganglia, brainstem nuclei and spinal cord with axonal swelling and microcalcification. This entity seems to be a new syndromic lissencephaly type III, because of epiphyseal calcifications and metacarpophalangeal bone dysplasia., (Copyright Wiley-Liss. Inc.)

Waardenburg syndrome type 4 (WS4), also called Shah-Waardenburg syndrome, is a rare neurocristopathy that results from the absence of melanocytes and intrinsic ganglion cells of the terminal hindgut. WS4 is inherited as an autosomal recessive trait attributable to EDN3 or EDNRB mutations. It is inherited as an autosomal dominant condition when SOX10 mutations are involved. We report on three unrelated WS4 patients with growth retardation and an as-yet-unreported neurological phenotype with impairment of both the central and autonomous nervous systems and occasionally neonatal hypotonia and arthrogryposis. Each of the three patients was heterozygous for a SOX10 truncating mutation (Y313X in two patients and S251X [corrected] in one patient). The extended spectrum of the WS4 phenotype is relevant to the brain expression of SOX10 during human embryonic and fetal development. Indeed, the expression of SOX10 in human embryo was not restricted to neural-crest-derived cells but also involved fetal brain cells, most likely of glial origin. These data emphasize the important role of SOX10 in early development of both neural-crest-derived tissues, namely melanocytes, autonomic and enteric nervous systems, and glial cells of the central nervous system.

A neuropathological study performed in 134 foetuses from HIV infected mothers, between 16 and 35 weeks of gestation, revealed two cases of hypoxic-ischemic brain damage, related to long labor and drug abuse. Immunostains against HIV proteins were negative in all cases. Nests of migrating cells in the cerebrum and cerebellar heterotopias were found in most cases and were considered to be common findings in fetal brain. Our study clearly showed the absence of cerebral HIV infection during early pregnancy and raises the question of the frequency of vertical transmission during HIV infection. However, the evaluation of cerebral changes in infants with HIV infection should take into consideration the features of the developing brain and the existence of other adverse factors that may interfere with its development during pregnancy.

We report on a distinct pattern of primary central nervous system (CNS) degeneration affecting neuronal survival in the brain and spinal cord in 5 fetuses with fetal akinesia sequence (FAS). This neuropathological pattern is characteristic of a lethal entity that we propose calling type III lissencephaly syndrome. Parental consanguinity and the recurrence in sibs support a genetic cause. The mechanism of neuronal death is not yet understood; abnormal apoptosis and/or deficiency in neurotropic factors may be considered possible causes.