Cobblestone lissencephaly is a peculiar brain malformation with characteristic radiological anomalies. It is defined as cortical dysplasia that results when neuroglial overmigration into the ...arachnoid space forms an extracortical layer that produces agyria and/or a “cobblestone” brain surface and ventricular enlargement. Cobblestone lissencephaly is pathognomonic of a continuum of autosomal-recessive diseases characterized by cerebral, ocular, and muscular deficits. These include Walker-Warburg syndrome, muscle-eye-brain disease, and Fukuyama muscular dystrophy. Mutations in POMT1, POMT2, POMGNT1, LARGE, FKTN, and FKRP identified these diseases as alpha-dystroglycanopathies. Our exhaustive screening of these six genes, in a cohort of 90 fetal cases, led to the identification of a mutation in only 53% of the families, suggesting that other genes might also be involved. We therefore decided to perform a genome-wide study in two multiplex families. This allowed us to identify two additional genes: TMEM5 and ISPD. Because TMEM has a glycosyltransferase domain and ISPD has an isoprenoid synthase domain characteristic of nucleotide diP-sugar transferases, these two proteins are thought to be involved in the glycosylation of dystroglycan. Further screening of 40 families with cobblestone lissencephaly identified nonsense and frameshift mutations in another four unrelated cases for each gene, increasing the mutational rate to 64% in our cohort. All these cases displayed a severe phenotype of cobblestone lissencephaly A. TMEM5 mutations were frequently associated with gonadal dysgenesis and neural tube defects, and ISPD mutations were frequently associated with brain vascular anomalies.
Patients with Kallmann syndrome (KS) have hypogonadotropic hypogonadism caused by a deficiency of gonadotropin-releasing hormone (GnRH) and a defective sense of smell related to olfactory bulb ...aplasia. Based on the findings in a fetus affected by the X chromosome–linked form of the disease, it has been suggested that hypogonadism in KS results from the failed embryonic migration of neuroendocrine GnRH1 cells from the nasal epithelium to the forebrain. We asked whether this singular observation might extend to other developmental disorders that also include arrhinencephaly. We therefore studied the location of GnRH1 cells in fetuses affected by different arrhinencephalic disorders, specifically X-linked KS, CHARGE syndrome, trisomy 13, and trisomy 18, using immunohistochemistry. Few or no neuroendocrine GnRH1 cells were detected in the preoptic and hypothalamic regions of all arrhinencephalic fetuses, whereas large numbers of these cells were present in control fetuses. In all arrhinencephalic fetuses, many GnRH1 cells were present in the frontonasal region, the first part of their migratory path, as were interrupted olfactory nerve fibers that formed bilateral neuromas. Our findings define a pathological sequence whereby a lack of migration of neuroendocrine GnRH cells stems from the primary embryonic failure of peripheral olfactory structures. This can occur either alone, as in isolated KS, or as part of a pleiotropic disease, such as CHARGE syndrome, trisomy 13, and trisomy 18.
Over the past three decades, significant efforts have been focused on unraveling congenital intestinal disorders that disrupt the absorption of dietary lipids and fat-soluble vitamins. The primary ...goal has been to gain deeper insights into intra-enterocyte sites, molecular steps, and crucial proteins/regulatory pathways involved, while simultaneously identifying novel therapeutic targets and diagnostic tools. This research not only delves into specific and rare malabsorptive conditions, such as chylomicron retention disease (CRD), but also contributes to our understanding of normal physiology through the utilization of cutting-edge cellular and animal models alongside advanced research methodologies. This review elucidates how modern techniques have facilitated the decoding of CRD gene defects, the identification of dysfunctional cellular processes, disease regulatory mechanisms, and the essential role of coat protein complex II-coated vesicles and cargo receptors in chylomicron trafficking and endoplasmic reticulum (ER) exit sites. Moreover, experimental approaches have shed light on the multifaceted functions of SAR1B GTPase, wherein loss-of-function mutations not only predispose individuals to CRD but also exacerbate oxidative stress, inflammation, and ER stress, potentially contributing to clinical complications associated with CRD. In addition to dissecting the primary disease pathology, genetically modified animal models have emerged as invaluable assets in exploring various ancillary aspects, including responses to environmental challenges such as dietary alterations, gender-specific disparities in disease onset and progression, and embryonic lethality or developmental abnormalities. In summary, this comprehensive review provides an in-depth and contemporary analysis of CRD, offering a meticulous examination of the CRD current landscape by synthesizing the latest research findings and advancements in the field.
L1 syndrome results from mutations in the
L1CAM
gene located at Xq28. It encompasses a wide spectrum of diseases, X-linked hydrocephalus being the most severe phenotype detected in utero, and whose ...pathophysiology is incompletely understood. The aim of this study was to report detailed neuropathological data from patients with mutations, to delineate the neuropathological criteria required for
L1CAM
gene screening in foetuses by characterizing the sensitivity, specificity and positive predictive value of the cardinal signs, and to discuss the main differential diagnoses in non-mutated foetuses in order to delineate closely related conditions without
L1CAM
mutations. Neuropathological data from 138 cases referred to our genetic laboratory for screening of the
L1CAM
gene were retrospectively reviewed. Fifty-seven cases had deleterious
L1CAM
mutations. Of these, 100 % had hydrocephalus, 88 % adducted thumbs, 98 % pyramidal tract agenesis/hypoplasia, 90 % stenosis of the aqueduct of Sylvius and 68 % agenesis/hypoplasia of the corpus callosum. Two foetuses had
L1CAM
mutations of unknown significance. Seventy-nine cases had no
L1CAM
mutations; these were subdivided into four groups: (1) hydrocephalus sometimes associated with corpus callosum agenesis (44 %); (2) atresia/forking of the aqueduct of Sylvius/rhombencephalosynapsis spectrum (27 %); (3) syndromic hydrocephalus (9 %), and (4) phenocopies with no mutations in the
L1CAM
gene (20 %) and in whom family history strongly suggested an autosomal recessive mode of transmission. These data underline the existence of closely related clinical entities whose molecular bases are currently unknown. The identification of the causative genes would greatly improve our knowledge of the defective pathways involved in these cerebral malformations.
Disease severity is tremendously variable in tuberous sclerosis complex (TSC). In contrast with the detailed guidelines available for TSC diagnosis and management, clinical practice lacks adequate ...tools to evaluate the prognosis, especially in the case of in utero diagnosis. In addition, the correlation between genotypes and phenotypes remains a challenge, in part due to the large number of mutations linked to TSC. In this report, we describe a case of severe TSC diagnosed in utero and associated with a specific mutation in the gene tuberous sclerosis complex 2 (TSC2).
A mother was referred for a thorough investigation following the observation by ultrasound of cardiac abnormalities in her fetus. The mother was healthy and reported frequent, intense and long-lasting hiccups/spasms in the fetus. The fetus of gestational age 33 weeks and 4 days was found to have multiple cardiac tumors with cardiac ultrasound. Brain magnetic resonance imaging (MRI) performed in utero revealed the presence of sub-ependymal nodules and of abnormal signals disseminated in the white matter, in the cerebral cortex and in the cerebellum. Following diagnosis of definite TSC, pregnancy interruption was chosen by the parents. Genetic testing of the fetus exposed a duplication in exon 41 of TSC2 (c.5169dupA), which was absent in the parents. The autopsy ascertained the high severity of brain damage characterized by an extensive disorganisation of white and grey matter in most cerebral lobes.
This case presentation is the first to depict the association between a de novo TSC2 c.5169dupA and multi-organ manifestation together with indications of a particularly high disease severity. This report can help physicians to perform early clinical diagnosis of TSC and to evaluate the prognosis.
Objectives
Congenital heart defects (CHD) are responsible for neurodevelopmental delays that were initially attributed to brain injury resulting from cardiac surgery. However, prenatal imaging have ...shown that brain anomalies are present at birth. The aim of this study was to assess in utero brain injuries before birth in fetuses/neonates with congenital cardiopathies.
Methods
A complete autopsy evaluation with detailed study of the cardiopathy and neuropathological study was performed in 40 fetuses/neonates. Syndromic congenital cardiopathies were excluded because of the potential other causes of brain injury. The patients were classified into two groups according to their term at death.
Results
Statistical analyses indicated the mean brain weight was not significantly different between subjects with different morphological types of congenital cardiopathies. However, the brain weight was at or below the fifth percentile in most third-trimester subjects compared to normal brain weight in second-trimester subjects. Low brain weight in third-trimester subjects was also associated with frequent lesions similar to those described in preterm infants, with a particular involvement of white matter and its components.
Conclusions
These observations allowed us to establish the timing and impact of prenatal neuropathological lesions on brain development, and to correlate them with imaging data reported in the literature.
Battistella M, Guedj N, Fallet‐Bianco C, Bodemer C, Brousse N & Fraitag S (2011) Histopathology59, 407–420
The histopathological spectrum of cutaneous meningeal heterotopias: clues and pitfalls
Aims: ... To describe the histopathological features of heterotopic cutaneous meningeal tissue.
Methods and results: Nineteen cases were collected between 1993 and 2010. Immunohistochemistry for epithelial membrane antigen (EMA), neuron specific enolase (NSE), S100, glial fibrillary acid protein (GFAP), progesterone receptor (PR), CD31, glucose transporter‐1 (Glut‐1), podoplanin and NKI‐C3 was performed. Lesions were congenital (100%) and presented as aplasia cutis with alopecia (63%) or lumps (37%), on the scalp (18 of 19) and sacral region. Resonance magnetic imaging revealed four underlying anomalies of the neuraxis. Histopathological analysis showed meningeal tissue arranged in four variably associated architectural patterns: fibrous (100%), pseudovascular (100%), cellular (68%) and pseudomyxoid (32%). Other features included collagen bodies (58%), calcifications (26%) and dermal melanocytes (32%). Heterotopic brain tissue or heterotopic ependymal cyst was associated in two cases. Arachnoidal cells expressed EMA and NSE, but not S100 protein, CD31 or GFAP. They expressed podoplanin (93%), especially in pseudovascular areas, NKI‐C3 (79%), and less frequently Glut‐1 (46%) and PR (30%).
Conclusions: Histopathological features of cutaneous meningeal heterotopias are various and sometimes misleading. Fibrous lesions should not be misdiagnosed as aplasia cutis. Podoplanin‐positive pseudovascular spaces represent the main pitfall and should not be diagnosed as lymphangioma. Correct diagnosis is confirmed by EMA and NSE coexpression within the lesion.
The Fetal Cerebellum Garel, Catherine; Fallet-Bianco, Catherine; Guibaud, Laurent
Journal of Child Neurology,
12/2011, Volume:
26, Issue:
12
Book Review, Journal Article
Peer reviewed
The cerebellum undergoes a protracted development, making it particularly vulnerable to a broad spectrum of developmental events. Acquired destructive and hemorrhagic insults may also occur. The main ...steps of cerebellar development are reviewed. The normal imaging patterns of the cerebellum in prenatal ultrasound and magnetic resonance imaging (MRI) are described with emphasis on the limitations of these modalities. Because of confusion in the literature regarding the terminology used for cerebellar malformations, some terms (agenesis, hypoplasia, dysplasia, and atrophy) are clarified. Three main pathologic settings are considered and the main diagnoses that can be suggested are described: retrocerebellar fluid enlargement with normal or abnormal biometry (Dandy-Walker malformation, Blake pouch cyst, vermian agenesis), partially or globally decreased cerebellar biometry (cerebellar hypoplasia, agenesis, rhombencephalosynapsis, ischemic and/or hemorrhagic damage), partially or globally abnormal cerebellar echogenicity (ischemic and/or hemorrhagic damage, cerebellar dysplasia, capillary telangiectasia). The appropriate timing for performing MRI is also discussed.
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