Expanding the genetic heterogeneity of intellectual disability

Intellectual disability (ID) is a common morbid condition with a wide range of etiologies. The list of monogenic forms of ID has increased rapidly in recent years thanks to the implementation of genomic sequencing techniques. In this study, we describe the phenotypic and genetic findings of 68 families (105 patients) all with novel ID-related variants. In addition to established ID genes, including ones for which we describe unusual mutational mechanism, some of these variants represent the first confirmatory disease-gene links following previous reports (TRAK1, GTF3C3, SPTBN4 and NKX6-2), some of which were based on single families. Furthermore, we describe novel variants in 14 genes that we propose as novel candidates (ANKHD1, ASTN2, ATP13A1, FMO4, MADD, MFSD11, NCKAP1, NFASC, PCDHGA10, PPP1R21, SLC12A2, SLK, STK32C and ZFAT). We highlight MADD and PCDHGA10 as particularly compelling candidates in which we identified biallelic likely deleterious variants in two independent ID families each. We also highlight NCKAP1 as another compelling candidate in a large family with autosomal dominant mild intellectual disability that fully segregates with a heterozygous truncating variant. The candidacy of NCKAP1 is further supported by its biological function, and our demonstration of relevant expression in human brain. Our study expands the locus and allelic heterogeneity of ID and demonstrates the power of positional mapping to reveal unusual mutational mechanisms

Endothelin: an endothelium-derived vasoactive peptide and its possible role in the pathogenesis of cerebral vasospasm.

The contractile response to endothelin has been examined in cerebral arteries from rats subjected to a prior subarachnoid haemorrhage (SAH) and compared with saline injected controls. Endothelin elicited strong concentration-dependent contraction of rat basilar artery segments. The response was slow in onset and long lasting. The endothelin-induced contraction was much stronger in the SAH compared to control animals. Our findings suggest a role of the peptide in the pathophysiology of cerebral vasospasm

Do spinal meningiomas penetrate the pial layer? Correlation between magnetic resonance imaging and microsurgical findings and intracranial tumor interfaces.

OBJECTIVE: To study the relationships between spinal dura-arachnoid and tumor-cord interfaces in spinal meningiomas and to investigate whether a disruption of the pial layer and penetration of the tumor in the spinal cord occurs. METHODS: Fifteen patients with histologically proven meningiomas underwent magnetic resonance imaging (MRI) preoperatively. All patients underwent microsurgery. The histological characteristics of the tumors were compared with MRI and microsurgical findings. RESULTS: At surgery, the peritumoral hypointense rim revealed by MRI in 10 of 15 patients corresponded to a well-defined cerebrospinal fluid-containing space confined between the outer arachnoidal layer and the inner leptomeningeal layer. In those patients in whom the hypointense peritumoral rim was absent, the inner layer was either difficult to identify or clearly absent, and the blood vessels were extremely adherent to the tumor, requiring a more cautious dissection. Penetration of the tumors through disruption of the pial surface was not documented. CONCLUSION: Previous anatomic and electron microscopy studies demonstrated, in human spinal meninges, the presence of an intermediate layer attached to the inner aspect of the arachnoid, extending laterally over the dorsal surface of the spinal cord and arborizing over the nerve roots and blood vessels. The intermediate layer is not present in human cerebral leptomeninges. The presence/absence of this layer might explain the hypointense rim detected by MRI and might also explain why no penetration and no peritumoral edema is observed in spinal meningiomas as compared with intracranial meningiomas

Landmarks for vertebral artery repositioning in bulbar compression syndrome: anatomic and microsurgical nuances

OBJECTIVE: The purpose of this study was to better elucidate the anatomic relationship between the vertebral artery (VA) along with its perforating vessels and the brainstem to develop anatomic guidelines that would be helpful when decompressing medulla oblongata compressed by the VA. METHODS: Microanatomy dissection was performed in six formalin-fixed cadaveric heads. The VA, posteroinferior cerebellar artery (PICA), anteroinferior cerebellar artery (AICA), and lower brainstem perforators were examined under magnification using a surgical microscope. The outer diameters of the VA, PICA, and AICA were measured. The distance between the VA, lying within the lateral cerebellomedullary cistern, and the medulla oblongata was quantified. The lower brainstem perforating vessels were examined in relation to their course, outer diameter, and length. RESULTS: In four of six brains, the left VA was dominant, presenting an outer diameter at least 0.8 mm larger than the contralateral VA. The average distance between the VA and the medulla oblongata was 3 mm. The perforating branches presented a mean outer diameter of 0.7 mm. In particular, perforators arising from the VA and PICA (Groups 1 and 2) presented an average outer diameter of 0.2 mm and an average length of 7 mm. Perforating vessels arising from the AICA and vertebrobasilar junction (Groups 3 and 4) presented an average outer diameter of 0.4 mm and an average length of 12 mm. CONCLUSION: This work provides new information that may be useful to minimize the risk of injury of perforators when operating on medulla oblongata compression by the VA

Peritumoral edema in meningiomas: microsurgical observations of different brain tumor interfaces related to computed tomography.

Although generally benign tumors, meningiomas may be associated with extensive peritumoral brain edema as seen on computed tomographic scans. Fifty-two patients with intracranial meningiomas were studied, and the hypodense areas on computed tomographic scans were related to the intraoperative microsurgical findings and to the sizes of the tumors. We have identified three kinds of tumor-brain interfaces characterized by different difficulties in microsurgical dissection: smooth type, transitional type, and invasive type. These different microsurgical interfaces seem to correlate very precisely with computed tomographic images of halo-like and finger-like hypodense areas, allowing prediction of the microsurgical effort to be made in the surgery of meningiomas. The size of the tumor seems to be important in our subjects in determining the amount of edema produced. Indeed, a positive correlation (P < 0.001) was found between the sizes of the tumors and the extent of peritumoral hypodensity. A positive correlation (P < 0.002) also has been found between grade of edema and cortical penetration. Cerebral cortex disruption was systematically observed by us in invasive-type meningiomas and in 3 of 21 cases (14.3%) in transitional-type meningiomas. No penetration was observed in smooth-type meningiomas

Brain metastases as first clinical manifestation of ovarian carcinoma

no abstract availabl