Novel VLDLR microdeletion identified in two Turkish siblings with pachygyria and pontocerebellar atrophy.

Congenital ataxia with cerebellar hypoplasia is a heterogeneous group of disorders that presents with motor disability, hypotonia, incoordination, and impaired motor development. Among these, disequilibrium syndrome describes a constellation of findings including non-progressive cerebellar ataxia, mental retardation, and cerebellar hypoplasia following an autosomal recessive pattern of inheritance and can be caused by mutations in the Very Low Density Lipoprotein Receptor (VLDLR). Interestingly, while the majority of patients with VLDL-associated cerebellar hypoplasia in the literature use bipedal gait, the previously reported patients of Turkish decent have demonstrated similar neurological sequelae, but rely on quadrupedal gait. We present a consanguinous Turkish family with two siblings with cerebellar atrophy, predominantly frontal pachygyria and ataxic bipedal gait, who were found to have a novel homozygous deletion in the VLDLR gene identified by using high-density single nucleotide polymorphism microarrays for homozygosity mapping and identification of CNVs within these regions. Discovery of disease causing homozygous deletions in the present Turkish family capable of maintaining bipedal movement exemplifies the phenotypic heterogeneity of VLDLR-associated cerebellar hypoplasia and ataxia.

Cervical Cord-Canal Mismatch: A New Method for Identifying Predisposition to Spinal Cord Injury.

The risk for spinal cord injuries (SCIs) ranging from devastating traumatic injuries, compression because of degenerative pathology, and neurapraxia is increased in patients with congenital spinal stenosis. Classical diagnostic criteria include an absolute anteroposterior diameter of <12-13 mm or a Torg-Pavlov ratio of <0.80-0.82; however, these factors do not take into account the size of the spinal cord, which varies across patients, independent of canal size. Recent large magnetic resonance imaging studies of population cohorts have allowed newer methods to emerge that account for both cord and canal size by measuring a spinal cord occupation ratio (SCOR). A SCOR defined as ≥70% on midsagittal imaging or ≥80% on axial imaging appears to be an effective method of identifying cord-canal mismatch, but requires further validation. Cord-canal size mismatch predisposes patients to SCI because of 1) less space within the canal lowering the amount of degenerative changes needed for cord compression, and 2) less cerebrospinal fluid surrounding the spinal cord decreasing the ability to absorb kinetic forces directed at the spine. Patients with cord-canal mismatch have been reported to be at a substantially higher risk of traumatic SCI, and present with degenerative cervical myelopathy at a younger age than patients without cord-canal mismatch. However, neurologic outcome after SCI has occurred does not appear to be different in patients with or without a cord-canal mismatch. Recognition that canal and cord size are both factors which predispose to SCI supports that cord-canal size mismatch rather than a narrow cervical canal in isolation should be viewed as the underlying mechanism predisposing to SCI.

Surgical management of nonvascular lesions around the oculomotor nerve.

OBJECTIVE: Schwannomas originating from the oculomotor nerve are extremely rare. We report our experience in the management of oculomotor schwannomas and other lesions mimicking them, and discuss operative strategy for these rare tumors emphasizing oculomotor nerve preservation. METHODS: The clinical records of our patients and all those reported in the literature focusing on oculomotor schwannomas were reviewed and analyzed. The clinical presentations, operative approaches, complications, and results were studied. RESULTS: Between 1983 and 2010, six patients with primary oculomotor nerve lesions were treated. Three of them had schwannomas. Two others had pathologies that mimicked an oculomotor schwannoma and one was suspected as schwannoma. In the literature there were 55 previous cases of oculomotor schwannomas reported (surgical treated, 41 cases; observed, 9; gamma knife surgery treated, 2; autopsy, 3). Patients presented most commonly with diplopia, followed by headache and ptosis as initial symptoms. Out of 55 patients including the present 3 cases (3 autopsy cases were excluded), 30 patients (54.5%) finally developed oculomotor nerve palsy. Fifteen of 44 patients (34.1%) who underwent surgery developed persistent postoperative oculomotor palsy. Among them, 6 patients developed total palsy after surgery. Five of 12 patients (41.7%) who did not undergo surgery also developed oculomotor palsy. Oculomotor schwannomas most often grow its cisternal segment (48.3%) followed by intracavernous (39.6%) and cisternocavernous segments (12.1%). CONCLUSION: The microsurgical resection of oculomotor schwannomas carries a risk of worsening preoperative oculomotor nerve function; however, this is often transient. Considerable technical training and microanatomical knowledge of the region is required to optimize outcome.

Genomic analysis of non-NF2 meningiomas reveals mutations in TRAF7, KLF4, AKT1, and SMO.

We report genomic analysis of 300 meningiomas, the most common primary brain tumors, leading to the discovery of mutations in TRAF7, a proapoptotic E3 ubiquitin ligase, in nearly one-fourth of all meningiomas. Mutations in TRAF7 commonly occurred with a recurrent mutation (K409Q) in KLF4, a transcription factor known for its role in inducing pluripotency, or with AKT1(E17K), a mutation known to activate the PI3K pathway. SMO mutations, which activate Hedgehog signaling, were identified in ~5% of non-NF2 mutant meningiomas. These non-NF2 meningiomas were clinically distinctive-nearly always benign, with chromosomal stability, and originating from the medial skull base. In contrast, meningiomas with mutant NF2 and/or chromosome 22 loss were more likely to be atypical, showing genomic instability, and localizing to the cerebral and cerebellar hemispheres. Collectively, these findings identify distinct meningioma subtypes, suggesting avenues for targeted therapeutics.

Four novel SCN1A mutations in Turkish patients with severe myoclonic epilepsy of infancy (SMEI).

Severe myoclonic epilepsy of infancy (SMEI) (OMIM #607208), also known as Dravet syndrome, is a rare genetic disorder characterized by frequent generalized, unilateral clonic or tonic-clonic seizures that begin during the first year of life. Heterozygous de novo mutations in the SCN1A gene, which encodes the neuronal voltage-gated sodium channel α subunit type 1 (Nav1.1), are responsible for Dravet syndrome, with a broad spectrum of mutations and rearrangements having been reported. In this study, the authors present 4 novel mutations and confirm 2 previously identified mutations in the SCN1A gene found in a cohort of Turkish patients with Dravet syndrome. Mutational analysis of other responsible genes, GABRG2 and PCDH19, were unrevealing. The authors' findings add to the known spectrum of mutations responsible for this disease phenotype and once again reinforce our understanding of the allelic heterogeneity of this disease.