Myelin-associated glycoprotein gene mutation causes Pelizaeus-Merzbacher disease-like disorder.

Pelizaeus-Merzbacher disease is an X-linked hypomyelinating leukodystrophy caused by mutations or rearrangements in PLP1. It presents in infancy with nystagmus, jerky head movements, hypotonia and developmental delay evolving into spastic tetraplegia with optic atrophy and variable movement disorders. A clinically similar phenotype caused by recessive mutations in GJC2 is known as Pelizaeus-Merzbacher-like disease. Both genes encode proteins associated with myelin. We describe three siblings of a consanguineous family manifesting the typical infantile-onset Pelizaeus-Merzbacher disease-like phenotype slowly evolving into a form of complicated hereditary spastic paraplegia with mental retardation, dysarthria, optic atrophy and peripheral neuropathy in adulthood. Magnetic resonance imaging and spectroscopy were consistent with a demyelinating leukodystrophy. Using genetic linkage and exome sequencing, we identified a homozygous missense c.399C>G; p.S133R mutation in MAG. This gene, previously associated with hereditary spastic paraplegia, encodes myelin-associated glycoprotein, which is involved in myelin maintenance and glia-axon interaction. This mutation is predicted to destabilize the protein and affect its tertiary structure. Examination of the sural nerve biopsy sample obtained in childhood in the oldest sibling revealed complete absence of myelin-associated glycoprotein accompanied by ill-formed onion-bulb structures and a relatively thin myelin sheath of the affected axons. Immunofluorescence, cell surface labelling, biochemical analysis and mass spectrometry-based proteomics studies in a variety of cell types demonstrated a devastating effect of the mutation on post-translational processing, steady state expression and subcellular localization of myelin-associated glycoprotein. In contrast to the wild-type protein, the p.S133R mutant was retained in the endoplasmic reticulum and was subjected to endoplasmic reticulum-associated protein degradation by the proteasome. Our findings identify involvement of myelin-associated glycoprotein in this family with a disorder affecting the central and peripheral nervous system, and suggest that loss of the protein function is responsible for the unique clinical phenotype.

Optic nerve vascular compression in a patient with a tuberculum sellae meningioma.

Background. Optic nerve vascular compression in patients with suprasellar tumor is a known entity but is rarely described in the literature. Case Description. We present a unique, well-documented case of optic nerve strangulation by the A1 segment of the anterior cerebral artery in a patient with a tuberculum sellae meningioma. The patient presented with pronounced progressive visual deterioration. Following surgery, there was immediate resolution of her visual deficit. Conclusion. Vascular strangulation of the optic nerve should be considered when facing progressive and/or severe visual field deterioration in patients with tumors proximal to the optic apparatus.

Parasellar meningiomas in pregnancy: surgical results and visual outcomes.

BACKGROUND: Rapid visual deterioration may occur as the result of the quick growth of parasellar meningiomas in the high-hormone/increased fluid retention milieu of pregnancy; however, surgery before delivery entails increased maternal-fetal risk. We present our experience in the management of parasellar meningiomas that compress the optic apparatus during pregnancy, with a focus on decisions regarding the timing of surgery. METHODS: Serial visual examinations and other clinical data for 11 women presenting from 2002 to 2012 with visual deterioration during pregnancy or delivery as the result of parasellar meningiomas involving the optic apparatus were reviewed. Indications for surgery during pregnancy included severely compromised vision, rapid visual deterioration, and early-to-midstage pregnancy with the potential for significant tumor growth and visual decrease before delivery. All patients underwent surgery with the use of skull base techniques via pterional craniotomy. An advanced extradural-intradural (i.e., Dolenc) approach, with modifications, was used in seven. RESULTS: All women achieved a Glasgow Outcome Score of 5 at discharge with no new neurologic deficits; all children are developing normally at a mean 4.5 years of age (range, 1-9.5 years). Surgery during pregnancy was recommended for six women: four operated at gestational weeks 20-23 had excellent postoperative visual recovery; two who delayed surgery until after delivery have permanent unilateral blindness. Among five others operated after delivery, four had good visual recovery and one has pronounced but correctable deficits. Three of five women diagnosed at gestational weeks 32-35 experienced spontaneous visual improvement after delivery, before surgery. CONCLUSIONS: We recommend that surgery be offered to patients during pregnancy when a delay may result in severe permanent visual impairment.

Safety of drilling for clinoidectomy and optic canal unroofing in anterior skull base surgery.

BACKGROUND: Skull base drilling is a necessary and important element of skull base surgery; however, drilling around vulnerable neurovascular structures has certain risks. We aimed to assess the frequency of complications related to drilling the anterior skull base in the area of the optic nerve (ON) and internal carotid artery (ICA), in a large series of patients. METHODS: We included anterior skull base surgeries performed from 2000 to 2012 that demanded unroofing of the optic canal, with extra- or intradural clinoidectomy and/or drilling of the clinoidal process and lateral aspect of the tuberculum sella. Data was retrieved from a prospective database and supplementary retrospective file review. Our IRB waived the requirement for informed consent. The nature and location of pathology, clinical presentation, surgical techniques, surgical morbidity and mortality, pre- and postoperative vision, and neurological outcomes were reviewed. RESULTS: There were 205 surgeries, including 22 procedures with bilateral optic canal unroofing (227 optic canals unroofed). There was no mortality, drilling-related vascular damage, or brain trauma. Complications possibly related to drilling included CSF leak (6 patients, 2.9 %), new ipsilateral blindness (3 patients, 1.5 %), visual deterioration (3 patients, 1.5 %), and transient oculomotor palsy (5 patients, 2.4 %). In all patients with new neuropathies, the optic and oculomotor nerves were manipulated during tumor removal; thus, new deficits could have resulted from drilling, or tumor dissection, or both. CONCLUSION: Drilling of the clinoid process and tuberculum sella, and optic canal unroofing are important surgical techniques, which may be performed relatively safely by a skilled neurosurgeon.

[Bilateral leukemic optic nerve infiltration as the first manifestation of extramedullary relapse in T-cell acute lymphoblastic leukemia].

T-cell acute lymphoblastic leukemia is a hematologic malignancy with propensity to involve extramedullary organs including the eyes. Optic nerve infiltration is relatively rare. This is the case study of a 25-year-old- man who was in full remission following treatment for T-cell acute lymphoblastic leukemia and presented with bilateral leukemic optic nerve infiltration as the first manifestation of extramedullary relapse. The patient was treated with urgent radiotherapy and systemic dexamethasone. Over the following period, gradual resolution of optic disc swelling was noted in both eyes with marked improvement in vision in the right eye. Unfortunately, a few weeks later, a full blown hematological relapse was diagnosed. Salvage chemotherapy was instituted but was complicated by tumor lysis syndrome and septicemia that proved to be fatal. Ophthalmic assessment is essential in patients with hematological malignancies in order to diagnose ocular involvement as a result of malignant infiltration, hematological disturbances or as a complication of systemic therapy.

Giant anterior clinoidal meningiomas: surgical technique and outcomes.

OBJECT: Surgery for giant anterior clinoidal meningiomas that invade vital neurovascular structures surrounding the anterior clinoid process is challenging. The authors present their skull base technique for the treatment of giant anterior clinoidal meningiomas, defined here as globular tumors with a maximum diameter of 5 cm or larger, centered around the anterior clinoid process, which is usually hyperostotic. METHODS: Between 2000 and 2010, the authors performed 23 surgeries in 22 patients with giant anterior clinoidal meningiomas. They used a skull base approach with extradural unroofing of the optic canal, extradural clinoidectomy (Dolenc technique), transdural debulking of the tumor, early optic nerve decompression, and early identification and control of key neurovascular structures. RESULTS: The mean age at surgery was 53.8 years. The mean tumor diameter was 59.2 mm (range 50-85 mm) with cavernous sinus involvement in 59.1% (13 of 22 patients). The tumor involved the prechiasmatic segment of the optic nerve in all patients, invaded the optic canal in 77.3% (17 of 22 patients), and caused visual impairment in 86.4% (19 of 22 patients). Total resection (Simpson Grade I or II) was achieved in 30.4% of surgeries (7 of 23); subtotal and partial resections were each achieved in 34.8% of surgeries (8 of 23). The main factor precluding total removal was cavernous sinus involvement. There were no deaths. The mean Glasgow Outcome Scale score was 4.8 (median 5) at a mean of 56 months of follow-up. Vision improved in 66.7% (12 of 18 patients) with consecutive neuroophthalmological examinations, was stable in 22.2% (4 of 18), and deteriorated in 11.1% (2 of 18). New deficits in cranial nerve III or IV remained after 8.7% of surgeries (2 of 23). CONCLUSIONS: This modified surgical protocol has provided both a good extent of resection and a good neurological and visual outcome in patients with giant anterior clinoidal meningiomas.

Necrobiotic xanthogranuloma associated with choroidal infiltration and syncytial giant cell hepatitis.

A 31-year-old woman developed necrobiotic xanthogranuloma (NXG), a thickened choroid, and syncytial giant cell hepatitis, a previously unreported association. NXG and syncytial giant cell hepatitis may have a common autoimmune pathogenesis.

A novel autosomal recessive myopathy with external ophthalmoplegia linked to chromosome 17p13.1-p12.

We describe a new autosomal recessive myopathy of early onset and very slow progression distinguished by the prominent external ophthalmoplegia in 16 subjects of eight families from a large and highly inbred Arab community. Characteristic clinical features include mild facial and skeletal muscle weakness and atrophy more pronounced proximally in the upper limbs, facial dysmorphism and scoliosis associated with conjugate, non-restrictive ocular motility impairment greatest in the upgaze and without ptosis or aberrant eye movements. Orbital MRI in the patients demonstrated atrophy with fatty replacement of the oculorotatory muscles. The major pathological alteration on skeletal muscle biopsy was a marked type 1 fibre predominance with core-like formations. A genome wide search for regions of homozygosity in the affected members from two informative families identified linkage with chromosome 17p13.1-p12 markers. Maximum two-point logarithm of odds scores were obtained at loci D17S1803 and AFMA070WD1 (Zmax = 3.74 at = 0). Two independent recombination events at D17S1812 and D17S947 further defined a critical region of 12 cM. Several genes map to this interval, including a cluster of sarcomeric myosin heavy chain genes. One of these genes, MYH2, is involved in inclusion body myopathy 3, but no exonic mutations were found by direct sequencing. The molecular basis for this new myopathy remains to be identified.