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1.  A Multicenter Study of Glucocerebrosidase Mutations in Dementia With Lewy Bodies 
JAMA neurology  2013;70(6):10.1001/jamaneurol.2013.1925.
Importance
While mutations in glucocerebrosidase (GBA1) are associated with an increased risk for Parkinson disease (PD), it is important to establish whether such mutations are also a common risk factor for other Lewy body disorders.
Objective
To establish whether GBA1 mutations are a risk factor for dementia with Lewy bodies (DLB).
Design
We compared genotype data on patients and controls from 11 centers. Data concerning demographics, age at onset, disease duration, and clinical and pathological features were collected when available. We conducted pooled analyses using logistic regression to investigate GBA1 mutation carrier status as predicting DLB or PD with dementia status, using common control subjects as a reference group. Random-effects meta-analyses were conducted to account for additional heterogeneity.
Setting
Eleven centers from sites around the world performing genotyping.
Participants
Seven hundred twenty-one cases met diagnostic criteria for DLB and 151 had PD with dementia. We compared these cases with 1962 controls from the same centers matched for age, sex, and ethnicity.
Main Outcome Measures
Frequency of GBA1 mutations in cases and controls.
Results
We found a significant association between GBA1 mutation carrier status and DLB, with an odds ratio of 8.28 (95% CI, 4.78–14.88). The odds ratio for PD with dementia was 6.48 (95% CI, 2.53–15.37). The mean age at diagnosis of DLB was earlier in GBA1 mutation carriers than in noncarriers (63.5 vs 68.9 years; P<.001), with higher disease severity scores.
Conclusions and Relevance
Mutations in GBA1 are a significant risk factor for DLB. GBA1 mutations likely play an even larger role in the genetic etiology of DLB than in PD, providing insight into the role of glucocerebrosidase in Lewy body disease.
doi:10.1001/jamaneurol.2013.1925
PMCID: PMC3841974  PMID: 23588557
2.  Clinical Neuropathology practice guide 6-2013: morphology and an appropriate immunohistochemical screening panel aid in the identification of synovial sarcoma by neuropathologists  
Clinical Neuropathology  2013;32(6):461-470.
Aims: Pathologists are under increasing pressure to accurately subclassify sarcomas, yet neuropathologists have limited collective experience with rare sarcoma types such as synovial sarcoma. We reviewed 9 synovial sarcomas affecting peripheral nerve diagnosed by neuropathologists and explored the morphologic and immunohistochemical differences between these and MPNST. Our goal was to make practical recommendations for neuropathologists regarding which spindle cell tumors affecting nerve should be sent for SYT-SSX testing. Methods: Clinical records and genetics were reviewed retrospectively and central pathology review of 9 synovial sarcomas and 6 MPNST included immunohistochemistry for SOX10, S100, BAF47, CK (lmw, pan, CK7, CK19), EMA, CD34, bcl2, CD99, and neurofilament. Results: Common synovial sarcoma sites were brachial plexus, spinal and femoral nerve, none were “intra-neural”, all had the SYT-SSX1 translocation, and 6/9 were monophasic with myxoid stroma and distinct collagen. Half of the monophasic synovial sarcomas expressed CK7, CK19 or panCK in a “rare positive cells pattern”, 8/9 (89%) expressed EMA, and all were SOX10 immunonegative with reduced but variable BAF47 expression. Conclusions: We recommend that upon encountering a cellular spindle cell tumor affecting nerve neuropathologists consider the following: 1) SYT-SSX testing should be performed on any case with morphology suspicious for monophasic synovial sarcoma including wiry or thick bands of collagen and relatively monomorphous nuclei; 2) neuropathologists should employ a screening immunohistochemical panel including one of CK7, panCK or CK19, plus EMA, S100 and SOX10, and 3) SYT-SSX testing should be performed on any spindle cell tumor with CK and/or EMA immunopositivity if SOX10 immunostaining is negative or only labels entrapped nerve elements.
doi:10.5414/NP300685
PMCID: PMC3852132  PMID: 24131748
synovial sarcoma; nerve; nervous system; SOX10; BAF47; malignant peripheral nerve sheath tumor
3.  Treatment of Granulomatous Amoebic Encephalitis with Voriconazole and Miltefosine in an Immunocompetent Soldier 
A 38-year-old male immunocompetent soldier developed generalized seizures. He underwent surgical debulking and a progressive demyelinating pseudotumor was identified. Serology and molecular testing confirmed a diagnosis of granulomatous amoebic encephalitis caused by Acanthamoeba sp. in this immunocompetent male. The patient was treated with oral voriconazole and miltefosine with Acanthamoeba titers returning to control levels and serial imaging demonstrating resolution of the residual lesion.
doi:10.4269/ajtmh.2012.12-0100
PMCID: PMC3516325  PMID: 22869634
4.  Pathophysiology of protein aggregation and extended phenotyping in filaminopathy 
Brain  2012;135(9):2642-2660.
Mutations in FLNC cause two distinct types of myopathy. Disease associated with mutations in filamin C rod domain leading to expression of a toxic protein presents with progressive proximal muscle weakness and shows focal destructive lesions of polymorphous aggregates containing desmin, myotilin and other proteins in the affected myofibres; these features correspond to the profile of myofibrillar myopathy. The second variant associated with mutations in the actin-binding domain of filamin C is characterized by weakness of distal muscles and morphologically by non-specific myopathic features. A frameshift mutation in the filamin C rod domain causing haploinsufficiency was also found responsible for distal myopathy with some myofibrillar changes but no protein aggregation typical of myofibrillar myopathies. Controversial data accumulating in the literature require re-evaluation and comparative analysis of phenotypes associated with the position of the FLNC mutation and investigation of the underlying disease mechanisms. This is relevant and necessary for the refinement of diagnostic criteria and developing therapeutic approaches. We identified a p.W2710X mutation in families originating from ethnically diverse populations and re-evaluated a family with a p.V930_T933del mutation. Analysis of the expanded database allows us to refine clinical and myopathological characteristics of myofibrillar myopathy caused by mutations in the rod domain of filamin C. Biophysical and biochemical studies indicate that certain pathogenic mutations in FLNC cause protein misfolding, which triggers aggregation of the mutant filamin C protein and subsequently involves several other proteins. Immunofluorescence analyses using markers for the ubiquitin–proteasome system and autophagy reveal that the affected muscle fibres react to protein aggregate formation with a highly increased expression of chaperones and proteins involved in proteasomal protein degradation and autophagy. However, there is a noticeably diminished efficiency of both the ubiquitin–proteasome system and autophagy that impairs the muscle capacity to prevent the formation or mediate the degradation of aggregates. Transfection studies of cultured muscle cells imitate events observed in the patient’s affected muscle and therefore provide a helpful model for testing future therapeutic strategies.
doi:10.1093/brain/aws200
PMCID: PMC3437028  PMID: 22961544
myofibrillar myopathy; filaminopathy; filamin C mutation; immunoglobulin-like domain; limb-girdle myopathy
5.  Exome sequencing identifies titin mutations causing hereditary myopathy with early respiratory failure (HMERF) in families of diverse ethnic origins 
BMC Neurology  2013;13:29.
Background
Hereditary myopathy with early respiratory failure (HMERF) was described in several North European families and recently linked to a titin gene (TTN) mutation. We independently studied HMERF-like diseases with the purpose to identify the cause, refine diagnostic criteria, and estimate the frequency of this disease among myopathy patients of various ethnic origins.
Methods
Whole exome sequencing analysis was carried out in a large U.S. family that included seven members suffering from skeletal muscle weakness and respiratory failure. Subsequent mutation screening was performed in further 45 unrelated probands with similar phenotypes. Studies included muscle strength evaluation, nerve conduction studies and concentric needle EMG, respiratory function test, cardiologic examination, and muscle biopsy.
Results
A novel TTN p.Gly30150Asp mutation was identified in the highly conserved A-band of titin that co-segregated with the disease in the U.S. family. Screening of 45 probands initially diagnosed as myofibrillar myopathy (MFM) but excluded based on molecular screening for the known MFM genes led to the identification of a previously reported TTN p.Cys30071Arg mutation in one patient. This same mutation was also identified in a patient with suspected HMERF. The p.Gly30150Asp and p.Cys30071Arg mutations are localized to a side chain of fibronectin type III element A150 of the 10th C-zone super-repeat of titin.
Conclusions
Missense mutations in TTN are the cause of HMERF in families of diverse origins. A comparison of phenotypic features of HMERF caused by the three known TTN mutations in various populations allowed to emphasize distinct clinical/pathological features that can serve as the basis for diagnosis. The newly identified p.Gly30150Asp and the p.Cys30071Arg mutation are localized to a side chain of fibronectin type III element A150 of the 10th C-zone super-repeat of titin.
doi:10.1186/1471-2377-13-29
PMCID: PMC3610280  PMID: 23514108
Myopathy; Respiratory failure; HMERF; Titin; Titin A-band mutation; Fibronectin type III
6.  FET proteins TAF15 and EWS are selective markers that distinguish FTLD with FUS pathology from amyotrophic lateral sclerosis with FUS mutations 
Brain  2011;134(9):2595-2609.
Accumulation of the DNA/RNA binding protein fused in sarcoma as cytoplasmic inclusions in neurons and glial cells is the pathological hallmark of all patients with amyotrophic lateral sclerosis with mutations in FUS as well as in several subtypes of frontotemporal lobar degeneration, which are not associated with FUS mutations. The mechanisms leading to inclusion formation and fused in sarcoma-associated neurodegeneration are only poorly understood. Because fused in sarcoma belongs to a family of proteins known as FET, which also includes Ewing’s sarcoma and TATA-binding protein-associated factor 15, we investigated the potential involvement of these other FET protein family members in the pathogenesis of fused in sarcoma proteinopathies. Immunohistochemical analysis of FET proteins revealed a striking difference among the various conditions, with pathology in amyotrophic lateral sclerosis with FUS mutations being labelled exclusively for fused in sarcoma, whereas fused in sarcoma-positive inclusions in subtypes of frontotemporal lobar degeneration also consistently immunostained for TATA-binding protein-associated factor 15 and variably for Ewing’s sarcoma. Immunoblot analysis of proteins extracted from post-mortem tissue of frontotemporal lobar degeneration with fused in sarcoma pathology demonstrated a relative shift of all FET proteins towards insoluble protein fractions, while genetic analysis of the TATA-binding protein-associated factor 15 and Ewing’s sarcoma gene did not identify any pathogenic variants. Cell culture experiments replicated the findings of amyotrophic lateral sclerosis with FUS mutations by confirming the absence of TATA-binding protein-associated factor 15 and Ewing’s sarcoma alterations upon expression of mutant fused in sarcoma. In contrast, all endogenous FET proteins were recruited into cytoplasmic stress granules upon general inhibition of Transportin-mediated nuclear import, mimicking the findings in frontotemporal lobar degeneration with fused in sarcoma pathology. These results allow a separation of fused in sarcoma proteinopathies caused by FUS mutations from those without a known genetic cause based on neuropathological features. More importantly, our data imply different pathological processes underlying inclusion formation and cell death between both conditions; the pathogenesis in amyotrophic lateral sclerosis with FUS mutations appears to be more restricted to dysfunction of fused in sarcoma, while a more global and complex dysregulation of all FET proteins is involved in the subtypes of frontotemporal lobar degeneration with fused in sarcoma pathology.
doi:10.1093/brain/awr201
PMCID: PMC3170539  PMID: 21856723
FUS; TAF15; EWS; amyotrophic lateral sclerosis; frontotemporal dementia
7.  Pathological heterogeneity in amyotrophic lateral sclerosis with FUS mutations: two distinct patterns correlating with disease severity and mutation 
Acta Neuropathologica  2011;122(1):87-98.
Mutations in the gene encoding the fused in sarcoma (FUS) protein are responsible for ~3% of familial amyotrophic lateral sclerosis (ALS) and <1% of sporadic ALS (ALS-FUS). Descriptions of the associated neuropathology are few and largely restricted to individual case reports. To better define the neuropathology associated with FUS mutations, we have undertaken a detailed comparative analysis of six cases of ALS-FUS that include sporadic and familial cases, with both juvenile and adult onset, and with four different FUS mutations. We found significant pathological heterogeneity among our cases, with two distinct patterns that correlated with the disease severity and the specific mutation. Frequent basophilic inclusions and round FUS-immunoreactive (FUS-ir) neuronal cytoplasmic inclusions (NCI) were a consistent feature of our early-onset cases, including two with the p.P525L mutation. In contrast, our late-onset cases, that included two with the p.R521C mutation, had tangle-like NCI and numerous FUS-ir glial cytoplasmic inclusions. Double-labeling experiments demonstrated that many of the glial inclusions were in oligodendrocytes. Comparison with the neuropathology of cases of frontotemporal lobar degeneration with FUS-ir pathology showed significant differences and suggests that FUS mutations are associated with a distinct pathobiology.
doi:10.1007/s00401-011-0838-7
PMCID: PMC3319073  PMID: 21604077
fused in sarcoma; FUS; amyotrophic lateral sclerosis; ALS; basophilic inclusions
8.  Aspergillosis of the Petrous Apex and Meckel's Cave 
Skull Base  2010;20(3):189-192.
ABSTRACT
Cranial cerebral aspergillosis is a rare entity in immunocompetent patients. Invasive disease involving the petrous apex and Meckel's cave has rarely been described. We present a case of localized invasive petrous apical and Meckel's cave disease in an immunocompetent patient who presented with hemicranial neuralgic pain.
doi:10.1055/s-0029-1246229
PMCID: PMC3037105  PMID: 21318037
Aspergillosis; petrous apex; Meckel's cave; computed tomography; MRI
9.  Immunohistochemical Investigation of Hormone Receptors and Vascular Endothelial Growth Factor Concentration in Vestibular Schwannoma 
Skull Base  2008;18(6):377-384.
ABSTRACT
Objectives: To determine if a relationship exists between the presence of estrogen receptors (ER), progesterone receptors (PR), or vascular endothelial growth factor (VEGF) and the size, growth rate, and behavior of vestibular schwannoma tumors. Design: Nine tumor samples from young female patients with large vestibular schwannoma tumors were preselected because they were presumed to be faster growing, more aggressive tumors. Immunohistochemical staining was performed using monoclonal mouse antibodies to ER, PR, and VEGF. Results: The mean age of the study sample was 32.3 years, mean tumor size was 3.2 cm, and the average growth rate was 0.4 cm per 2 months. The results of immunohistochemical staining for ER and PR in all nine samples were unequivocally negative. Eight of nine tumor samples stained positive for VEGF, with five demonstrating low intensity and three demonstrating moderate intensity staining. Conclusions: There is histopathological evidence for the expression of VEGF in vestibular schwannomas but not for ER and PR. Further studies are necessary to determine the role of VEGF and other molecular pathways in the growth of vestibular schwannomas and the application of anti-VEGF therapy as a potential treatment option in the future.
doi:10.1055/s-0028-1096198
PMCID: PMC2637072  PMID: 19412407
Vestibular schwannoma; acoustic neuroma; estrogen receptor; progesterone receptor; vascular endothelial growth factor; immunohistochemistry

Results 1-9 (9)