Double-seronegative myasthenia gravis (dSN-MG, without detectable AChR and MuSK antibodies) presents a serious gap in MG diagnosis and understanding. Recently, autoantibodies against the low-density lipoprotein receptor-related protein 4 (LRP4) have been identified in several dSN-MG sera, but with dramatic frequency variation (∼2-50%). We have developed a cell based assay (CBA) based on human LRP4 expressing HEK293 cells, for the reliable and efficient detection of LRP4 antibodies. We have screened about 800 MG patient sera from 10 countries for LRP4 antibodies. The overall frequency of LRP4-MG in the dSN-MG group (635 patients) was 18.7% but with variations among different populations (range 7-32.7%). Interestingly, we also identified double positive sera: 8/107 anti-AChR positive and 10/67 anti-MuSK positive sera also had detectable LRP4 antibodies, predominantly originating from only two of the participating groups. No LRP4 antibodies were identified in sera from 56 healthy controls tested, while 4/110 from patients with other neuroimmune diseases were positive. The clinical data, when available, for the LRP4-MG patients were then studied. At disease onset symptoms were mild (81% had MGFA grade I or II), with some identified thymic changes (32% hyperplasia, none with thymoma). On the other hand, double positive patients (AChR/LRP4-MG and MuSK/LRP4-MG) had more severe symptoms at onset compared with any single positive MG subgroup. Contrary to MuSK-MG, 27% of ocular dSN-MG patients were LRP4 antibody positive. Similarly, contrary to MuSK antibodies, which are predominantly of the IgG4 subtype, LRP4 antibodies were predominantly of the IgG1 and IgG2 subtypes. The prevalence was higher in women than in men (female/male ratio 2.5/1), with an average disease onset at ages 33.4 for females and 41.9 for males. Overall, the response of LRP4-MG patients to treatment was similar to published responses of AChR-MG rather than to MuSK-MG patients.
We describe clinical, electrophysiological, histopathological and molecular features of a unique disease caused by mutations in the glycyl-tRNA synthetase (GARS) gene. Sixty patients from five multigenerational families have been evaluated. The disease is characterized by adolescent onset of weakness, and atrophy of thenar and first dorsal interosseus muscles progressing to involve foot and peroneal muscles in most but not all cases. Mild to moderate sensory deficits develop in a minority of patients. Neurophysiologically confirmed chronic denervation in distal muscles with reduced compound motor action potentials were features consistent with both motor neuronal and axonal pathology. Sural nerve biopsy showed mild to moderate selective loss of small- and medium-sized myelinated and small unmyelinated axons, although sensory nerve action potentials were not significantly decreased. Based on the presence or absence of sensory changes, the disease phenotype was initially defined as distal spinal muscular atrophy type V (dSMA-V) in three families, Charcot-Marie-Tooth disease type 2D (CMT2D) in a single family, and as either dSMA-V or CMT2D in patients of another large family. Linkage to chromosome 7p15 and the presence of disease-associated heterozygous GARS mutations have been identified in patients from each of the five studied families. We conclude that patients with GARS mutations present a clinical continuum of predominantly motor distal neuronopathy/axonopathy with mild to moderate sensory involvement that varies between the families and between members of the same family. Awareness of these overlapping clinical phenotypes associated with mutations in GARS will facilitate identification of this disorder in additional families and direct future research toward better understanding of its pathogenesis.
Seronegative myasthenia gravis (MG) presents a serious gap in MG diagnosis and understanding. We applied a cell based assay (CBA) for the detection of muscle specific kinase (MuSK) antibodies undetectable by radioimmunoassay. We tested 633 triple-seronegative MG patients' sera from 13 countries, detecting 13% as positive. MuSK antibodies were found, at significantly lower frequencies, in 1.9% of healthy controls and 5.1% of other neuroimmune disease patients, including multiple sclerosis and neuromyelitis optica. The clinical data of the newly diagnosed MuSK-MG patients are presented. 27% of ocular seronegative patients were MuSK antibody positive. Moreover, 23% had thymic hyperplasia suggesting that thymic abnormalities are more common than believed.
Charcot-Marie-Tooth (CMT) disease is the most common hereditary neuropathy resulting from mutations in 430 genes expressed in either the Schwann cells or the axon of peripheral nerves. The disease is classified into demyelinating (CMT1), axonal (CMT2) or intermediate (CMTI) based on electrophysiological and pathological findings. Our study focused on the identification of a novel disease mutation in a large Sardinian family with CMT2 of autosomal dominant (AD) inheritance. All available family members were clinically evaluated and samples were collected from consenting individuals. Initially, we excluded known CMT2 genes/loci in this family. We then conducted a genome-wide linkage analysis and mapped the gene to chromosome 9q33-q34. Refined linkage and haplotype analyses defined an 11.6-Mb candidate region with a maximum LOD score of 8.06. Following exclusion of several candidate genes from the region, we targeted the LRSAM1 (leucine-rich repeat and sterile alpha motif-containing 1) gene, very recently found to be associated with autosomal recessive CMT2 in one family. For a more efficient investigation of this large gene, already available proband RNA (cDNA) was initially analyzed. Targeted DNA analysis then confirmed a novel LRSAM1 splice-site (c.2047-1G4A) mutation, causing a frameshift that introduces a stop codon three amino acids further down the new reading frame (p.Ala683ProfsX3). This mutation is located in the C-terminal RING finger motif of the encoded protein and leads to premature truncation of the protein. In the course of our work, a second LRSAM1 mutation dominantly transmitted was identified by another group. Our data further confirms that LRSAM1 mutations are associated with CMT2 of AD inheritance.
Background Hereditary transthyretin (ATTRv) amyloidosis is a rare, inherited, progressive disease caused by mutations in the transthyretin (TTR) gene. We aimed to assess the efficacy and safety of long-term treatment with patisiran, an RNA interference therapeutic that inhibits TTR production, in patients with ATTRv amyloidosis with polyneuropathy. MethodsThis multi-country, multi-centre, open-label extension (OLE) trial enrolled patients at 43 sites in 19 countries as of 24 September 2018. Patients were eligible if they had completed the phase 3 APOLLO (randomised, double-blind, placebo-controlled [2:1], 18-month study) or phase 2 OLE (single-arm, 24-month study) parent studies and tolerated the study drug. Eligible patients from APOLLO (APOLLO-patisiran [received patisiran during APOLLO] and APOLLO-placebo [received placebo during APOLLO] groups) and the phase 2 OLE (phase 2 OLE patisiran group) studies enrolled in this Global OLE trial and receive patisiran 0•3 mg/kg by intravenous infusion every 3 weeks for up to 5 years. Efficacy assessments include measures of polyneuropathy (modified Neuropathy Impairment Score +7 [mNIS+7]), quality of life, autonomic symptoms, nutritional status, disability, ambulation status, motor function, and cardiac stress. Patients included in the current efficacy analyses are those who had completed 12-month efficacy assessments as of the data cut-off. Safety analyses included all patients who received ≥1 dose of patisiran up to the data cut-off. The Global OLE is ongoing with no new enrolment, and current findings are based on the 12-month interim analysis. The study is registered with ClinicalTrials.gov, NCT02510261.
Background: Brain metastasis (BM) is an increasingly common and devastating complication of breast cancer (BC).Methods: A systematic literature search of EMBASE and MEDLINE was conducted to elucidate the current state of knowledge on known and novel prognostic factors associated with 1) the risk for BCBM and 2) the time to brain metastases (TTBM).Results: A total of 96 studies involving institutional records from 28 countries were identified. Of these, 69 studies reported risk factors of BCBM, 46 factors associated with the TTBM and twenty studies examined variables for both outcomes. Young age, estrogen receptor negativity (ER-), overexpression of human epidermal factor (HER2+), and higher presenting stage, histological grade, tumor size, Ki67 labeling index and nodal involvement were consistently found to be independent risk factors of BCBM. Of these, triple-negative BC (TNBC) subtype, ER-, higher presenting histological grade, tumor size, and nodal involvement were also reported to associate with shorter TTBM. In contrast, young age, hormone receptor negative (HR-) status, higher presenting stage, nodal involvement and development of liver metastasis were the most important risk factors for BM in HER2-positive patients.Conclusions: The study provides a comprehensive and individual evaluation of the risk factors that could support the design of screening tools and interventional trials for early detection of BCBM. Lymph node status (N-Stage)
SummaryAutosomal recessive cerebellar ataxias (ARCA) encompass a heterogeneous group of rare diseases that affect the cerebellum, the spinocerebellar tract and/or the sensory tracts of the spinal cord. We investigated a consanguineous Cypriot family with spastic ataxia, aiming towards identification of the causative mutation. Family members were clinically evaluated and studied at the genetic level. Linkage analysis at marker loci spanning known ARCA genes/loci revealed linkage to the APTX locus. Thorough investigation of the APTX gene excluded any possible mutation. Whole genome linkage screening using microsatellite markers and whole genome SNP homozygosity mapping using the Affymetrix GenomeWide Human SNP Array 6.0 enabled mapping of the disease gene/mutation in this family to Chromosome 9p21.1-p13.2. Due to the large number of candidate genes within this region, whole-exome sequencing of the proband was performed and further analysis of the obtained data focused on the mapped interval. Further investigation of the candidate variants resulted in the identification of a novel missense mutation in the GBA2 gene. GBA2 mutations have recently been associated with hereditary spastic paraplegia and ARCA with spasticity. We hereby report a novel GBA2 mutation associated with spastic ataxia and suggest that GBA2 mutations may be a relatively frequent cause of ARCA.
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