Management of Autoimmune Encephalitis: An Observational Monocentric Study of 38 Patients

Over the last years the clinical picture of autoimmune encephalitis has gained importance in neurology. The broad field of symptoms and syndromes poses a great challenge in diagnosis for clinicians. Early diagnosis and the initiation of the appropriate treatment is the most relevant step in the management of the patients. Over the last years advances in neuroimmunology have elucidated pathophysiological basis and improved treatment concepts. In this monocentric study we compare demographics, diagnostics, treatment options and outcomes with knowledge from literature. We present 38 patients suffering from autoimmune encephalitis. Antibodies were detected against NMDAR and LGI1 in seven patients, against GAD in 6 patients) one patient had coexisting antibodies against GABAA and GABAB), against CASPR2, IGLON5, YO, Glycine in 3 patients, against Ma-2 in 2 patients, against CV2 and AMPAR in 1 patient; two patients were diagnosed with hashimoto encephalitis with antibodies against TPO/TG. First, we compare baseline data of patients who were consecutively diagnosed with autoimmune encephalitis from a retrospective view. Further, we discuss when to stop immunosuppressive therapy since how long treatment should be performed after clinical stabilization or an acute relapse is still a matter of debate. Our experiences are comparable with data from literature. However, in contrary to other experts in the field we stop treatment and monitor patients very closely after tumor removal and after rehabilitation from first attack

Novel SCARB2 mutation in action myoclonus-renal failure syndrome and evaluation of SCARB2 mutations in isolated AMRF features

Background: Action myoclonus-renal failure syndrome is a hereditary form of progressive myoclonus epilepsy associated with renal failure. It is considered to be an autosomal-recessive disease related to loss-of-function mutations in SCARB2. We studied a German AMRF family, additionally showing signs of demyelinating polyneuropathy and dilated cardiomyopathy. To test the hypothesis whether isolated appearance of individual AMRF syndrome features could be related to heterozygote SCARB2 mutations, we screened for SCARB2 mutations in unrelated patients showing isolated AMRF features. Methods: In the AMRF family all exons of SCARB2 were analyzed by Sanger sequencing. The mutation screening of unrelated patients with isolated AMRF features affected by either epilepsy (n = 103, progressive myoclonus epilepsy or generalized epilepsy), demyelinating polyneuropathy (n = 103), renal failure (n = 192) or dilated cardiomyopathy (n = 85) was performed as high resolution melting curve analysis of the SCARB2 exons. Results: A novel homozygous 1 bp deletion (c.111delC) in SCARB2 was found by sequencing three affected homozygous siblings of the affected family. A heterozygous sister showed generalized seizures and reduction of nerve conduction velocity in her legs. No mutations were found in the epilepsy, renal failure or dilated cardiomyopathy samples. In the polyneuropathy sample two individuals with demyelinating disease were found to be carriers of a SCARB2 frameshift mutation (c.666delCCTTA). Conclusions: Our findings indicate that demyelinating polyneuropathy and dilated cardiomyopathy are part of the action myoclonus-renal failure syndrome. Moreover, they raise the possibility that in rare cases heterozygous SCARB2 mutations may be associated with PNP features

Genome-wide identification and phenotypic characterization of seizure-associated copy number variations in 741,075 individuals

Copy number variants (CNV) are established risk factors for neurodevelopmental disorders with seizures or epilepsy. With the hypothesis that seizure disorders share genetic risk factors, we pooled CNV data from 10,590 individuals with seizure disorders, 16,109 individuals with clinically validated epilepsy, and 492,324 population controls and identified 25 genome-wide significant loci, 22 of which are novel for seizure disorders, such as deletions at 1p36.33, 1q44, 2p21-p16.3, 3q29, 8p23.3-p23.2, 9p24.3, 10q26.3, 15q11.2, 15q12-q13.1, 16p12.2, 17q21.31, duplications at 2q13, 9q34.3, 16p13.3, 17q12, 19p13.3, 20q13.33, and reciprocal CNVs at 16p11.2, and 22q11.21. Using genetic data from additional 248,751 individuals with 23 neuropsychiatric phenotypes, we explored the pleiotropy of these 25 loci. Finally, in a subset of individuals with epilepsy and detailed clinical data available, we performed phenome-wide association analyses between individual CNVs and clinical annotations categorized through the Human Phenotype Ontology (HPO). For six CNVs, we identified 19 significant associations with specific HPO terms and generated, for all CNVs, phenotype signatures across 17 clinical categories relevant for epileptologists. This is the most comprehensive investigation of CNVs in epilepsy and related seizure disorders, with potential implications for clinical practice

The epsilon-sarcoglycan gene (SGCE), mutated in myoclonus-dystonia syndrome, is maternally imprinted

Myoclonus-dystonia syndrome (MDS) is a non-degenerative neurological disorder that has been described to be inherited in an autosomal dominant mode with incomplete penetrance. MDS is caused by loss of function mutations in the epsilon-sarcoglycan gene. Reinvestigation of MDS pedigrees provided evidence for a maternal imprinting mechanism. As differential methylated regions (DMRs) are a characteristic feature of imprinted genes, we studied the methylation pattern of CpG dinucleotides within the CpG island containing the promoter region and the first exon of the SGCE gene by bisulphite genomic sequencing. Our findings revealed that in peripheral blood leukocytes the maternal allele is methylated, while the paternal allele is unmethylated. We also showed that most likely the maternal allele is completely methylated in brain tissue. Furthermore, CpG dinucleotides in maternal and paternal uniparental disomy 7 (UPD7) lymphoblastoid cell lines show a corresponding parent-of-origin specific methylation pattern. The effect of differential methylation on the expression of the SGCE gene was tested in UPD7 cell lines with only a weak RT-PCR signal observed in matUPD7 and a strong signal in patUPD7. These results provide strong evidence for a maternal imprinting of the SGCE gene. The inheritance pattern in MDS families is in agreement with such an imprinting mechanism with the exception of a few cases. We investigated one affected female that inherited the mutated allele from her mother. Surprisingly, we found the paternal wild type allele expressed whereas the mutated maternal allele was not detectable in peripheral blood cDNA

PARK11 is not linked with Parkinson's disease in European families

Parkinson's disease (PD) is a genetically heterogeneous disease. Recently, significant linkage has been reported to a 39.5 cM region on the long arm of chromosome 2 (2q36-37; PARK11) in North American Parkinson families under an autosomal dominant model of inheritance. We have performed a replication study to confirm linkage to this region in a European population. Linkage analysis in 153 individuals from 45 European families with a strong family history of PD did not show any significant LOD score in this region. Therefore, PARK11 does not seem to play a major role for familial PD in the European population

Variant in the sequence of the LINGO1 gene confers risk of essential tremor

To access publisher full text version of this article. Please click on the hyperlink in Additional Links fieldWe identified a marker in LINGO1 showing genome-wide significant association (P = 1.2 x 10(-9), odds ratio = 1.55) with essential tremor. LINGO1 has potent, negative regulatory influences on neuronal survival and is also important in regulating both central-nervous-system axon regeneration and oligodendrocyte maturation. Increased axon integrity observed in Lingo1 mouse [corrected] knockout models highlights the potential role of LINGO1 in the pathophysiology of ET [corrected

Mutations in the gene encoding ε-sarcoglycan cause myoclonus-dystonia syndrome.

The dystonias are a common clinically and genetically heterogeneous group of movement disorders. More than ten loci for inherited forms of dystonia have been mapped, but only three mutated genes have been identified so far. These are DYT1, encoding torsin A and mutant in the early-onset generalized form, GCH1 (formerly known as DYT5), encoding GTP-cyclohydrolase I and mutant in dominant dopa-responsive dystonia, and TH, encoding tyrosine hydroxylase and mutant in the recessive form of the disease. Myoclonus-dystonia syndrome (MDS; DYT11) is an autosomal dominant disorder characterized by bilateral, alcohol-sensitive myoclonic jerks involving mainly the arms and axial muscles. Dystonia, usually torticollis and/or writer's cramp, occurs in most but not all affected patients and may occasionally be the only symptom of the disease. In addition, patients often show prominent psychiatric abnormalities, including panic attacks and obsessive-compulsive behavior. In most MDS families, the disease is linked to a locus on chromosome 7q21 (refs. 11-13). Using a positional cloning approach, we have identified five different heterozygous loss-of-function mutations in the gene for epsilon-sarcoglycan (SGCE), which we mapped to a refined critical region of about 3.2 Mb. SGCE is expressed in all brain regions examined. Pedigree analysis shows a marked difference in penetrance depending on the parental origin of the disease allele. This is indicative of a maternal imprinting mechanism, which has been demonstrated in the mouse epsilon-sarcoglycan gene