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Archive for July, 2016

Titin: a new piece in the puzzle of ALS

28 Jul, 16 | by Dr Jose Manuel Matamala, JNNP web editor.

 

In the current issue of JNNP, Watanabe and colleagues published a genome-wide association study (GWAS) in ALS to explore the effects of genetic variants in the disease course of sporadic ALS patients.

ALS is an incurable neurodegenerative disease that affects the motor neurons in the cortex, brainstem, and spinal cord, typically resulting in death within 2 – 3 years. Even though enormous advances in the comprehension of the disease have been achieved during the last decade, the huge clinical and genetic heterogeneity of the disease have hindered the development of new disease-modifying treatments. With the aim to explore the heterogeneity across ALS spectrum, a number of GWAS using large-scale genotyping of single nucleotide polymorphisms (SNPs) have failed to generate consistent results and reported associations were not strong enough to develop suitable disease models.

In the study, Watanabe and colleagues explore the impact of genetic variants (SNPs) in different patterns of functional decline in patients with sporadic ALS. A total of 465 ALS patients were clustered according to the longitudinal functional score (ALSFRS-R) in four groups: a rapid decline cluster, an intermediate decline cluster, a sigmoidal decline cluster and a moderate decline cluster. Amongst the 572.983 SNPs studied using genome-wide analysis, seven SNPs were associated with the rapid decline cluster (odds ratio: 5.5 to 5.84). Specifically, homozygosity for the minor alleles of the seven SNPs (linkage disequilibrium block) was associated with decreased expression of TNN (the gene that encodes Titin, a sarcomere protein). Finally, the authors described down-regulation of Titin in immortalised lymphocytes lines from such patients with ALS.

 

Titin associated SNPs and rapid functional decline in patients with ALS. In this GWAS study, seven SNPs were associated with the rapid functional decline cluster. These SPNs are linked to decreased expression of Tilin, a sarcomere protein that plays important roles in muscle function.

Titin associated SNPs and rapid functional decline in patients with ALS. In this GWAS study, seven SNPs were associated with the rapid functional decline cluster. These SPNs are linked to decreased expression of Tilin, a sarcomere protein that plays important roles in muscle function.

 

The studying of the genetic factors that influence the clinical course of ALS is extremely valuable in the design of new clinical trials. This study is the first that identifies genetic factors associated with rapid functional decline in sporadic ALS patients. The seven SNPs related to functional decline were associated to decreased Titin expression, an essential sarcomere protein. These results may suggest that Titin determines ALS disease progression through its role in muscle function. Previous studies have related Titin with different myopathies (e.g. limb-girdle muscle dystrophy). Given that there are not previous studies of Titin in ALS, these results represent a new opportunity to explore the role of Titin in ALS pathogenesis. From a clinical point of view, the impact of Tinin on the clinical disease course must be confirmed in future prospective studies, which must explore these genetic variants in ALS patients with different genetic backgrounds.

Finally, it is clear that this study provides a new candidate that might help to understand the complex heterogeneity behind the ALS spectrum.

 

Read more at http://jnnp.bmj.com/content/87/8/851.full.pdf

 

 

Neuronal autoantibodies as a new enemy in temporal lobe epilepsy

9 Jul, 16 | by Dr Jose Manuel Matamala, JNNP web editor.

 

In the current issue of JNNP, Vanli-Yavuz and colleagues published the largest systematic screening study of neuronal autoantibodies in mesial temporal lobe epilepsy with hippocampal sclerosis (MTLE-HS). Of relevance to the study, epilepsy is a prevalent neurological disorder affecting over 50 million people worldwide. Despite all the advances in this field, it is estimated that around 30% of all patients with epilepsy are refractory to antiepileptic treatment, MTLE-HS being one of the major causes of intractable epilepsy. Different mechanisms have been related to the development of this disease including a possible autoimmune dysfunction among others.

Returning to the study by Vanli-Yavuz and colleagues, the authors studied the prevalence of different neuronal autoantibodies in a large series of 111 patients with MTLE-HS and compared with 80 control subjects (30 healthy subjects and 50 patient with relapsing-remitting multiple sclerosis) (http://jnnp.bmj.com/content/87/7/684.full). Interestingly, they found the presence of neuronal autoantibodies in 22.5% of MTLE-HS patients principally against the VGKC-complex. The healthy and disease control group did not show any neuronal autoantibodies. The presence of neuronal autoantibodies was associated with a history of status epilepticus, diagnosis of psychosis, and involvement of temporal and extra-temporal regions on PET/SPECT studies. In addition, specifically, the VGKC-complex patient’s subgroup also was associated with cognitive dysfunction. Surprisingly, unexplained remission (either spontaneous or following antiepileptic drugs) was significantly more frequent in the seropositive group (28% vs 3.5%). Finally, the authors reported the absence of inflammatory activity in brain tissue from 7 operated seropositive patients.

In this study, approximately one-fourth of the patients showed seropositivity to neuronal autoantibodies, principally against the VGKC-complex.

Neuronal autoantibodies in mesial temporal lobe epilepsy with hippocampal sclerosis (MTLE-HS). In this study, approximately one-fourth of the patients showed seropositivity to neuronal autoantibodies, principally against the VGKC-complex.

 

Given the prevalence and the complex treatment approaches to MTLE-HS, the findings in this article seem highly relevant in the future consideration of immunomodulatory therapies in these patients. However, before this can happen, there are still many questions that need to be critically addressed. For instance, What is the role of these neuronal autoantibodies in MTLE-HS pathogenesis? Are they pathogenic or are they the consequence of neuronal destruction? Why are these neuronal autoantibodies associated with patients with unexplained remission?. Clearly, further studies will be needed to answer some of these questions. Nevertheless, this study provides hope to improve our understanding of this disease and suggest a new skyline for this neurological disease.

 

Well worth the read!!

 

 

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Latest from JNNP