Franziska Hopfner

Genetics of essential tremor Meta-analysis and review

Objective: To provide a comprehensive meta-analysis and review of the clinical and molecular genetics of essential tremor (ET). Methods: Studies were reviewed from the literature. Linkage studies were analyzed applying criteria used for monogenic disorders. For association studies, allele counts were extracted and allelic association calculated whenever possible. A meta-analysis was performed for genetic markers investigated in more than 3 studies. Results: Linkage studies have shown conclusive results in a single family only for the locus ETM2 (essential tremor monogenetic locus 2, logarithm of odds score [lod] > 3.3). None of the 3 ETM loci has been confirmed independently with a lod score >2.0 in a single family. A mutation in the FUS gene (fused in sarcoma) was found in one ET family by exome sequencing. Two genome-wide association studies demonstrated association between variants in the LINGO1 gene (leucine-rich repeat and Ig domain containing 1) and the SLC1A2 gene (solute carrier family 1 member 2) and ET, respectively. Our meta-analysis confirmed the association of rs9652490 in LINGO1 with ET. Candidate gene mutation analysis and association studies have not identified reproducible associations. Conclusion: Problems of genetic studies of ET are caused by the lack of stringent diagnostic criteria, small sample sizes, lack of biomarkers, a high phenocopy rate, evidence for nonmendelian inheritance, and high locus heterogeneity in presumably monogenic ET. These issues could be resolved by better worldwide cooperation and the use of novel genetic techniques.

Gut Microbiota in Parkinson Disease in a northern German cohort.

Pathologic and epidemiologic studies suggest that Parkinson disease (PD) may in some cases start in the enteric nervous system and spread via the vagal nerve to the brainstem. Mounting evidence suggests that the gut microbiome plays an important role in the communication between gut and brain and that alteration of the gut microbiome is involved in the pathogenesis of numerous diseases, including Parkinson disease. The aim of this study was to determine whether Parkinson disease is associated with qualitative or quantitative changes in the gut microbiome. We analyzed the gut microbiome in 29 PD cases and 29 age-matched controls by next-generation-sequencing of the 16S rRNA gene and compared diversity indices and bacterial abundances between cases and controls. Alpha diversity measures and the abundance of major phyla did not differ between cases and controls. Beta diversity analyses and analysis on the bacterial family level revealed significant differences between cases and controls for four bacterial families. In keeping with recently published studies, Lactobacillaceae were more abundant in cases. Barnesiellaceae and Enterococcacea were also more abundant in cases in this study but not in other studies. Larger studies, accounting for drug effects and further functional investigations of the gut microbiome are necessary to delineate the role of the gut microbiome in the pathogenesis of PD.

The role of SCARB2 as susceptibility factor in Parkinson's disease

Genetic variation in the glucocerebrosidase (GBA) gene is strongly associated with Parkinsons disease (PD). Transport of glucocerebrosidase to the lysosome involves the protein encoded by the SCARB2 gene. An association between the common SNP rs6812193, upstream of SCARB2, and PD has been reported previously. The role of exonic variants in the SCARB2 gene in PD has not been examined.

Genome-wide association study in essential tremor identifies three new loci.

Essential tremor has a high heritability, but its molecular genetic determinants remain unknown. Müller et al. conduct a genome-wide association study in more than 2800 patients with essential tremor and more than 6800 controls of European descent, and identify three new loci associated with the disease.

Knowledge gaps and research recommendations for essential tremor

Essential tremor (ET) is a common cause of significant disability, but its etiologies and pathogenesis are poorly understood. Research has been hampered by the variable definition of ET and by non-standardized research approaches. The National Institute of Neurological Disorders and Stroke (USA) invited experts in ET and related fields to discuss current knowledge, controversies, and gaps in our understanding of ET and to develop recommendations for future research. Discussion focused on phenomenology and phenotypes, therapies and clinical trials, pathophysiology, pathology, and genetics. Across all areas, the need for collaborative and coordinated research on a multinational level was expressed. Standardized data collection using common data elements for genetic, clinical, neurophysiological, and pathological studies was recommended. Large cohorts of patients should be studied prospectively to collect bio-samples, characterize the natural history of the clinical syndrome including patient-oriented outcomes, investigate potential etiologies of various phenotypes, and identify pathophysiological mechanisms. In particular, cellular and system-level mechanisms of tremor oscillations should be elucidated because they may yield effective therapeutic targets and biomarkers. A neuropathology consortium was recommended to standardize postmortem analysis and further characterize neuropathological observations in the cerebellum and elsewhere. Furthermore, genome-wide association studies on large patient cohorts (>10,000 patients) may allow the identification of common genes contributing to risk, and whole exome or genome sequencing may enable the identification of genetic risk and causal mutations in cohorts and well-characterized families.

Early- and late-onset essential tremor patients represent clinically distinct subgroups.

Essential tremor is a very common disease defined by sparse clinical criteria. It is unlikely that essential tremor is an etiologically homogeneous disease. Stratifying broadly defined diseases using clinical characteristics has often aided the etiopathological understanding. Most studies of essential tremor show 2 distinct age at onset peaks: early and late. This study investigates phenotypical differences between early‐ and late‐onset essential tremor patients.

ALS2 mutations Juvenile amyotrophic lateral sclerosis and generalized dystonia

Objective: To determine the genetic etiology in 2 consanguineous families who presented a novel phenotype of autosomal recessive juvenile amyotrophic lateral sclerosis associated with generalized dystonia. Methods: A combination of homozygosity mapping and whole-exome sequencing in the first family and Sanger sequencing of candidate genes in the second family were used. Results: Both families were found to have homozygous loss-of-function mutations in the amyotrophic lateral sclerosis 2 (juvenile) (ALS2) gene. Conclusions: We report generalized dystonia and cerebellar signs in association with ALS2-related disease. We suggest that the ALS2 gene should be screened for mutations in patients who present with a similar phenotype.

HTLV-1 associated myelopathy after renal transplantation

Department of Neurology, Christian-Albrecht University and University Medical Center Schleswig-Holstein, Schittenhelmstr. 10, 24105 Kiel, Germany Institute for Infection Medicine, Christian-Albrecht University and University Medical Center Schleswig-Holstein, Brunswiker Str. 4, 24105 Kiel, Germany Department of Nephrology, Christian-Albrecht University and University Medical Center Schleswig-Holstein, Schittenhelmstr. 12, 24105 Kiel, Germany Virology Institute, Friedrich-Alexander University and University Medical Center, Schlossgarten 4, 91054 Erlangen, Germany Department of Radiology and Neuroradiology, Christian-Albrecht University and University Medical Center Schleswig-Holstein, Schittenhelmstr. 10, 4105 Kiel, Germany

The impact of rare variants in FUS in essential tremor

We analyzed the coding region of the Fused in Sarcoma (FUS) gene in familial essential tremor (ET) and reviewed previous studies assessing FUS variants in ET.

Mutations in HTRA2 are not a common cause of familial classic ET.

Recently Gulsuner1 described a rare single-nucleotide variant (SNV, rs72470545, G399S) in the HTRA2 gene in a very large Turkish family as causing essential tremor (ET) as well as ET with Parkinson disease (PD). We tested the hypothesis that SNVs in HTRA2 also might be the cause of classical ET without PD. We analyzed all eight protein coding exons of HTRA2 (NM_013247) and the exon/intron boundaries by Sanger sequencing in 29 unrelated, earlyonset, German patients with classic ET with at least three affected siblings (mean age at onset, 19.2 6 13.4 y [standard deviation (SD)], mean age at examination 64.2 6 18.2 y). All patients fulfilled the diagnostic criteria of classic ET. None of the patients was reported to have relatives suffering from PD. Ethics review board approval and written consents were obtained. We found one heterozygous exonic missense SNV in HTRA2 (rs72470544, A141S, NM_013247) in a single sample. This SNP had been mentioned as potentially associated with, but not causing, PD in the initial study associating genetic variants in HTRA2 with PD. However, later large-scale studies did not reveal any significant association between PD and rs72470544. Exome-Variant-Server data show that rs72470544 is quite common. Approximately 5% of all European Americans carry at least one minor allele, whereas rs72470545 is much rarer, with approximately 1% heterozygote minor allele carriers and 0/4300 homozygotes (http://evs.gs.washington.edu/EVS/). The Gulsuner study implicates HTRA2 in the pathogenesis of ET and ET with PD. However, replication and convincing functional evidence for rs72470545 will be needed to regard disease causation as proven, especially in light of the conflicting, largely negative data for this variant in PD. Gulsuner attributes the coexistence of ET with PD in the same patient to homozygosity for rs72470545 in HTRA2. We do not agree completely with this notion, because three patients with ET with PD are homozgous and two are heterozygous. We agree with Gulsuner that zygosity is a possible factor contributing to disease severity. However, age rather than zygosity might be the pivotal factor determining progression from ET to ET with PD. Patients with ET only (mean age, 53.3 y) were significantly younger than ET with PD patients (mean age, 77.2 y) (t test, P value: 0.013; data extracted from Fig. 1 of Gulsuner). This and the fact that very slow progression and FIG. 1. Substantia nigra MRI scan and striatal I-FP-CIT uptake in LRRK2 carriers. Target MRI of the SN (upper row) is obtained at the level of the inferior third of the red nucleus (left image) and at the level of superior cerebellar peduncles decussation (right image) Arrows point out the normal substantia nigra aspect. On the bottom row, the I-FP-CIT scan feature is appreciable. (A) Case 1, LRRK2 carrier. Target MRI of the SN shows the loss of nigrosome formation and trilaminar structure of the right SN with the preservation of the normal anatomy of the left SN at the red nucleus level. On the bottom row, bilateral abnormal I-FP-CIT scan, predominant on the right side, is appreciable (38% reduction in the right putamen, 25% in the left putamen). (B) Case 2, LRRK2 carrier. Target MRI of the SN shows normal aspect of nigrosome formation and trilaminar structure on both sides; on the bottom row bilateral abnormal I-FP-CIT scan, predominant on the right side, is appreciable (48% reduction in the right putamen, 40% in the left putamen)