Elisa Rubino

SQSTM1 mutations in frontotemporal lobar degeneration and amyotrophic lateral sclerosis

Objective: There is increasing evidence that common genetic risk factors underlie frontotemporal lobar degeneration (FTLD) and amyotrophic lateral sclerosis (ALS). Recently, mutations in the sequestosome 1 (SQSTM1) gene, which encodes p62 protein, have been reported in patients with ALS. P62 is a multifunctional adapter protein mainly involved in selective autophagy, oxidative stress response, and cell signaling pathways. The purpose of our study was to evaluate the frequency of SQSTM1 mutations in a dataset of unrelated patients with FTLD or ALS, in comparison with healthy controls and patients with Paget disease of bone (PDB). Methods: Promoter region and all exons of SQSTM1 were sequenced in a large group of subjects, including patients with FTLD or ALS, healthy controls, and patients with PDB. The clinical characteristics of patients with FTLD or ALS with gene mutations were examined. Results: We identified 6 missense mutations in the coding region of SQSTM1 in patients with either FTLD or ALS, none of which were found in healthy controls or patients with PDB. In silico analysis suggested a pathogenetic role for these mutations. Furthermore, 7 novel noncoding SQSTM1 variants were found in patients with FTLD and patients with ALS, including 4 variations in the promoter region. Conclusions: SQSTM1 mutations are present in patients with FTLD and patients with ALS. Additional studies are warranted in order to better investigate the role of p62 in the pathogenesis of both FTLD and ALS.

A polymorphism of the hypocretin receptor 2 gene is associated with cluster headache

Several polymorphisms of the hypocretin/orexin system genes were evaluated in 109 cluster headache patients and 211 controls. The 1246 G>A polymorphism of the gene was significantly different between cases and controls. Homozygosity for the G allele was associated with an increased disease risk (OR: 6.79, 95% CI, 2.25 to 22.99). The data suggest that the HCRTR2 gene or a linked locus significantly modulates the risk for cluster headache.

Association of the C677T polymorphism in the MTHFR gene with migraine: a meta-analysis.

There are conflicting data concerning the association between migraine and C677T polymorphism of the MTHFR gene. The C677T polymorphism reduces enzymatic capability by 50% and causes hyperhomocysteinaemia. We performed a meta-analysis of all published studies investigating the association between the MTHFR gene and migraine. Pooled odds ratios (OR) were estimated using random (RE) and fixed effects (FE) models. Among the overall 2961 migraineurs there was no significant difference compared with controls. Only in migraine with aura was the TT genotype associated with a higher risk of disease compared with the CC genotype [FE OR 1.30, 95% confidence interval (CI) 1.06, 1.58; RE OR 1.66, 95% CI 1.06, 2.59]. In the same subgroup a significant difference was observed in the comparison between TT and CT + CC genotypes (FE OR 1.32, 95% CI 1.10, 1.59; RE OR 1.63, 95% CI 1.10, 2.43). This study provides evidence for an association of the MTHFR gene only in migraine with aura.

Autosomal Dominant Frontotemporal Lobar Degeneration Due to the C9ORF72 Hexanucleotide Repeat Expansion: Late-Onset Psychotic Clinical Presentation

BACKGROUND A hexanucleotide repeat expansion in the first intron of C9ORF72 has been shown to be responsible for a high number of familial cases of amyotrophic lateral sclerosis or frontotemporal lobar degeneration (FTLD). Atypical presentations have been described, particularly psychosis. METHODS We determined the frequency of the hexanucleotide repeat expansions in a population of 651 FTLD patients and compared the clinical characteristics of carriers and noncarriers. In addition, we genotyped 21 patients with corticobasal syndrome, 31 patients with progressive supranuclear palsy, and 222 control subjects. RESULTS The pathogenic repeat expansion was detected in 39 (6%) patients with FTLD (17 male and 22 female subjects); however, it was not detected in any corticobasal syndrome and progressive supranuclear palsy patients or controls. Twenty-four of 39 carriers had positive family history for dementia and/or amyotrophic lateral sclerosis (61.5%), whereas only 145 of 612 noncarriers had positive family history (23.7%; p<.000001). Clinical phenotypes of carriers included 29 patients with the behavioral variant frontotemporal dementia (bvFTD; 5.2% of all bvFTD cases), 8 with bvFTD/motor neuron disease (32% bvFTD/motor neuron disease cases), 2 with semantic dementia (5.9% of patients with semantic dementia), and none with progressive nonfluent aphasia. The presentation with late-onset psychosis (median age = 63 years) was more frequent in carriers than noncarriers (10/33 vs. 3/37, p = .029), as well as the presence of cognitive impairment at onset (15/33 vs. 5/37; p = .0039). CONCLUSIONS The repeat expansion in C9ORF72 is a common cause of FTLD and often presents with late-onset psychosis or memory impairment.

Insulin Sensitivity is Impaired in Patients with Migraine

Several studies have shown the presence of a comorbidity between migraine and vascular diseases, like hypertension and stroke. The mechanisms of this comorbidity are unknown. Impaired insulin sensitivity has recently emerged as a risk factor for hypertension and stroke. We evaluated insulin sensitivity in 30 young, nonobese, nondiabetic, normotensive migraine patients and in 15 healthy controls. During the OGTT, glucose plasma concentrations were significantly higher in migraineurs than in controls. Insulin sensitivity, as measured by ISI-stumvoll and OGIS-180 indexes, was significantly altered in migraine. Our data show that insulin sensitivity is impaired in migraine and suggest a role for insulin resistance in the comorbidity between migraine and vascular diseases.

Mutation analysis of CHCHD10 in different neurodegenerative diseases

Sir, A recent study by Bannwarth et al. (2014) implicated CHCHD10 as a novel gene for amyotrophic lateral sclerosis/frontotemporal lobar degeneration (ALS/FTLD), reporting a p.S59L substitution (c.176C > T; NM_213720.2) in a large French kindred. Affected family members were presented with a complex phenotype that included symptoms of amyotrophic lateral sclerosis (ALS), frontotemporal lobar degeneration (FTLD), cerebellar ataxia, Parkinson’s disease and a mitochondrial myopathy associated with multiple mitochondrial DNA deletions. So far, seven missense CHCHD10 mutations have been reported in patients with a broad phenotypic range, including ALS/FTLD (p.S59L and p.P34S) (Bannwarth et al. , 2014; Chaussenot et al. , 2014), ALS (p.R15L and p.G66V) (Johnson et al. , 2014; Muller et al. , 2014), myopathy (p.R15S and p.G58R) (Ajroud-Driss et al. , 2015) and late-onset spinal motor neuronopathy (p.G66V) (Penttila et al. , 2015). All of them affect exon 2 (a mutational hotspot of CHCHD10 ). Notably, mitochondrial dysfunction has been implicated in several neurodegenerative diseases (Lin and Beal, 2006; Cozzolino et al. , 2013); however, there are no studies evaluating the contribution of CHCHD10 to pure FTLD, Parkinson’s disease or Alzheimer’s disease. Hence, we sequenced CHCHD10 exon 2 in 204 ALS, 153 Parkinson’s disease and 141 Alzheimer’s disease patients from Canada and 158 FTLD patients from Italy in addition to 497 control subjects from USA/UK, Canada and Italy. The cases of ALS and FTLD were free from mutations in SOD1 , GRN , FUS , TARDBP and MATR3 or a repeat expansion in C9orf72 . We identified a known CHCHD10 pathogenic p.R15L mutation (Johnson et al. , 2014; Muller et al. , 2014) in a patient with sporadic ALS (Patient 8807) (Fig. 1A), who developed symptoms involving his upper limb at 54 years of age and remains alive 12 years later. The p.R15L …

Haplotype Analysis Confirms the Association Between the HCRTR2 Gene and Cluster Headache

Background.— Several studies suggested that genetic factors play a role in cluster headache (CH) susceptibility. We found a significant association between the 1246 G>A polymorphism of the hypocretin receptor‐2 (HCRTR2) gene and the disease. This association was confirmed in a large study from Germany but was not replicated in a dataset of CH patients from Northern Europe.

TUMOR NECROSIS FACTOR-α GENE AND CEREBRAL ANEURYSMS

OBJECTIVEThe pathogenesis of intracranial aneurysms is still uncertain. In addition to atherosclerosis, immunological factors may play a role in the disease. Recent studies have suggested that tumor necrosis factor-α (TNF-α), one of the main proinflammatory cytokines, may play a key role in the formation and rupture of cerebral aneurysms. The purpose of this study is to evaluate the association of a functionally active polymorphism (−308 G<A) in the TNF-α gene with the risk and the clinical features of aneurysmal subarachnoid hemorrhage. METHODSA total of 171 consecutive aneurysmal subarachnoid hemorrhage patients and 144 healthy controls were involved in the study. Computed tomographic scan findings were assessed by Fisher grade; clinical neurological assessment was performed using the Hunt and Hess grading system. Patients and controls were genotyped for the−308 biallelic (G<A) polymorphism of the TNF-α gene. RESULTSThe TNF-α G allele was significantly more frequent in patients than in controls (χ2 = 5.59; P = 0.0181) and homozygosity for the G allele, compared with remaining genotypes, was associated with a significantly increased risk of aneurysmal subarachnoid hemorrhage (odds ratio = 2.20; 95% confidence interval = 1.29<odds ratio<3.75). Allelic and genotypic frequencies of the examined polymorphism were not significantly different in disease subgroups. The different TNF-α genotypes do not seem to significantly modify the main clinical features of the disease. CONCLUSIONOur data suggests that the TNF-α gene or a linked locus significantly modulates the risk for aneurysmal subarachnoid hemorrhage. Additional studies in different populations are warranted to confirm our findings.

Association between the G1246A polymorphism of the hypocretin receptor 2 gene and cluster headache: a meta-analysis

The objective of this study was to investigate the association between polymorphisms of the hypocretin receptor 2 gene (HCRTR2) and the risk of cluster headache (CH). The study is a meta-analysis of published case-control studies investigating the association between polymorphisms of the HCRTR2 gene and CH. Pooled odds ratios (OR) were estimated using both random (RE) and fixed effects (FE) models. Three studies, performed in five different European countries, with 593 cases and 599 controls, were included in the study. Allele G of the G1246A HCRTR2 polymorphism was significantly associated with CH (FE OR 1.58, CI 95% 1.27–1.95; RE OR 1.55 (1.14–2.12)). Carriers of the GG genotype showed a higher disease risk compared to the remaining genotypes (FE OR 1.75, CI 95% 1.37–2.25; RE OR 1.69, CI 95% 1.11–2.58). Our data confirm that the G1246A polymorphism of the HCRTR2 gene may modulate the genetic risk for CH.

Endocrine function is altered in chronic migraine patients with medication-overuse.

Objective.—To evaluate the effects of analgesic overuse on endocrine function in patients with chronic migraine and medication‐overuse headache (CM‐MOH).