Late onset bipolar disorder and frontotemporal dementia with mutation in progranulin gene: a case report.

Bipolar disorder is a chronic psychiatric illness characterised by fluctuation in mood state, with a relapsing and remitting course. Frontotemporal dementia (FTD) is a clinically and genetically heterogeneous syndrome, with the most frequent phenotype being behavioural variant frontotemporal dementia (bvFTD). Here, we report the case of an Italian male presenting with late-onset bipolar disorder that developed into bvFTD over time, carrying a mutation in the GRN gene. Interestingly, the patient carried the c.1639 C > T variant in the GRN gene, resulting in a R547C substitution. Our case report further corroborates the notion that, in addition to FTD, progranulin may be involved in the neurobiology of bipolar disorder type 1, and suggests to screen patients with late-onset bipolar disorder for GRN mutations.

KCNK18 (TRESK) genetic variants in Italian patients with migraine.

OBJECTIVES: To evaluate the prevalence of KCNK18 gene mutations in a dataset of Italian migraineurs, with and without aura, and in healthy controls, and to investigate in silico the functional effects of the mutations. BACKGROUND: A role for the KCNK18 gene encoding for TRESK, a member of the family of potassium channel, has been recently suggested in migraine with aura. METHODS: We sequenced the KCNK18 gene in 425 migraineurs (255 with aura and 170 without aura) and 247 healthy controls. RESULTS: Five genetic variants (R10G, C110R, Y163Y, S231P, and F372L) were found in 13 (5.1%) out of 255 migraine with aura patients, and 6 variants (R10G, D46D, C110R, Y163Y, S178T, and S231P) were identified in 12 (7.1%) out of 170 migraine without aura patients. In 2.8% of controls, the R10G and L20V substitutions were found. In silico analysis suggested that C110R, S178T, S231P, and F372L mutations may have potential damaging effect on channel function, whereas the remaining mutations may have low damaging effect. CONCLUSIONS: Our study shows the presence of several KCNK18 gene mutations in both migraine with aura and migraine without aura. However, the precise role of this gene in migraine predisposition deserves further studies.

Genetic variants in the NOTCH4 gene influence the clinical features of migraine.

BACKGROUND: Recent studies suggested an important role for vascular factors in migraine etiopathogenesis. Notch4 belongs to a family of transmembrane receptors that play an important role in vascular development and maintenance. The aim of this study was to test the hypothesis that polymorphisms of the NOTCH4 gene would modify the occurrence and the clinical features of migraine. FINDINGS: Using a case-control strategy, we genotyped 239 migraine patients and 264 controls for three different non-synonymous polymorphisms (T320A, G835V, R1346P) of the NOTCH4 gene and for the (CTG) n-encoding polyleucine polymorphism in exon 1. Although the analyzed polymorphisms resulted not associated with migraine, the clinical characteristics of our patients were significantly influenced by the different NOTCH4 genotypes. Longer duration of disease and severity of neurovegetative symptoms during headache attacks were associated with the R1346P and G835V polymorphisms, respectively. In female patients, worsening of migraine symptoms at menarche was significantly correlated with T320A polymorphism. CONCLUSIONS: Our study shows that genetic variations within the NOTCH4 gene significantly modify the clinical characteristics of migraine and may have a role in disease pathogenesis.

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.

Proinflammatory cytokine gene polymorphisms and susceptibility to Paget's disease of bone: an association study.

BACKGROUND: Recent studies suggested that proinflammatory cytokines are involved in the pathophysiology of Paget's disease of bone (PDB). The purpose of this study was to evaluate whether functionally active polymorphisms of the interleukin-1α (IL-1α), interleukin-1ß (IL-ß), interleukin-6 (IL-6) and tumour necrosis factor-α (TNF-α) genes would modify the occurrence and the clinical features of PDB. METHODS: Genomic DNA was extracted from 144 PDB patients and 115 healthy controls. All subjects were genotyped for the following functionally active polymorphisms in the proinflammatory cytokine genes: IL-1α-889 C>T, IL-1ß-511 C>T, IL-6-174 G>C, and TNF-α-308 G>A. Allele and genotype frequencies were compared between cases and controls. The clinical characteristics of the disease were compared according to the different genotypes. RESULTS: Allele and genotype frequencies of the examined polymorphism resulted nearly identical in cases and controls. Examining the association with the clinical features, PDB patients carrying the C/C genotype of the IL-6 gene showed a significantly (p<0.001) higher frequency of hearing loss and primary hyperparathyroidism. No significant difference in the remaining clinical features was found. In conclusion, this study do not support the hypothesis that the examined proinflammatory genes are major genetic risk factor for PDB. However, our data suggests a role for the IL-6 gene in modifying the clinical features of the disease.

Evidence for an association between migraine and the hypocretin receptor 1 gene.

The aim of our study was to investigate whether genetic variants in the hypocretin receptor 1 (HCRTR1) gene could modify the occurrence and the clinical features of migraine. Using a case-control strategy we genotyped 384 migraine patients and 259 controls for three SNPs in the HCRTR1 gene. Genotypic and allelic frequencies of the rs2271933 non-synonymous polymorphism resulted different (χ(2)=9.872, p=0.007; χ(2)=8.108, p=0.004) between migraineurs and controls. The carriage of the A allele was associated with an increased migraine risk (OR 1.42, 95% CI 1.11-1.81). When we divided the migraine patients into different subgroups, the difference reached the level of statistical significance only in migraine without aura. The different genotypes had no significant effect on the examined clinical characteristics of the disease. In conclusion, our data supports the hypothesis that the HCRTR1 gene could represent a genetic susceptibility factor for migraine without aura and suggests that the hypocretin system may have a role in the pathophysiology of migraine.

Association between major mood disorders and the hypocretin receptor 1 gene.

BACKGROUND: Recent studies suggested a role for hypocretins in the neurobiology of Major Mood Disorders (MMD). The purpose of this study was to investigate hypocretin involvement in MMD evaluating whether particular alleles or genotypes of the hypocretin pathway genes (HCRT, HCRTR1 and HCRTR2) would modify the occurrence and clinical features of the disease. METHODS: We selected for the study 229 MMD patients and 259 healthy age-, sex- and ethnicity-matched controls. Cases and controls were genotyped for several single-nucleotide polymorphisms (SNPs) of the HCRT, HCRTR1, and HCRTR2 genes. RESULTS: We found that allelic and genotypic frequencies of the rs2271933 G>A polymorphism (Ile408Val) in the HCRTR1 gene were significantly different between cases and controls (p=0.003 and p=0.0004, respectively). The carriage of the A allele was associated with a significantly increased disease risk (OR:1.60, 95% C.I. 1.22-2.10). In addition, we found a significant association between HCRTR1 haplotypes and the disease (permutation p<0.0001). In the analysis of subgroups we confirmed the association only in patients with unipolar depression. LIMITATIONS: Our sample was relatively small and included only cases and controls recruited from Northern Italy. Analysis of the disease subgroups warrants reexamination with more subjects. Finally, the effects of the rs2271933 G>A polymorphism on the hypocretin-1 receptor function are unknown. CONCLUSIONS: Our study suggests that the HCRTR1 gene or a linked locus may modulate the risk for Major Mood Disorders and supports recent studies suggesting an involvement of hypocretin neurotransmitter system in affective disorders.

Interleukin-1 cluster gene polymorphisms and aneurysmal subarachnoid hemorrhage.

BACKGROUND: Emerging data indicate that proinflammatory cytokines may be involved in the pathogenesis of intracranial aneurysms. Interleukin (IL)-1 is a proinflammatory cytokine that plays a pivotal role in both acute and chronic central nervous system injuries. OBJECTIVE: To investigate whether select polymorphisms in the IL-1alpha, IL-1beta, and IL-1 receptor antagonist genes are associated with both susceptibility to and clinical characteristics of subarachnoid hemorrhage due to intracranial aneurysm rupture. METHODS: Allelic and genotypic frequencies of the IL-1alpha (-889), IL-1beta (-511), and IL-1 receptor antagonist (VNTR) genes were determined in 215 patients and 155 healthy controls. Patient files were reviewed for the clinical characteristics at hospital admission and at 6-month follow-up. RESULTS: No association between aneurysmal subarachnoid hemorrhage susceptibility and the examined cytokine gene polymorphisms was found. Haplotype analysis did not show any significant difference between cases and controls. However, aneurysmal subarachnoid hemorrhage patients carrying the T/T genotype of the IL-1beta gene showed a significant (P = .034) increase in the Hunt and Hess scores at hospital admission and a significant (P = .026) reduction in 6-month Glasgow Outcome Scale scores. The remaining polymorphisms showed no effect on the clinical features examined. CONCLUSION: Our results do not support the hypothesis that genetic variation in select polymorphisms of the IL-1 cluster genes is associated with aneurysmal subarachnoid cerebral hemorrhage. However, the IL-1beta gene may modify disease severity and may be regarded as disease severity gene.

SQSTM1 gene analysis and gene-environment interaction in Paget's disease of bone.

Even though SQSTM1 gene mutations have been identified in a consistent number of patients, the etiology of Paget's disease of bone (PDB) remains in part unknown. In this study we analyzed SQSTM1 mutations in 533 of 608 consecutive PDB patients from several regions, including the high-prevalence area of Campania (also characterized by increased severity of PDB, higher number of familial cases, and peculiar phenotypic characteristics as giant cell tumor). Eleven different mutations (Y383X, P387L, P392L, E396X, M401V, M404V, G411S, D423X, G425E, G425R, and A427D) were observed in 34 of 92 (37%) and 43 of 441 (10%) of familial and sporadic PDB patients, respectively. All five patients with giant cell tumor complicating familial PDB were negative for SQSTM1 mutations. An increased heterogeneity and a different distribution of mutations were observed in southern Italy (showing 9 of the 11 mutations) than in central and northern Italy. Genotype-phenotype analysis showed only a modest reduction in age at diagnosis in patients with truncating versus missense mutations, whereas the number of affected skeletal sites did not differ significantly. Patients from Campania had the highest prevalence of animal contacts (i.e., working or living on a farm or pet ownership) without any difference between patients with or without mutation. However, when familial cases from Campania were considered, animal contacts were observed in 90% of families without mutations. Interestingly, a progressive age-related decrease in the prevalence of animal contacts, as well as a parallel increase in the prevalence of SQSTM1 mutations, was observed in most regions except in the subgroup of patients from Campania. Moreover, patients reporting animal contacts showed an increased number of affected sites (2.54 +/- 2.0 versus 2.19 +/- 1.9, p < .05) over patients without animal contacts. This difference also was evidenced in the subgroup of patients with SQSTM1 mutations (3.84 +/- 2.5 versus 2.76 +/- 2.2, p < .05). Overall, these data suggest that animal-related factors may be important in the etiology of PDB and may interact with SQSTM1 mutations in influencing disease severity.

Cluster headache is associated with the alcohol dehydrogenase 4 (ADH4) gene.

BACKGROUND/OBJECTIVES: Alcohol is a well-known trigger factor for cluster headache attacks during the active phases of the disease. The alcohol dehydrogenase (ADH) pathway, which converts alcohol to the toxic substance acetaldehyde, is responsible for most of the alcohol breakdown in the liver. Humans have 7 ADH genes, tightly clustered on chromosome 4q21-q25, that encode different ADH isoforms. The ADH4 gene encodes the class II ADH4 pi subunit, which contributes, in addition to alcohol, to the metabolization of a wide variety of substrates, including retinol, other aliphatic alcohols, hydroxysteroids, and biogenic amines. The purpose of this study was to investigate the association of genetic variants within the ADH4 gene with cluster headache susceptibility and phenotype. METHODS: A total of 110 consecutive unrelated cluster headache patients and 203 age- and sex-matched healthy controls of Caucasian origin were involved in the study. Patients and controls were genotyped for 2 bi-allelic single nucleotide polymorphisms (SNPs) of the ADH4 gene: SNP1 - rs1800759 and SNP2 - rs1126671. Allele, genotype, and haplotype frequencies of the examined polymorphisms were compared between cases and controls. RESULTS: Genotype frequencies of the rs1126671 polymorphism resulted significantly different between cluster headache patients and controls (chi(2) = 10.269, P = .006). The carriage of the AA genotype, in comparison with remaining genotypes, was associated with a significantly increased disease risk (OR = 2.33, 95% CI: 1.25-4.37). Haplotype analysis confirmed the association between the ADH4 gene and the disease. No association between different clinical characteristics of cluster headache and the examined polymorphisms was found. CONCLUSION: Our data suggest that cluster headache is associated with the ADH4 gene or a linked locus. Additional studies are warranted to elucidate the role of this gene in the etiopathogenesis of the disease.

Absence of TARDBP gene mutations in an italian series of patients with frontotemporal lobar degeneration.

BACKGROUND/AIM: Recent studies showed that TAR DNA-binding protein 43 (TDP-43), encoded by the TARDBP gene, is a major pathological protein in both sporadic and familial frontotemporal lobar degeneration (FTLD). The aim of this study was to search for mutations of the TARDBP gene in the disease. METHODS: We sequenced the TARDBP gene in 172 unrelated FTLD patients recruited from 2 Italian memory clinics. RESULTS: We identified 3 different variants of the TARDBP gene in 12 FTLD patients. Three patients showed a silent variant, Ala66Ala (c.332T --> C) in exon 2. A novel heterozygous mutation was found in intron 4 (c.543 + 51A --> G) in 1 patient, which is not located at the splicing site. Finally, a c.208C --> T variant in the 3' untranslated region was detected in 8 probands. None of the aforementioned variants were predicted to affect TDP-43. Hence, pathogenic mutations were not identified in any of the FTLD cases. CONCLUSION: Our study, in accord with previous studies in different populations, found no evidence for a major genetic role of the TARDBP gene in FTLD.

Pro-inflammatory cytokine genes influence the clinical features of frontotemporal lobar degeneration.

BACKGROUND/AIMS: Recent studies suggested a role for pro-inflammatory mediators in frontotemporal lobar degeneration (FTLD). The objective of this study was to evaluate the association of functionally active polymorphisms in pro-inflammatory cytokine genes with the occurrence and the clinical features of the disease. METHODS: Using a case-control study, we compared allelic and genotypic frequencies of several polymorphisms in the interleukin (IL)-1alpha, interleukin (IL)-1beta, interleukin (IL)-6 and tumor necrosis factor (TNF)-alpha genes between 110 FTLD patients and 119 healthy controls. RESULTS: No significant association between the examined polymorphisms and the disease was found. However, in comparison with remaining genotypes, patients carrying the T/T genotype of the IL-1beta gene showed a significantly lower age at onset of the disease. In addition, scores of the Frontal Assessment Battery were significantly modified by the IL-6 -174G>C polymorphism. CONCLUSION: Our findings support a role for pro-inflammatory cytokine genes in the pathogenesis of frontotemporal lobar degeneration.

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. OBJECTIVE: The purpose of this study was to further evaluate the association between CH and the HCRTR2 gene using new polymorphisms, estimating the frequency of different gene haplotypes, searching for gene mutations, and evaluating the effects of the examined polymorphisms on hypocretin binding sites. METHODS: We genotyped 109 CH patients and 211 healthy controls for 5 new polymorphisms of the HCRTR2 gene and we inferred different gene haplotypes. Complete HCRTR2 sequencing was undertaken for 11 independent CH patients, 5 of whom had a positive family history. The effects of the 1246 G>A polymorphism on the hypocretin binding sites were evaluated using different computer-assisted analyses. RESULTS: Three new polymorphisms of the HCRTR2 gene resulted significantly associated with CH. The GTAAGG haplotype resulted more frequent in cases than in controls (OR: 3.68; 95% CI: 1.85-7.67). No point mutation of the HCRTR2 gene was found. Binding analyses showed that the 1246 G>A polymorphism (substitution of valine at position 308 by isoleucine) has no effect on the hypocretin binding sites but could influence the dimerization process of the receptor. CONCLUSION: Our data confirm previous studies suggesting that the HCRTR2 gene or a linked locus significantly modulates the risk for CH. In addition, we suggest that the V308I substitution of the HCRTR2 may interfere with the dimerization process of the receptor, thereby influencing its functional activity.

Tumor necrosis factor-alpha gene and cerebral aneurysms.

OBJECTIVE: The 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-alpha (TNF-alpha), 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