Serum biomarkers at disease onset for personalized therapy in multiple sclerosis.

The potential of combining serum neurofilament light chain (sNfL) and glial fibrillary acidic protein (sGFAP) levels to predict disability worsening in multiple sclerosis (MS) remains underexplored. We aimed to investigate whether sNfL and sGFAP values identify distinct subgroups of patients according to the risk of disability worsening and their response to disease-modifying treatments (DMTs). This multicentre study, conducted across thirteen European hospitals, spanned from July 15, 1994, to August 18, 2022, with follow-up until September 26, 2023. We enrolled MS patients who had serum samples collected within 12 months from disease onset and before initiating DMTs. Multivariable regression models were used to estimate the risk of relapse-associated worsening (RAW), progression independent of relapse activity (PIRA), and Expanded Disability Status Scale (EDSS) score of 3. Of the 725 patients included, median age was 34.2 years (IQR, 27.6-42.4), and 509 patients (70.2%) were female. Median follow-up duration was 6.43 years (IQR, 4.65-9.81). Higher sNfL values associated with an elevated risk of RAW (HR of 1.45; 95% CI 1.19-1.76; P < 0.001), PIRA (HR of 1.43; 95% CI 1.13-1.81; P = 0.003), and reaching an EDSS of 3 (HR of 1.55; 95% CI 1.29-1.85; P < 0.001). Moreover, higher sGFAP levels were linked to a higher risk of achieving an EDSS score of 3 (HR of 1.36; 95% CI 1.06-1.74; P = 0.02) and, in patients with low sNfL values, to PIRA (HR of 1.86; 95% CI 1.01-3.45; P = 0.04). We further examined the combined effect of sNfL and sGFAP levels. Patients with low sNfL and sGFAP values (NLGL) exhibited a low risk of all outcomes and served as reference. Untreated patients with high sNfL levels showed a higher risk of RAW, PIRA, and reaching an EDSS of 3. Injectable or oral DMTs reduced the risk of RAW in these patients but failed to mitigate the risk of PIRA and reaching an EDSS of 3. Conversely, high-efficacy DMTs counteracted the heightened risk of these outcomes, except for the risk of PIRA in patients with high sNfL and sGFAP levels. Patients with low sNfL and high sGFAP values (NLGH) showed an increased risk of PIRA and achieving an EDSS of 3, which remained unchanged with either high-efficacy or other DMTs. In conclusion, evaluating sNfL and sGFAP levels at disease onset in MS may identify distinct phenotypes associated with diverse immunological pathways of disability acquisition and therapeutic response.

Gamma-aminobutyric acid (GABA) receptors genes polymorphisms and risk for restless legs syndrome.

The possible role of gammaaminobutyric acid (GABA) in the pathophysiology of restless legs syndrome (RLS) is suggested by the symptomatic improvement achieved with GABAergic drugs. Thalamic GABA levels have shown positive correlation with periodic limb movements indices and with RLS severity. We tried to investigate the possible association between the most common single nucleotide polymorphisms (SNPs) in the GABA receptors (GABR) genes rho1, 2, and 3 (GABRR1, GABRR2, GABRR3), alpha4 (GABRA4), epsilon (GABRE), and theta (GABRQ) with the risk of developing RLS. We studied the genotype and allelic variant frequencies of the most common SNPs in the GABRR1(rs12200969, rs1186902), GABRR2(rs282129), GABRR3(rs832032), GABRA4(rs2229940), GABRE(rs1139916), and GABRQ(rs3810651) genes in 205 RLS patients and 230 age- and gender-matched healthy controls using specific TaqMan assays. The frequencies of the GABRR3 rs832032TT genotype and the allelic variant GABRR3 rs832032T were significantly higher in RLS patients than in controls (odds ratio [95% confidence intervals] 7.08[1.48-46.44] and 1.66[1.16-2.37], respectively), although only the higher frequency of the rs832032T allele remained as significant after multiple comparison analysis, both in the whole series and in the female gender. The frequencies of the other genotypes of allelic variants did not differ significantly between RLS patients and controls. RLS patients carrying the GABRA4 rs2229940TT genotype showed a significantly younger age at onset of RLS symptoms than those with the other two genotypes. These results suggest association between GABRR3rs832032 polymorphism and the risk for RLS, and a modifier effect of GABRA4 rs2229940 on the age of onset of RLS.

Association Between the rs1229984 Polymorphism in the Alcohol Dehydrogenase 1B Gene and Risk for Restless Legs Syndrome.

Background/Objectives: Several studies have raised the possibility of an association between alcohol consumption and the risk of developing restless legs syndrome (RLS). Moreover, an important percentage of patients under alcohol detoxification therapy develop RLS symptoms that fulfil the criteria for idiopathic RLS during alcohol withdrawal. We have aimed to establish the possible association between two common single nucleotide polymorphisms (SNPs) in the alcohol-dehydrogenase 1B (ADH1B) gene and the risk for RLS. Methods: We studied, using specific TaqMan assays, the genotype and allelic variant frequencies of ADH1B rs1229984 and ADH1B rs6413413 SNPs in 205 RLS patients and 505 gender-matched healthy controls. Results: The sum of the frequencies of rs1229984CT and rs1229984TT genotypes, as well as the frequency of the rs1229984T allelic variant, was significantly higher in RLS patients than in controls, both in the whole group and in females. The frequencies of genotypes and allelic variants of the rs6413413 SNP were similar between the two groups. RLS patients with the rs1229984CT genotype were younger, and those with the rs122984TT genotype older, at onset of RLS symptoms than those with the rs1229984CC genotype. None of the studied SNPs were related either with positivity of family history for RLS or with RLS severity. Conclusions: These results suggest an association between rs1229984 SNP and the risk for RLS.

Thr105Ile (rs11558538) polymorphism in the histamine-1-methyl-transferase (HNMT) gene and risk for restless legs syndrome.

A recent meta-analysis suggests an association between the rs11558538 single nucleotide polymorphism in the histamine-N-methyl-transferase (HNMT) gene and the risk for Parkinson's disease. Based on the possible relationship between PD and restless legs syndrome (RLS), we tried to establish whether rs11558538 SNP is associated with the risk for RLS. We studied the genotype and allelic variant frequencies of HNMT rs11558538 SNP 205 RLS patients and 410 healthy controls using a TaqMan assay. The frequencies of the HNMT rs11558538 genotypes allelic variants were similar between RLS patients and controls, and were not influenced by gender, family history of RLS, or RLS severity. RLS patients carrying the genotype rs11558538TT had an earlier age at onset, but this finding was based on three subjects only. These results suggest a lack of major association between HNMT rs11558538 SNP and the risk for RLS.

Association Between Vitamin D Receptor rs731236 (Taq1) Polymorphism and Risk for Restless Legs Syndrome in the Spanish Caucasian Population.

Several recent works suggest a possible role of vitamin D deficiency in the etiology or restless legs syndrome (RLS). We analyzed the possible relationship of 2 common single nucleotide polymorphisms (SNPs) in the vitamin D3 receptor (VDR) gene with the risk for RLS.We studied the genotype and allelic variant frequencies of VDR rs2228570 and VDR rs731236 SNPs in 205 RLS patients and 445 healthy controls using a TaqMan essay.The frequencies of the rs731236AA genotype and the allelic variant rs731236A were significantly lower in RLS patients than in controls (P < 0.005 and < 0.01, respectively). Restless legs syndrome patients carrying the allelic variant rs731236G had an earlier age at onset, and those carrying the rs731236GG genotype had higher severity of RLS, although these data disappeared after multivariate analyses. None of the SNPs studied was related with the positivity of family history of RLS.These results suggest a modest, but significant association between VDR rs731236 SNP and the risk for RLS.

Heme Oxygenase-1 and 2 Common Genetic Variants and Risk for Restless Legs Syndrome.

Several neurochemical, neuropathological, neuroimaging, and experimental data, suggest that iron deficiency plays an important role in the pathophysiology of restless legs syndrome (RLS). Heme-oxygenases (HMOX) are an important defensive mechanism against oxidative stress, mainly through the degradation of heme to biliverdin, free iron, and carbon monoxide. We analyzed whether HMOX1 and HMOX2 genes are related with the risk to develop RLS.We analyzed the distribution of genotypes and allelic frequencies of the HMOX1 rs2071746, HMOX1 rs2071747, HMOX2 rs2270363, and HMOX2 rs1051308 SNPs, as well as the presence of Copy number variations (CNVs) of these genes in 205 subjects RLS and 445 healthy controls.The frequencies of rs2071746TT genotype and rs2071746T allelic variant were significantly lower in RLS patients than that in controls, although the other 3 studied SNPs did not differ between RLS patients and controls. None of the studied polymorphisms influenced the disease onset, severity of RLS, family history of RLS, serum ferritin levels, or response to dopaminergic agonist, clonazepam or GABAergic drugs.The present study suggests a weak association between HMOX1 rs2071746 polymorphism and the risk to develop RLS in the Spanish population.

Neuronal nitric oxide synthase (nNOS, NOS1) rs693534 and rs7977109 variants and risk for restless legs syndrome.

Several biochemical, neuropathological, and experimental data suggest a possible role of nitric oxide (NO) in the pathophysiology of restless legs syndrome (RLS). Two single nucleotide polymorphisms (SNPs) neuronal nitric oxide synthase (nNOS or NOS1) gene (rs7977109 and rs693534) have been found to be associated with the risk for RLS in Germans, although only one of them (rs7977109) remained as significant after multiple comparison tests. The aim of our study was to replicate the possible association between these SNPs and risk for RLS in the Spanish population. We studied the allelic and genotype frequencies of the SNPs rs7977109 and rs693534 in 205 patients with RLS and 328 healthy controls using TaqMan genotyping. The rs7977109 and rs693534 genotypes and allelic frequencies did not significantly differ between patients with RLS and controls and were unrelated with the age at onset of RLS, gender, ferritin levels, and response to dopaminergic or gabaergic agents. The rs7999109GA genotype was overrepresented in RLS patients with positive family history of RLS, and in patients with symptomatic response to clonazepam. The results of our study suggest that these two NOS1 SNPs are not related to the overall risk for RLS in the Spanish population.

The solute carrier family 1 (glial high affinity glutamate transporter), member 2 gene, SLC1A2, rs3794087 variant and assessment risk for restless legs syndrome.

OBJECTIVE: A glutamatergic dysfunction has been postulated to play a role in restless legs syndrome (RLS) pathophysiology, as glutamate concentrations have been found to increase in the thalamus of RLS patients. The aim of our study was to investigate the possible association between the single nucleotide polymorphism (SNP) rs3794087 in the solute carrier family 1 (glial high affinity glutamate transporter), member 2 gene, SLC1A2, related with glutamate transport and the risk for RLS. METHODS: We studied the allelic and genotype frequencies of the SNP rs3794087 in 205 patients with RLS and 328 healthy controls using TaqMan genotyping. RESULTS: The rs3794087 genotype and allelic frequencies did not significantly differ between patients with RLS and controls and were unrelated with the age at onset of RLS, gender, and family history of RLS. CONCLUSIONS: The results of our study suggest that the rs3794087 polymorphism is not related to the risk for RLS.

MAPT1 gene rs1052553 variant is unrelated with the risk for restless legs syndrome.

Mutations in the microtubule-associated protein tau gene (MAPT) can cause frontotemporal dementia with Parkinsonism linked to the chromosome 17, and are associated with the risk for progressive supranuclear palsy, Parkinson's disease, corticobasal degeneration, and multiple system atrophy. We tried to establish, whether MAPT H1 discriminating haplotype single nucleotide polymorphisms (SNP) (rs1052553) is associated with the risk for restless legs syndrome (RLS). We studied the allelic and genotype frequencies of the SNP rs1052553 in 205 patients with RLS and 324 healthy controls using TaqMan genotyping. rs1052553 genotype and allelic frequencies did not differ significantly between patients with RLS and controls, and were unrelated with the age at onset of RLS, gender, family history of RLS, and severity of RLS. The results of the present study suggest that the SNP rs1052553 is not related with the risk for RLS.

Gamma-aminobutyric acid GABRA4, GABRE, and GABRQ receptor polymorphisms and risk for essential tremor.

Some clinical and experimental data suggest a possible role of γ-aminobutyrate (GABA)-ergic mechanisms in the pathophysiology of essential tremor (ET). We studied the allelic and genotype frequencies of the single nucleotide polymorphisms, such as GABRA4-L26M (Leu26Met, rs2229940), GABRE-S102A (Ser26Ala, rs1139916), and GABRQ-I478F (Ile26Phe, rs3810651), in 200 patients with familial ET and 250 healthy controls using TaqMan genotyping. GABRA4-L26M, GABRE-S102A, and GABRQ-I478F genotype and allelic frequencies did not differ significantly between patients with ET and controls, and were unrelated to the age at onset of tremor or sex. The GABRQ-478F allele seemed to be related to improvement of tremor with ethanol use among men (odds ratio=2.32, 95% confidence interval=0.26-4.3, P=0.007, Pc=0.021). The results of this study suggest that the single nucleotide polymorphisms studied in the GABRA4, GABRE, and GABRQ genes are not related to the risk for familial ET.

Gamma-aminobutyric acid (GABA) receptor rho (GABRR) polymorphisms and risk for essential tremor.

Some clinical and experimental data suggest a possible role of gamma-aminobutyrate (GABA)-ergic mechanisms in the pathophysiology of essential tremor (ET), such as the improvement of ET with some GABAergic drugs and the development of an experimental model of ET in GABA A receptor alpha-1 knockout mice (postural and kinetic tremor and motor incoordination similar to human ET). To investigate the possible association between the GABA receptor subtype rho1, rho2, and rho3 (GABRR1, GABRR2, and GABRR3) genotypes and allelic variants of the single nucleotide polymorphisms GABRR1-M26V (Met26Val, rs12200969), GABRR1-H27R (His26Arg, rs1186902), GABRR2-T455M (Thr55Met, rs282129), and GABRR3-Y205X (Tyr205X, rs832032), and the risk for ET, we studied the frequency of the previously mentioned GABRR genotypes and allelic variants in 200 patients with ET and 250 healthy controls using TaqMan genotyping. The frequencies of the GABBR1 genotypes and allelic variants of the studied polymorphisms did not differ significantly between patients with ET and controls, and were unrelated with the age at onset of tremor, gender, localization of tremor, and response of tremor to ethanol. These data suggest that the single nucleotide polymorphisms studied in the GABBR genes are not related to the risk for ET.

Influence of age and gender in motor performance in healthy subjects.

BACKGROUND/OBJECTIVES: Slowing of motor performance in human aging is a well demonstrated clinical observation. Information on the influence of gender in motor performance is less well-established. With the aim of analyzing the possible influence of age and gender in motor performance, we studied basic motor function in a large series of healthy sex-matched individuals aged >40 years. METHODS: We studied 246 subjects (123 males and 123 females; mean age 63.67 ± 10.79 and 63.61 ± 11.04 years, respectively), stratified by age in 7 groups for each gender. Evaluation included four timed tests (pronation-supination, finger tapping and movement between two points, all with both hands, and walking test), and the three tests performed on a personal computer (speed for pressing repetitively a key - frequency, visual reaction time and movement time, all with both hands). Statistical analysis included two-way analysis of variance (ANOVA) for two factors (age and gender) and Pearson's or Spearman's correlation tests where appropriate. RESULTS: The analysis of motor performance between subgroups showed a clear influence of age on motor performance of all the tests, with the exception of the left visual reaction time. The results of all the motor tests performed were inversely correlated with age. Gender influenced the performance (the speed of motor performance was significantly better in males) of all the tasks with the exception of left pronation-supination, and left and right visual reaction time. CONCLUSION: Our results confirm in a large series of healthy subjects that basic motor performance deteriorates with age and is influenced by gender.

Most of the Quality of Life in Essential Tremor Questionnaire (QUEST) psychometric properties resulted in satisfactory values.

OBJECTIVE: This study sought to assess the psychometric attributes of the Quality of Life in Essential Tremor Questionnaire (QUEST) by undertaking an independent validation. STUDY DESIGN AND SETTING: This was an observational, multicenter, cross-sectional study carried out in Neurology Departments of general hospitals. The following assessments were applied: Louis Rating Scale, Clinical Assessment of Tremor, Clinical Global Impression of Severity (CGI-ET), Hospital Anxiety and Depression Scale (HADS), EQ-5D, and QUEST (Spanish version). RESULTS: One hundred and eighteen consecutive patients were included. According to the CGI-ET, most of patients had mild (42.4%) or moderate (43.2%) impact of tremor on performing daily activities. Fully computable QUEST data were 60.2%. The QUEST Summary Index (QUEST-SI) displayed marginal floor or ceiling effect. On the whole, QUEST internal consistency and reproducibility were satisfactory (Cronbach's alpha values: 0.73-0.86; QUEST-SI intraclass correlation coefficient: 0.77). Factor analysis identified eight factors (73.6% of the variance) that could be grouped into six, relatively coincident with the questionnaire's dimensions. The QUEST-SI correlated moderately with the EQ-5D index (r(S)=-0.40), HADS-Depression (r(S)=0.39), and CGI-ET (r(S)=0.39), and strongly with the QUEST scale for self-evaluation of tremor severity (r(S)=0.63). The standard error of measurement was 8.00. CONCLUSION: Apart from a substantial problem of acceptability, most of the tested psychometric attributes of the QUEST resulted satisfactory.

Dopamine receptor D3 (DRD3) genotype and allelic variants and risk for essential tremor.

To investigate the possible association between dopamine receptor D3 genotype (DRD3) and allelic variants and the risk for developing essential tremor (ET). Leukocytary DNA from 201 patients with ET and 282 healthy controls was studied for the genotype DRD3 and the occurrence of DRD3 allelic variants by using allele-specific PCR amplification and MslI-RFLP's analyses. A meta-analysis of previous studies was performed. The frequencies of the DRD3Ser/Gly genotype and of the allelic variant DRDGly were significantly higher in patients with ET than in controls (P < 0.017 and <0.005, respectively), These findings were especially relevant in women (OR = 1.73, 95% CI: 1.15-2.59, P = 0.008), and in patients with earlier onset of the disease with (P = 0.014). The frequencies of the DRD3Ser/Gly and DRD3Gly/Gly genotypes and of the allelic variant DRD3Gly in patients were significantly higher in patients with voice tremor, but not with head, tongue, or chin tremor, than in controls. The meta-analysis indicated association of variant genotypes with ET risk (OR = 1.18, 95% CI 1.01-1.38). These results suggest that DRD3 genotype and the variant DRD3Gly allelic variant is associated with the risk for and age at onset of ET, and with the risk for voice tremor, in Caucasian Spanish people.

Motor performance in patients with restless legs syndrome.

Dopaminergic dysfunction could play a role in restless legs syndrome, and patients with central dopaminergic dysfunction exhibit difficulties in performing alternating movements or in the movement initiation. Therefore, we analyzed basic motor function performance in patients with idiopathic restless legs syndrome and in healthy matched controls. We studied 50 patients diagnosed with restless legs syndrome and 100 age and sex matched controls. Evaluation included four timed tests (pronation-supination, finger tapping and movement between two points with both hands, and walking test); and three tests performed on a personal computer (speed for pressing repetitively a key frequency, simple reaction time, and movement time with both hands). In a univariate study, restless legs patients showed lower mean values for right pronation-supination, minimum value for right frequency and movement time, and standard deviation, maximum and rank values of movement time with the left arm; and higher mean values for left finger tapping, right and left movement between two points, and standard deviation and rank for right and left frequency. With a multivariate study, restless legs patients showed significantly lower mean values for right pronation-supination, minimum right movement time, and rank of left movement time; and higher mean values for left finger tapping and movement between two points, and rank of right frequency. Motor performance of patients with restless legs syndrome is similar to that of healthy matched controls with the exception of impaired left finger tapping and movement between two points, and better performance of right pronation-supination movements.

The nonsynonymous Thr105Ile polymorphism of the histamine N-methyltransferase is associated to the risk of developing essential tremor.

OBJECTIVE: We analyzed in patients with essential tremor (ET) the Thr105Ile polymorphism of the Histamine N-methyltransferase (HNMT) enzyme that is associated to Parkinson's disease (PD) risk. METHODS: Leukocytary DNA from 204 ET patients and a control group of 295 unrelated healthy individuals was studied for the nonsynonymous HNMT Thr105Ile polymorphism by using amplification-restriction analyses. RESULTS: Patients with ET showed a higher frequency of homozygous HNMT 105Thr genotypes leading to high metabolic activity (p < 0.015) with a statistically significant gene-dose effect, as compared to healthy subjects. These findings were independent of gender, and of tremor localization, but the association of the HNMT polymorphism is more prominent among patients with late-onset ET (p < 0.007). CONCLUSION: These results, combined with previous findings indicating alterations in the frequency for the HNMT Thr105Ile polymorphism in patients with PD, suggest that alterations of histamine homeostasis in the SNC are associated with the risk of movement disorders.

Topiramate as treatment for hemifacial spasm.

OBJECTIVE: To report a patient with hemifacial spasm (HFS) which improved with topiramate. CASE REPORT: A 52-year-old woman diagnosed with migraine, who also had a right HFS, did experience a marked improvement of HFS after introduction of topiramate as prophylactic therapy for her migraine episodes. Topiramate withdrawal led to reappearance of HFS, which improved again after its reintroduction. CONCLUSIONS: Topiramate should be considered as a possible therapy for HFS.

Alcohol dehydrogenase 2 genotype and allelic variants are not associated with the risk for essential tremor.

OBJECTIVE: To investigate the possible association between alcohol dehydrogenase 1B, beta-polypeptide (ADH2) genotype and allelic variants and the risk for developing essential tremor (ET). METHODS: Leukocytary DNA from 204 ET patients and 200 healthy controls was studied for the genotype ADH2 and the occurrence of ADH2 allelic variants using allele-specific polymerase chain reaction amplification and MslI-restriction fragment length polymorphism's analyses. RESULTS: The frequencies of the ADH2*1/ADH2*2 genotype and of the allelic variant ADH2*2 did not differ significantly in ET patients when compared with those of the controls. The mean age at onset of ET did not differ significantly between patients with genotypes ADH2*1/ADH2*2 and ADH2*1/ADH2*1. The frequencies of the genotype ADH2*1/ADH2*2 and of the allelic variant ADH2*2 in patients with voice, tongue, and chin tremors did not differ from those of the controls, whereas patients with voice tremor showed lower frequencies of mutated genotypes and ADH2*2 alleles. The frequencies of ADH2 genotypes and ADH2 alleles did not differ significantly between patients who did not drink ethanol and those who reported improvement, no improvement, or unknown response of tremor to ethanol. CONCLUSIONS: These results suggest that ADH2 genotype and allelic variants are not associated with the risk for ET in white Spanish people.

Refractory hiccup: successful treatment with gabapentin.

OBJECTIVE: To report a patient with intractable hiccup which improved with gabapentin. CASE REPORT: A 69-year-old woman diagnosed with refractory hiccup that started 50 years before improved dramatically after a trial of gabapentin for essential tremor. Gabapentin withdrawal led to reappearance of hiccup, which improved again after its reintroduction. CONCLUSIONS: Gabapentin should be considered as a possible therapy for refractory hiccup.