Martina Petracca

The role of small intestinal bacterial overgrowth in Parkinson's disease

Parkinsons disease is associated with gastrointestinal motility abnormalities favoring the occurrence of local infections. The aim of this study was to investigate whether small intestinal bacterial overgrowth contributes to the pathophysiology of motor fluctuations. Thirty‐three patients and 30 controls underwent glucose, lactulose, and urea breath tests to detect small intestinal bacterial overgrowth and Helicobacter pylori infection. Patients also underwent ultrasonography to evaluate gastric emptying. The clinical status and plasma concentration of levodopa were assessed after an acute drug challenge with a standard dose of levodopa, and motor complications were assessed by Unified Parkinsons Disease Rating Scale–IV and by 1‐week diaries of motor conditions. Patients with small intestinal bacterial overgrowth were treated with rifaximin and were clinically and instrumentally reevaluated 1 and 6 months later. The prevalence of small intestinal bacterial overgrowth was significantly higher in patients than in controls (54.5% vs. 20.0%; P = .01), whereas the prevalence of Helicobacter pylori infection was not (33.3% vs. 26.7%). Compared with patients without any infection, the prevalence of unpredictable fluctuations was significantly higher in patients with both infections (8.3% vs. 87.5%; P = .008). Gastric half‐emptying time was significantly longer in patients than in healthy controls but did not differ in patients based on their infective status. Compared with patients without isolated small intestinal bacterial overgrowth, patients with isolated small intestinal bacterial overgrowth had longer off time daily and more episodes of delayed‐on and no‐on. The eradication of small intestinal bacterial overgrowth resulted in improvement in motor fluctuations without affecting the pharmacokinetics of levodopa. The relapse rate of small intestinal bacterial overgrowth at 6 months was 43%.

Mutation screening of the DYT6/THAP1 gene in Italy

Mutations in the THAP1 gene on chromosome 8p21‐p22 (DYT6 locus) have been recently reported as causative of autosomal dominant primary torsion dystonia (PTD) in four Amish–Mennonite families and in 12 additional probands of different ancestry. We sequenced the THAP1 gene in 158 patients with DYT1‐negative PTD who had onset of symptoms below 30 years and/or positive family history. One sporadic Greek male patient, aged 57 years, was found to carry a novel heterozygous missense variant in THAP1 exon 3 (p.Cys170Arg), of likely pathogenic significance. This subject first presented with right writers cramp at age of 10 years and, subsequently, developed left arm dystonia and an extremely severe left laterocollis, without further spreading to other body districts. Our findings expand the genotypic spectrum of THAP1 and strengthen the association with upper body involvement, including the cranial and cervical districts that are usually spared in DYT1‐PTD.

Novel mutations in SPG11 cause hereditary spastic paraplegia associated with early-onset levodopa responsive parkinsonism

Background: Autosomal recessive hereditary spastic paraplegia with thin corpus callosum is a neurodegenerative disorder characterized by spastic paraparesis, cognitive impairment, and peripheral neuropathy. The neuroradiologic hallmarks are thin corpus callosum and periventricular white matter changes. Mutations in the SPG11 gene have been identified to be a major cause of autosomal recessive hereditary spastic paraplegia with thin corpus callosum and recently also proven to be responsible for juvenile parkinsonism associated with spastic paraplegia.

Clinical differences between botulinum neurotoxin type A and B

In humans, the therapeutic use of botulinum neurotoxin A (BoNT/A) is well recognized and continuously expanding. Four BoNTs are widely available for clinical practice: three are serotype A and one is serotype B: onabotulinumtoxinA (A/Ona), abobotulinumtoxinA (A/Abo) and incobotulinumtoxinA (A/Inco), rimabotulinumtoxinB (B/Rima). A/Abo, A/Inco, A/Ona and B/Rima are all licensed worldwide for cervical dystonia. In addition, the three BoNT/A products are approved for blepharospasm and focal dystonias, spasticity, hemifacial spasm, hyperhidrosis and facial lines, with remarkable regional differences. These toxin brands differ for specific activity, packaging, constituents, excipient, and storage. Comparative literature assessing the relative safety and efficacy of different BoNT products is limited, most data come from reports on small samples, and only a few studies meet criteria of evidence-based medicine. One study compared the effects of BoNT/A and BoNT/B on muscle activity of healthy volunteers, showing similar neurophysiological effects with a dose ratio of 1:100. In cervical dystonia, when comparing the effects of BoNT/A and BoNT/B, results are more variable, some studies reporting roughly similar peak effect and overall duration (at a ratio of 1:66, others reporting substantially shorter duration of BoNT/B than BoNT/A (at a ratio 1/24). Although the results of clinical studies are difficult to compare for methodological differences (dose ratio, study design, outcome measures), it is widely accepted that: BoNT/B is clinically effective using appropriate doses as BoNT/A (1:40-50), injections are generally more painful, in most of the studies on muscular conditions, efficacy is shorter, and immunogenicity higher. Since the earliest clinical trials, it has been reported that autonomic side effects are more frequent after BoNT/B injections, and this observation encouraged the use of BoNT/B for sialorrhea, hyperhidrosis and other non-motor symptoms. In these indications the efficacy of toxins A and B are comparable and dose ratio is 1:25-30.

GIGYF2 variants are not associated with Parkinson's disease in Italy

We read with great interest the letter by Vilariño-Güell et al. on the prevalence of eight distinct variants of the GIGYF2 gene [MIM*612003] in two large series of Parkinson’s disease (PD) patients and controls from North America and Norway. The authors studied seven possibly pathogenic variants (p.N56S, p.T112A, p.I278V, p.S335T, p.N457T, p.D606E, p.V1242I) first described in French and Italian familial PD cases with an overall frequency of 4 and 5.7% respectively, as well as the p.H1171R variant, previously detected in one Italian control (0.8%). Among the cohorts screened by Vilariño-Güell et al., only two variants were found at very low frequency: p.N56S (0.7% American patients) and p.H1171R (0.2–0.4% patients and 0.5–0.9% controls in the two groups). Given the discrepancy between the two studies and the high frequency of GIGYF2 variants reported in Italian patients with PD, we sought to assess whether this finding could be replicated in a different Italian cohort. After obtaining written informed consent, we performed a mutation screening of the whole GIGYF2 gene in 144 Italian PD patients recruited at the Movement Disorders Clinic, Catholic University of Rome. Mean age at time of study was 66.7 6 12.4 years (range, 24–98), mean age at onset 55.3 6 11.2 years (range, 19–77), mean Hoehn and Yahr score 2.3 6 0.7 (range, 1–5). Ninety-two (64%) patients had at least one firstdegree affected relative (either one parent, 42%, or sibling, 22%) whereas the remaining 52 (36%) were sporadic. Furthermore, we searched for the eight above-mentioned variants in 180 unrelated controls from the same population (mean age, 68.6 6 10.1 years; range, 44–91). These were free of neurological symptoms and with negative family history for movement disorders. The 27 coding exons and exon–intron junctions of the GIGYF2 gene were PCR-amplified from genomic DNA and analyzed using denaturing high-performance liquid chromatography (primers and conditions available upon request). All samples with abnormal elution profiles were sequenced in both directions using standard procedures. In our PD cohort, we did not identify possibly pathogenic variants. Moreover, the eight variants tested by VilariñoGüell et al. were not found either in patients or controls. We detected two heterozygous variants previously considered nonpathogenic (p.A572A in 2 patients and p.delLPQQQQQQ1209-1216 in one), and 15 polymorphisms already annotated in dbSNP (rs11555646, rs2289913, rs2289912, rs34424361, rs2305139, rs1078323, rs3816334, rs1947105, rs7563724, rs12328151, rs60774345 rs1947105, rs60774345, rs6437074, and rs10555297, with heterozygous frequencies of 2.7–49.2%). Finally, a novel heterozygous change in intron 5 (c.491112T>C) was detected in 2 patients and one control. Our data are in line with the results reported by VilariñoGüell et al., and support their conclusion against a pathogenic role for the eight originally described GIGYF2 variants. These findings are also substantiated by two recent large screenings, one testing the entire gene in Portuguese and North American subjects, the other focused on analysis of p.N56S and p.N457T variants in German and Austrian patients. Overall, these eight variants have been tested in more than 2,200 patients and 2,300 controls (Table 1). Variants p.N457T and p.H1171R occurred with similar frequency in patients and controls, and are unlikely to be pathogenic. Five variants (p.T112A, p.I278V, p.S335T, p.D606E, and p.V1242I) were found only in isolated patients from the original study, and all were predicted as benign using PolyPhen (http://genetics.bwh.harvard.edu/pph/), a software estimating the possible impact of missense variants on a protein’s structure and function. An increased frequency in patients compared with controls (P 5 0.01 at Fisher’s exact test) was found only for p.N56S, a variant predicted as ‘‘possibly damaging’’ by PolyPhen. However, segregation of this variant with the disease was excluded in a familial case, and its pathogenic role in PD remains to be elucidated. Our findings do not substantiate the previously reported 5.7% frequency of GIGYF2 mutations in Italian PD patients. In their screening, Bras et al. reported other rare missense changes, but none of these was significantly enriched in PD cases compared with controls. These results are also in line with published studies that, using either haplotype tagging or genome-wide approaches, failed to detect any significant association between GIGYF2 polymorphisms and PD risk. Overall, currently available data argue against a major role for GIGYF2 in PD. The pathogenicity of the identified rare variants remains uncertain, and needs to be addressed by investigating the impact of such variants on the protein function.

Prevalence of Impulsive-Compulsive Symptoms in Elderly Parkinson’s Disease Patients: A Case-Control Study

BACKGROUND Impulse-control disorders (ICDs) are frequently described in patients with Parkinsons disease (PD), particularly among those treated with dopaminergic medications, but data on the prevalence of ICDs in elderly populations are lacking. OBJECTIVE The aim of this study was to estimate the prevalence of ICDs by using an Italian validation of the Questionnaire for Impulsive-Compulsive Disorders in Parkinsons Disease (QUIP) and to identify associated sociodemographic and clinical factors in a sample of elderly PD patients and in a control group of similarly aged healthy volunteers. METHODS Using the United Kingdom Parkinsons Disease Society Brain Bank diagnostic criteria, we included 115 consecutive PD and 105 healthy controls. They were recruited from June 2014 to December 2015. All participants completed the self-administered QUIP-Anytime for assessment of ICDs occurring any time during the course of PD. RESULTS Mean ± SD age was 75.7 ± 7.0 years in the PD patients and 76.1 ± 7.0 years in the control group. The mean disease duration was 6.8 years (range, 1-26 years). Among the PD patients, 44.7% (n = 51) had at least 1 ICD or related disorder compared to 25.2% (n = 26) in the control group (between-group difference: P = .003). Hypersexuality and compulsive shopping were significantly more common in the PD group than in the control group (P < .05). The prevalence of other compulsive behaviors was 42.5% in the PD group and 38.9% in the control group (P = NS). The Italian version of the QUIP-Anytime showed high test-retest reliability (κ > 0.70 for all items). CONCLUSIONS Our data confirm a high prevalence of ICD symptoms in elderly PD patients, approximately twice that seen in the general population.

Measuring Gait Quality in Parkinson’s Disease through Real-Time Gait Phase Recognition

Monitoring gait quality in daily activities through wearable sensors has the potential to improve medical assessment in Parkinson’s Disease (PD). In this study, four gait partitioning methods, two based on thresholds and two based on a machine learning approach, considering the four-phase model, were compared. The methods were tested on 26 PD patients, both in OFF and ON levodopa conditions, and 11 healthy subjects, during walking tasks. All subjects were equipped with inertial sensors placed on feet. Force resistive sensors were used to assess reference time sequence of gait phases. Goodness Index (G) was evaluated to assess accuracy in gait phases estimation. A novel synthetic index called Gait Phase Quality Index (GPQI) was proposed for gait quality assessment. Results revealed optimum performance (G < 0.25) for three tested methods and good performance (0.25 < G < 0.70) for one threshold method. The GPQI resulted significantly higher in PD patients than in healthy subjects, showing a moderate correlation with clinical scales score. Furthermore, in patients with severe gait impairment, GPQI was found higher in OFF than in ON state. Our results unveil the possibility of monitoring gait quality in PD through real-time gait partitioning based on wearable sensors.

Correction to: The Italian Dystonia Registry: rationale, design and preliminary findings

In the original article, Gina Ferrazzano was affiliated to Department of Neurology and Psychiatry, Neuromed Institute IRCCS, Sapienza University of Rome, Pozzilli, Italy.The corrected affiliation should be: Neuromed Institute IRCCS, Pozzilli, IS, Italy.

Spread of dystonia in patients with idiopathic adult-onset laryngeal dystonia.

Adult‐onset laryngeal dystonia (LD) can be isolated or can be associated with dystonia in other body parts. Combined forms can be segmental at the onset or can result from dystonia spread to or from the larynx. The aim of this study was to identify the main clinical and demographic features of adult‐onset idiopathic LD in an Italian population with special focus on dystonia spread.

2173 – Psychiatric symptoms in patients affected by huntington disease

Introduction The aim of the study is to assess the epidemiology of psychiatric symptoms in patients with Huntington Disease (HD). Subjects and methods All patients affected by HD attending our Movement Disorder Clinic in a 3-year period were evaluated by the Unified Huntington’ Disease Rating Scale and by the BPRS. Results Among 70 patients, 61 (87.1%) presented depressive symptoms in the course of illness, 56 (80.0%) anxiety, 36 (51.4%) manic symptoms, 47 (67.1%) irritability, 15 (21.4%) delusions, 9 (12.4%) hallucinations, 23 (32.9%) obsessivecompulsive symptoms, 57 (83.7%) apathy, 28 (40%) aggressiveness/violence, 26 (37.1%) suicidality, and 29 (41.4%) dementia. Discussion The results show that the nature of psychiatric manifestations cannot be generalized across all patients with HD for several reasons: 1) in the course of HD, symptoms change spontaneously reflecting the degenerative pathogenesis of the disease; 2) the phenomenology of symptoms depends on age of onset, patients gender, number of CAG triplets, gender of the affected parent; 3) drugs used to improve motor symptoms have psychiatric side effects which superimpose and merge with the mental abnormalities of the disease; 4) Huntington’ gene is just one of the 30,000 expressed in the brain. Therefore, the symptoms induced by the disease depend not only on the specific abnormal gene causing the disease but also on patients general genetic background of both paternal and maternal origin, and on personal non genetic factors. Rather than standardized approaches, the continuous re-evaluation of psychopathological dimensions in the individual patient with HD is essential for the proper management.