Crimella C, Baschirotto C, Arnoldi A, Tonelli A, Tenderini E, Airoldi G, Martinuzzi A, Trabacca A, Losito L, Scarlato M, Benedetti S, Scarpini E, Spinicci G, Bresolin N, Bassi MT. Mutations in the ...motor and stalk domains of KIF5A in spastic paraplegia type 10 and in axonal Charcot–Marie–Tooth type 2.
Spastic paraplegia type 10 (SPG10) is an autosomal dominant form of hereditary spastic paraplegia (HSP) due to mutations in KIF5A, a gene encoding the neuronal kinesin heavy chain implicated in anterograde axonal transport. KIF5A mutations were found in both pure and complicated forms of the disease; a single KIF5A mutation was also detected in a CMT2 patient belonging to an SPG10 mutant family. To confirm the involvement of the KIF5A gene in both CMT2 and SPG10 phenotypes and to define the frequency of KIF5A mutations in an Italian HSP patient population, we performed a genetic screening of this gene in a series of 139 HSP and 36 CMT2 affected subjects. We identified five missense changes, four in five HSP patients and one in a CMT2 subject. All mutations, including the one segregating in the CMT2 patient, are localized in the kinesin motor domain except for one, falling within the stalk domain and predicted to generate protein structure destabilization. The results obtained indicate a KIF5A mutation frequency of 8.8% in the Italian HSP population and identify a region of the kinesin protein, the stalk domain, as a novel target for mutation. In addition, the mutation found in the CMT2 patient strengthens the hypothesis that CMT2 and SPG10 are the extreme phenotypes resulting from mutations in the same gene.
Multiple sclerosis (MS) spasticity is currently evaluated on the basis of neurological examinations such as Ashworth Scale (AS) and 0–10 NRS. Severity of spasticity is difficult to quantify. We ...investigated the use of real time elastography (RTHE) ultrasounds for evaluating objectively the muscle fibers status in MS spasticity patients and their changes after a new antispasticity treatment. Two studies were performed. In study A, 110 MS patients underwent a neurological evaluation based on the AS and RTHE. The RTHE images were scored with the new 1-5 muscle fibers rigidity imaging scale, here called MEMSs (Muscle Elastography Multiple Sclerosis Score). The correlation between AS and MEMSs was found to be statistically significant. In study B, 55 MS patients treated with THC:CBD oromucosal spray for their resistant spasticity were followed prospectively. MS spasticity was evaluated by the 0–10 NRS scale at baseline and after 4 weeks of treatment. MEMSs’ figures were obtained at both timepoints. Responders to THC:CBD oromucosal spray (pre-defined as an improvement ≥20% in their 0–10 NRS spasticity score vs. baseline) were 65% of sample. These patients had a mean 0-10 NRS reduction of 1.87 and a MEMSs reduction of 1.97 (
P
values <0.0001). The remaining 35% of patients, classified as clinically non-responders, showed still a significant mean reduction in MEMSs (0.8,
P
= 0.002). Our overall results showed that RTHE, operativized throughout MEMSs, could be an objective gold standard to evaluate MS muscle spasticity as well as the effectiveness of antispasticity therapy.
Recently, nabiximols was approved as a treatment in MS spasticity. Data leading to approval and clinical use of nabiximols, although widely recognised, are based on subjective scales. Movement ...analysis procedures would obtain more detailed data about the impact on mobility. The aim of the study was to quantitatively assess the functional modification of gait patterns induced by nabiximols in MS. We evaluated three-dimensional gait analysis (spatial–temporal and kinematic) variation by means of one-way ANOVA. Twenty patients were enrolled—9 male and 11 female—with mean EDSS of 5.3 (SD ± 0.81) and mean reduction of numerical rating scale during nabiximols treatment of 1.88. The spatial–temporal parameters of gait revealed an increased speed (+15 %,
p
< 0.001), cadence (+6 %,
p
< 0.001) and stride length (+10 %,
p
< 0.001) after treatment. Regarding the kinematics data, the Gait Profile Score after treatment was reduced by 10 % (
p
< 0.001): Significant changes involved the pelvic area, hip rotation and knee flexion–extension. We found that nabiximols is able to improve the speed, cadence and stride length. Furthermore, the dynamics of the proximal segment of the legs and the knee movement results after treatment are closer to the physiologic values.
Paediatric onset multiple sclerosis (POMS) is associated with reduced brain and deep grey matter volume in comparison with that in healthy controls and individuals with adult onset multiple sclerosis ...(AOMS). The aim of our study was to evaluate the impact of POMS on adult brain volume with adjustment for other parameters, such as disease duration.
We recruited 20 POMS and 40 AOMS patients and 20 healthy controls matched for age and sex. All study participants were adults at the time of inclusion in the study. All study subjects underwent brain magnetic resonance imaging (MRI) to evaluate whole brain, white matter, grey matter, cortical, and deep grey matter volumes. Clinical features, such as the Expanded Disability Status Scale (EDSS) score and disease duration, were also assessed.
Brain (p = 0.01), grey matter (p = 0.01), and deep grey matter volume (p = 0.03) was significantly lower in POMS patients than in AOMS patients, while no differences were detected in the volume of white matter or cortical grey matter. A multiple linear regression analysis showed a relationship between brain volume (dependent variable) and the independent variables age (p < 0.000) and paediatric onset (p < 0.001), while other independent variables, including disease duration, sex, and disability, were not significantly different among groups. There were significant differences in thalamic volume among POMS and AOMS patients and healthy controls.
Our data support the previous findings that POMS patients have reduced brain and deep grey matter volume, particularly thalamic volume, compared with sex- and age-matched AOMS patients and healthy controls. These findings appear to be independent of disease duration and other clinical features.
•Several differences characterize paediatric (POMS) compared to adult onset MS (AOMS).•Radiological characteristics are among the aspects that differentiating POMS from AOMS.•We found significant reduction in brain volumes in POMS compared to AOMS and healthy controls.•This feature appears to be independent from disease duration and other features.
To assess the temporal trend in multiple sclerosis (MS) onset during the last 50 years in Sardinia, Italy.
The authors used a cohort study to assess age at onset in 1,513 MS patients at the MS clinic ...in Cagliari, all born and living in Sardinia. They also assessed age at onset in 41 pairs of familial patients from two generations and 78 pairs of affected sibs. Each familial couple was paired with three couples of sporadic patients born in the same year as the familial ones. The time interval between the first symptoms and diagnosis was analyzed in first and second-diagnosed patients from both familial and control couples.
Mean age at onset progressively decreased from the most remote to the most recent decade of birth (log-rank test 778.27, p < 0.0001), being 41 years in the former decade and 22 years in the latter. A genetic influence was ruled out, because the younger member of familial patients coming from two generations had onset 14.0 years earlier than the older one (p < 0.0001), as in the paired control couples (11.6 years, p < 0.0001). Moreover, mean onset in younger sibs was 3.4 years earlier than in older ones (p = 0.01), similar to that of control couples (4.1 years, p < 0.0001).
Age at onset decreases progressively from older to younger generations in Sardinian MS patients. Nongenetic but recent widespread environmental changes might contribute to shortening of the preclinical phase-overt disease interval.
The authors describe four members of a family with a novel P284S presenilin 1 mutation presenting a clinical phenotype characterized by early-onset dementia, paratetraparesis, dysarthria, dysphagia, ...and marked involvement of brain white matter. The distinctive clinical and MRI findings in the family studied extend the phenotypic spectrum of dementia associated with mutation of the PS1 gene.
To estimate the presence of familial aggregation and determine the contribution of genetic factors to familial clustering of MS in patients coming from Sardinia, a Mediterranean island considered a ...genetically homogeneous, isolated area having high disease incidence and prevalence.
Recurrence risk in siblings of 901 Sardinian patients and factors influencing risk (patient and sibling sex, patient age at onset, sibling birth cohort, and presence of affected relatives other than siblings) were examined. The presence of distant familial relationships among patients was evaluated by tracing the extended pedigrees of all patients with MS born in one Sardinian village.
Twenty-three brothers and 36 sisters of the 2,971 siblings were affected with MS. Recurrence risk was greater in siblings of index patients with onset age less than 30 years (p < 0.01, increased risk 2.33 times) and having a relative with MS other than a sibling or parent (p < 0.01, increased risk 2.90 times). Pedigree analysis of patients from the village of L. showed that all 11 patients descended from 3 pairs of ancestors, whereas no cases occurred in the remaining 2,346 inhabitants. In descendants from the 3 couples, MS prevalence was dramatically greater than the regional average and 1.5 times greater than that observed in siblings of affected cases.
Data from this study indicate that MS familial aggregation in Sardinians is influenced by genetic factors and that founder effect and the isolation of Sardinia can be considered causes of the enrichment of "etiologic" MS genes.
Multiple sclerosis (MS) is a highly symptomatic disease, with a wide range of disabilities affecting many bodily functions, even in younger persons with a short disease history. The availability of a ...cannabinoid oromucosal spray (Sativex) for the management of treatment-resistant MS spasticity has provided a new opportunity for many patients.
Our study aimed to assess the cost effectiveness of Sativex in Italian patients with treatment-resistant MS spasticity. The analysis was based on the real-world data of a large registry of Italian patients.
A cost-utility analysis was conducted using data collected prospectively from an electronic registry of all patients who began to use Sativex for MS-resistant spasticity between January 2014 and February 2015 in 30 specialized MS units across Italy and were followed up for ≤ 6 months. Data on drug consumption and spasticity/utility were used to estimate the incremental cost-effectiveness ratio (ICER) of Sativex, as compared with no intervention. No costs or spasticity/utility changes were assumed for no treatment intervention. The ICER was expressed as quality-adjusted life-years (QALYs) gained, using the Italian NHS perspective and a 6-month time horizon.
Sativex effectiveness and consumption was estimated analyzing data of 1350 patients from the registry. These patients reported a mean (SD) utility increment of 0.087 (0.069) after 1 month of treatment, 0.118 (0.073) after 3 months' treatment and 0.127 (0.080) after 6 months' treatment. The 6-month cost of treating the entire population with Sativex was €1,361,266, with a €1008 cost and 0.0284 QALYs gained per patient. The estimated ICER was €35,516 per QALY gained, with little variability around the central estimate of cost-effectiveness, as shown by the cost-effectiveness acceptability curve.
The use of Sativex could improve the quality of life of patients with a reasonable incremental cost resulting as a cost-effective option for patients with MS-resistant spasticity. These results could help clinicians and decision makers to develop improved management strategies for spasticity in patients with MS, optimizing the use of available resources.
Individuals from Sardinia, Italy, are at high risk of developing multiple sclerosis and type 1 diabetes mellitus. We attempted to assess the prevalence in this region of type 1 diabetes mellitus in ...individuals with multiple sclerosis, and to ascertain disease risk factors.
We did a cohort study to assess prevalence of type 1 diabetes in 1090 people with multiple sclerosis, and in their parents (n=2180) and siblings (n=3300), all born and living in Sardinia. All participants were patients at the multiple sclerosis clinic in Cagliari, and were judged representative of the total Sardinian outpatients and inpatients. We asked patients whether their parents or siblings had multiple sclerosis or diabetes, confirming replies by examining clinical records. We identified risk factors for diabetes with univariate and multivariate logistic regression analyses.
Diabetes prevalence in people with multiple sclerosis was, respectively, about three-fold and five-fold that in their healthy siblings (p=0·001) and in the general population (p<0·0001). Presence of other relatives with multiple sclerosis conferred increased risk of type 1 diabetes to healthy siblings of individuals with multiple sclerosis (odds ratio=3·41, p=0·0019). Diabetes risk was six-fold higher in patients with relatives having multiple sclerosis than in healthy siblings of multiple sclerosis patients without other relatives with the disease (p=0·0001).
In Sardinian families with genetic inheritance of multiple sclerosis type 1 diabetes is prevalent, both in multiple sclerosis patients and in healthy siblings. This finding indicates that common genes contribute to susceptibility to both diseases in this population.
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