Adult brain volume in multiple sclerosis: The impact of paediatric onset.

BACKGROUND: 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. PATIENTS AND METHODS: 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. RESULTS: 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. CONCLUSION: 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.

Muscle elastography: a new imaging technique for multiple sclerosis spasticity measurement.

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.

Walking improvements with nabiximols in patients with multiple sclerosis.

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.

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.

Dementia, pyramidal system involvement, and leukoencephalopathy with a presenilin 1 mutation.

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.

Anticipation of age at onset in multiple sclerosis: a Sardinian cohort study.

BACKGROUND: To assess the temporal trend in multiple sclerosis (MS) onset during the last 50 years in Sardinia, Italy. METHODS: 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. RESULTS: 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). CONCLUSION: 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.

Genetic factors and the founder effect explain familial MS in Sardinia.

OBJECTIVE: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.

Neuropsychological studies in families with fragile-X negative X-linked mental retardation.

Neuropsychological studies were performed in 82 subjects of 12 families with x-linked, fragile X negative, mental retardation (MR). Subjects were examined with Wechsler tests (WPPSI, WISC-R or WAIS, according to their capabilities), Progressive Matrices, Bender or Santucci and memory tests. Physical findings in 5 families were characterised by micro-orchidism (MiO), microcephaly (MiC), short stature (SS) and non-specific facial features (XMR +/- MiO +/- MiC +/- SS). The 11 males with MR had a very low IQ, ranging from 13 to 37 (mean 21.2 +/- 8.8); this did not constitute a profile definition. Among the females of their families, 4 had subnormal or borderline IQ, respectively 74, 66, 38 and 37. A second group (2 families) had MiO but with normal stature and occipito-frontal circumference (XMR +/- MiO). The 7 males with MR had an IQ ranging from 24 to 43 (mean 35.1 +/- 5.8) and showed frequently better results in performance than in verbal subtests. In these 2 families, 5 females had subnormal or borderline IQ, respectively 77, 72, 71, 70 and 20. In the 5 families of the third group, XMR +/- MaO (fraX-), several affected males had macro-orchidism (MaO) and facial changes similar to those of fragile X syndrome. IQ variability, also in the same family (e.g.: the 3 brothers of family 3 had, respectively, an IQ of 26, 28 and 68; and 2 brothers of family 1 had an IQ of 13 and 63) and different profiles. Two females were severely affected (IQ 16 and 24), while another 4 had an IQ, respectively, of 63, 69, 71 and 72.

Neuropsychological, psychiatric, and physical manifestations in 149 members from 18 fragile X families.

One hundred forty-nine subjects from 18 families with fragile X [fra(X)] syndrome were evaluated for their neuropsychological, psychiatric, and physical characteristics. The 36 fra(X) males had intelligence quotients ranging from less than 20 to 61, which prevented the delineation of a reliable neuropsychological profile. Behaviour fitted DSM-III-R and ADI diagnostic criteria of autism in only 2 subjects, both with very low intelligence level (IQ less than 20). Of 36 heterozygotes (HZ), 22 had an IQ between 20 and 80 and 14 between 81 and 99. The neuropsychological profile of the latter was compared with IQ-age-environment-matched 14 normal females and 14 normal males. Significantly poorer results in HZ were found on immediate digit memory and on Raven's progressive matrices (a visuo-spatial test of logical capabilities). The latter result, in conjunction with those results on the Bender visual-motor gestalt test and on some WAIS subtests, suggests a frequent deficit in spatial capabilities in such subjects. Such results tended to be confirmed by the profiles of the 22 HZ with IQ 20-80. No psychiatric abnormalities were found in HZ, except in one subject with IQ less than 20 which fitted DSM-III-R and ADI criteria for autism. Typical physical manifestations, especially cranio-facial, were more frequently present in the HZ group with lower IQ. Subnormal IQ was probably the most reliable abnormality for the detection of HZ in 49 females at 50% and 25% risk of heterozygosity.

Sardinian multiple sclerosis is associated with HLA-DR4: a serologic and molecular analysis.

HLA haplotypes in 45 unrelated Sardinian multiple sclerosis patients and in six multiplex families were defined, using both serologic and restriction fragment length polymorphism (RFLP) analysis. In unrelated MS patients, we found an association with HLA-DR4 (p less than 0.01, relative risk = 2.5) and DQw3 (p less than 0.04, relative risk = 2.2). Using a beta-DR cDNA probe, we observed no variation of the DR4 RFLP profile in sporadic or related MS patients compared with DR4-specific pattern in controls. Using a beta-DQ cDNA probe, we identified two DQw3 patterns (DQw3.1 and DQw3.2) with similar frequency in patients and in controls. No specific RFLPs were observed in association with different disease courses. The frequency of haplotype sharing in affected members of multiplex families was not different from that expected by chance. This study shows that Sardinian MS patients carry predominantly the HLA-DR4 allele, in contrast to the DR2 prevalence reported in Caucasian populations. The lack of association with HLA haplotypes in affected members of multiplex families may indicate that genetic factors outside the HLA system play a substantial role in families with MS.