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The etiology of sporadic Parkinson's disease is (PD) still not understood but it is believed that a complex interplay between environmental and genetic factors could trigger the pathology. Pro-inflammatory TNF-α is released by activated microglia and is up-regulated in the brain and cerebrospinal fluid of PD patients; TNF-α modulates neuroinflammation and can activate the molecular mechanisms that lead to neurotoxicity and neuronal death. We analyzed two functional SNPs within the TNF-α gene promoter (rs361525 and rs1800629) in 354 Italian PD patients and 443 healthy controls (HC). In our cohort of patients, no significant associations could be observed between rs361525 and rs1800629 SNPs and either PD onset risk or PD-associated clinical parameters including age at onset of fluctuations, UPDRS-ME (Unified Parkinson Disease Rating Scale-Motor Examination), Schwab & England, Hohen & Yahr stage scale, and MMSE (Mini-Mental State Examination) score. Conflicting results on the role played by TNF-α rs1800629 SNP on PD onset risk are present in the literature. We could not find any association between TNF-α rs361525 and rs1800629 and PD.

Background Patients with degenerative neurological diseases such as cerebellar ataxia, spastic paraplegia, and Parkinson’s disease often display progressive gait function decline that inexorably impacts their autonomy and quality of life. Therefore, considering the related social and economic costs, one of the most important areas of intervention in neurorehabilitation should be the treatment of gait abnormalities. This study aims to determine whether an entire dataset of gait parameters recorded in patients with degenerative neurological diseases can be clustered into homogeneous groups distinct from each other and from healthy subjects. Patients affected by three different types of primary degenerative neurological diseases were studied. These diseases were: i) cerebellar ataxia (28 patients), ii) hereditary spastic paraplegia (31 patients), and iii) Parkinson’s disease (70 patients). Sixty-five gender-age-matched healthy subjects were enrolled as a control group. An optoelectronic motion analysis system was used to measure time-distance parameters and lower limb joint kinematics during gait in both patients and healthy controls. When clustering single parameters, step width and ankle joint range of motion (RoM) in the sagittal plane differentiated cerebellar ataxia group from the other groups. When clustering sets of two, three, or four parameters, several pairs, triples, and quadruples of clusters differentiated the cerebellar ataxia group from the other groups. Interestingly, the ankle joint RoM parameter was present in 100% of the clusters and the step width in approximately 50% of clusters. In addition, in almost all clusters, patients with cerebellar ataxia showed the lowest ankle joint RoM and the largest step width values compared to healthy controls, patients with hereditary spastic paraplegia, and Parkinson’s disease subjects. This study identified several clusters reflecting specific gait patterns in patients with degenerative neurological diseases. In particular, the specific gait pattern formed by the increased step width, reduced ankle joint RoM, and increased gait variability, can differentiate patients with cerebellar ataxia from healthy subjects and patients with spastic paraplegia or Parkinson’s disease. These abnormal parameters may be adopted as sensitive tools for evaluating the effect of pharmacological and rehabilitative treatments.

The etiology of Parkinson's disease (PD) is presumably multifactorial and likely involves interactions between genetic and environmental factors, as well as mitochondrial dysfunction, oxidative stress and inflammation. Among environmental factors, Vitamin D was reported to associate with the risk of PD. Vitamin D activity is mediated by its binding to the vitamin D Receptor (VDR), a transcriptional factor for almost 3% of human genes. We genotyped for ApaI, BsmI, TaqI, FokI and rs1989969 VDR single nucleotide polymorphisms (SNPs) a cohort of 406 PD and 800 healthy controls (HC) and found a strong association between the FokI (rs2228570) VDR SNP and PD. Thus, the TT genotype and the T allele resulted associated with PD in the overall analyzed PD population. Gender-based stratification of data indicated that results were maintained for FokI TT genotype and T allele in male PD patients, whereas the FokI T allele alone was confirmed as a risk factor for PD in females. Co-segregation analyses indicated the TaqI ApaI FokI rs1989969 GCTG as a "risk" haplotype for PD. In a subgroup of patients and controls neural Vitamin D and VDR concentration was analyzed in extravesicles (NDEVs) isolated from peripheral blood: no differences emerged between PD and HC. NDEVs results will need to be validated in ampler cohort but we can speculate that, if at neuronal level the amounts of Vitamin D and of VDR are comparable, than the bioavailability of vitamin D and the efficacy of the vitamin D/VDR axis is differentially modulated in PD by VDR SNPs.

Objective Although deficit of coordination between the upper and lower body segments might play an important role in impairing gait and stability in ataxic patients, this deficit has not been investigated in subjects with ataxia so far. To evaluate the coordination between trunk and thigh in a sample of patients with ataxia compared with healthy controls and to correlate the coordination measures with the clinical severity. Design Prospective observational study. Subjects Sixteen patients with degenerative cerebellar ataxia and sixteen age- and sex-matched controls were studied. Methods We assessed the coordination on the sagittal plane between trunk and thigh, considered as rigid segments, by the continuous relative phase (CRP) method. We used the coefficient of multiple correlation (CMC) to measure the within-subject (CMCWS) variability, and the SARA scale to assess clinical severity. Results CRP curves are dissimilar between ataxic patients and controls, the former showing a chaotic behavior compared to the well-shaped CRP curves observed in the latter. Trunk-thigh coordination has a higher within-subject variability in ataxic patients (median CMCWS: 0.53 for patients, 0.89 for controls, p Conclusions Ataxia shows a deficit of spatio-temporal coordination between trunk and thigh. Such a deficit is correlated with the degree of the clinical impairment indicating an important role of inter-segmental coordination in determining the severity of ataxia.

Introduction: Epoetin alfa (Eprex®) is a subcutaneous, injectable formulation of short half-life recombinant human erythropoietin (rHuEPO). To current knowledge there are no published studies regarding the stability of rHuEPO once repackaging occurs (r-EPO) for clinical trial purposes. Materials and methods: We assessed EPO concentration in Eprex® and r-EPO syringes at 0, 60, 90, and 120days after repackaging in polypropylene syringes. R-EPO was administered to 56 patients taking part in a clinical trial in Friedreich Ataxia. Serum EPO levels were measured at baseline and 48h after r-EPO administration. Results: No differences were found between r-EPO and Eprex® syringes, but both globally decreased in total EPO content during storage at 4°C. Patients receiving r-EPO had similar levels in EPO content as expected from previous trials in Friedreich Ataxia and from pharmacokinetics studies in healthy volunteers. Discussion: We demonstrate that repackaging of EPO does not alter its concentration if compared to the original product (Eprex®). This is true both for repackaging procedures and for the stability in polypropylene tubes. The expiration date of r-EPO can be extended from 1 to 4 months after repackaging, in accordance with pharmacopeia rules.

A subgroup of neutral lipid storage disease has been recently associated with myopathy (NLSDM) and attributed to mutations in the gene (PNPLA2) encoding an adipose triglyceride lipase involved in the degradation of intracellular triglycerides. Five NLSDM patients have been described thus far and we reported three additional patients. A 44-year old Iranian woman and two Italian brothers, aged 40 and 35, presented with exercise intolerance and proximal limb weakness, elevated CK levels, and Jordan’s anomaly. Muscle biopsies showed marked neutral lipid accumulation in all patients. The 10 exons and the intron–exon junctions of the PNPLA2 gene were sequenced. Two novel homozygous mutations in exon 5 of PNPLA2 gene were found (c.695delT and c.542delAC). Both mutations resulted in frameshifts leading to premature stop codons (p.L255X and p.I212X, respectively). These mutations predict a truncated PNPLA2 protein lacking the C-terminal hydrophobic domain. These findings indicate that NLSDM is rare, but genetically heterogeneous.

A novel 4949-base pair mitochondrial DNA (mtDNA) deletion was detected in various tissues in a postmortem study of a patient with Kearns-Sayre syndrome (KSS). Deleted mtDNA levels were higher in skeletal muscle and brain and lower in kidney, working myocardium, and endocrine tissues (thyroid, parathyroids, pancreas, and adrenal glands). The distribution of the deletion in skeletal muscle and conducting myocardium was analyzed by means of laser capture microdissection (LCM). In skeletal muscle, the abundance of deleted mtDNA was slightly higher in cytochrome c oxidase (COX)-negative fibers (70%) than in COX-positive fibers (64%), whereas in the conducting myocardium it was lower in the atrioventricular node (9%) than in the sinus node and bundle of His (30% and 32%, respectively). In this study, LCM proved to be a reliable technique for a more accurate assessment of genotype/phenotype correlation when investigating mtDNA-related disorders.

ObjectivesThe purpose of this study was to understand the clinical and molecular features of familial hypertrophic cardiomyopathy (HCM) in which a mitochondrial abnormality was strongly suspected.BackgroundDefects of the mitochondrial genome are responsible for a heterogeneous group of clinical disorders, including cardiomyopathy. The majority of pathogenic mutations are heteroplasmic, with mutated and wild-type mitochondrial deoxyribonucleic acid (mtDNA) coexisting within the same cell. Homoplasmic mutations (present in every copy of the genome within the cell) present a difficult challenge in terms of diagnosis and assigning pathogenicity, as human mtDNA is highly polymorphic.MethodsA detailed clinical, histochemical, biochemical, and molecular genetic analysis was performed on two families with HCM to investigate the underlying mitochondrial defect.ResultsCardiac tissue from an affected child in the presenting family exhibited severe deficiencies of mitochondrial respiratory chain enzymes, whereas histochemical and biochemical studies of the skeletal muscle were normal. Mitochondrial DNA sequencing revealed an A4300G transition in the mitochondrial transfer ribonucleic acid (tRNA)Ilegene, which was shown to be homoplasmic by polymerase chain reaction/restriction fragment length polymorphism analysis in all samples from affected individuals and other maternal relatives. In a second family, previously reported as heteroplasmic for this base substitution, the mutation has subsequently been shown to be homoplasmic. The pathogenic role for this mutation was confirmed by high-resolution Northern blot analysis of heart tissue from both families, revealing very low steady-state levels of the mature mitochondrial tRNAIle.ConclusionsThis report documents, for the first time, that a homoplasmic mitochondrial tRNA mutation may cause maternally inherited HCM. It highlights the significant contribution that homoplasmic mitochondrial tRNA substitutions may play in the development of cardiac disease. A restriction of the biochemical defect to the affected tissue has important implications for the screening of patients with cardiomyopathy for mitochondrial disease.

Familial hemiplegic migraine type 1, spinocerebellar ataxia type 6 (SCA6) and episodic ataxia type 2 (EA2) are allelic disorders associated with mutations in the CACNA1A gene, which encodes the alpha1 subunit of the P/Q-type calcium channel (Ca(V)2.1). SCA6 and EA2 share a number of clinical features, such as prominent cerebellar involvement and good response to acetazolamide therapy. However, while SCA6 develops as a late-onset, progressive ataxia, EA2 has an earlier, and episodic, onset. We report on two sisters with a heterogeneous clinical phenotype. The first developed progressive cerebellar ataxia after age 30, without noticeable episodes of vertigo or headache. A 1 year trial with acetazolamide did not produce significant results. The other reported episodes of vertigo, headache and gait imbalance since late childhood, with good response to acetazolamide, before developing moderate chronic cerebellar ataxia. Brain MRI showed cerebellar atrophy, especially in the vermis, in both patients. Direct sequencing of CACNA1A identified a heterozygous 1360G>A mutation in exon 11 resulting in the substitution of alanine for threonine at residue 454 (p.Ala454Thr). This is the first description of a change residing in the cytoplasmic I-II loop associated with a clinical phenotype.

To investigate whether prefrontal cortex (PFC) activation is linked to compensatory mechanisms (time–distance parameters) or to gait features (kinematic parameters) specifically related to the functional role of the cerebellum in ataxic patients. We performed a correlation analysis between the PFC metabolic profile during gait and time–distance and kinematic parameters in a sample of 19 patients affected by neurodegenerative gait ataxia and 15 age/sex matched healthy subjects. PFC metabolism was evaluated by a 2-channel functional near-infrared imaging system while gait analysis was performed using a stereophotogrammetric system. We found a positive correlation between the PFC metabolism and the step width (the correlation coefficient was r : 0.54, p =0.02 for the right PFC, and r : 0.50, p =0.03 for the left PFC). No correlation was found between PFC activity, the other time–distance parameters and the intra-subject variability of gait. PFC activation during ataxic gait correlates with step width and therefore it seems involved in maintaining compensatory strategies rather than due to primary cerebellar deficits. To our knowledge this is the first study correlating cortical activity and gait characteristics in order to assess how cerebral cortex is modulated during a pathological gait.