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BACKGROUND Fampridine leads to significant walking improvements in many persons with multiple sclerosis (PwMS). However, a relevant proportion of PwMS does not respond to fampridine and predictors of initial drug responsiveness are unknown. METHODS Drug response to prolonged-release (PR)-fampridine was assessed in 55 PwMS using the timed 25-foot walk (T25FW), the 6-minute walk test (6MWT) and the 12-item multiple sclerosis walking scale (MSWS-12) as outcome parameters. Patients were treated with PR-fampridine and placebo each for 6 weeks in a randomised, double-blind, placebo-controlled trial with cross-over design (NCT01576354). Possible predictors of drug responsiveness were investigated by multiple correlation analysis and binary logistic regression models. An additional longitudinal analysis followed drug responses of 32 patients treated with PR-fampridine over 3 years to identify potential predictors of long-term drug responsiveness. RESULTS Severity of walking disability was positively correlated with enhanced responses to PR-fampridine. The strongest single predictor of drug responsiveness was poor 6MWT performance at baseline, which was positively correlated with enhanced drug response in the 6MWT (R=-0.541; P

Progressive multifocal leukoencephalopathy is the most common clinical presentation of JC virus (JCV)-associated central nervous system (CNS) disease and has emerged as a major safety concern in multiple sclerosis patients treated with the monoclonal antibody natalizumab. Here we report clinical, radiological, and histological findings of a case of cerebellar granule cell neuronopathy (GCN), a JCV-associated CNS disease, so far unreported amongst patients treated with natalizumab. GCN should be considered as a JCV CNS manifestation in patients with newly developed, progressive cerebellar signs under natalizumab treatment, especially in cases where cerebellar atrophy can be visualized by magnetic resonance imaging.

A role of ATP13A2 in early-onset Parkinsonism (EOP) has been proposed. Conversely, the contribution of this ATPase to late-onset Parkinson's disease (PD) remains unexplored. We therefore conducted a case-control association study in this age-of-onset group with PD. The initial sample was of German origin and consisted of 220 patients with late-onset PD (mean age of onset 60.1 years) and 232 age-matched unrelated controls. Five single nucleotide polymorphisms (SNPs) covering ATP13A2 and its common haplotypes were genotyped. The overall association results in this sample were negative. Interestingly, gender stratification gave a positive result for SNP rs11203280 (P(UNC) = 0.016) in men. This result could not be reproduced in a replication sample of German and Serbian origin composed of 161 patients with late-onset PD (mean age of onset 51.7 years) and 150 age- and ethnic-matched controls. In conclusion, we found no consistent evidence for an association between ATP13A2 and late-onset PD.

Deficiency of argininosuccinate lyase (ASLD; McKusick 207900) is a rare autosomal recessively inherited metabolic disease affecting the urea cycle (Brusilow and Horwich, 1995). A full-length ASL-cDNA clone containing an open reading frame of 1392bp was isolated from a human liver cDNA library (O'Brien et al 1986). The approximately 35 kb gene for ASL (EC 4.3.2.1.) contains 16 exons (Abramson et al 1991) and was located on chromosome 7cen → q11.2 (Todd et al 1989). Piatigorsky and colleagues (1988) demonstrated gene sharing of ASL and avian δ 2 -crystallin, which has significant ASL enzyme activity in duck and chicken. To our knowledge, 11 mutations R95C (Walker et al 1990), R111W, Q286R, R193Q, Q454X, c.ex2del and a 13 base-pair deletion within exon 13 (Barbosa et al 1991), D87G, Q286R, A398D, and c.ex13del (Walker et al 1997) have so far been identified within the ASL gene in ASLD patients. Recent studies have demonstrated considerable splice alterations of ASL (deletions of exons 2 or 7) appearing in all tissues investigated. The biological impact of this feature is unexplored. We describe a further ASLD patient with neonatal onset and severe course of disease and show the genetic basis of this individual case. We furthermore propose that genetic diagnostics of ASLD must take into account that RT-PCR-detected exon skipping in ASL is of much greater variability than reported earlier.

Hereditary homocystinuria due to cystathionine β-synthase (CBS) deficiency is a rare disease (about 1:20 000 in Germany) often complicated by thromboembolism. Single mutations, which affect the C-terminal region of the CBS enzyme, lead to isolated thrombosis without further symptoms typical for homocystinuria such as atherosclerosis, psychomotor retardation, and dislocation of the ocular lenses. In this study, DNA samples of patients with stroke (n=225) and sinus thrombosis (n=46) were screened for the most common homocystinuria mutation, CBS I278T. In each group one homozygous patient was identified. Thus, not only C-terminal mutations but also the most common mutation in classical homocystinuria, CBS I278T, can lead to isolated thrombophilic events. These data support the hypothesis that homocystinuria is an underdiagnosed disease.

Disturbed homocysteine metabolism is a risk factor for Alzheimer's disease (AD) and may contribute to the disease pathophysiology by increasing both amyloid-beta (Abeta) production and phosphorylated tau (P-tau) accumulation. Here, we evaluated the relationship between the cerebrospinal fluid (CSF) concentrations of homocysteine (Hcys), S-adenosylmethionine (SAM), S-adenosylhomocysteine (SAH), and 5-methyltetrahydrofolate (5-MTHF), and the markers for AD pathology, amyloid-beta (Abeta) _{1-42} and P-tau181, in 98 cognitively healthy subjects aged 16-81 years and 54 AD patients. In multivariate regression tests including age, gender, creatinine, and presence of the apolipoprotein E epsilon4 allele, P-tau181 was associated with SAH (beta = 0.490; p _{1-42} were not associated with the CSF concentrations of Hcys, SAM, SAH, or 5-MTHF neither in the AD nor in the control group. The results suggest that alteration of the homocysteine metabolism is related to increased accumulation of phosphorylated tau and may contribute to the neurofibrillary pathology in normal aging and in AD.