We demonstrate that not only frameshift and nonsense mutations but also splice mutations result in SPG11. Mutations are distributed throughout the spatacsin gene and emerge as major cause for ARHSP with TCC associated with severe motor and cognitive impairment. The clinical phenotype and the ultrastructural analysis suggest a disturbed axonal transport of long projecting neurons.

Hypomyelinating leukodystrophies are genetic disorders characterized by insufficient myelin deposition during development. They are diagnosed on the basis of both clinical and MRI features followed by genetic confirmation. Here, we report on four unrelated affected individuals with hypomyelination and bi-allelic pathogenic variants in EPRS, the gene encoding cytoplasmic glutamyl-prolyl-aminoacyl-tRNA synthetase. EPRS is a bifunctional aminoacyl-tRNA synthetase that catalyzes the aminoacylation of glutamic acid and proline tRNA species. It is a subunit of a large multisynthetase complex composed of eight aminoacyl-tRNA synthetases and its three interacting proteins. In total, five different EPRS mutations were identified. The p.Pro1115Arg variation did not affect the assembly of the multisynthetase complex (MSC) as monitored by affinity purification-mass spectrometry. However, immunoblot analyses on protein extracts from fibroblasts of the two affected individuals sharing the p.Pro1115Arg variant showed reduced EPRS amounts. EPRS activity was reduced in one affected individual's lymphoblasts and in a purified recombinant protein model. Interestingly, two other cytoplasmic aminoacyl-tRNA synthetases have previously been implicated in hypomyelinating leukodystrophies bearing clinical and radiological similarities to those in the individuals we studied. We therefore hypothesized that leukodystrophies caused by mutations in genes encoding cytoplasmic aminoacyl-tRNA synthetases share a common underlying mechanism, such as reduced protein availability, abnormal assembly of the multisynthetase complex, and/or abnormal aminoacylation, all resulting in reduced translation capacity and insufficient myelin deposition in the developing brain.

A comprehensive review of published literature was conducted to elucidate the genetics, neuropathology, imaging findings, prevalence, clinical course, diagnosis/clinical evaluation, potential biomarkers, and current and proposed treatments for adult-onset leukoencephalopathy with axonal spheroids and pigmented glia (ALSP), a rare, debilitating, and life-threatening neurodegenerative disorder for which disease-modifying therapies are not currently available. Details on potential efficacy endpoints for future interventional clinical trials in patients with ALSP and data related to the burden of the disease on patients and caregivers were also reviewed. The information in this position paper lays a foundation to establish an effective clinical rationale and address the clinical gaps for creation of a robust strategy to develop therapeutic agents for ALSP, as well as design future clinical trials, that have clinically meaningful and convergent endpoints.

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We reviewed 29 patients with intraosseous lipoma treated between 1985 and 2002. Mean patient age was 48 (20-75) years. According to Milgram's classification, ten cases were classified as stage I, 14 as stage II, and three as stage III. All patients were initially treated by curettage. In 11 cases an additional phenolization was performed. The average follow-up was 32 (6-208) months. At the last follow-up, none had any clinical or radiological signs of recurrence. The adequate treatment of a symptomatic intraosseous lipoma is curettage and bone grafting. In the current study, phenolization showed no added benefit. An asymptomatic intraosseous lipoma without impending pathological fracture can be treated conservatively. Résumé

Alexander disease is a rare, progressive, and generally fatal neurological disorder that results from dominant mutations affecting the coding region of GFAP, the gene encoding glial fibrillary acidic protein, the major intermediate filament protein of astrocytes in the CNS. A key step in pathogenesis appears to be the accumulation of GFAP within astrocytes to excessive levels. Studies using mouse models indicate that the severity of the phenotype correlates with the level of expression, and suppression of GFAP expression and/or accumulation is one strategy that is being pursued as a potential treatment. With the goal of identifying biomarkers that indirectly reflect the levels of GFAP in brain parenchyma, we have assayed GFAP levels in two body fluids in humans that are readily accessible as biopsy sites: CSF and blood. We find that GFAP levels are consistently elevated in the CSF of patients with Alexander disease, but only occasionally and modestly elevated in blood. These results provide the foundation for future studies that will explore whether GFAP levels can serve as a convenient means to monitor the progression of disease and the response to treatment.

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Objectives: Multiple sclerosis (MS) is an autoimmune disease affecting young people and is a major cause of disability. In the course of time, disability progresses and symptoms like spasticity may occur. Spasticity is a major cost factor in MS patients. Various agents are approved for the treatment of spasticity, but each of those agents may have several side effects. Intrathecally administered steroids (triamcinolone-acetonide (TCA)) may be efficient in treating spasticity in patients with lesions in the spinal cord and no response to first-line therapeutics. The aim of this study is to show effects of TCA treatment on clinical parameters in patients with MS. Methods: This multicentre open label study included 54 patients with MS. The clinical outcome parameters were spasticity, disability, maximum walking distance, bladder function and quality of life. All patients received physiotherapy in addition to TCA treatment to obtain optimal effects on clinical parameters. Results: Spasticity, maximum walking distance as well as disability improved significantly (Pp0.001) during TCA applications. Bladder function improved in every seventh patient. Conclusion: We observed the effects of intrathecally administered TCA on different clinical parameters including bladder function. TCA administration is a safe method to treat different symptoms in MS patients. Longitudinal trials with repeated TCA cycles are needed to show long-term effects. Besides TCA treatment, physiotherapy contributes to the improvement of clinical parameters.