Neural stem cell transplantation can ameliorate the phenotype of a mouse model of spinal muscular atrophy

Spinal muscular atrophy (SMA), a motor neuron disease (MND) and one of the most common genetic causes of infant mortality, currently has no cure. Patients with SMA exhibit muscle weakness and hypotonia. Stem cell transplantation is a potential therapeutic strategy for SMA and other MNDs. In this study, we isolated spinal cord neural stem cells (NSCs) from mice expressing green fluorescent protein only in motor neurons and assessed their therapeutic effects on the phenotype of SMA mice. Intrathecally grafted NSCs migrated into the parenchyma and generated a small proportion of motor neurons. Treated SMA mice exhibited improved neuromuscular function, increased life span, and improved motor unit pathology. Global gene expression analysis of laser-capture-microdissected motor neurons from treated mice showed that the major effect of NSC transplantation was modification of the SMA phenotype toward the wild-type pattern, including changes in RNA metabolism proteins, cell cycle proteins, and actin-binding proteins. NSC transplantation positively affected the SMA disease phenotype, indicating that transplantation of NSCs may be a possible treatment for SMA.     

Inclusion body myopathy and frontotemporal dementia caused by a novel VCP mutation

Hereditary inclusion body myopathy (IBM) with Paget's disease of the bone (PDB) and frontotemporal dementia (FTD) is a rare autosomal dominant disease caused by mutations in the valosin-containing protein (VCP) gene. We report a novel heterozygous VCP gene mutation (R159C) in a 69-year-old Italian patient presenting with slowly progressive muscle weakness of the distal upper and proximal lower limbs since the age of 50 years, 18 years later FTD supervened. No dementia or myopathies were revealed in the family history covering two generations. Degenerative changes and rimmed vacuoles together with VCP- and ubiquitin-positive cytoplasmic and nuclear aggregates were observed at the muscle biopsy. Several elements support the pathogenic role of the R159C VCP gene mutation: the occurrence at the same codon of a different, previously identified pathogenic mutation within a VCP gene mutational hot-spot, the histopathological and biochemical evidence of muscle VCP accumulation and the combined clinical presentation of IBM and FTD. These findings suggest VCP gene investigation even in apparently sporadic cases.     

Neurological features of Fabry disease: clinical, pathophysiological aspects and therapy

Fabry disease is a multisystem, X-linked, lysosomal storage disorder caused by a mutation in the GLA gene on chromosome Xq22 resulting in alpha-galactosidase A enzyme (α-Gal A) deficiency. Neurological manifestations other than cerebrovascular accidents include small fibre neuropathy and dysautonomic disorders, which may be the presenting clinical features in a proportion of patients. An atypical disease onset may be misdiagnosed until the emergence of a more typical clinical picture, characterized by chronic renal and cardiac failure. Thus, neurologists should consider Fabry disease in differential diagnosis and provide an appropriate diagnostic work up. This review focuses on central and peripheral nervous system involving available diagnostic tools and diagnostic work up in Fabry disease. It also covers the most recent evidence regarding enzyme replacement therapy.     

A novel nonsense mutation in the APTX gene associated with delayed DNA single-strand break removal fails to enhance sensitivity to different genotoxic agents

APTX is the gene involved in ataxia with oculomotor apraxia type 1 (AOA1), a recessive disorder with early-onset cerebellar ataxia, oculomotor apraxia and peripheral neuropathy. The encoded protein, aprataxin, is a DNA repair protein processing the products of abortive ligations, 5'-adenylated DNA. We describe a novel nonsense mutation in APTX, c.892C>T (p.Gln298X), segregating in two AOA1 patients and leading to the loss of aprataxin protein in patient's cells. These cells, while exhibiting reduced catalase activity, are not hypersensitive to toxicity elicited by H(2)O(2) exposure at either physiologic or ice-bath temperature. On the other hand, the rate of repair of DNA single-strand-breaks (SSBs) induced in both conditions is always significantly slower in AOA1 cells. By using the alkylating agent methyl methane sulphonate (MMS) we confirmed the association of the APTX mutation with a DNA repair defect in the absence of detectable changes in susceptibility to toxicity. These results, while consistent with a role of aprataxin in the repair of SSBs induced by H(2)O(2), or MMS, demonstrate that other mechanisms may be recruited in AOA1 cells to complete the repair process, although at a slower rate. Lack of hypersensitivity to the oxidant, or MMS, also implies that delayed repair is not per se a lethal event.     

Nitric oxide donor and non steroidal anti inflammatory drugs as a therapy for muscular dystrophies: evidence from a safety study with pilot efficacy measures in adult dystrophic patients

This open-label, single centre pilot study was designed to evaluate safety and tolerability of the combination of the drugs isosorbide dinitrate, a nitric oxide donor, and ibuprofen, a non steroid anti-inflammatory drug, in a cohort of adult dystrophic patients (Duchenne, Becker and Limb-Girdle Muscular Dystrophy). Seventy-one patients were recruited: 35, treated with the drug combination for 12 months, and 36 untreated. Safety and adverse events were assessed by reported signs and symptoms, physical examinations, blood tests, cardiac and respiratory function tests. Exploratory outcomes measure, such as the motor function measure scale, were also applied. Good safety and tolerability profiles of the long-term co-administration of the drugs were demonstrated. Few and transient side effects (i.e. headache and low blood pressure) were reported. Additionally, exploratory outcomes measures were feasible in all the disease population studied and evidenced a trend towards amelioration that reached statistical significance in one dimension of the MFM scale. Systemic administration of ibuprofen and isosorbide dinitrate provides an adequate safety margin for clinical studies aimed at assessing efficacy.     

Gender-specific influence of the chromosome 16 chemokine gene cluster on the susceptibility to Multiple Sclerosis

Macrophage-derived chemokine (MDC/CCL22) plays a role in Experimental Autoimmune Encephalomyelitis (EAE), the animal model of Multiple Sclerosis (MS). MDC/CCL22 gene is part of a chemokine cluster, which includes also thymus and Activation-Regulated Chemokine (TARC/CCL17). The frequency of the C/T and C/A Single Nucleotide Polymorphisms (SNPs) in the promoter and coding sequence of CCL22 as well as the C/T SNP in the promoter of CCL17 were determined in 370 patients with Multiple Sclerosis (MS) compared with 380 controls. A trend towards a decreased allelic frequency of the A allele of the CCL22 C/A SNP as well as of the T allele of the CCL17 C/T SNP was found in patients compared with controls. The frequency of the AT haplotype was significantly decreased in MS patients (P=0.017, OR: 0.49, CI: 0.28-0.87). Stratifying patients according to gender, the observed association was even more pronounced in male patients compared with male controls (P=0.004, OR=0.18, 95% CI: 0.06-0.50), whereas no significant differences were observed in females. Therefore, the presence of the AT haplotype in chromosome 16 chemokine cluster is likely to confer a decreased risk of developing MS, particularly in males.