Concurrent AFG3L2 and SPG7 mutations associated with syndromic parkinsonism and optic atrophy with aberrant OPA1 processing and mitochondrial network fragmentation

Mitochondrial dynamics and quality control are crucial for neuronal survival and their perturbation is a major cause of neurodegeneration. m-AAA complex is an ATP-dependent metalloprotease located in the inner mitochondrial membrane and involved in protein quality control. Mutations in the m-AAA subunits AFG3L2 and paraplegin are associated with autosomal dominant spinocerebellar ataxia (SCA28) and autosomal recessive hereditary spastic paraplegia (SPG7), respectively. We report a novel m-AAA-associated phenotype characterized by early-onset optic atrophy with spastic ataxia and L-Dopa-responsive parkinsonism. The proband carried a de-novo AFG3L2 heterozygous mutation (p.R468C) along with a heterozygous maternally-inherited intragenic deletion of SPG7. Functional analysis in yeast demonstrated the pathogenic role of AFG3L2 p.R468C mutation shedding light on its pathogenic mechanism. Analysis of patient's fibroblasts showed an abnormal processing pattern of OPA1, a dynamin-related protein essential for mitochondrial fusion and responsible for most cases of hereditary optic atrophy. Consistently, assessment of mitochondrial morphology revealed a severe fragmentation of the mitochondrial network, not observed in SCA28 and SPG7 patients\u2019 cells. This case suggests that coincidental mutations in both components of the mitochondrial m-AAA protease may result in a complex phenotype and reveals a crucial role for OPA1 processing in the pathogenesis of neurodegenerative disease caused by m-AAA defects

In vivo evidence for GABA(A) receptor changes in the sensorimotor system in primary dystonia.

Preclinical and clinical evidence suggests that impaired gamma-aminobutyric (GABA) control, leading to disinhibition within the sensorimotor system, might play a role in dystonia. Aim of this study is the in vivo assessment of the GABAergic system in dystonia using positron emission tomography (PET) and (11) C-flumazenil, a selective GABA(A) receptor ligand.Fourteen subjects with primary dystonia (9 carriers of the DYT1 mutation and 5 sporadic cases) were compared to 11 controls, using a simplified reference tissue model to measure binding potential.Voxel-based analyses showed a reduction in GABA(A) receptor expression/affinity both in DYT1 carriers and sporadic patients in primary motor and premotor cortex, primary and secondary somatosensory cortex, and in the motor component of the cingulate gyrus.Dysfunction of GABA(A) receptors in sensorimotor systems in primary (genetic and sporadic) dystonia supports the view that lack of GABAergic control may be associated with the generation of dystonic movements. \ua9 2011 Movement Disorder Society

Enteral (oral or tube administration) nutritional support and eicosapentaenoic acid in patients with cancer: A systematic review

The aim of this systematic review was to determine the efficacy and potential benefits of enteral nutritional support [oral nutritional supplements (ONS) or enteral tube feeding (ETF)], and eicosapentaenoic acid (EPA, free acid, ethyl esters or fish oil; provided as capsules or enriched ONS or ETF) in patients with cancer. Clinical studies were identified using electronic databases, and studies were selected according to predetermined criteria. For each treatment modality (chemo/radiotherapy, surgery, and palliative care), the comparisons of interest were nutritional support vs. routine care (no nutritional support), EPA supplement (capsule or enriched ONS or ETF) vs. routine care (no supplement or standard supplement), ETF vs. parenteral nutrition (PN). The reviewed outcomes were dietary intake, anthropometry, clinical (mortality, length of hospital stay, complications, and quality of life) and haematological/biochemical (white blood cell count, serum transferrin and albumin, CD3-positive lymphocytes, and inflammatory markers). Meta-analyses were performed where possible. In patients undergoing radiotherapy, meta-analysis showed that ONS significantly increase dietary intake (381 kcal/day, 95% CI 193 to 569 in 3 RCTs) compared to routine care. In patients undergoing surgery, meta-analyses showed that ETF results in a significantly shorter length of hospital stay (1.72 fewer days, 95% CI 0.90 to 2.54 in 8 RCTs), lower incidence of any complications (OR 0.62, 95% CI 0.50 to 0.77 in 4 RCTs) and infectious complications (OR 0.67, 95% CI 0.55 to 0.82 in 11 RCTs) and lower sepsis scores (2.21 points, 95% CI 1.49 to 2.92 in 2 RCTs), but no difference in mortality (OR 0.72, 95% CI 0.40 to 1.29 in 7 RCTs) compared to PN. There was also no difference in mortality between ONS or ETF vs. routine care in patients undergoing chemotherapy/radiotherapy (OR 1.00, 95% CI 0.62-1.61 in 4 RCTs) or surgery (OR 2.44, 95% CI 0.75 to 7.95 in 4 RCTs). Individual studies of EPA supplementation as capsules showed improvements in survival, complications and inflammatory markers in patients undergoing bone marrow transplant (BMT). In palliative care patients receiving EPA-enriched ONS or capsules, there were inconsistent positive effects on survival and quality of life. In those undergoing surgery, EPA-enriched ETF had no effect. Further research is required to elucidate the clinical efficacy of enteral nutrition support, including the potential benefits of EPA supplementation, in patients with cancer

Tauroursodeoxycholic acid in the treatment of patients with amyotrophic lateral sclerosis

Background and purpose: Tauroursodeoxycholic acid (TUDCA) is a hydrophilic bile acid that is produced in the liver and used for treatment of chronic cholestatic liver diseases. Experimental studies suggest that TUDCA may have cytoprotective and anti-apoptotic action, with potential neuroprotective activity. A proof of principle approach was adopted to provide preliminary data regarding the efficacy and tolerability of TUDCA in a series of patients with amyotrophic lateral sclerosis (ALS). Methods: As a proof of principle, using a double-blind placebo controlled design, 34 ALS patients under treatment with riluzole who were randomized to placebo or TUDCA (1 g twice daily for 54 weeks) were evaluated after a lead-in period of 3 months. The patients were examined every 6 weeks. The primary outcome was the proportion of responders [those subjects with improvement of at least 15% in the Amyotrophic Lateral Sclerosis Functional Rating Scale Revised (ALSFRS-R) slope during the treatment period compared to the lead-in phase]. Secondary outcomes included between-treatment comparison of ALSFRS-R at study end, comparison of the linear regression slopes for ALSFFRS-R mean scores and the occurrence of adverse events. Results: Tauroursodeoxycholic acid was well tolerated; there were no between-group differences for adverse events. The proportion of responders was higher under TUDCA (87%) than under placebo (P = 0.021; 43%). At study end baseline-adjusted ALSFRS-R was significantly higher (P = 0.007) in TUDCA than in placebo groups. Comparison of the slopes of regression analysis showed slower progression in the TUDCA than in the placebo group (P < 0.01). Conclusions: This pilot study provides preliminary clinical data indicating that TUDCA is safe and may be effective in ALS

Rare causes of early-onset dystonia-parkinsonism with cognitive impairment: a de novo PSEN-1 mutation

none15noneCarecchio M.; Picillo M.; Valletta L.; Elia A.E.; Haack T.B.; Cozzolino A.; Vitale A.; Garavaglia B.; Iuso A.; Bagella C.F.; Pappata S.; Barone P.; Prokisch H.; Romito L.; Tiranti V.Carecchio, M.; Picillo, M.; Valletta, Luana; Elia, A. E.; Haack, T. B.; Cozzolino, A.; Vitale, A.; Garavaglia, B.; Iuso, A.; Bagella, C. F.; Pappata, S.; Barone, FRANCESCA PROMETEA; Prokisch, H.; Romito, L.; Tiranti, V