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Retinal vasculopathy with cerebral leukodystrophy (RVCL) is an adult-onset disorder caused by C-terminal heterozygous frameshift (fs) mutations in the human 3′–5′ DNA exonuclease TREX1. Hereditary systemic angiopathy (HSA) is considered a variant of RVCL with systemic involvement of unknown genetic cause, described in a unique family so far. Here we describe the second case of RVCL with systemic involvement, characterized by cerebral calcifications and pseudotumoral lesions, retinopathy, osteonecrosis, renal and hepatic failure. The genetic screening of TREX1 in this patient revealed the novel heterozygous T270fs mutation on the C-terminal region. On the same gene, we found the V235fs mutation, formerly shown in RVCL, in one patient previously reported with HSA. These mutations lead to important alterations of the C-terminal of the protein, with the loss of the transmembrane helix (T270fs) and the insertion of a premature stop codon, resulting in a truncated protein (V235fs). Functional analysis of T270fs-mutated fibroblasts showed a prevalent localization of the protein in the cytosol, rather than in the perinuclear region. RVCL with systemic involvement is an extremely rare condition, whose diagnosis is complex due to multiorgan manifestations, unusual radiological and histopathological findings, not easily attributable to a single disease. It should be suspected in young adults with systemic microangiopathy involving retina, liver, kidney, bones and brain. Here we confirm the causative role played by TREX1 autosomal dominant fs mutations disrupting the C-terminal of the protein, providing a model for the study of stroke in young adults.

Neurofibromatosis type 2 (NF2) is a dominantly inherited syndrome caused by mutations of the tumour-suppressor NF2, which encodes the merlin protein. Mutations are associated with a predisposition to development of benign tumours in the central nervous system. Even though cerebral cortical lesions are frequently associated with seizures, epilepsy is rarely described in NF2. Here, we describe an adult case of NF2 in which the onset of symptoms was characterised by status epilepticus. In this patient, we identified the novel c.428-430delCTTdel mutation in NF2, involving the amino-terminal FERM domain, which is fundamental for the correct tumour suppressor function of the protein. Bioinformatic analyses revealed an important structural perturbation of the FERM domain, with a predicted impairment of the anti-tumour activity

Chaperone-mediated autophagy (CMA) impairment is recognized to play a pathogenetic role in Parkinson's disease (PD). A reduced expression of lysosomal-associated membrane protein (lamp) 2A and heat shock cognate (hsc) 70 protein, the two key regulators of CMA, has been reported in brains of PD patients. To verify the existence of a possible systemic CMA dysfunction in PD, in this study the expression of hsc70 and lamp2A was assessed in peripheral blood mononuclear cells (PBMC) of patients with sporadic PD and compared to healthy subjects. The expression of myocyte enhancer factor 2D (MEF2D), a transcriptional factor implicated in neuronal survival and specific substrate of CMA, was also evaluated. Protein and gene expression was assessed by Western blot and real-time PCR, respectively, in PBMC obtained from 53 sporadic PD patients and 53 healthy subjects. A significant reduction of hsc70 levels was observed in PBMC of PD patients, both under basal conditions and after autophagy induction obtained with serum deprivation. No difference emerged in lamp2A and MEF2D expression between patients and controls. No influence of the clinical characteristics of patients emerged on hsc70, lamp2A and MEF2D expression. These results, despite being not suggestive of the existence of a CMA impairment in PBMC of PD patients, identify a systemic hsc70 reduction in PD patients. Further studies on specific mechanisms and biological significance of such alteration are needed to corroborate this finding that could lead to the identification of a new trait biomarker for PD

Generation of reactive oxygen species during dopamine (DA) oxidation could be one of the factors leading to the selective loss of nigral dopaminergic neurons in Parkinson's disease (PD). Vesicular monoamine transporter type 2 (VMAT2) proteins in nerve terminals uptake dopamine into synaptic vesicles, preventing its cytoplasmic accumulation and toxic damage to nigral neurons. Polymorphisms in VMAT2 gene and in its regulatory regions might therefore serve as genetic risk factors for PD. In the present study, we have analyzed 8 single-nucleotide polymorphisms (SNPs) located within/around the VMAT2 gene for association with PD in an Italian cohort composed of 704 PD patients and 678 healthy controls. Among the 8 SNPs studied, only the 2 located within the promoter region (rs363371 and rs363324) were significantly associated with PD. In the dominant model, odds ratios were 0.72 (95% confidence interval [CI]: 0.6-0.9, p < 0.005) for rs363371 and 0.76 (95% CI: 0.6-0.9, p = 0.01) for rs363324; in the additive model, odds ratios were 0.78 (95% CI: 0.65-0.94, p = 0.008) for rs363371 and 0.85 (95% CI: 0.7-20.92, p = 0.04) for rs363324. There were no significant relationships between the remaining SNPs (rs363333, rs363399, rs363387, rs363343, rs4752045, and rs363236) and the risk of sporadic PD in any genetic model. This study adds to the previous evidence suggesting that variability in VMAT2 promoter region may confer a reduced risk of developing PD, presumably via mechanisms of gene overexpression

Alpha-synuclein accumulation in intracellular inclusions, oxidative stress and microglia-mediated inflammation in the substantia nigra are crucial events in the pathogenesis of Parkinson's disease (PD). Poly (ADP-ribose) polymerase-1 (PARP1), a DNA-binding enzyme and transcriptional regulator, plays an important role in modulating the cellular response to oxidative stress, inflammatory stimuli, and in apoptotic cell death. Inhibition of PARP1 results in significant neuroprotection in PD animal models; moreover PARP1 has a physiological role in the regulation of alpha-synuclein expression. A previous study had demonstrated that variants located within the PARP1 gene promoter reduce the risk of PD and delay the disease age at onset. In light of these data, we carried out an association study to investigate whether variability within this gene is associated with PD risk and disease age at onset in an Italian cohort composed of 600 PD patients and 592 healthy controls. To this purpose, we used a comprehensive tag SNP approach spanning the entire gene and the upstream and downstream regions. We did not detect any significant association of the PARP1 gene with PD either at genotypic or haplotypic level; none of the 11 genotyped SNPs was significantly associated with PD age at onset. We conclude that, despite previous evidence, PARP1 is not a susceptibility gene for PD in our population.

La malattia di Parkinson è una patologia neurodegenerativa a decorso progressivo cronico caratterizzata dal coinvolgimento della pars compacta della sostanza nera e dalla presenza in fase conclamata di una classica sintomatologia extrapiramidale (riassunta nella triade rigidità, tremore a riposo e bradicinesia). Nonostante la rilevanza del quadro motorio nella definizione della sindrome clinica, nell’ultimo decennio si è però compreso che un insieme di segni e sintomi non motori (SNM) di vario genere possono presentarsi nel corso della malattia. In questa revisione della letteratura verranno trattati i più importanti SNM della malattia di Parkinson secondo il percorso cronologico che ne caratterizza la progressione patologica e clinica.