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ObjectiveThe aim of this study was to evaluate the correlation between the various NOTCH3 mutations and their clinical and genetic profile, along with the presentation of a novel mutation in a patient.MethodsHere, we describe the phenotype of a patient with cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) harboring a novel mutation. We also performed an extensive literature research for NOTCH3 mutations published since the identification of the gene and performed a systematic review of all published cases with NOTCH3 mutations. We evaluated the mutation pathogenicity in a great number of patients with detailed clinical and genetic evaluation and investigated the possible phenotype-genotype correlations.ResultsOur patient harbored a novel mutation in the NOTCH3 gene, the c.3084 G > C, corresponding to the aminoacidic substitution p.Trp1028Cys, presenting with seizures as the first neurologic manifestation. We managed to find a correlation between the pathogenicity of mutations, severity of the phenotype, and age at onset of CADASIL. Significant differences were also identified between men and women regarding the phenotype severity.ConclusionsThe collection and analysis of these scarce data published since the identification of NOTCH3 qualitatively by means of a systematic review and quantitatively regarding genetic profile and pathogenicity scores, highlight the significance of the ongoing trend of investigating phenotypic genotypic correlations.

Objectives Studies investigating the association between angiotensin-converting enzyme (ACE) insertion/deletion (I/D) polymorphism and the risk of intracerebral hemorrhage (ICH) have provided conflicting results. Moreover, it is possible that the ACE I/D polymorphism may not represent the functional variant of the gene. The objective of this study was to clarify the influence of the ACE gene region on the risk of ICH by genotyping tag polymorphisms along ACE gene in two independent ethnically different cohorts. Methods We included 250 Greek and 169 Polish unrelated patients with ICH and 250 Greek and 322 Polish normal controls in the study. To cover the majority of the genetic variability across the extended ACE gene region, we identified five tag single nucleotide polymorphisms (rs4343, rs4461142, rs7221780, rs8066276, rs8066114) from the HapMap using a pairwise tagging approach and an r2 greater than or equal to 0.8. Single nucleotide polymorphisms and haplotypes were analyzed for associations with ICH risk, ICH subtype (lobar/nonlobar), and age of disease onset using logistic and Cox regression models. Correction for multiple comparisons was carried out. Results In the Polish cohort, we observed a trend toward an association between the rs4461142 and the age of ICH onset (hazard ratio 0.50, 95% confidence interval 0.27-0.90, P=0.02). A common haplotype (GTCTC) also showed a trend for increased ICH risk in the Polish cohort (odds ratio 0.19, 95% confidence interval 0.04-0.85, P= 0 . 02 ). These results were not replicated in the Greek cohort. Conclusions Our results did not provide clear evidence for a role of ACE gene in the development of ICH.

Rapid progress in genetics has meant that there are now five genes identified for 'Parkinson's disease'. The detailed phenotypes vary, but generally the dominant genes cause a Lewy body disease spectrum whereas recessive genes cause a milder parkinsonism with variable inclusion body pathology. The subject of this review is to highlight these discoveries and to discuss their relationships to idiopathic Parkinson's disease.In January 2004, mutations in PINK1, coding for a mitochondrial kinase, were found to be causal for recessive parkinsonism. Subsequently, several studies have found additional mutations associated with early onset parkinsonism. Some cases have been described with a phenotype much closer to idiopathic Parkinson's disease, but it does not appear that PINK1 is a major risk factor for the sporadic disease. Later in the same year, the LRRK2 gene was shown to cause a dominant disease with a broader phenotype. The protein product was named dardarin and contains GTPase and kinase domains. Lewy bodies have been reported in LRRK2 cases, potentially linking this gene with sporadic Parkinson's disease. One mutation, G2019S, is found in a significant percentage of cases, including sporadic Parkinson's disease.Mutations in these two genes, along with previously described Mendelian variants, are beginning to yield important information about loss of specific neuronal groups or to protein inclusion pathology. How this relates to sporadic Parkinson's disease, however, is not yet fully defined. There are clear phenotypic overlaps with genetic and sporadic Parkinson's disease, especially for the dominant genes, suggesting that common facets of pathogenesis may exist.