Whole-exome sequencing associates novel CSMD1 gene mutations with familial Parkinson disease.

OBJECTIVE: Despite the enormous advancements made in deciphering the genetic architecture of Parkinson disease (PD), the majority of PD is idiopathic, with single gene mutations explaining only a small proportion of the cases. METHODS: In this study, we clinically evaluated 2 unrelated Spanish families diagnosed with PD, in which known PD genes were previously excluded, and performed whole-exome sequencing analyses in affected individuals for disease gene identification. RESULTS: Patients were diagnosed with typical PD without relevant distinctive symptoms. Two different novel mutations were identified in the CSMD1 gene. The CSMD1 gene, which encodes a complement control protein that is known to participate in the complement activation and inflammation in the developing CNS, was previously shown to be associated with the risk of PD in a genome-wide association study. CONCLUSIONS: We conclude that the CSMD1 mutations identified in this study might be responsible for the PD phenotype observed in our examined patients. This, along with previous reported studies, may suggest the complement pathway as an important therapeutic target for PD and other neurodegenerative diseases.

The unexpected co-occurrence of GRN and MAPT p.A152T in Basque families: Clinical and pathological characteristics.

BACKGROUND: The co-occurrence of the c.709-1G>A GRN mutation and the p.A152T MAPT variant has been identified in 18 Basque families affected by frontotemporal dementia (FTD). We aimed to investigate the influence of the p.A152T MAPT variant on the clinical and neuropathological features of these Basque GRN families. METHODS AND FINDINGS: We compared clinical characteristics of 14 patients who carried the c.709-1G>A GRN mutation (GRN+/A152T-) with 21 patients who carried both the c.709-1G>A GRN mutation and the p.A152T MAPT variant (GRN+/A152T+). Neuropsychological data (n = 17) and plasma progranulin levels (n = 23) were compared between groups, and 7 subjects underwent neuropathological studies. We genotyped six short tandem repeat markers in the two largest families. By the analysis of linkage disequilibrium decay in the haplotype block we estimated the time when the first ancestor to carry both genetic variants emerged. GRN+/A152T+ and GRN+/A152T- patients shared similar clinical and neuropsychological features and plasma progranulin levels. All were diagnosed with an FTD disorder, including behavioral variant FTD or non fluent / agrammatic variant primary progressive aphasia, and shared a similar pattern of neuropsychological deficits, predominantly in executive function, memory, and language. All seven participants with available brain autopsies (6 GRN+/A152T+, 1 GRN+/A152T-) showed frontotemporal lobar degeneration with TDP-43 inclusions (type A classification), which is characteristic of GRN carriers. Additionally, all seven showed mild to moderate tau inclusion burden: five cases lacked ß-amyloid pathology and two cases had Alzheimer's pathology. The co-occurrence of both genes within one individual is recent, with the birth of the first GRN+/A152T+ individual estimated to be within the last 50 generations (95% probability). CONCLUSIONS: In our sample, the p.A152T MAPT variant does not appear to show a discernible influence on the clinical phenotype of GRN carriers. Whether p.A152T confers a greater than expected propensity for tau pathology in these GRN carriers remains an open question.

Tau/α-synuclein ratio and inflammatory proteins in Parkinson's disease: An exploratory study.

BACKGROUND: No CSF or plasma biomarker has been validated for diagnosis or progression of PD. OBJECTIVES: To assess whether the CSF and plasma levels of proteins associated with PD neuropathological inclusions and with neuroinflammation might have value in the diagnosis of PD or in relation to disease severity. METHODS: CSF levels of α-synuclein, amyloid-ß1-42, total tau, and threonine-181 phosphorylated tau, as well as CSF and plasma levels of cytokines (interleukin-1ß, interleukin-2, interleukin, interferon-γ, and tumor necrosis factor α) were studied in 40 PD patients and 40 healthy controls. Plasma levels of cytokines were measured in 51 patients and 26 aditional controls. We also explored the Parkinson's Progression Markers Initiative data set as a replication cohort. RESULTS: CSF levels of α-synuclein, amyloid-ß1-42, and tumor necrosis factor α were lower in patients than in controls, and the total tau/α-synuclein, phosphorylated tau/α-synuclein, total tau/amyloid-ß1-42+α-synuclein, and phosphorylated tau/amyloid-ß1-42+α-synuclein ratios were higher in patients. The best area under the curve value was obtained for the phosphorylated tau/α-synuclein ratio alone (0.86) and also when this was combined with tumor necrosis factor α in CSF (0.91; sensitivity 92.9%, specificity 75% for a cut-off value of ≤ 0.71). Phosphorylated tau/α-synuclein and phosphorylated tau/amyloid-ß1-42+α-synuclein were higher in patients than in controls of the Parkinson's Progression Markers Initiative database. Plasma cytokines did not differ between groups, although interleukin-6 levels were positively correlated with UPDRS-I, -II, and -III scores. CONCLUSIONS: The CSF phosphorylated tau/α-synuclein ratio alone, and in combination with tumor necrosis factor α and plasma interleukin-6 levels, might serve as biomarkers to diagnose PD and monitor its severity. © 2017 International Parkinson and Movement Disorder Society.

Rombencefalitis y endocarditis por Listeria monocytogenes: una asociación no descrita / Rhomboencephalitis and endocarditis caused by Listeria monocytogenes: an unreported association

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Clinical correlations with Lewy body pathology in LRRK2-related Parkinson disease.

IMPORTANCE: Mutations in leucine-rich repeat kinase 2 (LRRK2) are the most common cause of genetic Parkinson disease (PD) known to date. The clinical features of manifesting LRRK2 mutation carriers are generally indistinguishable from those of patients with sporadic PD. However, some PD cases associated with LRRK2 mutations lack Lewy bodies (LBs), a neuropathological hallmark of PD. We investigated whether the presence or absence of LBs correlates with different clinical features in LRRK2-related PD. OBSERVATIONS: We describe genetic, clinical, and neuropathological findings of 37 cases of LRRK2-related PD including 33 published and 4 unpublished cases through October 2013. Among the different mutations, the LRRK2 p.G2019S mutation was most frequently associated with LB pathology. Nonmotor features of cognitive impairment/dementia, anxiety, and orthostatic hypotension were correlated with the presence of LBs. In contrast, a primarily motor phenotype was associated with a lack of LBs. CONCLUSIONS AND RELEVANCE: To our knowledge, this is the first report of clinicopathological correlations in a series of LRRK2-related PD cases. Findings from this selected group of patients with PD demonstrated that parkinsonian motor features can occur in the absence of LBs. However, LB pathology in LRRK2-related PD may be a marker for a broader parkinsonian symptom complex including cognitive impairment.

Prevalence of cancer in Parkinson's disease related to R1441G and G2019S mutations in LRRK2.

An inverse relationship between Parkinson's disease (PD) and cancer has been described. However, the association between cancers and genetic forms of PD, in particular the R1441G mutation in the LRRK2 gene, is not well known. The objective of this work was to analyze cancer prevalence in PD patients with R1441G or G2019S mutations in LRRK2, and in idiopathic PD (iPD). A total of 732 patients with PD (70 and 25 carriers of R1441G or G2019S mutations, respectively), and 177 controls, were linked using a population-based cancer registry of the Spanish province of Gipuzkoa. Cancer prevalence was not significantly higher in PD-G2019S carriers (20%) than in PD-R1441G carriers (14.3%), iPD (13.8%), or controls (12.5%). With the exception of a high prevalence of hematological cancers (crude odds ratio of 7.1) in the R1441G group, specific cancer types were not increased in PD mutation carriers. In both the carrier and iPD groups, cancers were diagnosed after the onset of PD. PD patients had a similar prevalence of cancer to control subjects. There was no increased association between G2019S or R1441G mutations and any type of cancer. Although there was a higher prevalence of hematological cancers in the R1441G group, the low number of such cancers overall makes this finding of uncertain significance. There was a slightly higher but not statistically significant prevalence of non-skin cancers in the G2019S group, suggesting that further study to evaluate the association should be undertaken prior to ascribing an increased cancer risk to this population.

[Response to treatment with corticoids in a case of inflammatory amyloid angiopathy without performing a biopsy]. / Respuesta al tratamiento con corticoides en un caso de angiopatía amiloide inflamatoria sin realización de biopsia.

INTRODUCTION: Inflammatory amyloid angiopathy (IAA) is an infrequent presenting symptom of the recently recognised cerebral amyloid angiopathy and its definitive diagnosis is reached by means of pathological analyses. AIM: We report the case of a male patient with IAA and good clinical, neuropsychological and neuroimaging response to treatment with corticoids; a biopsy of brain tissue was not considered necessary. CASE REPORT: The patient, 68 years old and diagnosed with Alzheimer's disease, suffered from generalised seizures followed by a language disorder and hemiparesis of the right-hand side. A magnetic resonance imaging scan showed a lesion displaying infiltrating behaviour in the left hemisphere and multiple instances of microbleeding. Clinical and radiological features suggested IAA and treatment was established with corticoids. Neuroimaging and neuropsychological tests revealed a notable improvement at 30 days after beginning treatment with immunosuppressants. The genotype was ApoE e4/e4. The need to perform a biopsy of brain tissue was ruled out. CONCLUSIONS: The case described here suggests that, in individualised cases with clinical and radiological features that are characteristic of IAA, it may be possible to establish an empirical treatment with corticoids with a probability diagnosis and perform a biopsy of brain tissue in the event of a lack of response to treatment.

Αlpha-synuclein levels in blood plasma from LRRK2 mutation carriers.

The diagnosis of Parkinson's disease (PD) remains primarily a clinical issue, based mainly on phenotypic patterns. The identification of biomarkers capable of permitting the preclinical detection of PD is critically needed. α-Synuclein is a key protein in PD, with missense and multiplication mutations in the gene encoding α-synuclein (SNCA) having been reported in familial cases of PD, and accumulation of the protein identified in Lewy bodies (LBs) and Lewy neurites (LNs) in affected brain regions. With the objective of validating the use of α-synuclein as a clinical or progressive biomarker in an accessible tissue, we used an enzyme-linked immunosorbent assay (ELISA) to measure α-synuclein levels in the peripheral blood plasma of idiopathic PD and LRRK2 mutation carrier patients and compared our findings with healthy control subjects. Compared to healthy controls, we found a significant decrease in plasma total α-synuclein levels in idiopathic PD (iPD) patients (n = 134, p = 0.010). However, the reduction was less significant in patients who were LRRK2 mutation carriers (n = 32, p = 0.133). This lack of significance could be due to the small number of individuals employed in this group. No predictive value of total α-synuclein in the diagnosis of PD was found in a receiver operating characteristic (ROC) curve analysis. Although this is a pilot study requiring corroboration on a larger cohort of patients, our results highlight the possible use of plasma α-synuclein as a biomarker for PD.

Olfactory deficits and cardiac 123I-MIBG in Parkinson's disease related to the LRRK2 R1441G and G2019S mutations.

It has been proposed that olfactory tests and metaiodobenzylguanidine cardiac scintigraphy may help diagnose idiopathic Parkinson's disease in the premotor phase. However, it is not clear what value these tests have in all patients with Parkinson's disease and, particularly, in those who carry mutations in LRRK2. The objective was to analyze olfactory dysfunction and the changes in cardiac I-metaiodobenzylguanidine uptake in patients with Parkinson's disease carrying the R1441G and G2019S mutations in LRRK2, and in patients with Parkinson's disease with no known mutations. Patients with Parkinson's disease were screened for R1441G and G2019S LRRK2 gene mutations and classified as LRRK2 mutation carriers or noncarriers. A total of 190 patients with Parkinson's disease (44 LRRK2 mutation carriers) were tested for olfactory dysfunction using the Brief Smell Identification Test. Cardiac (123) I-metaiodobenzylguanidine scintigraphy was performed on 90 patients with Parkinson's disease (27 LRRK2 mutation carriers). Thirty-six percent of patients with LRRK2 mutations have hyposmia, compared to 75% of noncarrier patients with Parkinson's disease (P < .001). Sixty-six percent of LRRK2 mutation carriers have low early metaiodobenzylguanidine uptake, compared to 86% of noncarriers (P = .048). Similarly, the heart/mediastinum ratio in delayed metaiodobenzylguanidine images appeared to differ between these groups of patients with Parkinson's disease, although these results did not reach statistical significance. The data obtained indicate that olfactory and cardiac impairment is less prevalent when Parkinson's disease is associated with mutations in LRRK2, although the underlying mechanisms for this difference remain unclear. Thus, such screening would be less useful to detect the premotor phase in asymptomatic relatives who carry mutations in LRRK2 than in cases not associated with LRRK2.

Prion protein codon 129 polymorphism modifies age at onset of frontotemporal dementia with the C.709-1G>A progranulin mutation.

Frontotemporal lobar degeneration because of mutations in the progranulin (PGRN) gene presents a high variability both in the clinical phenotype and age of onset of disease. Factors that influence this variability remain largely unknown. The aim of our study was to determine whether selected genetic variables modify age at onset of disease in our series of 21 patients with a single splicing mutation (c.709-1G>A) in the PGRN gene, all of whom were of Basque descent. In our analysis, we included the following genetic variables: PGRN rs5848 and rs9897526 polymorphisms, APOE and microtubule-associated protein tau genotypes, and PRNP codon 129 polymorphism. We found no association between PGRN polymorphisms, APOE and microtubule-associated protein tau genotypes, and age at onset of the disease; whereas we report evidence for an association between PRNP codon 129 polymorphism and age at onset of disease in frontotemporal dementia-PGRN(+) patients. MM homozygous carriers presented onset of disease on average 8.5 years earlier than patients who carried at least 1 valine on their PRNP codon 129 (MV or VV). The biological justification for this association remains speculative.

Penetrance in Parkinson's disease related to the LRRK2 R1441G mutation in the Basque country (Spain).

The LRRK2 R1441G mutation was first identified in Basque families and it is responsible for 46% of familial Parkinson's disease (PD) and for 2.5% of sporadic PD in the PD population of Basque ascent. The aim of this study was to determine LRRK2 R1441G penetrance in PD in the Basque Country (Spain) to help in a more accurate genetic counseling. A total of 59 sibships containing 244 individuals, with a total of 40 PD-affected relatives, were studied. Genetic testing for the R1441G mutation in the LRRK2 gene was performed in 133 individuals and was positive in 51% of them. Lifetime penetrance of R1441G mutations turned out to be 12.5% at 65 years to 83.4% at 80 years. No gender differences were found in penetrance.

Familial Parkinson's disease: clinical and genetic analysis of four Basque families.

During the last few years several loci have been linked to Mendelian forms of Parkinson's disease (PD). To date, 5 causative genes of 10 identified loci are known, and they have provided enormous insight into the molecular pathways involved in this common neurodegenerative disorder. One of the recently identified loci, PARK8, causes autosomal dominant PD with, apparently, various degrees of abnormal deposition of alpha-synuclein or tau in the neuronal cells in the pedigrees currently reported. We genetically characterized four Basque families and found evidence for linkage of autosomal dominant PD to the PARK8 locus, with a maximum 2-point logarithm of odds score of 3.21 (theta = 0.00) for marker D12S345. The clinical features of these families are those of typical PD, including good response to levodopa therapy, rigidity, and akinesia, and a mean age of 55 years at disease onset.

Familial prion diseases in the Basque Country (Spain).

In 1995, a surveillance system for prion diseases was set up in the Basque Country, an autonomous region in northern Spain (2.1 million inhabitants). In the period from January 1993 to December 2003, we diagnosed 21 patients with familial prion diseases prospectively and another 4 patients retrospectively. They represent 35% of all the cases referred to the epidemiological registry. Two main possible explanations for this unusual high incidence of familial prion diseases are proposed: first, comprehensive case ascertainment by public health neurologists; second, a probable cluster of the D178N mutation within families of Basque origin related to a still unconfirmed common ancestor. Further genetic and genealogical studies should resolve this issue.

Mutations in the LGI1/Epitempin gene on 10q24 cause autosomal dominant lateral temporal epilepsy.

Autosomal dominant lateral temporal epilepsy (EPT; OMIM 600512) is a form of epilepsy characterized by partial seizures, usually preceded by auditory signs. The gene for this disorder has been mapped by linkage studies to chromosomal region 10q24. Here we show that mutations in the LGI1 gene segregate with EPT in two families affected by this disorder. Both mutations introduce premature stop codons and thus prevent the production of the full-length protein from the affected allele. By immunohistochemical studies, we demonstrate that the LGI1 protein, which contains several leucine-rich repeats, is expressed ubiquitously in the neuronal cell compartment of the brain. Moreover, we provide evidence for genetic heterogeneity within this disorder, since several other families with a phenotype consistent with this type of epilepsy lack mutations in the LGI1 gene.