Genetic screening for the LRRK2 R1441C and G2019S mutations in Parkinsonian patients from Campania.

BACKGROUND: PARK8 is the most common known mendelian form of Parkinson's Disease (PD). It is due to mutations in the leucine-rich repeat kinase 2 (LRRK2) gene and G2019S is considered the most frequent mutation in the Caucasian population, in particular in the Southern Europe and Mediterranean countries. OBJECTIVE: We assessed the frequency of the G2019S and R1441C/H/G mutations in 513 (311 M and 202 F) unrelated PD patients from Campania, in Southern Italy. METHODS: Three hundreds and thirty-six patients presented a sporadic disease, and 177 had a familial history of PD or tremor. Three hundreds and eighty cases originated from the province of Naples. We compared our LRRK2 mutation carriers to idiopathic PD patients matched for recruiting center, gender, age and age at onset. RESULTS: Thirteen patients (8 M and 5 F) carried the R1441C mutation and 4 (3 M and 1 F) the G2019S mutation, all in heterozygous state. All carriers originated from the province of Naples. No carriers of the R1441H or R1441G mutations were found. The LRRK2 mutation carriers were clinically similar to idiopathic PD patients. The R1441C and G2019S mutations are not rare causes of PD in Campania, especially in the province of Naples and among the familial cases, where the overall mutation prevalence is 6.8%. CONCLUSIONS: The R1441C prevalence was higher than that of G2019S (2.5% vs 0.8%), underlining the importance of the geographical differencies in LRRK2 mutation frequency for molecular screening and genetic counseling of PD patients.

Cholestenoic acids regulate motor neuron survival via liver X receptors.

Cholestenoic acids are formed as intermediates in metabolism of cholesterol to bile acids, and the biosynthetic enzymes that generate cholestenoic acids are expressed in the mammalian CNS. Here, we evaluated the cholestenoic acid profile of mammalian cerebrospinal fluid (CSF) and determined that specific cholestenoic acids activate the liver X receptors (LXRs), enhance islet-1 expression in zebrafish, and increase the number of oculomotor neurons in the developing mouse in vitro and in vivo. While 3ß,7α-dihydroxycholest-5-en-26-oic acid (3ß,7α-diHCA) promoted motor neuron survival in an LXR-dependent manner, 3ß-hydroxy-7-oxocholest-5-en-26-oic acid (3ßH,7O-CA) promoted maturation of precursors into islet-1+ cells. Unlike 3ß,7α-diHCA and 3ßH,7O-CA, 3ß-hydroxycholest-5-en-26-oic acid (3ß-HCA) caused motor neuron cell loss in mice. Mutations in CYP7B1 or CYP27A1, which encode enzymes involved in cholestenoic acid metabolism, result in different neurological diseases, hereditary spastic paresis type 5 (SPG5) and cerebrotendinous xanthomatosis (CTX), respectively. SPG5 is characterized by spastic paresis, and similar symptoms may occur in CTX. Analysis of CSF and plasma from patients with SPG5 revealed an excess of the toxic LXR ligand, 3ß-HCA, while patients with CTX and SPG5 exhibited low levels of the survival-promoting LXR ligand 3ß,7α-diHCA. Moreover, 3ß,7α-diHCA prevented the loss of motor neurons induced by 3ß-HCA in the developing mouse midbrain in vivo.Our results indicate that specific cholestenoic acids selectively work on motor neurons, via LXR, to regulate the balance between survival and death.

A randomized clinical trial of lithium in multiple system atrophy.

The aim of our study was to test the safety and tolerability of lithium in multiple system atrophy (MSA). The study was randomized, placebo-controlled, and double-blind. The primary endpoint of the study was safety and tolerability. An interim analysis, performed 1 year after the first patient was randomized, showed a higher proportion of trial abandon (P < 0.01) and a higher number of adverse events (P < 0.02) in the lithium group. The trial was stopped by the Data Monitoring Committee. Overall, lithium was not well tolerated, and we do not encourage future studies with lithium in MSA patients.

Two novel CYP7B1 mutations in Italian families with SPG5: a clinical and genetic study.

Hereditary spastic paraplegias (HSPs) are a heterogeneous group of neurodegenerative disorders characterized by progressive weakness and spasticity in the lower limbs. Spasticity may occur in isolation (''pure'' HSP) or may be accompanied by other features. Although autosomal recessive HSPs usually have clinically complex phenotypes, mutations within a few genes underlie pure forms. Recently the gene (CYP7B1) responsible for SPG5, a pure recessive HSP, has been identified. The six CYP7B1 coding exons were analysed in four Italian families. Complete clinical assessment was performed in all patients. Blood CYP7B1 mRNA levels were assessed in three patients and six controls. Brain MRI and (18)F-fluoro-deoxy-glucose positron emission tomography (PET) scan were conducted in three patients. Two novel homozygous mutations were identified. Both result in a frameshift and the introduction of a premature stop codon at the C-terminal of the protein. Patients have reduced blood CYP7B1 mRNA levels, suggesting nonsense mediated RNA decay. Although clinical assessment showed a pure form of spastic paraplegia, MRI demonstrated white matter abnormalities in three patients and PET scan revealed cerebellar hypometabolism in one. Based on the results, we report the first Italian families with SPG5 molecular characterization and describe two novel truncating mutations in CYP7B1. The recessive character, the truncating nature of the mutations, and the reduced peripheral blood CYP7B1 mRNA levels suggest that the development of the disease is associated with a loss of function. SPG5 is considered a pure form of HSP, but MRI and PET findings in our patients suggest that SPG5 phenotype may be broader than the pure presentation.