Relative high frequency of the c.255delA parkin gene mutation in Spanish patients with autosomal recessive parkinsonism

BACKGROUND: Autosomal recessive juvenile parkinsonism is a neurodegenerative disorder associated with mutations in the parkin gene. OBJECTIVES: To search for the presence of parkin gene mutations in Spanish patients with Parkinson's disease (PD) and characterise the phenotype associated with these mutations. METHODS: Thirty seven PD patients with either early onset or autosomal recessive pattern of inheritance were selected for genetic study. RESULTS: Mutations were identified in seven index patients (19%). Homozygous mutations were detected in six patients and a heterozygous mutation in one. The age at onset was lower in patients with mutations than in patients without mutations. Dystonia at onset was present in two patients with parkin gene mutations. The disease began in two patients with postural tremor in the upper limbs mimicking essential tremor. Four patients exhibited a long term response to dopamine agonists. The c.255delA mutation was identified in four unrelated families. This is a frameshift mutation leading to protein truncation. CONCLUSIONS: Parkin gene mutations are present in Spanish patients with early onset and/or an autosomal recessive parkinsonism. The c.255delA is the most frequent mutation found, suggesting a relative high prevalence in the Spanish population.     

Heptaspanning membrane receptors and cytoskeletal/scaffolding proteins

Most cellular functions are mediated by multiprotein complexes. In neurons, these complexes are directly involved in the proper neuronal transmission, which is responsible for phenomena like learning, memory, and development. In recent years studies based on two-hybrid screens and proteomic, biochemical, and cell biology approaches have shown that intracellular domains of G protein-coupled receptors (GPCRs) or heptaspanning membrane receptors (HSMRs) interact with intracellular proteins. These interactions are the basis of a protein network associated with these receptors, which includes scaffolding proteins containing one or several PDZ (post-synaptic-density-95/discs-large/zona occludens-1) domains, signaling proteins, and proteins of the cytoskeleton. The present article is focused on the emerging evidence for interactions of adenosine, dopamine, and metabotropic glutamate receptors, with scaffolding and cytoskeletal proteins that play a role in the targeting and anchoring of these receptors to the plasma membrane, thus contributing to neuronal development and plasticity. Finally, given the complexity of neurological disorders such as ischemic stroke, Alzheimer’s disease, and epilepsy, exploitation of these HSMR-associated interactions might prove to be efficient in the treatment of such disorders.     

Myotatic reflexes and the on-off effect in patients with Parkinson's disease.

Reflex activity in the biceps and triceps muscles evoked by applied torque perturbations was studied in patients with Parkinson''s disease. The perturbations consisted of single pulses or of pseudo-random sequences of pulses of torque. The patients were treated with levodopa and some exhibited marked fluctuations in their clinical disabilities ("on-off" effect). The study was undertaken to see if reflex activity changed in parallel with the fluctuations of their clinical symptoms. It was found that the reflex activity in these patients could be classified into two types, a Type I response differing little from normal and a Type II response exhibiting marked high-frequency (8-14 Hz) oscillations in EMG activity. Both Type I and Type II responses were virtually the same in the "on" as in the "off" state.     

Narrow beneficial effect of dextromethorphan on levodopa-induced motor response alterations in an experimental model of parkinsonism

The effects of acute and chronic dextromethorphan on levodopa-induced motor response alterations have been studied in rats with unilateral lesion of nigrostriatal pathway induced by 6-hydroxydopamine (6-OHDA). Male Sprague-Dawley rats received a 6-OHDA injection (8 microg) into the left medial forebrain bundle. To validate the effect of acute dextromethorphan administration, groups of rats were treated with levodopa (25 mg/kg, twice daily) for 22 days. On day 23, animals received dextromethorphan (20, 30 or 40 mg/kg) immediately before levodopa. In a second set of experiments, lesioned rats were concomitantly treated with levodopa plus dextromethorphan (20, 30 or 40 mg/kg, twice at day) for 22 consecutive days in order to investigate the potential effect of chronic dextromethorphan administration in preventing the decrease in the duration of motor response. As expected, the duration of the motor response to levodopa had significantly decreased by the 22nd day of levodopa in each group of treatment. Acute administration of dextromethorphan on day 23 reversed the reduction in the duration of the levodopa response only when administered at the lowest dose used in the present study (20 mg/kg) (p<0.05). Chronic administration of dextromethorphan concomitant to levodopa did not prevent levodopa effect showing a significant decrease on motor response duration (124+/-4 on day 1 vs. 88+/-16 on day 22, p<0.05, 30 mg/kg, twice a day). Our results indicate that in parkinsonian rats dextromethorphan is not a useful drug to prevent levodopa-induced motor alterations, however, low doses of dextromethorphan may be beneficial to reverse these alterations in motor response.     

The kappa opioid agonist U50,488 potentiates 6-hydroxydopamine-induced neurotoxicity on dopaminergic neurons

Several observations support the hypothesis that kappa opioid (kappa-opioid) receptor agonism may contribute to neurotoxicity, but other reports have suggested that certain kappa-agonists can attenuate neurological dysfunction. Degeneration of dopaminergic neurons in the substantia nigra is the pathological hallmark of Parkinson's disease. Therefore, it is of particular interest to study whether kappa-opioid receptor agonism has an influence on the progressive degeneration of dopaminergic neurons. We have investigated the effect exerted by the selective kappa-agonist U50,488 on the neurotoxicity induced by intrastriatal 6-hydroxydopamine (6-OHDA) administration on dopaminergic neurons. Male Sprague-Dawley rats received an acute (0.5 mg/kg) or subacute (0.5 mg/kg, twice at day, for 7 days) administration of U50,488, receiving the last dose 30 min before intrastriatal 6-OHDA administration. Acute or subacute U50,488 pretreatment potentiated the 6-OHDA-induced decrease in the number of nigral tyrosine hydroxylase immunoreactive neurons (P < 0.05). Acute U50,488 pretreated animals showed a tendency, although not statistically significant to increase striatal mRNA encoding for enkephalin (PPE mRNA). Subacute U50,488 significantly potentiated the increase in PPE mRNA induced by 6-OHDA (P < 0.05). The present results show a neurotoxic effect of the kappa agonist U50,488 on dopaminergic neurons in rats with a striatal lesion induced by 6-OHDA. This neurotoxic effect is associated to an increase in striatal PPE mRNA levels, suggesting that an increase in the indirect pathway activity and consequently an increase in the activity of the subthalamo-nigral pathway might be involved in this phenomenon.     

A novel intronic mutation in the DDP1 gene in a family with X-linked dystonia-deafness syndrome

BACKGROUND: X-linked dystonia-deafness syndrome (Mohr-Tranebjaerg syndrome) is a rare neurodegenerative disease characterized by hearing loss and dystonia. So far, 7 mutations in the coding region of the DDP1 gene have been described. They consist of frameshift, nonsense, missense mutations or deletions. OBJECTIVE: To investigate the presence of mutations in the DDP1 gene in a family with dystonia-deafness syndrome. DESIGN: Seven members belonging to 2 generations of a family with 2 affected subjects underwent genetic analysis. Mutational screening in the DDP1 gene was made through DNA direct sequencing. RESULTS: We found an intronic mutation in the DDP1 gene. It consists of an A-to-C substitution in the position -23 in reference to the first nucleotide of exon 2 (IVS1-23A>C). The mutation was present in 2 affected men and their respective unaffected mothers, whereas it was absent in the healthy men from this family and in 90 healthy controls. CONCLUSIONS: Intronic mutations in the DDP1 gene can also cause X-linked dystonia-deafness syndrome. In our case, the effect of the mutation could be due to a splicing alteration.     

Prediction of preterm delivery with transvaginal ultrasonography of the cervix in patients with high-risk pregnancies: does cerclage prevent prematurity?

OBJECTIVES: We sought to determine the predictive accuracy for preterm delivery of transvaginal ultrasonography of the cervix between 14 and 24 weeks' gestation in high-risk patients and to determine whether cerclage prevents preterm delivery in patients with ultrasonographic cervical changes. STUDY DESIGN: Patients with asymptomatic singleton pregnancies at high risk for preterm delivery were followed prospectively from 14 weeks' to 23 weeks 6 days' gestation with transvaginal ultrasonography of the cervix. The subgroup of patients with either a cervical length of <25 mm or funneling of >25% or both was offered McDonald salvage cerclage, which was performed at the discretion of the patient and the obstetrician. The 2 groups (with and without cerclage) were compared for the primary outcome of preterm delivery at <35 weeks' gestation. RESULTS: One hundred sixty-eight women were followed, including 97 (58%) with >/=1 prior 14- to 34-week preterm deliveries. Of 63 (37. 5%) patients identified as having cervical changes, 23 (37%) had preterm delivery; of 105 patients with no cervical changes, 8 (8%) had preterm delivery (relative risk, 4.8; 95% confidence interval, 2. 3-10.1). The sensitivity, specificity, and positive and negative predictive values of either a short cervix of <25 mm or funneling of >25% or both were 74%, 70%, 37%, and 92%, respectively. Of 63 pregnancies in which there were cervical changes, 39 underwent cerclage and 24 did not. These 2 groups were similar for demographic characteristics, risk factors, and transvaginal ultrasonographic cervical length and funneling but dissimilar for gestational age at identification of cervical changes (18.3 vs 21.2 weeks' gestation in the groups with and without cerclage, respectively; P <.001). Multivariate logistic regression analysis after adjustment for gestational age at cervical changes showed no difference in the rate of preterm delivery between the groups with and without cerclage (odds ratio, 1.1; 95% confidence interval, 0.3-4.6). Stratified analysis of patients identified between 18 and 24 weeks revealed 22 pregnancies with cerclage and 22 pregnancies without cerclage, which was similar for all characteristics studied. The incidence of preterm delivery remained similar (27% vs 23%, respectively; P =.7), as did days from cervical changes to delivery (111 vs 96, respectively; P =.2). CONCLUSIONS: Transvaginal ultrasonography of the cervix between 14 and 24 weeks' gestation is a good predictor of preterm delivery in high-risk pregnancies. Cerclage may not prevent preterm delivery in patients identified to be at high risk for this outcome by transvaginal ultrasonography.     

Contribution of Neurophysiological Guidance to Stereotactic Posteroventral Pallidotomy for Parkinson's Disease

The usefulness of microrecording guidance to adequately place pallidotomy lesions is not thoroughly accepted. We have analysed in 23 consecutive Parkinsonian patients the deviation of the first recording track (FRT), which was directed to the theoretical stereotactic target, from the sensorimotor area of the internal pallidum, the internal capsule and the center of the lesion. Standard stereotactic co-ordinates were calculated applying a digitized brain atlas adapted to neuro-imaging techniques. The first recording track (FRT) was located out of the sensorimotor area of the pallidum in 13 cases and out of the internal pallidum in 11 cases. In four of these cases the FRT was within the fibers of the internal capsule. The FRT was displaced posteriorly in 9 patients, anteriorly in 11, medially in 9 and laterally in 9. The mean deviation was 1.8 mm (+/- 1.5) in the medial-lateral axis, and 2.5 mm (+/- 1.9) in the antero-posterior plane. In none of the patients the center of the lesion was co-incident with the theoretical anatomical target. The center of the lesion presented a mean deviation from the theoretical anatomical target of 1,4 mm (+/- 1,1) in the medial-lateral, plane, and 2.5 mm (+/- 1.3) in the antero-posterior plane. In addition, 8 patients presented a deviation from the theoretical anatomical target of more than 3 mm in the antero-posterior plane (mean 4.2+/-0.7 mm) and 4 patients presented deviation in the medial-lateral plane of more than 3 mm (mean 3,4+/-0,2 mm). Lesion location was checked by magnetic resonance imaging. All patients improved to a similar extent to that previously reported by the other groups performing pallidotomy under neurophysiological guidance. At 3 months follow-up, pallidotomy ameliorated contralateral bradykinesia in the off condition by 41%, rigidity by 38%, tremor by 52% and dyskinesias by 92%. No major side effects were noted. We conclude that microrecording guidance is a useful tool for avoiding damage to adjacent structures and to precisely localize the sensorimotor area of the internal pallidum in order to obtain optimal clinical results.