LRRK2 mutations are a common cause of Parkinson's disease in Spain.

Pathogenic mutations in the leucine-rich repeat kinase 2 gene (LRRK2; PARK8) have been implicated in autosomal dominant, late-onset parkinsonism. The LRRK2 6055G > A (G2019S) mutation is the most common reported to date, and has been observed in a number of different European populations. So far, only the LRRK2 4321C > G (R1441G) mutation has been identified in the Spanish population. Herein we have assessed the frequency of G2019S in a referral-based series of 225 patients with Parkinson's disease (PD) from the region of Asturias, Northern Spain. The mutant allele was identified in five (2.7%) of the sporadic late-onset patients and was not present in control subjects. All carriers displayed genetic profiles consistent with the same haplotype, as previously reported for Lrrk2 G2019S-positive subjects. None of these patients presented with a family history of parkinsonism at the time of diagnosis. Thus, approximately 5% of sporadic patients with PD from the North of Spain have either Lrrk2 G2019S or R1441G substitutions.

Early-onset Parkinson's disease associated with a new parkin mutation in a Spanish family.

Mutations in the PARKIN gene are associated with early-onset (juvenile) Parkinson's disease. We analyzed the coding sequence of this gene (exons 1-12) in patients from a family with three affected siblings, born to first-degree consanguineous parents, with an onset before 23 years and foot dystonia as the initial clinical symptom. The three patients were alive without cognitive impairment at ages of 70, 69, and 65 years, showing a marked response to levodopa treatment. A 2 bp-deletion at exon 11 (1276-1277 del GA) was found. The three patients were homozygous for this frameshift mutation, which would introduce a Stop at codon 394. This is a new PARKIN-mutation that would produce a truncated protein, lacking exon 12 and most the 11th. This region includes the C-terminal ring-finger domain of parkin, essential for its function as a ubiquitin-protein ligase. Compared to patients from other families with truncating mutations, our patients had an earlier onset. In addition, the three patients had dystonia at onset. In conclusion, we described a new PARKIN truncating mutation associated with an early onset parkinsonism, and the presence of foot dystonia as the initial symptom.

Angiotensin converting enzyme and endothelial nitric oxide synthase DNA polymorphisms and late onset Alzheimer's disease.

OBJECTIVES: Several lines of evidence suggest that the endothelial constitutive nitric oxide synthase (ecNOS) and angiotensin converting enzyme (ACE) may have a role in Alzheimer's disease. ACE is widely expressed in the brain, and a DNA polymorphism at the ACE gene has been linked to the risk for late onset Alzheimer's disease. Nitric oxide (NO) production by microglial cells, astrocytes, and brain microvessels is enhanced in patients with Alzheimer's disease. There is a growing evidence that NO is involved in neuronal death in Alzheimer's disease, and the oxidative stress caused by NO in the brain could be a pathogenic mechanism in Alzheimer's disease. The objective was to determine if two DNA polymorphisms at the ecNOS and ACE genes that have been linked with different levels of enzyme expression, have some effect on the risk of developing late onset Alzheimer disease. METHODS: A total of 400 healthy controls younger than 65 years and 350 patients with Alzheimer's disease (average age 72 years) were genotyped for the ACE and ecNOS polymorphisms. To define a possible role for these polymorphisms in longevity 117 healthy controls older than 85 years were also analysed. Genomic DNA was obtained and amplified by polymerase chain reaction, and genotypes were defined following a previously described procedure. Gene and genotype frequencies between patients and controls were compared statistically. RESULTS: Gene and genotype frequencies for the ecNOS and ACE polymorphisms did not differ between both groups of healthy controls (<65 years and >85 years). EcNOS gene and genotype frequencies were similar between patients and controls. There was a slight but significantly increased frequency of the ACE-I allele among patients with Alzheimer's disease compared with controls (p=0.03; OR=1.28, 95%CI= 1.04;1.58). CONCLUSIONS: The ACE-I allele was associated with a slightly increased risk of developing late onset Alzheimer's disease.

Association between an alpha(2) macroglobulin DNA polymorphism and late-onset Alzheimer's disease.

An association between a five-base-pair deletion/insertion DNA polymorphism at the alpha(2) macroglobulin gene (A2M) and late-onset Alzheimer's disease (LOAD) has been recently described. We developed a PCR assay to analyze this polymorphism in 190 LOAD patients (older than 65 years) and 400 controls from Spain. Controls were stratified into three groups: <65 years (n = 200), 65 to 80 years (n = 100), and 81 years or older (n = 100). We found a significantly higher frequency of carriers of the D allele in patients older than 81 years compared to controls older than 81 years (p = 0.0012). In addition, the frequency of the D allele was significantly lower in controls older than 81 years compared to controls younger than 65 (p = 0.048). Our work suggests that the D allele confers an age-dependent increased risk to develop late-onset Alzheimer's disease.

[Prognostic factors of supratentorial cerebrovascular accidents]. / Factores pronósticos en los accidentes cerebrovasculares supratentoriales.

Our aim was to delimit prognostic factors in supratentorial stroke based on data obtained upon hospitalization. We studied two series of patients, the first being 150 with brain infarct and the second 135 having intracerebral haemorrhage. We analyzed: age, Glasgow and Canadian scales, glucose and urgence haemogram and the size of the lesion across its greatest diameter using computerized tomography (CT). Follow-up time was until death or one year after the stroke. Those who lived longer than one year after were subclassified according to the Rankin scale as < 3 and > or = 3. There was a significant difference between those who survived for less than one month and those surviving more than one year: their age (p < 0.01), average score on the scale (p < 0.001) and size of infarct (p < 0.05) or haematoma (p < 0.001). The Rankin subgroups < 3 and > or = 3 also differed significantly with regard to age. Noteworthy were the unfavourable data: Glasgow < 10 points and Canadian < 5 points, in infarcts > 6 cm and haematomas > 4 cm in diameter. We comment on other evolutionary variables which may influence prognostic assessment such as clinical deterioration or CT sensitivity of the infarct depending on the carry-out time.

[Nodular subependymal heterotopia and epilepsy]. / Heterotopia nodular subependimaria y epilepsia.

Neuronal migration disorders may manifest as epilepsy alone and this is usually the case in nodular subependymal heterotopia, of which we present 5 cases. We consider this entity to be a well-defined epileptic syndrome because it is found nearly exclusively in women and is characterized by nearly constant seizures which start in the second or third decade of life, familial aggregation of cases, a clinical and EEG profile that suggests a temporal focus and the absence of associated cognitive or motor deficits. Seizures are usually controllable with medication.

[Janz's juvenile myoclonic epilepsy: a little-known frequent syndrome. A study of 85 patients]. / La epilepsia mioclónica juvenil de Janz: un síndrome frecuente poco conocido. Estudio de 85 pacientes.

BACKGROUND: Juvenile myoclonic epilepsy (JME) constitutes 10% of all epilepsies. Despite this syndrome being well defined, its diagnosis is usually delayed. The aim of this study was to analyze the clinical and electroencephalographic characteristics to facilitate guidelines to contribute to its recognition. METHODS: From January 1986 to July 1993 the clinical and EEG data of 85 patients with JME were prospectively studied. In 68 cases (80%) the polygraphic study of sleep was also analyzed during a nap period. RESULTS: The series included 44 males and 41 females of a mean age of 28 years (range: 13-63). Fifty-six percent of the cases showed family history of epilepsy and/or febrile convulsions. All the patients had myoclonic crisis with the age of 15 being the mean age of initiation (range: 8-27). Eighty-seven percent also had generalized tonic-clonic crisis and 18% typical absences. Myoclonias were presented daily up the administration of adequate treatment in 60% of the cases with 21% having myoclonic status. The mean interval from the initiation of the myoclonic crisis to diagnosis of JME was of 10.6 years. On monotherapy with valproic acid and following a mean follow up period of 23.8 months, 86% of the patients remained free of crisis. Nonetheless, the rate of recurrence was 100% in the 19 patients who discontinued the treatment. Surveillance EEG was normal on some occasion in 88% of the cases. The most characteristic paroxysms were the following: wave-point at 4-5 Hz and generalized rapid wave-polypoint. Light stimulation provoked a paroxysmal response in one third of the cases. Sleep EEG was abnormal in all the patients. An activation of the paroxysms during non-REM sleep in 78% of the cases and on waking up in 25%. CONCLUSIONS: Juvenile myoclonic epilepsy is a well defined syndrome. Its diagnosis is based on directed anamnesis allowing myoclonic jerks to be collected which often remain unperceived, and EEG exploration with sleep tracing in which the characteristic outbreaks of wave-point or generalized rapid wave-polypoints may be discovered.

[Prognosis of supratentorial parenchymal hemorrhages]. / Pronóstico de las hemorragias intracerebrales supratentoriales.

The prognostic value of a group of parameters recorded upon hospital admission was assessed in a series of 135 supratentorial hemorrhages. The patients were divided into 3 groups based on survival < 30 days, between 30 days and 1 year, or > 1 year. Patients in the group with the shortest survival period were older; had more Glasgow scale scores < or = 10 and more Canadian scale scores < or = 5; had more hematomas > or = 4 cm in diameter revealed in computerized tomography with frequent midline shift and frequent ventricular hemorrhagic invasion; had higher stress reaction (hyperglycemia, leukocytosis and heart arrhythmia). Cholesterinemia, however, was lower in the shortest survival group. A range of quality of life was observed in the group (44%) with survival longer than 1 year. The subgroup with motor independence (Rankin < 3) (19%) differed from those with less motor independence (Rankin > or = 3) in that they were younger, more often had mean scores > or = 5 on the Canadian scale and normal blood pressure levels. We conclude that prognostic value of the clinical evaluation scales used, along with age and size of hematoma, was good.

[Drug-resistant focal epilepsy with normal cranial CT. Electroclinical correlation and magnetic resonance in 45 patients]. / Epilepsia focal resistente a fármacos con TC craneal normal. Correlación electroclínica y resonancia magnética en 45 pacientes.

Forty-five patients between 15 and 60 years of age with pharmacoresistant focal epilepsy of more than 4 years duration with normal cranial CT were analyzed. Magnetic resonance and sleep EEG were performed. In 82% of the patients epilepsy had initiated prior to 20 years of age with 89% having partial complex crises and 75% also having secondary generalized crises. EEG demonstrated abnormalities in the temporal lobe in 78% of the cases. Activation of the abnormalities was observed during REM sleep in 24% of the patients. MR was pathologic in 38%, with the most frequent finding corresponding to a sole hyperintense T2 signal (76%). A good correlation was observed between the electroclinical findings and MR in 72% of the cases with pathologic MR. Most of these patients should, thus, be considered as candidates for surgical evaluation of their epilepsy.

[Epilepsy with myoclonic absences]. / La epilepsia con ausencias mioclónicas.

Within generalized epilepsy, the syndrome of epilepsy with myoclonic absences is considered as intermediate between idiopathic and symptomatic forms. This syndrome is characterized by developing in childhood with a male predominance. Critical EEG shows paroxysms of PO at 3 Hz, and in the polygraphic recording rhythmic 3 Hz myoclonus is observed with a strict correspondence between EEG spike and myoclonus. The response to therapy is generally poor, and 18% develop generalized symptomatic epilepsy. We report 3 patients with epilepsy with myoclonic absences and good outcome, to emphasize the importance of a precise diagnosis by means of the polygraphic recording of the attack, the fact the association of sodium valproate and ethosuximide is the most useful therapy and, finally, the possibility that some patients with epilepsy with myoclonic absence may develop Janz's juvenile myoclonic epilepsy.