J.F. Martí-Massó

Autosomal dominant lateral temporal epilepsy: Clinical and genetic study of a large basque pedigree linked to chromosome 10q

We report a large family with a temporal partial epilepsy syndrome inherited in an autosomal dominant mode, with a penetrance of about 80%. This epilepsy syndrome is benign, with age of onset in the second or third decade of life. It is characterized by rare partial seizures, usually secondarily generalized, arising mostly during sleep, without postictal confusion. There is a good response to the antiepileptic therapy but often a recurrence of seizures after drug withdrawal. The partial component, visual (lights, colors, and simple figures) or auditory (buzzing or “humming like a machine”), the existence of temporo‐occipital interictal electroencephalographic epileptiform abnormalities, and the hypoperfusion in the temporal lobe detected by interictal hexamethylpropyleneamine oxime–technetium 99m (HMPAO‐Tc99m) single‐photon emission computed tomography, strongly suggest a lateral temporal lobe origin. The genetic analysis found linkage to chromosome 10q, and localized a gene in a 15‐cM interval that overlaps a previously found localization for partial epilepsy in a large three‐generation family. This syndrome could be called autosomal dominant lateral temporal epilepsy. Ann Neurol 1999;45:182–188

Phenotypic variability in familial prion diseases due to the D178N mutation

Background: Between January 1993 and December 2003, 19 patients with familial prion diseases due to the D178N mutation were referred to the regional epidemiological registry for spongiform encephalopathies in the Basque Country in Spain, a small community of some 2 100 000 inhabitants. Methods: Ten further patients belonging to the same pedigrees were retrospectively ascertained through neurological or neuropathological records. In four of the patients, the diagnosis was confirmed by analysing DNA obtained from paraffin blocks. In this article, we report on the clinical, genetic, and pathological features of the 23 patients carrying the D178N mutation confirmed by genetic molecular analysis. Haplotyping studies suggest a founder effect among Basque born families, explaining in part this unusually high incidence of the D178N mutation in a small community. Only two patients (8%) lack familial antecedents. Results: We have observed a phenotypic variability even among homozygous 129MM patients. Our findings challenge the currently accepted belief that MM homozygosity in codon 129 is always related to a fatal familial insomnia (FFI) phenotype. Indeed, seven out of 17 patients with a 129MM genotype in this series presented with a Creutzfeldt-Jakob disease (CJD) clinicopathological picture. Conclusions: The considerable clinical and pathological overlapping observed among homozygous 129MM patients favours the view that FFI and CJD178 are the extremes of a spectrum rather than two discrete and separate entities. Other genetic or environmental factors apart from the polymorphism in codon 129 may play a role in determining the phenotypic expression of the D178N mutation in the PRNP gene.

Prevalence of Parkinson’s disease and other types of Parkinsonism

Abstract.Objectives:To assess the prevalence of Parkinson’s disease and parkinsonism in two Spanish populations (Irun and Hondarribia, Bidasoa Region) and to compare the results with those of similar surveys.Methods:The survey included 2000 participants aged 65 years or older in a door-to-door, three-phase design. In the screening phase we used the SNES (Sicilian Neuro-Epidemiologic Study) screening questionnaire, which has 100% sensitivity. In phases 2 and 3 we carried out a 3-year follow-up of all cases diagnosed with parkinsonism in phase 2. Progressively stricter diagnostic criteria were chosen in order to minimize the impact of false positives on the final results.Results:The prevalence of Parkinson’s disease (PD) was 1.5 % (95% confidence interval, 0.9 to 2.3) and the prevalence of other types of parkinsonism (OP) was 1.1 % (95% confidence interval 0.6 to 1.9). The overall prevalence by age group was 0.4 % (65–74 years), 4.7% (75–84 years), and 2.9% (≥ 85 years) for Parkinson’s disease and 0.7%, 2%, and 3.9 % for parkinsonism, respectively. The other parkinsonism prevalence was 1.3 % in men and 1.6 % in women.Conclusions:These prevalence rates are similar than those found in studies made in other European countries. The prevalence of both Parkinson’s disease and other types of parkinsonism increased with age, with no significant differences between men and women.

Parkinson's disease due to the R1441G mutation in Dardarin: A founder effect in the basques

The recent discovery of mutations in Dardarin (LRRK2) have been related to the appearance of Parkinsons disease in several families. Notably, one single mutation in this gene (R1441G) not only appeared in familial, but also in apparently sporadic Parkinson disease (PD) patients of Basque descent. A clinical population was ascertained, and subjects were classified into Basque and non‐Basque descent according to their known ancestry. The R1441G mutation was assayed using an allele‐specific polymerase chain reaction, and several single nucleotide polymorphisms surrounding this mutation were analyzed by direct sequencing. In addition to 22 members of the original Basque families where R1441G was identified, we observed 17 carriers of the mutation who were apparently related through a common ancestor. From a clinical perspective, the disease observed in mutation carriers is indistinguishable from that in noncarriers. The R1441G mutation causes a form of Parkinsons disease that is equivalent to that observed in idiopathic Parkinsons disease. This mutation appears in 16.4% and 4.0% of familial and sporadic PD in this Basque population, respectively.

Neuropathology of Parkinson's Disease with the R1441G Mutation in LRRK2

We report the neuropathological findings in a patient with Parkinsons disease (PD) associated with Basque R1441G‐LRRK2/dardarin mutation. The patient was a man with disease onset at 68 years of age, with unilateral rest tremor; the Parkinsonism was well controlled with medication for 15 years. He died at the age of 86, after 18 years of evolution. The neuropathological examination disclosed mild neuronal loss in the substantia nigra pars compacta without α‐synuclein, tau, LRRK2, or ubiquitin cytoplasmic inclusions. Lewy bodies and Lewy neurites were absent. This is the first neuropathological study of PD associated with brain with the R1441G mutation in LRRK2.

Tremor dominant parkinsonism: Clinical description and LRRK2 mutation screening

Tremor dominant parkinsonism (TDP) is characterized by initial prominent resting and action tremor, mild parkinsonism, unpredictable response to medication, and a better prognosis than idiopathic Parkinsons disease (PD). We report on clinical features and longitudinal course of 26 patients suffering from TDP. Mean disease duration was 6.5 ± 3 years, 61.5% of patients had a positive family history of tremor, 73% did not need drug treatment, performance of 123I‐Ioflupane SPECT showed reduced striatal tracer uptake in 65.4% of patients, and odor identification testing was pathologic in all the patients tested (n = 22). Co‐occurrence of action and resting tremor were the most annoying and disabling symptoms in all the patients, whereas rigidity and/or bradykinesia were clinically irrelevant in most of them. We also sequenced the full coding region of the Leucine‐rich repeat kinase 2 gene (LRRK2) in all patients. We found a novel Val2390Met mutation that was not found in 864 chromosomes. Our results suggest a broader clinical heterogeneity related to LRRK2 mutations and points towards TDP as a subtype within the spectrum of PD, in which disabling tremor but otherwise mild parkinsonian signs and a better prognosis are the main characteristics.

Apolipoprotein E ɛ4 allele in familial and sporadic Parkinson's disease

Abstract Parkinsons disease (PD) is the second most common age-related neurodegenerative disease after Alzheimers disease (AD). Common risk factors for both diseases have been explored to study potential etiologic interactions between these two neurodegenerative disorders. The APOEɛ4 allele, previously associated with AD, has also been associated with risk of PD and with the presence of some clinical features in PD patients. However, the role of APOE ɛ4 allele in risk of PD remains unclear. We studied the distribution of APOE alleles in 276 unrelated familial and sporadic PD patients and in 212 controls. Patients and controls were classified by ethnicity. No genetic heterogeneity between Basques and people from other regions of Spain was found. No significant differences in APOE allele distribution between PD patients and controls were found; however, lower ɛ4 allele frequency was observed when the sporadic PD group was analyzed separately. By contrast, an increase in ɛ4 allele frequency was found in familial PD patients with cognitive decline. We conclude that the APOE ɛ4 allele may be associated with the risk of developing PD in isolated cases and that it is linked to the presence of cognitive decline in familial PD in our sample.

Mitochondrial polymporphisms in Parkinson's Disease

The mtDNA polymorphisms A4336G, A10398G and T4216C have been associated with PD. While A4336G is thought to be a genetic risk factor, A10398G appears to be a protective factor and T4216C is only weakly associated with the disease. In this work we analyzed the association between these three genetic polymorphisms and PD in a Spanish-PD population. The samples were classified by ethnic origin in Basques or other origin. Our analysis confirm the association between A4336G and PD. Our results with A10398G polymorphism highlight the importance of performing the association studies in ethnically homogeneous populations.

Prevalence of Essential Tremor: A Door-to-Door Survey in Bidasoa, Spain

Objectives: To assess the prevalence of essential tremor (ET) in two Spanish populations (Irun and Hondarribia, Bidasoa region) and to compare the results with those of similar surveys. Methods: The survey included 2,000 participants aged 65 years or older in a door-to-door, two-phase design. ET was defined as postural or kinetic tremor of the head or limbs. Results: ET prevalence after age adjustment was 4.8% (95% confidence interval, 3.6–6.4). Prevalence increased significantly with age and there were no sex differences. Conclusions: The age-adjusted prevalence rate of ET in people 65 years old and older in Bidasoa, Spain, is close to those described in other studies using a similar design and suggest no geographical variation. ET prevalence increases with age and has a similar distribution in males and females.

Clinical signs of brain death simulated by Guillain-Barré syndrome

A 58-year-old woman with relapsing acute Guillain-Barré syndrome separated by long asymptomatic intervals presented clinical symptoms resembling those of brain death. She remained in this situation for 15 days and recovered with amnesia for this period. The amnesia was not explained either by metabolic encephalopathy or by sedative drugs. This case stresses the importance of the precise etiologic diagnosis of severe brain disease and the isoelectric EEG in brain death.