M. Urtasun

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.

Mutations in Progranulin Gene: Clinical, Pathological, and Ribonucleic Acid Expression Findings

BACKGROUND There is an increasing interest in the clinico-pathological correlation of mutations in progranulin (PGRN) and frontotemporal lobar degeneration (FTLD) complex diseases. We aim to study the PGRN expression variability in patients with different clinical features for a better understanding of its roles in FTLD disease. METHODS We sequenced the PGRN gene in 72 patients suffering from FTLD (25 familial and 47 sporadic cases) and in 24 asymptomatic at-risk relatives. We also analyzed PGRN expression in blood by quantitative real-time polymerase chain reaction from 37 patients, 8 asymptomatic mutation carriers, and 10 control subjects as well as in brain tissue from 16 patients and 9 control subjects. RESULTS Four novel mutations were associated with familial and sporadic FTLD and familial dementia associated with amyotrophic lateral sclerosis. We identified a close association between the IVS6-1G>A mutation in PGRN and corticobasal syndrome. Brain tissue was available for carriers of two of the four mutations (IVS6-1 G>A and P357HfsX3). Immunohistochemical analysis revealed ubiquitin- and TDP-43positive and tau/alpha-synuclein negative immunoreactive neuronal intranuclear inclusions. The relative expression of PGRN in the clinical sample was significantly lower in carriers of the IVS6-1 G>A than in control subjects. CONCLUSIONS Progranulopathies are a major cause of the main phenotypes included in the FTLD complex. According to our results, the level of expression of PGRN in blood could be a useful marker both for diagnostics of part of the spectrum of FTLD conditions and for monitoring future treatments that might boost the level of PGRN in this disorder.

Marchiafava-Bignami disease with widespread extracallosal lesions and favourable course.

Abstract We report a 61-year-old alcoholic man who presented with subacute physical deterioration and severe dysarthria. MRI, suggestive of corpus callosum demyelination with associated white matter involvement in both cerebral hemispheres, indicated the diagnosis of Marchiafava-Bignami disease. During his stay in hospital the patient showed remarkable improvement, and was discharged 22 days after admission. On MRI 2 months later, the extracallosal lesions had disappeared. This case raises questions about some previous ideas on this disease, such as the prognosis of its acute forms and the significance of the extracallosal lesions seen on neuroimaging.

The validity of Hodkinson's Abbreviated Mental Test for dementia screening in Guipuzcoa, Spain

The objective of this research was to evaluate the validity of Hodkinson’s Abbreviated Mental Test (AMT) in screening for dementia and to identify the optimum cut‐off point to use in a prevalence survey. The study included two groups of persons: (i) a random sample of 183 individuals selected from census data, 96 of whom completed the study and (ii) another 36 persons with dementia were selected from a hospital outpatients department by sampling consecutive cases. The DSM‐IV criteria were used as the ‘gold standard’ to establish a diagnosis of dementia. The AMT was administered to the 132 participants who subsequently underwent independent clinical evaluation. In the community sample, 11 persons were diagnosed with dementia and 85 without. In the total sample, a score of 7 maximizes the efficacy of the test. The sensitivity for this cut‐off point is 91.5% (78.7–97.2%) and the specificity is 82.4% (72.2–89.5%). A score of 9 gives 100% sensitivity, but the proportion of false positives rises to 66%. Our results are consistent with other studies and suggest that the AMT is a valid instrument for use in screening for dementia in populations similar to the one in this study.

A Common Haplotype Associated with the Basque 2362AG-TCATCT Mutation in the Muscular Calpain-3 Gene

Limb-girdle muscular dystrophy type 2A (LGMD2A) is caused by any of over 150 mutations in the calpain-3 (CAPN3) gene. Of those, 2362AG → TCATCT is particularly prevalent in Basque patients, and this mutation was hypothesized to have arisen in the Basque Country. To explore the natural history of this mutation, we genotyped 65 Basque and non-Basque patients with LGMD2A who carry the 2362AG → TCATCT mutation for four microsatellites within or flanking the gene. A particular haplotype was found in three-fourths of the patients and was assumed to be ancestral. From the average number of recombinations and mutations accumulated from this ancestral haplotype, the age of the 2362AG → TCATCT mutation was estimated to be 50 generations (i.e., 1,250 years), which is more recent than the Paleolithic Basque heritage. The subsequent spread of the 2362AG → TCATCT mutation can be related to gene flow out of the Basque Country, even across a cultural border.

Does the severity of the LGMD2A phenotype in compound heterozygotes depend on the combination of mutations

Introduction: Limb‐girdle muscular dystrophy type 2A (LGMD2A) is caused by a deficiency of calpain‐3/p94. Although the symptoms in most LGMD2A patients are generally homogeneous, some variation in the severity and progression of the disease has been reported. Methods: We describe 2 patients who carry the same combination of compound heterozygous mutations (pG222R/pR748Q) and whose symptoms are exceptionally benign compared to homozygotes with each missense mutation. Results: The benign phenotype observed in association with the combined pG222R and pR748Q mutations suggested that it may result from a compensatory effect of compound heterozygosity rather than the individual mutations themselves. Our analyses revealed that these two mutations exert different effects on the protease activity of calpain‐3, suggesting “molecular complementation” in these patients. Conclusion: We propose several hypotheses to explain how this specific combination of mutations may rescue the normal proteolytic activity of calpain‐3, resulting in an exceptionally benign phenotype. Muscle Nerve, 2011