Somatic mosaicism in a case of apparently sporadic Creutzfeldt-Jakob disease carrying a de novo D178N mutation in the PRNP gene.

Transmissible spongiform encephalopathies (TSEs) are a group of rare fatal neurodegenerative disorders. Creutzfeldt-Jakob disease (CJD) represents the most common form of TSE and can be classified into sporadic, genetic, iatrogenic and variant forms. Genetic cases are related to prion protein gene mutations but they only account for 10-20% of cases. Here we report an apparently sporadic CJD case with negative family history carrying a mutation at codon 178 of prion protein gene. This mutation is a de novo mutation as the parents of the case do not show it. Furthermore the presence of three different alleles (wild type 129M-178D and 129V-178D and mutated 129V-178N), confirmed by different methods, indicates that this de novo mutation is a post-zygotic mutation that produces somatic mosaicism. The proportion of mutated cells in peripheral blood cells and in brain tissue was similar and was estimated at approximately 97%, suggesting that the mutation occurred at an early stage of embryogenesis. Neuropathological examination disclosed spongiform change mainly involving the caudate and putamen, and the cerebral cortex, together with proteinase K-resistant PrP globular deposits in the cerebrum and cerebellum. PrP typing was characterized by a lower band of 21 kDa. This is the first case of mosaicism described in prion diseases and illustrates a potential etiology for apparently sporadic neurodegenerative diseases. In light of this case, genetic counseling for inherited and sporadic forms of transmissible encephalopathies should take into account this possibility for genetic screening procedures.

"Frontotemporoparietal" dementia: clinical phenotype associated with the c.709-1G>A PGRN mutation.

BACKGROUND: Mutations in the progranulin gene (PGRN) are a major cause of frontotemporal lobar degeneration with tau-negative and ubiquitin-positive neuronal inclusions. Most previous studies aimed at characterizing the clinical and neuropsychological phenotype of PGRN mutation carriers included patients with different PGRN mutations, assuming that the common proposed pathogenetic mechanism of haploinsufficiency will lead to a comparable phenotype. METHODS: We studied 21 patients with a single pathogenic splicing mutation in the PGRN gene (c.709-1G>A) in the same tertiary referral center using homogenous diagnostic criteria and protocols. All patients were of Basque descent. RESULTS: Patients exhibited a variable phenotype both in age at onset and initial symptoms. Behavioral variant frontotemporal dementia (52.4%) and progressive nonfluent aphasia (23.8%) were the most common presenting syndromes. Apathy was the most common behavioral symptom. Patients developed a relatively rapidly progressive dementia with features that led to a secondary diagnosis in 61.9% of cases 2 years after primary diagnosis. Notably, this secondary or tertiary diagnosis was corticobasal syndrome in 47.6% of cases, which confirmed the neuropsychological features of parietal lobe dysfunction seen at the initial assessment in 81.8% of patients. CONCLUSIONS: Patients carrying the c.709-1G>A mutation in the PGRN gene showed heterogeneous clinical and neuropsychological features and commonly developed corticobasal syndrome as the disease progressed.

[Coma associated with migraine]. / Coma asociado a migraña.

INTRODUCTION: Basilar migraine is a particular form of migraine with an aura in which crises of headache are accompanied by symptoms of dysfunction in the vertebro-basilar territory, including alteration of consciousness in the form of stupor or coma. CLINICAL CASES: We report four patients, three men of 14, 17 and 83 years of age and one woman of 21. All had previous histories of migraine and presented with transitory episodes of coma. During the coma, the woman woke up spontaneously with intense bulimia. In the three men, it was seen, on injecting flumazenil, that the state of consciousness and the EEG returned to normal transiently. Neuroimaging studies (CT and MR) were normal in all patients. CONCLUSIONS: Migraine-coma is an exceptional, emergency condition in which structural, infectious, toxic and metabolic pathology of the Central Nervous System should be ruled out. As well as in patients with basilar migraine, the association of migraine and coma may also be seen in patients with familial hemiplegic migraine and CADASIL and MELAS syndromes. It may be that gabaergic mechanisms are involved in the theoretical dysfunction of the ascending reticular activating system causing alteration of consciousness, since in the three patients in whom flumazenil was injected, there was a response.

[Multiple nerve root tumors and neurofibromatosis: contribution of magnetic resonance imaging]. / Tumores radiculares múltiples y neurofibromatosis: aportación de la resonancia magnética.

Three patients (two females and one male) with radiculospinal neurologic involvement secondary to different forms of neurofibromatosis are reported. The first two met the diagnostic criteria for NF-1, although case 2 had a posterior fossa meningioma, which is an uncommon finding in this group. The male patient had an apparently sporadic NF-2, with bilateral acoustic nerve neurinoma, multiple meningioma, multiple radicular neurinoma and an intraspinal tumor apparent in magnetic resonance imaging. In the three cases the whole central nervous system was evaluated with gadolinium-enhanced magnetic resonance imaging. A great number of radicular tumors, many of which were asymptomatic, were detected. In spite of the severity of the clinical features, the three patients showed a dramatic improvement after the surgical removal of the symptomatic tumors. The use of magnetic resonance is encouraged, owing to its high resolution and safety, for the assessment of incidence, character and localization of tumors in neurofibromatosis and to establish a good clinico-lesional correlation before surgery. This technique may help to a better understanding of the spectrum of abnormalities in each type of neurofibromatosis, thus facilitating the evaluation of this complex condition.

[Parkinsonism after methyl alcohol poisoning]. / Parkinsonismo tras intoxicación por alcohol metílico.

Two cases of parkinsonism due to methyl alcohol poisoning are reported. In the first patient, parkinsonism features were mild and stable, while in the second they progressively developed in the weeks following the poisoning. None of the two patients had significant visual abnormalities during the clinical evolution. Both patients had symmetrical putaminal lesions in CT, and one in NMR imaging. The response to antiparkinsonism drugs was absent in one case and it could not be evaluated in the other because of patient's death. On the basis of theses two cases the clinical and therapeutic features of this type of striatal parkinsonism are compared with those with parkinsonism due to other toxic agents. In view of the topography of the lesions of this poisoning, which is shared by other conditions such as Leber's disease or Leigh's syndrome, and the analogy with the presynaptic action of MPP+ in the parkinsonism due to MPTP, a possible implication of mitochondrial metabolism in the pathogenesis of this syndrome is discussed. The lack of knowledge of the real incidence of this complication in the survivors of methyl alcohol poisoning suggests the need to perform studies with a prolonged and systematic clinical follow up.