Corticobasal syndrome (CBS) is a rare cognitive and movement disorder characterized by asymmetric rigidity, apraxia, alien-limb phenomenon, cortical sensory loss, myoclonus, focal dystonia, and dementia. It occurs along the clinical spectrum of frontotemporal lobar degeneration (FTLD), which has recently been shown to segregate with truncating mutations in progranulin (PGRN), a multifunctional growth factor thought to promote neuronal survival. This study identifies a novel splice donor site mutation in the PGRN gene (IVS7+1G-->A) that segregates with CBS in a Canadian family of Chinese origin. We confirmed the absence of the mutant PGRN allele in the RT-PCR product which supports the model of haploinsufficiency for PGRN-linked disease. This report of mutation in the PGRN gene in CBS extends the evidence for genetic and phenotypic heterogeneity in FTLD spectrum disorders.

Objective-Mutations in the Progranulin gene (PGRN) recently have been discovered to be associated with frontotemporal dementia (FTD) linked to 17q21 without identified MAPT mutations. The range of mutations of PGRN that can result in the FTD phenotype and the clinical presentation of patients with PGRN mutations have yet to be determined.Methods-In this study, we examined 84 FTD patients from families not known previously to have illness linked to chromosome 17 for identified PGRN and MAPT mutations and sequenced the coding exons and the flanking intronic regions of PGRN. We compared the prevalence, clinical characteristics, magnetic resonance imaging and 18-fluoro-deoxyglucose positron emission tomography results, and neuropsychological testing of patients with the PGRN R493X mutation with those patients without identified PGRN mutations.Results-We discovered a new PGRN mutation (R493X) resulting in a stop codon in two patients. This was the only PGRN mutation identified in our sample. The patients with the PGRN R493X mutation had a rapid illness course and had predominant right-sided atrophy and hypometabolism on magnetic resonance imaging and 18-fluoro-deoxyglucose positron emission tomography. The affected father of one of the patients with the PGRN R493X mutation showed frontal and temporal atrophy without neurofibrillary tangles on neuropathological examination.Interpretation-Known PGRN and MAPT mutations were rare and of similar prevalence in our sample (2 compared with 1/84). The patients with the PGRN R493X mutation had a clinical presentation comparable with other behavior-predominant FTD patients. The neuropathology of an affected family member of a patient with the PGRN R493X mutation appears not to be Alzheimer's disease. Frontotemporal dementia (FTD) is an umbrella term for a set of progressive disorders affecting predominantly the frontal and/or the anterior temporal lobes of the brain. FTD usually presents clinically with behavior or language changes, or both, and is associated with atrophy and decreased metabolism of the frontal and anterior temporal lobes on imaging. 1,2 The mean age of onset for FTD is in the mid-50s. 3,4 It is the second most common cause of dementia in people younger than 65 (after Alzheimer's disease), comprising approximately one third of these cases. 4,5 Between 35 and 50% of cases are reported to have a family history of FTD. [4][5][6][7][8][9][10] In the majority of these cases, the illness is inherited in a manner consistent with an autosomal dominant mechanism. 5,6,9 Fourteen percent of FTD patients have clinical motor neuron disease (MND), 11 and up to about 40% of patients with behavioral variant FTD show MND-type inclusions. 12 Several mutations have been associated with rare cases of FTD. 13 Mutations in the MAPT gene at 17q21 coding for the tau protein are the most commonly associated with FTD. 14-18 More than 30 MAPT mutations associated with the development of FTD have been discovered (a list of these mutations is available online at: http://www.molgen...

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Objective: Mutations in the progranulin (PGRN) gene were recently described as the cause of ubiquitin positive frontotemporal dementia (FTD). Clinical and pathological overlap between amyotrophic lateral sclerosis (ALS) and FTD prompted us to screen PGRN in patients with ALS and ALS-FTD. Methods: The PGRN gene was sequenced in 272 cases of sporadic ALS, 40 cases of familial ALS and in 49 patients with ALS-FTD. Results: Missense changes were identified in an ALS-FTD patient (p.S120Y) and in a single case of limb onset sporadic ALS (p.T182M), although the pathogenicity of these variants remains unclear. Conclusion: PGRN mutations are not a common cause of ALS phenotypes.A myotrophic lateral sclerosis (ALS) is a neurodegenerative disorder predominantly involving motor neurons leading to paralysis and death within 3-5 years from symptom onset. The pathogenic mechanism leading to motor neuron degeneration is unknown in the majority of cases. Frontotemporal dementia (FTD) is a degenerative disorder of the frontal and anterior temporal lobes.1 Clinical, pathological and genetic data suggest that ALS and FTD form a spectrum of disease.2 Approximately 5% of ALS patients have FTD (ALS-FTD) 3 and approximately half of patients with ''classical'' ALS have subtle frontal and temporal lobe cognitive impairment. 4 Many FTD cases similarly develop symptoms of motor neuron involvement during the course of their illness 5 and up to one third of FTD patients without overt motor symptoms have loss of anterior horn cells with characteristic ubiquitin inclusions in surviving motor neurons on autopsy. 6 Recently, mutations in the progranulin (PGRN) gene have been described as the cause of ubiquitin positive FTD. 7 8 The overlap between ALS and FTD prompted us to screen 272 cases of sporadic ALS, 40 familial ALS cases and 49 patients diagnosed with ALS-FTD for mutations in this gene. METHODS SubjectsGenetic studies were approved by local research ethics committees (NIA IRB protocol #2003-081). Diagnosis of ALS was based on the El Escorial diagnostic criteria.9 Samples used are outlined in table 1. The samples from the Coriell NINDS DNA repository consisted of 45 Caucasian women and 89 Caucasian men, with an average age of symptom onset of 54.3 years (range 26-81). Of these, 34 (25.4%) had bulbar onset disease, 98 (73.1%) had limb onset weakness and the remaining 2 (1.5%) cases presented with respiratory symptoms. Three sporadic ALS patients were reported to have cognitive changes, but did not have a formal diagnosis of FTD or dementia.Of the 48 Irish cases, 20 were women and 28 were men. Average age of symptom onset was 58.9 years (range 29-79). Eight (16.7%) patients initially manifested symptoms in bulbar musculature, 38 (79.2%) cases reported limb onset symptoms and the site of onset was unspecified in the remaining 2 (4.1%) cases.Samples obtained from the brain banks at Johns Hopkins University, Columbia University and the University of Miami, consisted of 26 women and 40 men (missing data = 15), with an average onset of 65.5 years...

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Introduction:Drug-seeking behavior (DSB) in the emergency department (ED) is a very common problem, yet there has been little quantitative study to date of such behavior. The goal of this study was to assess the frequency with which drug seeking patients in the ED use classic drug seeking behaviors to obtain prescription medication.Methods:We performed a retrospective chart review on patients in an ED case management program for DSB. We reviewed all visits by patients in the program that occurred during a 1-year period, and recorded the frequency of the following behaviors: complaining of headache, complaining of back pain, complaining of dental pain, requesting medication by name, requesting a refill of medication, reporting medications as having been lost or stolen, reporting 10/10 pain, reporting greater than 10/10 pain, reporting being out of medication, and requesting medication parenterally. These behaviors were chosen because they are described as “classic” for DSB in the existing literature.Results:We studied 178 patients from the case management program, who made 2,486 visits in 1 year. The frequency of each behavior was: headache 21.7%, back pain 20.8%, dental pain 1.8%, medication by name 15.2%, requesting refill 7.0%, lost or stolen medication 0.6%, pain 10/10 29.1%, pain greater than 10/10 1.8%, out of medication 9.5%, and requesting parenteral medication 4.3%. Patients averaged 1.1 behaviors per visit.Conclusion:Drug-seeking patients appear to exhibit “classically” described drug-seeking behaviors with only low to moderate frequency. Reliance on historical features may be inadequate when trying to assess whether or not a patient is drug-seeking.