Mutation screening of patients with Alzheimer disease identifies APP locus duplication in a Swedish patient

BACKGROUND: Missense mutations in three different genes encoding amyloid-β precursor protein, presenilin 1 and presenilin 2 are recognized to cause familial early-onset Alzheimer disease. Also duplications of the amyloid precursor protein gene have been shown to cause the disease. At the Dept. of Geriatric Medicine, Karolinska University Hospital, Sweden, patients are referred for mutation screening for the identification of nucleotide variations and for determining copy-number of the APP locus. METHODS: We combined the method of microsatellite marker genotyping with a quantitative real-time PCR analysis to detect duplications in patients with Alzheimer disease. RESULTS: In 22 DNA samples from individuals diagnosed with clinical Alzheimer disease, we identified one patient carrying a duplication on chromosome 21 which included the APP locus. Further mapping of the chromosomal region by array-comparative genome hybridization showed that the duplication spanned a maximal region of 1.09 Mb. CONCLUSIONS: This is the first report of an APP duplication in a Swedish Alzheimer patient and describes the use of quantitative real-time PCR as a tool for determining copy-number of the APP locus

Current status on Alzheimer disease molecular genetics: from past, to present, to future

Linkage studies, candidate gene and whole-genome association studies have resulted in a tremendous amount of putative risk genes for Alzheimer's disease (AD). Yet, besides the three causal genes—amyloid precursor protein and presenilin 1 and 2 genes—and one risk gene apolipoprotein E (APOE), no single functional risk variant was identified. Discussing the possible involvement of rare alleles and other types of genetic variants, this review summarizes the current knowledge on the genetic spectrum of AD and integrates different approaches and recent discoveries by genome-wide association studies

Modulation of γ-Secretase Activity by Multiple Enzyme-Substrate Interactions: Implications in Pathogenesis of Alzheimer's Disease

BACKGROUND: We describe molecular processes that can facilitate pathogenesis of Alzheimer's disease (AD) by analyzing the catalytic cycle of a membrane-imbedded protease γ-secretase, from the initial interaction with its C99 substrate to the final release of toxic Aβ peptides. RESULTS: The C-terminal AICD fragment is cleaved first in a pre-steady-state burst. The lowest Aβ42/Aβ40 ratio is observed in pre-steady-state when Aβ40 is the dominant product. Aβ42 is produced after Aβ40, and therefore Aβ42 is not a precursor for Aβ40. The longer more hydrophobic Aβ products gradually accumulate with multiple catalytic turnovers as a result of interrupted catalytic cycles. Saturation of γ-secretase with its C99 substrate leads to 30% decrease in Aβ40 with concomitant increase in the longer Aβ products and Aβ42/Aβ40 ratio. To different degree the same changes in Aβ products can be observed with two mutations that lead to an early onset of AD, ΔE9 and G384A. Four different lines of evidence show that γ-secretase can bind and cleave multiple substrate molecules in one catalytic turnover. Consequently depending on its concentration, NotchΔE substrate can activate or inhibit γ-secretase activity on C99 substrate. Multiple C99 molecules bound to γ-secretase can affect processive cleavages of the nascent Aβ catalytic intermediates and facilitate their premature release as the toxic membrane-imbedded Aβ-bundles. CONCLUSIONS: Gradual saturation of γ-secretase with its substrate can be the pathogenic process in different alleged causes of AD. Thus, competitive inhibitors of γ-secretase offer the best chance for a successful therapy, while the noncompetitive inhibitors could even facilitate development of the disease by inducing enzyme saturation at otherwise sub-saturating substrate. Membrane-imbedded Aβ-bundles generated by γ-secretase could be neurotoxic and thus crucial for our understanding of the amyloid hypothesis and AD pathogenesis

À propos d'une famille atypique d'adrénoleucodystrophie liée à l'X

Résumé en français : L'adrénoleucodystrophie récessive liée à l'X (X-ALD) est la maladie peroxysomale la plus commune, conséquence d'une mutation du gène ABCDI (Xq28). Elle est liée à une accumulation d'acides gras à très longue chaîne (AGTLC) due à un défaut de la bêta-oxydation des AGTLC dans les peroxysomes par carence d'une protéine transmembranaire appelée ALDP. L'incidence est de 1 pour 17 000 naissances, incluant les hémizygotes et les femmes hétérozygotes. Cette pathologie se manifeste par une démyélinisation progressive du système nerveux central plus ou moins associée à une maladie d'Addison. Cette maladie comporte une grande diversité phénotypique y compris intra-familiale associant des formes cérébrales progressives et graves de l'enfant à des formes médullaires lentement progressives de l'adulte dite adrénomyéloneuropathie (AMN). La pathogénie est complexe et la physiopathologie de l'atteinte reste méconnue. Notre propositus âgé de 38 ans présentait des troubles psychiatriques inauguraux à type d'apathie, d'euphorie, troubles de la personnalité. L'évolution était marquée par un syndrome démentiel et un état végétatif. L'examen clinique, l'analyse biochimique et moléculaire confirmèrent le diagnostic. Nous décrivons une famille d'X-ALD qui illustre la diversité phénotypique. Il n'y a pas de corrélation génotype et phénotype ce qui suggère l'intervention de facteurs environnementaux ou facteurs modificateurs de gènes. Le conseil génétique est indispensable pour identifier les femmes conductrices et les garçons encore asymptomatiques sur le plan neurologique d'autant qu'un traitement ne peut être proposé qu'au stade asymptomatique. La seule thérapie ayant démontré une efficacité certaine est la greffe allogénique de moelle osseuse.Résumé en anglais :The X-linked adrenoleukodystrophy (X-ALD) is the most frequent peroxisomal disorder caused by mutations of the ABCDl gene located at Xq28. The incidence is 1/17 000 births, including hemizygotes and heterozygotes women. This gene encodes for the adrenoleukodystrophy protein (ALDP), an adenosine triphosphate (ATP) binding cassette transporter, subfamily D, member 1 in the peroxisomal membrane. Phenotype is characterized by adrenal insufficiency and progressive demyelinisation of the central nervous system. This neurological disease ranges from the childhood cerebral ALD characterized by rapidly progressive demyelinisation that leads to vegetative stage or death within 2-5 years to the adult milder adrenomyeloneuropathy characterized by progressive paraparesis. The ALDP defects lead to accumulation of satured very-long-chain fatty acids (VLCFA) in the serum and tissues, due to reduced P-oxidation of VLCFA in peroxisomes. The exact role of ALDP in the metabolism of VLCFA is still not understood. Our propositus was 38-year-old and presented a gradual development of psychiatric symptomatology. Since one year, behavioural changes such as fluctuation of apathy, euphoria and personality disturbance progress. Evolution was marked by dementia and vegetative status. The clinical, biochemical and genetic examination confirmed the diagnosis. We described his family, which illustrated diversity of phenotype. No genotype phenotype correlation has been found, which suggests modifier genes or environmental factors. Diagnosis is very important because of genetic counseling and therapeutic can be performed: allogenic bone-barrow transplantation and the first autologous bone-marrow transplants genetically corrected ex vivo.ROUEN-BU Médecine-Pharmacie (765402102) / SudocSudocFranceF

Acute hemichorea revealing atrial flutter

Transient ischemic attacks (TIAs) typically present with easily recognizable neurological focal deficits. Symptoms such as paroxysmal involuntary movements are not usually considered to be a manifestation of TIA. We report a case with video documentation of TIA due to permanent atrial flutter presenting as acute left hemichorea. To our knowledge, such a case has not yet been reported. The present case constitutes a crucial diagnostic challenge in neurological practice in order to prevent a high risk of subsequent ischemic stroke

Novel VCP mutations in inclusion body myopathy associated with Paget disease of bone and frontotemporal dementia

Inclusion body myopathy associated with Paget disease of bone and frontotemporal dementia (IBMPFD, OMIM 167320) has recently been attributed to eight missense mutations in valosin-containing protein (VCP). We report novel VCP mutations N387H and L198W in six individuals from two families who presented with proximal muscle weakness at a mean age of diagnosis of 40 years, most losing the ability to walk within a few years of onset. Electromyographic studies in four individuals were suggestive of \u27myopathic\u27 changes, and neuropathic pattern was identified in one individual in family 1. Muscle biopsy in four individuals showed myopathic changes characterized by variable fiber size, two individuals showing rimmed vacuoles and IBM-type cytoplasmic inclusions in muscle fibers, and electron microscopy in one individual revealing abundant intranuclear inclusions. Frontotemporal dementia associated with characteristic behavioral changes including short-term memory loss, language difficulty, and antisocial behavior was observed in three individuals at a mean age of 47 years. Detailed brain pathology in one individual showed cortical degenerative changes, most severe in the temporal lobe and hippocampus. Abundant ubiquitin-positive tau-, alpha-synuclein-, polyglutamine repeat-negative neuronal intranuclear inclusions and only rare intracytoplasmic VCP positive inclusions were seen. These new mutations may cause structural changes in VCP and provide some insight into the functional effects of pathogenic mutations