4 results on '"Natowicz MR"'
Search Results
2. Dravet syndrome patient-derived neurons suggest a novel epilepsy mechanism.
- Author
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Liu Y, Lopez-Santiago LF, Yuan Y, Jones JM, Zhang H, O'Malley HA, Patino GA, O'Brien JE, Rusconi R, Gupta A, Thompson RC, Natowicz MR, Meisler MH, Isom LL, and Parent JM
- Subjects
- Cell Differentiation, Cells, Cultured, Child, Female, Fibroblasts physiology, Humans, Inhibitory Postsynaptic Potentials genetics, Male, Membrane Potentials, Patch-Clamp Techniques, Epilepsies, Myoclonic genetics, Epilepsies, Myoclonic pathology, Mutation genetics, NAV1.1 Voltage-Gated Sodium Channel genetics, Neurons physiology
- Abstract
Objective: Neuronal channelopathies cause brain disorders, including epilepsy, migraine, and ataxia. Despite the development of mouse models, pathophysiological mechanisms for these disorders remain uncertain. One particularly devastating channelopathy is Dravet syndrome (DS), a severe childhood epilepsy typically caused by de novo dominant mutations in the SCN1A gene encoding the voltage-gated sodium channel Na(v) 1.1. Heterologous expression of mutant channels suggests loss of function, raising the quandary of how loss of sodium channels underlying action potentials produces hyperexcitability. Mouse model studies suggest that decreased Na(v) 1.1 function in interneurons causes disinhibition. We aim to determine how mutant SCN1A affects human neurons using the induced pluripotent stem cell (iPSC) method to generate patient-specific neurons., Methods: Here we derive forebrain-like pyramidal- and bipolar-shaped neurons from 2 DS subjects and 3 human controls by iPSC reprogramming of fibroblasts. DS and control iPSC-derived neurons are compared using whole-cell patch clamp recordings. Sodium current density and intrinsic neuronal excitability are examined., Results: Neural progenitors from DS and human control iPSCs display a forebrain identity and differentiate into bipolar- and pyramidal-shaped neurons. DS patient-derived neurons show increased sodium currents in both bipolar- and pyramidal-shaped neurons. Consistent with increased sodium currents, both types of patient-derived neurons show spontaneous bursting and other evidence of hyperexcitability. Sodium channel transcripts are not elevated, consistent with a post-translational mechanism., Interpretation: These data demonstrate that epilepsy patient-specific iPSC-derived neurons are useful for modeling epileptic-like hyperactivity. Our findings reveal a previously unrecognized cell-autonomous epilepsy mechanism potentially underlying DS, and offer a platform for screening new antiepileptic therapies., (© 2013 American Neurological Association.)
- Published
- 2013
- Full Text
- View/download PDF
3. Adult polyglucosan body disease: Natural History and Key Magnetic Resonance Imaging Findings.
- Author
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Mochel F, Schiffmann R, Steenweg ME, Akman HO, Wallace M, Sedel F, Laforêt P, Levy R, Powers JM, Demeret S, Maisonobe T, Froissart R, Da Nobrega BB, Fogel BL, Natowicz MR, Lubetzki C, Durr A, Brice A, Rosenmann H, Barash V, Kakhlon O, Gomori JM, van der Knaap MS, and Lossos A
- Subjects
- 1,4-alpha-Glucan Branching Enzyme genetics, 1,4-alpha-Glucan Branching Enzyme metabolism, Adult, Aged, Cerebral Cortex pathology, Female, France, Humans, Israel, Kaplan-Meier Estimate, Male, Middle Aged, Mutation genetics, Netherlands, Neurologic Examination, Spinal Cord pathology, United States, Glycogen Storage Disease genetics, Glycogen Storage Disease pathology, Glycogen Storage Disease physiopathology, Magnetic Resonance Imaging, Nervous System Diseases genetics, Nervous System Diseases pathology, Nervous System Diseases physiopathology
- Abstract
Objective: Adult polyglucosan body disease (APBD) is an autosomal recessive leukodystrophy characterized by neurogenic bladder, progressive spastic gait, and peripheral neuropathy. Polyglucosan bodies accumulate in the central and peripheral nervous systems and are often associated with glycogen branching enzyme (GBE) deficiency. To improve clinical diagnosis and enable future evaluation of therapeutic strategies, we conducted a multinational study of the natural history and imaging features of APBD., Methods: We gathered clinical, biochemical, and molecular findings in 50 APBD patients with GBE deficiency from Israel, the United States, France, and the Netherlands. Brain and spine magnetic resonance images were reviewed in 44 patients., Results: The most common clinical findings were neurogenic bladder (100%), spastic paraplegia with vibration loss (90%), and axonal neuropathy (90%). The median age was 51 years for the onset of neurogenic bladder symptoms, 63 years for wheelchair dependence, and 70 years for death. As the disease progressed, mild cognitive decline may have affected up to half of the patients. Neuroimaging showed hyperintense white matter abnormalities on T2 and fluid attenuated inversion recovery sequences predominantly in the periventricular regions, the posterior limb of the internal capsule, the external capsule, and the pyramidal tracts and medial lemniscus of the pons and medulla. Atrophy of the medulla and spine was universal. p.Y329S was the most common GBE1 mutation, present as a single heterozygous (28%) or homozygous (48%) mutation., Interpretation: APBD with GBE deficiency, with occasional exceptions, is a clinically homogenous disorder that should be suspected in patients with adult onset leukodystrophy or spastic paraplegia with early onset of urinary symptoms and spinal atrophy., (Copyright © 2012 American Neurological Association.)
- Published
- 2012
- Full Text
- View/download PDF
4. Pelizaeus-Merzbacher disease presenting as spinal muscular atrophy: clinical and molecular studies.
- Author
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Kaye EM, Doll RF, Natowicz MR, and Smith FI
- Subjects
- Brain pathology, Child, Preschool, Diagnosis, Differential, Diffuse Cerebral Sclerosis of Schilder genetics, Humans, Infant, Newborn, Magnetic Resonance Imaging, Male, Pedigree, Point Mutation genetics, Diffuse Cerebral Sclerosis of Schilder diagnosis, Spinal Muscular Atrophies of Childhood diagnosis
- Abstract
Two brothers with profound neonatal hypotonia and hyporeflexia and electrodiagnostic testing consistent with lower motor neuron pathology were found to have a leukodystrophy. Using single-strand conformational polymorphism analysis and direct sequencing, a mutation within exon 3 of the gene encoding proteolipid protein (Gly73Arg substitution) was previously detected in both brothers and their mother, establishing the diagnosis of Pelizaeus-Merzbacher disease. Despite reported sparing of the peripheral nervous system in Pelizaeus-Merzbacher disease, we suggest that proteolipid protein gene products may influence the development of anterior horn cells or peripheral nervous system myelin and that some individuals affected with this disease may present with clinical and electromyographic features suggestive of neonatal spinal muscular atrophy.
- Published
- 1994
- Full Text
- View/download PDF
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