Terry Heiman-Patterson
Temple University, Neurology, Faculty Member
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Background Edaravone slowed the rate of functional decline in subjects with amyotrophic lateral sclerosis (ALS) in phase 3 study MCI186-19 (Study 19). One of the Study 19 inclusion criteria was forced vital capacity (FVC) ≥80% of... more
Background Edaravone slowed the rate of functional decline in subjects with amyotrophic lateral sclerosis (ALS) in phase 3 study MCI186-19 (Study 19). One of the Study 19 inclusion criteria was forced vital capacity (FVC) ≥80% of predicted (≥80%p). Therefore, the study provided no information on edaravone efficacy in subjects with FVC <80%p. In Study 19, 24-week, double-blind treatment was followed by open-label treatment where all subjects received edaravone. At 24 weeks, some subjects had FVC <80%p (FVC24 <80%p). This allowed for post-hoc assessment of the effects of edaravone in subgroups of subjects with FVC24 ≥80%p vs <80%p. Objective To address the question of the efficacy of edaravone in ALS patients with FVC <80%p. Methods Post-hoc analysis of Study 19 comparing edaravone efficacy at week 48 in subjects with FVC24 ≥80%p vs <80%p. Results With edaravone treatment, subjects in both the FVC24 ≥80%p and the FVC24 <80%p subgroups experienced a reduction in AL...
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Myophosphorylase deficiency (McArdle disease) is one of the most common causes of exercise intolerance, cramps, and recurrent myoglobinuria. We have described nine mutations in the myophosphorylase gene associated with McArdle disease.... more
Myophosphorylase deficiency (McArdle disease) is one of the most common causes of exercise intolerance, cramps, and recurrent myoglobinuria. We have described nine mutations in the myophosphorylase gene associated with McArdle disease. One of them, a nonsense mutation (CGA to TGA) at codon 49 (mut-49), was the most frequently observed and was present in at least one allele in 75% of
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We present a family with severe exercise intolerance, progressive proximal weakness, and lactic acidemia. Fifteen of 24 family members in five generations were affected. Since the affected males do not have offspring at this time, the... more
We present a family with severe exercise intolerance, progressive proximal weakness, and lactic acidemia. Fifteen of 24 family members in five generations were affected. Since the affected males do not have offspring at this time, the family pedigree is consistent with either maternal or autosomal dominant inheritance. Muscle histochemistry showed ragged-red fibers and electron microscopy showed globular mitochondrial inclusions. Biochemical analysis showed reduced muscle activities of mitochondrial NADH-cytochrome c reductase (1 of 2 patients), succinate-cytochrome c reductase (2 patients), and cytochrome c oxidase (2 patients). For 1 patient, sequence analysis of 44% of the muscle mitochondrial DNA including all 22 transfer RNA regions showed no point mutation with pathogenic significance. Southern blot analysis showed no deletion. Six affected members of the family were treated with methylprednisolone (0.25 mg/kg) for 3 months. Muscle strength, serum lactate, and energy metabolism at rest (measured by 31P magnetic resonance spectroscopy) significantly improved with treatment.
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To describe a syndrome of severe progressive myopathy, cardiomyopathy, and gastrointestinal dysmotility in 2 patients with asymptomatic primary biliary cirrhosis (PBC) and circulating antimitochondrial autoantibodies, and to review... more
To describe a syndrome of severe progressive myopathy, cardiomyopathy, and gastrointestinal dysmotility in 2 patients with asymptomatic primary biliary cirrhosis (PBC) and circulating antimitochondrial autoantibodies, and to review pertinent literature concerning this syndrome. Clinical, electrophysiologic, serologic, and pathologic studies of the 2 affected patients were conducted. Skeletal muscle involvement was manifested by progressive weakness of the proximal muscles, marked diaphragmatic dysfunction with consequent hypoventilation and respiratory failure, and moderately elevated levels of muscle-associated enzymes. Serum from both patients contained antimitochondrial antibodies that reacted with components of the mitochondrial keto acid dehydrogenase enzyme complex. Results of electromyography were consistent with a myopathic process. The microscopic and ultrastructural changes in the skeletal muscles were distinct from those of typical myositis, and were notable for striking subsarcolemmal aggregation of abnormal mitochondria in the absence of significant inflammation. Severe skeletal muscle, cardiac, and gastrointestinal pathology with abnormalities of the muscle mitochondria develops in a subset of patients with mild PBC and antimitochondrial antibodies. The pathogenesis of this syndrome is unclear, but may be related to the presence of the antimitochondrial autoantibodies.
Research Interests: Pathology, Immunology, Mitochondria, Medicine, Humans, and 14 moreFemale, Muscles, Arthritis, Clinical Sciences, Middle Aged, Fluorescent Antibody Technique, Adult, Myositis, Myopathy, Public health systems and services research, Asymptomatic, Primary Biliary Cirrhosis, Multiple Organ Failure, and Autoantibodies
Objectives: To examine background effects on disease phenotype in the Dynactin p150 glued mouse model of motor neuron disease(MND). Background: The G93AmSOD1 mouse model of ALS, originally bred on a mixed B6/SJL background, has a more... more
Objectives: To examine background effects on disease phenotype in the Dynactin p150 glued mouse model of motor neuron disease(MND). Background: The G93AmSOD1 mouse model of ALS, originally bred on a mixed B6/SJL background, has a more severe phenotype on a pure SJL background but a milder phenotype on the B6 background compared to the mixed background. These differences are linked to a genetic modifier within a Chromosome 17 QTL. Once identified, these modifiers would be of great interest, especially if they were shown to affect other MND phenotypes. The Dynactin p150glued mouse model is based on a slowly progressive lower motor neuron disease, linked to a mutation in the p150Glued subunit of the dynactin complex, that demonstrates clinical and pathologic changes of motor neuron disease. Methods: We developed two inbred strains (C57BL/6J and SJL/J) expressing the mutant human Dynactin p150 glued originally bred on a mixed background of C57BL/6J and SJL/J. Onset of tremor along with ...
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Limited evidence exists on real-world adherence to nusinersen for the treatment of spinal muscular atrophy (SMA). Data are presented from a multi-site retrospective chart review of 86 adults with SMA initiating nusinersen at nine US... more
Limited evidence exists on real-world adherence to nusinersen for the treatment of spinal muscular atrophy (SMA). Data are presented from a multi-site retrospective chart review of 86 adults with SMA initiating nusinersen at nine US centers between January 2017 and February 2019. Seventy-nine (92%) adults remained on nusinersen during the study; 454 (92%) of 493 total nusinersen doses were received on time. Fifty-eight (67%) adults received all nusinersen doses on time. The majority of patients with at least one nonadherent dose resumed nusinersen on time. Most patients followed the dosing schedule across the loading and maintenance dose periods.
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Objective: To examine whether the responses to standard dyspnea questionnaires and a new functional dyspnea scale modified for use in ALS correlate with measures of pulmonary function and can be administered by phone Background:... more
Objective: To examine whether the responses to standard dyspnea questionnaires and a new functional dyspnea scale modified for use in ALS correlate with measures of pulmonary function and can be administered by phone Background: Noninvasive ventilation (NIV) is initiated in ALS when Forced Vital Capacity (FVC) falls below 50% or the patient is dyspneic. While several respiratory scales measure symptoms of dyspnea in patients with pulmonary diseases, it is unclear if these scales are applicable to ALS patients and correlate with FVC Design/Methods: 153 ALS subjects in a pilot study of Nutrition (80) and NIV 73) in ALS completed three dyspnea scales: the Medical Research Council Dyspnea Scale (MDS,0 to 5), the Borg Dyspnea score (0 to 10) and the ALSFDS score(sum of 12 questions, each 1-10) at baseline and follow-up (16,32, and 48 weeks). All participants had sitting FVC(sFVC), and NIV subjects had supine FVC (lFVC) and nasal inspiratory pressure(SNIP). Relationship between measurements was evaluated using Pearson/Spearman Correlation Coefficients. NIV subjects had telephone administration of scales before week 16 and 48 visits. Results: 153 subjects completed baseline visits. Fewer than 1% had a total score of zero on the ALSFDS scale, while 76.9% and 34.0% scored zero (indicating no symptoms) on the Borg and MDC scales respectively whereas the ALSFDS was more sensitive. The ALSFDS was significantly correlated with laying and sitting FVC and SNIP at baseline, 32 and 48 weeks and with the ALSFRS-R. ALSFDS phone scores correlated with office scores at 16(ρ=0.73; p\u3c0.001) and 48(ρ=0.67; p\u3c0.001) weeks Conclusions: The ALSFDS scale is a more sensitive measure of dyspnea in ALS than MDS or Borg scales; correlates with the ALSFRS-R and pulmonary impairment, and is validated for telephone administration. This scale may be important for determining who is at risk for pulmonary compromise and in assessing efficacy of respiratory interventions in ALS trials
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An orally administered, fixed‐dose coformulation of sodium phenylbutyrate‐taurursodiol (PB‐TURSO) significantly slowed functional decline in a randomized, placebo‐controlled, phase 2 trial in ALS (CENTAUR). Herein we report results of a... more
An orally administered, fixed‐dose coformulation of sodium phenylbutyrate‐taurursodiol (PB‐TURSO) significantly slowed functional decline in a randomized, placebo‐controlled, phase 2 trial in ALS (CENTAUR). Herein we report results of a long‐term survival analysis of participants in CENTAUR. In CENTAUR, adults with ALS were randomized 2:1 to PB‐TURSO or placebo. Participants completing the 6‐month (24‐week) randomized phase were eligible to receive PB‐TURSO in the open‐label extension. An all‐cause mortality analysis (35‐month maximum follow‐up post‐randomization) incorporated all randomized participants. Participants and site investigators were blinded to treatment assignments through the duration of follow‐up of this analysis. Vital status was obtained for 135 of 137 participants originally randomized in CENTAUR. Median overall survival was 25.0 months among participants originally randomized to PB‐TURSO and 18.5 months among those originally randomized to placebo (hazard ratio, 0.56; 95% confidence interval, 0.34‐0.92; P = .023). Initiation of PB‐TURSO treatment at baseline resulted in a 6.5‐month longer median survival as compared with placebo. Combined with results from CENTAUR, these results suggest that PB‐TURSO has both functional and survival benefits in ALS.
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Our research aim was to develop a novel clinimetric scale sensitive enough to detect disease progression in primary lateral sclerosis (PLS).
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The hereditary spastic paraplegias (HSPs; Strümpell-Lorrain syndrome, MIM number 18260) are a diverse class of disorders characterized by insidiously progressive lower-extremity spastic weakness (reviewed in refs. 1-3). Eight autosomal... more
The hereditary spastic paraplegias (HSPs; Strümpell-Lorrain syndrome, MIM number 18260) are a diverse class of disorders characterized by insidiously progressive lower-extremity spastic weakness (reviewed in refs. 1-3). Eight autosomal dominant HSP (ADHSP) loci have been identified, the most frequent of which is that linked to the SPG4 locus on chromosome 2p22 (found in approximately 42%), followed by that linked to the SPG3A locus on chromosome 14q11-q21 (in approximately 9%). Only SPG4 has been identified as a causative gene in ADHSP. Its protein (spastin) is predicted to participate in the assembly or function of nuclear protein complexes. Here we report the identification of mutations in a newly identified GTPase gene, SPG3A, in ADHSP affected individuals.
Research Interests: Genetics, Biology, Membrane Proteins, Medicine, Biological Sciences, and 15 moreIdentification, Humans, Mutation, Female, Male, Gene, Pedigree, Gen, Hereditary spastic paraplegia, Amino Acid Sequence, Base Sequence, Gtp Binding Proteins, Molecular Sequence Data, Autosomal Dominant, and Medical and Health Sciences
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Research Interests: Genetics, Cognitive Science, Medical Genetics, Biology, Medicine, and 15 moreBiological Sciences, Humans, Child, Female, Clinical Genetics, Male, Infant, Genetic linkage analysis, Clinical Sciences, Family Health, Hereditary spastic paraplegia, Gtp Binding Proteins, Medical, Child preschool, and Medical and Health Sciences
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Amyotrophic lateral sclerosis (ALS) is the most common degenerative motor neuron disorder. Although most cases of ALS are sporadic, 5–10% of cases are familial, with mutations associated with over 40 genes. There is variation of ALS... more
Amyotrophic lateral sclerosis (ALS) is the most common degenerative motor neuron disorder. Although most cases of ALS are sporadic, 5–10% of cases are familial, with mutations associated with over 40 genes. There is variation of ALS symptoms within families carrying the same mutation; the disease may develop in one sibling and not in another despite the presence of the mutation in both. Although the cause of this phenotypic variation is unknown, it is likely related to genetic modifiers of disease expression. The identification of ALS causing genes has led to the development of transgenic mouse models of motor neuron disease. Similar to families with familial ALS, there are background-dependent differences in disease phenotype in transgenic mouse models of ALS suggesting that, as in human ALS, differences in phenotype may be ascribed to genetic modifiers. These genetic modifiers may not cause ALS rather their expression either exacerbates or ameliorates the effect of the mutant ALS ...
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Current therapeutic development in amyotrophic lateral sclerosis (ALS) relies on individual randomized clinical trials to test a specific investigational product in a single patient population. This approach has intrinsic limitations,... more
Current therapeutic development in amyotrophic lateral sclerosis (ALS) relies on individual randomized clinical trials to test a specific investigational product in a single patient population. This approach has intrinsic limitations, including cost, time, and lack of flexibility. Adaptive platform trials represent a novel approach to investigate several interventions for a single disease in a continuous manner. Already in use in oncology, this approach is now being employed more often in neurology. Here, we describe a newly launched platform trial for ALS. The Healey ALS Platform Trial is testing multiple investigational products concurrently in people with ALS, with the goal of rapidly identifying novel treatments, biomarkers, and trial endpoints. ANN NEUROL 2022;91:165–175
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Objective: To understand preferred clinical practices and identify obstacles regarding initiation/use of noninvasive ventilation (NIV) in amyotrophic lateral sclerosis (ALS). Background: ALS patients require respiratory support as... more
Objective: To understand preferred clinical practices and identify obstacles regarding initiation/use of noninvasive ventilation (NIV) in amyotrophic lateral sclerosis (ALS). Background: ALS patients require respiratory support as symptoms progress, and NIV improves quality of life and extends survival. However, differences in timing and clinical parameters for NIV initiation and insurance requirements may impact when it is prescribed. Design/Methods: A 25-item questionnaire was sent via SurveyMonkey® to ALS specialists identified through membership in NEALS (US) and ENCALS (EU). Descriptive statistics/comparisons between US/EU responders were summarized. Results: 74/119 (62.2%) of respondents treat ≥76 ALS patients/year (US: 40/71 [56.3%]; EU: 34/48 [70.8%]). When considering NIV, US and EU specialists value upright FVC most but differ regarding upright MIP (US: 2 nd ; EU: 5 th ) and overnight pulse oximetry (US: 6 th ; EU: 2 nd ). In patients without respiratory symptoms, most US ...
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This study analyzes and describes atypical presentations of Charcot-Marie-Tooth disease type 4C (CMT4C). We present clinical and physiologic features of 5 patients with CMT4C caused by biallelic private mutations of SH3TC2. All patients... more
This study analyzes and describes atypical presentations of Charcot-Marie-Tooth disease type 4C (CMT4C). We present clinical and physiologic features of 5 patients with CMT4C caused by biallelic private mutations of SH3TC2. All patients manifested scoliosis, and nerve conduction study indicated results in the demyelinating range. All patients exhibited signs of motor impairment within the first years of life. We describe 2 or more different genetic diseases in the same patient, atypical presentations of CMT, and 3 new mutations in CMT4C patients. A new era of unbiased genetic testing has led to this small case series of individuals with CMT4C and highlights the recognition of different genetic diseases in CMT4C patients for accurate diagnosis, genetic risk identification, and therapeutic intervention. The phenotype of CMT4C, in addition, appears to be enriched by a number of features unusual for the broad CMT category. Muscle Nerve 57: 749-755, 2018.
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Amyotrophic lateral sclerosis is a late-onset degenerative disease affecting motor neurons in the spinal cord, brainstem, and motor cortex. There is great variation in the expression of ALS symptoms even between siblings who both carry... more
Amyotrophic lateral sclerosis is a late-onset degenerative disease affecting motor neurons in the spinal cord, brainstem, and motor cortex. There is great variation in the expression of ALS symptoms even between siblings who both carry the same Cu/Zn superoxide dismutase (SOD1) mutations. One important use of transgenic mouse models of SOD1-ALS is the study of genetic influences on ALS severity. We utilized multiple inbred mouse strains containing the SOD1-G93A transgene to demonstrate a major quantitative trait locus (QTL) on mouse chromosome 17 resulting in a significant shift in lifespan. Reciprocal crosses between long- and short-lived strains identified critical regions, and we have narrowed the area for potential genetic modifier(s) to &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt; 2Mb of the genome. Results showed that resequencing of this region resulted in 28 candidate genes with potentially functional differences between strains. In conclusion, these studies provide the first major modifier locus affecting lifespan in this model of FALS and, once identified, these candidate modifier genes may provide insight into modifiers of human disease and, most importantly, define new targets for the development of therapies.
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Amyotrophic lateral sclerosis (ALS) is a progressive motor neuron disease of unknown cause. Mortality in the population is frequently due to aspiration pneumonia. Although typically considered to be a disorder limited to motor neuron... more
Amyotrophic lateral sclerosis (ALS) is a progressive motor neuron disease of unknown cause. Mortality in the population is frequently due to aspiration pneumonia. Although typically considered to be a disorder limited to motor neuron involvement, some investigators have indicated that decreased sensory function in ALS patients additionally contributes to the disease process. The objective of this study was to evaluate laryngopharyngeal sensation in the ALS population in order to quantify the range of sensory deficits and correlate any abnormalities with demographic data to determine which patients are at risk of having sensory deficits. We examined the sensation of the larynx in 22 patients with ALS to determine whether a sensory deficit was present. After completion of a dysphagia questionnaire and medical history, patients underwent flexible endoscopic evaluation of swallowing with sensory testing (FEESST) to evaluate sensory function. Threshold values were determined and recorded...
Research Interests: Dysphagia, Medicine, Physical Medicine and Rehabilitation, Amyotrophic Lateral Sclerosis, Prospective studies, and 15 morePopulation, Humans, Sensation, Female, Male, ENT, Clinical Sciences, Aged, Middle Aged, Adult, Prognosis, Severity of Illness Index, Larynx, Deglutition, and Deglutition disorders
Research Interests: Orthopedic Surgery, Adolescent, Medicine, Pediatric Neurology, Humans, and 14 moreChild, Caffeine, Muscular Dystrophy, Muscular Dystrophies, Duchenne Muscular Dystrophy, Genetic linkage analysis, Muscle contraction, X chromosome, Contracture, Halothane, Malignant Hyperthermia, Neurosciences, Anesthetic, and Paediatrics and reproductive medicine
Research Interests: Chemistry, Electrophysiology, RNA, Medicine, DNA, and 15 moreHumans, Mutation, Medical Physiology, Pedigree, Clinical Sciences, Sodium channel, Neuromuscular Disorders, Channelopathy, Amino Acid Sequence, Base Sequence, Neuromuscular, Neurosciences, Patch Clamp, Molecular Sequence Data, and sodium channels
Hereditary spastic paraplegia (HSP) is a diverse group of inherited disorders characterized by progressive lower-extremity spasticity and weakness. Insight into the genetic basis of these disorders is expanding rapidly. Uncomplicated... more
Hereditary spastic paraplegia (HSP) is a diverse group of inherited disorders characterized by progressive lower-extremity spasticity and weakness. Insight into the genetic basis of these disorders is expanding rapidly. Uncomplicated autosomal dominant, autosomal recessive, and X-linked HSP are genetically heterogeneous: different genes cause clinically indistinguishable disorders. A locus for autosomal recessive HSP is on chromosome 8q. Loci for autosomal dominant HSP have been identified on chromosomes 2p, 14q, and 15q. One locus (Xq22) has been identified for X-linked, uncomplicated HSP and shown to be due to a proteolipoprotein gene mutation in one family. The existence of HSP families for whom these loci are excluded indicates the existence of additional, as yet unidentified HSP loci. There is marked clinical similarity among HSP families linked to each of these loci, suggesting that gene products from HSP loci may participate in a common biochemical cascade, which, if disturbe...
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Objective: To characterize cognitive involvement with neuropsychological tests measuring visuoconstruction (figure copy) and executive control/ mental search (letter F-word output) in patients with amyotrophic lateral sclerosis (ALS) to... more
Objective: To characterize cognitive involvement with neuropsychological tests measuring visuoconstruction (figure copy) and executive control/ mental search (letter F-word output) in patients with amyotrophic lateral sclerosis (ALS) to determine how limb versus bulbar onset and selected cognitive measures might be related to FVC. Background Previously a relationship between forced vital capacity (FVC) and cognitive involvement in ALS has been reported but the type of cognitive involvement has not been characterized nor the relationship of FVC and site of onset to that cognitive change. Design/Methods: 28 ALS patients were studied (age=61.76+12.26; MMSE=27.18+2.89; ALSFRS=29.42+9.48). Seated FVC was obtained and bulbar versus limb onset was determined by expert clinicians (LR, AD, THP). Neuropsychological functioning was assessed with subtests from the Philadelphia Brief Assessment of Cognition (PBAC), a neuropsychological protocol designed for to assess for dementia in Alzheimer9s disease and frontotemporal dementia phenotypes. Results: Simple correlations associated better FVC with limb rather than bulbar onset (r= 0.373, p 2 = 0.139, p 2 = 0.299, p 2 = 0.515, p Conclusions: These data suggest better erect FVC is associated with and limb rather than bulbar onset and better a figure copy test (visuoconstruction) greater output on letter fluency tests (executive control/ sustained mental search). Longitudinal assessment is necessary to determine the utility and clinical significance of these relatationships. Disclosure: Dr. Nieves has nothing to disclose. Dr. Eppig has nothing to disclose. Dr. Libon has nothing to disclose. Dr. Harris has nothing to disclose. Dr. Feldman has nothing to disclose. Dr. Paolone has nothing to disclose. Dr. Rojas has nothing to disclose. Dr. Deboo has nothing to disclose. Dr. Heiman-Patterson has nothing to disclose.
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Research Interests: Clinical Psychology, Cognitive Science, Medicine, Distress, Anxiety, and 15 moreAmyotrophic Lateral Sclerosis, Marriage, Humans, Female, Male, Clinical Sciences, Aged, Convergent Validity, Adult, Disease Progression, ANXIETY, Adjustment Disorders, Discriminant Validity, Medicine and Health Sciences, and Disability Evaluation
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Research Interests: Medicine, Biopsy, Humans, Caffeine, Muscle, and 14 moreMuscular Dystrophy, Anesthesia, Muscles, Myotonic Dystrophy, Risk factors, Neuromuscular Disease, Neuromuscular diseases, Muscle contraction, Risk Factors, Contracture, Halothane, Malignant Hyperthermia, Anesthetic, and Medical and Health Sciences
Amyotrophic lateral sclerosis (ALS) is a progressive neuromuscular disorder. While most cases of ALS are sporadic, 10-15% are familial, and of these 15-20% possess a mutation in the gene that codes for the enzyme Cu/Zn superoxide... more
Amyotrophic lateral sclerosis (ALS) is a progressive neuromuscular disorder. While most cases of ALS are sporadic, 10-15% are familial, and of these 15-20% possess a mutation in the gene that codes for the enzyme Cu/Zn superoxide dismutase (SOD1). In families of ALS patients with specific SOD1 mutations, affected members demonstrate significant heterogeneity of disease and a large variation in age of onset and severity, suggesting that there are genetic modifiers of disease expression. Transgenic mice expressing mutant forms of SOD1 demonstrate symptoms similar to those seen in patients with ALS. We have observed in our colony of G93A SOD1 transgenic mice a milder phenotype in mice in a C57BL/6J background than the C57BL/6JxSJL/J hybrid background used by Jackson Laboratories to maintain their colony. To investigate the effect of genetic background on phenotype, we have constructed congenic lines on two genetic backgrounds, C57BL/6J (B6) and SJL/J (SJL). We report the influence of background and gender on the survival of these congenic lines compared to the hybrid C57BL/6JxSJL/J background. The mean survival of G93A SOD1 mice in the hybrid B6/SJL background was 130 days, with females surviving significantly longer than males. When compared to the hybrid B6/SJL background, the survival of mice in the SJL background significantly decreased, and the gender difference in survival was maintained. On the other hand, mean survival in the B6 background significantly increased, and in contrast to the B6/SJL and SJL backgrounds, there was no difference in survival between males and females. Transgene copy numbers were verified in all animals to ensure that any phenotypic differences observed were not due to alterations in copy number. This is the first report of a shortened lifespan when the G93A SOD1 transgene is placed on the SJL/J background and an increased survival with the loss of gender influences when the transgene is placed on the C57BL/6J background.
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Research Interests: Endocrinology, Aging, Biology, Immunohistochemistry, Medicine, and 15 moreAmyotrophic Lateral Sclerosis, Glutamate, Humans, Mice, Female, Animals, Male, Central Nervous System, Clinical Sciences, Molecular weight, Glutamic Acid, Glutamate Transporter, Dimerization, Glutamate Receptor, and Brain stem
Transgenic mice expressing a mutated (G93A) human Cu/Zn superoxide dismutase (SOD1) develop motor neuron pathology and clinical symptoms similar to those seen in patients with amyotrophic lateral sclerosis. Loss of motor neurons is most... more
Transgenic mice expressing a mutated (G93A) human Cu/Zn superoxide dismutase (SOD1) develop motor neuron pathology and clinical symptoms similar to those seen in patients with amyotrophic lateral sclerosis. Loss of motor neurons is most prominent in lumbar, followed by cervical cord and then brainstem. No significant cell death has been reported in motor cortex. The integrity of the cortical glutamate reuptake systems was evaluated using intracerebral microdialysis and western immunoblot assays for the glutamate transporters GLT-1, GLAST, and EAAC1. The basal extracellular fluid levels of aspartate, glutamate, glutamine, 3,4-dihydroxyphenylacetic acid, and 5-hydroxyindole-3-acetic acid were evaluated by HPLC. The extraction fraction of L-3H]glutamate, corrected with [14C]mannitol, was also evaluated. GLT-1, EAAC1, and GLAST protein levels were determined by semiquantitative chemiluminescence immunoblot of proteins from membrane-enriched fractions. The relative optical density of film was translated into relative protein level by comparison with a standard control mouse. The SOD1 mutant mice demonstrated a significant (p &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt; 0.05) increase in basal levels of extracellular aspartate and glutamate. In addition, when the glutamate extraction fraction was challenged with exogenous unlabeled glutamate (500 microM) by reversed microdialysis, the glutamate extraction fraction in the mutant SOD1 mice was decreased significantly from control levels. The SOD1 mutant mice demonstrated no difference in the cortical protein levels of the glutamate transporter subtypes. This study demonstrates that in areas of no visible pathology and no loss of glutamate transporter proteins, SOD1 mutant mice have elevated extracellular fluid aspartate and glutamate levels and a decreased capacity to clear glutamate from the extracellular space.
Research Interests: Biology, Neurochemistry, Medicine, Transgenic Mice, Amyotrophic Lateral Sclerosis, and 15 moreGlutamate, Humans, Cerebral Cortex, Mice, Animals, D-Aspartic Acid, SOD, Superoxide Dismutase, Phenotype, Microdialysis, Transporter, Neurosciences, Extracellular Space, Glutamic Acid, and Glutamate Receptor
Two cases of CT-documented extraocular muscle atrophy are presented. Unilateral atrophy was observed in a patient with a lesion of the cavernous sinus. Atrophic extraocular muscles were noted bilaterally in a young woman with... more
Two cases of CT-documented extraocular muscle atrophy are presented. Unilateral atrophy was observed in a patient with a lesion of the cavernous sinus. Atrophic extraocular muscles were noted bilaterally in a young woman with &quot;ophthalmoplegia plus&quot; (probable Kearns-Sayre syndrome).