67 results on '"John M. Shoffner"'
Search Results
2. Next-Generation Sequencing to Diagnose Muscular Dystrophy, Rhabdomyolysis, and HyperCKemia
- Author
-
Mark A. Tarnopolsky, Lauren Brady, John M. Shoffner, and Lily Wu
- Subjects
0301 basic medicine ,Adult ,Male ,medicine.medical_specialty ,Canada ,Adolescent ,Disease ,DNA sequencing ,Muscular Dystrophies ,Rhabdomyolysis ,Cohort Studies ,03 medical and health sciences ,Young Adult ,0302 clinical medicine ,Muscle pathology ,Internal medicine ,medicine ,Humans ,In patient ,Genetic Predisposition to Disease ,Genetic Testing ,Muscular dystrophy ,Child ,Creatine Kinase ,Aged ,Aged, 80 and over ,business.industry ,Infant, Newborn ,Muscle weakness ,Infant ,General Medicine ,Neuromuscular Diseases ,Middle Aged ,medicine.disease ,Congenital myopathy ,030104 developmental biology ,Phenotype ,Neurology ,Child, Preschool ,Female ,Neurology (clinical) ,medicine.symptom ,business ,030217 neurology & neurosurgery - Abstract
Background:Neuromuscular disorders are a phenotypically and genotypically diverse group of diseases that can be difficult to diagnose accurately because of overlapping clinical features and nonspecific muscle pathology. Next-generation sequencing (NGS) is a high-throughput technology that can be used as a more time- and cost-effective tool for identifying molecular diagnoses for complex genetic conditions, such as neuromuscular disorders.Methods:One hundred and sixty-nine patients referred to a Canadian neuromuscular clinic for evaluation of possible muscle disease were screened with an NGS panel of muscular dystrophy–associated genes. Patients were categorized by the reason of referral (1) muscle weakness (n=135), (2) recurrent episodes of rhabdomyolysis (n=18), or (3) idiopathic hyperCKemia (n=16).Results:Pathogenic and likely pathogenic variants were identified in 36.09% of patients (61/169). The detection rate was 37.04% (50/135) in patients with muscle weakness, 33.33% (6/18) with rhabdomyolysis, and 31.25% (5/16) in those with idiopathic hyperCKemia.Conclusions:This study shows that NGS can be a useful tool in the molecular workup of patients seen in a neuromuscular clinic. Evaluating the utility of large panels of a muscle disease-specific NGS panel to investigate the genetic susceptibilities of rhabdomyolysis and/or idiopathic hyperCKemia is a relatively new field. Twenty-eight of the pathogenic and likely pathogenic variants reported here are novel and have not previously been associated with disease.
- Published
- 2018
3. MERRF Classification: Implications for Diagnosis and Clinical Trials
- Author
-
John M. Shoffner, Sinda Zarrouk-Mahjoub, and Josef Finsterer
- Subjects
0301 basic medicine ,Phenocopy ,business.industry ,Clinical study design ,Mitochondrial disease ,Disease ,medicine.disease ,Bioinformatics ,MERRF Syndrome ,Clinical trial ,03 medical and health sciences ,MT-TK ,030104 developmental biology ,0302 clinical medicine ,Developmental Neuroscience ,Neurology ,Mitochondrial myopathy ,Pediatrics, Perinatology and Child Health ,medicine ,Myoclonic epilepsy ,Humans ,Neurology (clinical) ,business ,030217 neurology & neurosurgery - Abstract
Background Given the etiologic heterogeneity of disease classification using clinical phenomenology, we employed contemporary criteria to classify variants associated with myoclonic epilepsy with ragged-red fibers (MERRF) syndrome and to assess the strength of evidence of gene-disease associations. Standardized approaches are used to clarify the definition of MERRF, which is essential for patient diagnosis, patient classification, and clinical trial design. Methods Systematic literature and database search with application of standardized assessment of gene-disease relationships using modified Smith criteria and of variants reported to be associated with MERRF using modified Yarham criteria. Results Review of available evidence supports a gene-disease association for two MT-tRNAs and for POLG. Using modified Smith criteria, definitive evidence of a MERRF gene-disease association is identified for MT-TK. Strong gene-disease evidence is present for MT-TL1 and POLG. Functional assays that directly associate variants with oxidative phosphorylation impairment were critical to mtDNA variant classification. In silico analysis was of limited utility to the assessment of individual MT-tRNA variants. With the use of contemporary classification criteria, several mtDNA variants previously reported as pathogenic or possibly pathogenic are reclassified as neutral variants. Conclusions MERRF is primarily an MT-TK disease, with pathogenic variants in this gene accounting for ~90% of MERRF patients. Although MERRF is phenotypically and genotypically heterogeneous, myoclonic epilepsy is the clinical feature that distinguishes MERRF from other categories of mitochondrial disorders. Given its low frequency in mitochondrial disorders, myoclonic epilepsy is not explained simply by an impairment of cellular energetics. Although MERRF phenocopies can occur in other genes, additional data are needed to establish a MERRF disease-gene association. This approach to MERRF emphasizes standardized classification rather than clinical phenomenology, thus improving patient diagnosis and clinical trial design.
- Published
- 2017
4. Response to Newman et al
- Author
-
David Griesemer, Marie Josee Raboisson, Carolyn M. Sue, Richard H. Haas, John M. Shoffner, Amel Karaa, Richard E. Frye, Tyler Reimschisel, Russell P. Saneto, Annette Feigenbaum, Mary Kay Koenig, Bruce H. Cohen, Mark A. Tarnopolsky, Michael C. Kruer, Patrick F. Chinnery, Rita Horvath, Mark S. Korson, David Dimmock, Irina Anselm, Amy Goldstein, John Christodoulou, Lynne A. Wolfe, Zarazuela Zolkipli Cunningham, Michelangelo Mancuso, Shana E. McCormack, Marni J. Falk, Shamima Rahman, Sumit Parikh, Peter W. Stacpoole, Gregory M. Enns, Ramona Salvarinova, Clara D.M. van Karnebeek, Jaya Ganesh, Catherine Brunel-Guitton, Fernando Scaglia, Paediatric Metabolic Diseases, AGEM - Inborn errors of metabolism, and ANS - Cellular & Molecular Mechanisms
- Subjects
0301 basic medicine ,03 medical and health sciences ,Information retrieval ,Text mining ,Mitochondrial Diseases ,Eye Diseases ,business.industry ,MEDLINE ,Medicine ,030105 genetics & heredity ,business ,Genetics (clinical) ,Article - Published
- 2017
5. Patient care standards for primary mitochondrial disease: a consensus statement from the Mitochondrial Medicine Society
- Author
-
Sumit Parikh, Michelangelo Mancuso, Bruce H. Cohen, David Dimmock, Marie Josee Raboisson, Michael C. Kruer, David Griesemer, Catherine Brunel-Guitton, Annette Feigenbaum, John Christodoulou, Mark S. Korson, Carolyn M. Sue, Lynne A. Wolfe, Tyler Reimschisel, Gregory M. Enns, Rita Horvath, Shamima Rahman, Clara D.M. van Karnebeek, Peter W. Stacpoole, Jaya Ganesh, Richard H. Haas, John M. Shoffner, Mark A. Tarnopolsky, Irina Anselm, Patrick F. Chinnery, Mary Kay Koenig, Zarazuela Zolkipli Cunningham, Richard E. Frye, Amel Karaa, Russell P. Saneto, Amy Goldstein, Fernando Scaglia, Marni J. Falk, Ramona Salvarinova, Shana E. McCormack, AGEM - Amsterdam Gastroenterology Endocrinology Metabolism, ANS - Cellular & Molecular Mechanisms, and Paediatric Metabolic Diseases
- Subjects
0301 basic medicine ,medicine.medical_specialty ,Statement (logic) ,business.industry ,Mitochondrial disease ,education ,Delphi method ,MEDLINE ,medicine.disease ,Article ,Patient care ,Optimal management ,03 medical and health sciences ,030104 developmental biology ,0302 clinical medicine ,Family medicine ,medicine ,Disease management (health) ,business ,Routine care ,030217 neurology & neurosurgery ,Genetics (clinical) - Abstract
The purpose of this statement is to provide consensus-based recommendations for optimal management and care for patients with primary mitochondrial disease. This statement is intended for physicians who are engaged in the diagnosis and management of these patients. Working group members were appointed by the Mitochondrial Medicine Society. The panel included members with several different areas of expertise. The panel members utilized surveys and the Delphi method to reach consensus. We anticipate that this statement will need to be updated as the field continues to evolve. Consensus-based recommendations are provided for the routine care and management of patients with primary genetic mitochondrial disease.
- Published
- 2017
6. Author response: CSF concentrations of 5-methyltetrahydrofolate in a cohort of young children with autism
- Author
-
John M. Shoffner
- Subjects
Pediatrics ,medicine.medical_specialty ,5-Methyltetrahydrofolate ,Cohort Studies ,03 medical and health sciences ,Folinic acid ,0302 clinical medicine ,Folic Acid ,medicine ,Humans ,030212 general & internal medicine ,Autistic Disorder ,Child ,Tetrahydrofolates ,medicine.diagnostic_test ,Lumbar puncture ,Cognition ,medicine.disease ,Autism spectrum disorder ,Cohort ,Autism ,Neurology (clinical) ,Psychology ,030217 neurology & neurosurgery ,Decision limit ,medicine.drug - Abstract
On behalf of my coauthors, I thank Dr. Barrett for the comment on our article.1 Dr. Barrett correctly recognizes that one of the central aspects of our study was to investigate whether a relationship of CSF 5-MTHF levels to symptoms in young children with autism exists. As addressed in the article, a major difficulty in diagnosing cerebral folate deficiency using CSF 5-MTHF levels was the lack of reference intervals from a normal population that would allow defining clinical decision limits.1 To gain insight into the relationship between CSF 5-MTHF levels and clinical decision limits for young children with autism, we assessed CSF 5-MTHF over time and correlated these levels with detailed clinical assessments. The CSF 5-MTHF levels varied significantly and were not associated with any measures of adaptive behavior, cognitive ability, or autism spectrum disorder symptom severity. As discussed in the article, pediatric CSF normative data that consider natural CSF 5-MTHF variability over time are essential to defining reference intervals as well as critical decision limits.1 In our cohort of young children with autism, a critical decision limit for CSF 5-MTHF levels was not identified. Further research in patients with autism is needed before CSF 5-MTHF levels can be used to justify lumbar puncture to diagnose cerebral folate deficiency or treatment of patients with compounds such as folinic acid or 5-MTHF.
- Published
- 2016
7. Fever Plus Mitochondrial Disease Could Be Risk Factors for Autistic Regression
- Author
-
Stephanie Cossette, Lauren Hyams, Lisa Ollis, Audra Aliberti, Sara Kuoch, John M. Shoffner, Lauren Mylacraine, Kevin Bennett, Jeffrey Dale, Genevieve Niedziela Langley, and Keith Hyland
- Subjects
Male ,medicine.medical_specialty ,Mitochondrial Diseases ,Adolescent ,Fever ,Mitochondrial disease ,Population ,Comorbidity ,Biology ,Young Adult ,Recurrence ,Risk Factors ,Stress, Physiological ,Internal medicine ,Prevalence ,medicine ,Humans ,Young adult ,Child ,education ,Psychiatry ,Retrospective Studies ,education.field_of_study ,Incidence ,Incidence (epidemiology) ,Brain ,Infant ,Retrospective cohort study ,medicine.disease ,Regression ,Mitochondria ,Regression, Psychology ,Vaccination ,Child Development Disorders, Pervasive ,Child, Preschool ,Pediatrics, Perinatology and Child Health ,Female ,Neurology (clinical) ,Energy Metabolism - Abstract
Autistic spectrum disorders encompass etiologically heterogeneous persons, with many genetic causes. A subgroup of these individuals has mitochondrial disease. Because a variety of metabolic disorders, including mitochondrial disease show regression with fever, a retrospective chart review was performed and identified 28 patients who met diagnostic criteria for autistic spectrum disorders and mitochondrial disease. Autistic regression occurred in 60.7% (17 of 28), a statistically significant increase over the general autistic spectrum disorder population (P < .0001). Of the 17 individuals with autistic regression, 70.6% (12 of 17) regressed with fever and 29.4% (5 of 17) regressed without identifiable linkage to fever or vaccinations. None showed regression with vaccination unless a febrile response was present. Although the study is small, a subgroup of patients with mitochondrial disease may be at risk of autistic regression with fever. Although recommended vaccinations schedules are appropriate in mitochondrial disease, fever management appears important for decreasing regression risk.
- Published
- 2009
- Full Text
- View/download PDF
8. Heterozygous mutations of the kinesin KIF21A in congenital fibrosis of the extraocular muscles type 1 (CFEOM1)
- Author
-
Monte A. Del Monte, Berendina De Vries, Arnold London, Wai-Man Chan, Emin Cumhur Sener, Anat Loewenstein, Joseph L. Demer, Elizabeth C. Engle, Nakamichi Saito, Robert P. Cruse, Michael C. Brodsky, A. Nurten Akarsu, Roger H. Johnson, Mark S. Ruttum, Alina A. Zubcov, Alex V. Levin, Naomichi Matsumoto, Blaine L. Hart, Teresa de Berardinis, Lionel Kowal, Ravi Battu, Marlene C. Vogel, Michael O'Keefe, Thomas J. Carlow, Frank Hanisch, Banu T. Öztürk, Caroline Andrews, Robert D. Letson, Moshe Lazar, Eiichiro Uyama, Craig A. McKeown, James A. Katowitz, Scott M. Goldstein, Piergiorgio Franceschini, Richard M. Robb, Lisa Morris, Adriano Magli, Koki Yamada, Peter Roggenkäemper, Nicolas Krawiecki, Willem A. Houtman, John M. Shoffner, Anna Newlin, Elias I. Traboulsi, Irene Gottlob, Yamada, K, Andrews, C, Chan, Wm, Mckeown, Ca, Magli, A, DE BERARDINIS, Teresa, Loewenstein, A, Lazar, M, O'Keefe, M, Letson, R, London, A, Ruttum, M, Matsumoto, N, Saito, N, Morris, L, DEL MONTE, M, Johnson, Rh, Uyama, E, Houtman, Wa, DE VRIES, B, Carlow, Tj, Hart, Bl, Krawiecki, N, Shoffner, J, Vogel, Mc, Katowitz, J, Goldstein, Sm, Levin, Av, Sener, Ec, Ozturk, Bt, Akarsu, An, Brodsky, Mc, Hanisch, F, Cruse, Rp, Zubcov, Aa, Robb, Rm, Roggenkaemper, P, Gottlob, I, Kowal, L, Battu, R, Traboulsi, Ei, Franceschini, P, Newlin, A, Demer, Jl, and Engle, E. C.
- Subjects
Proband ,Male ,Heterozygote ,congenital, hereditary, and neonatal diseases and abnormalities ,genetic structures ,Genetic Linkage ,Molecular Sequence Data ,Kinesins ,Nerve Tissue Proteins ,Biology ,REGION ,Motor protein ,Mutational hotspot ,Congenital fibrosis of the extraocular muscles ,MAPS ,Genetics ,medicine ,Missense mutation ,Humans ,Amino Acid Sequence ,Strabismus ,Child ,Ophthalmoplegia ,Sequence Homology, Amino Acid ,CHROMOSOME-12 ,REFINEMENT ,Oculomotor nerve ,Genetic Variation ,EXTERNAL OPHTHALMOPLEGIA ,medicine.disease ,Fibrosis ,eye diseases ,Pedigree ,Phenotype ,Oculomotor Muscles ,Mutation ,Kinesin ,Female - Abstract
Congenital fibrosis of the extraocular muscles type 1 (CFEOM1; OMIM #135700) is an autosomal dominant strabismus disorder associated with defects of the oculomotor nerve. We show that individuals with CFEOM1 harbor heterozygous missense mutations in a kinesin motor protein encoded by KIF21A. We identified six different mutations in 44 of 45 probands. The primary mutational hotspots are in the stalk domain, highlighting an important new role for KIF21A and its stalk in the formation of the oculomotor axis.
- Published
- 2003
9. Abnormalities in gastrointestinal motility are associated with diseases of oxidative phosphorylation in children
- Author
-
John M Shoffner, Timothy Buie, Samuel Nurko, Denesh K. Chitkara, and Alejandro Flores
- Subjects
Male ,inorganic chemicals ,Pathology ,medicine.medical_specialty ,Mitochondrial Diseases ,Motility ,macromolecular substances ,Oxidative phosphorylation ,Outcome assessment ,Mitochondrion ,environment and public health ,Internal medicine ,Outcome Assessment, Health Care ,Humans ,Medicine ,Child ,Retrospective Studies ,Hepatology ,business.industry ,Age Factors ,Infant, Newborn ,Gastroenterology ,Motility disorder ,enzymes and coenzymes (carbohydrates) ,Endocrinology ,Child, Preschool ,bacteria ,Female ,Gastrointestinal Motility ,business ,Intracellular transport - Abstract
Disorders of the mitochondrial electron transport chain enzymes of oxidative phosphorylation (OXPHOS) have neurologic, musculoskeletal, ophthalmologic, cardiac, and GI manifestations. Many adult and pediatric patients with disorders of OXPHOS have abnormalities in intestinal motility. The purpose of this study was to describe pediatric patients who initially presented with signs of GI dysmotility and were later evaluated and found to have a disorder of OXPHOS.Data were collected on six patients, including initial GI and neurologic symptoms, histology of skeletal muscle biopsies, mitochondrial DNA mutational analysis, OXPHOS enzyme assay, upper GI barium imaging, technetium-99M liquid gastric emptying scan, upper GI endoscopy, esophageal manometry, and antroduodenal manometry.All six children presented with symptoms of GI dysmotility within 2 wk of life. Patients later developed symptoms of neurologic disorders. All patients had abnormalities in OXPHOS enzyme analysis. Muscle histology showed nonspecific changes with no ragged red fibers. Sequencing of the mitochondrial DNA showed no recognized mutations. No patient had any evidence of intestinal obstruction or malrotation by upper GI barium imaging. Four patients had delayed gastric emptying. Three patients had endoscopic and histologic evidence of esophagitis. All six had demonstrable neuropathic abnormalities by antroduodenal manometry, including the following: nonpropagated antral bursts, absent migrating motor complexes, postprandial antral hypomotility, retrograde migrating motor complexes, and tonic contractions with the migrating motor complex.Abnormalities in GI motility may be an early presenting sign of disorders of OXPHOS in children.
- Published
- 2003
- Full Text
- View/download PDF
10. Oxidative phosphorylation defects and Alzheimer's disease
- Author
-
John M. Shoffner
- Subjects
Glutamic Acid ,Oxidative phosphorylation ,Biology ,medicine.disease_cause ,DNA, Mitochondrial ,Models, Biological ,Oxidative Phosphorylation ,Electron Transport Complex IV ,Cellular and Molecular Neuroscience ,Alzheimer Disease ,Genetics ,medicine ,Humans ,Cytochrome c oxidase ,Genetics (clinical) ,Mutation ,Amyloid beta-Peptides ,Glutamate receptor ,Pyruvate dehydrogenase complex ,Molecular medicine ,Citric acid cycle ,Biochemistry ,Cancer research ,biology.protein ,Oxoglutarate dehydrogenase complex - Abstract
Abnormalities in cellular bioenergetics have been identified in patients with Alzheimer's disease (AD) as well as in patients with other neurodegenerative diseases. The most commonly reported enzyme abnormalities are in the pyruvate dehydrogenase complex, the alpha-ketoglutarate dehydrogenase complex, and oxidative phosphorylation (OXPHOS). Although genetic evidence supporting primary OXPHOS defects as a cause for AD is weak, functionally important reductions in OXPHOS enzyme activities appear to occur in AD and may be related to beta-amyloid accumulation or other neurodegenerative processes. Since reduced neuronal ATP may enhance susceptibility to glutamate toxicity, OXPHOS defects could play an important role in the pathophysiology of AD.
- Published
- 1997
- Full Text
- View/download PDF
11. Mechanisms of Mitochondrial Defects in Gulf War Syndrome
- Author
-
John M Shoffner
- Subjects
Pathology ,medicine.medical_specialty ,Neurology ,business.industry ,Somatic cell ,Gulf War syndrome ,Mitochondrion ,medicine.disease ,Bioinformatics ,Gene expression ,medicine ,Chronic fatigue syndrome ,Amyotrophic lateral sclerosis ,business ,Gene - Abstract
Gulf War syndrome (GWS) is associated with increased incidences of amyotrophic lateral sclerosis, pain syndromes, muscle complaints that include fatigue and myalgias, as well as other neurological symptoms. Approximately 100,000 individuals have medical complaints consistent with GWS. Clinical manifestations are similar to those identified in Chronic Fatigue Syndrome (CFS). Mitochondrial defects are identified pathologically, metabolically, and genetically in some patients with CFS. GWS has significant evidence for mitochondrial dysfunction with abnormalities in exercise physiology, abnormalities in mitochondrial morphology, biochemical defects in mitochondrial function, abnormalities in free radical generation affecting mitochondrial integrity, gene expression in genes affecting mitochondrial function, and mtDNA mutations (inherited, somatic, and sporadic during embryogenesis). Gene expression abnormalities in CFS show abnormalities in genes that are related to mitochondrial function. Hence, investigation of mitochondrial dysfunction in GWS is a priority.
- Published
- 2013
- Full Text
- View/download PDF
12. Oxidative phosphorylation defect associated with primary adrenal insufficiency
- Author
-
Ingrid A. Holm, John M. Shoffner, Nicolas Krawiecki, Mark S. Korson, and Kathryn N. North
- Subjects
medicine.medical_specialty ,Mitochondrial disease ,Oxidative phosphorylation ,Mitochondrion ,Cataract ,Lipid Metabolism, Inborn Errors ,Oxidative Phosphorylation ,Primary Adrenal Insufficiency ,Adrenocorticotropic Hormone ,Internal medicine ,Adrenal insufficiency ,medicine ,Humans ,Chronic lactic acidosis ,Acidosis ,Dichloroacetic Acid ,business.industry ,Infant, Newborn ,Lipid metabolism ,medicine.disease ,Mitochondria, Muscle ,Phenotype ,Endocrinology ,Pediatrics, Perinatology and Child Health ,Acidosis, Lactic ,Female ,medicine.symptom ,business - Abstract
An 18-month-old girl with an oxidative phosphorylation defect had neonatal onset of chronic lactic acidosis, lipid storage myopathy, bilateral cataracts, and primary adrenal insufficiency. Chronic lactic acidosis responded to treatment with dichloroacetate. Sequential muscle biopsies demonstrated resolution of the lipid storage myopathy associated with the return to normal muscle free carnitine levels. This case demonstrates a new clinical phenotype associated with a defect in oxidative phosphorylation and the need to consider mitochondrial disorders in the differential diagnosis of primary adrenal insufficiency in childhood.
- Published
- 1996
- Full Text
- View/download PDF
13. Insulin resistance associated with maternally inherited diabetes and deafness
- Author
-
Deborah A. Koontz, John M. Shoffner, Douglas C. Wallace, Allan Kaufman, and Suzanne S. P. Gebhart
- Subjects
Adult ,Blood Glucose ,Male ,medicine.medical_specialty ,Adolescent ,Biopsy ,Endocrinology, Diabetes and Metabolism ,medicine.medical_treatment ,Oxidative phosphorylation ,Deafness ,Biology ,Carbohydrate metabolism ,medicine.disease_cause ,DNA, Mitochondrial ,Endocrinology ,Insulin resistance ,Diabetes mellitus ,Internal medicine ,MELAS Syndrome ,medicine ,Humans ,Insulin ,Phosphorylation ,Muscle, Skeletal ,Mutation ,Clinical course ,Glucose Tolerance Test ,medicine.disease ,Diabetes Mellitus, Type 2 ,Coenzyme Q – cytochrome c reductase ,Female ,Insulin Resistance - Abstract
Maternally inherited diabetes and deafness (MIDD) is a form of diabetes associated with mutation of mitochondrial DNA (mtDNA) that occurs in 1% to 2% of individuals with diabetes. Understanding the clinical course and abnormalities in insulin secretion and action in affected individuals should allow better understanding of how this genetic defect alters glucose metabolism. We report the clinical course of three individuals with mtDNA mutations and deafness. Subjects no. 1 and 2 had diabetes not yet requiring insulin therapy, and subject no. 3, the son of subject no. 2, had normal glucose tolerance. Defective oxidative phosphorylation (OXPHOS) based on OXPHOS enzymology of skeletal muscle biopsy of subjects no. 1 and 2 showed activity of less than 5% of the tolerance level in complex III for subject no. 1 and in complexes I, I + III, and IV for subject no. 2. Assessing insulin secretion using insulin response to intravenous glucose and insulin sensitivity based on minimal model analysis of an insulin-modified frequently sampled intravenous glucose tolerance test (FSIGT), first-phase insulin secretion was abnormal in subjects no. 1 and 2 and normal in subject no. 3 (AUC, 57, 93, and 1,235 pmol/mL, respectively). In contrast, all three subjects had low insulin sensitivity indices (0.04, 0.14, and 0.27 × 10 −4 × min/pmol/L, respectively). Subject no. 2, who underwent three FSIGT studies over a 16-month interval, showed transient improvement in insulin release in response to modification of diet and exercise (first-phase insulin AUC, 57 pmol/min v 287 pmol/min 10 months later; fasting insulin, 97 pmol/L v 237 pmol/L 10 months later), but by 16 months, first-phase insulin release and fasting insulin had decreased (AUC, 64 and 136 pmol/L, respectively) despite higher fasting glucose. We conclude that in our subjects with MIDD, insulin resistance is present and appears to precede defects in insulin release.
- Published
- 1996
- Full Text
- View/download PDF
14. Use of Transmitochondrial Cybrids To Assign a Complex I Defect to the Mitochondrial DNA-Encoded NADH Dehydrogenase Subunit 6 Gene Mutation at Nucleotide Pair 14459 That Causes Leber Hereditary Optic Neuropathy and Dystonia
- Author
-
Douglas C. Wallace, John M. Shoffner, Ian A. Trounce, Albert S. Jun, and Michael D. Brown
- Subjects
Herpesvirus 4, Human ,Mitochondrial DNA ,Mutation ,biology ,Transition (genetics) ,Mutant ,NADH dehydrogenase ,Wild type ,NADH Dehydrogenase ,Cell Biology ,Hybrid Cells ,Gene mutation ,medicine.disease_cause ,DNA, Mitochondrial ,Molecular biology ,Optic Atrophies, Hereditary ,Biochemistry ,Coenzyme Q – cytochrome c reductase ,biology.protein ,medicine ,Humans ,Molecular Biology ,Research Article ,Cell Line, Transformed - Abstract
A heteroplasmic G-to-A transition at nucleotide pair (np) 14459 within the mitochondrial DNA (mtDNA)-encoded NADH dehydrogenase subunit 6 (ND6) gene has been identified as the cause of Leber hereditary optic neuropathy (LHON) and/or pediatric-onset dystonia in three unrelated families. This ND6 np 14459 mutation changes a moderately conserved alanine to a valine at amino acid position 72 of the ND6 protein. Enzymologic analysis of mitochondrial NADH dehydrogenase (complex I) with submitochondrial particles isolated from Epstein-Barr virus-transformed lymphoblasts revealed a 60% reduction (P < 0.005) of complex I-specific activity in patient cell lines compared with controls, with no differences in enzymatic activity for complexes II plus III, III and IV. This biochemical defect was assigned to the ND6 np 14459 mutation by using transmitochondrial cybrids in which patient Epstein-Barr virus-transformed lymphoblast cell lines were enucleated and the cytoplasts were fused to a mtDNA-deficient (p 0) lymphoblastoid recipient cell line. Cybrids harboring the np 14459 mutation exhibited a 39% reduction (p < 0.02) in complex I-specific activity relative to wild-type cybrid lines but normal activity for the other complexes. Kinetic analysis of the np 14459 mutant complex I revealed that the Vmax of the enzyme was reduced while the Km remained the same as that of wild type. Furthermore, specific activity was inhibited by increasing concentrations of the reduced coenzyme Q analog decylubiquinol. These observations suggest that the np 14459 mutation may alter the coenzyme Q-binding site of complex I.
- Published
- 1996
- Full Text
- View/download PDF
15. Novel mitochondrial DNA deletion found in a renal cell carcinoma
- Author
-
Abdelaziz Heddi, Terzah M. Horton, Sam D. Graham, Douglas C. Wallace, John M. Shoffner, Terry L. Gramlich, John A. Petros, and Allan Kaufman
- Subjects
Cancer Research ,Kidney ,Mitochondrial DNA ,biology ,Sequence analysis ,Base pair ,Molecular biology ,3. Good health ,law.invention ,Restriction fragment ,EcoRV ,medicine.anatomical_structure ,Transcription (biology) ,law ,Genetics ,medicine ,biology.protein ,Polymerase chain reaction - Abstract
Polymerase chain reaction (PCR) was used to analyze a rarely deleted region of mitochondrial DNA (mtDNA) from 39 human renal cell carcinomas (RCC) and matched normal kidney tissue removed during radical nephrectomy. One tumor specimen (E.R.) had a unique PCR product approximately 250 base pairs (bp) smaller than the PCR product found in the normal E.R. kidney. Sequence analysis of the tumor-specific PCR fragment revealed a 264 bp deletion in the first subunit (NDI) of NADH:ubiquinone oxidoreductase (complex I) of the electron transport chain. Southern analysis of the RCCs demonstrated that approximately 50% of the mtDNA molecules in the primary RCC contained a unique 3.2 kb EcoRV restriction fragment found only in E.R. tumor mtDNA. Northern analysis demonstrated preferential transcription of the truncated NDI mRNA. None of the five metastases or any normal tissue from E.R. contained levels of the NDI deletion detectable by PCR. This is the first reported case of an intragenic NDI mtDNA deletion.
- Published
- 1996
- Full Text
- View/download PDF
16. Mitochondrial DNA sequence analysis of four Alzheimer's and Parkinson's disease patients
- Author
-
Yoon L. Kim, Brett H. Graham, Albert S. Jun, Daniel S. Gurley, Margaret F. Cabell, Michael D. Brown, John M. Shoffner, and Douglas C. Wallace
- Subjects
Genetics ,Mitochondrial DNA ,Transition (genetics) ,Sequence analysis ,Nucleic acid sequence ,Missense mutation ,Gene mutation ,Mitochondrion ,Biology ,Gene ,Genetics (clinical) - Abstract
The mitochondrial DNA (mtDNA) sequence was determined on 3 patients with Alzheimer's disease (AD) exhibiting AD plus Parkinson's disease (PD) neuropathologic changes and one patient with PD. Patient mtDNA sequences were compared to the standard Cambridge sequence to identify base changes. In the first AD+PD patient, 2 of the 15 nucleotide substitutions may contribute to the neuropathology, a nucleotide pair (np) 4336 transition in the tRNA(Gln) gene found 7.4 times more frequently in patients than in controls, and a unique np 721 transition in the 12S rRNA gene which was not found in 70 other patients or 905 controls. In the second AD+PD patient, 27 nucleotide substitutions were detected, including an np 3397 transition in the ND1 gene which converts a conserved methionine to a valine. In the third AD+PD patient, 2 polymorphic base substitutions frequently found at increased frequency in Leber's hereditary optic neuropathy patients were observed, an np 4216 transition in ND1 and an np 13708 transition in the ND5 gene. For the PD patient, 2 novel variants were observed among 25 base substitutions, an np 1709 substitution in the 16S rRNA gene and an np 15851 missense mutation in the cytb gene. Further studies will be required to demonstrate a causal role for these base substitutions in neurodegenerative disease.
- Published
- 1996
- Full Text
- View/download PDF
17. Apolipoprotein E genotype in patients with alzheimer's disease: Implications for the risk of dementia among relatives
- Author
-
Valerie Clarke, Robert C. Green, S. A. Auerbach, L. Adrienne Cupples, John H. Growdon, John M. Wells, Ulrich Müller, John M. Shoffner, Christine Van Broeckhoven, Lindsay A. Farrer, Helena C. Chui, Alexander Kurz, Steven D. Flanagan, Reinhilde Zimmer, Jonathan L. Haines, Douglas C. Wallace, Peter St George-Hyslop, Ranjan Duara, Cornelia M. van Duijn, and Ladislav Volicer
- Subjects
Apolipoprotein E ,Gerontology ,Proband ,medicine.medical_specialty ,Offspring ,Polymorphism (biology) ,medicine.disease ,Neurology ,Internal medicine ,Genotype ,medicine ,Dementia ,lipids (amino acids, peptides, and proteins) ,Neurology (clinical) ,Allele ,Age of onset ,Psychology - Abstract
Numerous studies have shown that the risk of Alzheimer's disease (AD) is associated with the dose of the epsilon 4 allele of apolipoprotein E (ApoE). However, more than one third of AD patients lack epsilon 4 and many persons having epsilon 4 survive cognitively intact to old age. We evaluated the lifetime risk of disease in 3,999 first-degree relatives of 549 probands who met the criteria for probable or definite AD and whose ApoE genotypes were known. ApoE genotypes for relatives were not determined. After age 65 the risk among relatives was proportional, as much as 7 to 10% at age 85, to the number of epsilon 4 alleles present in the proband. Risks to relatives of ApoE 2/2 and 2/3 probands were nearly identical at all ages to risks for relatives of ApoE 3/3 probands. The expected proportion of relatives having at least one epsilon 4 allele was calculated for each genotype group based on the distribution of parents, sibs, and offspring in the sample. Among relatives in the ApoE 3/3 group, the lifetime risk for AD by age 90 was three times greater than the expected proportion of epsilon 4 carriers, suggesting that factors other than ApoE contribute to AD susceptibility. Furthermore, the 44% risk of AD by age 93 among relatives of ApoE 4/4 probands indicates that as many as 50% of people having at least one epsilon 4 allele do not develop AD. We also found that among male relatives, risk of AD in the ApoE 3/4 group was similar to that for the ApoE 3/3 group but significantly less than the risk for the ApoE 4/4 group. In contrast, among female relatives the risk for the ApoE 3/4 group was nearly twice that for the ApoE 3/3 group and identical to the risk for the ApoE 4/4 group. These findings are consistent with a sex-modification effect of the E4 isoform on disease susceptibility.
- Published
- 1995
- Full Text
- View/download PDF
18. Leber's hereditary optic neuropathy plus dystonia is caused by a mitochondrial DNA point mutation
- Author
-
Deborah A. Koontz, Richard H. Haas, John M. Shoffner, John Dixon, Albert S. June, Edwin R. Smith, Carol Stugard, Michael D. Brown, Yoon L. Kim, Stephen C. Pollock, Douglas C. Wallace, Jennifer R. Graham, and Allan Kaufman
- Subjects
Adult ,Dystonia ,Genetics ,congenital, hereditary, and neonatal diseases and abnormalities ,Mitochondrial DNA ,Adolescent ,Point mutation ,Neurodegeneration ,Leber's hereditary optic neuropathy ,Middle Aged ,Biology ,medicine.disease ,DNA, Mitochondrial ,eye diseases ,Optic neuropathy ,Optic Atrophies, Hereditary ,Neurology ,Mutation (genetic algorithm) ,medicine ,Optic nerve ,Humans ,Point Mutation ,Female ,Neurology (clinical) - Abstract
A novel point mutation in the ND6 subunit of complex I at position 14,459 of the mitochondrial DNA (MTND6*LDY T14459A) was identified as a candidate mutation for the highly tissue-specific disease. Leber's hereditary optic neuropathy plus dystonia. Since the MTND6*LDYT14459A mutation was identified in a single family, other pedigrees with the mutation are needed to confirm its association with the disease. Clinical, biochemical, and genetic characterization is reported in two additional pedigrees. Leber's hereditary optic neuropathy developed in two family members in one pedigree. The daughter had clinically silent basal ganglia lesions. In a second pedigree, a single individual presented with childhood-onset generalized dystonia and bilateral basal ganglia lesions. Patient groups that included individuals with Leigh's disease, dystonia plus complex neurodegeneration, and Leber's hereditary optic neuropathy did not harbor the MTND6*LDYT14459A mutation, suggesting that this mutation displays a high degree of tissue specificity, thus producing a narrow phenotypic range. These results confirm the association of the MTND6*LDYT14459A mutation with Leber's hereditary optic neuropathy and/or dystonia. As the first genetic abnormality that has been identified to cause generalized dystonia, this mutation suggests that nuclear DNA or mitochondrial DNA mutations in oxidative phosphorylation genes are important considerations in the pathogenesis of dystonia.
- Published
- 1995
- Full Text
- View/download PDF
19. Renal amino acid transport in adults with oxidative phosphorylation diseases
- Author
-
Allan Kaufman, William E. Mitch, Douglas C. Wallace, John Dixon, Alexander S. Voljavec, and John M. Shoffner
- Subjects
Adult ,Male ,medicine.medical_specialty ,Mitochondrial DNA ,Biopsy ,Mitochondrial disease ,Molecular Sequence Data ,Kearns-Sayre Syndrome ,Oxidative phosphorylation ,Biology ,DNA, Mitochondrial ,Oxidative Phosphorylation ,Kidney Tubules, Proximal ,Excretion ,03 medical and health sciences ,Adenosine Triphosphate ,0302 clinical medicine ,Internal medicine ,medicine ,Humans ,Amino Acids ,Muscle, Skeletal ,Aged ,030304 developmental biology ,chemistry.chemical_classification ,0303 health sciences ,Kidney ,Ion Transport ,Base Sequence ,Sodium ,Mitochondrial Myopathies ,Middle Aged ,medicine.disease ,MERRF Syndrome ,3. Good health ,Amino acid ,Blotting, Southern ,Endocrinology ,medicine.anatomical_structure ,Biochemistry ,chemistry ,Nephrology ,Aminoaciduria ,Renal physiology ,Mutation ,Female ,030217 neurology & neurosurgery - Abstract
Renal amino acid transport in adults with oxidative phosphorylation diseases. The clinical manifestations of mitochondrial DNA (mtDNA) mutations depend on a variety of factors including ratios of normal to abnormal mtDNA and tissue-specific differences in ATP production by oxidative phosphorylation (OXPHOS). In order to investigate the effects of OXPHOS defects on renal tubule function, we characterized sodium-coupled transport processes in six individuals with OXPHOS diseases. Pathogenic mtDNA mutations were identified in five of these individuals. Sodium coupled transport processes were evaluated by determining fractional excretions of amino acids, glucose, lactate, urate, and phosphate in patients and controls. Four of the six individuals had high fractional excretions of neutral amino acids, indicating abnormal renal tubule reabsorbtion of these amino acids. Abnormalities in fractional excretions of lactate, glucose, urate, and phosphate were less pronounced. These results demonstrate that sodium-coupled transport processes in the kidney are sensitive to OXPHOS impairment. When abnormalities in these processes are encountered, an OXPHOS disease should be included in the differential diagnosis.
- Published
- 1995
- Full Text
- View/download PDF
20. Mitochondria1 encephalomyopathy associated with a single nucleotide pair deletion in the mitochondrial tRNALeu(UUR) gene
- Author
-
M. G. Bialer, S. G. Pavlakis, Douglas C. Wallace, J. Dixon, Allan Kaufman, M. T. Lott, John M. Shoffner, and S. Teichberg
- Subjects
Genetics ,Mitochondrial encephalomyopathy ,Mutation ,Mitochondrial DNA ,Lineage (genetic) ,Mitochondrion ,Biology ,medicine.disease_cause ,medicine.disease ,Human mitochondrial genetics ,Mitochondrial myopathy ,medicine ,Neurology (clinical) ,Chronic progressive external ophthalmoplegia - Abstract
Article abstract—The investigation of pathogenic mitochondrial DNA (mtDNA) mutations has revealed a complex relation between patient genotype and phenotype. For unknown reasons, some mtDNA mutations produce specific clinical manifestations such as chronic progressive external ophthalmoplegia; myoclonic epilepsy and ragged-red fiber disease (MERRF); and mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS). To enhance our understanding of the association between genotype and phenotype, we investigated a patient with mitochondrial encephalomyopathy and severe cerebral calcifications for a mtDNA mutation. There was a deletion of one of three T:A nucleotide pairs in the tRNA Leu(UUR) gene of the mtDNA involving positions 3271 to 3273. Pedigree analysis suggested that this mutation may have occurred spontaneously in the proband. This analysis represents the smallest mtDNA deletion observed to date and is the first deletion identified within a mitochondrial tRNA. This observation emphasizes the importance of delineating the precise mutation responsible for an oxidative phosphorylation disease for patient diagnosis as well as for genetic counseling of maternal lineage relatives.
- Published
- 1995
- Full Text
- View/download PDF
21. Marked increase in the number and variety of mitochondrial DNA rearrangements in aging human skeletal muscle
- Author
-
John M. Shoffner, Simon Melov, Allan Kaufman, and Douglas C. Wallace
- Subjects
Adult ,Aging ,Mitochondrial DNA ,Somatic cell ,Oxidative phosphorylation ,Biology ,DNA, Mitochondrial ,Polymerase Chain Reaction ,law.invention ,chemistry.chemical_compound ,law ,Genetics ,medicine ,Humans ,Muscle, Skeletal ,Polymerase chain reaction ,Aged ,Sequence Deletion ,Southern blot ,Gene Rearrangement ,Skeletal muscle ,Gene rearrangement ,Middle Aged ,Molecular biology ,Molecular Weight ,medicine.anatomical_structure ,chemistry ,DNA - Abstract
Several reports have shown that individual mitochondrial DNA (mtDNA) deletions accumulate with age. However, the overall extent of somatic mtDNA damage with age remains unclear. We have utilized full-length PCR to concurrently screen for multiple mtDNA rearrangements in total DNA extracted from skeletal muscle derived from physiologically normal individuals (n = 35). This revealed that both the number and variety of mtDNA rearrangements increases dramatically between young and old individuals (P < 0.0001). We further examined the mtDNA from both the younger and older subjects by Southern blot analysis and observed an age-related increase in mtDNA(s) comparable in size to mtDNA products unique to patients with known mtDNA deletions. These data imply that a wide spectrum of mtDNA rearrangements accumulate in old individuals, which correlates with the marked age related decrease in OXPHOS capacity observed in post-mitotic tissues.
- Published
- 1995
- Full Text
- View/download PDF
22. Marked Changes in Mitochondrial DNA Deletion Levels in Alzheimer Brains
- Author
-
Marisol Corral-Debrinski, Terzah M. Horton, Douglas C. Wallace, M. T. Lott, M F Beal, Ann C. McKee, Brett H. Graham, and John M. Shoffner
- Subjects
Male ,Mitochondrial DNA ,medicine.medical_specialty ,Cerebellum ,Biology ,medicine.disease_cause ,DNA, Mitochondrial ,Oxidative Phosphorylation ,Central nervous system disease ,Degenerative disease ,Alzheimer Disease ,Internal medicine ,Genetics ,medicine ,Humans ,Tissue Distribution ,Aged ,Sequence Deletion ,Aged, 80 and over ,Cerebral Cortex ,Mutation ,Putamen ,Age Factors ,Middle Aged ,medicine.disease ,Pathophysiology ,Endocrinology ,medicine.anatomical_structure ,Female ,Alzheimer's disease ,DNA Damage - Abstract
Levels of the common 4977 nucleotide pair (np) mitochondrial DNA (mtDNA) deletion (mtDNA4977) were quantitated in the cortex, putamen, and cerebellum of patients with Alzheimer disease (AD) and compared to age-matched controls. Although cerebellum deletion levels were comparably low in AD patients and controls of all ages, cortical deletion levels were clearly different. The levels of mtDNA deletions in control brains started low, but rose markedly after age 75, while those of AD patients started high and declined to low levels by age 80. Choosing age 75 to arbitrarily delineate between younger and older subjects, younger patients had 15 times more mtDNA deletions than younger controls, while older patients had one-fifth the deletion level of older controls. Younger AD patients also had fourfold more deletions than older AD patients. These results support the hypothesis that OXPHOS defects resulting from somatic mtDNA mutations may play a role in AD pathophysiology.
- Published
- 1994
- Full Text
- View/download PDF
23. Mitochondrial DNA Variants Observed in Alzheimer Disease and Parkinson Disease Patients
- Author
-
M. Flint Beal, Marie T. Lott, Ray L. Watts, Antonio Torroni, Calvin L. Reckord, Jorge L. Juncos, Rino Salvo, John M. Shoffner, Douglas C. Wallace, Barbara J. Crain, Chi Chuan Yang, Marla Gearing, Margaret F. Cabell, Lawrence A. Hansen, Michel Fayad, Suzanne S. Mirra, and Michael D. Brown
- Subjects
Male ,Mitochondrial DNA ,DNA Mutational Analysis ,Molecular Sequence Data ,Biology ,Gene mutation ,medicine.disease_cause ,Animal Population Groups ,DNA, Mitochondrial ,DNA, Ribosomal ,White People ,Cohort Studies ,Species Specificity ,Alzheimer Disease ,Polymorphism (computer science) ,RNA, Ribosomal, 16S ,Genetics ,medicine ,Animals ,Humans ,Point Mutation ,Missense mutation ,Gene ,Phylogeny ,Aged ,Aged, 80 and over ,Mutation ,Base Sequence ,Racial Groups ,Genetic Variation ,NADH Dehydrogenase ,Parkinson Disease ,Middle Aged ,Plants ,Molecular biology ,RNA, Transfer, Glu ,Heteroplasmy ,Restriction enzyme ,RNA, Ribosomal ,Nucleic Acid Conformation ,Female ,Polymorphism, Restriction Fragment Length - Abstract
Mitochondrial DNA (mtDNA) variants associated with Alzheimer disease (AD) and Parkinson disease (PD) were sought by restriction endonuclease analysis in a cohort of 71 late-onset Caucasian patients. A tRNAGln gene variant at nucleotide pair (np) 4336 that altered a moderately conserved nucleotide was present in 9/173 (5.2%) of the patients surveyed but in only 0.7% of the general Caucasian controls. One of these patients harbored an additional novel 12S rRNA 5-nucleotide insertion at np 956-965, while a second had a missense variant at np 3397 that converted a highly conserved methionine to a valine. This latter mutation was also found in an independent AD + PD patient, as was a heteroplasmic 16S rRNA variant at np 3196. Additional studies will be required to determine the significance, if any, of these mutations.
- Published
- 1993
- Full Text
- View/download PDF
24. Genetic Mapping of Human Heart-Skeletal Muscle Adenine Nucleotide Translocator and Its Relationship to the Facioscapulohumeral Muscular Dystrophy Locus
- Author
-
John M. Shoffner, M.R. Altherr, J.J. Wasmuth, Georges Stepien, Andrew B. Chung, Douglas C. Wallace, Meraida Polak, Y. Haraguchi, Antonio Torroni, S.T. Winokur, and D.A. Costigan
- Subjects
Male ,musculoskeletal diseases ,congenital, hereditary, and neonatal diseases and abnormalities ,Genetic Linkage ,Molecular Sequence Data ,Muscle Proteins ,Locus (genetics) ,Hybrid Cells ,Biology ,Muscular Dystrophies ,Oxidative Phosphorylation ,Gene mapping ,Adenine nucleotide ,Genetic linkage ,Cricetinae ,Genetics ,medicine ,Animals ,Humans ,Facioscapulohumeral muscular dystrophy ,Muscular dystrophy ,Alleles ,Base Sequence ,Adenine nucleotide translocator ,Chromosome Mapping ,medicine.disease ,Molecular biology ,Pedigree ,Chromosome 4 ,Genes ,biology.protein ,Female ,Chromosomes, Human, Pair 4 ,Mitochondrial ADP, ATP Translocases ,Polymorphism, Restriction Fragment Length - Abstract
The mitochondrial heart-skeletal muscle adenine nucleotide translocator (ANT1) was regionally mapped to 4q35-qter using somatic cell hybrids containing deleted chromosome 4. The regional location was further refined through family studies using ANT1 intron and promoter nucleotide polymorphisms recognized by the restriction endonucleases MboII, NdeI, and HaeIII. Two alleles were found, each at a frequency of 0.5. The ANT1 locus was found to be closely linked to D4S139, D4S171, and the dominant skeletal muscle disease locus facioscapulohumeral muscular dystrophy (FSHD). A crossover that separated D4S171 and ANT1 from D4S139 was found. Since previous studies have established the chromosome 4 map order as centromere-D4S171-D4S139-FSHD, it was concluded that ANT1 is located on the side of D4S139, that is opposite from FSHD. This conclusion was confirmed by sequencing the exons and analyzing the transcripts of ANT1 from several FSHD patients and finding no evidence of aberration.
- Published
- 1993
- Full Text
- View/download PDF
25. Mitochondrial DNA deletions in human brain: regional variability and increase with advanced age
- Author
-
Terzah M. Horton, Marie T. Lott, Marisol Corral-Debrinski, John M. Shoffner, M F Beal, and Douglas C. Wallace
- Subjects
Adult ,Male ,Aging ,Cerebellum ,Mitochondrial DNA ,Somatic cell ,DNA damage ,Molecular Sequence Data ,Biology ,DNA, Mitochondrial ,Oxidative Phosphorylation ,Cortex (anatomy) ,Genetics ,medicine ,Humans ,Tissue Distribution ,Aged ,Sequence Deletion ,Aged, 80 and over ,Base Sequence ,Putamen ,Brain ,Human brain ,medicine.anatomical_structure ,Ageing ,Female ,DNA Damage - Abstract
We have examined the role of somatic mitochondrial DNA (mtDNA) mutations in human ageing by quantitating the accumulation of the common 4977 nucleotide pair (np) deletion (mtDNA4977) in the cortex, putamen and cerebellum. A significant increase in the mtDNA4977 deletion was seen in elderly individuals. In the cortex, the deleted to total mtDNA ratio ranged from 0.00023 to 0.012 in 67-77 year old brains and up to 0.034 in subjects over 80. In the putamen, the deletion level ranged from 0.0016 to 0.010 in 67 to 77 years old up to 0.12 in individuals over the age of 80. The cerebellum remained relatively devoid of mtDNA deletions. Similar changes were observed with a different 7436 np deletion. These changes suggest that somatic mtDNA deletions might contribute to the neurological impairment often associated with ageing.
- Published
- 1992
- Full Text
- View/download PDF
26. Diseases resulting from mitochondrial DNA point mutations
- Author
-
John M. Shoffner, Douglas C. Wallace, Marie T. Lott, and Michael D. Brown
- Subjects
Mitochondrial encephalomyopathy ,Genetics ,Mutation ,Mitochondrial DNA ,Base Sequence ,Point mutation ,Molecular Sequence Data ,Genetic Diseases, Inborn ,Biology ,medicine.disease_cause ,medicine.disease ,DNA, Mitochondrial ,Molecular biology ,Human mitochondrial genetics ,Oxidative Phosphorylation ,RNA, Transfer ,Mitochondrial myopathy ,medicine ,Humans ,Missense mutation ,Gene ,Genetics (clinical) - Abstract
A number of mitochondrial DNA (mtDNA) mutations have been identified which cause familial, late onset neuromuscular degenerative diseases. These include missense mutations in most of the mtDNA polypeptide genes as well as base substitutions in several tRNA genes. Missense mutations in the mitochondrial electron-transport genes cause Leber hereditary optic neuropathy. Ten mutations have been associated with this disease, but four at nps 11,178, 3460, 4160 and 15,257 appear sufficient in themselves to cause the disease. One missense mutation in the ATPase 6 gene at np 8993 causes a second phenotype, neurogenic muscle weakness, ataxia and retinitis pigmentosum. Transfer RNA mutations have been identified for myoclonic epilepsy and ragged-red fibre disease in the tRNA(Lys) gene at np 8344 and for the mitochondrial encephalomyopathy, lactic acidosis and stroke-like episodes syndrome and for maternal mitochondrial myopathy and cardiomyopathy syndrome in the tRNA(Leu)(UUR) gene at nps 3234 and 3260, respectively. Deficiencies in mitochondrial oxidative phosphorylation enzymes have been observed in several common neurodegenerative diseases such as Alzheimer and Parkinson diseases. Perhaps mtDNA mutations play a role in these as well.
- Published
- 1992
- Full Text
- View/download PDF
27. Rolandic mitochondrial encephalomyelopathy and MT-ND3 mutations
- Author
-
John M. Shoffner, Adam Kirton, Chantal F. Morel, Susanne M. Benseler, Susan Blaser, Delilah Burrowes, Jane B. L. Addis, Annette Feigenbaum, Leon G. Epstein, Brian H. Robinson, and Klaus G.E. Werner
- Subjects
Mitochondrial DNA ,Pathology ,medicine.medical_specialty ,Magnetic Resonance Spectroscopy ,Adolescent ,Mitochondrial disease ,DNA Mutational Analysis ,Epilepsia partialis continua ,Mitochondrion ,Biology ,medicine.disease_cause ,DNA, Mitochondrial ,Diagnosis, Differential ,Developmental Neuroscience ,Mitochondrial Encephalomyopathies ,medicine ,Humans ,Child ,Muscle, Skeletal ,Mutation ,Electron Transport Complex I ,Skeletal muscle ,Brain ,Cytochromes b ,medicine.disease ,Magnetic Resonance Imaging ,Heteroplasmy ,Mitochondria, Muscle ,medicine.anatomical_structure ,Neurology ,Spinal Cord ,RNA, Ribosomal ,Pediatrics, Perinatology and Child Health ,Cervical Vertebrae ,Female ,Neurology (clinical) ,MT-ND3 - Abstract
Mitochondrial encephalopathies may be caused by mutations in the respiratory chain complex I subunit genes. Described here are the cases of two pediatric patients who presented with MELAS-like calcarine lesions in addition to novel, bilateral rolandic lesions and epilepsia partialis continua, secondary to MT-ND3 mutations. Data were collected included neurologic symptoms, serial brain imaging, metabolic evaluations, skeletal muscle biopsies, mitochondrial biochemical and molecular testing. Permission for publication was given by the families. Muscle histology revealed nonspecific changes, with no ragged red or blue or COX-negative fibers. Sequencing of the mitochondrial DNA indicated patient 2 to be homoplasmic in muscle for the mt.10158T>C mutation in the ND3 subunit and Patient 1 to be 75% heteroplasmic for the mt.10191T>C mutation, also in ND3. Bilateral rolandic lesions and epilepsia partialis continua accompanied by suspicion of mitochondrial disease are indications to search for an underlying mutation in the MT-ND3 gene.
- Published
- 2008
28. Developmental regression and mitochondrial dysfunction in a child with autism
- Author
-
Jon S. Poling, John M Shoffner, Richard E. Frye, and Andrew W. Zimmerman
- Subjects
medicine.medical_specialty ,Pathology ,Mitochondrial Diseases ,Biopsy ,Developmental Disabilities ,Cytochrome-c Oxidase Deficiency ,Article ,Diagnosis, Differential ,03 medical and health sciences ,Electron Transport Complex III ,0302 clinical medicine ,Atrophy ,030225 pediatrics ,Internal medicine ,medicine ,Cytochrome c oxidase ,Humans ,Aspartate Aminotransferases ,Autistic Disorder ,Child ,Muscle, Skeletal ,Creatine Kinase ,Muscle biopsy ,Electron Transport Complex I ,biology ,medicine.diagnostic_test ,Infant, Newborn ,Infant ,medicine.disease ,Regression, Psychology ,Muscular Atrophy ,Endocrinology ,Child, Preschool ,Pediatrics, Perinatology and Child Health ,biology.protein ,Childhood Autism Rating Scale ,Autism ,Creatine kinase ,Female ,Neurology (clinical) ,Developmental regression ,030217 neurology & neurosurgery ,Follow-Up Studies - Abstract
Autistic spectrum disorders can be associated with mitochondrial dysfunction. We present a singleton case of developmental regression and oxidative phosphorylation disorder in a 19-month-old girl. Subtle abnormalities in the serum creatine kinase level, aspartate aminotransferase, and serum bicarbonate led us to perform a muscle biopsy, which showed type I myofiber atrophy, increased lipid content, and reduced cytochrome c oxidase activity. There were marked reductions in enzymatic activities for complex I and III. Complex IV (cytochrome c oxidase) activity was near the 5% confidence level. To determine the frequency of routine laboratory abnormalities in similar patients, we performed a retrospective study including 159 patients with autism ( Diagnostic and Statistical Manual of Mental Disorders-IV and Childhood Autism Rating Scale) not previously diagnosed with metabolic disorders and 94 age-matched controls with other neurologic disorders. Aspartate aminotransferase was elevated in 38% of patients with autism compared with 15% of controls ( P < .0001). The serum creatine kinase level also was abnormally elevated in 22 (47%) of 47 patients with autism. These data suggest that further metabolic evaluation is indicated in autistic patients and that defects of oxidative phosphorylation might be prevalent. ( J Child Neurol 2006;21:170—172; DOI 10.2310/7010.2006.00032).
- Published
- 2006
29. Rod photoreceptor function in children with mitochondrial disorders
- Author
-
Anne B. Fulton, Mark S. Korson, Frances E. Dougherty, Basil T. Darras, Linda L. Cooper, Ronald M. Hansen, and John M. Shoffner
- Subjects
Male ,medicine.medical_specialty ,Pathology ,Mitochondrial Diseases ,genetic structures ,Adolescent ,Mitochondrial disease ,Dark Adaptation ,Mitochondrion ,Biology ,DNA, Mitochondrial ,Retinal Rod Photoreceptor Cells ,Internal medicine ,medicine ,Electroretinography ,Humans ,Rod cell ,Scotopic vision ,Child ,Vision, Ocular ,Retina ,medicine.diagnostic_test ,Infant ,medicine.disease ,eye diseases ,Mitochondria, Muscle ,Ophthalmology ,medicine.anatomical_structure ,Endocrinology ,Child, Preschool ,Female ,sense organs ,Oxidoreductases ,Erg ,Visual phototransduction - Abstract
Objective: To test the hypothesis that function of the rod photoreceptors is abnormal in pediatric patients with mitochondrial disorders. Methods: Patients (n=22; median age, 5 years) with a deficiency of 1 or more of the mitochondrial enzyme complexes, or a mutation in mitochondrial DNA, were studied by means of scotopic, full-field electroretinography (ERG). The conditions of ERG testing allowed derivation of the parameters of the activation of rod phototransduction from the ERG a-wave, and postreceptoral function from b-wave and P2 stimulus-response functions. The deactivation of phototransduction was studied in 5 patients. The patients’ ERG responses were compared with those of healthy control subjects (n=25). Results: Responses from 19 patients were sufficient for analysis of rod photoreceptor and postreceptoral function. Saturated amplitudes of the rod photoresponse and b-wave sensitivity were significantly depressed in the patients. Saturated amplitudes of rod cell and P2 responses were correlated. The kinetics of deactivation of phototransduction were slowed even if the kinetics of activation were normal. Conclusions: In patients with mitochondrial disorders, some abnormalities of the scotopic ERG responses originate in the rod photoreceptors, but postreceptoral processes may also be abnormal. From a practical perspective, ERG testing can contribute to diagnosis of mitochondrial disorders.
- Published
- 2002
30. Oxidative phosphorylation disease diagnosis
- Author
-
John M. Shoffner
- Subjects
Mitochondrial encephalomyopathy ,Adult ,Mitochondrial DNA ,Genetic counseling ,Genetic Counseling ,Disease ,Oxidative phosphorylation ,Biology ,medicine.disease_cause ,DNA, Mitochondrial ,General Biochemistry, Genetics and Molecular Biology ,Oxidative Phosphorylation ,Kearns–Sayre syndrome ,History and Philosophy of Science ,Mitochondrial myopathy ,medicine ,Humans ,Leigh disease ,Child ,Cell Nucleus ,Genetics ,chemistry.chemical_classification ,Mutation ,business.industry ,General Neuroscience ,Brain Diseases, Metabolic, Inborn ,Mitochondrial Myopathies ,DNA ,medicine.disease ,Nuclear DNA ,Enzyme ,Neurology ,chemistry ,Neurology (clinical) ,Nervous System Diseases ,Chronic progressive external ophthalmoplegia ,business ,Algorithms ,Function (biology) - Abstract
Although the mitochondrial (mtDNA) encodes only 13 polypeptide subunits of the oxidative phosphorylation (OXPHOS) enzymes, approximately 1,000 proteins are estimated to be necessary for proper OXPHOS function. Over the past ten years, a wide variety of adult and pediatric OXPHOS diseases were found to be caused by or associated with mtDNA mutations and nuclear DNA mutations. These advances enhanced the ability to definitively diagnose patients, develop management plans, and provide genetic counseling. However, in most individuals, diagnosing OXPHOS diseases is difficult and depends on assessing complex data derived from clinical, neuroradiologic, metabolic, biochemical, and pathologic evaluations. As understanding of nuclear OXPHOS genes grows, a more coherent approach to diagnosis, management, and treatment is likely to emerge. This article reviews major classes of OXPHOS diseases, a diagnostic algorithm, and recent advances in this complex field.
- Published
- 2000
31. Mitochondrial myopathy diagnosis
- Author
-
John M. Shoffner
- Subjects
Pathology ,medicine.medical_specialty ,Central nervous system ,Mitochondrion ,DNA, Mitochondrial ,Oxidative Phosphorylation ,Diagnosis, Differential ,chemistry.chemical_compound ,Mitochondrial myopathy ,Mitochondrial Encephalomyopathies ,Medicine ,Humans ,Neuromuscular Manifestations ,business.industry ,Cardiac muscle ,Skeletal muscle ,Mitochondrial Myopathies ,Neuromuscular Diseases ,medicine.disease ,medicine.anatomical_structure ,Phenotype ,chemistry ,Peripheral nervous system ,Neurology (clinical) ,business ,Adenosine triphosphate ,Algorithms - Abstract
Oxidative phosphorylation (OXPHOS) accounts for approximately 95% of the adenosine triphosphate (ATP) produced by the cell. The central nervous system, peripheral nervous system, cardiac muscle, skeletal muscle, and smooth muscle are highly susceptible to dysfunction of this complex enzyme system. Although most OXPHOS diseases are multisystem disorders, the neuromuscular manifestations are often prominent and play an important role in patient diagnosis. To assist the neurologist in evaluating these complex patients, this article focuses on selected samples of OXPHOS diseases with identifiable neuromuscular abnormalities and presents an evaluation algorithm to facilitate patient diagnosis.
- Published
- 2000
32. Tau pathology in a family with dementia and a P301L mutation in tau
- Author
-
Maria Grazia Spillantini, Suzanne S. Mirra, Michel Goedert, Bernardino Ghetti, Marie L. Schmidt, John Q. Trojanowski, Jill R. Murrell, Marla Gearing, Joanne Green, Allan I. Levey, R. Anthony Crowther, Randi Jones, Bruce H. Wainer, and John M. Shoffner
- Subjects
Proband ,Male ,Pathology ,medicine.medical_specialty ,Canada ,Tau protein ,Blotting, Western ,DNA Mutational Analysis ,Restriction Mapping ,tau Proteins ,Polymerase Chain Reaction ,Pathology and Forensic Medicine ,Frontotemporal dementia and parkinsonism linked to chromosome 17 ,Cellular and Molecular Neuroscience ,Epitopes ,Parietal Lobe ,mental disorders ,medicine ,Missense mutation ,Corticobasal degeneration ,Humans ,Point Mutation ,Family Health ,Neurons ,biology ,Neurofibrillary Tangles ,Parkinson Disease ,General Medicine ,Middle Aged ,medicine.disease ,Temporal Lobe ,Frontal Lobe ,Pedigree ,Microscopy, Electron ,Neurology ,Solubility ,biology.protein ,Dementia ,Female ,Neurology (clinical) ,Tauopathy ,France ,Alzheimer's disease ,Atrophy ,DNA Probes ,Frontotemporal dementia - Abstract
Familial forms of frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17) have recently been associated with coding region and intronic mutations in the tau gene. Here we report our findings on 2 affected siblings from a family with early-onset dementia, characterized by extensive tau pathology and a Pro to Leu mutation at codon 301 of tau. The proband, a 55-year-old woman, and her 63-year-old brother died after a progressive dementing illness clinically diagnosed as Alzheimer disease. Their mother, 2 sisters, maternal aunt and uncle, and several cousins were also affected. Autopsy in both cases revealed frontotemporal atrophy and degeneration of basal ganglia and substantia nigra. Sequencing of exon 10 of the tau gene revealed a C to T transition at codon 301, resulting in a Pro to Leu substitution. Widespread neuronal and glial inclusions, neuropil threads, and astrocytic plaques similar to those seen in corticobasal degeneration were labeled with a battery of antibodies to phosphorylation-dependent and phosphorylation-independent epitopes spanning the entire tau sequence. Isolated tau filaments had the morphology of narrow twisted ribbons. Sarkosyl-insoluble tau exhibited 2 major bands of 64 and 68 kDa and a minor 72 kDa band, similar to the pattern seen in a familial tauopathy associated with an intronic tau mutation. These pathological tau bands predominantly contained the subset of tau isoforms with 4 microtubule-binding repeats selectively affected by the P301L missense mutation. Our findings emphasize the phenotypic and genetic heterogeneity of tauopathies and highlight intriguing links between FTDP-17 and other neurodegenerative diseases.
- Published
- 1999
33. Conflict of Interest Statement Concerning 'Developmental Regression and Mitochondrial Dysfunction in a Child With Autism'
- Author
-
Andrew W. Zimmerman, John M. Shoffner, and Richard E. Frye
- Subjects
Statement (logic) ,Pediatrics, Perinatology and Child Health ,Conflict of interest ,medicine ,Autism ,Neurology (clinical) ,medicine.disease ,Psychology ,Developmental regression ,Clinical psychology ,Developmental psychology - Published
- 2008
- Full Text
- View/download PDF
34. Molecular Analysis of Oxidative Phosphorylation Diseases for Detection of Mitochondrial DNA Mutations
- Author
-
John M. Shoffner
- Subjects
Mitochondrial DNA ,Mitochondrial Diseases ,Genetics, Medical ,DNA Mutational Analysis ,Oxidative phosphorylation ,Biology ,DNA, Mitochondrial ,Polymerase Chain Reaction ,Oxidative Phosphorylation ,law.invention ,law ,Genetics ,Humans ,Point Mutation ,Genetic Testing ,Genetics (clinical) ,Polymerase chain reaction ,Southern blot ,Gene Rearrangement ,Point mutation ,Molecular biology ,Nuclear DNA ,Molecular analysis ,Blotting, Southern ,Mutation ,DNA Probes - Abstract
Oxidative phosphorylation (OXPHOS) diseases are caused by inherited or spontaneously occurring mutations in the mitochondrial DNA (mtDNA) or the nuclear DNA. Mutations in the mtDNA can be classified into two groups, rearrangements and point mutations. This unit describes a method for detecting rearrangements of the mtDNA, which involves Southern blot hybridization. Another protocol detects mtDNA point mutations using restriction analysis of polymerase chain reaction (PCR) products. The Southern blot method requires an mtDNA-specific probe.
- Published
- 1997
- Full Text
- View/download PDF
35. Strabismus and mitochondrial defects in chronic progressive external ophthalmoplegia
- Author
-
Hans E. Grossniklaus, Arlene V. Drack, John M. Shoffner, Scott R. Lambert, and Jeffrey A. Sorkin
- Subjects
Adult ,medicine.medical_specialty ,genetic structures ,Eye disease ,Mitochondrial DNA deletions ,DNA, Mitochondrial ,Ophthalmoparesis ,Mitochondrial myopathy ,Ptosis ,medicine ,Humans ,Strabismus ,Ophthalmoplegia ,business.industry ,Mitochondrial Myopathies ,Middle Aged ,medicine.disease ,eye diseases ,Surgery ,Ophthalmology ,Treatment Outcome ,Chronic Disease ,Disease Progression ,Female ,sense organs ,medicine.symptom ,Chronic progressive external ophthalmoplegia ,business ,Gene Deletion ,Strabismus surgery - Abstract
Purpose To describe the results of strabismus surgery on three patients with chronic progressive external ophthalmoplegia, a group of rare disorders characterized by ptosis and slowly progressive ophthalmoparesis that has been shown to result from defects in mitochondrial DNA. Methods Strabismus surgery using the adjustable suture technique was performed in three patients with strabismus and chronic progressive external ophthalmoplegia confirmed by clinical, biochemical, histopathologic, and genetic criteria. All three patients had mitochondrial DNA deletions. Two patients were exotropic; one patient was esotropic. Results Rectus muscle recessions were initially unsuccessful in correcting strabismus in one patient, although a subsequent procedure employing rectus muscle resections was successful in alleviating a significant head turn and improved ocular alignment. In the two other patients, a single procedure consisting of rectus muscle recessions combined with large rectus muscle resections successfully achieved good postoperative alignment. The amount of surgery performed in these three patients exceeded that predicted in standard strabismus tables. Conclusions The myopathic process that results in chronic progressive external ophthalmoplegia renders rectus muscle recessions less effective compared with resections for correcting the associated strabismus seen in these patients. Rectus muscle resections therefore should be an integral procedure in the surgical management of the strabismus associated with chronic progressive external ophthalmoplegia.
- Published
- 1997
36. Maternal inheritance and the evaluation of oxidative phosphorylation diseases
- Author
-
John M. Shoffner
- Subjects
Non-Mendelian inheritance ,Mitochondrial DNA ,Extrachromosomal Inheritance ,Kearns-Sayre Syndrome ,Biology ,medicine.disease_cause ,DNA, Mitochondrial ,Oxidative Phosphorylation ,Kearns–Sayre syndrome ,symbols.namesake ,Mitochondrial Encephalomyopathies ,medicine ,MELAS Syndrome ,Humans ,Point Mutation ,Genetics ,Gene Rearrangement ,Mutation ,Cerebellar ataxia ,food and beverages ,Mitochondrial Myopathies ,General Medicine ,DNA ,medicine.disease ,Phenotype ,MERRF Syndrome ,Nuclear DNA ,Mendelian inheritance ,symbols ,Female ,medicine.symptom ,Leigh Disease - Abstract
Mitochondrial DNA is more susceptible than nuclear DNA to mutations. Mitochondrial mutations have been associated with a range of disorders, some of which can be inherited maternally as well as by mendelian patterns. The oxidative phosphorylation diseases are a group of such disorders characterised by a complex phenotype; the Kearns-Sayre syndrome, for example, can include cardiac abnormalities, diabetes mellitus, cerebellar ataxia, and deafness. An understanding of the genetic and biochemical basis of these disorders will help in the adoption of a systematic approach to their diagnosis and to patient management.
- Published
- 1996
37. Mitochondrial defects in basal ganglia diseases
- Author
-
John M. Shoffner
- Subjects
Mitochondrial DNA ,Pathology ,medicine.medical_specialty ,Movement disorders ,Movement Disorders ,macromolecular substances ,Disease ,Oxidative phosphorylation ,Degeneration (medical) ,Biology ,medicine.disease ,Oxidative Phosphorylation ,nervous system diseases ,Mitochondria ,Neurology ,Basal Ganglia Diseases ,Basal ganglia ,Generalized dystonia ,medicine ,Humans ,Neurology (clinical) ,medicine.symptom ,Basal ganglia disease - Abstract
Mitochondrial DNA mutations are important causes of movement disorders and are often associated with basal ganglia degeneration. Leigh's disease and a form of generalized dystonia are caused by mitochondrial DNA mutations. Recent biochemical and genetic evidence suggests that some cases of Parkinson's disease may be caused by oxidative phosphorylation defects.
- Published
- 1995
38. Marked increase in mitochondrial DNA deletion levels in the cerebral cortex of Huntington's disease patients
- Author
-
Allan Kaufman, Marisol Corral-Debrinski, Terzah M. Horton, Douglas C. Wallace, Brett H. Graham, M F Beal, and John M. Shoffner
- Subjects
Adult ,Male ,Pathology ,medicine.medical_specialty ,Mitochondrial DNA ,Molecular Sequence Data ,Biology ,DNA, Mitochondrial ,Polymerase Chain Reaction ,Degenerative disease ,Huntington's disease ,Cortex (anatomy) ,medicine ,Humans ,Repetitive Sequences, Nucleic Acid ,Cerebral Cortex ,Base Sequence ,Putamen ,Neurodegeneration ,Middle Aged ,medicine.disease ,medicine.anatomical_structure ,Huntington Disease ,Cerebral cortex ,Female ,Neurology (clinical) ,Occipital lobe - Abstract
To determine if somatic mtDNA mutations might contribute to the neurodegeneration observed in Huntington's disease (HD), we quantitated the amount of the common mitochondrial 4977 nucleotide pair deletion (mtDNA4977) in cortex and putamen of HD patients and age-matched controls by the serial dilution-polymerase chain reaction method. Cortical deletion levels were analyzed in the temporal, frontal, and occipital lobes. HD temporal lobes had an 11-fold greater mean mtDNA4977 deletion level than age-matched controls, and HD frontal lobes had fivefold greater levels. HD occipital lobe and putamen deletion levels were comparable with control levels. These results support the hypothesis that HD is associated with elevated cortical mtDNA damage.
- Published
- 1995
39. Mitochondrial DNA mutations in human degenerative diseases and aging
- Author
-
Ian A. Trounce, John M. Shoffner, Scott W. Ballinger, Albert S. Jun, Michael D. Brown, Douglas C. Wallace, Marisol Corral-Debrinski, Terzah M. Horton, and Marie T. Lott
- Subjects
Adult ,Male ,Mitochondrial DNA ,Aging ,Bioenergetics ,Molecular Sequence Data ,Disease ,Oxidative phosphorylation ,Mitochondrion ,Biology ,medicine.disease_cause ,Human mitochondrial genetics ,DNA, Mitochondrial ,Oxidative Phosphorylation ,Optic Atrophies, Hereditary ,medicine ,Animals ,Humans ,Point Mutation ,Amino Acid Sequence ,Child ,Molecular Biology ,Conserved Sequence ,Aged ,Genetics ,Mutation ,Sequence Homology, Amino Acid ,Skeletal muscle ,mtDNA mutation ,Mitochondrial Myopathies ,Middle Aged ,Biological Evolution ,Mitochondria ,Pedigree ,medicine.anatomical_structure ,Molecular Medicine ,Female ,Nervous System Diseases ,Energy Metabolism - Abstract
A wide variety of mitochondrial DNA (mtDNA) mutations have recently been identified in degenerative diseases of the brain, heart, skeletal muscle, kidney and endocrine system. Generally, individuals inheriting these mitochondrial diseases are relatively normal in early life, develop symptoms during childhood, mid-life, or old age depending on the severity of the maternally-inherited mtDNA mutation; and then undergo a progressive decline. These novel features of mtDNA disease are proposed to be the product of the high dependence of the target organs on mitochondrial bioenergetics, and the cumulative oxidative phosphorylation (OXPHOS) defect caused by the inherited mtDNA mutation together with the age-related accumulation mtDNA mutations in post-mitotic tissues.
- Published
- 1995
40. Rapid and Dramatic Decreases of Cerebral 5-Methyltetrahydrofolate: A Treatable Form of Progressive Neurodegeneration (S28.007)
- Author
-
Keith Hyland, John M. Shoffner, and Maureen Starnes
- Subjects
Pediatrics ,medicine.medical_specialty ,Neurology ,Movement disorders ,business.industry ,Mitochondrial disease ,Neurogenetics ,5-Methyltetrahydrofolate ,Disease ,Progressive neurodegeneration ,medicine.disease ,Epilepsy ,medicine ,Neurology (clinical) ,medicine.symptom ,business - Abstract
Objective: We provide evidence demonstrating that CSF 5-MTHF decreases over time and in some cases, very quickly. Hence, progressive neurologic symptoms may indicate the development of Cerebral Folate Deficiency (CFD), even if prior determinations were normal. Background The cerebral folate deficiency (CFD) syndrome describes any neurological condition where low levels of CSF 5-methyltetrahydrofolate (5-MTHF) are found within the CNS and where systemic folate levels are normal. CFD can be primary (inherited defect), or secondary (as in mitochondrial disease or an autoimmune disorder). In practice, once CSF 5-MTHF levels are measured, clinicians generally consider CFD excluded if levels are normal. Design/Methods: Nine children were identified with progressive neurologic symptoms that included epilepsy, movement disorders, and neurobehavioral difficulties. Previously documented CSF 5-MTHF levels were normal in all (>50 nmol/L). Eight of nine were scored as Probable or Highly Probably Mitochondrial Disease using the Nijmegen Diagnostic Criteria (Neurology 2002;59:1402). Results: CSF 5-MTHF levels dropped by 44.2% in an average of 37 months, with a majority dropping into the abnormal range. The most dramatic of these was a 50% reduction in CSF 5-MTHF in 9 months. Data regarding treatment outcomes will be presented. Conclusions: Findings suggest that CSF 5-MTHF levels are not static over time and repeat assessment of CSF 5-MTHF should be considered in patients with progressive neurologic abnormalities. Supported by: Medical Neurogenetics, LLC. Disclosure: Dr. Starnes has received personal compensation for activities with Medical Neurogenetics, LLC as an employee. Dr. Shoffner has received personal compensation for activities with Medical Neurogenetics, LLC. Dr. Shoffner holds stock and/or stock options in Medical Neurogenetics, LLC. Dr. Hyland has received personal compensation for activities with Medical Neurogenetics as co-owner.Dr. Hyland has received compensation for serving as the vice president of Medical Neurogenetics.Dr. Hyland has received research support from National Institute of Health and Neurotransmitter Disease Foundation.
- Published
- 2012
- Full Text
- View/download PDF
41. Chronic Progressive External Ophthalmoplegia and Cerebral Folate Defect in a Patient Undergoing Antiretroviral Treatment for HIV: Effects on Mitochondrial Function (P01.264)
- Author
-
Keith Hyland, John M. Shoffner, Lauren Mylacraine, and William A. Langley
- Subjects
Pediatrics ,medicine.medical_specialty ,business.industry ,Antiretroviral treatment ,medicine ,Human immunodeficiency virus (HIV) ,Neurology (clinical) ,medicine.disease_cause ,Chronic progressive external ophthalmoplegia ,medicine.disease ,business - Published
- 2012
- Full Text
- View/download PDF
42. Detection of Anti-Folate Receptor Antibodies in the Serum and CSF of Cerebral Folate Deficiency Patients (P02.171)
- Author
-
Lauren Mylacraine, William A. Langley, John M. Shoffner, and Keith Hyland
- Subjects
education.field_of_study ,Psychomotor retardation ,business.industry ,Population ,Autoantibody ,Neurogenetics ,Disease ,Cerebrospinal fluid ,Folate receptor ,Immunology ,Etiology ,Medicine ,Neurology (clinical) ,medicine.symptom ,business ,education - Abstract
Objective: To develop an assay to quantify and determine the isotype of autoantibodies recognizing the folate receptor protein (FOLR1) in order to aid in the diagnosis of patients suffering from cerebral folate deficiency (CFD). Background CFD is a neurological syndrome in which a low concentration of 5-methyltetrahydrofolate (5MTHF) is present in the cerebrospinal fluid (CSF) of afflicted patients, while peripheral levels are normal. Symptoms of CFD can range from irritability and learning difficulties to seizures, psychomotor retardation, and brain damage. A variety of inherited disorders can lead to CFD, including dyhydropteridine reductase deficiency, 3-phosphoglycerate dehydrogenase deficiency, Kearns-Sayre syndrome, and mutations in the folate receptor gene (FOLR1). In addition to these inherited causes, CFD has also been attributed to autoantibodies directed against the FOLR1 protein. Design/Methods: An ELISA was developed to detect and quantify anti-FOLR1 antibodies of different isotypes. Serum from over 150 patients was analyzed with this assay in order to determine the prevalence of these autoantibodies in this population. Additionally, CSF from over 50 patients with low CSF 5MTHF levels was analyzed in order to determine if anti-FOLR1 antibodies could be detected. Results: The prevalence, quantity, and isotypes of anti-FOLR1 autoantibodies in the serum of patients in our cohort were determined. We were also able to detect anti-FOLR1 antibodies in the CSF of some of the patients with low CSF 5MTHF levels. To our knowledge, this is the first time that anti-FOLR1 antibodies have been reported in CSF samples from patients suffering from CFD. Conclusions: In patients with CFD where inherited disorders do not appear to be causative, the ability to detect autoantibodies may allow for improved diagnosis and treatment options. Our findings of autoantibodies in the CSF of some patients with suspected CFD give further insight into the etiology of the disease in these patients. Supported by: Medical Neurogenetics, LLC. Disclosure: Dr. Langley has received personal compensation for activities with Medical Neurogenetics, LLC as an employee. Dr. Hyland has received personal compensation for activities with Medical Neurogenetics as co-owner.Dr. Hyland has received compensation for serving as the vice president of Medical Neurogenetics.Dr. Hyland has received research support from National Institute of Health and Neurotransmitter Disease Foundation. Dr. Mylacraine has received personal compensation for activities with Medical Neurogenetics, LLC as an employee. Dr. Shoffner has received personal compensation for activities with Medical Neurogenetics, LLC. Dr. Shoffner holds stock and/or stock options in Medical Neurogenetics, LLC.
- Published
- 2012
- Full Text
- View/download PDF
43. Mitochondrial diabetes revisited
- Author
-
John M. Shoffner, Susan Gebhart, Scott W. Ballinger, Douglas C. Wallace, and Deborah A. Koontz
- Subjects
Male ,Mitochondrial Diabetes ,Oxidative phosphorylation ,Pharmacology ,Mitochondrion ,Biology ,medicine.disease ,DNA, Mitochondrial ,Oxidative Phosphorylation ,Mitochondria ,chemistry.chemical_compound ,chemistry ,Diabetes Mellitus, Type 2 ,Diabetes mellitus ,Genetics ,medicine ,Humans ,Female ,DNA - Published
- 1994
44. Mitochondrial DNA mutations in epilepsy and neurological disease
- Author
-
Marie T. Lott, Scott W. Ballinger, John M. Shoffner, and Douglas C. Wallace
- Subjects
Adult ,Male ,Mitochondrial DNA ,Mitochondrial disease ,DNA Mutational Analysis ,Molecular Sequence Data ,Biology ,Deafness ,medicine.disease_cause ,Human mitochondrial genetics ,DNA, Mitochondrial ,Oxidative Phosphorylation ,Mitochondrial myopathy ,medicine ,Diabetes Mellitus ,Humans ,Gene ,Aged ,Genetics ,Mutation ,Homoplasmy ,Epilepsy ,Base Sequence ,Middle Aged ,medicine.disease ,Molecular biology ,MERRF Syndrome ,Pedigree ,Neurology ,DNAJA3 ,Female ,Neurology (clinical) ,Nervous System Diseases - Abstract
Summary: Recent discoveries in mitochondrial clinical genetics have revealed that a broad spectrum of clinical phenotypes are associated with mutations in mitochondrial DNA. Diseases caused by mutations in mitochondrial DNA are by nature quantitative. Myoclonic epilepsy and ragged-red fiber disease are caused by a mutation in the transfer RNA gene lysine. Although everyone in a maternal lineage will harbor the same mutation, the nature and severity of the symptoms vary markedly among individuals. This variability correlates with the inherited percentage of mutations in the individual's mitochondrial DNA and the individual's age. Age-related expression of mitochondrial disease has also been demonstrated for mitochondrial DNA deletions. Although deletions that retain both origins of replication result in late-onset disease because of the progressive enrichment of the deleted mitochondrial DNA, a 10.4-kb deletion that lacks the light-strand replication origin and maintains a stable mutant percentage in both tissues and cultured cells has been discovered. This deletion is associated with adult-onset diabetes and deafness, but not with ophthalmoplegia, ptosis, or mitochondrial myopathy. Biochemically, it causes a generalized defect in mitochondrial protein synthesis and oxidative phosphorylation. The age-related decline in oxidative phosphorylation could reflect the accumulation of somatic mitochondrial DNA mutations. Inhibition of oxidative phosphorylation stimulates this accumulation. The general paradigm for mitochondrial DNA diseases may be that inherited mutations inhibit the electron transport chain. This damages the mitochondrial DNA, further reducing oxidative phosphorylation. Ultimately, oxidative phosphorylation drops below the expression threshold of cells and tissues, and clinical symptoms appear.
- Published
- 1994
45. Mitochondrial Myopathies: Genetic Aspects
- Author
-
John M. Shoffner, Douglas C. Wallace, and Scott W. Ballinger
- Subjects
Mitochondrial DNA ,Mitochondrial myopathy ,biology ,Biochemistry ,Adenine nucleotide translocator ,medicine ,biology.protein ,Promoter ,ATP–ADP translocase ,Mitochondrion ,Mitochondrial carrier ,medicine.disease ,Inner mitochondrial membrane - Abstract
Publisher Summary This chapter discusses the genetic aspects of mitochondrial myopathies. Mitochondria are the major producers of cellular adenosine triphosphate (ATP) by the process of oxidative phosphorylation (OXPHOS). The mitochondrial OXPHOS system encompasses five multiple subunit enzyme complexes plus the adenine nucleotide translocator (ANT), all of which are embedded in the mitochondrial inner membrane. Four of these five OXPHOS enzyme complexes contain polypeptide subunits encoded by both the nucleus and the mitochondria. The two promoters, light strand promoter (LSP) and heavy-strand promoter (HSP), of mtDNA transcription are adjacent to each other within the displacement loop (D-loop). Inverted sequences located upstream from both promoters bind mitochondrial transcription factor (mtTFl). MtTFl is required in addition to the mitochondrial RNA (mtRNA) polymerase for efficient transcription. The genetic code of the mtDNA differs from nucleus and virtually all other organisms. The mtDNA genetic code is highly degenerate, so that only 22 tRNAs are required for translation. When uridine is in the wobble position, all 4 members of a codon family can be read by 1 mitochondrial tRNA.
- Published
- 1994
- Full Text
- View/download PDF
46. Oxidative phosphorylation diseases and mitochondrial DNA mutations: diagnosis and treatment
- Author
-
Douglas C. Wallace and John M. Shoffner
- Subjects
Genetics ,Mitochondrial DNA ,Mutation ,Nutrition and Dietetics ,Respiratory chain ,Medicine (miscellaneous) ,Oxidative phosphorylation ,Biology ,medicine.disease_cause ,DNA, Mitochondrial ,Oxidative Phosphorylation ,medicine ,DNAJA3 ,Animals ,Humans ,Congenital disease ,Metabolism, Inborn Errors - Published
- 1994
47. Recent advances in mitochondrial genetics
- Author
-
Douglas C. Wallace and John M. Shoffner
- Subjects
Genetics ,Mitochondrial DNA ,Cytosol ,ATP synthase ,biology ,Biochemistry ,Adenine nucleotide translocator ,biology.protein ,Oxidative phosphorylation ,ATP–ADP translocase ,Electrochemical gradient ,Inner mitochondrial membrane - Abstract
Publisher Summary This chapter examines some of the recent advances in mitochondrial genetics and the way in which they have altered our understanding of rare and common age-related diseases. Normal ATP generation by oxidative phosphorylation (OXPHOS) is a complex process requiring the coordinated expression of two genomes: (1) the nuclear DNA (nDNA) and (2) the mitochondrial DNA (mtDNA). OXPHOS is carried out by five enzyme complexes assembled from subunits encoded by the mtDNA. The first four complexes (I–IV) create the electron-transport chain which oxidizes electrons from NADH or FADH 2 and uses the energy to pump protons out of the mitochondrial inner membrane. This electrochemical gradient is utilized by Complex V to synthesize ATP from ADP+P i . The ATP is then exchanged across the mitochondrial inner membrane for cytosolic ADP by the adenine nucleotide translocator (ANT). The ANT and the catalytic ATP synthase β subunit share a muscle specific cis element, the OXBOX, which results in their coordinated elevated expression in heart and skeletal muscle. In addition to the 13 OXPHOS polypeptides, the mtDNA also encodes the rRNAs and tRNAs of mitochondrial protein synthesis.
- Published
- 1994
- Full Text
- View/download PDF
48. Variable retinal and neurologic manifestations in patients harboring the mitochondrial DNA 8993 mutation
- Author
-
Deborah A. Koontz, Douglas C. Wallace, John M. Shoffner, Allan Kaufman, Rafael G. Ortiz, and Nancy J. Newman
- Subjects
Adult ,Male ,Pathology ,medicine.medical_specialty ,Mitochondrial DNA ,Adolescent ,Fundus Oculi ,Mitochondrial disease ,Eye disease ,Visual Acuity ,Retinitis ,Biology ,DNA, Mitochondrial ,chemistry.chemical_compound ,Internal medicine ,medicine ,Electroretinography ,Humans ,Point Mutation ,Child ,Genetics ,business.industry ,Point mutation ,Infant ,Retinal ,medicine.disease ,Magnetic Resonance Imaging ,Pedigree ,Ophthalmology ,Migraine ,chemistry ,Child, Preschool ,Mutation (genetic algorithm) ,Maculopathy ,Female ,Neurology (clinical) ,sense organs ,Headaches ,medicine.symptom ,Nervous System Diseases ,Visual Fields ,business ,Retinitis Pigmentosa - Abstract
Objective: Ophthalmologic and neurologic manifestations of the mitochondrial DNA mutation at position 8993 ( MTATP*NARP8993 ) are reported and compared with previously published reports of patients with the 8993 mutation and other mitochondrial disorders. Design: Pedigree analysis. Setting: University referral center. Patients: Eight subjects from two unrelated pedigrees that were positive for the mitochondrial DNA replacement mutation at nucleotide position 8993 were evaluated ophthalmologically and neurologically. Results: Retinal abnormalities ranged from mild salt-and-pepper changes to severe retinitis pigmentosa—like changes with maculopathy. Neurologic manifestations were also highly variable and ranged from migraine headaches to severe dementia and Leigh's disease. Conclusions: The type and extent of retinal pigmentary changes and neurologic findings varied substantially, even among members of the same family. These changes, although not specific for the MTATP*NARP8993 mutation, are highly suggestive of mitochondrial disease.
- Published
- 1993
49. Oxidative damage to mitochondrial DNA shows marked age-dependent increases in human brain
- Author
-
M F Beal, Deborah A. Koontz, John M. Shoffner, Douglas C. Wallace, Usha MacGarvey, Allan Kaufman, and Patrizia Mecocci
- Subjects
Senescence ,Adult ,Male ,medicine.medical_specialty ,Mitochondrial DNA ,Aging ,Biology ,DNA, Mitochondrial ,chemistry.chemical_compound ,Internal medicine ,medicine ,Deoxyguanosine ,Humans ,Aged ,Aged, 80 and over ,Cell Nucleus ,8-Hydroxy-2'-deoxyguanosine ,Brain ,Human brain ,DNA ,Middle Aged ,Nuclear DNA ,medicine.anatomical_structure ,Endocrinology ,Neurology ,chemistry ,Biochemistry ,Cerebral cortex ,8-Hydroxy-2'-Deoxyguanosine ,Female ,Neurology (clinical) ,Oxidation-Reduction - Abstract
A major theory of aging is that oxidative damage may accumulate in DNA and contribute to physiological changes associated with aging. We examined age-related accumulation of oxidative damage to both nuclear DNA (nDNA) and mitochondrial DNA (mtDNA) in human brain tissue. We measured the oxidized nucleoside, 8-hydroxy-2'-deoxyguanosine (OH8dG), in DNA isolated from 3 regions of cerebral cortex and cerebellum from 10 normal humans aged 42 to 97 years. The amount of OH8dG, expressed as a ratio of the amount of deoxyguanosine (dG) or as fmol/micrograms of DNA, increased progressively with normal aging in both nDNA and mtDNA; however, the rate of increase with age was much greater in mtDNA. There was a significant 10-fold increase in the amount of OH8dG in mtDNA as compared with nDNA in the entire group of samples, and a 15-fold significant increase in patients older than 70 years. These results show for the first time that there is a progressive age-related accumulation in oxidative damage to DNA in human brain, and that the mtDNA is preferentially affected. It is possible that such damage may contribute to age-dependent increases in incidence of neurodegenerative diseases.
- Published
- 1993
50. Response to ‘‘The Appalling Poling Saga’’
- Author
-
John M. Shoffner
- Subjects
business.industry ,Pediatrics, Perinatology and Child Health ,Poling ,Optoelectronics ,Neurology (clinical) ,business ,Psychology - Published
- 2010
- Full Text
- View/download PDF
Catalog
Discovery Service for Jio Institute Digital Library
For full access to our library's resources, please sign in.