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Urs Giger - One of the best experts on this subject based on the ideXlab platform.
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missense mutation in pfkm associated with muscle type Phosphofructokinase Deficiency in the wachtelhund dog
Molecular and Cellular Probes, 2012Co-Authors: Inal G Gultekin, Kenneth Raj, S Lehman, A Hillstrom, Urs GigerAbstract:Hereditary muscle-type Phosphofructokinase (PFK) Deficiency causing intermittent hemolytic anemia and exertional myopathy due to a single nonsense mutation in PFKM has been previously described in English Springer and American Cocker Spaniels, Whippets, and mixed breed dogs. We report here on a new missense mutation associated with PFK Deficiency in Wachtelhunds. Coding regions of the PFKM gene were amplified from genomic DNA and/or cDNA reverse-transcribed from RNA of EDTA blood of PFK-deficient and clinically healthy Wachtelhunds and control dogs. The amplicons were sequenced and compared to the published canine PFKM sequence. A point mutation (c.550C>T, in the coding sequence of PFKM expressed in blood) was found in all 4 affected Wachtelhunds. This missense mutation results in an amino acid substitution of arginine (Arg) to tryptophan (Trp) at position 184 of the protein expressed in blood (p.Arg184Trp). The mutation is located within an alpha-helix, and based on the SIFT analysis, this amino acid substitution is not tolerated. Amplifying the region around this mutation and digesting the PCR fragment with the restriction enzyme MspI, produces fragments that readily differentiate between PFK-deficient, carrier, and normal animals. Furthermore, we document 2 additional upstream PFKM exons expressed in canine testis but not in blood. Despite their similar phenotypic appearance and use for hunting, Wachtelhunds and English Springer Spaniels are not thought to have common ancestors. Thus, it is not surprising that different mutations are responsible for PFK Deficiency in these breeds. Knowledge of the molecular basis of PFK Deficiency in Wachtelhunds provides an opportunity to screen and control the spread of this deleterious trait.
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hereditary Phosphofructokinase Deficiency in wachtelhunds
Journal of The American Animal Hospital Association, 2011Co-Authors: Anna Hillstrom, Harold Tvedten, Andre Rowe, Urs GigerAbstract:Hereditary Phosphofructokinase (PFK) Deficiency was diagnosed in two Wachtelhund dogs and suspected in three related Wachtelhund dogs with exercise intolerance, hemolytic anemia, and pigmenturia. Severe, persistent reticulocytosis in light of only mild anemia together with hemoglobinuria after strenuous exercise suggested PFK Deficiency. Low erythrocyte PFK activity together with low 2,3-diphosphoglycerate concentrations and a high hemoglobin-oxygen affinity confirmed the diagnosis. The PFK Deficiency is due to a single missense mutation in the muscle-type PFK M-PFK gene in English springer and American cocker spaniels, whippets, and mixed-breed dogs; however, these PFK-deficient Wachtelhunds do not have the same PFK mutation.
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hemolysis myopathy and cardiac disease associated with hereditary Phosphofructokinase Deficiency in two whippets
Veterinary Clinical Pathology, 2009Co-Authors: Karen L Gerber, John W Harvey, Sara Dagorne, Jonathan Wood, Urs GigerAbstract:Two male castrated Whippet littermates were presented at 1 year of age for pallor, tachycardia, systolic heart murmur, dark yellow to orange feces, intermittent lethargy, pigmenturia, and muscle shivering or cramping after exercise. Persistent macrocytic hypochromic anemia with marked reticulocytosis and metarubricytosis was found when CBC results were compared with reference values for Whippets. Increased serum creatine kinase activity and hyperkalemia also were sometimes present over the 4-year period of evaluation. Progressively increasing serum concentrations of N-terminal prohormone brain natriuretic peptide suggested cardiac disease. Erythrocytes from the whippets were less osmotically fragile but more alkaline fragile than those from control dogs. Erythrocyte Phosphofructokinase (PFK) activities and 2,3-diphosphoglycerate concentrations were decreased. Restriction enzyme-based DNA test screening and DNA sequencing revealed the same mutation in the muscle-PFK gene of the Whippets as seen in English Springer Spaniel dogs with PFK Deficiency. This is the first report of PFK Deficiency in Whippet dogs. In addition to causing hemolysis and exertional myopathy, heart disease may be a prominent clinical component of PFK Deficiency in this breed and has not been previously recognized in PFK-deficient English Springer Spaniels.
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disturbed erythrocyte calcium homeostasis and adenine nucleotide dysregulation in canine Phosphofructokinase Deficiency
Comparative Haematology International, 2008Co-Authors: Richard L Sabina, Jeffrey Woodliff, Urs GigerAbstract:Muscle-type Phosphofructokinase Deficiency (PFKD) causes a hemolytic disorder and exertional myopathy in humans and dogs. In humans, PFKD is accompanied by a disturbed calcium homeostasis and associated adenine nucleotide dysregulation, which may potentiate the erythroenzymopathy associated with this inherited disorder. This study shows that canine PFKD also manifests these erythrocyte abnormalities. Compared to normal, healthy red cells, PFK-deficient erythrocytes contain lower concentrations of ATP and higher concentrations of IMP and calcium, the latter as per a calcium indicator dye. Adenosine monophosphate deaminase (AMPD) enriched 5000-fold from canine erythrocytes adsorbs to immobilized calcium–calmodulin and the interaction between these two proteins activates AMPD through a K mapp effect. This behavior is similar to that of the human erythrocyte enzyme and provides a potential contributing mechanism for accelerated adenine nucleotide turnover in canine PFKD. We propose that adenine nucleotide replacement strategies could benefit the erythroenzymopathy in human and canine PFKD and that the dog model of this disorder is an appropriate vehicle for further elucidating this hypothesis.
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haemolytic anaemia and exercise intolerance due to Phosphofructokinase Deficiency in related springer spaniels
Journal of Small Animal Practice, 2001Co-Authors: E Skibild, B.f. Smith, K Dahlgaard, Y Rajpurohit, Urs GigerAbstract:Phosphofructokinase (PFK) Deficiency is an autosomal recessive inherited disorder in dogs causing haemolytic crises and exertional myopathy. The clinical signs may be confused with those of recurrent immune-mediated haemolytic anaemia. The Deficiency has been commonly observed in field trial (working) English springer spaniels (ESSPs), but also in the conformation line of ESSPs in the USA over the past two decades. This report documents the first family of ESSPs found with PFK Deficiency in Europe. Two related adult ESSPs in Denmark had intermittent signs of pigmenturia after exercise (hunting) and had evidence of a regenerative haemolytic anaemia. Based upon DNA sequencing data, both dogs had the previously described nonsense point mutation in the muscle-type PFK gene (delta2228G-->A). Study of 17 related family members using a simple and accurate PFK-DNA test revealed one additional PFK-deficient dog (with minor exercise intolerance), nine carriers and seven normal (or 'clear') ESSPs. Recently, the authors have also identified PFK carriers and affected ESSPs in the UK. Screening for PFK Deficiency is recommended for ESSPs with suspicious clinical signs and before using any for field trials or breeding in order to prevent the further spread of this hereditary disorder.
Nina Raben - One of the best experts on this subject based on the ideXlab platform.
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Phosphofructokinase Deficiency past present and future
Current Molecular Medicine, 2002Co-Authors: Hiromu Nakajima, Nina Raben, Tomoya Hamaguchi, Tomoyuki YamasakiAbstract:Phosphofructokinase Deficiency (Tarui disease, glycogen storage disease VII, GSD VII) stands out among all the GSDs. PFK Deficiency was the first recognized disorder that directly affects glycolysis. Ever since the discovery of the disease in 1965, a wide range of biochemical, physiological and molecular studies of the disorder have greatly expanded our understanding of the function of normal muscle, general control of glycolysis and glycogen metabolism. The studies of PFK Deficiency vastly enriched the field of glycogen storage diseases, as well as the field of metabolic and neuromuscular disorders. This article cites a historical overview of this clinical entity and the progress that has been made in molecular genetic area. We will also present the results of a search in-silico, which allowed us to identify a previously unknown sequence of the human platelet PFK gene (PFK-P). In addition, we will describe phylogenetic analysis of evolution of PFK genes.
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various classes of mutations in patients with Phosphofructokinase Deficiency tarui s disease
Muscle & Nerve, 1995Co-Authors: Nina Raben, Zohar Argov, Hiromu Nakajima, Jeffrey B Sherman, Elizabeth Adams, Paul H PlotzAbstract:Muscle Phosphofructokinase (PFK-M) Deficiency (glycogenosis type VII, Tarui's disease) is characterized by intolerance to vigorous exercise, often accompanied by myoglobinuria. The disease is inherited as an autosomal recessive trait. The clinical manifestations are similar to those in myophosphorylase Deficiency (McArdle's disease), and the diagnosis required demonstration of the enzyme defect in muscle biopsy. In the Western hemisphere PFK Deficiency appears to be prevalent among people of Ashkenazi Jewish descent. To define the molecular basis of this myopathy, we have studied 11 Ashkenazi and 2 non-Ashkenazi families with the disease. Ashkenazi patients share two common pathogenic mutations, a splicing defect and a nucleotide deletion, which account for approximately 95% of mutant alleles. The molecular diagnosis is now possible in this population by using simple PCR-based tests to screen for these mutations.
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functional expression of human mutant Phosphofructokinase in yeast genetic defects in french canadian and swiss patients with Phosphofructokinase Deficiency
American Journal of Human Genetics, 1995Co-Authors: Nina Raben, Jeffrey B Sherman, R Exelbert, R Spiegel, H Nakajima, P H Plotz, J HeinischAbstract:Human Phosphofructokinase (PFK) is a tetrameric enzyme, encoded by muscle, liver, and platelet genes. Deficiency of muscle PFK (PFK-M), glycogenosis type VII (Tarui disease), is an autosomal recessive disorder characterized by an exertional myopathy and hemolytic syndrome. Several disease-causing mutations have been identified in the PFK-M gene in Japanese, Ashkenazi Jewish, and Italian patients. We describe the genetic defects in French Canadian and Swiss patients with the disease, and we use a genetically well-defined yeast system devoid of endogenous PFK for structure-function studies of the mutant PFKs. A G-to-A transition at codon 209-in exon 8 of the PFK-M gene, changing an encoded Gly to Asp, is responsible for the disease in a homozygous French Canadian patient. Gly-209-mutated protein is completely inactive in the yeast system. The Swiss patient is a genetic compound, carrying a G-to-A transition at codon 100 in exon 6 (Arg to Gln) and a G-to-A transition at codon 696 in exon 22 (Arg to His). The mutants expressed in yeast generate functional enzyme with modest changes in thermal stability. The advantages and limitations of the yeast system for expression of human mutant PFKs are discussed.
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late onset muscular weakness in Phosphofructokinase Deficiency due to exon 5 intron 5 junction point mutation a unique disorder or the natural course of this glycolytic disorder
Neurology, 1994Co-Authors: Zohar Argov, Varda Barash, Dov Soffer, J Sherman, Nina RabenAbstract:Late-onset muscle weakness is rare in glycolytic disorders. There are two reports in the literature of Phosphofructokinase (PFK)-deficient Ashkenazi Jews with severe vacuolar myopathy manifesting in late adulthood. The genetic abnormality in these patients is unknown. We report a third patient with a similar syndrome: early-onset exercise intolerance in young childhood and progressive weakness in a limb-girdle distribution appearing at 57 years of age, leading to severe incapacity. Muscle histology showed diffuse vacuolar changes, and muscle fibers contained excess glycogen-like material. Muscle biochemistry was diagnostic for PFK Deficiency. DNA analysis from the patient and his family showed that he was homozygous for a recently identified point mutation at the exon 5/intron 5 junction (a G-to-A change); two other family members were heterozygous for this mutation. It is not clear whether late-onset weakness is the natural course for all PFK-deficient patients or whether the exon 5 mutation carries increased risk for this severe myopathy.
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a 5 splice junction mutation leading to exon deletion in an ashkenazic jewish family with Phosphofructokinase Deficiency tarui disease
Journal of Biological Chemistry, 1993Co-Authors: Nina Raben, Jeffrey B Sherman, Frederick W Miller, Hernando Mena, Paul H PlotzAbstract:Abstract A Deficiency of the muscle isoform of the enzyme, Phosphofructokinase (PFK, EC 2.7.1.11), leads to an illness (glycogenosis, Type VII) characterized by myopathy and hemolysis. A patient with this disease and an affected sister were found to have a G to A substitution at the 5' donor site of intron 5 of the PFK-M gene. This mutation led to a splicing defect: a complete deletion of the preceding exon in the patient's mRNA. The patient, an affected sister, and related and unrelated family members, who were of Ashkenazic Jewish background, were screened for the mutation by denaturing gradient gel electrophoresis and by allele specific hybridization of genomic DNA. The affected sisters are homozygous for the mutation, and their children, who are unaffected, are heterozygous. The only previously characterized genetic defect in this disease, found in a Japanese patient, was a G to T mutation at the beginning of intron 15 with splicing to a cryptic site within exon 15 (1). Both mutations lead to inframe deletions, but of different parts of the protein. The differences between the two aberrant proteins may account for clinical differences between our patients and the Japanese patient.
Marinos C Dalakas - One of the best experts on this subject based on the ideXlab platform.
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Muscle Phosphofructokinase Deficiency
Neurology, 1997Co-Authors: Kumaraswamy Sivakumar, Olavo M. Vasconcelos, Lev G. Goldfarb, Marinos C DalakasAbstract:Reply from the Authors: We appreciated the interest of Massa et al. and their support of our view that the late-onset myopathy of Phosphofructokinase (PFK) Deficiency may not be distinct from the early-onset form of the disorder. We reported a late-onset myopathy in three Ashkenazi Jewish patients of two successive generations who had the unique constellation of vacuolar changes …
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late onset muscle weakness in partial Phosphofructokinase Deficiency a unique myopathy with vacuoles abnormal mitochondria and absence of the common exon 5 intron 5 junction point mutation
Neurology, 1996Co-Authors: Kumaraswamy Sivakumar, Olavo M. Vasconcelos, Lev G. Goldfarb, Marinos C DalakasAbstract:Three patients (ages 51, 59, and 79) from two generations of an Ashkenazi Jewish family had partial (33% activity) Phosphofructokinase (PFK) Deficiency that presented with fixed muscle weakness after the age of 50 years. MR spectroscopy revealed accumulation of phosphomonoesters during exercise. Muscle biopsy showed a vacuolar myopathy with increased autophagic activity and several ragged-red and cytochrome c oxidase-negative fibers. The older patient, age 79 at biopsy, had several necrotic fibers. Electron microscopy revealed subsarcolemmal and intermyofibrillar glycogen accumulation and proliferation of mitochondria with paracrystalline inclusions, probably related to reduced availability of energy due to impaired glycolysis. The common point mutation of exon 5/intron 5 junction seen in Jewish Ashkenazi patients with PFK Deficiency was excluded. We conclude that late-onset fixed muscle weakness occurs in partial PFK Deficiency and it may represent the end result of continuing episodes of muscle fiber destruction. Partial enzyme Deficiency in two successive generations suggests a unique molecular mechanism.
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coexistence of diabetes and Phosphofructokinase Deficiency
Endocrine Practice, 1996Co-Authors: Sandra I Rubio, Kakan K Naha, Kumaraswamy Sivakumar, Marinos C Dalakas, Leonid PoretskyAbstract:Objective: To report the first case of coexisting diabetes mellitus and Phosphofructokinase Deficiency. Methods: We describe a 50-year-old woman who had a history of diabetes mellitus, muscle weakn...
Ronald G Haller - One of the best experts on this subject based on the ideXlab platform.
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Reproducibility and Absolute Quantification of Muscle Glycogen in Patients with Glycogen Storage Disease by 13C NMR Spectroscopy at 7 Tesla
2016Co-Authors: Katja Heinicke, Ivan E. Dimitrov, Nadine Romain, Sergey Cheshkov, Jimin Ren, Craig R. Malloy, Ronald G HallerAbstract:Carbon-13 magnetic resonance spectroscopy (13C MRS) offers a noninvasive method to assess glycogen levels in skeletal muscle and to identify excess glycogen accumulation in patients with glycogen storage disease (GSD). Despite the clinical potential of the method, it is currently not widely used for diagnosis or for follow-up of treatment. While it is possible to perform acceptable 13C MRS at lower fields, the low natural abundance of 13C and the inherently low signal-to-noise ratio of 13C MRS makes it desirable to utilize the advantage of increased signal strength offered by ultra-high fields for more accurate measurements. Concomitant with this advantage, however, ultra-high fields present unique technical challenges that need to be addressed when studying glycogen. In particular, the question of measurement reproducibility needs to be answered so as to give investigators insight into meaningful inter-subject glycogen differences. We measured muscle glycogen levels in vivo in the calf muscle in three patients with McArdle disease (MD), one patient with Phosphofructokinase Deficiency (PFKD) and four healthy controls by performing 13C MRS at 7T. Absolute quantification of the MRS signal was achieved by using a reference phantom with known concentration of metabolites. Muscle glycogen concentration was increased in GSD patients (31.562.9 g/kg w. w.) compared with controls (12.462.2 g/kg w. w.). In three GSD patients glycogen was also determined biochemically in muscle homogenates from needle biopsies and showed a similar 2.5-fol
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a distinctive delayed form of exertional rhabdomyolysis s36 005
Neurology, 2014Co-Authors: Lydia Sharp, Ronald G HallerAbstract:OBJECTIVE: To describe the clinical characteristics of a distinct form of exertional rhabdomyolysis, and compare this entity to exertional rhabdomyolysis attributable to metabolic myopathies. BACKGROUND: Rhabdomyolysis after exercise commonly alerts clinicians to the presence of a metabolic myopathy, such as McArdle disease or carnitine palmitoyltransferase 2 Deficiency. However, rhabdomyolysis can occur in normal individuals after intense exercise, particularly with unaccustomed eccentric exercise. DESIGN/METHODS: We identified 4 patients who were referred to our institution for exertional rhabdomyolysis, who had no evidence of a metabolic defect with exercise, histological and biochemical testing. The clinical history in these patients was compared to patients referred with a history of exercise-induced rhabdomyolysis that proved to be secondary to metabolic myopathies, including patients with McArdle disease, carnitine palmitoyltransferase 2 Deficiency, and Phosphofructokinase Deficiency. RESULTS: The timing between exercise and the onset of symptoms of muscle injury differed between the two groups. In metabolic myopathy patients, symptoms of muscle injury occurred immediately and myoglobinuria within hours of exercise. Commonly, these patients also had a life-long history of exercise intolerance. In contrast, patients with exertional rhabdomyolysis not associated with a metabolic myopathy, had minimal symptoms immediately after exercise and developed muscle pain, swelling, and myoglobinuria 12-36 hours after exercise which typically involved unaccustomed eccentric muscle contractions. These patients also had no history of prior exercise intolerance. CONCLUSIONS: Symptoms of muscle injury which develop 12-36 hours after exercise is not typical of metabolic myopathies, and instead suggests a distinctive form of exertional rhabdomyolysis attributable to a severe form of delayed onset muscle soreness. The diagnosis is suggested by preceding normal exercise tolerance, the involvement of eccentric muscle contractions, and by the typical latent period between exercise and muscle symptoms. Affected patients can generally be reassured of a low risk of recurrence. Disclosure: Dr. Haller has nothing to disclose.
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Skeletal muscle metabolites - 13C NMR spectroscopy.
2014Co-Authors: Katja Heinicke, Ivan E. Dimitrov, Nadine Romain, Sergey Cheshkov, Jimin Ren, Craig R. Malloy, Ronald G HallerAbstract:Values are expressed individually or group means ± SD. MD, McArdle disease; PFKD, Phosphofructokinase Deficiency; mM, millimoles per liter.Skeletal muscle metabolites - 13C NMR spectroscopy.
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Figure 3A–B. Skeletal muscle glycogen (3A) and total creatine concentrations (3B) measured by 13C MRS.
2014Co-Authors: Katja Heinicke, Ivan E. Dimitrov, Nadine Romain, Sergey Cheshkov, Jimin Ren, Craig R. Malloy, Ronald G HallerAbstract:Values are expressed individually or group means ± SD. GSD, glycogen storage diseases; MD, McArdle disease; PFKD, Phosphofructokinase Deficiency; controls, healthy control subjects; g/kg w. w., grams per kilogram wet weight.
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no spontaneous second wind in muscle Phosphofructokinase Deficiency
Neurology, 2004Co-Authors: Ronald G Haller, John VissingAbstract:Objective: The spontaneous second wind in myophosphorylase Deficiency (MD, McArdle’s disease) represents a transition from low to a higher exercise capacity attributable to increased oxidation of blood-borne fuels, principally glucose and free fatty acids. Muscle Phosphofructokinase Deficiency (PFKD) blocks the metabolism of muscle glycogen and blood glucose. The authors inquired whether the additional restriction in glucose metabolism in PFKD prevents a spontaneous second wind. Methods: The authors compared the ability of 29 patients with MD and 5 patients with muscle PFKD to achieve a spontaneous second wind during continuous cycle exercise after an overnight fast. Patients cycled at a constant workload for 15 to 20 minutes (3 MD patients, 3 PFKD patients) and at variable workloads in which peak exercise capacity was determined at 6 to 8 minutes of exercise and again at 25 to 30 minutes of exercise (29 MD patients, 4 PFKD patients). Heart rate was monitored continuously, and perceived exertion (Borg scale) was recorded during each minute of exercise. Oxygen utilization and blood levels of lactate and ammonia were determined at rest and during peak workloads. Results: All variables in both patient groups were similar at 6 to 8 minutes of exercise. Thereafter exercise responses diverged. Each MD patient developed a second wind with a decrease in heart rate and perceived exertion and an increase in work and oxidative capacity. In contrast, no PFKD patient developed a spontaneous second wind. Conclusions: Patients with muscle Phosphofructokinase Deficiency are unable to achieve a spontaneous second wind under conditions that consistently produce one in patients with McArdle’s disease. The authors conclude that the ability to metabolize blood glucose is critical to the development of a typical spontaneous second wind.
Kumaraswamy Sivakumar - One of the best experts on this subject based on the ideXlab platform.
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Muscle Phosphofructokinase Deficiency
Neurology, 1997Co-Authors: Kumaraswamy Sivakumar, Olavo M. Vasconcelos, Lev G. Goldfarb, Marinos C DalakasAbstract:Reply from the Authors: We appreciated the interest of Massa et al. and their support of our view that the late-onset myopathy of Phosphofructokinase (PFK) Deficiency may not be distinct from the early-onset form of the disorder. We reported a late-onset myopathy in three Ashkenazi Jewish patients of two successive generations who had the unique constellation of vacuolar changes …
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late onset muscle weakness in partial Phosphofructokinase Deficiency a unique myopathy with vacuoles abnormal mitochondria and absence of the common exon 5 intron 5 junction point mutation
Neurology, 1996Co-Authors: Kumaraswamy Sivakumar, Olavo M. Vasconcelos, Lev G. Goldfarb, Marinos C DalakasAbstract:Three patients (ages 51, 59, and 79) from two generations of an Ashkenazi Jewish family had partial (33% activity) Phosphofructokinase (PFK) Deficiency that presented with fixed muscle weakness after the age of 50 years. MR spectroscopy revealed accumulation of phosphomonoesters during exercise. Muscle biopsy showed a vacuolar myopathy with increased autophagic activity and several ragged-red and cytochrome c oxidase-negative fibers. The older patient, age 79 at biopsy, had several necrotic fibers. Electron microscopy revealed subsarcolemmal and intermyofibrillar glycogen accumulation and proliferation of mitochondria with paracrystalline inclusions, probably related to reduced availability of energy due to impaired glycolysis. The common point mutation of exon 5/intron 5 junction seen in Jewish Ashkenazi patients with PFK Deficiency was excluded. We conclude that late-onset fixed muscle weakness occurs in partial PFK Deficiency and it may represent the end result of continuing episodes of muscle fiber destruction. Partial enzyme Deficiency in two successive generations suggests a unique molecular mechanism.
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coexistence of diabetes and Phosphofructokinase Deficiency
Endocrine Practice, 1996Co-Authors: Sandra I Rubio, Kakan K Naha, Kumaraswamy Sivakumar, Marinos C Dalakas, Leonid PoretskyAbstract:Objective: To report the first case of coexisting diabetes mellitus and Phosphofructokinase Deficiency. Methods: We describe a 50-year-old woman who had a history of diabetes mellitus, muscle weakn...