Douglas Kerr - Academia.edu (original) (raw)
Papers by Douglas Kerr
Mitochondrial Case Studies, 2016
Pyruvate dehydrogenase complex (PDHc) deficiency usually first manifests at a young age and is ra... more Pyruvate dehydrogenase complex (PDHc) deficiency usually first manifests at a young age and is rarely diagnosed in adulthood. The clinical picture varies from neonatal death with overwhelming lactic acidosis to a relatively benign course early in life. The three main presentations are congenital lactic acidosis, Leigh syndrome, and episodic ataxia. Treatment consists of a ketogenic diet and cofactor supplementation with thiamine. Successful therapy is rare.
Pediatrics, 1978
The relationship between infant malnutrition and maternal psychosocial behavior was explored by c... more The relationship between infant malnutrition and maternal psychosocial behavior was explored by comparing mothers of malnourished children with mother whose children were matched for age and family income but were not malnourished. The mothers were interviewed and asked to describe their relationships with their children, their children's fathers, extended families, friends, and employers. The mothers of malnourished children described more chronically disrupted lives. Their housing conditions and employment records reflected disorganization. They had fewer social contacts except with extended families who supervised excessively. The fathers of their babies were either not present or unsupportive. Relationships were more stereotyped, transient, and focused on material aspects. The mothers narcissistic concerns took precedence over the needs of their children. Nearly all the mothers, including the controls, had suffered severe deprivation in childhood. Some mothers of malnourishe...
Molecular Genetics and Metabolism, 2005
Molecular Genetics and Metabolism
Molecular genetics and metabolism, Apr 2, 2017
Mutations in ECHS1 result in short-chain enoyl-CoA hydratase (SCEH) deficiency which mainly affec... more Mutations in ECHS1 result in short-chain enoyl-CoA hydratase (SCEH) deficiency which mainly affects the catabolism of various amino acids, particularly valine. We describe a case compound heterozygous for ECHS1 mutations c.836T>C (novel) and c.8C>A identified by whole exome sequencing of proband and parents. SCEH deficiency was confirmed with very low SCEH activity in fibroblasts and nearly absent immunoreactivity of SCEH. The patient had a severe neonatal course with elevated blood and cerebrospinal fluid lactate and pyruvate concentrations, high plasma alanine and slightly low plasma cystine. 2-Methyl-2,3-dihydroxybutyric acid was markedly elevated as were metabolites of the three branched-chain α-ketoacids on urine organic acids analysis. These urine metabolites notably decreased when lactic acidosis decreased in blood. Lymphocyte pyruvate dehydrogenase complex (PDC) activity was deficient, but PDC and α-ketoglutarate dehydrogenase complex activities in cultured fibroblasts...
Molecular genetics and metabolism, Mar 12, 2016
Mutations in SUCLA2 result in succinyl-CoA ligase (ATP-forming) or succinyl-CoA synthetase (ADP-f... more Mutations in SUCLA2 result in succinyl-CoA ligase (ATP-forming) or succinyl-CoA synthetase (ADP-forming) (A-SCS) deficiency, a mitochondrial tricarboxylic acid cycle disorder. The phenotype associated with this gene defect is largely encephalomyopathy. We describe two siblings compound heterozygous for SUCLA2 mutations, c.985A>G (p.M329V) and c.920C>T (p.A307V), with parents confirmed as carriers of each mutation. We developed a new LC-MS/MS based enzyme assay to demonstrate the decreased SCS activity in the siblings with this unique genotype. Both siblings shared bilateral progressive hearing loss, encephalopathy, global developmental delay, generalized myopathy, and dystonia with choreoathetosis. Prior to diagnosis and because of lactic acidosis and low activity of muscle pyruvate dehydrogenase complex (PDC), sibling 1 (S1) was placed on dichloroacetate, while sibling 2 (S2) was on a ketogenic diet. S1 developed severe cyclic vomiting refractory to therapy, while S2 develope...
Alpha-Keto Acid Dehydrogenase Complexes, 1996
... to PDC deficiency as they also occur in certain nuclear and mitochondrial DNA encoded defects... more ... to PDC deficiency as they also occur in certain nuclear and mitochondrial DNA encoded defects of the electron transport chain (Miranda et al ... proline, which is highly conserved, may limit mobility of the" hinge" region of the loop, thereby facilitating TPP binding (Hemalatha et al ...
Pediatrics, Apr 1, 1990
Page 1. 1990;85;625 Pediatrics STUART C. MORRISON and DOUGLAS S. KERR Rickets and Metabolic Disor... more Page 1. 1990;85;625 Pediatrics STUART C. MORRISON and DOUGLAS S. KERR Rickets and Metabolic Disorders http://pediatrics.aappublications.org/content/85/4/ 625.1 the World Wide Web at: The online version of this article ...
Methods in Enzymology, 1971
The Journal of biological chemistry, Jan 10, 1971
An enzyme was purified 500-fold from Neurospora which catalyzes the formation of homocysteine fro... more An enzyme was purified 500-fold from Neurospora which catalyzes the formation of homocysteine from O-acetylhomoserine and sulfide or methionine from O-acetylhomoserine and methyhnercaptan. The two activities were not separated by purification. The rate with methyhnercaptan is 1.8 times that with sulfide. No cystathionine is formed from cysteine, and there is essentially no oc-ketobutyrate formed from 0-acetylhomoserine or cystathionine. The enzyme is highly specific for 0-acetylhomoserine, having negligible activity with homoserine, serine, and several of their other acyl derivatives. The apparent Michaelis constants are 7 X 10m3 M for 0-acetylhomoserine in both reactions, 7 x 10e4 M for sulfide, and 8 X 10V4 M for methylmercaptan. A requirement for pyridoxal phosphate can be shown after dialyzing the enzyme with cysteine. Moderate inhibition was observed with methionine, S-adenosyhnethionine, and S-adenosylhomocysteine, but not with cystathionine. No repression by methionine was observed. No mutants were found which are defective in this activity. Previous evidence led to the conclusion that these reactions are not the primary mechanisms in vivo for homocysteine and methionine synthesis. A possible temporary function for this enzyme may be formation of methionine from methylmercaptan at times of exhaustion of an exogenous source of sulfur.
Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics, 2013
Over the last 15 years, some 16 open and controlled clinical trials for potential treatments of m... more Over the last 15 years, some 16 open and controlled clinical trials for potential treatments of mitochondrial diseases have been reported or are in progress, and are summarized and reviewed herein. These include trials of administering dichloroacetate (an activator of pyruvate dehydrogenase complex), arginine or citrulline (precursors of nitric oxide), coenzyme Q10 (CoQ10; part of the electron transport chain and an antioxidant), idebenone (a synthetic analogue of CoQ10), EPI-743 (a novel oral potent 2-electron redox cycling agent), creatine (a precursor of phosphocreatine), combined administration (of creatine, α-lipoate, and CoQ10), and exercise training (to increase muscle mitochondria). These trials have included patients with various mitochondrial disorders, a selected subcategory of mitochondrial disorders, or specific mitochondrial disorders (Leber hereditary optic neuropathy or mitochondrial encephalopathy, lactic acidosis, and stroke-like episodes). The trial designs have v...
Biochimica et biophysica acta, Jan 31, 1962
Methods in Enzymology, 2000
Methods in Molecular Biology, 2011
Pyruvate dehydrogenase complex (PDC) and pyruvate carboxylase (PC) are mitochondrial enzymes that... more Pyruvate dehydrogenase complex (PDC) and pyruvate carboxylase (PC) are mitochondrial enzymes that provide the initial steps of the two main alternatives for pyruvate metabolism: oxidative decarboxylation vs. anaplerotic carboxylation, gluconeogenesis, and glycerogenesis. Assays of the enzymatic activity of these two enzymes in cells and tissues are described in this chapter, based on evolution or fi xation of 14 CO 2. These assays are both suitable for use in crude homogenates of cultured skin fi broblasts, lymphocytes, and frozen muscle (PDC) or liver (PC). Activities of these two enzymes are related to spectrophotometric assays of two other mitochondrial enzymes, dihydrolipoamide dehydrogenase (E3) and citrate synthase (CS), providing initial indices of sample integrity and mitochondrial content. These parameters have proven useful for initial detection of inherited human disorders due to defi ciencies of these enzymes, and in combination with available genetic analyses can lead to confi rmation of specifi c diagnoses.
Molecular Genetics and Metabolism Reports, 2014
Pyruvate dehydrogenase complex (PDC) deficiencies are mostly due to mutations in the X-linked PDH... more Pyruvate dehydrogenase complex (PDC) deficiencies are mostly due to mutations in the X-linked PDHA1 gene. Males with hemizygous PDHA1 mutations are clinically more severely affected, while those with mosaic PDHA1 mutations may manifest milder phenotypes. We report a patient harboring a novel, mosaic missense PDHA1 mutation, c.523G N A (p.A175T), with a severe clinical presentation of congenital microcephaly, significant brain abnormalities, persistent seizures, profound developmental delay, and failure to thrive. We review published cases of PDHA1 mosaicism.
Pediatric Research, 1988
Pyruvate dehydrogenase complex (PDC) deficiency usually has been detected by decreased activity i... more Pyruvate dehydrogenase complex (PDC) deficiency usually has been detected by decreased activity in cultured skin fibroblasts. We investigated two brothers in whom PDC activity was less than 10% of controls in lymphocytes but normal in skin fibroblasts. They both had abnormal neuromuscular development and lactic acidosis which was aggravated by ingestion of carbohydrate. One brother died at age 3 yr and tissues were obtained at autopsy soon after death. The brain was swollen with diffuse acute hemorrhages but without the lesions characteristic of Leigh's disease. PDC activity was virtually undetectable in mitochondria or homogenates of liver, skeletal muscle, and heart, but was about 30% of controls in kidney. The activity of the first component E1 was not detectable in mitochondria from liver, whereas the activities of the second and third components were normal; the activities of all components were normal in fibroblasts. Western immunoblot analysis showed absent to trace amounts of both the E1 alpha and E1 beta subunits in liver, skeletal muscle, and heart, with normal amounts of the second and third components. About one-fourth of control amounts of E1 alpha and E1 beta were present in kidney and normal levels were present in fibroblasts. PDC activity in lymphocytes from the mother was 35% of controls; she had normal PDC activity in her fibroblasts. PDC activity was normal in lymphocytes from the brothers' sister, father, and maternal grandparents and great-grandmother. The mode of inheritance was not established. In conclusion, PDC deficiency may not be detected in skin fibroblasts in some cases; the mechanism of variable tissue expression of E1 remains to be delineated.
Mitochondrial Case Studies, 2016
Pyruvate dehydrogenase complex (PDHc) deficiency usually first manifests at a young age and is ra... more Pyruvate dehydrogenase complex (PDHc) deficiency usually first manifests at a young age and is rarely diagnosed in adulthood. The clinical picture varies from neonatal death with overwhelming lactic acidosis to a relatively benign course early in life. The three main presentations are congenital lactic acidosis, Leigh syndrome, and episodic ataxia. Treatment consists of a ketogenic diet and cofactor supplementation with thiamine. Successful therapy is rare.
Pediatrics, 1978
The relationship between infant malnutrition and maternal psychosocial behavior was explored by c... more The relationship between infant malnutrition and maternal psychosocial behavior was explored by comparing mothers of malnourished children with mother whose children were matched for age and family income but were not malnourished. The mothers were interviewed and asked to describe their relationships with their children, their children's fathers, extended families, friends, and employers. The mothers of malnourished children described more chronically disrupted lives. Their housing conditions and employment records reflected disorganization. They had fewer social contacts except with extended families who supervised excessively. The fathers of their babies were either not present or unsupportive. Relationships were more stereotyped, transient, and focused on material aspects. The mothers narcissistic concerns took precedence over the needs of their children. Nearly all the mothers, including the controls, had suffered severe deprivation in childhood. Some mothers of malnourishe...
Molecular Genetics and Metabolism, 2005
Molecular Genetics and Metabolism
Molecular genetics and metabolism, Apr 2, 2017
Mutations in ECHS1 result in short-chain enoyl-CoA hydratase (SCEH) deficiency which mainly affec... more Mutations in ECHS1 result in short-chain enoyl-CoA hydratase (SCEH) deficiency which mainly affects the catabolism of various amino acids, particularly valine. We describe a case compound heterozygous for ECHS1 mutations c.836T>C (novel) and c.8C>A identified by whole exome sequencing of proband and parents. SCEH deficiency was confirmed with very low SCEH activity in fibroblasts and nearly absent immunoreactivity of SCEH. The patient had a severe neonatal course with elevated blood and cerebrospinal fluid lactate and pyruvate concentrations, high plasma alanine and slightly low plasma cystine. 2-Methyl-2,3-dihydroxybutyric acid was markedly elevated as were metabolites of the three branched-chain α-ketoacids on urine organic acids analysis. These urine metabolites notably decreased when lactic acidosis decreased in blood. Lymphocyte pyruvate dehydrogenase complex (PDC) activity was deficient, but PDC and α-ketoglutarate dehydrogenase complex activities in cultured fibroblasts...
Molecular genetics and metabolism, Mar 12, 2016
Mutations in SUCLA2 result in succinyl-CoA ligase (ATP-forming) or succinyl-CoA synthetase (ADP-f... more Mutations in SUCLA2 result in succinyl-CoA ligase (ATP-forming) or succinyl-CoA synthetase (ADP-forming) (A-SCS) deficiency, a mitochondrial tricarboxylic acid cycle disorder. The phenotype associated with this gene defect is largely encephalomyopathy. We describe two siblings compound heterozygous for SUCLA2 mutations, c.985A>G (p.M329V) and c.920C>T (p.A307V), with parents confirmed as carriers of each mutation. We developed a new LC-MS/MS based enzyme assay to demonstrate the decreased SCS activity in the siblings with this unique genotype. Both siblings shared bilateral progressive hearing loss, encephalopathy, global developmental delay, generalized myopathy, and dystonia with choreoathetosis. Prior to diagnosis and because of lactic acidosis and low activity of muscle pyruvate dehydrogenase complex (PDC), sibling 1 (S1) was placed on dichloroacetate, while sibling 2 (S2) was on a ketogenic diet. S1 developed severe cyclic vomiting refractory to therapy, while S2 develope...
Alpha-Keto Acid Dehydrogenase Complexes, 1996
... to PDC deficiency as they also occur in certain nuclear and mitochondrial DNA encoded defects... more ... to PDC deficiency as they also occur in certain nuclear and mitochondrial DNA encoded defects of the electron transport chain (Miranda et al ... proline, which is highly conserved, may limit mobility of the" hinge" region of the loop, thereby facilitating TPP binding (Hemalatha et al ...
Pediatrics, Apr 1, 1990
Page 1. 1990;85;625 Pediatrics STUART C. MORRISON and DOUGLAS S. KERR Rickets and Metabolic Disor... more Page 1. 1990;85;625 Pediatrics STUART C. MORRISON and DOUGLAS S. KERR Rickets and Metabolic Disorders http://pediatrics.aappublications.org/content/85/4/ 625.1 the World Wide Web at: The online version of this article ...
Methods in Enzymology, 1971
The Journal of biological chemistry, Jan 10, 1971
An enzyme was purified 500-fold from Neurospora which catalyzes the formation of homocysteine fro... more An enzyme was purified 500-fold from Neurospora which catalyzes the formation of homocysteine from O-acetylhomoserine and sulfide or methionine from O-acetylhomoserine and methyhnercaptan. The two activities were not separated by purification. The rate with methyhnercaptan is 1.8 times that with sulfide. No cystathionine is formed from cysteine, and there is essentially no oc-ketobutyrate formed from 0-acetylhomoserine or cystathionine. The enzyme is highly specific for 0-acetylhomoserine, having negligible activity with homoserine, serine, and several of their other acyl derivatives. The apparent Michaelis constants are 7 X 10m3 M for 0-acetylhomoserine in both reactions, 7 x 10e4 M for sulfide, and 8 X 10V4 M for methylmercaptan. A requirement for pyridoxal phosphate can be shown after dialyzing the enzyme with cysteine. Moderate inhibition was observed with methionine, S-adenosyhnethionine, and S-adenosylhomocysteine, but not with cystathionine. No repression by methionine was observed. No mutants were found which are defective in this activity. Previous evidence led to the conclusion that these reactions are not the primary mechanisms in vivo for homocysteine and methionine synthesis. A possible temporary function for this enzyme may be formation of methionine from methylmercaptan at times of exhaustion of an exogenous source of sulfur.
Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics, 2013
Over the last 15 years, some 16 open and controlled clinical trials for potential treatments of m... more Over the last 15 years, some 16 open and controlled clinical trials for potential treatments of mitochondrial diseases have been reported or are in progress, and are summarized and reviewed herein. These include trials of administering dichloroacetate (an activator of pyruvate dehydrogenase complex), arginine or citrulline (precursors of nitric oxide), coenzyme Q10 (CoQ10; part of the electron transport chain and an antioxidant), idebenone (a synthetic analogue of CoQ10), EPI-743 (a novel oral potent 2-electron redox cycling agent), creatine (a precursor of phosphocreatine), combined administration (of creatine, α-lipoate, and CoQ10), and exercise training (to increase muscle mitochondria). These trials have included patients with various mitochondrial disorders, a selected subcategory of mitochondrial disorders, or specific mitochondrial disorders (Leber hereditary optic neuropathy or mitochondrial encephalopathy, lactic acidosis, and stroke-like episodes). The trial designs have v...
Biochimica et biophysica acta, Jan 31, 1962
Methods in Enzymology, 2000
Methods in Molecular Biology, 2011
Pyruvate dehydrogenase complex (PDC) and pyruvate carboxylase (PC) are mitochondrial enzymes that... more Pyruvate dehydrogenase complex (PDC) and pyruvate carboxylase (PC) are mitochondrial enzymes that provide the initial steps of the two main alternatives for pyruvate metabolism: oxidative decarboxylation vs. anaplerotic carboxylation, gluconeogenesis, and glycerogenesis. Assays of the enzymatic activity of these two enzymes in cells and tissues are described in this chapter, based on evolution or fi xation of 14 CO 2. These assays are both suitable for use in crude homogenates of cultured skin fi broblasts, lymphocytes, and frozen muscle (PDC) or liver (PC). Activities of these two enzymes are related to spectrophotometric assays of two other mitochondrial enzymes, dihydrolipoamide dehydrogenase (E3) and citrate synthase (CS), providing initial indices of sample integrity and mitochondrial content. These parameters have proven useful for initial detection of inherited human disorders due to defi ciencies of these enzymes, and in combination with available genetic analyses can lead to confi rmation of specifi c diagnoses.
Molecular Genetics and Metabolism Reports, 2014
Pyruvate dehydrogenase complex (PDC) deficiencies are mostly due to mutations in the X-linked PDH... more Pyruvate dehydrogenase complex (PDC) deficiencies are mostly due to mutations in the X-linked PDHA1 gene. Males with hemizygous PDHA1 mutations are clinically more severely affected, while those with mosaic PDHA1 mutations may manifest milder phenotypes. We report a patient harboring a novel, mosaic missense PDHA1 mutation, c.523G N A (p.A175T), with a severe clinical presentation of congenital microcephaly, significant brain abnormalities, persistent seizures, profound developmental delay, and failure to thrive. We review published cases of PDHA1 mosaicism.
Pediatric Research, 1988
Pyruvate dehydrogenase complex (PDC) deficiency usually has been detected by decreased activity i... more Pyruvate dehydrogenase complex (PDC) deficiency usually has been detected by decreased activity in cultured skin fibroblasts. We investigated two brothers in whom PDC activity was less than 10% of controls in lymphocytes but normal in skin fibroblasts. They both had abnormal neuromuscular development and lactic acidosis which was aggravated by ingestion of carbohydrate. One brother died at age 3 yr and tissues were obtained at autopsy soon after death. The brain was swollen with diffuse acute hemorrhages but without the lesions characteristic of Leigh's disease. PDC activity was virtually undetectable in mitochondria or homogenates of liver, skeletal muscle, and heart, but was about 30% of controls in kidney. The activity of the first component E1 was not detectable in mitochondria from liver, whereas the activities of the second and third components were normal; the activities of all components were normal in fibroblasts. Western immunoblot analysis showed absent to trace amounts of both the E1 alpha and E1 beta subunits in liver, skeletal muscle, and heart, with normal amounts of the second and third components. About one-fourth of control amounts of E1 alpha and E1 beta were present in kidney and normal levels were present in fibroblasts. PDC activity in lymphocytes from the mother was 35% of controls; she had normal PDC activity in her fibroblasts. PDC activity was normal in lymphocytes from the brothers' sister, father, and maternal grandparents and great-grandmother. The mode of inheritance was not established. In conclusion, PDC deficiency may not be detected in skin fibroblasts in some cases; the mechanism of variable tissue expression of E1 remains to be delineated.