Stanley Korman - Academia.edu (original) (raw)

Papers by Stanley Korman

Nature, 2015

Cancer cells hijack and remodel existing metabolic pathways for their benefit. Argininosuccinate ... more Cancer cells hijack and remodel existing metabolic pathways for their benefit. Argininosuccinate synthase (ASS1) is a urea cycle enzyme that is essential in the conversion of nitrogen from ammonia and aspartate to urea. A decrease in nitrogen flux through ASS1 in the liver causes the urea cycle disorder citrullinaemia. In contrast to the well-studied consequences of loss of ASS1 activity on ureagenesis, the purpose of its somatic silencing in multiple cancers is largely unknown. Here we show that decreased activity of ASS1 in cancers supports proliferation by facilitating pyrimidine synthesis via CAD (carbamoyl-phosphate synthase 2, aspartate transcarbamylase, and dihydroorotase complex) activation. Our studies were initiated by delineating the consequences of loss of ASS1 activity in humans with two types of citrullinaemia. We find that in citrullinaemia type I (CTLN I), which is caused by deficiency of ASS1, there is increased pyrimidine synthesis and proliferation compared with citrullinaemia type II (CTLN II), in which there is decreased substrate availability for ASS1 caused by deficiency of the aspartate transporter citrin. Building on these results, we demonstrate that ASS1 deficiency in cancer increases cytosolic aspartate levels, which increases CAD activation by upregulating its substrate availability and by increasing its phosphorylation by S6K1 through the mammalian target of rapamycin (mTOR) pathway. Decreasing CAD activity by blocking citrin, the mTOR signalling, or pyrimidine synthesis decreases proliferation and thus may serve as a therapeutic strategy in multiple cancers where ASS1 is downregulated. Our results demonstrate that ASS1 downregulation is a novel mechanism supporting cancerous proliferation, and they provide a metabolic link between the urea cycle enzymes and pyrimidine synthesis.

American journal of diseases of children (1960), 1990

The duodenal string test capsule is a cheap and simple device used for sampling the contents of t... more The duodenal string test capsule is a cheap and simple device used for sampling the contents of the upper gastrointestinal tract. Its major applications in pediatrics are in diagnosis of enteric parasitic infestations, confirmation of contaminated small-bowel syndrome, diagnosis of Salmonella infection, and assessment of neonatal cholestasis. Pediatricians should be aware of this invaluable diagnostic aid.

Gastrointestinal Endoscopy, 1989

In vitro axenic cultures of Giardia lamblia were successfully established in 14 successive subjec... more In vitro axenic cultures of Giardia lamblia were successfully established in 14 successive subjects by a method employing the string test (Entero-Test) for obtaining samples of fluid from the proximal small intestine. This method is applicable to isolating G. lamblia from unselected subjects, including asymptomatic carriers, children, and individuals in diverse or remote geographic regions.

J Inherit Metab Dis, 2001

Oral lysine administration to three patients with B 6 -nonresponsive gyrate atrophy reduced plasm... more Oral lysine administration to three patients with B 6 -nonresponsive gyrate atrophy reduced plasma ornithine concentrations by 21^31% within 1^2 days. No further reduction was noted with time.

Journal of Inherited Metabolic Disease, Jan 5, 2001

Oral lysine administration to three patients with B 6 -nonresponsive gyrate atrophy reduced plasm... more Oral lysine administration to three patients with B 6 -nonresponsive gyrate atrophy reduced plasma ornithine concentrations by 21^31% within 1^2 days. No further reduction was noted with time.

Journal of Pediatric Gastroenterology and Nutrition, May 1, 1991

A pseudocyst of the pancreas in a 6-year-old girl persisted for 2 months despite bowel rest and n... more A pseudocyst of the pancreas in a 6-year-old girl persisted for 2 months despite bowel rest and nutritional support. Following percutaneous introduction of a catheter into the cyst under ultrasound guidance and external catheter drainage for 11 days, the pseudocyst resolved completely and permanently. Nonoperative percutaneous techniques for drainage of pancreatic pseudocysts in children may be an effective alternative to surgical intervention.

Journal of Inherited Metabolic Disease, Oct 1, 2009

L-2-hydroxyglutaric aciduria (L-2-HGA) is a rare inherited autosomal recessive neurometabolic dis... more L-2-hydroxyglutaric aciduria (L-2-HGA) is a rare inherited autosomal recessive neurometabolic disorder caused by mutations in the gene encoding L-2-hydroxyglutarate dehydrogenase. An assay to evaluate L-2-hydroxyglutarate dehydrogenase (L-2-HGDH) activity in fibroblast, lymphoblast and/or lymphocyte lysates has hitherto been unavailable. We developed an L-2-HGDH enzyme assay in cell lysates based on the conversion of stable-isotope-labelled L-2-hydroxyglutarate to 2-ketoglutarate, which is converted into L-glutamate in situ. The formation of stable isotope labelled L-glutamate is therefore a direct measure of L-2-HGDH activity, and this product is detected by liquid chromatography-tandem mass spectrometry. A deficiency of L-2-HGDH activity was detected in cell lysates from 15 out of 15 L-2-HGA patients. Therefore, this specific assay confirmed the diagnosis unambiguously affirming the relationship between molecular and biochemical observations. Residual activity was detected in cells derived from one L-2-HGA patient. The L-2-HGDH assay will be valuable for examining in vitro riboflavin/FAD therapy to rescue L-2-HGDH activity.

Advances in experimental medicine and biology, 2003

Peroxisomes perform a multitude of biosynthetic and catabolic functions, many of which are relate... more Peroxisomes perform a multitude of biosynthetic and catabolic functions, many of which are related to lipid metabolism. Peroxisomal disorders result either from deficiency of a single peroxisomal enzyme or protein, or from a defect in the complex mechanism of peroxisomal biogenesis, resulting in deficiency of several or multiple peroxisomal functions. These can be assessed by a battery of biochemical assays, enabling a biochemical phenotype to be defined that is specific and diagnostic for each of the peroxisomal disorders. Some peroxisomal disorders have unique and specific clinical phenotypes, which may be diagnostic. Others share patterns of clinical abnormalities (particularly neurological dysfunction, craniofacial dysmorphism, skeletal defects, sensory deafness, retinopathy) consistent with defined clinical phenotypes, but with considerable overlap and heterogeneity. To a certain extent, the clinical features of a particular disorder reflect the accumulation or deficiency of sp...

Journal of inherited metabolic disease, 2000

The Pediatric Infectious Disease Journal, 1989

Giardia lamblia infection was identified in 33 of 89 (37%) 3-month-old to 3-yr-old children who w... more Giardia lamblia infection was identified in 33 of 89 (37%) 3-month-old to 3-yr-old children who were followed with monthly stool examinations for up to 12 months in a day care center. The infection was mainly asymptomatic and usually associated with prolonged carriage of the parasite. There were no significant differences for height and weight achievements and mean hemoglobin values between Giardia-positive and Giardia-negative children. However, Giardia-positive children tended to achieve higher weight and height for age than Giardia-negative children; weight for age was above the 50th percentile in 69% of Giardia-positive vs. 40% of Giardia-negative children (alpha = 0.01). Giardia-positive children tended to have fewer symptoms related to the gastrointestinal and respiratory tracts as recorded by a weekly questionnaire. Lactase deficiency was detected by breath hydrogen testing in 8 of 26 Giardia-positive vs. only 1 of 21 Giardia-negative children (P less than 0.02). Healthy day care children with asymptomatic Giardia infection show no disadvantage and perhaps even an advantage in nutritional status and freedom from other illnesses.

Pediatric Dermatology, 2000

Simultaneous occurrence of Henoch-Schönlein purpura (HSP) in family members is not well documente... more Simultaneous occurrence of Henoch-Schönlein purpura (HSP) in family members is not well documented. We describe simultaneous onset of HSP in two sisters 1 day after the wearing of new synthetic slippers. Such an occurrence of the disease implies a common cause, however, in most patients the search for a causative agent is usually futile. There was no clear evidence of infection in our patients. The association of the appearance of the disease with the use of the slippers in our patients could indicate a possible, although unlikely, cause for their HSP.

Nucleic Acids Research, 1991

The ribosomal RNA (rRNA) genes in Giardia lamblia are present as short tandem arrays of a 5.6 Kb ... more The ribosomal RNA (rRNA) genes in Giardia lamblia are present as short tandem arrays of a 5.6 Kb repeat unit on at least six telomeres. Four of these telomeres have the same overall organisation comprising a domain ranging in size from 25 to 300 Kb, delineated chromosome internally by a conserved island of restriction enzyme sites. Cloned lines of G. lamblia derived from the WB strain contain polymorphic subsets of chromosomes encoding rRNA genes. However, changes in the size of the rRNA telomere domains of these polymorphic chromosomes alone cannot account for the total size changes in the chromosomes. The rearrangement events are very frequent: 60% of subcloned lines had discrete rearranged karyotypes that differed from each other, suggesting either an estimated rearrangement rate that may be as high as 3% per division or a cloning-induced rearrangement event. The extreme plasticity of the genome has obvious implications for the maintenance of a functional genome and the control of gene expression in Giardia.

Neuropediatrics, 2004

Glutaric aciduria type 1 (GA1) and D-2-hydroxyglutaric aciduria ( D-2-HGA) are cerebral organic a... more Glutaric aciduria type 1 (GA1) and D-2-hydroxyglutaric aciduria ( D-2-HGA) are cerebral organic acidurias characterized by the excretion of 3-hydroxyglutaric and D-2-hydroxyglutaric acids, respectively. GA1 is caused by a deficiency of glutaryl-CoA dehydrogenase encoded by the GCDH gene; the biochemical and genetic basis of D-2-HGA is unknown. We diagnosed GA1 in the son of consanguineous Palestinian parents, and D-2-HGA in his sister and brother. All three siblings were neurologically and developmentally normal. A small but abnormal increase in excretion of D-2-hydroxyglutaric acid was also found in the sibling with GA1. These observations suggested a possible pathophysiological link between these two disorders. The sibling with GA1 was homozygous whilst his siblings with D-2-HGA were heterozygous for a 1283 C>T missense mutation (T416I) in exon 11 of the GCDH gene. However, sequence analysis of the GCDH gene in 8 additional unrelated patients with D-2-HGA and 3 with combined D/ L-2-HGA did not reveal any pathogenic mutations. The biochemical and genetic basis of D-2-HGA remains to be determined.

Molecular Genetics and Metabolism, 2007

Molecular Genetics and Metabolism, 2007

Molecular Genetics and Metabolism, 2006

Three inborn errors have been identiWed in the pathway of isoleucine degradation. DeWciency of -k... more Three inborn errors have been identiWed in the pathway of isoleucine degradation. DeWciency of -ketothiolase ( -KT, also known as T2, mitochondrial acetoacetyl-CoA thiolase and acetyl-CoA acetyltransferase 1) is a well-described disorder which presents with acute episodic ketoacidosis. In contrast, short/branched-chain acyl-CoA dehydrogenase (SBCAD) and 2-methyl-3-hydroxybutyryl-CoA dehydrogenase (MHBD) deWciencies are recently described and relatively rare defects which present with predominantly neurological manifestations, although acute metabolic decompensation may occur in the early newborn period. Careful examination of urine organic acids is required for identiWcation and diVerential diagnosis of these disorders, with awareness that the abnormalities may be subtle and variable. Tandem MS analysis of acylcarnitines may reveal elevated C5 (SBCAD) or C5:1 and/or OH-C5 species (MHBD and -KT deWciencies) but the abnormalities are non-diagnostic and may be intermittent or absent. ConWrmation of diagnosis is therefore advisable by speciWc enzyme assay and/or mutation analysis of the ACAT1 ( -KT), ACADSB (SBCAD) or HADH2 (MHBD) genes. The latter is located on the X chromosome, accounting for the milder clinical phenotype in females. If -KT deWciency is diagnosed early and treated by fasting avoidance and modest protein restriction, ketoacidosis episodes can be prevented and the prognosis is excellent. The role of treatment in SBCAD deWciency remains unclear pending further delineation of its clinical phenotype and pathogenicity, particularly regarding asymptomatic individuals detected by expanded newborn screening. The ineVectiveness of isoleucine restriction in MHBD deWciency is consistent with the additional roles of this multifunctional enzyme in sex steroid and neurosteroid metabolism and its interaction with amyloid-peptide.

Molecular Genetics and Metabolism, 2010

Methionine adenosyltransferases (MAT's) are central enzymes in living organisms that have been co... more Methionine adenosyltransferases (MAT's) are central enzymes in living organisms that have been conserved with a high degree of homology among species. In the liver, MAT I and III, tetrameric and dimeric isoforms of the same catalytic subunit encoded by the gene MAT1A, account for the predominant portion of total body synthesis of S-adenosylmethionine (SAM), a versatile sulfonium ion-containing molecule involved in a variety of vital metabolic reactions and in the control of hepatocyte proliferation and differentiation. During the past 15 years 28 MAT1A mutations have been described in patients with elevated plasma methionines, total homocysteines at most only moderately elevated, and normal levels of tyrosine and other aminoacids. In this study we describe functional analyses that determine the MAT and tripolyphosphatase (PPPase) activities of 18 MAT1A variants, six of them novel, and none of them previously assayed for activity. With the exception of G69S and Y92H, all recombinant proteins showed impairment (usually severe) of MAT activity. Tripolyphosphate (PPPi) hydrolysis was decreased only in some mutant proteins but, when it was decreased MAT activity was always also impaired.

The Journal of Pediatrics, 1990

Chronic granulomatous disease is an inherited disorder of neutrophil oxidative metabolism that re... more Chronic granulomatous disease is an inherited disorder of neutrophil oxidative metabolism that results in recurrent infections with catalase-producing organisms and the development of inflammatory granulomas.l We describe the occurrence of hydronephrosis secondary to proximal ureteric obstruction in a child with long-standing CGD, and its resolution after proximal decompression in combination with intensive antibiotic therapy. We also review previous reports of genitourinary involvement in CGD.

Journal of Pediatric Gastroenterology and Nutrition, 2004

Nature, 2015

Cancer cells hijack and remodel existing metabolic pathways for their benefit. Argininosuccinate ... more Cancer cells hijack and remodel existing metabolic pathways for their benefit. Argininosuccinate synthase (ASS1) is a urea cycle enzyme that is essential in the conversion of nitrogen from ammonia and aspartate to urea. A decrease in nitrogen flux through ASS1 in the liver causes the urea cycle disorder citrullinaemia. In contrast to the well-studied consequences of loss of ASS1 activity on ureagenesis, the purpose of its somatic silencing in multiple cancers is largely unknown. Here we show that decreased activity of ASS1 in cancers supports proliferation by facilitating pyrimidine synthesis via CAD (carbamoyl-phosphate synthase 2, aspartate transcarbamylase, and dihydroorotase complex) activation. Our studies were initiated by delineating the consequences of loss of ASS1 activity in humans with two types of citrullinaemia. We find that in citrullinaemia type I (CTLN I), which is caused by deficiency of ASS1, there is increased pyrimidine synthesis and proliferation compared with citrullinaemia type II (CTLN II), in which there is decreased substrate availability for ASS1 caused by deficiency of the aspartate transporter citrin. Building on these results, we demonstrate that ASS1 deficiency in cancer increases cytosolic aspartate levels, which increases CAD activation by upregulating its substrate availability and by increasing its phosphorylation by S6K1 through the mammalian target of rapamycin (mTOR) pathway. Decreasing CAD activity by blocking citrin, the mTOR signalling, or pyrimidine synthesis decreases proliferation and thus may serve as a therapeutic strategy in multiple cancers where ASS1 is downregulated. Our results demonstrate that ASS1 downregulation is a novel mechanism supporting cancerous proliferation, and they provide a metabolic link between the urea cycle enzymes and pyrimidine synthesis.

American journal of diseases of children (1960), 1990

The duodenal string test capsule is a cheap and simple device used for sampling the contents of t... more The duodenal string test capsule is a cheap and simple device used for sampling the contents of the upper gastrointestinal tract. Its major applications in pediatrics are in diagnosis of enteric parasitic infestations, confirmation of contaminated small-bowel syndrome, diagnosis of Salmonella infection, and assessment of neonatal cholestasis. Pediatricians should be aware of this invaluable diagnostic aid.

Gastrointestinal Endoscopy, 1989

In vitro axenic cultures of Giardia lamblia were successfully established in 14 successive subjec... more In vitro axenic cultures of Giardia lamblia were successfully established in 14 successive subjects by a method employing the string test (Entero-Test) for obtaining samples of fluid from the proximal small intestine. This method is applicable to isolating G. lamblia from unselected subjects, including asymptomatic carriers, children, and individuals in diverse or remote geographic regions.

J Inherit Metab Dis, 2001

Oral lysine administration to three patients with B 6 -nonresponsive gyrate atrophy reduced plasm... more Oral lysine administration to three patients with B 6 -nonresponsive gyrate atrophy reduced plasma ornithine concentrations by 21^31% within 1^2 days. No further reduction was noted with time.

Journal of Inherited Metabolic Disease, Jan 5, 2001

Oral lysine administration to three patients with B 6 -nonresponsive gyrate atrophy reduced plasm... more Oral lysine administration to three patients with B 6 -nonresponsive gyrate atrophy reduced plasma ornithine concentrations by 21^31% within 1^2 days. No further reduction was noted with time.

Journal of Pediatric Gastroenterology and Nutrition, May 1, 1991

A pseudocyst of the pancreas in a 6-year-old girl persisted for 2 months despite bowel rest and n... more A pseudocyst of the pancreas in a 6-year-old girl persisted for 2 months despite bowel rest and nutritional support. Following percutaneous introduction of a catheter into the cyst under ultrasound guidance and external catheter drainage for 11 days, the pseudocyst resolved completely and permanently. Nonoperative percutaneous techniques for drainage of pancreatic pseudocysts in children may be an effective alternative to surgical intervention.

Journal of Inherited Metabolic Disease, Oct 1, 2009

L-2-hydroxyglutaric aciduria (L-2-HGA) is a rare inherited autosomal recessive neurometabolic dis... more L-2-hydroxyglutaric aciduria (L-2-HGA) is a rare inherited autosomal recessive neurometabolic disorder caused by mutations in the gene encoding L-2-hydroxyglutarate dehydrogenase. An assay to evaluate L-2-hydroxyglutarate dehydrogenase (L-2-HGDH) activity in fibroblast, lymphoblast and/or lymphocyte lysates has hitherto been unavailable. We developed an L-2-HGDH enzyme assay in cell lysates based on the conversion of stable-isotope-labelled L-2-hydroxyglutarate to 2-ketoglutarate, which is converted into L-glutamate in situ. The formation of stable isotope labelled L-glutamate is therefore a direct measure of L-2-HGDH activity, and this product is detected by liquid chromatography-tandem mass spectrometry. A deficiency of L-2-HGDH activity was detected in cell lysates from 15 out of 15 L-2-HGA patients. Therefore, this specific assay confirmed the diagnosis unambiguously affirming the relationship between molecular and biochemical observations. Residual activity was detected in cells derived from one L-2-HGA patient. The L-2-HGDH assay will be valuable for examining in vitro riboflavin/FAD therapy to rescue L-2-HGDH activity.

Advances in experimental medicine and biology, 2003

Peroxisomes perform a multitude of biosynthetic and catabolic functions, many of which are relate... more Peroxisomes perform a multitude of biosynthetic and catabolic functions, many of which are related to lipid metabolism. Peroxisomal disorders result either from deficiency of a single peroxisomal enzyme or protein, or from a defect in the complex mechanism of peroxisomal biogenesis, resulting in deficiency of several or multiple peroxisomal functions. These can be assessed by a battery of biochemical assays, enabling a biochemical phenotype to be defined that is specific and diagnostic for each of the peroxisomal disorders. Some peroxisomal disorders have unique and specific clinical phenotypes, which may be diagnostic. Others share patterns of clinical abnormalities (particularly neurological dysfunction, craniofacial dysmorphism, skeletal defects, sensory deafness, retinopathy) consistent with defined clinical phenotypes, but with considerable overlap and heterogeneity. To a certain extent, the clinical features of a particular disorder reflect the accumulation or deficiency of sp...

Journal of inherited metabolic disease, 2000

The Pediatric Infectious Disease Journal, 1989

Giardia lamblia infection was identified in 33 of 89 (37%) 3-month-old to 3-yr-old children who w... more Giardia lamblia infection was identified in 33 of 89 (37%) 3-month-old to 3-yr-old children who were followed with monthly stool examinations for up to 12 months in a day care center. The infection was mainly asymptomatic and usually associated with prolonged carriage of the parasite. There were no significant differences for height and weight achievements and mean hemoglobin values between Giardia-positive and Giardia-negative children. However, Giardia-positive children tended to achieve higher weight and height for age than Giardia-negative children; weight for age was above the 50th percentile in 69% of Giardia-positive vs. 40% of Giardia-negative children (alpha = 0.01). Giardia-positive children tended to have fewer symptoms related to the gastrointestinal and respiratory tracts as recorded by a weekly questionnaire. Lactase deficiency was detected by breath hydrogen testing in 8 of 26 Giardia-positive vs. only 1 of 21 Giardia-negative children (P less than 0.02). Healthy day care children with asymptomatic Giardia infection show no disadvantage and perhaps even an advantage in nutritional status and freedom from other illnesses.

Pediatric Dermatology, 2000

Simultaneous occurrence of Henoch-Schönlein purpura (HSP) in family members is not well documente... more Simultaneous occurrence of Henoch-Schönlein purpura (HSP) in family members is not well documented. We describe simultaneous onset of HSP in two sisters 1 day after the wearing of new synthetic slippers. Such an occurrence of the disease implies a common cause, however, in most patients the search for a causative agent is usually futile. There was no clear evidence of infection in our patients. The association of the appearance of the disease with the use of the slippers in our patients could indicate a possible, although unlikely, cause for their HSP.

Nucleic Acids Research, 1991

The ribosomal RNA (rRNA) genes in Giardia lamblia are present as short tandem arrays of a 5.6 Kb ... more The ribosomal RNA (rRNA) genes in Giardia lamblia are present as short tandem arrays of a 5.6 Kb repeat unit on at least six telomeres. Four of these telomeres have the same overall organisation comprising a domain ranging in size from 25 to 300 Kb, delineated chromosome internally by a conserved island of restriction enzyme sites. Cloned lines of G. lamblia derived from the WB strain contain polymorphic subsets of chromosomes encoding rRNA genes. However, changes in the size of the rRNA telomere domains of these polymorphic chromosomes alone cannot account for the total size changes in the chromosomes. The rearrangement events are very frequent: 60% of subcloned lines had discrete rearranged karyotypes that differed from each other, suggesting either an estimated rearrangement rate that may be as high as 3% per division or a cloning-induced rearrangement event. The extreme plasticity of the genome has obvious implications for the maintenance of a functional genome and the control of gene expression in Giardia.

Neuropediatrics, 2004

Glutaric aciduria type 1 (GA1) and D-2-hydroxyglutaric aciduria ( D-2-HGA) are cerebral organic a... more Glutaric aciduria type 1 (GA1) and D-2-hydroxyglutaric aciduria ( D-2-HGA) are cerebral organic acidurias characterized by the excretion of 3-hydroxyglutaric and D-2-hydroxyglutaric acids, respectively. GA1 is caused by a deficiency of glutaryl-CoA dehydrogenase encoded by the GCDH gene; the biochemical and genetic basis of D-2-HGA is unknown. We diagnosed GA1 in the son of consanguineous Palestinian parents, and D-2-HGA in his sister and brother. All three siblings were neurologically and developmentally normal. A small but abnormal increase in excretion of D-2-hydroxyglutaric acid was also found in the sibling with GA1. These observations suggested a possible pathophysiological link between these two disorders. The sibling with GA1 was homozygous whilst his siblings with D-2-HGA were heterozygous for a 1283 C>T missense mutation (T416I) in exon 11 of the GCDH gene. However, sequence analysis of the GCDH gene in 8 additional unrelated patients with D-2-HGA and 3 with combined D/ L-2-HGA did not reveal any pathogenic mutations. The biochemical and genetic basis of D-2-HGA remains to be determined.

Molecular Genetics and Metabolism, 2007

Molecular Genetics and Metabolism, 2007

Molecular Genetics and Metabolism, 2006

Three inborn errors have been identiWed in the pathway of isoleucine degradation. DeWciency of -k... more Three inborn errors have been identiWed in the pathway of isoleucine degradation. DeWciency of -ketothiolase ( -KT, also known as T2, mitochondrial acetoacetyl-CoA thiolase and acetyl-CoA acetyltransferase 1) is a well-described disorder which presents with acute episodic ketoacidosis. In contrast, short/branched-chain acyl-CoA dehydrogenase (SBCAD) and 2-methyl-3-hydroxybutyryl-CoA dehydrogenase (MHBD) deWciencies are recently described and relatively rare defects which present with predominantly neurological manifestations, although acute metabolic decompensation may occur in the early newborn period. Careful examination of urine organic acids is required for identiWcation and diVerential diagnosis of these disorders, with awareness that the abnormalities may be subtle and variable. Tandem MS analysis of acylcarnitines may reveal elevated C5 (SBCAD) or C5:1 and/or OH-C5 species (MHBD and -KT deWciencies) but the abnormalities are non-diagnostic and may be intermittent or absent. ConWrmation of diagnosis is therefore advisable by speciWc enzyme assay and/or mutation analysis of the ACAT1 ( -KT), ACADSB (SBCAD) or HADH2 (MHBD) genes. The latter is located on the X chromosome, accounting for the milder clinical phenotype in females. If -KT deWciency is diagnosed early and treated by fasting avoidance and modest protein restriction, ketoacidosis episodes can be prevented and the prognosis is excellent. The role of treatment in SBCAD deWciency remains unclear pending further delineation of its clinical phenotype and pathogenicity, particularly regarding asymptomatic individuals detected by expanded newborn screening. The ineVectiveness of isoleucine restriction in MHBD deWciency is consistent with the additional roles of this multifunctional enzyme in sex steroid and neurosteroid metabolism and its interaction with amyloid-peptide.

Molecular Genetics and Metabolism, 2010

Methionine adenosyltransferases (MAT's) are central enzymes in living organisms that have been co... more Methionine adenosyltransferases (MAT's) are central enzymes in living organisms that have been conserved with a high degree of homology among species. In the liver, MAT I and III, tetrameric and dimeric isoforms of the same catalytic subunit encoded by the gene MAT1A, account for the predominant portion of total body synthesis of S-adenosylmethionine (SAM), a versatile sulfonium ion-containing molecule involved in a variety of vital metabolic reactions and in the control of hepatocyte proliferation and differentiation. During the past 15 years 28 MAT1A mutations have been described in patients with elevated plasma methionines, total homocysteines at most only moderately elevated, and normal levels of tyrosine and other aminoacids. In this study we describe functional analyses that determine the MAT and tripolyphosphatase (PPPase) activities of 18 MAT1A variants, six of them novel, and none of them previously assayed for activity. With the exception of G69S and Y92H, all recombinant proteins showed impairment (usually severe) of MAT activity. Tripolyphosphate (PPPi) hydrolysis was decreased only in some mutant proteins but, when it was decreased MAT activity was always also impaired.

The Journal of Pediatrics, 1990

Chronic granulomatous disease is an inherited disorder of neutrophil oxidative metabolism that re... more Chronic granulomatous disease is an inherited disorder of neutrophil oxidative metabolism that results in recurrent infections with catalase-producing organisms and the development of inflammatory granulomas.l We describe the occurrence of hydronephrosis secondary to proximal ureteric obstruction in a child with long-standing CGD, and its resolution after proximal decompression in combination with intensive antibiotic therapy. We also review previous reports of genitourinary involvement in CGD.

Journal of Pediatric Gastroenterology and Nutrition, 2004