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Marshall L Summar - One of the best experts on this subject based on the ideXlab platform.
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Urea Cycle Disorders Overview
2015Co-Authors: Nicholas Ah Mew, Kara L Simpson, Andrea L. Gropman, Brendan C. Lanpher, Kimberly A. Chapman, Marshall L SummarAbstract:The goals of this overview on Urea Cycle disorders are the following: Goal 1 To define the Urea Cycle and to describe the clinical characteristics of Urea Cycle disorders Goal 2 To review the causes of Urea Cycle disorders and their prevalence Goal 3 To provide an evaluation strategy to identify the specific type and genetic cause of a Urea Cycle defect in a proband Goal 4 To review the differential diagnosis of Urea Cycle disorders Goal 5 To inform genetic risk assessment in family members of the proband Goal 6 To provide a brief summary of the acute management of a Urea Cycle disorder
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The incidence of Urea Cycle disorders.
Molecular genetics and metabolism, 2013Co-Authors: Marshall L Summar, Johannes Häberle, Stefan Koelker, Debra Freedenberg, Cynthia Le Mons, Hye-seung Lee, Brian KirmseAbstract:A key question for Urea Cycle disorders is their incidence. In the United States two UCDs, argininosuccinic synthetase and lyase deficiency, are currently detected by newborn screening. We used newborn screening data on over 6million births and data from the large US and European longitudinal registries to determine how common these conditions are. The incidence for the United States is predicted to be 1 Urea Cycle disorder patient for every 35,000 births presenting about 113 new patients per year across all age groups.
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Urea Cycle disorders clinical presentation outside the newborn period
Critical Care Clinics, 2005Co-Authors: Wendy E Smith, Priya S Kishnani, Brendan Lee, Rani H Singh, William J Rhead, Lisa Sniderman King, Michael L Smith, Marshall L SummarAbstract:Although most commonly associated with infancy, the majority of individuals with Urea Cycle disorders (UCDs) present outside the neonatal period, frequently in childhood. Signs and symptoms are often vague, but recurrent; fulminant presentations associated with acute illness are also common. A disorder of Urea Cycle metabolism should be considered in children who have recurrent symptoms, especially neurologic abnormalities associated with periods of decompensation. Routine laboratory tests, including measurement of plasma ammonia concentrations, can indicate a potential UCD; however, specific metabolic testing and ultimately enzymatic or molecular confirmation are necessary to establish a diagnosis. Treatment with dietary protein restriction and medications may be challenging in children.
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Nutritional management of Urea Cycle disorders
Critical Care Clinics, 2005Co-Authors: Rani H Singh, Wendy E Smith, Brendan Lee, William J Rhead, Lisa Sniderman King, Marshall L SummarAbstract:Nutritional management of patients who have Urea Cycle disorders is one of the most challenging tasks in clinical nutrition. The degree to which protein intake should be restricted in Urea Cycle disorders requires complex calculations which depend on many variables such as specific enzyme defect, age-related growth rate, current health status, level of physical activity, amount of free amino acids administered, energy intake, residual Urea Cycle function, family lifestyle, use of nitrogen-scavenging medications, and the patient's eating behaviors. This paper presents two case histories and a series of recommendations outlining the nutrition management of Urea Cycle disorders. It also identifies difficulties that arise in the course of treatment, and suggests practical solutions for overcoming them.
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Unmasked adult-onset Urea Cycle disorders in the critical care setting.
Critical care clinics, 2005Co-Authors: Marshall L Summar, Brendan Lee, Rani H Singh, William J Rhead, Frederick Barr, Sheila Dawling, Wendy Smith, Lisa Sniderman King, Brian W ChristmanAbstract:Most often, Urea Cycle disorders have been described as acute onset hyperammonemia in the newborn period; however, there is a growing awareness that Urea Cycle disorders can present at almost any age, frequently in the critical care setting. This article presents three cases of adult-onset hyperammonemia caused by inherited defects in nitrogen processing in the Urea Cycle, and reviews the diagnosis, management, and pathophysiology of adult-onset Urea Cycle disorders. Individuals who have milder molecular Urea Cycle defects can lead a relatively normal life until a severe environmental stress triggers a hyperammonemic crisis. Comorbid conditions such as physical trauma often delay the diagnosis of the Urea Cycle defect. Prompt recognition and treatment are essential in determining the outcome of these patients.
Brendan Lee - One of the best experts on this subject based on the ideXlab platform.
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Urea Cycle disorders clinical presentation outside the newborn period
Critical Care Clinics, 2005Co-Authors: Wendy E Smith, Priya S Kishnani, Brendan Lee, Rani H Singh, William J Rhead, Lisa Sniderman King, Michael L Smith, Marshall L SummarAbstract:Although most commonly associated with infancy, the majority of individuals with Urea Cycle disorders (UCDs) present outside the neonatal period, frequently in childhood. Signs and symptoms are often vague, but recurrent; fulminant presentations associated with acute illness are also common. A disorder of Urea Cycle metabolism should be considered in children who have recurrent symptoms, especially neurologic abnormalities associated with periods of decompensation. Routine laboratory tests, including measurement of plasma ammonia concentrations, can indicate a potential UCD; however, specific metabolic testing and ultimately enzymatic or molecular confirmation are necessary to establish a diagnosis. Treatment with dietary protein restriction and medications may be challenging in children.
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Nutritional management of Urea Cycle disorders
Critical Care Clinics, 2005Co-Authors: Rani H Singh, Wendy E Smith, Brendan Lee, William J Rhead, Lisa Sniderman King, Marshall L SummarAbstract:Nutritional management of patients who have Urea Cycle disorders is one of the most challenging tasks in clinical nutrition. The degree to which protein intake should be restricted in Urea Cycle disorders requires complex calculations which depend on many variables such as specific enzyme defect, age-related growth rate, current health status, level of physical activity, amount of free amino acids administered, energy intake, residual Urea Cycle function, family lifestyle, use of nitrogen-scavenging medications, and the patient's eating behaviors. This paper presents two case histories and a series of recommendations outlining the nutrition management of Urea Cycle disorders. It also identifies difficulties that arise in the course of treatment, and suggests practical solutions for overcoming them.
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Unmasked adult-onset Urea Cycle disorders in the critical care setting.
Critical care clinics, 2005Co-Authors: Marshall L Summar, Brendan Lee, Rani H Singh, William J Rhead, Frederick Barr, Sheila Dawling, Wendy Smith, Lisa Sniderman King, Brian W ChristmanAbstract:Most often, Urea Cycle disorders have been described as acute onset hyperammonemia in the newborn period; however, there is a growing awareness that Urea Cycle disorders can present at almost any age, frequently in the critical care setting. This article presents three cases of adult-onset hyperammonemia caused by inherited defects in nitrogen processing in the Urea Cycle, and reviews the diagnosis, management, and pathophysiology of adult-onset Urea Cycle disorders. Individuals who have milder molecular Urea Cycle defects can lead a relatively normal life until a severe environmental stress triggers a hyperammonemic crisis. Comorbid conditions such as physical trauma often delay the diagnosis of the Urea Cycle defect. Prompt recognition and treatment are essential in determining the outcome of these patients.
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Urea Cycle Disorders.
Current treatment options in neurology, 2003Co-Authors: Soledad Kleppe, Asad Mian, Brendan LeeAbstract:Urea Cycle disorders comprise a group of inborn errors of metabolism that represent unique gene-nutrient interactions whose significant morbidity arises from acute and chronic neurotoxicity associated with often massive hyperammonemia. Current paradigms of treatment are focused on controlling the flux of nitrogen transfer through the hepatic Urea Cycle by a combination of dietary and pharmacologic approaches. Evolving paradigms include the development of cell and gene therapies. Current research is focused on understanding the pathophysiology of ammonia-mediated toxicity and prevention of neural injury.
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Long-term correction of Urea Cycle disorders.
The Journal of Pediatrics, 2001Co-Authors: Brendan Lee, John A. GossAbstract:Long-term correction of Urea Cycle disorders is achieved by correction of the enzymatic defect in hepatocytes. Currently, orthotopic liver transplantation is the primary means of achieving this correction. In the United States most liver transplantations for Urea Cycle disorders have been restricted to patients with ornithine transcarbamylase deficiency and argininosuccinic aciduria. However, patients with citrullinemia have also received transplants, but more so in Europe and Japan. Recent advances in organ procurement, surgical technique, and immunosuppression have significantly decreased morbidity and mortality. However, unique short-term complications associated with surgery and long-term complications associated with chronic immunosuppression have spurred continued efforts to develop gene replacement therapies for management of acute metabolic decompensations as intercurrent therapy until liver transplantation, and ultimately, for long-term correction. The pathophysiology of Urea Cycle disorders requires gene vector delivery systems that are highly efficient for liver transduction and transgene expression. To date, adenoviral vectors are unique in fulfilling these criteria, and significant data have been gained in both animal and human studies with early versions of adenoviral vectors. Ultimately, the development of helper-dependent adenoviral vectors may offer the long-term expression and increased margin of safety necessary for adjunctive therapies.
Rani H Singh - One of the best experts on this subject based on the ideXlab platform.
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Urea Cycle disorders clinical presentation outside the newborn period
Critical Care Clinics, 2005Co-Authors: Wendy E Smith, Priya S Kishnani, Brendan Lee, Rani H Singh, William J Rhead, Lisa Sniderman King, Michael L Smith, Marshall L SummarAbstract:Although most commonly associated with infancy, the majority of individuals with Urea Cycle disorders (UCDs) present outside the neonatal period, frequently in childhood. Signs and symptoms are often vague, but recurrent; fulminant presentations associated with acute illness are also common. A disorder of Urea Cycle metabolism should be considered in children who have recurrent symptoms, especially neurologic abnormalities associated with periods of decompensation. Routine laboratory tests, including measurement of plasma ammonia concentrations, can indicate a potential UCD; however, specific metabolic testing and ultimately enzymatic or molecular confirmation are necessary to establish a diagnosis. Treatment with dietary protein restriction and medications may be challenging in children.
-
Nutritional management of Urea Cycle disorders
Critical Care Clinics, 2005Co-Authors: Rani H Singh, Wendy E Smith, Brendan Lee, William J Rhead, Lisa Sniderman King, Marshall L SummarAbstract:Nutritional management of patients who have Urea Cycle disorders is one of the most challenging tasks in clinical nutrition. The degree to which protein intake should be restricted in Urea Cycle disorders requires complex calculations which depend on many variables such as specific enzyme defect, age-related growth rate, current health status, level of physical activity, amount of free amino acids administered, energy intake, residual Urea Cycle function, family lifestyle, use of nitrogen-scavenging medications, and the patient's eating behaviors. This paper presents two case histories and a series of recommendations outlining the nutrition management of Urea Cycle disorders. It also identifies difficulties that arise in the course of treatment, and suggests practical solutions for overcoming them.
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Unmasked adult-onset Urea Cycle disorders in the critical care setting.
Critical care clinics, 2005Co-Authors: Marshall L Summar, Brendan Lee, Rani H Singh, William J Rhead, Frederick Barr, Sheila Dawling, Wendy Smith, Lisa Sniderman King, Brian W ChristmanAbstract:Most often, Urea Cycle disorders have been described as acute onset hyperammonemia in the newborn period; however, there is a growing awareness that Urea Cycle disorders can present at almost any age, frequently in the critical care setting. This article presents three cases of adult-onset hyperammonemia caused by inherited defects in nitrogen processing in the Urea Cycle, and reviews the diagnosis, management, and pathophysiology of adult-onset Urea Cycle disorders. Individuals who have milder molecular Urea Cycle defects can lead a relatively normal life until a severe environmental stress triggers a hyperammonemic crisis. Comorbid conditions such as physical trauma often delay the diagnosis of the Urea Cycle defect. Prompt recognition and treatment are essential in determining the outcome of these patients.
Andrea L. Gropman - One of the best experts on this subject based on the ideXlab platform.
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The Urea Cycle Disorders
Oxford Medicine Online, 2017Co-Authors: Andrea L. Gropman, Belen Pappa, Nicholas Ah MewAbstract:The Urea Cycle is the primary nitrogen disposal pathway in humans. The Urea Cycle requires the coordinated function of six enzymes and two mitochondrial transporters to catalyze the conversion of a molecule of ammonia, the α-nitrogen of aspartate and bicarbonate into Urea. Whereas ammonia is toxic, Urea is relatively inert, soluble in water, and readily excreted by the kidney in the urine. The accumulation of ammonia and other toxic intermediates of the Cycle lead to predominantly neurological sequelae. All of the genes have been identified. The disorders may present at any age from the neonatal period to adulthood, with the more severe patients presenting earlier in life. Patients are at risk for metabolic decompensation throughout life, often triggered by illness, fasting, surgery and postoperative states, peripartum, stress, and increased exogenous protein load. This chapter addresses common somatic and neurological presentation, differential diagnosis, laboratory testing, and treatments.
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Improving long term outcomes in Urea Cycle disorders-report from the Urea Cycle Disorders Consortium
Journal of inherited metabolic disease, 2016Co-Authors: Susan E. Waisbren, Andrea L. Gropman, Mark L. BatshawAbstract:The Urea Cycle Disorders Consortium (UCDC) has conducted, beginning in 2006, a longitudinal study (LS) of eight enzyme deficiencies/transporter defects associated with the Urea Cycle. These include N-acetylglutamate synthase deficiency (NAGSD); Carbamyl phosphate synthetase 1 deficiency (CPS1D); Ornithine transcarbamylase deficiency (OTCD); Argininosuccinate synthetase deficiency (ASSD) (Citrullinemia); Argininosuccinate lyase deficiency (ASLD) (Argininosuccinic aciduria); Arginase deficiency (ARGD, Argininemia); Hyperornithinemia, hyperammonemia, homocitrullinuria (HHH) syndrome (or mitochondrial ornithine transporter 1 deficiency [ORNT1D]); and Citrullinemia type II (mitochondrial aspartate/glutamate carrier deficiency [CITRIN]). There were 678 UCD patients enrolled in 14 sites in the U.S., Canada, and Europe at the writing of this paper. This review summarizes findings of the consortium related to outcome, focusing primarily on neuroimaging findings and neurocognitive function. Neuroimaging studies in late onset OTCD offered evidence that brain injury caused by biochemical dysregulation may impact functional neuroanatomy serving working memory processes, an important component of executive function and regulation. Additionally, there were alteration in white mater microstructure and functional connectivity at rest. Intellectual deficits in OTCD and other Urea Cycle disorders (UCD) vary. However, when neuropsychological deficits occur, they tend to be more prominent in motor/performance areas on both intelligence tests and other measures. In some disorders, adults performed significantly less well than younger patients. Further longitudinal follow-up will reveal whether this is due to declines throughout life or to improvements in diagnostics (especially newborn screening) and treatments in the younger generation of patients.
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Urea Cycle Disorders Overview
2015Co-Authors: Nicholas Ah Mew, Kara L Simpson, Andrea L. Gropman, Brendan C. Lanpher, Kimberly A. Chapman, Marshall L SummarAbstract:The goals of this overview on Urea Cycle disorders are the following: Goal 1 To define the Urea Cycle and to describe the clinical characteristics of Urea Cycle disorders Goal 2 To review the causes of Urea Cycle disorders and their prevalence Goal 3 To provide an evaluation strategy to identify the specific type and genetic cause of a Urea Cycle defect in a proband Goal 4 To review the differential diagnosis of Urea Cycle disorders Goal 5 To inform genetic risk assessment in family members of the proband Goal 6 To provide a brief summary of the acute management of a Urea Cycle disorder
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Urea Cycle Disorders
Rosenberg's Molecular and Genetic Basis of Neurological and Psychiatric Disease, 2015Co-Authors: Nicholas Ah Mew, Maria Belen Pappa, Andrea L. GropmanAbstract:The Urea Cycle is the primary biochemical pathway in humans by which excess nitrogen is disposed. Through the coordinated function of six enzymes and two mitochondrial transporters, the pathway catalyzes the conversion of a molecule of ammonia, the α-nitrogen of aspartate and bicarbonate into Urea. Whereas ammonia is toxic, Urea is relatively inert, soluble in water, and readily excreted in the urine. The major sequelae of Urea Cycle disorders are neurological. All of the genes have been identified. The disorders may present at any age from the neonatal period to adulthood. In this chapter, the most common presentations are discussed along with inheritance patterns and treatments.
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The Urea Cycle Disorders
Seminars in neurology, 2014Co-Authors: Guy Helman, Ileana Pacheco-colón, Andrea L. GropmanAbstract:The Urea Cycle is the primary nitrogen-disposal pathway in humans. It requires the coordinated function of six enzymes and two mitochondrial transporters to catalyze the conversion of a molecule of ammonia, the α-nitrogen of aspartate, and bicarbonate into Urea. Whereas ammonia is toxic, Urea is relatively inert, soluble in water, and readily excreted by the kidney in the urine. Accumulation of ammonia and other toxic intermediates of the Cycle lead to predominantly neurologic sequelae. The disorders may present at any age from the neonatal period to adulthood, with the more severely affected patients presenting earlier in life. Patients are at risk for metabolic decompensation throughout life, often triggered by illness, fasting, surgery and postoperative states, peripartum, stress, and increased exogenous protein load. Here the authors address neurologic presentations of ornithine transcarbamylase deficiency in detail, the most common of the Urea Cycle disorders, neuropathology, neurophysiology, and our studies in neuroimaging. Special attention to late-onset presentations is given.
Mark L. Batshaw - One of the best experts on this subject based on the ideXlab platform.
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Improving long term outcomes in Urea Cycle disorders-report from the Urea Cycle Disorders Consortium
Journal of inherited metabolic disease, 2016Co-Authors: Susan E. Waisbren, Andrea L. Gropman, Mark L. BatshawAbstract:The Urea Cycle Disorders Consortium (UCDC) has conducted, beginning in 2006, a longitudinal study (LS) of eight enzyme deficiencies/transporter defects associated with the Urea Cycle. These include N-acetylglutamate synthase deficiency (NAGSD); Carbamyl phosphate synthetase 1 deficiency (CPS1D); Ornithine transcarbamylase deficiency (OTCD); Argininosuccinate synthetase deficiency (ASSD) (Citrullinemia); Argininosuccinate lyase deficiency (ASLD) (Argininosuccinic aciduria); Arginase deficiency (ARGD, Argininemia); Hyperornithinemia, hyperammonemia, homocitrullinuria (HHH) syndrome (or mitochondrial ornithine transporter 1 deficiency [ORNT1D]); and Citrullinemia type II (mitochondrial aspartate/glutamate carrier deficiency [CITRIN]). There were 678 UCD patients enrolled in 14 sites in the U.S., Canada, and Europe at the writing of this paper. This review summarizes findings of the consortium related to outcome, focusing primarily on neuroimaging findings and neurocognitive function. Neuroimaging studies in late onset OTCD offered evidence that brain injury caused by biochemical dysregulation may impact functional neuroanatomy serving working memory processes, an important component of executive function and regulation. Additionally, there were alteration in white mater microstructure and functional connectivity at rest. Intellectual deficits in OTCD and other Urea Cycle disorders (UCD) vary. However, when neuropsychological deficits occur, they tend to be more prominent in motor/performance areas on both intelligence tests and other measures. In some disorders, adults performed significantly less well than younger patients. Further longitudinal follow-up will reveal whether this is due to declines throughout life or to improvements in diagnostics (especially newborn screening) and treatments in the younger generation of patients.
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A longitudinal study of Urea Cycle disorders.
Molecular genetics and metabolism, 2014Co-Authors: Mark L. Batshaw, M Summar, Mendel Tuchman, Jennifer SeminaraAbstract:The Urea Cycle Disorders Consortium (UCDC) is a member of the NIH funded Rare Diseases Clinical Research Network and is performing a longitudinal study of 8 Urea Cycle disorders (UCDs) with initial enrollment beginning in 2006. The consortium consists of 14 sites in the U.S., Canada and Europe. This report summarizes data mining studies of 614 patients with UCDs enrolled in the UCDC's longitudinal study protocol. The most common disorder is ornithine transcarbamylase deficiency, accounting for more than half of the participants. We calculated the overall prevalence of Urea Cycle disorders to be 1/35,000, with 2/3rds presenting initial symptoms after the newborn period. We found the mortality rate to be 24% in neonatal onset cases and 11% in late onset cases. The most common precipitant of clinical hyperammonemic episodes in the post-neonatal period was intercurrent infections. Elevations in both blood ammonia and glutamine appeared to be biomarkers for neurocognitive outcome. In terms of chronic treatment, low protein diet appeared to result in normal weight but decreased linear growth while N-scavenger therapy with phenylbutyrate resulted in low levels of branched chain amino acids. Finally, we found an unexpectedly high risk for hepatic dysfunction in patients with ornithine transcarbamylase deficiency. This natural history study illustrates how a collaborative study of a rare genetic disorder can result in an improved understanding of morbidity and disease outcome.
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Cognitive outcome in Urea Cycle disorders
Molecular Genetics and Metabolism, 2004Co-Authors: Andrea L. Gropman, Mark L. BatshawAbstract:Despite treatment, cognitive and motor deficits are common in individuals with inherited Urea Cycle disorders. However, the extent to which the deficits involve specific cognitive or sensorimotor domains is unknown. Furthermore, little is known about the neurochemical basis of cognitive impairment in these disorders. This paper reviews studies of cognitive and motor dysfunction in Urea Cycle disorders, and discusses potential venues for investigation of the underlying neural basis that may elucidate these defects. Such methods of investigation may serve as a model for studying the relationship between genes, biochemical markers, brain function, and behavior in other metabolic diseases.
