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Inborn Error of Small Molecule Metabolism

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101. Infections in the Immunocompromised Host (Treatment)

, joint, peritoneal, wound, or ventricular access or drainage devices Internal foreign bodies [ ] Major surgery [ ] Treatment For leukemia or lymphoma Bone marrow or stem-cell transplantation Solid organ transplantation [ ] Therapy for autoimmune or inflammatory disorders TNF-alpha inhibitors [ ] Monoclonal antibodies and related small molecules Transfusion (which may lead to iron overload) Previous Next: Alternate Diagnoses Table. Differential Diagnoses Previous Next: Infections In general (...) , [ ] histoplasmosis, [ ] Listeria infection, [ ] and severe falciparum malaria. [ ] Other monoclonal antibodies and related small molecules have been associated with numerous infections. [ ] For example, therapy with eculizumab, a C5 inhibitor, is associated with invasive meningococcal infection. Similarly, treatment with natalizumab (for multiple sclerosis) is associated with progressive multifocal leukoencephalopathy. [ , ] Treatment with infliximab has been associated with disseminated cutaneous varicella

2014 eMedicine Pediatrics

102. Absence Seizures (Diagnosis)

and neurologic findings may be abnormal, reflecting the underlying disorder. Physical examination may reveal stigmata of a genetic disease, such as a neurocutaneous disorder (eg, tuberous sclerosis) or an inborn error of metabolism. Neurologic examination may show signs of developmental delay or more specific signs, such as spastic paresis in cerebral palsy. Table 1. Clinical and EEG Findings in Typical and Atypical Absence Seizures* Type of Clinical Seizure EEG Findings Typical absence Impairment (...) on duration of the seizure; the longer the seizure, the more likely automatisms are to occur (see image below). [ ] Percentage of absence seizures with automatisms as a function of duration in seconds. (Data gathered from Penry et al, 1975.) Previous Next: Laboratory Studies When evaluating a child for staring spells, laboratory tests for metabolic abnormalities or toxic or drug ingestion (especially in older children) may be indicated. If a clear history of the episodic nature of the attacks is obtained

2014 eMedicine.com

103. Menkes Kinky Hair Disease (Overview)

in Australia, where wool production remained a major industry. [ , ] He measured serum copper in 7 patients with Menkes kinky hair disease and found low levels in all 7 individuals. Serum levels of ceruloplasmin, an important copper enzyme, were also subnormal. Thus, observations made 35 years apart concerning the effects of copper deficiency in Australian sheep became extremely relevant to a human inborn error of metabolism. This important biochemical finding sparked renewed interest in the phenotype (...) of Menkes Kinky Hair Disease Updated: Sep 08, 2015 Author: Stephen G Kaler, MD, MPH; Chief Editor: Maria Descartes, MD Share Email Print Feedback Close Sections Sections Genetics of Menkes Kinky Hair Disease Overview Background In the 52 years since the original description of Menkes kinky hair disease (MKHD), advances in understanding the clinical, biochemical, and molecular aspects of this rare disorder of copper metabolism have outstripped progress in the design of effective therapies. [ ] The most

2014 eMedicine Pediatrics

104. Congenital Hypothyroidism (Overview)

to thyroglobulin, forming monoiodotyrosine (MIT) and diiodotyrosine (DIT). The coupling of 2 molecules of DIT forms tetraiodothyronine (ie, T4). The coupling of one molecule of MIT and one molecule of DIT forms T3. Thyroglobulin, with T4 and T3 attached, is stored in the follicular lumen. TSH activates the enzymes needed to cleave T4 and T3 from thyroglobulin. In most situations, T4 is the primary hormone produced by and released from the thyroid gland. Inborn errors of thyroid metabolism can result (...) Hypothyroidism Updated: Oct 14, 2017 Author: Maala S Daniel, MBBS; Chief Editor: Sasigarn A Bowden, MD Share Email Print Feedback Close Sections Sections Congenital Hypothyroidism Overview Practice Essentials Congenital hypothyroidism (CH) is inadequate thyroid hormone production in newborn infants. It can occur because of an anatomic defect in the gland, an inborn error of thyroid metabolism, or iodine deficiency. (See the image below.) CH is the most common neonatal endocrine disorder, and historically

2014 eMedicine Pediatrics

105. Glycogen-Storage Disease Type III (Overview)

> Genetics of Glycogen-Storage Disease Type III Updated: Feb 18, 2019 Author: David H Tegay, DO, FACMG; Chief Editor: Maria Descartes, MD Share Email Print Feedback Close Sections Sections Genetics of Glycogen-Storage Disease Type III Overview Background Glycogen-storage disease (GSD) type III (GSD III) is an autosomal recessive inborn error of metabolism caused by loss of function mutations of the glycogen debranching enzyme (Amylo-1,6-glucosidase [ AGL ]) gene, which is located at chromosome band (...) . [ ] The clinical status of both patients had significantly improved since their conditions were originally described in 1928. Although Snappes and van Creveld's patients with GSD III were the first individuals in whom a defect in glycogen metabolism was reported, Cori and Cori demonstrated in 1952 that the absence of glucose-6-phosphatase activity was the enzyme defect in GSD I (von Gierke disease). Indeed, GSD I was the first inborn error of metabolism in which the precise enzyme defect was identified. Since

2014 eMedicine Pediatrics

106. Hematopoietic Stem Cell Transplantation (Overview)

Aplastic anemia Pure red-cell aplasia Paroxysmal nocturnal hemoglobinuria Fanconi anemia Thalassemia major Sickle cell anemia Severe combined immunodeficiency (SCID) Wiskott-Aldrich syndrome Hemophagocytic lymphohistiocytosis Inborn errors of metabolism Epidermolysis bullosa Severe congenital neutropenia Shwachman-Diamond syndrome Diamond-Blackfan anemia Leukocyte adhesion deficiency HSCT-related morbidity and mortality Complications associated with HSCT include both early and late effects. Early-onset (...) leukemia Chronic lymphocytic leukemia Myeloproliferative disorders Myelodysplastic syndromes Non-Hodgkin lymphoma Hodgkin lymphoma Pure red cell aplasia Paroxysmal nocturnal hemoglobinuria major (SCID) Wiskott-Aldrich syndrome Hemophagocytic lymphohistiocytosis (HLH) Inborn errors of metabolism - Eg, mucopolysaccharidosis, Gaucher disease, metachromatic leukodystrophies, and adrenoleukodystrophies Epidermolysis bullosa Severe congenital neutropenia Shwachman-Diamond syndrome Diamond-Blackfan anemia

2014 eMedicine Pediatrics

107. Hematopoietic Stem Cell Transplantation (Diagnosis)

Aplastic anemia Pure red-cell aplasia Paroxysmal nocturnal hemoglobinuria Fanconi anemia Thalassemia major Sickle cell anemia Severe combined immunodeficiency (SCID) Wiskott-Aldrich syndrome Hemophagocytic lymphohistiocytosis Inborn errors of metabolism Epidermolysis bullosa Severe congenital neutropenia Shwachman-Diamond syndrome Diamond-Blackfan anemia Leukocyte adhesion deficiency HSCT-related morbidity and mortality Complications associated with HSCT include both early and late effects. Early-onset (...) leukemia Chronic lymphocytic leukemia Myeloproliferative disorders Myelodysplastic syndromes Non-Hodgkin lymphoma Hodgkin lymphoma Pure red cell aplasia Paroxysmal nocturnal hemoglobinuria major (SCID) Wiskott-Aldrich syndrome Hemophagocytic lymphohistiocytosis (HLH) Inborn errors of metabolism - Eg, mucopolysaccharidosis, Gaucher disease, metachromatic leukodystrophies, and adrenoleukodystrophies Epidermolysis bullosa Severe congenital neutropenia Shwachman-Diamond syndrome Diamond-Blackfan anemia

2014 eMedicine.com

108. Pyruvate Carboxylase Deficiency (Diagnosis)

the following: Lactic acidosis Metabolic acidosis Fatty acid beta-oxidation deficiencies Leigh encephalopathy Pyruvate dehydrogenase complex deficiency Phosphoenolpyruvate carboxykinase deficiency 2-Ketoglutarate dehydrogenase deficiency Dihydrolipoamide dehydrogenase deficiency Fumarase deficiency Previous Next: Lab Studies and Histologic Findings Lactate and pyruvate levels High blood lactate and pyruvate levels with or without lactic aciduria suggests an inborn error of energy metabolism. An increased (...) ) scans. Most patients with the type A pyruvate carboxylase deficiency live into adulthood but have global neurologic and cognitive dysfunction. Previous Next: Patient History Patient history in pyruvate carboxylase (PC) deficiency is characterized as follows: Birth - Low and an infant small for dates are nonspecific signs of a metabolic disturbance during gestation General - Development of poor feeding, vomiting, and lethargy are nonspecific, but common, symptoms of metabolic illnesses; symptoms can

2014 eMedicine.com

109. Pellagra (Diagnosis)

, which can, as well, be considered an alcoholism indicator. [ ] Clinical manifestations of pellagra are a less sensitive indicator than biochemical niacin deficiency in carcinoid patients with carcinoid syndrome. Occasionally, an abortive form called pellagroid (eg, erythema pellagroids, pseudopellagra) is present. Hartnup syndrome is an inborn error of tryptophan metabolism. In addition, the use of isoniazid is known to cause the symptoms of pellagra, as does the long-term administration of 5 (...) induces a pellagralike state; plasma tryptophan levels are decreased in patients with HIV infection. High-dose nicotinamide treatment may successfully reverse this HIV-induced metabolic abnormality. Niacin is proposed to be a secondary preventive factor of AIDS in patients with HIV infection. [ , , ] Next: Pathophysiology Pellagra is the late stage of severe niacin deficiency. Niacin, or vitamin B-3, is a water-soluble vitamin. In 1926, Goldberger reported that nicotinamide was a preventive factor

2014 eMedicine.com

110. Lactic Acidosis (Diagnosis)

is secondary to inborn errors of metabolism, such as defects in gluconeogenesis, pyruvate dehydrogenase, the tricarboxylic acid (TCA) cycle, or the respiratory chain. These disorders generally reflect situations in which the disposal of pyruvate by biosynthetic or oxidative routes is impaired. Lactic acidosis may not necessarily produce acidemia in a patient. The development of lactic acidosis depends on the magnitude of hyperlactatemia, the buffering capacity of the body, and the coexistence of other (...) in association with systemic disease, such as renal and hepatic failure, diabetes and malignancy. [ ] Type B2 is caused by several classes of drugs and toxins, including biguanides, alcohols, iron, isoniazid, zidovudine, and salicylates. [ ] Type B3 is due to inborn errors of metabolism. Within these categories, septic shock may move from type A to type B, as the initial presentation is often associated with hypoperfusion, and with aggressive fluid resuscitation little evidence of tissue hypoperfusion exists

2014 eMedicine.com

111. Hyperkalemia (Diagnosis)

and therapeutic implications. Heart . 2003 Apr. 89(4):e14. . . New MI. Inborn errors of adrenal steroidogenesis. Mol Cell Endocrinol . 2003. 211:75-83. . White PC. Aldosterone synthase deficiency and related disorders. Mol Cell Endocrinol . 2004. 217:81-87. . Sartorato P, Khaldi Y, Lapeyraque AL, et al. Inactivating mutations of the mineralocorticoid receptor in Type I pseudohypoaldosteronism. Mol Cell Endocrinol . 2004 Mar 31. 217(1-2):119-25. . Geller DS, Rodriguez-Soriano J, Vallo Boado A, Schifter S (...) Urine potassium, sodium, and osmolality Complete blood count (CBC) Metabolic profile If the BUN and serum creatinine levels suggest renal insufficiency, using the MDRD or CKD-EPI equation to determine the estimated glomerular filtration rate (eGFR) is recommended. [ ] Chronic kidney disease alone generally will not cause hyperkalemia until the eGFR is less than 20-25 mL/min. Depending on the clinical findings and the results of the above laboratory work, the following may be indicated: Glucose level

2014 eMedicine.com

112. Prenatal Diagnosis for Congenital Malformations and Genetic Disorders (Diagnosis)

biopsies, including liver and muscle biopsy Case reports have described fetal liver biopsy to diagnose an inborn error of metabolism, such as ornithine transcarbamylase deficiency, [ ] glucose-6-phosphatase deficiency, [ ] glycogen storage disease type IA, nonketotic hyperglycemia, [ ] and carbamoyl-phosphate synthetase deficiency. [ ] Fetal muscle biopsy has also been described to analyze the muscle fibers histochemically for prenatal diagnosis of Becker-Duchenne muscular dystrophy (...) (10):763-8. . Mathis J, Raio L, Baud D. Fetal laser therapy: applications in the management of fetal pathologies. Prenat Diagn . 2015 Jul. 35 (7):623-36. . Galjaard H. Fetal diagnosis of inborn errors of metabolism. Baillieres Clin Obstet Gynaecol . 1987 Sep. 1(3):547-67. . Burton BK, Schulz CJ, Burd LI. Limb anomalies associated with chorionic villus sampling. Obstet Gynecol . 1992 May. 79(5 (Pt 1)):726-30. . Wang BB, Rubin CH, Williams J 3rd. Mosaicism in chorionic villus sampling: an analysis

2014 eMedicine.com

113. Argininosuccinate Lyase Deficiency (Diagnosis)

acid metabolism. Low-level synthesis of certain cycle intermediates in extrahepatic tissues makes a small contribution to waste nitrogen disposal. A portion of the cycle is mitochondrial in nature; mitochondrial dysfunction may impair urea production and may result in hyperammonemia. Overall, the cycle’s activity is regulated by the rate of synthesis of , the enzyme activator that initiates incorporation of ammonia into the cycle. The rate-limiting step is disposal of waste nitrogen. However (...) characterization. Mol Genet Metab . 2003 Jan. 78(1):11-6. . Saudubray JM, Rabier D. Biomarkers identified in inborn errors for lysine, arginine, and ornithine. J Nutr . 2007 Jun. 137(6 Suppl 2):1669S-1672S. . Stadler S, Gempel K, Bieger I, et al. Detection of neonatal argininosuccinate lyase deficiency by serum tandem mass spectrometry. J Inherit Metab Dis . 2001 Jun. 24(3):370-8. . Steiner RD, Cederbaum SD. Laboratory evaluation of urea cycle disorders. J Pediatr . 2001 Jan. 138(1 Suppl):S21-9. . Stephenne X

2014 eMedicine Pediatrics

114. Arginase Deficiency (Diagnosis)

arginase activity, whereas type II is inducible and found in extrahepatic tissues. The disease is caused by a deficiency of arginase type I in the liver. Next: Pathophysiology The hepatic urea cycle is the major route for waste nitrogen disposal, which is chiefly generated from protein and amino acid metabolism. Low-level synthesis of certain cycle intermediates in extrahepatic tissues also makes a small contribution to waste nitrogen disposal. A portion of the cycle takes place in mitochondria (...) . 2004 Nov. 24(11):857-60. . Picker JD, Puga AC, Levy HL, et al. Arginase deficiency with lethal neonatal expression: evidence for the glutamine hypothesis of cerebral edema. J Pediatr . 2003 Mar. 142(3):349-52. . Qureshi IA, Letarte J, Ouellet R, Batshaw ML, et al. Treatment of hyperargininemia with sodium benzoate and arginine- restricted diet. J Pediatr . Mar 1984. 104(3):473-6. . Saudubray JM, Rabier D. Biomarkers identified in inborn errors for lysine, arginine, and ornithine. J Nutr . 2007 Jun

2014 eMedicine Pediatrics

115. Anemia, Megaloblastic (Diagnosis)

and certain rare inborn errors such as thiamine-responsive megaloblastic anemia, [ , ] Lesch-Nyhan syndrome, and hereditary orotic aciduria (see Etiology). Treatment of megaloblastic anemia depends on the underlying cause. Supplemental folate or vitamin B-12 may be indicated (see Treatment). Go to , , , , and for complete information on these topics. Vitamin B-12 deficiency Vitamin B-12 is commonly ingested with meat or fish. It binds to salivary haptocorrins, which are digested in the stomach, allowing (...) allow neurologic damage to progress. Folate deficiency Folate is ingested in the diet in many different types of food. It enters the enterocyte and is transported into the portal circulation by a carrier molecule. It circulates in the plasma mostly as 5-methyl tetrahydrofolate (THF). It enters the cell via a carrier (methotrexate competes with this carrier). In the cell, folate binds to and acts as a coenzyme with enzymes responsible for single carbon metabolism. Folate deficiency can be caused

2014 eMedicine Pediatrics

116. White Blood Cell Function (Overview)

myeloblast precursor. This change indicates a heavily anaerobic metabolism. Primary granules contain myeloperoxidase, arginine-rich (cationic) proteins, lysozymes with a bactericidal function, sulfated mucopolysaccharides, acid phosphatases, proteases, and hydrolases, among other contents. Microperoxisomes that contain catalase are also present at the promyelocytic stage of development. The myelocyte represents the next stage. This cell is smaller and rounder than its predecessor, with a smaller Golgi (...) apparatus and endoplasmic reticulum. Glycogen appears at this stage and serves as a glucose store that the hexose monophosphate shunt can directly oxidize. These changes indicate an increase in the amount of cellular anaerobic metabolism. Secondary granules appear at this stage of development. Contents of secondary granules include collagenase and lysozyme. The secondary granules do not contain peroxidase. The production of primary granules ceases during the myelocyte stage of development. Appearance

2014 eMedicine Pediatrics

117. Infections in the Immunocompromised Host (Follow-up)

, joint, peritoneal, wound, or ventricular access or drainage devices Internal foreign bodies [ ] Major surgery [ ] Treatment For leukemia or lymphoma Bone marrow or stem-cell transplantation Solid organ transplantation [ ] Therapy for autoimmune or inflammatory disorders TNF-alpha inhibitors [ ] Monoclonal antibodies and related small molecules Transfusion (which may lead to iron overload) Previous Next: Alternate Diagnoses Table. Differential Diagnoses Previous Next: Infections In general (...) , [ ] histoplasmosis, [ ] Listeria infection, [ ] and severe falciparum malaria. [ ] Other monoclonal antibodies and related small molecules have been associated with numerous infections. [ ] For example, therapy with eculizumab, a C5 inhibitor, is associated with invasive meningococcal infection. Similarly, treatment with natalizumab (for multiple sclerosis) is associated with progressive multifocal leukoencephalopathy. [ , ] Treatment with infliximab has been associated with disseminated cutaneous varicella

2014 eMedicine Pediatrics

118. Hematopoietic Stem Cell Transplantation (Follow-up)

Aplastic anemia Pure red-cell aplasia Paroxysmal nocturnal hemoglobinuria Fanconi anemia Thalassemia major Sickle cell anemia Severe combined immunodeficiency (SCID) Wiskott-Aldrich syndrome Hemophagocytic lymphohistiocytosis Inborn errors of metabolism Epidermolysis bullosa Severe congenital neutropenia Shwachman-Diamond syndrome Diamond-Blackfan anemia Leukocyte adhesion deficiency HSCT-related morbidity and mortality Complications associated with HSCT include both early and late effects. Early-onset (...) leukemia Chronic lymphocytic leukemia Myeloproliferative disorders Myelodysplastic syndromes Non-Hodgkin lymphoma Hodgkin lymphoma Pure red cell aplasia Paroxysmal nocturnal hemoglobinuria major (SCID) Wiskott-Aldrich syndrome Hemophagocytic lymphohistiocytosis (HLH) Inborn errors of metabolism - Eg, mucopolysaccharidosis, Gaucher disease, metachromatic leukodystrophies, and adrenoleukodystrophies Epidermolysis bullosa Severe congenital neutropenia Shwachman-Diamond syndrome Diamond-Blackfan anemia

2014 eMedicine Pediatrics

119. White Blood Cell Function (Diagnosis)

myeloblast precursor. This change indicates a heavily anaerobic metabolism. Primary granules contain myeloperoxidase, arginine-rich (cationic) proteins, lysozymes with a bactericidal function, sulfated mucopolysaccharides, acid phosphatases, proteases, and hydrolases, among other contents. Microperoxisomes that contain catalase are also present at the promyelocytic stage of development. The myelocyte represents the next stage. This cell is smaller and rounder than its predecessor, with a smaller Golgi (...) apparatus and endoplasmic reticulum. Glycogen appears at this stage and serves as a glucose store that the hexose monophosphate shunt can directly oxidize. These changes indicate an increase in the amount of cellular anaerobic metabolism. Secondary granules appear at this stage of development. Contents of secondary granules include collagenase and lysozyme. The secondary granules do not contain peroxidase. The production of primary granules ceases during the myelocyte stage of development. Appearance

2014 eMedicine Pediatrics

120. EPI-743 in Friedreich's Ataxia Point Mutations

bleeding condition or abnormal PT/PTT INR (INR > two; PTT > two-times normal). Liver insufficiency with LFTs greater than three-times upper normal limit at screening. Renal insufficiency with creatinine > 1.5 at screening. Fat malabsorption syndromes. Any other respiratory chain diseases of the mitochondria or inborn errors of metabolism. Any other ophthalmologic conditions. Clinically significant cardiomyopathy with ejection fraction < 40 percent at screening. Clinically significant arrhythmia within (...) in Friedreich's Ataxia Patients With Point Mutations Study Start Date : October 2013 Actual Primary Completion Date : June 2016 Actual Study Completion Date : June 2016 Resource links provided by the National Library of Medicine related topics: related topics: resources: Arms and Interventions Go to Arm Intervention/treatment Experimental: EPI-743 EPI-743, oral, 400mg three times daily for 3 months Drug: EPI-743 EPI-743 (alpha-tocotrienol quinone) is a small molecule therapeutic that was rationally designed

2013 Clinical Trials

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