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Metabolic Errors

Stack #176538

QuestionAnswer
Three functions of metabolism Obtaining energy from food, breakdown and detoxification of waste products, synthesis and breakdown of complex molecules
Pathogenesis intoxications, acute or progressive, accumulation of toxic compounds, problems of energy metabolism
Pathogenesis symptoms from deficiency in energy production or utilization, problems of complex molecules
Pathogenesis disturbed synthesis or catabolism, symptoms are permanent and progressive
Inheritance autosomal recessive
Exceptions in inheritance x-linked recessive ornithine transcarbamylase (OTC), Hunter syndrome
Clinical presentation patterns uncommon to note defects at birth, symptom free period, early and late signs
Early signs energy deficits, toxic products, obtundation, vomiting, seizures, brain damage
Late signs Accumulated material, cell damage, seizures, brain damage
Typical signs and symptoms very nonspecific, depends on genetic defect and environment
late adult onset signs are variable
New born Screening Intoxications Amino acid disorders (some), Organic acidurias, Some urea cycle defects
Newborn screening energy metabolism defects fatty acid oxidation defects
NOT identified on Newborn Screening Complex molecule defects, Glycogen metabolism defects, Congenital lactic acidosis, Mitochondrial defects
Amino acid and organic acid metabolism disorders Group of inherited disorders involved in the catabolism of selected amino acids and other compounds. Individually rare. Varied presentations
Clinical features of amino acid and organic acid metabolism disorders Acute presentation, neurological signs, Insidious onset, missing milestones- PKU, chronic skin problems, abnormality of routine labs
Acute presentation MSUD (maple syrup urine disease), Either in neonatal period or later in life, May be recurrent problem
Clinical features of amino acid and organic acid metabolism disorders Neurological signs Seizures, Mental retardation, Ataxia, Abnormal tone
Clinical features of amino acid and organic acid metabolism disorders Abnormality of routine labs Anion gap metabolic acidosis, Hypoglycemia, Hyperammonemia
Amino acid and organic acid metabolism disorders Diagnosis Screening for specific organic acids detected by chromatography or mass spectrometry, Abnormal amino acid levels in the blood and/or urine, Enzyme (or other biochemical) testing based on screening test results
Amino acid and organic acid metabolism disorders Treatments vary Low protein diet, Special formula without offending amino acids, Vitamins or cofactors
Amino acid and organic acid metabolism disorders Phenylketonuria (PKU) Prototype for screening and management, Phenylalanine (Phe) is an essential amino acid, most common disorder of amino acid metabolism, caused by deficiency of hepatic phenylalanine hydroxylase, which converts phenylalanine to tyrosine
other disorders with elevated plasma phenylalanine hyperphenylalaninemia and disorders of pteridine biosynthesis resulting in deficient cofactor levels
PKU Clinical features if untreated, mental retardation, seizures, autism, microcephaly, decreased skin pigmentation, musty odor
PKU Laboratory findings/diagnosis high serum phenylalanine > 20 mg/dl (normal <2 mg/dl), low serum tyrosine, Classic PKU has normal pteridine cofactor.
PKU Newborn screening Blood spots on filter paper. Tandem mass spectrometry to quantitate amount of Phe present
PKU Treatment low phenylalanine diet for life; if started early in infancy, can prevent significant mental retardation
PKU Inheritance autosomal recessive, chromosome 12q
Maternal PKU teratogenic effects on fetus from elevated maternal, phenylalanine (microcephaly 73%; congenital heart disease 12-15%; low birth weight 40-50%; mental retardation 70-90%)
Carbohydrate disorders Galactosemia Etiology caused by deficiency of galactose-1-phosphate uridyltransferase (GALT), which in turn causes an increase in galactose and galactose-1-phosphate. Less common forms of galactosemia caused by galactokinase and epimerase deficiencies
Galactosemia Incidence 1/30,000 - 1/100,000
Galactosemia Clinical features vomiting and diarrhea in 1st weeks of life, liver disease with jaundice can progress to failure, cataracts, sepsis E.coli
Galactosemia Diagnosis newborn screening- direct enzyme assay of RBCs, florumetic determination of enzyme amount
Galactosemia Treatment galactose/lactose-free diet (soy formula)
Urea cycle disorders Six enzyme deficiencies
Urea cycle disorders N-acetyl-glutamate synthetase deficiency (NAGS)
Urea cycle disorders Carbamoylphosphate synthetase deficiency (CPS),
Urea cycle disorders Ornithine transcarbamylase deficiency (OTC),
Urea cycle disorders Argininosuccinic synthase deficiency (Citrullinemia)
Urea cycle disorders Argininosuccinic lyase deficiency (ASA)
Urea cycle disorders Arginase deficiency (Argininemia)
Urea cycle disorders Symptoms caused by deficiency of enzymes in the urea cycle, which metabolizes waste nitrogen (ammonia) formed from protein turnover or ingestion. High ammonia results in toxicity to the CNS.
urea cycle disorders Diagnosis hyperammonemia, increased glutamine and elevated or decreased citrulline and arginine on serum amino acids, with some abnormalities on urine organic acids.
urea cycle Clinical features lethargy, poor feeding, vomiting, coma and death
urea cycle disorders Ornithine transcarbamylase (OTC) deficiency 2nd enzyme in the urea cycle; catalyzes carbamyl phosphate + ornithine to form citrulline OTC inheritance
OTC Untreated coma and cerebral edema and death, Outcome depends on how long patient with elevated ammonia.
OTC Treatment low protein diet, medications for alternative pathways for nitrogen removal; arginine or citrulline
• Fatty acid oxidation primary source of energy for skeletal and cardiac muscle during fasting. Provides ketone bodies rather than glucose.
• Oxidation in the mitochondria mediated by acyl-CoA dehydrogenases in progressive shortening of the fatty acid chain
• Fatty acid oxidation disorders Clinical features hypoglycemia with fasting or increased metabolic demands; cardiomyopathy may occur; may present as sudden death
• Fatty acid oxidation disorders Diagnosis urine organic acids, plasma acylcarnitine profile- some detected on NBS with tandem mass spectrometry
• Fatty acid oxidation disorders Inheritance autosomal recessive
Medium-chain acyl-CoA dehydrogenase deficiency (MCAD) most common of fatty acid oxidation disorders, peak symptoms at 4-24 months of age, contributes to SIDS cases, treatment=avoid fasting, avoid medium chain fats
Glycogen metabolism defects in making or breaking down glycogen
Glycogen metabolism: Nine different diseases caused by various enzyme defects in the glycogen pathway Symptoms arise from inability to utilize glycogen for energy=hypoglycemia; storage of glycogen in cells=toxic to cells
Mitochondrial metabolism defects Defect in the respiratory chain pathway; • Variable presentation with variable age of onset
Mitochondrial metabolism defects Unable to convert glucose, fat or protein to ATP
Mitochondrial metabolism defects Inheritance autosomal recessive or mitochondrial
Lysosomal storage diseases Lysosomes are cytoplasmic organelles which have enzymes with phagocytic (degradative) function of macromolecules
Lysosomal storage diseases These disorders result in accumulation of macromolecules in target organs (mucopolysaccharides, glycoproteins, various lipids)
Lysosomal storage diseases Include the broad categories of disorders= mucopolysaccharidoses, oligosaccharidoses, gangliosidoses (or sphingolipidoses) and related lipid storage diseases
Lysosomal storage diseases Inheritance recessive, most autosomal (X-linked - Hunter syndrome, Fabry disease)
• Lysosomal storage diseases Clinical features Mostly normal at birth, Regression in development is key finding, All disorders are progressive and most are fatal.
Lysosomal storage diseases Mucopolysaccharidoses (MPS) 10 known enzyme deficiencies produce 6 distinct MPS disorders.
Lysosomal storage diseases Examples Hurler, Hunter and Sanfilippos syndromes
Mucopolysaccharidoses (MPS) share similar clinical features
Lipid storage diseases Tay-Sachs disease affecting primarily the CNS; caused by molecular defects, which result in deficiency of Hexosaminidase A in α subunit, on chromosome 15. Results in accumulation of GM2 gangliosides in neurons.
Tay-Sachs High incidence in Jewish population, no treatment
Lipid storage diseases Tay-Sachs disease Clinical features classic infantile form - normal at birth; onset at 6-12 months; loss of milestones; exaggerated startle response; motor weakness; apathy; cherry red spot in the retina; later onset of seizures, blindness, spasticity and death by age 2-5 years
Lipid storage diseases Tay-Sachs disease Inheritance autosomal recessive
Lipid storage diseases Tay-Sachs disease Diagnosis enzyme assay; DNA in high risk population ~40- 50% of obligate carriers can be identified by mutation detection
Lipid storage diseases Tay-Sachs disease Prevention heterozygote screening by enzyme assay of high risk populations has led to a marked decrease in the disease frequency in those populations
Steroid Biosynthetic Disorders Steroid hormone abnormalities, Mineralocorticoid, glucocorticoid, sex steroid pathways interlinked
Steroid Biosynthetic Disorders Varied effects ambiguous genitalia to life threatening electrolyte disturbances.
Steroid Biosynthetic Disorders example Congenital adrenal hyperplasia, Several forms, 21-hydroxylase (CYP21) deficiency is most common.
Steroid Biosynthetic Disorders example Congenital adrenal hyperplasia expressed in the adrenal cortex, produces cortisol
Steroid Biosynthetic Disorders example Congenital adrenal hyperplasia Lab findings show increases in cortisol precursors, which then flux through other steroid synthetic enzyme pathways, including androgen production. See a decrease in cortisol production
Steroid Biosynthetic Disorders example Congenital adrenal hyperplasia affect on males Males severely affected have salt-wasting variety. Present in adrenal crisis.
Steroid Biosynthetic Disorders example Congenital adrenal hyperplasia affect on females Female severely affected are detected earlier with ambiguous genitalia in addition to cortisol deficiency.
Steroid Biosynthetic Disorders example Congenital adrenal hyperplasia Less severe forms have virilization only, or just signs of mild androgen excess in females.
Steroid Biosynthetic Disorders example Congenital adrenal hyperplasia Treatment provide patient with cortisol
Hypercholesterolemia / hypertriglyceridemia Lipid disorder
α1- Antitrypsin Protein disorder; Liver accumulation of abnormal protein, lung damaged because of deficiency of enzyme action; results in too much protease activity
Hemachromatosis metal cofactors; excessive absorption of iron leads to serious overload as an adult.
Created by: knpearso on 2008-11-14



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