Metabolic Disorders Flashcards
The incidence of metabolic disorders is ________
1:2000
When do most metabolic disorders present?
48h
Family history concerning for M.D.:
Undiagnosed neonatal death
Neurologic deterioration
Multiple miscarriages
Consanguinity
Clinical signs of M.D.:
Poor feeding/vomiting Lethargy, seizures, poor tone Cardiomegaly Hepatosplenomegaly Dysmorphic features Cataracts Developmental delay, FTT
Infants with a progressive asymptomatic-> ill course likely have a ____ M.D.
Intoxication, build up of metabolic byproducts
- Organic acidemia
- Urea cycle defect
Infants who present immediately after birth with a profoundly abnormal neuro exam most likely have a M.D. marked by ______
Energy deficiencies
- Mitochondrial disorder
- Nonketotic hyperglycinemia
Lab workup for M.D should include
Glucose Electrolytes ABG LFT's Bilirubin UA Ammonia Urine reducing substances Urine organic acids/Serum amino acids
Absence of ______________ causes galactosemia
Galactose-1-phosphate-uridyltransferase
Absence of __________ causes galactokinase deficiency.
Patients have ________
Galactokinase
Cataracts
Galactosemia is _________ inheritance pattern
autosomal recessive
Galactosemia presents
after feedings introduced poor feeding, vomiting lethargy jaundice hepatomegaly liver failure renal tubular dysfunction
The metabolic disorder associated with recurrent E coli infection is
Galactosemia
Labs in galactosemia are
Elevated LFT’s
Galactosuria (reducing substances)
Hyperchloremic metabolic acidosis
Findings of cataracts with increased glucose, increased urine reducing substances, and low blood galactokinase activity suggest
Galactokinase deficiency
Glycogen storage diseases found in infants include
Von Gierke, type 1
Pompe, type 2
Glycogen storage diseases affect the metabolism from
UDP (urine-diphospho-glucose)
To
Glycogen+ glucose
Type 1 /von Gierke glycogen storage disease is a defect in
Glucose 6 phosphatase
Von Gierke, type 1 glycogen storage disease causes
Lactic acidosis, low glucose due to inability to convert glucose 6 phosphate to glycogen / glucose
Type 2, Pompe disease is a defect in
Lysosomal alpha glucosidase
Type 2 glycogen storage disease, Pompe, causes
Cardiomegaly
CHF
No affect on glucose or anaerobic function
Glycogen storage disease should be managed with
Support euglycemia, avoid glycogenolysis Liver transplant (residually type 4)
Fructosemia is inherited ______ and caused by ________
Autosomal recessive
Defect in fructokinase or fructose-1-phosphate aldolase
Intake of ____, _____ , or _____ can cause clinical fructosemia
Sucrose
Fructose
Sorbitol
Labs in fructosemia are
Hypoglycemia (blocked glycogenolysis)
Absent fructose 1 phosphate aldolase
Abnormal LFT’s
Defect enzymes in fructosemia block metabolism of ____ to ______
Fructose To Fructose 1 phosphate To Glyceraldehyde+ dihydroxyacetone
Deficiency of ________ causes low orotic acid
N acetylglutamate synthetase
Deficiency of _______ causes congenital hyperammonemia type 1.
Carbamyl phosphate synthetase
Autosomal recessive
Deficiency of _______ causes congenital hyperammonemia type 2
ornithine carbamyl transferase
X lined recessive
Extremely elevated urine orotic acid
Deficiency of ________ causes citrullinemia
Arginosuccinic acid synthetase
Deficiency of _______ causes arginosuccinic aciduria
Arginosuccinic aciduria
Autosomal recessive
Arginosuccinic aciduria is inherited
Autosomal recessive
Deficiency of _______ causes argininemia
Arginase
Autosomal recessive
Spastic diplegia, orotic aciduria
Severe hyperammonemia and respiratory alkalosis suggests
Urea cycle defects
Elevated glutamine and alanine are found in
N acetylglutamate synthetase deficiency
Carbamyl phosphate synthetase deficiency
________ deficiency has elevated glutamine, alanine, orotic acid, citrulline, and arginine
Arginase
Argininemia
_______ and _______ have elevated ____, ____, and _____ but low _______
Glutamine
Alanine
Citrulline
Arginine
_______ and _______ have elevated ____, ____, and _____ but low _______
Arginosuccinic lyase
Arginosuccinic acid synthetase
Glutamine
Alanine
Citrulline
Arginine
Citrulline supplementation should be given to patients with
Carbamyl phosphate synthetase
Ornithine carbamyl transferase
N acetylglutamate synthetase
Increased leucine, valine and isoleucine indicate
Maple syrup urine disease
MSUD is inherited
Autosomal recessive
MSUD is caused by
Thiamine deficiency for ketoacid dehydrogenases
Cognitive outcomes of MSUD are based on
Plasma leucine levels
Phenylketonuria is inherited _____ and due to _____
Autosomal recessive
Phenylalanine hydroxylase deficiency
Labs in phenylketonuria are
Elevated phenylalanine
Decreased tyrosine
A defect in _____ can mimic classic PKU
Tetrahydrobiopterin
Classic PKU is diagnosed by
Newborn screen ^ phenylalanine
Phenylpyruvic acid in urine
Pterin defect PKU is diagnosed by
Dihydrobiopterin reductase in RBC’s
Elevated phenylalanine with elevated tyrosine is
Transient tyrosinemia
Fumarylacetoacetate hydrolase deficiency causes
Tyrosinemia
Blood and urine succinylacetone indicates
Maple syrup urine disease
Severe liver disease with albinism and fanconi syndrome is
Maple syrup urine disease
Labs in MSUD are
Increased tyrosine, urinary fumarylacetoacetate, methionine
Normal phenylalanine
MSUD is treated with
Nitisinone
Homocystinuria can be caused by either
Defect in betaine-methyltransferase/methyltetrahydrofolate-homocysteine methyltransferase —> low methionine
OR
cystathionine synthetase deficiency
The most common cause of homocysteinuria is _____ and can mimic _____
Cystathionine synthetase deficiency
Marfan’s (except with joint decreased movement)
Labs in homocysteinuria are
Elevated methionine
Elevated homocysteinuria
+Nitroprusside test
Decreased cystathionine synthetase levels in skin
Homocystinuria is treated with
High pyridoxine supplement
Limit methionine, increase cysteine/folate in diet
A defect in the glycine cleavage pathway causes
Nonketotic hyperglycinemia
Defective conversion of glycine to ammonia
Nonketotic hyperglycinemia is inherited _____ and prognosis is ______
Autosomal recessive
Very poor, high risk of death in first few weeks
A metabolic disorder associated with agenesis of the corpus collosum is
Nonketotic hyperglycinemia
Labs in nonketotic hyperglycinemia are
Elevated glycine
No ketoacidosis
Nonketotic hyperglycinemia is treated with
Sodium benzoate
Diazepam sectionalism
Dextromethorphan
Histidine deficiency causes
Histidinemia
Autosomal recessive
Benign-> mild delays
Blue green urine when combined with ferric chloride
Cystinuria is
Autosomal recessive
Amino acid transport defect–> cysteine deficiency
Urolithiasis, nitroprusside shows cysteine in urine
Rx: methionine restriction, urine alkalinization, d-penicillamine
Lysine, arginine, ornithine deficiency due to amino acid transport defect is
Lysinuric protein intolerance
Lysinuric protein intolerance presents when
Infants diet begins to include protein
Labs in lysinuric protein intolerance are:
Treated with:
Hyperammonemia
High lysine in urine/low lysine in plasma
Rx: citrulline, glucose energy, sodium benzoate, sodium phenylacetate
Decreased tryptophan due to defective amino acid transport is
Hartnup disease
The cause of ‘blue diaper syndrome’ is
Blue colored urine due to abnormal intestinal tryptophan transport
Deficient isovaleryl-CoA dehydrogenase causes
isovaleric acidemia
Isovaleric acidemia causes
Buildup of leucine, urine isovalerylglycine and isovaleric acid
Diagnosis of isovaleric acidemia
Decreased isovaleryl-CoA dehydrogenase activity in skin
Sweaty feet odor
Defective function of isovaleryl-CoA dehydrogenase due to biotin deficiency causes
3-methylcrotonyl glycinuria
Both isovaleric acidemia and 3-methycrotonyl glycinuria can be treated with
Glycine
Carnitine
3-methylcrotonyl glycinuria: biotin
Propionic acidemia is caused by
Autosomal recessive deficiency of propionyl -CoA carboxylase
Methylmalonyl-CoA isomerase deficiency causes
Methylmalonic acidemia
Both ketotic hyperglycinemia, propionic acidemia and methylmalonic acidemia, have required cofactors _____ and ______ for enzymes to function.
Biotin : propionyl -CoA carboxylase
Cobalamin : Methylmalonyl-CoA isomerase
Labs in both ketotic hyperglycinemia are
Ketoacidosis Hyperglycinemia Hypoglycemia Hyperammonemia Elevated blood and urine acylcarnitines
Treat both ketotic hyperglycinemias (propionic acidemia and methylmalonic acidemia) with
Cofactor replacement
Limit amino acid methionine, threonine, valine, leucine
Antibiotics to reduce intestinal flora
Carnitine
Defective mevalonate kinase causes
Mevalonic aciduria–>
Dysmorphic features
Cataracts
Increased creatine kinase, LFT’s, mevalonic acid
Mevalonic aciduria can be treated with
Ubiquinone
High cholesterol diet
Steroids during acute crisis
Glutaryl-CoA dehydrogenase deficiency causes
Glutaric aciduria type 1
Mitochondrial enzyme
Cofactor: riboflavin
Decompensation following an infection with macrocephaly, neuro symptoms and hepatic dysfunction suggests
Glutaric aciduria type 1
Glutaric aciduria type 1 labs are
Hypoglycemia Hyperammonemia Elevated urine glutaric avoid Carnitine deficiency Low Glutaryl-CoA dehydrogenase activity
Imaging: frontotemporal atrophy
Glutaric aciduria type 1 is treated with
Carnitine
Riboflavin
Low protein diet (Low lysine and tryptophan)
Hypoketotic hypoglycemia is caused by
Hydroxymethylglutaryl-CoA lyase deficiency
Avoid fasting
Fatty acid oxidation defects are broadly caused by
Fatty acid acyl CoA dehydrogenases
Hydroxylase-CoA dehydrogenases
Medium chain acyl-CoA dehydrogenase deficiency prevents infants from converting _____ to ______ resulting in
Fat to glucose (fatty acids can’t complete process to acetyl-CoA)
Hypoketotic hypoglycemia
Carnitine deficiency
3-hydroxyacyl CoA dehydrogenase causes
Long chain 3-hydroxylacyl-CoA deficiency
Increased 3-hydroxy-dicarboxylic acid, plasma 3-,hydroxylacyl carnitine and decreased carnitine is diagnostic for
Long chain 3-hydroxyacyl-CoA deficiency
Management of fatty acid oxidation disorders should include
High carbohydrate, low fat diet
Avoid fasting
+/- carnitine
Carnitine is produced from
Lysine
A transport cofactor for long chain FA is
carnitine
Carnitine deficiency is the result of
Failed synthesis from lysine
Defective transport
Excess carnitine depletion due to carnityl ester excretion (propionate and fatty acid defect pathways)
Prematurity +/- TPN
Carnitine deficiency causes
Hypoketotic hypoglycemia
Impaired ketone production
Rx: carnitine supplementation
Multiple acyl-CoA dehydrogenase deficiency causes
Glutaric aciduria type 2
Glutaric aciduria type 2 presents with
Dysmorphic features Cardiomyopathy Sweaty feet Macrocephaly Rocker bottom feet Metabolic acidosis/hypoglycemia Urine organic acid abnormalities
Ann absence of a hydrolytic enzyme with accumulation of cellular material is a
Lysosomal storage disease
The hallmark sign of mucopolysaccharidoses is
Dysostosis multiplex
______ is a pathognomonic sign for lupus storage disease that affects the brain
Macular cherry red spots
The only mucopolysaccharidoses disease with x-linked inheritance (instead of autosomal recessive) is
Type 2, Hunter syndrome
Both Hurler (type 1) and type 2 (Hunter) MPS present around ______ and present with ______
1 year
Coarse features
Short statute
CNS functional loss
Stiff joints
Lipidoses are more likely that MPS to present
In infancy
______ lipidosis disease is more common in Ashkenazi Jewish population
Gaucher 1 and 2
Gaucher disease is caused by
Defect in glucocetebrosidase
Niemann Pick is a ______ disease caused by _____
Lipidosis
Sphingomyelinase
Bone marrow foam cells
Cherry red spots in macula (Lipidosis/Niemann Pick A» B)
Tay Sachs disease is a _____ disease caused by _____
Lipidosis
Defect in hexosaminidase A
*Cherry red macular spots
Profound CNS losses
Defect in B-galactosidase is the cause of _____ that presents with ________
Generalized gangliosidosis/infantile GM 1
Cherry red macular spots
Profound CNS losses
Inclusions in WBC
Metachromatic leukodystrophy is caused by ____ and presents mainly with ______
Arylsulfatase A
Profound CNS losses
Fabry disease is a ______ disease caused by _______
Lipidosis
A-galactosidase
Fabry disease presents with ____ and is the lipidoses inherited
Cloudy cornea
HSM
X-linked
Defect in B-galactosidase causes birth infantile GM 1 and ____ which has ____
Krabbe disease
Optic atrophy
Profound CNS losses
Acid lipase defect causes
Wolman disease–>
Adrenal calcifications
Most lipidoses have pristine CNS effects except
Gaucher 1
Niemann-Pick
Fabry
The lipidoses with cherry red spots present are
Niemann-Pick
Tay Sachs
Infantile GM 1
Gaucher 1 has _____ while Tay Sachs has ______ and Niemann-Pick had _____
HSM
Cherry red spots AND CNS disease
HSM AND cherry red spots AND CNS disease
