Metabolism Flashcards
What does galactokinase do and what results from a deficiency of it?
Converts glucose and galactose to galactose 1-phosphate + UDP glucose; deficiency is galactokinase deficiency where only symptom is cataracts
Galactosemia cause and symptoms
Deficiency of galactose-1-phosphate uridyl transferase (GALT)
Autosomal recessive
Poor feeding, vomiting, jaundice, helatomegaly, liver failure, lethargy, cataracts, E. coli sepsis
Cause of cataracts in galactosemia
Excess galactitol in lens, regress with good control of dietary lactose
Long term consequences of galactosemia
Older children with learning disabilities despite therapy; increased risk of premature ovarian failure even if treated appropriately
Laboratory findings in galactosemia
- Low glucose
- elevated liver function tests, elevated indirect bilirubin
- Decreased coagulation factors
- increased galactose in urine (represented by reducing substances, a positive urine Clinitest but negative clinistix urine test)
- Elevated galactose-1 phosphate
- Hyperchloremic metabolic acidosis due to rental tubular dysfunction
Enzyme in glycogen storage disease type I
Glucose-6-phosphatase (von Gierke’s disease)
Symptoms of glycogen storage disease type I
Lactic acidosis
Low glucose
Neutropenia (and increased risk of infection)
Hepatomegaly
FTT
Bleeding disorder (due to liver dysfunction)
Enzyme affected in type II glycogen storage disease
Lysosomal alpha-1,4-glucosidase (acid maltase)
Symptoms of Pompe’s disease
(Type II glycogen storage disease)
Symmetric severe muscle weakness
Cardiomegaly, CHF
Enzyme in type III glycogen storage disease
Debranching enzyme (alpha-1,6-glucosidase)
Cori disease vs Forbes disease
Symptoms of type III glycogen storage disease
Low glucose, ketonuria, hepatomegaly, muscle fatigue, normal lactate!
Enzyme in type IV glycogen storage disease
Branching enzyme
Symptoms of type IV glycogen storage disease
Cirrhosis beginning at several months of age, hypotonia, muscle weakness; no signs in neonatal period; very poor prognosis-death from liver failure <4 years of age unless liver transplant
Enzyme in type V glycogen storage disease
Muscle phosphorylase (McArdle)
Symptoms of type V glycogen storage disease
Muscle fatigue in adolescence, myoglobinuria with strenuous exercise, arrhythmia from electrolyte abnormalities, no increase in lactate after exercise
Enzyme in type VI glycogen storage disease, affected organ and symtpoms
Liver phosphorylase, liver affected
Mild hypoglycemia, ketonuria
Hepatomegaly
Enzyme in type VII glycogen storage disease, affected organ, and symptoms
Muscle phosphorfructokinase, muscle, muscle fatigue in adolescence
Enzyme in type VIII glycogen storage disease, affected organ, and symptoms
Phosphorylase kinase, liver
Similar to type III but no myopathy
Low glucose, ketonuria, hepatomegaly
What do you have to remove from diet in fructosemia?
Fructose, sucrose (fructose+glucose), and sorbitol (alcohol form of glucose but to use is converted to fructose)
Enzyme deficiency in fructosemia
Fructose 1-phosphate aldolase (aldolase B)
Expressed in liver, intestine, kidney
Symptoms of fructosemia
Vomiting, lethargy, seizures, failure to thrive, liver disease, proximal renal tubular dysfunction
Lab findings in fructosemia
Low glucose, abnormal LFTs, reducing substances in urine
Genetics and pathway affected in OTC deficiency
X-linked recessive
OTC converts carbamyl phosphate to citrulline in the mitochondria
Symptoms and labs in otc deficiency
Extremely elevated urine orotic acid, hyperammonemia, increased glutamine and alanine, decreased citrulline, decreased arginine
Hyperammonemia with normal or low orotic acid, increased glutamine and alanine, decreased citrulline, decreased arginine
Carbamoyl phosphate synthetase deficiency (congenital hyperammonemia type I)
Hyperammonemia, respiratory alkalosis, normal glucose
Urea cycle defects
Why do you have respiratory alkalosis in urea cycle defects
Thought to result from central hyperventilation, because of cerebral edema from hyperammonemia
Brittle hair, very high citrulline, orotic aciduria, decreased arginine
Arginosuccinic acid synthetase deficiency
Only urea cycle defect with high arginine
Argininenia (arginase deficiency, which should convert arginine to urea and ornithine); increased risk of progressive spastic diplegia
Which amino acid needs supplementation in urea cycle disorders
Arginine (except if arginase deficiency)
OTC, carbamoyl synthase, and n-acetylglutamate deficiencies may also need small doses of citrulline
Amino acids in MSUD
Leucine, isoleucine, valine
Ketonuria, hypoglycemia, metabolic acidosis, maple syrup odor
Maple syrup urine disease
What to send if state screen high leucine
Urine ketones
Plasma amino acids
Urine organic acids
Definitive diagnosis of MSUD
Lettie dehydrogenase assay of skin fibroblasts or WBCs (while definitive, not necessary)
Cognitive outcomes correlate with what is MSUD
Plasma leucine concentrations
Management of MSUD
Restrict intake of branched chain amino acids (need some because all at essential), consider thiamine (B1), may require dialysis if severe, avoid protein catabolism
Enzyme deficiency in MSUD
Ketoacid dehydrogenases
What to send if elevated citrulline on state screen
Ammonia, plasma amino acids, urine organic acids
Genetics of phenylketonuria
Autosomal recessive
Mousy or musty odor, severe mental deficiency, seizures, microcephaly, hypertonia, hypopigmentation
Phenylketonuria
Enzyme and reaction in phenylketonuria
Phenylalanine hydroxylase, converts phenylalanine to tyrosine
What to send if elevated phenylalanine on state screen
Plasma amino acids
Presentation of tyrosinemia I
Failure to thrive, acute liver, disease, or chronic liver disease, leading to cirrhosis, increased risk of rickets and cardiomyopathy, increased risk of hepatic malignancy later in life may also have renal tubular dysfunction, presenting with Fanconi syndrome
Enzyme involved in and typical laboratory findings in tyrosinemia I
Femarylacetoacetate hydrolase deficiency
Elevated tyrosine and elevated succinylacetone
Ocular lesions, skin lesions, neurological abnormalities
Tyrosinemia II
Treatment for tyrosinemia I
Diet low in tyrosine and phenylalanine, nitisinone (NTBC), which prevents breakdown of phenylpyruvate
Genetics of homocysteinuria
Autosomal recessive
Downward dislocated lens, osteoporosis, scoliosis, increased risk of fractures, tall stature, arachnodactyly, decreased joint mobility, developmental delay, seizures, increased risk of large thromboses and increased risk of bleeding
Homocysteinuria
What to send if elevated or decreased methionine on state screen
Plasma amino acids
Plasma homocysteine
Plasma methylmalonic acid
Most common cause of homocysteinuria
Cystathionine beta-synthase deficiency (requires B6 for enzyme to work); converts homocysteine to cystathionine
Management of cystathionine synthase deficiency
Administer high amounts of pyridoxine (B6), supplement B12 and folate, decrease methionine in diet, supplement with cysteine, consider vitamin C to improve endothelial function, antithrombotic agents may be need if poorly controlled
Lethargy, profound CNS deterioration with hypotonia, seizures, coma, respiratory depression, hiccups; most in 48 hours
Non-ketotic hyperglycinemia
Autosomal recessive, results from a defect in glycine cleavage pathway
Lab and EEG findings in non-ketotic hyperglycinemia
Elevated glycine (urine, plasma, CSF), no ketoacidosis
Diagnosis with elevated glycine in CSF and abnormal ratio of glycine in csf to plasma (>0.08)
EEG with burst suppression pattern that can become hypsarrhythmia
Management of non-ketotic hyperglycinemia
Sodium benzoate (decreases plasma glycine) can decrease seizures, dextromethomorphan (and NMDA antagonist) may improve neurological signs, variable response to ketogenic diet
Clinical and lab finds of cysteinuria
Urolithiasis, hematuria, pyuria, urinary obstruction and possible renal failure, labs: increased cysteine in urine with decreased cysteine levels in blood due to defect in amino acid transport and decreased reabsorption in kidney
Test for cystinuria
Positive nitroprusside blue test
Management of cysteinuria
Hydration, alkalinization of urine with sodium bicarbonate, potassium or sodium citrate, restrict methionine in diet, start thiol drug if above not effective
Diagnosis of histidinemia
Add aqueous ferric chloride to urine to detect imidazole pyruvic acid (turns blue-green)
Lab findings in lysinuric protein intolerance
Hyperammonemia, lysinuria with low plasma lysine levels, also with low plasma arginine and ornithine levels, increased LDH
Treatment of lysinuric protein intolerance
Citrulline supplementation, sodium benzoate or sodium phenylbutyrate to decreased nitrogen load, may need carnitine supplementation, calcium, vitamin and trace element supplementation, growth hormone, statins if hypercholesterolemia
Pellagra-like skin diseases ataxia, muscle pain, weakness, occasional mental deficiency or seizures
Hartnip disease (autosomal recessive defect in amino acid transport across cell membranes, leading to decreased tryptophan availability)
Management of Hartnup disease
Oral niacin or nictinamide, high-quality protein diet, oral neomycin (delays tryptophan degradation), avoid sunlight
Isobaric aciduria results from:
Abnormal leucine metabolism
Inheritance pattern of isovaleric aciduria
Enzyme deficiency in isovaleric aciduria
Isovaleryl-coa dehydrogenase
Which enzyme requires biotin?
The enzyme to convert 3-methylcrotonyl-coa to 3-methylglutaconyl-coa
So if biotin deficient, get 3-methtlcrotonyl glycinuria
Odor of sweaty feet, poor feeding, vomiting, lethargy, moderate hematomegaly, intermittent neurological signs (hypotonia, tremor, developmental delay)
Isovaleric aciduria
Lab findings in isovaleric aciduria
Metabolic acidosis (increased anion gap), urine ketones, majority with normal glucose, hypocalcemia, elevated lactate, may have neutropenia/thrombocytopenia
Diagnosis of isovaleric aciduria
Increased C5 acylcarnitine on state newborn screen
Increased urine isovalerylglycine and isovaleric acid
Decreased isovaleryl-coa dehydrogenase activity in skin fibroblasts or blood leukocytes
Management of isovaleric aciduria
Acute: glucose infusion, possible toxin removal by exchange or dialysis, l-carnitine to increased isovalerylglycine excretion, administer glycine, carbamyl glutamine
Chronic: restrict protein intake, supplemental glycine and carnitine
Symptoms of 3-methylcrotonyl glycinuria
Lethargy, poor oral intake, vomiting, hypotonia, hyperreflexia, seizures
Lab findings in 3-methylcrotonyl glycinuria
- Increased 3-methylcrotonyl glycine in urine with extremely low total and free plasma carnitine levels
- metabolic acidosis
- urine ketones
- hyperammonemia
- hypoglycemia
- urine odor similar to male cat urine
Diagnosis of 3-methylcrotonyl glycinuria
Increased 3-hydroxylisovaleric acid and 3-methtlcrotinylglycine during acute episodes; confirmation by decreased enzyme assay
Management of 3-methylcrotonyl glycinuria
Oral glycine and carnitine may be beneficial, unclear if mildly decreased protein diet is beneficial
Deficiency in propionic aciduria
Priopionyl-coa carboxylase
Also requires biotin
Deficiency is autosomal recessive
Enzyme deficiency in methylmalonic aciduria
Methylmalonyl-coa isomerase
Requires cobalamin (B12)
Lab findings in propionate pathway abnormalities
Metabolic acidosis, ketonuria, hypocalcemia, increased lactate, neutropenia, thrombocytopenia, normal to low glutamine, hyperammonemia
Diagnosis of propionate pathway defects
Plasma carnitine reveals increased C3 acylcarnitine, increased glycine, testing of urine organic acids reveals increased metabolites
Outcome of propionate pathway defects
Can improve outcomes with early treatment, but still at risk for cognitive defects, survival into early childhood is greater than 70%, renal transplant likely needed if methylmalonic aciduria, MMA associated with more severe neurological outcomes
Management of oropionate pathway defects
Treatment for hyperammonemia as needed
Hydration, low protein diet, thiamine and B12 supplementation
Carnitine supplementation
Metronidazole therapy to decreased urinary excretion of metabolites
Growth hormone
Enzyme deficiency in glutamic aciduria type I
Glutaryl-coa dehydrogenase
Dependent on riboflavin (B2)
Macrocephaly, progressive neurologic symptoms, hepatic dysfunction, motor delay
Glutaric aciduria
Neuro imaging in glutaric aciduria often shows
Frontotemporal atrophy
What is elevated in newborn screen for glutaric aciduria
C5 dicarboxylic
Management of glutaric aciduria type I
Emergent treatment during illness: Frequent feedings with increased carbs, carnitine, anti-pyretics
Carnitine supplementation, consider riboflavin, low protein intake (specifically lysine and tryptophan, but increased arginine)
What does hydroxylmethylglutaryl-coated lyase do
Important last step of ketone synthesis from fatty acids (also last step in leucine oxidation)
Symptoms of HMG-coa lyase deficiency
Vomiting, seizures, hypotonia, hypotonic hypoglycemia, metabolic acidosis, increased lactate, abnormal LFYs
What is the most common brain abnormality seen in patients with non-ketotic hyperglycinemia?
Agenesis of the corpus callosum
The combination of metabolic acidosis, ketosis, and hyperammonemia is most suggestive of:
Organic acidemia
Why does hyperammonemia occur in patients with an organic acidemia
Because excess levels of propionyl-coa need to inhibition of carbamyl phosphate synthase I
Abnormal plasma acylcarnitines associated with: short chain acyl-coated dehydrogenase deficiency
C4, C5
Abnormal plasma acylcarnitines associated with: medium-chain acyl-coa dehydrogenase deficiency
C6, C8, C10:1
Abnormal plasma acylcarnitines associated with: long-chain acyl-coa dehydrogenase deficiency
C16:1-OH, C16-OH, C18:1-OH, C18-OH
Abnormal plasma acylcarnitines associated with: very long-chain acyl-coa dehydrogenase deficiency
C14:1, C14:2, C16:1, C18:1
Most common and mildest fatty acid oxidation disorder
MCAD
Symptoms of MCAD
Typically asymptomatic in newborn, but may present with hypoglycemia and arrhythmias
Carnitine deficiency, no ketones, hypoketotic hypoglycemia in starvation state, encephalopathy, severe acidosis
Enzyme involved in and inheritance of LCHAD
3-hydroxylacyl CoA dehydrogenase
Autosomal recessive
Feeding difficulty, vomiting, lethargy, cardiomyopathy, severe liver disease with cholestasis, hepatic encephalopathy, hypotonia, episodic rhabdomyolysis
LCHAD
Suspect when mother with acute fatty liver disease and or HELLP
Heterozygous LCHAD-affected pregnant woman
Has a 1 in 5 chance of delivering infant with LCHAD
Labs in LCHAD
Hypoketotic or nonketotic hypoglycemia, increased serum creatine phosphokinase, hyperammonemia, elevated LFTs, lactic acidosis
Poor feeding, high forehead, flat, nasal bridge, short anteverted nose, midface hypoplasia, renal cyst, sweaty feet, hepatomegaly, rocker, bottom, feet, hypospadia, macrocephaly, cardiomyopathy, neuron migration abnormalities
Multiple acyl-coated dehydrogenase deficiency, aka glutamic aciduria type II
Dysostosis multiplex is pathognomonic of
Mucopilysaccharidoses
Macular cherry red spot is pathognomonic of
Lipid storage diseases affecting the brain
Where are Alder-Reilly bodies found and when are they seen?
In white blood cells, seen in mucopolysaccharidosis
Cloudy cornea, normal retina, hepatosplenomegaly, profound decrease in CNs function, short stature, kyphosis, hirsutism, stiff joints
Hurler syndrome
Alpha-iduronidase
Mucopolysaccharoidosis with x-linked inheritance
Type II
Hunter syndrome
Clear cornea, retinitis papilledema, hepatosplenomegaly, slow loss of CNS function, coarse facial features, short stature
Hunter syndrome
Enzyme defect in gaucher disease
Glucocerebrisidase
Defect in Neimann-Pick
Sphingomylenase
Cherry red spot, hepatosplenomegaly, foam cells in bone marrow
Neimann-Pick A
Cherry red spot, NO heparosplenomegaly, normal bone marrow, profound CNS loss
Tay-Sachs
Defect in Tay-Sachs
Hexosasminidase A
Cherry red spots, inclusions in WBC
Generalized gangliosidosis, infantile GM 1
X-linked lipidosis
Fabry disease
Enzyme in Fabry disease
Alpha-galactosidase
Enzymes in Krabbe disease
Beta-galactosidase
Lipidosis with adrenal calcifications
Wolman disease
What vitamin does pyruvate dehydrogenase need
Thiamine (B1)
Agenesis of corpus callosum, developmental delay, hypotonia, seizures, elevated pyruvate and lactate with normal lactate:pyruvate ratio (<25), metabolic acidosis
Pyruvate dehydrogenase complex deficiency
Management of pyruvate dehydrogenase complex deficiency
Ketogenic diet to increase acetyl-coated levels, restriction of carbohydrates
Hypothermia, hypotonia, severe neurological abnormalities, cystic periventricular leukomalacia, hepatmegaly, metabolic acidosis, elevated pyruvate and lactate, low hydroxybutyrate/acetoacetate ratio, ketonuria
Pyruvate carboxylase deficiency
Which vitamin does pyruvate carboxylase require
Biotin
Lactic acidosis with lactate levels»_space; pyruvate levels
Respiratory chain disorders
Genetics and pathway in mevalonic aciduria
Autosomal recessive- defect of mevalonate kinase, a component of cholesterol synthesis pathway
Failure to thrive, developmental delay, dysmorphism, cataracts, malabsorption, recurrent episodes of fever with vomiting and diarrhea, lymphadenopathy, hepatosplenomegaly, arthralgia, hypotonia, ataxia
Mevalonic aciduria
Labs in mevalonic acidosis
No metabolic acidosis, normal glucose, increased creatine kinase, increased LFTs, increased mevalonic acid
Management of mevalonic aciduria
No effective treatment, minority benefit from corticosteroids, colchicine, or cyclosporine; minority benefit from simvastatin, a few may improve with etanercept, interleukin-1 receptor antagonists
Seizures, immune deficits, alopecia, developmental delay, hearing deficits, episodes of hypoglycemia, lethargy, hypotonia
Biotinidase deficiency
Metabolic condition associated with: biotin
Biotinidase deficiency, beta-methylcrotonyl glycinuria, propionic acidemia, pyruvate carboxylate deficiency
Metabolic condition associated with: folic acid
Homocystinuria
Dihydropterine reductase deficiency
Metabolic condition associated with: riboflavin
Glutamic aciduria I
MCAD deficiency
Glutaric aciduria II
Metabolic condition associated with: pyridoxine
Cystathione beta-synthase deficiency (type of homocystenuria)
Metabolic condition associated with: thiamine
MSUD
Pyruvate dehydrogenase complex deficiency
Metabolic condition associated with: tetrahydrobiopterin
PKU
Dihydropteridine reductase deficiency
Metabolic condition associated with: cobalamin
Methylamlonic aciduria
Homocysteinuria
Metabolic condition associated with: vitamin C
Transient tyrosinemia
Chstathionjne synthase deficiency
Genetics of Menkes disease
X-linked recessive
Cause of menkes
Defect in a membrane copper transport channel, leading to poor absorption, and cellular distribution of copper
Increased risk of pROM, increase risk of hypothermia and conjugated hyperbilirubinemia; brittle, kinky, steely hair, pudgy faces with sagging lips and abnormal eyebrow, developmental delay, skin and joint laxity, wormy and bones, osteoporosis, increase risk of UTI
Menkes disease
Management of Menkes disease
Parental copper histidine
Lab findings in Zellweger spectrum disorder
Absent of decreased peroxizomes
Increased very long chain FA
Increased methyl-branched fatty acids, increased urine pipecolic acid, bile acid accumulation
