Inborn Errors of Amino Acid Metabolism (IEM) Flashcards
IEM Amino Acid Disorders Topics
Urea cycle disorders
–_________ end product of amino acid metabolism
–__________an intermediate by-product
Organic acidemias
–Defects in ___________ metabolism
Urea
Ammonia
amino acid
Autosomal Recessive Inheritance
Affected must have ___________ mutant recessive genes (aa) to express the IEM disorder
Homozygotes (aa) symptomatic early in life
Heterozygotes (Aa) asymptomatic __________
New mutations uncommon
Complete penetrance common
High proportion exhibit similar clinical symptoms at early age (often newborn)
two
carriers
Therapy of Metabolic Disorders/IEM
Restriction of toxic substrates
–_____________ in PKU
Providing needed/missing products
–___________ in urea cycle defects
Inhibitors of toxic products/byproducts
–2(2-nitro-4-trifluoro-methyl-benzoyl)-1,3-cyclohexanedione (NTBC) in ____________
Drugs to bypass/reduce metabolic block effect
–phenylbutyrate/benzoate in ______________defects
–_____________in isovaleric acidemia
phenylalanine
arginine
Tyrosinemia type I
urea cycle
glycine
Therapy of Metabolic Disorders/IEM
Pharmacologic amounts of vitamins to stabilize or bypass mutant enzymes (____________ in MSUD, __________ in MMA, _________ in biotinidase deficiency,___________ in homocystinuria)
Enzyme or hormone replacement (glucocerebrosidase in _____________, alpha-L-iduronidase in _____________, acid maltase/glucosidase in _________)
Organ transplantation
Stem cell therapy
Gene therapy
Thiamine; B12; biotin; B6
Gaucher disease; Hurler-Scheie; Pompe
Odors Associated with Amino Acid Disorders
Burnt sugar, curry, or maple syrup – _______________
Sweaty socks or cheese-like – ______________
Fruity, ammoniacal – ___________ or _________
Mouse urine, musty – ___________
Cabbage-like, rotten eggs – ____________
Malt or hops – ________________
Cat urine – ______________ and __________
Fish-like – ______________ and _____________
Maple syrup urine disease
Isovaleric acidemia
Methylmalonic acidemia or propionic acidemia
Phenylketonuria
Tyrosinemia
Methionine malabsorption
3-methylcrotonic acidemia, 3-hydroxy-3-methylglutaric aciduria
Trimethylaminuria and carnitine excess
Phenylketonuria (PKU)
Most common aminoaciduria individual incidence 1:10,000
____________ inheritance
Phenylalanine hydroxylase (PAH) on 12q24.1
–Mediates __________ to_____________- conversion
–>400 mutations of PAH identified
–98% PKU due to ______________
Defect in _______________- metabolism
–____________cofactor required for PAH activity
–2% PKU due to _____________- deficiency
–Called ‘malignant’ PKU
Phenylalanine (PA) shunted to form ______________ and other phenylketones (phenyllactate, phenylpyruvate)
-Odor?
Autosomal recessive
phenylalanine; tyrosine
PAH deficiency
tetrahydrobiopterin (BH4)
BH4
dihydropterin reductase
phenylacetic acid
–Mousy/musty/animal-like odor in sweat and urine
Classic Phenylketonuria (PKU)
Diagnosed by what age? _____________
–severe intellectual disability
–IQ 50 if no dietary restriction
–Inability to __________
Pale skin, blonde hair, blue eyes (similar to ___________)
Eczema skin rash
Aromatic amino acid: ______________ odor
Vomiting, irritability, hyperactivity
Widely spaced teeth
–Poorly developed _____________
Decreased ______________
6 months
speak
albinism
Mousy/musty
enamel
body growth
Diagnosis PKU
Newborn Screen: 2-3 days after birth
Normal at birth:
–Presence of ____________-enzyme during fetal period
______________ added to urine in presence of phenylalanine metabolites – resulting in __________ color
Increased plasma levels ____________-
maternal
Ferric chloride; dark green
phenylalanine (PA)
Treatment PKU
Dietary restriction of ____________with ___________ supplementation
Supplement other essential amino acids
Glucogenic: __________, _________, and _________
Glucogenic/ketogenic: ____________, _________,__________ and __________
Ketogenic: ___________ and ____________
Avoid __________ (artificial sweetener) contains PA
Phenylalanine levels followed at regular intervals
–1-2 X/wk in newborns; once per month older children and adults
Phenylalanine levels maintained at___________mg/dL
FDA approved ___________ as a treatment for PKU
Preliminary studies for injectable ________________, an enzyme substitute
PA ;tyrosine
methionine, histidine, valine
isoleucine, PA, threonine, tryptophan
leucine, lysine
aspartame
2-6
sapropterin
phenylamine ammonium lyase
Avoid High Protein Foods
Examples?
Meat, chicken, fish
Dairy products including milk, cheese, yogurt, ice cream
Eggs
Nuts including peanut butter
Seeds
Vegetarian sources of protein including soy, tofu, legumes (beans), hummus
‘Malignant’ PKU
______________ deficiency
_____________ and progressive neurologic deterioration during infancy
–Due to decreased production of the neurotransmitters, ____________, ___________,_________, and _________
Untreated typically die <1 year of age
–‘Malignant’ PKU
Diagnosis
–Elevated _____________ and __________in blood, urine, cerebrospinal fluid
–Decreased DHPR activity in __________
Treatment
–Diet low in _____________
–Supplementation with __________
–Neurotransmitter precursors ____________, ___________, and ___________
Dihydropterin reductase (DHPR)
Hyperphenylalaninemia (HPA)
dopamine, epinephrine, norepinephrine, and serotonin
biopterin or neopterin
red blood cells
phenylalanine
BH4
L-dopa, carbidopa, and serotonin
Oculocutaneous Albinism (OCA)
Autosomal recessive
7 classical syndromes
___________: most severe type
–White skin, hair, eyelashes, eyebrows
–Irises completely translucent
–Visual acuity range of __________ to ________
–Photophobia, nystagmus, strabismus
–Symptoms do not vary with age or race
–_______________ unable to synthesize melanin from tyrosine (Type 1A)
–Increased risk skin cancer no tanning
Squamous cell carcinoma
Basal cell carcinoma
RARE melanoma
Treatment
–Low vision aids, tinted glasses
–____________used in clinical trials
OCA1A
20/100 to 20/400
Tyrosinase
Nitisinone
Alkaptonuria/Ochronosis
Rare, autosomal recessive, relatively benign
Congenital deficiency of _______________ in degradation of__________to ___________
Build up of __________________
–Endogenous pigment, breakdown of _____________
–Urine darkens after prolonged exposure to air
___________ color in urine soaked diaper due to oxidized _________
–Dark HA deposits in
- Articular cartilage of joints with degenerative arthritis/debilitating arthralgias
- Intervertebral discs, external ear cartilage, bridge of nose cartilage
- Sclerae
- Heart valves (aortic stenosis), endocardium, pericardium, aorta
- Coronary arteries with earlier onset of coronary _______________
homogentisic oxidase; tyrosine ; fumarate
homogentisic acid (HA)
tyrosine
Black; alkapton
- atherosclerosis
Treatment Alkaptonuria
Reduction of ___________and ________
–Reduced ____________ excretion
Vitamin C, up to 1 g/d, for older children and adults
–Mild ___________ feature of ascorbic acid
–Helps to retard conversion of ___________ to polymeric material deposited in _________-
_____________, an inhibitor of the enzyme 4-hydroxyphenylpyruvate dioxygenase
–Clinical trials ongoing, shows promise
–Mediates formation of ____________
–Markedly reduced urinary homogentisate excretion but safety of prolonged use unknown
phenylalanine ; tyrosine
homogentisic acid
antioxidant
homogentisate; cartilage
Nitisinone
homogentisic acid
Hereditary Tyrosinemia (HT) Type I Hepatorenal Tyrosinemia
Deficient ________________ on 15q23-25
____________ accumulates in _____________ and ________________epithelial cells
Severe, progressive ____________ disease
–Jaundice, cirrhosis
–Hepatic failure & death
–________________carcinoma (37%)
Renal tubular dysfunction
–_____________ syndrome
____________ acidosis
Aminoaciduria
Hypophosphatemia (due to phosphate wasting)
Neurologic crises – pain, paresthesia due to peripheral neuropathy
Rickets (_____________deficiency)
fumarylacetoacetate hydrolase (FAH)
fumarylacetoacetate ; hepatocytes; proximal renal tubular
liver
Hepatocellular
Fanconi
Renal tubular
vitamin D
HT Type II
Oculocutaneous Tyrosinemia
Deficient _________________ on 16q22
Eye and skin abnormalities within 1st year of life
Keratitis, dendritic corneal ulcers
–Photophobia, pain, excessive lacrimation, and redness
Cloudy_____________ with central opacities, scarring
Corneal dystrophy
Impaired vision
Glaucoma
hepatic tyrosine aminotransferase
corneas
HT Type II
Oculocutaneous Tyrosinemia
Painful _________________ plaques
–Primarily on palms and soles
–Also elbows, knees, and ankles
Intellectual disability (50%)
Hyperactivity, irritability, abnormal language
Increased ___________in urine
Treatment with diet low in _________ and ____________
hyperkeratotic
tyrosine
tyrosine; phenylalanine
HT Type III
Rare disorder
______________deficiency
Neurologic dysfunction (ataxia, seizures, mild psychomotor retardation)
+/- skin hyperkeratosis
+/- corneal ulcers
+/- intellectual disability
Diagnosis confirmed by detection of mutations in the HPD gene on 12q24 in cultured skin _____________ or __________
Prenatal detection is available using this technique
Treatment
–Diet low in _____________ and __________
4-hydroxyphenylpyruvate dioxygenase (HPD)
fibroblasts; blood
tyrosine and phenylalanine
Classical Homocystinuria
Autosomal recessive
2nd most treatable _________________
Reported incidence:1 in 344,000 worldwide to 1 in 65,000 in ___________
Due to __________________deficiency (21q22.3)
–Treat with low _____________diet (low sulfur)
–Treat with __________________
Reduces homocysteine by promoting conversion of __________back to ______________
–Treat with increased B6 and cysteine in diet
Decreased affinity of CBS for _____________
Blood total homocysteine (tHcy) + plasma amino acid analysis
–tHcy >100 µmol/L + high methionine
Biochemical assays: CBS activity
Molecular genetic testing
–Direct sequence analysis of the CBS gene on 21q
aminoacidopathy
Ireland
cystathionine beta-synthase (CBS)
methionine
N,N,N-Trimethylglycine (betaine)
homocysteine
methionine
pyridoxal phosphate
Homozygous Cystathionine Beta Synthase (CBS) Deficiency
Infants normal
Malar flush
Intellectual disability
Seizures
Psychiatric problems
Tall long limbs, thin, _____________
Skin:______________
Defective connective tissue
–Knock-knee genu valgum
–Pectus excavatum or carinatum
–High arches feet pes cavus
–Tight joints Charlie Chaplin gait
–Defective ___________ collagen
–____________ injury due to elastic fiber damage
marfanoid
livedo reticularis
crosslinking
Vascular
CBS Deficiency Complications
Eye anomalies/problems
–____________________
–__________________
–_______________
–_________________
CNS
–__________________
–__________,___________,_______,_____
Skeletal
–____________
–___________
–_____________
Vascular large & small arteries, veins
–_____________
–______________
–__________________
–_________________
Cerebrovascular accident (stroke)
Myocardial infarct (untreated 25% die <30 yr)
90% ectopia lentis, downward subluxation/dislocation of lens
Myopia (Nearsightedness)
Glaucoma
Optic atrophy
Intellectual disability
Depression, behavioral, OCD, bipolar
Kyphosis
Scoliosis
Osteoporosis
Deep venous thrombosis
Pulmonary emboli
Sagittal sinus thrombosis
Premature atherosclerosis
Urea Cycle Disorders (UCD)
___________= end-product of amino acid metabolism
_______ = intermediate by-product of amino acid metabolism
–Normally metabolized to urea through urea cycle
Several enzymes
–Congenital deficiency leading to ______________
Urea
Ammonia
hyperammonemia
Hyperammonemia
Metabolic Emergency
Acquired
–Severe ___________disease with _________
Hereditary
–Presentation in infancy
Urea cycle disorders
Organic acidemias
Fatty acid oxidation defects
Disorders of pyruvate metabolism
Excess ammonia
–Depletion _________________
–Leading to inhibition of ________________
–
liver; liver failure
α-ketoglutarate
tricarboxylic acid (TCA) cycle
Clinical Presentation Hyperammonemia in UCDs
Complete deficiency: most profoundly affected: ___________ and _______
Severe enzyme deficiency often presenting soon after birth
–Lethargy and poor feeding
–Vomiting
–Acute metabolic _______________(astrocyte swelling glutamine accumulation)
Seizures
Somnolence/coma
Cerebral edema (papilledema fundus) disrupted ____________ system, electrolyte homeostasis
Acidosis if _________________
No acidosis if ____________
Urgent treatment
–Prevent catabolism by limiting ___________intake
–Maintain____________by IV glucose and IV lipids in infants
Duration of hyperammonemia correlates with
–Intellectual disability
–Developmental delay
brain and liver
encephalopathy
aquaporin
organic aciduria/acidemia
urea cycle disorder
protein
caloric intake
Hyperammonemia/UCD Treatment
Lactulose
–Acidification of _____________
–Trapping_____________ so that it can be excreted
Antibiotics e.g., _________
–Decrease____________ producing ammonia
Forming products that are renally excreted
–Initial intravenous administration of a combination preparation of _____________ and _____________
–Followed by maintenance with ______________ or _____________
–Mechanism of action
Scavenge ammonia by creating an alternate pathway to excrete ___________precursors
Bind amino acid leading to excretion
_____________ for comatose patient with extremely high ammonia
________transplantation (CPSI or OTC deficiency)
gastrointestinal tract
NH4+
rifaximin
colonic bacteria
sodium phenylacetate; sodium benzoate
oral sodium phenylbutyrate (Buphenyl); glycerol phenylbutyrate (Ravicti)
nitrogen
Hemodialysis
Liver
Ornithine Transcarbamylase Deficiency (OTC)
____________enzyme on Xp2.1
____________ semi-dominant
1 in 100,000
90% mortality if neonatal presentation
Symptoms at 24-48 hours
–Poor feeding
–Difficulty t_____________
–Lethargy
If survive, length of time of hyperammonemic coma closely correlate with
–Intellectual disability
–Developmental delay
Hepatic
X-linked
hermoregulation
Neonatal OTC
Failure to feed
Loss of_______________ with a low core temperature
______________ progressing to lethargy and coma
Abnormal posturing and hepatic ______________related to the brain swelling and pressure on the brain stem
About 50% of neonates with severe hyperammonemia seizures
If closed cranial sutures higher risk for rapid neurologic deterioration from the cerebral edema that results from ammonia elevation
_________________ secondary to effect of hyperammonemia on brain stem, common early finding, results in respiratory alkalosis
Hypoventilation, respiratory arrest, death follow as pressure increases on brain stem
thermoregulation
Somnolence
encephalopathy
Hyperventilation
Ornithine Transcarbamylase Deficiency
X-linked
Range in female due to degrees of inactivation of normal X
Female infancy to 9 years – cyclic vomiting, headache, slurring of speech, screaming, ataxia, muscular rigidity
Hyperammonemic crisis
Treat _________,__________, and __________
_____________ transplantation
arginine, benzoate, & phenylacetate
Liver
Ornithine Transcarbamylase Deficiency
Hemizygous males
–Fulminant presentation in newborn (40%) with 90% mortality
Late onset (60%) triggered by catabolism (average 13% mortality)
Laboratory findings in infant
–Markedly increased plasma _____________
–Increased plasma ______________
–Increased _____________in blood and urine
–Reduced plasma____________
Targeted DNA mutation analysis
–Microdeletion of the OTC gene: false-negative results on DNA sequencing
array comparative genomic hybridization (aCGH) or chromosome microarray analysis to detect microdeletions
Next-generation DNA sequencing high sensitivity
Prenatal diagnosis if DNA mutation known
ammonia
glutamine
orotic acid
citrulline
UCD Late Onset
Late onset after 1 month
–Headaches
–Chronic episodic vomiting
–Ataxia
–Tremor (asterixis)
–Episodes of delirium, erratic behavior, or reduced consciousness
–Seizure disorder
–Aversion to foods high in protein
–Slurred speech
Precipitated by increased ______________ intake or _____________ stress (infection)
Precipitated by drugs (__________ and ____________)
_____________deficiency with more specific symptoms
–________________ and/or _______________
protein; catabolic
valproic acid, steroids
Arginase
Spastic diplegia and/or dystonia
Organic Acidemias
Increased excretion of_____________in urine
–Due to enzyme deficiencies in ____________breakdown pathways
Clinically apparent during newborn period or early infancy
–Initial period of well-being
–Life-threatening _____________ with increased anion gap
–Mistaken for ____________
–If unrecognized, significant mortality
Susceptible to metabolic decompensation with
–Episodes of increased catabolism with _______________
Intercurrent illness
–Trauma
–Anesthesia and surgery or
–Prolonged fasting
organic acids
amino acid
metabolic acidosis
sepsis
hyperammonemia
General Symptoms Common to All Organic Acidemias
Decreased resistance to _________
Intermittent coma, ____________syndrome
Vomiting/poor feeding/failure to thrive
Lethargy
Neurologic
–___________ (involuntary writhing movements arms, legs)
–__________ (failure of muscular coordination)
Peculiar odor (especially MSUD)
In older children
–Developmental delay
–Developmental regression
infections
Reye-like
Athetosis
Ataxia
Organic Acidemias/Organic Acidurias
Symptoms
Metabolic acidosis
Increased anion gap (unmeasured organic acid)
Increased ketones (beta-hydroxybutyrate, acetoacetate)
Mild to moderate hyperammonemia
Liver dysfunction, other abnormal liver function tests
Hypoglycemia
Neutropenia
–Sepsis-like features due to bone marrow suppression
Organic Acidemias
Types
Maple syrup urine disease (MSUD)
Methylmalonic acidemia
Proprionic acidemia
Multiple carboxylase deficiency
Isovaleric acidemia
Glutaric aciduria type II
3-hydroxy-3-methylglutaric aciduria
Classic Maple Syrup Urine Disease (MSUD)
Branched Chain Oxoaciduria
Classic most common
Symptoms at 2-3 days
Disrupted activity of ___________________complex
–2nd step in catabolic pathway for branched- chain amino acids (BCAAs) so degradation blocked
Increased plasma ___________,__________,_____________, and __________
Metabolic acidosis
–Increased anion gap
–Elevated plasma and urine ketones
1st week vomiting, seizures, coma
_____________ odor
–In urine, hair, sweat, saliva, cerumen (ear wax)
Oil at top of frozen urine soloton derived from _____________
branched-chain α-ketoacid dehydrogenase (BCKAD)
valine, isoleucine, leucine, alloisoleucine
Sweet, caramel-like
isoleucine
Maple Syrup Urine Disease
Neonate with classic MSUD
–Irritability, poor feeding, lethargy, apnea
–___________[“fencing” and “cycling”]
–Increasing hypertonia, opisthotonus (arched back), exaggerated deep tendon reflexes, ankle clonus, spasticity
–________________failure and death in some
–Sweet caramel odor in cerumen and urine
Infant and toddler:
–Nausea, anorexia, dystonia, ataxia
Older:
–Intellectual disability, hyperactivity, sleep disturbances, hallucinations
–Focal dystonia, choreoathetosis, ataxia
Repeat episodes triggered by excess protein consumption, infection
Athetoid
Respiratory
MSUD Diagnosis
Prenatal diagnosis
–Measurement of _____________ enzyme activity in cultured ____________ or chorionic _________ cells
–Mutation analysis if known specific gene defect
Newborn screening
–Tandem mass spectrometry
–Analysis of alloisoleucine in dry blood spots
Positive family history
–DNA mutation testing
–Plasma for amino acid analysis
branched-chain alpha-ketoacid dehydrogenase complex (BCKDC); amniocytes; villous
Classic MSUD
Management
–Dietary restriction of ______________ amino acids throughout life
–Aggressive treatment of episodes of acute metabolic decompensation
Plasma and tissue concentrations of leucine lowered rapidly by inhibition of protein catabolism and enhancement of protein synthesis
Liver transplantation indications
–Poor metabolic control
–Poor quality of life significant psychomotor disabilities
Initial studies using retroviral vectors to infect MSUD lymphocytes shown stable correction of the enzyme deficiency
–Human gene therapy trials for MSUD remain to be performed
branched-chain
