Inborn Errors of Amino Acid Metabolism (IEM) Flashcards

1
Q

IEM Amino Acid Disorders Topics

Urea cycle disorders

–_________ end product of amino acid metabolism

–__________an intermediate by-product

Organic acidemias

–Defects in ___________ metabolism

A

Urea

Ammonia

amino acid

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
2
Q

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)

A

two

carriers

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
3
Q

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

A

phenylalanine

arginine

Tyrosinemia type I

urea cycle

glycine

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
4
Q

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

A

Thiamine; B12; biotin; B6

Gaucher disease; Hurler-Scheie; Pompe

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
5
Q

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 _____________

A

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

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
6
Q

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?

A

Autosomal recessive

phenylalanine; tyrosine

PAH deficiency

tetrahydrobiopterin (BH4)

BH4

dihydropterin reductase

phenylacetic acid

–Mousy/musty/animal-like odor in sweat and urine

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
7
Q

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 ______________

A

6 months

speak

albinism

Mousy/musty

enamel

body growth

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
8
Q

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 ____________-

A

maternal

Ferric chloride; dark green

phenylalanine (PA)

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
9
Q

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

A

PA ;tyrosine

methionine, histidine, valine

isoleucine, PA, threonine, tryptophan

leucine, lysine

aspartame

2-6

sapropterin

phenylamine ammonium lyase

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
10
Q

Avoid High Protein Foods

Examples?

A

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

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
11
Q

‘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 ___________

A

Dihydropterin reductase (DHPR)

Hyperphenylalaninemia (HPA)

dopamine, epinephrine, norepinephrine, and serotonin

biopterin or neopterin

red blood cells

phenylalanine

BH4

L-dopa, carbidopa, and serotonin

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
12
Q

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

A

OCA1A

20/100 to 20/400

Tyrosinase

Nitisinone

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
13
Q

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 _______________
A

homogentisic oxidase; tyrosine ; fumarate

homogentisic acid (HA)

tyrosine

Black; alkapton

  • atherosclerosis
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
14
Q

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

A

phenylalanine ; tyrosine

homogentisic acid

antioxidant

homogentisate; cartilage

Nitisinone

homogentisic acid

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
15
Q
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)

A

fumarylacetoacetate hydrolase (FAH)

fumarylacetoacetate ; hepatocytes; proximal renal tubular

liver

Hepatocellular

Fanconi

Renal tubular

vitamin D

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
16
Q

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

A

hepatic tyrosine aminotransferase

corneas

17
Q

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 ____________

A

hyperkeratotic

tyrosine

tyrosine; phenylalanine

18
Q

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 __________

A

4-hydroxyphenylpyruvate dioxygenase (HPD)

fibroblasts; blood

tyrosine and phenylalanine

19
Q

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

A

aminoacidopathy

Ireland

cystathionine beta-synthase (CBS)

methionine

N,N,N-Trimethylglycine (betaine)

homocysteine

methionine

pyridoxal phosphate

20
Q

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

A

marfanoid

livedo reticularis

crosslinking

Vascular

21
Q

CBS Deficiency Complications

Eye anomalies/problems

–____________________

–__________________

–_______________

–_________________

CNS

–__________________

–__________,___________,_______,_____

Skeletal

–____________

–___________

–_____________

Vascular large & small arteries, veins

–_____________

–______________

–__________________

–_________________

Cerebrovascular accident (stroke)

Myocardial infarct (untreated 25% die <30 yr)

A

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

22
Q

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 ______________

A

Urea

Ammonia

hyperammonemia

23
Q

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 ________________

A

liver; liver failure

α-ketoglutarate

tricarboxylic acid (TCA) cycle

24
Q

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

A

brain and liver

encephalopathy

aquaporin

organic aciduria/acidemia

urea cycle disorder

protein

caloric intake

25
Hyperammonemia/UCD Treatment ## Footnote 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
26
Ornithine Transcarbamylase Deficiency (OTC) ## Footnote \_\_\_\_\_\_\_\_\_\_\_\_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
27
Neonatal OTC ## Footnote 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
28
Ornithine Transcarbamylase Deficiency ## Footnote 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
29
Ornithine Transcarbamylase Deficiency ## Footnote 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
30
UCD Late Onset ## Footnote 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
31
Organic Acidemias ## Footnote 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
32
General Symptoms Common to All Organic Acidemias ## Footnote 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
33
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
34
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
35
Classic Maple Syrup Urine Disease (MSUD) Branched Chain Oxoaciduria ## Footnote 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
36
Maple Syrup Urine Disease ## Footnote 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
37
MSUD Diagnosis ## Footnote 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
38
Classic MSUD ## Footnote 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