Inborn Errors of Amino Acid Metabolism (IEM) Flashcards by Camelita Thrift

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

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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

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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

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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

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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

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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

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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

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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)

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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

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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

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‘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

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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

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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

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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

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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

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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

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Inborn Errors of Amino Acid Metabolism (IEM) Flashcards

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