Most things Metabolic Flashcards
Amino Acidemias
Typical Onset & Presentation
Typical Onset: within first few months of life
Variable; DD/ID, seizures, lethargy, poor feeding, vomiting, certain odors*
Amino Acidemias
Biochemical presentation & Key Tests
Biochemical presentation: elevated amino acids
Key tests: serum amino acids
Organic Acidemias
Typical Onset & Presentation
Neonatal period
lethargy, poor feeding, respiratory problems, hypoglycemia (seizures), hypotonia, and vomitting
Organic Acidemias
Biochemical presentation & key tests
Hyperammonemia, metabolic acidosis, urine ketones, pancytopenia
Key tests: acylcarintine profile, urine organic acids
Urea Cycle Disorders
Typical onset and presentation
neonatal period
lethargy, poor feeding, vomiting, seizures, coma
Urea Cycle disorders
Biochemical presentation & key tests
hyperammonemia, respiratory alkalosis, NO URINE KETONES or PANCYTOPENIA
key tests: ammonia, serum amino acids, urine orotic acid
Lysosomal Storage
typical onset and presentation
infancy to adulthood
progressively coarsening features, hepatosplenomegaly, skeletal abnormalites
Lysosomal storage
biochemical and key tests
enyzme assay
OLIG: urine oligos
MPS: Urine GAGs
Fatty Acid Oxidation
Typical onset & presentation
neonatal period
Lethargy, vomiting, cardiomyopathy, skeletal myopathy, sudden death*
Fatty Oxidation
Biochemical and key tests
Hypoglycemia and low ketones
acylcarnitine profile and blood glucose
Peroxisomal disorders
Typical onset and presentation
infancy to adulthood
dysmorphic features, hypotonia, liver disease, seizures, ID, cataracts
Peroxisomal disorders
biochemical and key tests
Elevated VLCFAs
Acylcarnitine profile
Key feature in Isovaleric Academia
Gene + MOI
Smelly feet odor in acute crisis
IVD
Problem and the Management for Isovaleric Academia
problem: problems breaking down leucine
manage with leucine restricted diet (MEATS)
X linked organic acidemia; gene
Lesch-Nyhan; HPRT1
Features of Lesch-Nyhan and biochemical finding
Self-injury, DD/ID, renal stones / failure, gout like arthritis
Biochemical: excess URIC ACID in blood
Methylmalonic Acidemnia; symptoms
prevent the body from breaking down proteins and fats (lipids) properly
vomiting, dehydration, hypotonia, DD, lethargy, an hepatomegaly, and FTD
B12 non-responsive is most severe and earlier onset; B12 responsive is less severe
Main gene and MOI of Methylmalonic Acidemia
MMUT, AR
X-linked urea cycle disorder
Ornithine transcarbamylase (OTC) deficiency
General feature of urea cycle disorders
hyperammonia
Plasma amino acids for OTC Deficiency
low: citrulline, arginine
high: glutamine, orotic acid
Forms of OTC deficiency
Severe neonatal: floppy; seizures
later onset partial deficiency; carrier females: altered mental status, headaches, vomiting, aversion to protein foods, and seizures
Dietary treatment for Urea Cycle disorders
Low protein
Treatment for Urea Cycle disorders
dialysis to lower ammonia, liver transplant; restrict protein diet
General features of Fatty Acid Oxidation Disorders
Hypoglycemia and low ketones;
lethargy, vomiting, transient hepatomegaly, sudden death*
General treatment for Fatty Acid Oxidation Disorders
Avoid fasting, carntiine supplementation if necessary
Testing for Fatty Acid Oxidation Disorders
Acylcarnitine profile
Acyl-carnitine profile C8, C10, C10:1
Cause of apparent SIDS; most common Fatty acid oxidation disorder
Medium Chain acyl CoA dehydrogenenase deficiency (MCADD)
Acyl-carnitine profile C12; C14s; C16s
Rhabdomyolysis, skeletal myopathy, cardiomyopathy, liver dysfunction
VLCADD- very long chain acyl CoA dehydrogenenase deficiency
Acyl-carnitine profile C16-OHs C18-OHs
Retinopathy, Rhabdomyolysis, skeletal myopathy, cardiomyopathy, liver dysfunction
Mother can have acute fatty liver
LCHADD - long chain acyl CoA dehydrogenenase deficiency
Biochemical findings of Homocystinuria
Gene + MOI
increased homocysteine and methionine
CBS; AR
Ectopia lentis (dislocation of lens), ID osteoporosis, long bones, thromboembolism
often mistaken for Marfan syndrome
Homocystinuria
Biochemical findings of Maple Syrup Urine Disease
elevated leucine, isoleucine, and valine
Management for Maple syrup urine disease
Leucine restricted diet
(limiting animal proteins and eating more plant-based foods)
Sweet odor in urine; respiratory depression
Maple syrup urine disease
Biochemical findings of phenylketonuria (PKU) & tests used
increased phenylalanine and low tyrosine
serum/plasma amino acids
Management for PKU
Life long low protein diet
Features of PKU
Fair skin, microcephaly, ID, seizures, musty odor
PKU types
Classic v. variant PKU v. non- PKU hyperphenyalaninemia
Classic: most severe; CNS damage in early childhood due to phenylaline accumulation
Variant PKU: there is residual enzyme activity; typically just need dietary phenylalanine restriction
Non-PKU: plasma phenylalanine concentrations above upper limit of normal; get flagged in NBS… if less than <400umol/L no treatment needed
Biochemical findings of Tyrosenmia and treatment
elevated tyrosine levels
medication: Nitisinome
presents in early infancy- liver and kidney failure, rickets, increases risk to hepatocellular carcinoma
Tyrosenmia type 1 (most severe type)
Similarities + Difference between Tyrosenmia II and III
Same: No liver involvement!
II: childhood presentation- skin and eyes (corneal ulcers/ opacity; hypekertosis)
III: ID, seizures, intermittent ataxia
Gene and disease mechanism in Zelwegger spectrum disorder
13 PEX genes; AR
Infants with severe Zelwegger’s
typically die first year of life; usually without developmental progress
Dysmoprhic facies of Zelwegger
flat face, broad nasal bridge, larger anterior fontanelle, and widely split sutures
Features of indeterminate / mild Zellwegger
Vision loss (retinal dystrophy), SNHL, neurologic involvement (ataxia, polynueropathy, leukodystrophy), liver dysfunction, adrenal insufficiency, renal stones
hypotonia; amelogenesis imperfect of secondary teeth
sometimes normal intellect
Most common peroxisomal disorder + gene
X-linked adrednoleukodystrophy ; ABCD1
Clinical presentation of XL-ALD in females
20% develop mild to moderate spastic paraparesis in middle age or latter; progressive disorder
Clinical signs of XL-ALD: childhood cerebral form
cognitive decline, impairement of behavior, vision, hearing, and motor function
adrenal dysfunction develops
Clinical signs of XL-ALD: AMN form
(Adrenomyeloneuropathy)
Onset: early adult to middle age
progressive: stiff/weak legs, sphincter disturbances, sexual dysfunction
Clinical signs of XL-ALD: Addison’s disease
(Adrenal insufficiency)
Onset: 2y to adulthood
primary adrenocortical insufficiency: unexplained vomiting, weakness, or coma
Some degree of neurologic disability (typically AMN) by middle age
Diagnosising XL-ALD
Plasma VLCFA’s are abnormal in all men; about 80% of females will have increased concentration of VLCFA’s
Glycogen Storage Disease
Typical onset and presentations
Onset: Neonatal - Adulthood
Signs: enlarged liver, hypoglycemia
Hepatic GSDs- ketosis, fasting hypoglycemia
Muscle GSDs- fatigue, exercise intolerance
Glycogen Storage Diseases
Biochemical findings & tests
Lactic acidosis (GSD I)
fasting blood glucose test
liver enzymes (elevated)
CK (elevated= GSD III)
urinary myoglobin
Lipids (elevated LDL)
Most common GSD and gene/MOI
GSD I: Von Gierke Disease
GSD IA: G6PC AR
Name that condition: frequent nose bleeds & easy bruising
Poor growth/short stature; hepato- and nephromegaly, hypoglycemia and seizures, lactic acidosis; hyperlipidemia, uricemia
doll-like faces, thin limbs
GSD Type I - Von Gierke
GENE: G6PC
Clinical and manifestations of Infantile Pompe (GSD II) and GAA enzyme activity
muscle weakness (myopathy), poor muscle tone (hypotonia), an enlarged liver (hepatomegaly), and heart defects.
HCM by 1y if left untreated; <1% GAA enzyme
GSD with risk to hepatocellular carcinoma
GSD I: Von Gierke
Clinical and manifestations of late Pompe (GSD II) and GAA enzyme activity
milder than the infantile-onset and is less likely to involve the heart.
progressive muscle weakness, especially in the legs and the trunk, including the muscles that control breathing (lead to respiratory failure)
2-40% GAA enzyme
Metabolic diseases to avoid fasting
GSDs and FAODs
When symptoms occur after shorter durations of fasting
think GSDs > FAODs
Examples of Sphingolipidoses
(heterogeneous group of inherited disorders of lipid metabolism affecting primarily the central nervous system)
Gaucher, Fabry, Krabbe, Niemann-Pick, Tay-Sachs
Gene + MOI + deficiency in Fabry disease
GLA, X-linked
alpha-galactosidase deficiency
Age of onset for Fabry disease and clinical features
Childhood - adolescence
(Acroparesthesia) severe pain in extremities, sweating abnormalities, cataracts, angiokeratoma (red wart), corneal whorl, cataracts, renal disease
Can women be affected with Fabry disease
female carrier presentation varies form asymptomatic to as severely affected as males
Can males pass on Fabry disease
yes, because unlike other metabolic conditions boys can live long enough to reproduce
Gene + MOI + deficiency in Gaucher disease
and age on onset
GBA, AR; onset variable
beta-glucocerebrosidase deficiency
Most common genetic disorder in the AJ population and its carrier frequency
Gaucher; 1/18
If you see the following radiographic finding what is in your differential: Erlenmeyer flask deformity (on distal end of femur)
Gaucher
Most common form of Gaucher and its features
Type 1: bone disease, hepatoslpenomegaly, anemia, lung disease
NO CNS involvement; variable onset
Gaucher type II features + prognosis
death by age 3-4y
CNS symptoms: seizures, brain damage, pneumonia
Gaucher type III features + prognosis
death by mid adulthood
CNS slower progression; seizures, gaze palsy, ataxia
Heart finding in Gaucher
Heart valve calcification
Carriers of Gaucher are at an increased risk for
Parkinson’s Disease
What to be aware of when performing gene sequencing for Gaucher
GBA has a pseudogene that can result in false positives / false negatives
Genes, MOI and biochemical findings in Niemann-Pick
SMPD1, NPC1, NPC2
AR
impaired cholesterol esterification
Eye findings in Niemann-pick and which subtypes its in
cherry red spot seen in type A and B
Onset and clinical features of Niemann-pick type A `
onset by 3m; death in early childhood
hepatosplenomegaly, loss of mental abilities and movement, recurrent lung infections
Onset and clinical features of Niemann-pick type B
onset mid childhood; live to adulthood
less severe form of A
Short stature, nuerological involvement
Onset and clinical features of Niemann-pick type C
childhood-onset, vertical gaze palsy (can’t move eyes up), liver disease, lung disease; progressive decline in cognitive function (dementia)
Genes, MOI and biochemical finding of Krabbe Disease
GALC; AR
Deficient galactocerebrosidase enzyme
elevated serum psychosine
Presentation and clinical symptoms of Krabbe disease
normal development for few months followed by constant irritability
Tightly fisted hands, poor feeding, seizures, severe hypotonia. rapid neurological deterioration, death by 2y
Gene, MOI, and biochemical findings in Tay-Sachs
HEXA; AR
deficiency beta-hexosaminidase A
Testing used for carrier screening for Tay-Sachs
HEXA enzyme assay has higher sensitivity than targeted variant analysis
Onset and features of Tay Sachs
EYE: Cherry red spot
Regression (by 3-6m), seizures, death by 2y
increased startle response, vision and hearing loss, ID
Gene, MOI and biochemical findings of MPS I and onset
Hurler syndrome; IDUA - AR; infancy
elevated GAGs; low IDUA enzyme activity
List Hurler syndrome subtypes form least to most severe
Hurler syndrome (MPS I-H), Hurler-Scheie syndrome (MPS I-H/S), and Scheie syndrome (MPS I-S
Clinical features of MPS I (Hurler)
umbilical hernia, corneal clouding, DD, Gibbus deformity (hump scoliosis)
progressive coarsening features, carpal tunnel, macrocephaly, hearing loss, chronic ear infections, short stature
Gene, MOI, onset and biochemical findings in MPS II
Hunter; IDS, X-linked - childhood
death by 20s
elevated urine GAGs- high dermatan and heparan
Clinical features of MPS II
coarsening features in toddler, macroglosia, respiratory infections, apnea, macrocephaly, ivory lesions on back
NO CORNEAL CLOUDING
MPS with elevated GAGS dermatan and heparan
MPS I & II
Genes, MOI, onset and biochemical findings in MPS III
Sanfillipo; AR; childhood (death in teens)
SGSH, NAGLU, HGSNAT, GNS
may have elevated GAGs (heparan)
General features of MPS III
CNS nad behavioral symptoms, aggression, autism, social differences, sleep and movement disorders, hearing and vision problems,
NO CARDIAC whereas other MPSs can have cardio, normal stature
general features of most MPSs
regression, coarsening features, inguinal / umbilical hernias, cardiac valve dysfunction, corneal clouding , claw hand, hepatosplenomegaly
Gene, MOI, and onset of MPS IV
biochemical findings
Morquio
GALNS, GLB1, childhood, live to adult hood
elevated GAGS- elevated Keraton
General features of MPS IV
short trunk dwarfism; NORMAL INTELLECT
Gene MOI and onset of Batten disease
Biochemical findings
CLN genes, AR, childhood (death in teens)
elevated urine dolichol
Clinical features of Batten disease
normal development until 4-6y; then regression, Vision, movement, and cognition
Gene + MOI for Alpha-1 Antitrypsin Deficiency
SERPINA1 ; Autosomal Co-Dominant
two different alleles expressed (M, S, Z, etc) and both contribute to the phenotype
General features of Alpha 1 Antittrypsin Deficiency
lung and liver disease- adult onset
Levels of AAT produced by following alleles
M, S, Z , F, I
M: most common; produced normal AAT
S: low levels of AAT
Z: Very low levels of AAT
F: functionally impaired, quantitatively normal
I: mild quant deficiency
Phone type based on Alleles
MS/SS
MZ
SZ
ZZ
MS/SS - Produce enough AAT
MZ - Slight increased risk for impaired lung/ liver
SZ - increased risk for lung disease
ZZ - high res for lung and liver disease
Gene + and clinical features of Biotinidase Deficiency
BTD - unable to recycle biotin
rashes, alopecia, treated with biotin supplements
severe form can have neurological symptoms, hearing and vision loss (irreversible)
Infant who is missing milestone, has macrocephaly, seizures, and feeding / sleep issues
Brain MRI shows leukodystrophy (white matter changes)
WES reveals biallelic mutations in ASPA
Canavan disease
Anemia caused by certain triggers; Fava beans being one of them
G6PD deficiency - X linked
Gene + MOI and biochemical findings of Smith Lemli Optiz
DHCR7; AR
Elevated serum 7-DHC and low Cholesterol
Differential when very low uE3 (estriol) on quad screen
Smith Lemli Opitz
General features of Smith Lemli Optiz
2-3 syndactyl, polydactyl, genital abnormalities
growth deficiency (pre + post natal); moderate to severe ID
Gene and general features of Galactosemia
and what to avoid
GALT
cataracts, jaundice, liver damage, lethargy
avoid breast feeding; no lactose
See a baby with bilateral cataracts and mild galactosemia
Galactokinase 1- GALK
Symptoms: arthritis in early adult hood, heart problems
kidney and liver stones
Black urine!
Alkaprotunuria - restrict tyrosine and phenylalanine
An individual presents with homozygous variants within the GALT gene, but has never experienced symptoms of a metabolic condition. Why might this be?
homozygous for the Duarte variant. These individuals often do not display symptoms of galactosemia. If found on NBS, individuals are usually monitored for 2 years, and if no symptoms arise, they are discharged from care.
A 12-year-old child has been experiencing rhabdomyolysis and myoglobinuria after physical activity.
What enzyme is likely deficient in this child?
Answer:
a) myophosphorylase
The child likely has McArdle Disease (GSD-V)
What is the metabolic function of peroxisomes?
breaks down fatty acids that are too long to be transported into the mitochondria, including VLCFAs and LCFAs
What dietary restrictions benefit individuals with peroxisomal disorders?
most VLCFAs are made endogenously, and are not consumed in diet. Thus, restricting them via diet will not lessen the amount of them still being produced within the body…
A newborn is noted to have a large anterior fontanelle with a broad forehead, micrognathia, hypotonia and seizures. At 6 months of age, he is found to have hearing loss, hepatomegaly, cysts in his liver and kidney, and corneal clouding. His plasma acylcarnitine profile is abnormal.
1) What is the most likely genetic condition at play?
2) Which metabolite is this patient likely unable to process correctly?
Zellweger syndrome
2) very-long chain fatty acids (VLCFAs)
When very-long-chain fatty acids accumulate, what is the most deleterious effect within the body?
(hint: affects a particular organ system)
VLCADs destroy the myelin sheath surrounding nerve cells (ie: demyelination), affecting brain function
accumulation of VLCADS causes white matter disease
What organs are most affected by disorders of lysosomal storage?
Hint: There are 5
brain, bone marrow, liver, kidney, spleen
This is where lysosomes are functioning to store and metabolize specific substrates. In these disorders, these substances accumulate within the lysosomes causing cell destruction and organ damage
What clinical feature can be seen in both Scheie syndrome and Hunter syndrome?
a) coarse facial features
b) life expectancy in teenage years
c) corneal clouding
d) “claw” hand
d) “claw” hand
An 6 month old child is found to have an excess of glycosaminoglycans in her urine. Which condition could possibly fit her diagnosis?
a) Hurler syndrome
b) Scheie syndrome
c) Hunter syndrome
d) SanFillipo syndrome
Answer: a) Hurler syndrome
Hurler syndrome can present between 6-12 months of age
The earliest age of onset for Scheie, Hunter, and SanFillipo is 2 years
