inborn errors of metabolism Flashcards
deficiency in pku
phenylalanine transferase (cant convert phe to tyrosine); mild problem with BH4
lab results for pku
UOA: inc phenylketones
PAA: inc Phe, low tyrosine
due to low tyrosine-
1. low neurotransmitters: dopamine, norepinephrine, and adrenaline
2. fair skin (Tyr is a precursor of the skin pigment melanin)
PKU as teratogen (features)
dysmorphic features, microcephaly, IUGR, congenital heart
clinical features in infant with PKU
fair skin
eczematoid rash
mousy/musty odor
treatment of PKU
restrict phe, BH4 supplement
first test for change in mental status
blood glucose
condition could falsely elevate NH4
use torniquet, prolonged process in lab (result in 1 hr), no ice
how to collect NH4
free flow, ice, process within 1 hr
Condition with elevated lactate:pyruvate
mitochondrial d/o
What presents with elevated plasma AA
aminoacidopathies, urea cycle, organic acedemia
What presents with abnormal urine organic acid
AA, FAOD, organic acid
Mode of inheritance of aminoacidopathies
autosomal recessive
Labs suggestive urea cycle do
AbN PAA, elevated NH4, respiratory alkalosis
Labs suggestive Organic Acids
Abn PAA, metabolic acidosis, AbN UOAs
Deficiency in MSUD
branched chain alpha ketoacid dehydrogenase
What are the Branched-chain AA
Isoleucine, valine, LEUCINE
MSUD and ethnic group
Old order Mennonites
presentation MSUD
diminished arousal
poor feeding
hypertonia
coma
death
maple syrup smell
which branched-chain AA causes Sx in MSUD
Leucine (neurotoxic and osmotic effect)
Acute mgt of MSUD
high dextrose isotonic Iv and lipids; serum Na high normal
long term mgt for MSUD
diet, liver transplant
deficiency in homocystinuria
cystathionine beta synthetase
labs finding homocystinuria
elevated homocysteine and methionine in blood, urine, NBS, plasma AA
clincal features of homocystinuria
intellectual disability
tall stature
osteoporosis
recurrent thrombosis
ectopia lentis (lens dislocation- downwards)
differential for homocystinuria
marfans
Management of homocystinuria
vit B6 (cofactor)
betaine (dec homocysteine in bld)
aspirin (prevent stroke)
deficiency in tyrosinemia (hepatorenal tyrosinemia)
fumarylacetoacetase
pathognomonic tyrosinemia
inc tyrosine (lacks specificity and sensitivity) must differentiate from transient tyrosinemia of newborn
inc urine and bld succinyl acetone
Confirmation tyrosinemia
UOA: succinylacetone
PAA inc tyrosine and methionine (liver issue)
Treatment tyrosinemia
Nitisinone, tyrosine restrict
Deficiency Hyperglycinemia (nonketotic hyperglycinemia)
deficiency in glycine cleavage
lab and clinical findings in hyperglycinemia
inc CSF glycine
seizure
hiccups
apnea
Absent corpus collosum
EEG burst supression
urea cycle
A- N-acetylglutamate synthetase
B- Carbamyl phosphate synthetase
C- Ornithine carbamyl transferase
D- Arginosuccinic acid synthetase
E- Argininosiccinic lyase
F- Arginase
findings in urea cycle oct def
high: glutamine, orotic acid
low: citrulline, arginine
urea cycle def arginosuccinic acid synthetase
high: glutamine, orotic acid, citrulline low: arginine
urea cycle arginase def
cant change arginine last step- all high: glutamine, orotic acid, citrulline, arginine
Which inborn metab defect is X-linked recessive
OCT (ornithine carbamyl transferase)
Treatment to remove ammonia
- hemodialysis (fastest)
- Hydration
- Remove nitrogen: sodium benzoate and sodium phenylacetate- scavenger, water soluble
- Sodium phenylbutyrate- once stable
What to monitor when treating with Benzoate for NH4
Na and Cl
(high Na content, hence improtance of hydration)
What affects outcome for urea cycle DO
length of time with high NH4
Outcome/Risk for arginase deficiency
Spastic diplegia
What is organic acids
deaminated remains of amino acids
What is lab finding for organic acidemia
- metabolic acidosis with elevated anion gap
- NBS: odd chain acylcarnitine (C3, C5)
Treatment of acute episode organic acidemia (6)
- high dose carnitine
- IVF D10 with NS
- IV lipid
- Insulin (anabolic)
- Biotin and Vit B12 (cofactor)
- Glycine (binds to nontoxic form)
lab findings pathognomic of urea cycle DO
Elevated ammnonia
Respiratory alkalosis
No ketoacidosis
What is the major metabolite of AA and lipid
Propionyl-CoA
Defect in glutaric acid acidemia
defect in glutaryl CoA dehydrogenase (metabolism of tryptophan and lysine)
Ethnic group associated with glutaric acidemia
Amish
Which organic acidemia does not present with metabolic acidosis, ketosis and hyperammoniemia
Glutaric acidemia
Long term morbidity in glutaric acidemia
Involuntary movements (due to basal ganglia injury)
What organic acidemia is child abuse a differential?
Glutaric acidemia (risk for subdural hemorrhage and retinal hemorrhage)
What triggers the sequela of glutaric acidemia
Fever
(resulting in dystonia and movement disorder)
Associated with sweaty feet
Isovaleric aciduria
Associate with male cat urine
3 methylcrotonyl glycinuria
Key feature of FAOD (fatty acid oxidation do)
hypoketotic hypoglycemia with prolonged fasting
Long Term complication of LCHAD and VLCAD
- rhabdomyolysis
- cardiomyopathy
- liver dysfunction
- retinopathy
- peripheral neuropathy
Complication of heterozygous LCHAD preg women
- fatty liver
- HELLP
- if with this- 1:5 chance of delivering baby with LCHAD
Management with LCHAD
- frequent feed
- mct formula
- Avoid breastfeeding initially
What AA is carnitine made by human de novo from?
Lysine and methionine
What causes carnitine deficiency
- failure to synthasize (Glutaric acidemia)
- Defective carnitine transport (defect in OCTN2 carnitine transporter- dec intestinal absorption and renal reabsroption)
- Depletion of carnityl esters (FAO)
- preterm infants
Function of carnitine
- Transport long chain FA into the mitochondria to produce energy
- Metabolic scavenger
presentation of galactosemia
- poor feeding
- vomiting 2-3 DOL
- Jaundice- hepatomegaly, liver failure
- RTA (acidosis, glycosuria, aminoaciduira)
- Cataract (from excess galactitol)
Sepsis from E coli think of…
galactosemia
Long term risk with galactosemia even wth proper treatment
- premature ovarian failure
- tremors
- learning disability
lab test for galactosemia
- LFT
- low glucose
- Inc galactose in urine (use clinitest- use to identify reducing substance)
Management for galactosemia
- initiate tx immediately with positive NBS result
- No BM (avoid lactose and galactose)- switch to soy or elemental formula
- estrogen replacement for female
- screen for learning disability
What are the 2 glycogen storage do can present in neonates
- von Gierke disease (type I)
- Pompe (type II)
GSD that affects the liver with direct influence with blood glucose and present with lactic acidosis
Von Gierke
Enzyme: glucose 6 phosphatase
Which GSD affects various tissue but no direct effect on blood glucose
Pompe (Type II)
Enzyme lysosomal alpha glucosidase
which GSD can have cardiomyopathy
Pompe disease
Which GSD can have hepatic tumor
Von Gierke
Presents with introduction of formula, fruit or vegtables
fructosemia
- contains sucrose (formula), fructose or sorbitol
Which organelle digests complex molecules for recycling or degradation
lysosome
Pathognomonic for mucopolysaccharidoses
Dystosis multiplex (defects of bones and joints)
Alder-Reilly bodies in WBC
Urine with mucopolysacharrides
pathognomonic for lipid storage disease affecting the brain
Macular cherry red spot
(Gaucher does not have macular cherry- does not affect CNS)
difference between lipidoses presenting in infancy
symptoms of Tay-Sachs
from accumulation of sphingolipid GM2
- weakness
- exagerated startle
- myoclonic jerks
- mental regression (unresponsive to environment)
- cheery red spot
- progressive macroecphaly
symptom of Gaucher dis Type I (Ga-OUCH)
from accumulation of glucocebroside in liver, spleen and bone marrow
- anemia/thrombocytopenia
- HSM
- bone pain
Most common lysosomal storage disease
Gaucher Disease type 1
-non CNS disease with splenomegaly
Ethnicity: Ashkenazi Jews
What is the late complication of propionic acidemia
Cardiomyopathy
What are the findings in propionic acidemia
Severe ketoacidosis w or w/o hyperammonemia
Encephalopathy, vomiting, bone marrow suppression
Infant presents normal at birth but few weeks later presents with:
hypotonia, muscle weakness
Macroglossia
Hepatomegaly
CHF due to hypertrophic cardiomyopathy
Elevated CPK, AST, LDH
Muscle biopsy: vacuoles full of glycogen on staining
Pompe disease
-defect in lysosomal acid alpha 1,4 glucosidase (acid maltase)
What defect has cataract as the only finding (completely asymptomatic)
Galactokinase deficiency
Defect in chromsome 17
What is mode of inheritance of Mekes disease
X-linked recessive disease (only in boys)
Impaired uptake of copper
What is the triad of holocarboxylase synthetase or biotinidase deficiency
Alopecia
Skin rash (similar to acrodermatitis enteropathica)
Encephalopathy
What is the bone marrow finding in niemann-pick
Foam cells
Which lysosomal disease presents as infantile neurodegeneration
(inc muscle tone, profound irritabililty, FUO)
Krabbe disease
Which GSD presents with heart failure, respiratory insuffiency, death
Pompe disease
- accumulation of glycogen in lysosome of muscles
CK elevated, shortened P-R interval
How are mitochondrial disorders transmitted
Point mutation in mitochondrial genome via maternal inheritance (Passed from mom)
Mode of inheritance: autosomal recessive
most important function of mitochondria
production of cellular energy in the form of ATP from respiratory chain
- result: dysfuntion in tissue with highes energy demand (brain, skeletal, cardiac)
lab findings in mitochondrial do
Lactic acidosis (metabolic acidosis)
MELaS- myopathy, encephalopathy, lactic acidosis, stroke
Ragged red fibers (muscle myopathy)
What is the defect in Wilsons disease
Hepatic copper transport
Deposition of copper in liver, cornea, basal ganglia, renal tubules
Mode of inheritance: Autosomal recessive
What are the clinical symptoms of Wilsons
hepatic disease
neurologic
hemolysis, dyarthria, extrapyramidal movement
kayser fleischer ring (eye exam)
What is the defect in Menkes disease
Defect in copper membrane transport channel leading to poor absorption and distribution of copper
What is the treatment for Wilsons
D-penicillamine (chelate copper)
What are the clinical symptoms of Menkes
Brittle kinky steely hair
Pudy sagging lips abN eyebrow
skin and joint laxity, wormian bones, osteoporosis
Diagnosis of Wilson and Menkes
Low ceruloplasmin
genetic testing
What are peroxisome
cellular organelle with disparate function: oxidation of very long chain fatty acids
results in neurodegenerative do
what is Zellweger syndrome
also known as neonatal adrenoleukodystrophy
findings:
- dysmorphic features (prominent forehead, wide open fontanel, hypertelorism, broad flat nasal brdige, micrognathia)
- liver disease, cholestasis
- bone involvement (calcified stippling)
- hypotonia
- hearing and vision deficits
What is the deficiency in galactosemia type II
Galactokinase
-Long term complication: Cataract and pseudotumor cerebri (due to osmotic effect of galactitol)
What is deficient in Niemann-Pick
Sphingomyelinase
What is the defect in Gaucher
Glucocerbrosidase
symptoms of biotinidase deficiency
neuro: seizure, hypotonia, ataxia, blindness, hearing loss
immune deficit
alopecia
developmental delay
Sugar found in:
a. breastmilk
b. formula
a. lactose (galactose and glucose)
b. lactose plus sucrose (fructose and glucose)
findings in transient hyperammonemia of the newborn
elevated ammonia in the 1st 24 HOL
normal PAA
No acidosis
What medication can be considered for refractory seizures?
Pyridoxine
(Consider possible inborn error of metabolism- cofactor or vitamin deficiency)
Caution: apnea and respiratory compromise may occur during administration
Neonate presents with
* cleft palate
* congenital heart disease
* hypospadias
* polydactyly
* syndactyly of the second and third toe
What is this condition?
Smith-Lemli-Opitz syndrome
* Diagnostic: elevated plasma 7-
dehydrocholesterol
Cholesterol synthesis
