Inborn Errors of Metabolism 1 Flashcards
What are inborn errors of metabolism? (4)
- Congenital disorders caused by an inherited defect in a single specific enzyme that results in a disruption or abnormality in a specific metabolic pathway.
- Inborn errors of metabolism (IEM) are genetic/congenital disorders in which specific enzyme defects interfere with the normal metabolism of exogenous (dietary) or endogenous protein, carbohydrate, or fat.
- Enzyme deficiency metabolic pathway disruption → abnormality
- Many IEM are detected through state newborn screening (NBS) programs
Classification of IEM: Time of onset (4)
- Onset in the neonatal period and early infancy
- Onset can occur in later infancy or adolescence and this presentation should not exclude IEM diagnosis
- Some present clinically before they are detected on NBS
- NBS – results must be followed up
i. Some are initially asymptomatic (PKU) so NBS results must be checked!
Classification of IEM: Clinical presentation (3)
- Most useful approach to correct diagnosis
- Will discuss 5 major presentations
i. Encephalopathy, liver, cardiac, dysmorphic and nonimmune hydrops - Some clinically asymptomatic in the newborn period
i. PKU
Classification of IEM: According to biochemical basis of disease (3)
- Divides IEM according to the biochemical characteristics
- Helps in understanding the pathogenesis of symptoms and treatment approaches
- But less useful for those providing patient care
Disorders of Protein metabolism (3)
If you feed a child protein the child gets sicker:
- Urea cycle disorders (Think elevated ammonia Levels)
- Amino Acidopathies (PKU)
- Organic Acidurias (Propyonic academia)
Disorders of fatty acid metabolism
Fatty acids are bring broken & used for energy → LCFA-MCFA→Hypoglycemia
Disorders of carbohydrate metabolism (3)
- These are gluconeogenesis disorders → Galactosemia
- Pts are not able to metabolize galactose that is found in milk
- This baby will be doing really well initially, then doing ok, then around day 4 they aren’t eating well and they are very lethargic
* Due to the influx of milk, whether breast or formula of cow’s milk protein
Storage Disorders (4)
a. Lysosomal and Glycogen storage disorders
b. Purely neurologic – nerves and spinal cord destroy
c. Tay Sachs and Pompe
d. Think Dor Yeshorim
Peroxismal Disorders (3)
- Defects in function can → severe neurodegenerative disorders
- Zellweger Syndrome
- ALD (X-linked adrenoleukodystrophy)
Mitochondrial Disorders (2)
- Complex multi-systemic conditions from mutations in the mitochondrial genome
- MELAS
Incidence (4)
- Presentation is usually in the neonatal period
- 1:500 live births (1:800)
- The frequencies for each individual inborn error of metabolism vary, but most are very rare
- Term infants who develop symptoms of sepsis without known risk factors
* (As many as 20%) may have an inborn error of metabolism
Pathophysiology of IEMs (3)
- Metabolic processes are catalyzed by genetically encoded enzyme proteins
- The classical mechanism of a metabolic defect is
a. Lack or deficiency of an enzyme resulting in substrate accumulation…increased level of normal substrate
b. And conversion of metabolites to products not usually not present
* *Ex. Urea cycle disorders (substrate ammonia is toxic) –> cerebral edema - End products of the normal pathway will be deficient
IEM symptoms result from (4 w/ description)
- Increased level of the normal substrate
* Ex- Urea cycle disorders → (substrate ammonia is toxic) → cerebral edema - Lack of normal end products
* Ex- 21-hydroxylase deficiency –> lack of cortisol - Alternative products interfere with normal metabolic processes
* propionic acidemia –> Accumulated propionyl-CoA may interfere with the reactions normally using acetyl- CoA - Inability to degrade end products
* Ex- GSD type 2→myocardial dysfunction
* GSD type →hepatomegaly
IEM Risk Factors (5)
- IEMs are genetic disorders
- No definite behavioral or environmental risk factors
- Most IEM’s are recessive – a negative family history is not reassuring
- History (may be risk factors)
a. FAMILY HISTORY:
i. Relatives with MR
ii. Relatives with protein-avoidance/special diet
iii. Unexplained neonatal death / SIDS?
iv. Consanguinity
v. Ethnic background - Positive family history may be helpful!
Infant history (3)
a. Onset of symptoms after a period of “healthy infancy”
b. Onset after introduction of enteral feeds
c. Failure of “usual therapies” to improve condition
i. EX- antibiotics do not work for rule out sepsis
Clinical symptoms that strongly indicate IEM (5)
- History of unexplained neonatal death in the family
- Consanguinity
- Onset of symptoms after a period of “healthy infancy”
- Onset after introduction and progression of enteral feedings
- Failure of ‘usual’ therapies to alleviate symptoms – abx
Misdiagnosis of IEMs (8)
- Bacterial sepsis
- Acute viral infection
- Asphyxia
- Gastrointestinal obstruction
- Hepatic failure
- CNS catastrophe
- Cardiomyopathy
- Neuromuscular disorder
Dif Dx of IEMs (10)
- Child abuse (mimics GA1=glutaric aciduria)
- Sepsis
- Heart Failure
- MS
- Pediatric Apnea
- Pyloric stenosis
- Hypoglycemia
- Meningitis
- Encephalitis
- SIDS
Evaluation: Asymptomatic IEMs in the newborn (4)
- Ex - untreated PKU does not cause any symptoms in the newborn
- Causes irreversible brain damage while the baby appears clinically well
- Check the NBS
- Early detection of PKU in the newborn allows for early treatment plan
Symptomatic IEMs: 5 Major Clinical Presentations
a. Encephalopathy
b. Liver disease
c. Impaired cardiac function
d. Dysmorphic features
e. Non immune hydrops
IEM Presenting with Encephalopathy (3)
- Abnormal tone (hypotonia or hypertonia)
- Seizures
- Lip smacking, tongue thrust, bicycling, generalized tonic-clonic movements
IEM Presenting with Encephalopathy: Diagnostic Studies (6)
- Assess metabolic acidosis
- ABG
- Serum electrolytes (calculate anion gap)
- Ammonia level
- Lactate and pyruvate levels
- Imaging studies
Encephalopathy without (or with mild) metabolic acidosis: differential dx (4)
a. Urea Cycle Defects
b. MSUD
c. Nonketotic hyperglycinemia
d. Peroxisomal disorders
Encephalopathy with severe metabolic acidosis: differential dx (2)
a. Organic aciduria
b. Congenital lactate acidosis
Liver disease IEM presentation (3)
a. Liver enlargement
b. Jaundice
c. Hypoglycemia
Associated IEMs with liver disease (5)
a. Galactosemia
b. Tyrosinemia type 1
c. IE bilirubin metabolism (Crigler-Najjar syndrome)
d. Fatty oxidation disorders
e. GSD type 1 (von Gierke disease)
Impaired Cardiac Function IEMs: Fatty oxidation disorders (3)
- Suspect with an infant that has impairment of cardiac function
- Cardiac arrhythmias can occur
- Severe cardiomyopathy (rare) in some resulting in cardiac failure
Impaired Cardiac Function IEMs: Pompe disease (storage disorder) (3)
- May present in early neonatal period
- ECG changes
- Build up of glycogen in the cardiac muscle and cause damage
Dysmorphic Feature IEMs: Smith-Lemli-Opitz syndrome (4)
a. Microcepahly
b. High forehead, ptosis, epicanthal folds, strabismus,
c. Low set ears, nose with a wide tip and micrognathia
d. Genital abnormalities, syndactyly of the 2-3rd toes
Dysmorphic Feature IEMs: Zellweger syndrome and other peroxisomal disorders (5)
a. High forehead
b. wide and flat nasal bridge
c. epicanthal folds
d. dysplastic ears
e. wide open fontanelles
Non-Immune hydrops IEM presentation (2) and inherited hematologic conditions (2)
Presentation
a. Severe hemolysis
b. Hydrops due to anemia and heart failure
Inherited hematologic conditions
a. G6PD
b. Pyruvate kinase deficiency
Index of suspicion for IEMs (12)
- Rapid deterioration in an otherwise healthy infant
- Septic appearing infant (up to 20% have IEM)
- Failure to thrive (FTT)
- Regression in milestones
- Recurrent emesis or feeding difficulty
- Alteration in respiratory status
- Abnormal odor (body or urine)
- Changing mental status (lethargy)
- Jaundice
- Seizures
- ANION GAP→METABOLIC ACIDOSIS
- Hypoglycemia
Prenatal IEM lab testing (2)
a. Biochemical methods
b. DNA analysis
Diagnostic procedures for IEMs (2)
a. Chorionic villus sampling (CVS)
b. Amniocentesis
Postnatal testing for IEMs (7)
i. CBC
ii. Blood gas
iii. Electrolytes- anion gap
iv. Ammonia level
v. LFTs
vi. Urine for ketones
vii. Urine for reducing substances
Lab tests specific for IEMs (8)
a. Lactic acid
b. Lactate to pyruvate ratio
c. Amino acid analysis (urine)
d. Urine for organic acids
e. Tandem Mass Spectrometry (MS/MS) →NBS
f. Galactosemia testing
g. Muscle/liver/skin biopsies
h. DNA analysis and sequencing
Key steps/questions to ask (4)
- Determine if there is metabolic acidosis
- Is anion gap >16?
- Is there hypoglycemia?
- Is there hyperammonemia?
a. Are the symptoms before or after the first 24 hours of life?
Post-Mortem Evaluation (6)
a. Blood
b. Urine
c. Skin
d. CSF
e. Liver biopsy
f. Autopsy and geneticist consult
Acute care management while waiting for dx (5)
i. Supportive care
ii. Nutritional
iii. Dialysis
iv. Vitamin treatment
v. Medications
Long-term care (6)
a. Diet
b. Provision of deficient substance
c. Vitamin, cofactor, and other disease specific therapy
d. Lifelong therapies
e. Early intervention
f. Liver, bone or stem cell transplant
