Inborn Errors of Metabolism 2

Question 1

What is the approximate overall frequency of inborn errors of metabolism?

Answer 1

1/5000

Question 2

What can be unusually diagnostic of neonates in the absence of definitive symptoms (lethargy, convulsion, coma, vomiting, poor feeding)?

Answer 2

Unusual odors

Question 3

What are the five major components to evaluation of a newborn with a suspected metabolic disorder?

Answer 3

1. History
2. Physical examination
3. Initial screening tests - CBC, electrolytes, ABG, urinalysis
4. Advanced screening - plasma amino acids, urine amino acids, plasma acylcarnitine
5. Definitive diagnosis - molecular + enzymatic methods

Question 4

What tests can differentiate between a metabolic disorder and an infection when these symptoms are not responsive to glucose or calcium?

Answer 4

1. Plasma ammonia

2. Blood pH + CO2

Question 5

What will be diagnostic of a urea cycle disorder with plasma ammonia + blood pH?

Answer 5

1. High ammonia

2. Blood pH is normal

Question 6

What will be diagnostic of an organic acedemia with plasma ammonia + blood pH?

Answer 6

1. Ammonia can be high or normal

2. Blood pH is low (Acidosis)

Question 7

What will be diagnostic of an aminoacidopathy or galactosemia?

Answer 7

1. Ammonia is normal

2. Blood pH is normal

Question 8

How are life-threatening emergencies in metabolic disease acutely managed?

Answer 8

1. Prevention of catabolism - preventing breakdown of fatty acids or amino acids which may be toxic
2. Halt catabolism via administration of IV glucose
3. Toxin removal if needed -> hemodialysis for hyperammonemia
4. Stop dietary source substrate

Question 9

How does chronic management of metabolic disease differ from acute?

Answer 9

Continued avoidance of substrate, but may choose to supplement with cofactor + use alternative pathways + enzyme replacement therapy.

Organ transplantation (liver, bone marrow) may be needed in some diseases

Question 10

What is the use of saproterin in PKU?

Answer 10

Synthetic form of BH4 - improved blood phe levels in 20-56% off patients, allowing increased ingestion of dietary protein

Question 11

What two compounds can be used to increase ammonia excretion and what do they bind to?

Answer 11

1. Benzoate - Glycine
2. Phenylacetate - glutamine

These are both rapidly excreted in urine when complexed (hippurate, phenylacetylglutamine)

Question 12

When is the blood sample collected, and what are the three goals of newborn screening?

Answer 12

24 hours after birth - state law in Michigan

3 P’s

1. Prediction - identifying patients before manifesting disease
2. Prevention - initiate therapeutic interventions to stall disease
3. Personalization - optimize their outcomes by knowing the exact issue

Question 13

What device has been critical in the advancement of newborn screening? What does each chamber do?

Answer 13

Tandem mass spectrometer -
First chamber - separates ions v`ia collision chamber
Second chamber - sorts pieces and weighs them to produce mass spectrum

Question 14

What clinic in Michigan is the referral site for diagnostic confirmation and lifelong management of metabolic diseease?

Answer 14

Children’s Hospital of Michigan Metabolic Clinic

Question 15

What is one unanticipated consequence of expanded NBS (newborn screening)?

Answer 15

Asymptomatic infants with disorders typically associated with devastating course -> genotype does not correlate with phenotype

Question 16

What are two avenues for further improvements of newborn screening technologies?

Answer 16

1. Proteomics - look for the proteins

2. Next gen sequencing - screen for any disorder which the mutations are known

Question 17

What are three other disorders currently being considered for newborn screening?

Answer 17

1. Duchenne Muscular Dystrophy - Creatine Kinase
2. Lysosomal Storage diseases - enzyme therapy has been good for some
3. Spinal muscular atrophy
4. Fragile X