Inborn Errors of Metabolism (all DEMS)

Question 1

When you see the following things elevated, what do you think?
ELEVATED: succinylacetone, plasma ketones, tyrosine, methionine, phenylalanine
ELEVATED: urine tyrosine metabolites
ELEVATED: delta-ALA

Answer 1

Tyrosinemia Type I

Question 2

What would you look for to make the dx of Tyrosinemia Type I

Answer 2

When you see the following things elevated, what do you think?
ELEVATED: succinylacetone, plasma ketones, tyrosine, methionine, phenylalanine
ELEVATED: urine tyrosine metabolites
ELEVATED: delta-ALA

Question 3

what is the classic symptom presentation of Homocysteinuria?

Answer 3

developmental delay
skeletal abnormalities (marfanoid habitus, osteoporosis)
severe myopia AND/OR ectopia lentis****
Thromboembolic events (major source of mortality in these patients)

Question 4

What is the more ATYPICAL sxs constellation of homocysteinuria?

Answer 4

seizures, psych problems, dystonia, hypopigmentation, malar flush

Question 5

What markers help you make a homocysteinuria diagnosis?

Answer 5

increased plasma homocysteine
genetic testing evidence of CBS mutation
increased levels of methionine
nL levels of methylmalonic acid, nL levles of B12 (these are to help you distinguish btw other problems and this one

Question 6

What are the treatment options for homocysteinuria?

Answer 6

Prevention of primary manifestations:

• (goal is keep the plasma levels of homocysteine about normal)
• protein-restricted and methionine-restricted diets; possibly betaine treatment;
• folate and vitamin B12 supplementation.
• Those responsive to B6 (pyridoxine) receive pyridoxine therapy.
• Betaine therapy is a major treatment in adolescents and adults.

Question 7

Urea Cycle inborn errors can result in hyperammonemia. What is this?

Answer 7

Acute symptoms - encephalopathy (seizures, ataxia, personality changes, temperature instability, ppt of psychosis), vomiting, respirator alkalosis
*for respiratory alkalosis - check ammonia in a child hyperventilating for no other apparent reason

Chronic symptoms - developmental delay, migraines, liver damage (enlarged and increased LFTs)

Question 8

What are the acute symptoms of hyperammonemia?

Answer 8

Acute symptoms - encephalopathy (seizures, ataxia, personality changes, temperature instability, ppt of psychosis), vomiting, respirator alkalosis
*for respiratory alkalosis - check ammonia in a child hyperventilating for no other apparent reason

Question 9

What are the chronic symptoms of hyperammonemia?

Answer 9

Chronic symptoms - developmental delay, migraines, liver damage (enlarged and increased LFTs)

Question 10

What are the myriad Urea Cycle errors we covered (only recognize them, but know the starred one)

Answer 10

ARG-1 - arginase-1 deficiency
ASS-1 - argininosuccinate synthase deficiency
CPS-1 (most severe)** - carbamoyl phosphate synthetase I - the eznyme responsible for starting (kick start) the urea cycle
NAGS - n-acetylglutamate synthase (the required activator for CPS-1)
OTC**(most common)
ASL (arginosuccinate lyase)

Question 11

What is the most common inborn error of the urea cycle?

Answer 11

OTC deficiency - ornithine transcarbamylase

*from ornithine to citrulline, adding carbamoyl phosphate to ornithine to make citrulline

Question 12

Why might a young child come in with OTC deficiency and nobody would ever know?

Answer 12

• main point here is that it’s not covered in a newborn screen
• you need to be vigilant for hyperammonemia symptoms and have an inborn error at least in mind

Question 13

What are the diagnostic criteria for a Urea Cycle Problem?

Answer 13

• decreased citrulline
• increased glutamine
• increased orotic acid (pathognomonic)****

Question 14

What is the most severe of the OTC deficiencies?

Answer 14

The X-linked version where they get the null mutation

• if these boys don’t die before or during birth they WILL present within days
• you must dialyze these babies and get their liver transplanted

Question 15

What do you do in the case of OTC deficiency?

Answer 15

• same treatment for any Urea cycle disorder
• Treatment of manifestations:
• Acute severe hyperammonemia: Dialysis and hemofiltration to reduce plasma ammonia concentration;
• intravenous administration of arginine hydrochloride and nitrogen scavenger drugs to allow alternative pathway excretion of excess nitrogen;
• restriction of protein for 12 to 24 hours to reduce the amount of nitrogen in the diet
• calories given as carbohydrates and fat
• physiologic stabilization with intravenous fluids and cardiac pressors while avoiding overhydration.

Question 16

What’s going on in PKU?

Answer 16

• phenylalanine hydroxylase deficiency
• buildup of phe in the blood, which has direct toxicity on the brain
• fairly common disorder, checked in the heelstick on the newborn
• PKU = phenylketouria
• native history (don’t really see this any more) = decreased pigmentation (can’t get to tyrosine which goes eventually to melanin), eczema, and hypomyelination on MRI

Question 17

What are the treatments for PKU?

Answer 17

restricted diet (pretty much the MO for all the AA inborn errors of metabolism)

• most important to start the diet restriction in the first 6 years to prevent the intellectual disability
• sapropterin*****(essentially supplement of BH4, which can help the residual enzyme not KO by the mutation work)

Question 18

What is a special population of PKU patients you need to be pretty aggressive with in treatment?

Answer 18

• MOTHERS
• increased Phe levels in teh blood will cross the placenta and mess with the fetus
• heart disease, microcephaly and growth retardation can be the natural history
• thus have a very strict diet with mothers before, during pregnancy

Question 19

What are the key associations for Gaucher disease?

Answer 19

*Beta-glucosidase deficiency
*adult onset
HSM
anemia and decreased platelets
x-ray pathognomonic finding = eherlenmyer flask abnormality of the femur
highest prevalance in ashkinazi jews
BONY PAIN on presentation (avascular necrosis)
*Gaucher cells - waxy paper, tissue paper, crumpled paper, etc on bone marrow aspirate

Question 20

what are the organs involved in Gaucher Disease?

Answer 20

skeleton
liver
spleen
bone marrow
NOT CNS - these people have normal intellect and present in adulthood (type 1. Type 2 does have CNS findings)

Question 21

while type 1 gaucher disease is the far higher yield, type 2 differs in what very specific manner?

Answer 21

CNS symptoms are NOT in type 1 but they are in type 2

• type 2 is more severe, presents in infancy or childhood
• look for hyperreflexia in children for this one

Question 22

What are the key associations for Tay Sachs disease?

Answer 22

• Beta-hexosaminidase A deficiency
• increased STARTLE REFLEX
• normal liver and spleen
• onion skin lysosomes
• CHERRY RED SPOT - probably the most pathognomonic
• progressive neuro degeneration

Question 23

How many types of Tay-Sachs are there?

Answer 23

3. Type 1 is the highest yeild and the cherry red spot one
   type 2 is juvenile and ataxia is the first symptom
   type 3 is the adult presentation (variable neuro findings and they have normal IQ)

Question 24

What is the treatment for Tay-Sachs?

Answer 24

• main point here is that there is none
• patients have a life expectancy of about 5 years maximum
• most die from airway management complications and pneumonia