Aminoacidopathies, Organic Acidemias, and Defects of Urea Cycle

Question 1

Name the aminoacidopathies.

Answer 1

PKU (classic, cofactor deficiency, maternal)
Non-PKU Hyperphenylalanemia
Maple Syrup Urine Disease
Homocystenuria
Hyperhomocysteinemia
Tyrosinemia

Question 2

Name the organic acidemias discussed in class.

Answer 2

Methylmalonic Acidemia
Propionic Acidemia
Cobalamine Deficiencies (Cblc disease)
Isovaleric Acidemia
3MCC

Question 3

Name the urea cycle defects.

Answer 3

OTC Deficiency (X-linked)
Argininosuccinate Lyase deficiency
Arginemia

Question 4

What is classic PKU?

Answer 4

phenylalanine dehydrogenase deficiency
when untreated, presents with severe, irreversible mental retardation, hypopigmentation (Phe –> Tyr –> melanin), seizures, behavioral problems
with treatment most have normal intellect but some develop ADHD, mood disorders, or executive function defects related to plasma phenylalanine levels

Question 5

What is Cofactor deficiency PKU?

Answer 5

deficiency of tetrahydrobiopterin that presents with the same symptoms as classic PKU

Question 6

How are PKUs (general) treated?

Answer 6

restriction of substrate (Phe free formula, some natural protein, non-protein foods)
provide product (all formulas supplemented with tyrosin)
provide cofactors (tetrahydrobiopterin)
substitute enzyme (clinical trials with alternate enzyme)
block transport (large neutral amino acids to compete at blood brain barrier)
goal is to maintain Phe level between 2-6

Question 7

What is Maternal PKU?

Answer 7

when a mother has untreated PKU –> elevated Phe levels which are teratogenic (causes microcephally, ID, congenital heart disease, low birth weight)
severity of effects correlated with [Phe]
necessary to keep [Phe] between 2 and 5 prior to conception and throughout pregnancy because organogenesis is early in gestation (if not well managed women may not detect the pregnancy in time for treating to matter –> babies normally highly affected)

Question 8

What gene is associated with PKU?

Answer 8

PAH gene
>500 mutations
panethnic

Question 9

What is Non-PKU Hyperphenylalanemia?

Answer 9

less severe form of PKU that does not require treatment because some PAH has residual function normally resulting in Phe <20mg/dl

Question 10

What is the difference between Hyperphenylalaninemia and Variant PKU?

Answer 10

<6mg/dl Phe due to residual PAH activity = hyperphenylalanemia (no known adverse effects; do not treat)
620mg/dl Phe due to residual PAH activity = variant PKU (treat with phenylalanine restricted diet)

Question 11

What is Maple Syrup Urine Disease?

Answer 11

on NBS but low incidence
deficiency of BCKAD (branching amino acid cannot be properly digested –> high levels of leucine and branched fatty acids)
presents with altered mental state, poor feeding, and lethargy progressing to coma
in older children, ataxia and slurred speech, waxing/waning mental status changes
severe neurological damage or death due to cerebral edema

Question 12

How is Maple Syrup Urine Disease treated?

Answer 12

initial and acute decompensations treated with intensive care (monitoring of neurological status, fluids status, and sometimes hemodialysis)
long term maintenance with dietary restrictions of BCAA (BCAA deficient formulas and protein restricted diet), provide cofactors (thiamine trial), liver transplant is curative

Question 13

Explain the genetics of MSUD.

Answer 13

mutation in the E1alpha/E1beta subunit of the multimeric enzyme (mutations in other subunits cause different conditions)
AR
panethnic
incidence increased in menonites (E1alpha) and AJ (E1beta) populations

Question 14

What is homocystenuria?

Answer 14

found on NBS
deficiency of CBS (required for connective tissue proper development) leading to accumulation of homocystein and methionine
presents as marfanoid habitus (tall, long arm span), dislocated optic lenses, osteoporosis, ID (distinct from Marfans), thromboembolic events
good prognosis if well managed (if homocystein level >100 there is high liklihood of thrombolytic event)

Question 15

How is homocystenuria treated?

Answer 15

restrict substrate (dietary restriction of methionine)
provide cofactors (vitamin B12 and B6)
provide alternative routes of elimination (betaine/cystadade)

Question 16

What is Tyrosinemia Type I?

Answer 16

Hepatorenal/classical
fumaryl acetoacetate hydrolase deficiency
characterized by liver failure, hepatocellular carcinoma, renal Fanconi’s, porphyria-like attacks
due to fumarylacetoacitate and succinylacetone accumulations

Question 17

What is Tyrosinemia Type 2?

Answer 17

Occulocutaneous
tyrosine aminotransferase deficiency
less severe than Type 1 (no accumulation of metabolites because disruption is higher in pathway)
results in lesions on corneas, palms, and soles of feet as well as hyperkeratosis
tyrosine accumulations result in crystals in eyes and under skin (painful)

Question 18

How are tyrosinemias treated?

Answer 18

low Phe and tyrosine in diet
some natural protein
protein free foods
Type 1 use NTBC (inhibitor of HPD which blocks higher in the pathway to prevent the accumulation of toxic metabolites –> artificial Type 2)

Question 19

How do organic acidemias (in general) typically present?

Answer 19

emesis
failure to thrive
developmental delay
metabolic acidosis (normal blood pH= 7.4 so anything other than that is acidotic and needs attention)
hyperammonemia

Question 20

What is methylmalonic acidemia?

Answer 20

deficiency of methylmalonyl CoA mutase (or adenosylcobalamin cofactor deficiency or defects in cobalamin synthesis and transport)
“benign” form with lower level of elevation or transient form persisting up to a year after birth (detected on NBS)
some patients are vitamin B12 responsive (because it is a cofactor of the reaction)- which can be determined genetically because they are distinct

Question 21

What complications are associated with methylmalonic acidemia?

Answer 21

renal disease (MMA attacks kidneys)
gout and hyperuricemia (can present)
pancreatitis (common)
metabolic “stroke” with subsequent involuntary movements (may occur)
optic atrophy or retinitis may be late complications
prolonged QT waves
can mimic mitochondrial disease in long term untreated patients

Question 22

What is propionic acidemia?

Answer 22

propionyl CoA carboxylase deficiency (or due to deficiency of biotin cofactor)

Question 23

What complications are associated with propionic acidemia?

Answer 23

no biotin response (pts with isolated PA)
recurrent pancreatitis (common cause of death)
prolonged QT (with or without cardiomyopathy due to secondary respiratory chain defects)
optic atrophy (due to secondary respiratory chain defects) and retinitis
metabolic stroke (may occur; acute or progressive extrapyramidal syndrome)

Question 24

How do you acutely manage MMA/PA?

Answer 24

NPO- cut protein dose
reversal of catabolism (main goal)
correction (bicarb replacement)
detoxification (levocarnitine and hemodialysis for the refractory acidosis)

Question 25

What are the long term treatments available for MMA?

Answer 25

restrict substrate (low protein, restruct substrate of amino acid, antibiotics to lower gut bacteria's production of propionic acid) provide cofactors (hydroxy B12 if applicable) alternate routes of elimination (carnitine) other (bicitra for acid-base stabilization)

Question 26

What are the long term treatments available for PA?

Answer 26

restrict substrate (low protein, restrict substrate of amino acids, antibiotics to decrease gut bacteria's production of propionic acid) provide cofactors (biotin) alternative routes of elimination (carnitine) other (biactra for acid-base stabilization)

Question 27

What are the features of Cbl C disease?

Answer 27

``` methylmalonic acidemia homocystinuria mental retardation seizures nystagmus cardiac abnormalities abnormal dentition ```

Question 28

What is isovaleric acidemia?

Answer 28

``` AR deficiency of isovaleryl CoA dehydrogenase resulting in an inability to fully metabolize leucine accumulation of isovaleric acid, isovalerylglycine, isovalerylcarnitine, 3-hydroxyisovaleric good prognosis (normal neuro outcomes) most notable symptom is foot odor acute form (presents in neonatal period with emesis, lethargy, metabolic acidosis, hyperammonemia, ketonuria, odor, and pancytopenia) or chronic intermittent form (1st decompensation follows stressor) or asymptomatic form ```

Question 29

What options are available for treatment of isovaleric acidemia?

Answer 29

restrict substrate (low protein and leucine) alternate routes of elimination (carnitine and glycine) other (bicitra for acid-base stabilization)

Question 30

What is 3MCC?

Answer 30

3-methylcrotonyl CoA carboxylase deficiency leucine catabolic pathway most commonly seen acidemia most are asymptomatic but those who do have symptoms present with emesis, hypoglycemia, and ketosis

Question 31

How do you treat 3-MCC?

Answer 31

protein restriction biotin carnitine

Question 32

What is the general presentation of Urea Cycle Disorders?

Answer 32

young age of onset (typically >24 hours of age) lethargy, poor feeding, emesis, seizures, bleeding, hyperventilation, coma death with no treatment later onset defects (caused by less severe mutations/ better enzyme activity) present with ID, recurrent emesis, failure to thrive, recurrent coma, and history of protein aversion

Question 33

What alternative diagnosis can be considered when a newborn presents with symptoms of a urea cycle disorder?

Answer 33

sepsis (most common cause of these symptoms) | use ammonia levels to distinguish

Question 34

How are Urea Cycle Disorders treated (generally)?

Answer 34

``` restrict substrate (essential aa formulas) provide product (arginine and citruline supplementation) replace enzyme (liver transplant- especially in patients with difficulty in compliance) provide alternative routes of elimination (ammonia scavengers like sodium phenylbutyrate and sodium phenylacetate plus sodium benzoate) treat secondary effects (increased intracranial pressure, DIC, etc.) ```

Question 35

Describe the inheritance of OTC deficiency.

Answer 35

x-linked female carriers tend to have mild symptoms (due to X inactivation) but can have severe symptoms during stressors (eg. pregnancy, surgery)

Question 36

What are symptoms or arginosuccinate lyase deficiency?

Answer 36

typical coarse hair | cirrhotic changes

Question 37

What is the characteristic feature of Argininemia?

Answer 37

lower limb spasticity (most patients)