Organic Acidemias and Urea Cycle Disorders

Question 1

Isovaleric Acidemia: Genetics

Answer 1

Inheritance: Autosomal recessive
(kind of an amino acid disorder too – prevents breakdown of leucine)
Deficient enzyme: Isovaleric acid CoA dehydrogenase deficiency

Labs:
•Acylglycines, acylcarnitine profile
•NBS mass spec

Question 2

Isovaleric Acidemia: Features

Answer 2

Major features:
•Smelly feet odor
•Metabolic acidosis
•Protein aversion
•Thrombocytopenia
•Vomiting, poor feeding, coma
•Seizures
•Developmental delay
•50% severe acute neonatal with rapid death
•50% chronic, episodic with asymptomatic intervals

Treatment
•Dietary leucine restriction
•Glycine supplementation during acute episodes

Biotin deficiency can mimic this disorder

Question 3

Lesch-Nyhan Syndrome

Answer 3

Inheritance: X-linked
Deficient enzyme: Hypoxanthine-guanine phosphoribosyltranserase (Gesundheit!)

Major features:
•Intellectual disability
•Developmental delay
•Growth retardation
•Opisthotonic posturing
•Dysphagia
•Self-injuring behavior
•Hyperuricemia
•Renal failure

Treatment is based on management of symptoms
Affected females typically only present with hyperuricemia

Question 4

General features of Urea Cycle Disorders

Answer 4

Inheritance: Autosomal recessive (OTC IS EXCEPTION!!!!! X-LINKED!!!!!!)

General symptoms:
  •Protein intolerance/avoidance
  •Poor feeding
  •Acute metabolic crises
    oRespiratory alkalosis
    oHyperammonemia
    oVomiting
    oLethargy
    oSeizures
    oComa
  •Untreated illness can lead to ID and DD

Question 5

Urea Cycle Disorders: Labs

Answer 5

Labs:
•Plasma concentration of Citrulline helps to distinguish between proximal (CSP1, NAGS, OTC) and distal (ASS, ASL, ARG) disorders
oAbsent or low in proximal disorders
oElevated in distal disorders
•Arginine is often reduced in all disorders except Arginase deficiency (ARG)

Question 6

Urea Cycle Disorders: Treatment

Answer 6

Treatment:
•Dietary protein restriction
•Medications that provide alternate pathways for ammonia removal (Ammonul)
•Glutamine can act as a nitrogen buffer
•Nitrogen scavenger therapy (Ravicti – sodium phenylbutyrate) – helps kidneys excrete excess ammonia
oOnly for NAGS, OTC, and CPS1
•Arginine supplementation can be effective for ASS and ASL
•Special formulas to supplement amino acids not obtained through diet due to dietary restriction of protein
•Liver transplant for severe cases

Question 7

Proximal Urea Cycle Disorders

Answer 7

•Function within the mitochondria
CPS1
NAGS
OTC

Question 8

Distal Urea Cycle Disorders

Answer 8

•Function in the cytosol
ASS
ASL
ARG

Question 9

CPS1

Answer 9

Deficient enzyme: Carbamoyl Phosphate Synthetase 1
Distinguishing features:
•Severe lethal neonatal onset or less severe later onset
•Elevated ammonia levels

Question 10

NAGS

Answer 10

Deficient enzyme: N-acetylglutamate synthetase
Distinguishing features:
•Elevated ammonia levels
•Similar to CPS1

Question 11

OTC

Answer 11

Deficient enzyme: Ornithine transcarbamylase (ornithine carbamoyl transferase)
Distinguishing features:
•X-linked!!!!!!!!!!!!!!!!
•MOST COMMON UREA CYCLE DISORDER
•Elevated ornithine, uracil, and orotic acid
•Females can be affected
•May present neonatally or in childhood after illness or high protein intake

Question 12

ASS

Answer 12

Deficient enzyme: Arginosuccinic acid synthetase
Distinguishing features:
•Elevated citrulline

Question 13

ASL

Answer 13

Deficient enzyme: Arginosuccinic acid lyase
Distinguishing features:
•Elevated citrulline and arginiosuccinic acid

Question 14

ARG

Answer 14

Deficient enzyme: Arginase
Distinguishing features:
•Elevated arginine
•HYPERAMMONEMIA IS RARELY PRESENT
•Different metabolic presentation – slower onset, muscle weakness often present