Amino Acid Disorders Flashcards
Deficiency of hepatic phenylalanine hydroxylase (PAH, which converts Phe Tyrosine with help of BH4 cofactor)
PKU
Branched chain ketoacid dehydrogenase (BCKAD) deficiency
Maple Syrup Urine Disease
Autosomal Recessive; fumarylacetoacetate hydrolase (FAH) deficiency
Tyrosinemia Type I
Defect in CBS enzyme (which normally converts homocysteine cystathionine)
Homocysteinuria
Newborn Screening in 2014
> 40 disorders screened for in Colorado
Minimum screen of ‘mandated disorders’ signed into federal law 2008
ex: PKU, MSUD, galactosemia, etc
PKU Pathophysiology
Due to elevated total body phenylalanine
No direct pathologic effect on the liver
Mental retardation and autistic behaviors
White matter hyperintensities (pseudoleukodystrophy)
Seizures
PKU
therapy for PKU
Restrict dietary protein – Phe tolerance depends on residual enzyme activity
Supplement with phenylalanine-free medical beverage
Strict rx in prego mommy w/ pku
Branched chain ketoacid dehydrogenase (BCKD) deficiency
Maple syrup urine disease
Autosomal recessive inheritance
Incidence 1/185,000 births
Few abnormalities on routine lab tests
Maple syrup odor in urine (2-hydroxyisoleucine)
Severe neonatal form MSUD
Late onset
Ataxia
Ketoacidotic coma sometimes with hypoglycemia
Amino acids and keto acids can be normal between attacks
Acute intermittent form MSUD
-with residual activity
Hypotonia and developmental delay
Failure to thrive
Spastic paraplegia
Subacute chronic form MSUD
Acute treatment of MSUD
- Eliminate dietary protein
- Supplement val and isoleucine
- Provide adequate non-protein energy source and amino acids that are not BCAA
- Avoid hypotonic fluids
- Treat cerebral edema if symptoms develop
Fumarylacetoacetate hydrolase (FAH) deficiency Autosomal recessive inheritance
Tyrosinemia type 1
Early in infancy– Liver disease (hepatic failure or cholestatic jaundice or cirrhosis with renal tubulopathy)
Tyrosinemia type 1
Porphyria-like attack at any age (can be presenting sign)
- Ketonuria, irritability, poor feeding
- Encephalopathy (lethargy, intermittent apnea, opisthotonus, stereotyped mvmts i.e. “fencing” or “bicycling”) progressing to coma and resp failure within 10 days
MSUD
- -Developmental delay, autistic behaviors, seizures
- Musty odor to urine
- Decreased hair/skin pigmentation (from tyrosinase inhibition)
- Later in life: exaggerated DTRs tremor, para/hemiplegia
untreated PKU
Late infancy: Rickets due to renal tubulopathy (Fanconi syndrome) with no obvious liver failure
Tyrosinemia type 1
Porphyria-like attack at any age (can be presenting sign)
Tyrosinemia type 1: Treatment
Phe and Tyr restriction==> avoid excessive hypertyrosinemia (risk of keratitis,or Palmoplantar keratosis )
Liver transplant if hepatocellular carcinoma develops
Eye abnormalities
Skeletal defects (Marfanoid habitus, osetoporosis, scoliosis; most common in B6 non-responsive) *looks like marfan
Developmental disability and neuropyschiatric s/s
Homocysteinuria
- B6 responsive: usually milder
- B6 non-responsive
If untreated: repeated neurologic crises and death before age 10
Type 1: hepatorenal–> nitisinone
Type 2: oculocutaneous; tyrosine crystals in eyes, hyperkeratosis of palms and soles
Type 3: may be asymptomatic, some developmental delay
Tyrosinemia Type I
Autosomal Recessive; fumarylacetoacetate hydrolase (FAH) deficiency
Cystathionine β-synthase deficiency
Autosomal recessive inheritance
Classical homocystinuria
Homocystinuria treatment
Pyridoxine (B6) challenge
750 mg orally per day for one week
Restrict dietary protein
Supplemented with methionine free medical foods
Oral betaine
Consider supplementation with B12, folate, and/or cysteine
50% of CBS (Cystathionine β-synthase) mutations are __________ responsive
pyridoxine (vitamin B6)
