Disorders of Amino Acid Metabolism

Question 1

Phenylketonuria (PKU)

Answer 1

• Phenylalanine hydroxylase deficiency
• Converts Phe to Tyr
• PAH gene
• Autosomal recessive
• When untreated: severe intellectual disability, microcephaly, epilepsy, behavioral concerns, musty odor, pale skin/hair, exaggerated neurological reflex
• When treated: psychiatric issues, may still be learning difficulties
• NBS analysis of Phe and Tyr levels
• Treat with low Phe diet, special low Phe formula, BH4 supplementation
• Maternal PKU - women with PKU who are pregnant must be well maintained on diet or high Phe levels are teratogenic to fetus - risk for congenital heart disease, IUGR, microcephaly, intellectual disability

Question 2

Maple Syrup Urine Disease (MSUD)

Answer 2

• Branched-chain alpha-ketoacid dehydrogenase complex deficiency
• Breaks down branched-chain amino acids (Leucine, Isoleucine, Valine)
• BCKDHA, BCKDHB, DBT genes
• Autosomal recessive
• Classic phenotype: maple syrup odor to urine (caused by cerumen), poor feeding, lethargy, opisthotonic posturing, respiratory failure, coma
• Intermediate phenotype: maple syrup odor to urine, poor feeding, poor growth, developmental delay, encephalopathy with illness
• NBS analysis of combined Leucine-Isoleucine ratio
• Treat with dietary leucine restriction, high-calorie leucine-free formulas, monitoring for illness that could lead to crisis

Question 3

Homocystinuria

Answer 3

-Cystathionine beta-synthase deficiency
-Catalyzes the first step in the breakdown of homocysteine
-CBS gene
-Autosomal recessive
-Ocular symptoms: myopia, ectopia lentis
-Skeletal symptoms: Marfanoid habitus, osteoporosis, scoliosis, high palate, pectus deformity
-Vascular symptoms - thromboembolism may lead to death
-CNS symptoms - developmental delay, possible intellectual disability, seizures, psychiatric concerns
-NBS analysis of methionine levels
-Treat with vitamin B6 (pyroxidine) in individuals who are responsive to this therapy, protein restricted diet
-Betaine can provide an alternate pathway to convert homocysteine to methionine, but must be used carefully to avoid over-elevating methionine levels
-Folate and vitamin B12 optimize conversion of
homocysteine to methionine (can help individuals with residual enzyme activity)

Question 4

Tyrosinemia Type I

Answer 4

-Most severe form
-FAH gene
-Autosomal recessive
Phenotypes
-Acute with liver failure at infancy
-Jaundice
-Renal tubular dysfunction
-Rickets (liver failure leads to lack of vitamin D activation)
-Hepatic carcinoma
-80-90% mortality in childhood
-NBS analysis for elevated succinylacetoacetate levels
-Treat with Orfadin - blocks second step in pathway, preventing accumulation of FAA (harmful compound that causes tyrosinemia)

Question 5

Tyrosinemia Type II

Answer 5

• TAT gene
• Autosomal recessive
• Tyrosine aminotransferase deficiency
• Characteristic: Keratosis palmoplantaris
• hyperkaratosis of palms and feet
• Ocular and cutaneous symptoms
• Half of pts have intellectual disability
• Treatment: Dietary restriction of Phe and Tyr

Question 6

Tyrosinemia Type III

Answer 6

• Rarest form
• HPD gene
• Autosomal recessive
• Intellectual disability, seizures, intermittent ataxia
• Treatment: Dietary restriction of Phe, Tyr, and Met

Question 7

Distinctions between Homocystinuria and Marfan

Answer 7

Homocystinuria:
   -Stiffening of the joints
   -Dev delays/mental retardation
   -Thromboembolic phenomena/thrombosis
Marfan:
   -Hyperextensible joints
   -No developmental issues
   -Dissection of the aorta