Aminoacidopathies

Question 1

Classic PKU: Treated vs. untreated

Answer 1

TREATED

• most have normal intellect and functioning
• some have issues with ADHD, mood disorders, executive function deficits (related to plasma Phe levels)

UNTREATED

• severe, irreversible mental retardation
• behavioral problems
• hypopigmentation
• seizures

Question 2

Treatment of PKU

Answer 2

Restrict substrate
- avoid protein foods, take Phe-free formula

Provide product
-formula supplemented with tyrosine

Provide cofactor - THB

Substitute enzyme
- clinical trials with alternate enzyme

Block transport
- large amino acids to compete at BBB

Question 3

Maternal PKU syndrome

Answer 3

Phenylalanine is teratogenic, can cause:

• microcephaly
• mental retardation
• congenital heart disease
• low birth weight

more phenylalanine –> increased severity

Keep phenylalanine levels >2, <5 mg/dl prior to conception and throughout pregnancy

Question 4

PKU newborn screening

• methods
• diagnosis

Answer 4

Methods:

• bacterial inhibition assay
• fluorometric assay
• Tandem MS

2.5-5 mg/dl - borderline
>6 mg/dl: presumptive (contact metabolic center)

Question 5

Tetrahydrobiopterin deficiency

• symptoms
• treatment

Answer 5

cofactor deficiency that results in hyperphenylalaninemia
can cause neurological issues
Treatment: administer L-DOPA

Question 6

Non-PKU Hyperphenylalaninemia

Answer 6

Untreated, phenylalanine levels <20 mg/dl because of residual Phenylalanine Hydroxylase activity

treat with phenylalanine restricted diet

Question 7

Cause and clinical characteristics of Maple Syrup Urine Disease

Answer 7

Deficiency of branched-chain alpha-keto acid dehydrogenase (BCKAD) complex

Neurologic issues

• altered mental status progressing to coma
• ataxia, slurred speech, waxing/waning mental status changes
• severe neurologic damage or death due to cerebral edema

Question 8

Treatment of MSUD

• acute
• long-term

Answer 8

initial and acute care:

• monitor neurologic status, fluid status, +/- hemodialysis
• usually requires intensive care

long term maintenance care:

• dietary restriction of BCAA + formulas
• provide cofactors

Liver transplantation

Question 9

Genetics of MSUD

Answer 9

Multimeric enzyme with 3 subunits

• E1 (alpha and beta)
• E2
• E3

AR

VERY high incidence in Mennonite population (E1 alpha) (1:176)

high incidence in Ashkenazi Jewish pop (E1- beta) (1:50,000)

Question 10

Homocysteinuria

• cause
• phenotype

Answer 10

CAUSE: deficiency of CBS (cystathionine beta-synthase) , leads to accumulation of homocysteine

PHENOTYPE

• marfanoid habitus
• dislocated optic lenses
• osteoporosis
• mental retardation
• thromboembolic events

*homocysteine plays role in connective tissue development

Question 11

Treatment of Homocysteinuria

Answer 11

RESTRICT SUBSTRATE
- restrict methionine

PROVIDE COFACTOR

• vitamin B12
• vitamin B6

Provide alt routes of elimination
- betaine (cystadene)

Question 12

Hyperhomocysteinemia

Answer 12

partial CBS deficiency
abnormal B6, folate, B12 metabolism
risk factor for cardiovascular disease

Question 13

Type I Tyrosinemia

- symptoms

Answer 13

Hepatorenal

Fumarylacetoacetate hydrolase deficiency results in accumulated fumarylacetoacetate, which will cause toxic metabolite accumulation of succinylacetone

Liver failure, hepatocellular carcinoma, renal Fanconi’s, poryphoria-like attacks

Question 14

Type II tyrosinemia

Answer 14

Oculocutaneous

Tyrosine Aminotransferase deficiency causes slightly elevated tyrosine

lesions on corneas, palms, soles. Can cause corneal injury and sight problems

Question 15

Tyrosinemia treatment

Answer 15

diet:

• low Phe. low Tyr
• some natural protein, but eat mostly protein free foods

For type I: use nitisinone/NTBC, which inhibits an enzyme in the middle of the pathway (between type I and type II)
- blocks production of toxic metabolites, protecting the liver