Introduction to inborn errors of metabolism

Question 1

Most common inborn error of metabolism

Answer 1

PKU

• recessive
• stall developmentally at first year (microcephaly, mustly odor, blonde hair; severe intellectual disability)
• deficiency of phenylalanine hydroxylase
• remove phenylalanine from diet (more normal development)

-Eventually helped to precipitate development of newborn screening

Question 2

Cause of PKU

Answer 2

• Deficiency of phenylalanine hydroxylse
• Catalyzes conversion (hydroxylation)of phenylalanine to tryosine
• Cofactor: tetrahydrobiopterin
• regulation by phos/dephos system. Phenylalanine reaches physiologic levels and shuts down enzyme (negative feedback loop)

Question 3

Tyrosine

Answer 3

• precursor of NTs like dopamine and L-DOPA
• May help explain neurologic effects of untreated PKU
• Tyrosine is also a precursor for melanin (explains hypopigmentation)

Question 4

General effects of an enzyme/co-factor defect

Answer 4

• Disease phenotypes may result from:
• accum of metabolite precursor
• overflow to products (alternative pathway–> could be toxic)
• reduced formation of desired metabolite (product deficiency)

Question 5

PKU summary

Answer 5

Liver phenylalanine hydroxylase (PAH) deficiency
Autosomal recessive
1:16,000 live births in the US; higher prevalence in other areas

Pathophysiology:
Due to elevated total body phenylalanine
No direct pathologic effect on the liver

Rare variants of biopterin synthesis or recycling (about 1% of severe hyperphenyalaninemia)

Question 6

PKU phenotpye

Answer 6

Hyperphenylalaninemia
Severe classical PKU: Plasma Phe >1200 µM
Moderate PKU: 600-1200 µM
Mild/benign hyperphe:

Question 7

Dietary therapy for PKU

Answer 7

Restrict dietary protein – Phe tolerance depends on residual enzyme activity

• Supplement with phenylalanine-free medical beverage
• Maternal PKU (so manage carefully at time of pregnancy)(microcephaly, low birth weight, mental retardation, and malformations in infants of mothers with poorly controlled PKU)
• Need for diet controversial for individuals with Phe in 360-600 uM range off diet

Question 8

Long term management of PKU

Answer 8

Restrict Phe, but do not eliminate it
Provide adequate calories; provide adequate protein, vitamins, minerals (Phe-free formula)
Maintain normal growth and development
“Treatment for life” (adult nutrition)

Newer approaches to treatment
Biopterin (Sapropterin)
Large neutral amino acid (LNAA) supplement (compete for aa for transport into brain)
Phenylalanine ammonia lyase
Macroglyoprotein
Liver cell transplant?

Question 9

Example of aminoacidopathy with acute presentation

Answer 9

• Metabolic encephalopathies

- Liver failure

Question 10

Management of IEM coma/encephalopathy

Answer 10

Remove offending agent:
NPO
STOP catabolism
Dialysis (sparingly used)

Clinical phenotypes depend on enzyme activity
Variable age onset
Variable severity of symptoms
Variable tolerance to protein load
Variable response to meds

Vitamins and nutrition are medical necessities for these patients

Question 11

Ketones in newborns

Answer 11

VERY unusual (shouldn’t be present in healthy babies)

Question 12

Maple Syrup Urine Disease Presentation

Answer 12

Newborn term breast-fed female
Poor feeding, progressive lethargy
Coma and seizures at 6 days age
Mild hypoglycemia
Mild metabolic acidosis
Ketonuria

Leucine (neurotoxic), Valine, Isoleucine high
-Alloisoleucine present
-Urine dinitrophenylhydrazine (DNPH) test positive
Branched chain ketoacids on urine organic acid analysis

Question 13

MSUD deficiency

Answer 13

Branched chain ketoacid dehydrogenase (BCKD) deficiency

Autosomal recessive inheritance
Incidence 1/185,000 births
4 subunits – E1alpha, E1beta, E2, and E3

Mutations known in all four genes
p.Y391N substitution in E1alpha protein is a common founder mutation in the Mennonite population
Mutations in E2 subunit most likely to be ?thiamine (vitamin B1) responsive

Question 14

3 presentations of MSUD

Answer 14

Severe neonatal form (

Question 15

Acute tx of MSUD

Answer 15

Eliminate dietary protein intake
Supplement valine and isoleucine
Provide adequate non-protein energy source and amino acids that are not BCAA

Avoid hypotonic fluids
Treat cerebral edema if symptoms
develop (from leucine usually)
Hemodialysis?

Question 16

Chronic therapy of MSUD

Answer 16

Protein restricted diet supplemented with branched chain amino acid free medical foods (MSUD “coolers”)

Leucine intake about 400-600 mg per day (childhood) in severe neonatal forms. Then 600-800 after adolescence.

Supplement valine and isoleucine (rapid depletion with dietary exclusion)

Thiamine supplementation in some cases of E2 subunit deficiency

Question 17

Tyrosinemia Type 1

Answer 17

deficiency: Fumarylacetoacetate hydrolase (FAH)
- see high tyrosine, high succinylacetone (urine), and delta aminolevulinic acid (urine)

Autosomal recessive inheritance

Founder mutations
Quebecois
Finland

3 presenting forms:
Early in infancy (1 to 6 months): Liver disease (hepatic failure or cholestatic jaundice or cirrhosis with renal tubulopathy)
Late infancy: Rickets due to renal tubulopathy (Fanconi syndrome) with no obvious liver failure
Porphyria-like attack at any age (can be presenting sign)

*liver failure in first 2 weeks of life is NOT from tyrosinemia type 1

Question 18

Main player for liver and kidney toxicity in tyrosinemia type 1

Answer 18

succinylacetone (from succinylacetoacetate)

Question 19

Succinylacetone

Answer 19

Succinylacetone inhibits ∂-aminolevulinic acid dehydratase activity
Porphyria like abdominal pain crises
Peripheral neuropathy

Tyrosine is very proximal to the block and only moderately elevated

Question 20

Cellular effects of tryosinemia type 1

Answer 20

Toxic compounds:
Fumarylacetoacetate, maleylacetoacetate, succinylacetone

Hepatocellular damage:
Cirrhosis, hepatocellular carcinoma, high alpha fetoprotein (unreliable as a a marker in neonates)

Renal tubular disease:
Renal Fanconi syndrome (leaky kidneys: leak aa, phos, etc into urine), hypophosphatemic rickets

Question 21

Tyrosinemia Type 1 treatment

Answer 21

2-(2-nitro-4-trifluoromethylbenzoyl)-1,3-cyclohexane-dione (NTBC)
Inhibits 4-hydroxyphenylpyruvic acid dioxygenase
Further increases plasma tyrosine
Decreased production of FAA and succinylacetone
?May not prevent hepatocellular carcinoma

Phe and Tyr restriction necessary to avoid excessive hypertyrosinemia (risk of keratitis and palmoplantar keratosis)
>800-1000 tyrosine can cause corneal ulcers and keratosis

Liver transplant if hepatocellular carcinoma develops

Question 22

Clinical features of tyrosine disorders

Answer 22

-Liver enlargement, ascites
-rickets
-Palmoplantar keratosis (high levels of tyrosine)
-corneal lesions
-Alkaptonuria:
black urine
black pigmentation of cartilage and collagen
-degenerative arthritis from fourth decade

Question 23

CBS (cystathionine b-synthase) deficiency

Answer 23

homocysteine elevation and eventually methionine elevation (methionine synthase)
-use methionine as secondary marker for disease in newborn screening

Presentation:
-Methionine high
Homocystine present (normally undetectable)
-Urine aa: homocystine (norm undetectable)
-urine cyanide nitroprusside test positive

Question 24

Classical untreated homocystinuria (CBS def)

Answer 24

Skel malformations:
Marfanoid habitus
Osteoporosis
Scoliosis
Most common in B6 non-responsive forms

Recurrent thromboembolism:

• may be isolated sign in late onset B6 responsive forms
• also:phlebitis, pulmonary embolism, cerebrovascular accident
• Premature atherosclerotic disease

Environmental triggers
Anesthesia
Catabolism
Smoking
Oral contraceptives

Other findings:
eye abnormalities:
Ectopia lentis 
Myopia
May be an isolated presenting sign in children or adults

Developmental disability and neuropyschiatric symptoms

Question 25

Classical Homocystinuria

Answer 25

Cystathionine β-synthase deficiency Autosomal recessive inheritance Incidence = 1/200,000 to 1/400,000 births Incomplete ascertainment Cases often missed on newborn screens obtained during the first week of life 50% of CBS mutations are pyridoxine (vitamin B6) responsive

Question 26

Homocystinuria tx

Answer 26

Pyridoxine (B6) challenge 750 mg orally per day for one week Monitor plasma methionine, total homocysteine Hyperhomocysteinemia will normalize in pyridoxine responsive forms Restrict dietary protein Supplemented with methionine free medical foods Oral betaine Consider supplementation with B12, folate, and/or cysteine

Question 27

Possible outcomes of urea cycle disorders

Answer 27

encephalopathy coma irreversible neurologic damage death -must check ammonia levels to get dx (hard to recognize, can be missed)

Question 28

When might ammonia be elevated?

Answer 28

Urea cycle disorders (primary) ``` Organic acidemias Fatty acid oxidation disorders Carnitine cycle disorders Transient hyperammonemia of the newborn (THAN) Liver failure Asparaginase treatment Valproate therapy ```

Question 29

UCD presentation

Answer 29

- ALC - encephalopathy - seizures - vomiting - multiorgan failure - peripheral circulatory failure - psych sx Neonates: sepsis-like resp distress, hypervent ``` Chronic: confusion/lethargy liver disease migraines learning disability MR Protein aversion hepatomegaly FTT HTN (abnormal arginine metabolism) fragile hair episodic ``` Goals of care: ammonia at appropriate levels avoid hyperammonemia good growth, devel

Question 30

Potential triggers of hyperammonemic crises in UCD pts

Answer 30

``` infections fever vomiting GI/internal bleeding decreased energy or protein intake catabolism and involution of uterus in postpartum period prolonged or intense physical exercise surgery under GA chemo unusual protein load drugs: ***Valproate (seizures) and L-asparaginase/pegaspargase ```

Question 31

OTC Deficiency

Answer 31

Ornithine transcarbamylase deficiency X-linked (males more impacted than females) - most common urea cycle disorder - Male hemizygotes may not survive newborn period - 15% F hetero will have clinical sx from mild to severe (X inactivation pattern)

Question 32

Presentation of OTC def

Answer 32

lethargy, poor feeding, emesis - altered mental status - minimally responsive - hypertonic - hyperreflexic - poss sz - RESPIRATORY ALKALOSIS and high PLASMA AMMONIA Will likely see: low plasma citulline, elevated glutamine and elevate urine orotic acid

Question 33

Ammonia scavenging agents

Answer 33

Glutamine Glycine $$$ bad smell sodium phenylacetate sodium benoate

Question 34

UCD treatment strategies

Answer 34

Dietary protein restriction Ammonia scavenging medications L-arginine or L-citrulline supplementation (depending on the specific defect) Acute, severe hyperammonemia may require hemodialysis or intravenous scavengers Consider liver transplantation for patients with recurrent hyperammonemia or brittle disease refractory to medical management Risks versus benefits Many restricted to 20-30 g protein per day

Question 35

Wrap up

Answer 35

Newborn screening detects many, but not all, disorders of amino acid metabolism (aminoacidopathies, urea cycle disorders, and disorders of organic acid metabolism) Urea cycle defects can present at any age (check an ammonia level for unexplained vomiting, seizures, progressive obtundation) Newborn screening does not detect all disorders of the urea cycle; always test if there is a clinical concern: plasma ammonia, plasma amino acids, urine orotic acid, urine amino acids