Introduction to inborn errors of metabolism Flashcards
Most common inborn error of metabolism
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
Cause of PKU
- 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)
Tyrosine
- 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)
General effects of an enzyme/co-factor defect
- Disease phenotypes may result from:
- accum of metabolite precursor
- overflow to products (alternative pathway–> could be toxic)
- reduced formation of desired metabolite (product deficiency)
PKU summary
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)
PKU phenotpye
Hyperphenylalaninemia
Severe classical PKU: Plasma Phe >1200 µM
Moderate PKU: 600-1200 µM
Mild/benign hyperphe:
Dietary therapy for PKU
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
Long term management of PKU
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?
Example of aminoacidopathy with acute presentation
- Metabolic encephalopathies
- Liver failure
Management of IEM coma/encephalopathy
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
Ketones in newborns
VERY unusual (shouldn’t be present in healthy babies)
Maple Syrup Urine Disease Presentation
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
MSUD deficiency
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
3 presentations of MSUD
Severe neonatal form (
Acute tx of MSUD
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?
Chronic therapy of MSUD
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
Tyrosinemia Type 1
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
Main player for liver and kidney toxicity in tyrosinemia type 1
succinylacetone (from succinylacetoacetate)
Succinylacetone
Succinylacetone inhibits ∂-aminolevulinic acid dehydratase activity
Porphyria like abdominal pain crises
Peripheral neuropathy
Tyrosine is very proximal to the block and only moderately elevated
Cellular effects of tryosinemia type 1
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
Tyrosinemia Type 1 treatment
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
Clinical features of tyrosine disorders
-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
CBS (cystathionine b-synthase) deficiency
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
Classical untreated homocystinuria (CBS def)
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
Classical Homocystinuria
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
Homocystinuria tx
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
Possible outcomes of urea cycle disorders
encephalopathy
coma
irreversible neurologic damage
death
-must check ammonia levels to get dx (hard to recognize, can be missed)
When might ammonia be elevated?
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
UCD presentation
- 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
Potential triggers of hyperammonemic crises in UCD pts
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
OTC Deficiency
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)
Presentation of OTC def
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
Ammonia scavenging agents
Glutamine
Glycine
$$$
bad smell
sodium phenylacetate
sodium benoate
UCD treatment strategies
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
Wrap up
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
