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My DEMS 3 > Introduction to inborn errors of metabolism > Flashcards

Introduction to inborn errors of metabolism Flashcards

1
Q

Most common inborn error of metabolism

A

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

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2
Q

Cause of PKU

A
  • 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)
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3
Q

Tyrosine

A
  • 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)
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4
Q

General effects of an enzyme/co-factor defect

A
  • Disease phenotypes may result from:
  • accum of metabolite precursor
  • overflow to products (alternative pathway–> could be toxic)
  • reduced formation of desired metabolite (product deficiency)
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5
Q

PKU summary

A

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)

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6
Q

PKU phenotpye

A

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

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7
Q

Dietary therapy for PKU

A

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
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8
Q

Long term management of PKU

A

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?
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9
Q

Example of aminoacidopathy with acute presentation

A
  • Metabolic encephalopathies

- Liver failure

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10
Q

Management of IEM coma/encephalopathy

A

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

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11
Q

Ketones in newborns

A

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

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12
Q

Maple Syrup Urine Disease Presentation

A 
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

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13
Q

MSUD deficiency

A

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

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14
Q

3 presentations of MSUD

A

Severe neonatal form (

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15
Q

Acute tx of MSUD

A

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?

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16
Q

Chronic therapy of MSUD

A

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

17
Q

Tyrosinemia Type 1

A

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

18
Q

Main player for liver and kidney toxicity in tyrosinemia type 1

A

succinylacetone (from succinylacetoacetate)

19
Q

Succinylacetone

A

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

Tyrosine is very proximal to the block and only moderately elevated

20
Q

Cellular effects of tryosinemia type 1

A

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

21
Q

Tyrosinemia Type 1 treatment

A

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

22
Q

Clinical features of tyrosine disorders

A

-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

23
Q

CBS (cystathionine b-synthase) deficiency

A

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

24
Q

Classical untreated homocystinuria (CBS def)

A 
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

25
Q

Classical Homocystinuria

A

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

26
Q

Homocystinuria tx

A

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

27
Q

Possible outcomes of urea cycle disorders

A

encephalopathy
coma
irreversible neurologic damage
death

-must check ammonia levels to get dx (hard to recognize, can be missed)

28
Q

When might ammonia be elevated?

A

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
29
Q

UCD presentation

A
  • 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

30
Q

Potential triggers of hyperammonemic crises in UCD pts

A 
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
31
Q

OTC Deficiency

A

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)
32
Q

Presentation of OTC def

A

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

33
Q

Ammonia scavenging agents

A

Glutamine
Glycine
$$$
bad smell

sodium phenylacetate
sodium benoate

34
Q

UCD treatment strategies

A

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

35
Q

Wrap up

A

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

My DEMS 3 (19 decks)

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