Inborn Errors Flashcards
phenylalanine hydroxylase deficiency
Autosomal Recessive
Phenylalanine cannot get converted to tyrosine
PKU
Intellectual Disability
Hypopigmentation
Eczema
Hypomyelination on brain MR
PKU
PKU Treatment
Restrict protein
Sapropterin (BH4 cofactor)
Supplement non-PHE amino acids
Deficiency of the branched chain ketoacid dehydrogenase complex
4 different mutations that are causative
Most manifestations are due to leucine accumulation in the brain
Maple Syrup Urine Disease
Irritability and poor feeding at 48 hours
Lethargy, opisthotonus, apnea
Cerebral edema, encephalopathy
Reversible with treatment
Severe Neonatal presentation of Maple Syrup Urine Disease
Diagnosis of MSUD
Elevation of leucine
Presence of allo-isoleucine
Presence of urine ketones in a neonate
Assessment of lactate, alpha-ketoglutarate for combined enzyme deficiencies (DLD)
Branched chain ketoacid dehydrogenase complex enzyme activity
Treatment of MSUD
Trial thiamine supplementation (specific genotypes)
Limit dietary protein
Leucine-free formula, regular serum leucine levels
Close monitoring of nutritional status, especially isoleucine and valine
Consider liver transplant
Liver can be given to another person on the transplant list for a different indication
Leucine is likely a teratogen, though data are sparse in comparison to PKU
Fumaryl Acetoacetate Hydrolase
Tyrosinemia type 1 (hepatorenal tyrosinemia)
Typically presents as acute liver failure in infancy, later hepatocellular carcinoma
Hyperbilirubinemia, jaundice, ascites, coagulopathy, hepatomegaly, rickets
Acute neurologic crisis with abd pain and neuropathy due to secondary porphyria
Tyrosinemia type 1 (hepatorenal tyrosinemia)
Diagnosis of Tyrosinemia type 1 (hepatorenal tyrosinemia
succinylacetone in urine
Treatment of Tyrosinemia type 1 (hepatorenal tyrosinemia
An unusual treatment paradigm - use medication (NTBC) to induce a different (milder) metabolic disease (tyrosinemia III)
Considerations with NTBC therapy for Tyrosinemia type 1
Still need monitoring for hepatocellular carcinoma (HCC)
On NTBC need dietary therapy (avoid phenylalanine and tyrosine) to prevent oculo-cutaneous manifestations
Results from 4-OH phenylpyruvic acid dehydrogenase deficiency
Causes much higher tyrosine elevations
Tyrosinemia Type 2, AKA oculocutaneous tyrosinemia
Results in palmoplantar hyperkeratosis and keratitis
Tyrosinemia Type 2, AKA oculocutaneous tyrosinemia
cystathionine beta synthase deficiency
Homocystinuria
toxic effect on several tissues - skeleton, eye, vasculature
Untreated patients will have lens dislocation, scoliosis, pectus carinatum, mild developmental delays
Homocystinuria
Similar to Marfans
Homocystinuria
Treatment of homcystinuria
Mainstay of treatment is methionine restricted diet and betaine
B12 and folate supplementation are also often needed
Patients are often on coumadin or other anticoagulants
Encephalopathy, seizures, ataxia, visual loss, hallucinations, mania
Vomiting and loss of appetite
In neonates: temperature instability, hyperventilation
Acute Hyperammonemia
Developmental delay Nausea, failure to thrive, protein avoidance Migraines Anxiety, depression, disinhibition Hepatomegaly, elevated liver enzymes
Chronic Hyperammonemia
Triggers for Hyperammonemia
Illness, fever, vomiting, fasting, surgery
Postpartum period, menarche
Intense exercise
Dietary protein load
Medications - valproate, peg asparaginase
UTI
Most common deficiency in hyperammonemia
Ornithine transcarbamylase deficiency- gene only
X-linked
Diagnosis of Ornithine transcarbamylase deficiency
Diagnostic metabolite is orotic acid; also with low citrulline, high glutamine
Treatment of OTC
Very low protein diet (lowest of all IEMs)
Supplement citrulline or arginine
Ammonia scavenging medications (sodium phenylacetate and sodium benzoate)
Close nutritional monitoring
Aggressive support during illness
Dialysis
Liver transplantation
