Disorders of metabolism Flashcards
What causes PKU
AR
phenylalanine can not be converted to tyrosine
enzyme defect is phenylalanine hydroxylase
What is the common presentation of PKU and what would be seen in the blood and in the urine?
vomiting irritability eczematoid rash mousy, wolf like or musty odor (often fair hair with fair skin) high levels of phenylalanine in blood high levels of phenyl-pyruvic acid in urine
What does an infant have if mother has untreated PKU?
growth deficiency, microcephaly, intellectual disability and congenital heart defects
What can cause hyperphenylalaninemia
could have a milder deficiency is the PAH enzyme
defect in synthesis or recycling or biopterin a cofactor of the PAH enzyme needed to make tyrosine
What are the symptoms of hyperphenylalaninemia and what is the treatment?
neurologic symptoms despite low ingestion of phenylalanine.
also affects ability to make serotonin, dopa and norepinephrine
treatment includes phenylalanine restriction and biopterin supplementation, and supplementation of precursors like dopa and 5-hydroxytryptophan
What is seen in hereditary tyrosinemia Type 1
AR
deficiency of fumarylacetoacetate hydroxylase (tyrosine metabolism)
accumulation of succinylacetone
rapid course to death or FFT, liver failure, hepatomegaly with hepatoblastoma, renal tubular acidosis, xr findings consistent with rickets
How is hereditary tyrosinemia type 1 diagnosed and treated?
elevated plasma tyrosine
succinylacetone in the urine
liver failure and Fanconi syndrome treated with NTBC {2-(nitro-4-trifuoro-methylbenzoyl)-1,3cyclohexanedione}
and low tyrosine diet
How does tyrosinemia type 2 present
AR oculocutaneous tyrosinemia deficiency of tyrosine aminotransferase corneal ulcers or dendritic keratitis red papular or keratotic lesion on their palms and soles 50% have intellectual disability
What is alkaptonuria?
deficiency in homogentisic acid dioxygenase
3rd step in tyrosine metabolism
urine darkens as it sits due to oxygenation of the homogentisic acid in the urine
What are the symptoms of alkaptonuria?
pigment deposition in ears and sclera as an adult: ochronosis
can also cause ochronosis arthritis
some have aortic root dilatation or valvular involvement
How does maple syrup urine disease present?
urine, hair or skin smells like maple syrup
symptoms start day 3-5 with progression to death in 2-4 weeks
feeding difficulties, irregular breathing, loss of the moro reflex, seizures, opisthotonos and rigidity
What is the defect in maple syrup urine disease and what is the treatment?
defect in oxidative decarboxylation of ketoacids formed from the catabolism of branched amino acids:
leucine, isoleucine and valine
increased amounts of valine, leucine and isoleucine in the urine, or alloisoleucine in the urine
decrease intake of these proteins
What is the clinical presentation of homocystinuria
AR
elevation in homocysteine
in those with the cystathionine beta-synthetase deficiency have a marfanoid habitus, developmental delay, lens dislocation and increased risk of thromboembolism (both venous and arterial)
joints are NOT hypermobile, osteoporosis
What is the treatment for homocystinuria
pyridoxine in the vitamin responsive form
diet low in methionine
What is nonketotic hyperglycinemia
large amounts of glycine in the body and in the CSF, with highest amounts being in the CSF
intractable seizures in the neonatal period, with hiccups in utero
results in severe intellectual disability
What are the six main enzyme defects that can cause hyperammonemias?
- N acetylglutamate synthetase deficiency
- carbamoyl phosphate synthase deficiency
- ornithine transcarbamylase deficiency (X-linked)
- argininosuccinate synthetase deficiency (citrullinemia)
- argininosuccinate lyase deficiency
- arginase deficiency (argininemia)
How does a urea cycle disorder present?
intoxication
lethargy, vomiting, confusion to coma
more proximal the defect, the more severe
What labs should be ordered to help determine the location of the defect
plasma and urine organic acids
arginine is low except in argininemia
citrulline level: low if a proximal disorder (otc or cps)
check a urinary orotic acid level:
elevated in ornithine transcarbamylase , low in carbamoyl phosphate synthase deficiency
What are some clinical findings in someone with Argininemia
progressive spastic diplegia/quadriplegia, tremor, ataxia, choreoathetosis
What are some of the clinical findings in HHH syndrome
hyperammonemia, hyperorniththinemia, homocitrullinuria
defect in mitochondrial ornithine transporter
progressive spastic diplegia/quadriplegia, retinal depigmentation, chorioretinal thinning
What are some of the clinical findings of LPI, Lysinuric protein intolerance
defect in amino acid transporter gene SLC7A7
interstitial pneumonia, glomerulonephritis, osteoporosis, underlying immune deficiency
What are some of the clinical findings of Argininosuccinic aciduria.
trichorrhexis nodose (node-like appearance of fragile hair) episodic coma
What is seen in propionic acidemia?
AR
severe ketoacidosis with or without hyperammonemia
encephalopathy, bone marrow suppression, vomiting
due to inability to catabolize valine, methionine, isoleucine and threonine
What are the common presenting symptoms of fatty oxidation defects?
hepatic, skeletal muscular like rhabdomyolysis after exercise, cardiac arrhythmias and sudden death
What main laboratory studies are done to detect fatty oxidation defect disorders?
CBC, CMP, ammonia, lactate CPK, urine ketones
free and acylcarnitine levels in the blood
GC-MS analysis of organic acids
analysis of plasma acylcarnitine and urine acylglycines by specialized techniques
