Biochemical Genetics and Newborn Screening Flashcards
Inheritance of disorders affecting enzymatic proteins
typically autosomal recessive
inheritance of disorders affecting structural proteins
often autosomal dominant
Phenylketonuria (PKU) clinical presentation
- autosomal recessive
- normal neonate
- DD beginning around 3-4 months
- treated with diet low in protein
mechanism of PKU
- deficiency of enzyme: phenylalanine hydroxylase (PAH)
- conversion of phenylalanine to tyrosine is blocked
- buildup of PHE is neurotoxic
Methylmalonic Aciduria presentation
- severe acidosis in first week of life
* treated with diet low in protein
mechanism of methylmalonic aciduria
- lack of enzyme activity: methylmalonyl-CoA mutase
* it converts methylmalonyl-CoA into succinyl-CoA (krebs cycle)
test for PKU
phenylalanine elevated on plasma amino acid quantitation
test for methylmalonic aciduria
methylmalonic acid elevated on urine organic acid quantitation
important urea cycle defect
- defect in pathway converting toxic ammonia to non-toxic urea
- ornithine transcarbamylase (OTC) deficiency -> low citrulline
- ^it is X LINKED
- severe neurologic damage if not treated rapidly
test for ornithine transcarbamylase (OTC) deficiency
low citrulline on plasma amino acid quantitation
other urea cycle defects
- many enzymes; autosomal recessive
- neurologic damage if not treated rapidly
- plasma amino acid quantitation will have elevations of a diagnosic aa
treatment for ornithine transcarbamylase (OTC) deficiency
- diet low in protein
* ammonia scavenger medications
hereditary fructose intolerance mechanism
•fructoaldolase (aldolase B) metabolized fructose to glucose (gluconeogenesis)
hereditary fructose intolerance presentation
- key: NO fructose in breast milk, symptom onset with introduction of juices
- ingestion of fructose acutely -> vomiting and hypoglycemia
- chronic ingestion of fructose -> hepatomegaly and renal dysfunction
diagnosis of hereditary fructose intolerance
- clinical syspicion
* molecular analysis of aldolase B
treatment of hereditary fructose intolerance
restricting fruit, vegetables, corn syrup, table sugar
lesch-nyhan disease presentation
- X linked recessive
- neurologic dysfunction
- hypotonic
- self-mutilation behavior
mechanism of lesch-nyhan disease
- disorder of purine reclamation
* due to defect in hypoxanthine-guanine phosphoribosyltransferase (HGPRT) activity
treatment of lesch-nyhan disease
- low purine diet
- allopurinol
- medication for neurologic signs and symptoms
diagnosis of lesch-nyhan disease
- clinical suspicion
- elevated uric acid
- molecular analysis of HGPRT
most common fatty acid oxidation disorder
- medium chain acyl-CoA dehydrogenase (MCAD) deficiency
* it is autosomal recessive
presentation of MCAD deficiency
- child with lethargy and vomiting following fasting
- classically presents with hypoketotic hypoglycemia
- may be entirely asymptomatic
other fatty acid oxidation disorders often involve
•cardiac and/or hepatic involvement
VLCAD, LCAD, SCAD, LCHAD, SCHAD
testing for MCAD deficiency
and other fatty acid oxidation disorders
- elevations of fatty acid oxidation intermediates on urine organic acid quantitation
- acylcarnitine analysis
treatment of MCAD deficiency
and other fatty acid oxidation disorders
- avoidance of fasting
* rapid treatment of hypoglycemia (epinephrine?)
biotinidase defect
- results in biotin deficiency
* biotin important in carboxylation reaction
presentation of biotinidase defect
- alopecia
- dermatitis
- deafness
- seizures
- neurologic deterioration starting about 4-6 months of age
diagnosis of biotinidase defect
enzyme assay of biotinidase
treatment of biotinidase defect
biotin supplementation
Mechanism of Tay-Sachs disease
- autosomal recessive
- β-hexosaminidase (A isoenzyme) mutation
- lysosomal storage disease
clinical features of tay-sachs
hypotonia, spasticity, seizures, blindness
hunter syndrome mechanism
- x-linked recessive
- iduronidate-2-sulfatase defect
- accumulation of mucopolysaccharides such as dermatan and heparin sulfate
diagnosis of hunter syndrome
enzyme assay of iduronidate-2-sulfatase
treatment of hunter syndrome
- can be treated with enzyme replacement therapy (ERT)
- an example name is elaprase
- (enzyme being replaced is iduronidate-2-sulfatase
menke disease mechanism
- x-linked recessive
- inability to absorb copper across intestinal epithelium
- ^copper deficiency
testing for menke disease
- diagnosis suspected by low blood copper and ceruloplasmin
* molecular analysis of ATP7A gene
treatment for menke disease
- no real effective treatment
* copper histidinate infusion under investigation
presentation of menke disease
- severe neurodegenerative disorder beginning in first year of life
- copper deficiency
Zellweger syndrome
- no peroxisomes formed
- severe, fatal disease
- diagnosis: elevation of very long chain fatty acids
- no effective treatment
what are peroxisomes
cytoplasmic organelles with variety of biochemical functions:
•peroxide metabolism
•catabolism of very long chain fatty acids
•catabolism of bile acids
•synthesis of complex lipids
(zellweger syndrome=peroxisomal disorder)
List of biochemical laboratory tests
- amino acid quantitation
- urine organic acid quantitation
- carnitine levels and acylcarnitine analysis
- ammonia
- lactic acid
- urine mucopolysaccharides
- very long chain fatty acids
