Biochemical Genetics and Newborn Screening

Question 1

Inheritance of disorders affecting enzymatic proteins

Answer 1

typically autosomal recessive

Question 2

inheritance of disorders affecting structural proteins

Answer 2

often autosomal dominant

Question 3

Phenylketonuria (PKU) clinical presentation

Answer 3

• autosomal recessive
• normal neonate
• DD beginning around 3-4 months
• treated with diet low in protein

Question 4

mechanism of PKU

Answer 4

• deficiency of enzyme: phenylalanine hydroxylase (PAH)
• conversion of phenylalanine to tyrosine is blocked
• buildup of PHE is neurotoxic

Question 5

Methylmalonic Aciduria presentation

Answer 5

• severe acidosis in first week of life

* treated with diet low in protein

Question 6

mechanism of methylmalonic aciduria

Answer 6

• lack of enzyme activity: methylmalonyl-CoA mutase

* it converts methylmalonyl-CoA into succinyl-CoA (krebs cycle)

Question 7

test for PKU

Answer 7

phenylalanine elevated on plasma amino acid quantitation

Question 8

test for methylmalonic aciduria

Answer 8

methylmalonic acid elevated on urine organic acid quantitation

Question 9

important urea cycle defect

Answer 9

• 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

Question 10

test for ornithine transcarbamylase (OTC) deficiency

Answer 10

low citrulline on plasma amino acid quantitation

Question 11

other urea cycle defects

Answer 11

• many enzymes; autosomal recessive
• neurologic damage if not treated rapidly
• plasma amino acid quantitation will have elevations of a diagnosic aa

Question 12

treatment for ornithine transcarbamylase (OTC) deficiency

Answer 12

• diet low in protein

* ammonia scavenger medications

Question 13

hereditary fructose intolerance mechanism

Answer 13

•fructoaldolase (aldolase B) metabolized fructose to glucose (gluconeogenesis)

Question 14

hereditary fructose intolerance presentation

Answer 14

• 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

Question 15

diagnosis of hereditary fructose intolerance

Answer 15

• clinical syspicion

* molecular analysis of aldolase B

Question 16

treatment of hereditary fructose intolerance

Answer 16

restricting fruit, vegetables, corn syrup, table sugar

Question 17

lesch-nyhan disease presentation

Answer 17

• X linked recessive
• neurologic dysfunction
• hypotonic
• self-mutilation behavior

Question 18

mechanism of lesch-nyhan disease

Answer 18

• disorder of purine reclamation

* due to defect in hypoxanthine-guanine phosphoribosyltransferase (HGPRT) activity

Question 19

treatment of lesch-nyhan disease

Answer 19

• low purine diet
• allopurinol
• medication for neurologic signs and symptoms

Question 20

diagnosis of lesch-nyhan disease

Answer 20

• clinical suspicion
• elevated uric acid
• molecular analysis of HGPRT

Question 21

most common fatty acid oxidation disorder

Answer 21

• medium chain acyl-CoA dehydrogenase (MCAD) deficiency

* it is autosomal recessive

Question 22

presentation of MCAD deficiency

Answer 22

• child with lethargy and vomiting following fasting
• classically presents with hypoketotic hypoglycemia
• may be entirely asymptomatic

Question 23

other fatty acid oxidation disorders often involve

Answer 23

•cardiac and/or hepatic involvement

VLCAD, LCAD, SCAD, LCHAD, SCHAD

Question 24

testing for MCAD deficiency

and other fatty acid oxidation disorders

Answer 24

• elevations of fatty acid oxidation intermediates on urine organic acid quantitation
• acylcarnitine analysis

Question 25

treatment of MCAD deficiency | and other fatty acid oxidation disorders

Answer 25

* avoidance of fasting | * rapid treatment of hypoglycemia (epinephrine?)

Question 26

biotinidase defect

Answer 26

* results in biotin deficiency | * biotin important in carboxylation reaction

Question 27

presentation of biotinidase defect

Answer 27

* alopecia * dermatitis * deafness * seizures * neurologic deterioration starting about 4-6 months of age

Question 28

diagnosis of biotinidase defect

Answer 28

enzyme assay of biotinidase

Question 29

treatment of biotinidase defect

Answer 29

biotin supplementation

Question 30

Mechanism of Tay-Sachs disease

Answer 30

* autosomal recessive * β-hexosaminidase (A isoenzyme) mutation * lysosomal storage disease

Question 31

clinical features of tay-sachs

Answer 31

hypotonia, spasticity, seizures, blindness

Question 32

hunter syndrome mechanism

Answer 32

* x-linked recessive * iduronidate-2-sulfatase defect * accumulation of mucopolysaccharides such as dermatan and heparin sulfate

Question 33

diagnosis of hunter syndrome

Answer 33

enzyme assay of iduronidate-2-sulfatase

Question 34

treatment of hunter syndrome

Answer 34

* can be treated with enzyme replacement therapy (ERT) * an example name is elaprase * (enzyme being replaced is iduronidate-2-sulfatase

Question 35

menke disease mechanism

Answer 35

* x-linked recessive * inability to absorb copper across intestinal epithelium * ^copper deficiency

Question 36

testing for menke disease

Answer 36

* diagnosis suspected by low blood copper and ceruloplasmin | * molecular analysis of ATP7A gene

Question 37

treatment for menke disease

Answer 37

* no real effective treatment | * copper histidinate infusion under investigation

Question 38

presentation of menke disease

Answer 38

* severe neurodegenerative disorder beginning in first year of life * copper deficiency

Question 39

Zellweger syndrome

Answer 39

* no peroxisomes formed * severe, fatal disease * diagnosis: elevation of very long chain fatty acids * no effective treatment

Question 40

what are peroxisomes

Answer 40

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)

Question 41

List of biochemical laboratory tests

Answer 41

* amino acid quantitation * urine organic acid quantitation * carnitine levels and acylcarnitine analysis * ammonia * lactic acid * urine mucopolysaccharides * very long chain fatty acids