1. Biochemical Genetics And Newborn Screening

Question 1

List the groups of biochemical disorders (objective)

Answer 1

Answer later

Question 2

Explain the clinical laboratory findings suggestive for each of the presented biochemical disorders (objective)

Answer 2

Answer later

Question 3

Give the treatment regimen for each of the presented biochemical disorders (objective)

Answer 3

Answer later

Question 4

Discuss the NM newborn screening process (objective)

Answer 4

Answer later

Question 5

Biochemical Genetics (overview)

Answer 5

“Metabolic diseases”
Products of genes are usually proteins (mostly loss of function)

Amino/organic acids, fatty acid oxidation, nucleic acids, vitamins and minerals

Question 6

Metabolic Diseases (frequency)

Answer 6

Each individual disease is rare

If protein is enzyme, typically autosomal recessive

If protein is structural, typically autosomal dominant

Question 7

Biochemical Classification

Answer 7

Amino Acids
Organic Acids
Urea Cycle
Carbohydrates
Purines/pyrimidines
Lipids
Minerals
Vitamins
Mitochondria
Peroxisomes
Lysosomal disorders
Membrane Transport

Question 8

Amino Acid Disorders (basic)

Answer 8

Phenylketonuria (PKU)

Elevation of diagnostic amino acids on amino acid quantitation

Question 9

Organic Acid Disorders (basic)

Answer 9

Methylmalonic Aciduria

Elevation of diagnostic organic acid in urine

Question 10

Urea Cycle Defects (basic)

Answer 10

Ornithine Transcarbamylase (OTC)

Elevation of ammonia and diagnostic amino acid

Question 11

Carbohydrate Disorders (basic)

Answer 11

Hereditary fructose intolerance (HFI)

Clinical Suspicion

Question 12

Purines/Pyrimidines Disorders (basic)

Answer 12

Lesch-Nyhan syndrome

Hyperuricemia

Question 13

Lipids Disorders (basic)

Answer 13

Medium acyl-CoA dehydrogenase (MCAD)

Diagnostic intermediates on urine organic acid quantitation

Question 14

Vitamins Disorders (basic)

Answer 14

Biotinidase

Clinical suspicion and relevant laboratory studies

Question 15

Mineral Disorders (basic)

Answer 15

Menke disease

Relevant laboratory studies: low ceruloplasmin and copper

Question 16

Lysosomal Storage Disorders (basic)

Answer 16

Hunter syndrome

Clinical and radiologic signs and symptoms
Relevant laboratory studies for disorder

Question 17

Peroxisomal Disorders (basic)

Answer 17

Zellweger Syndrome

Elevated very long chain fatty acids and phytanic acid

Question 18

Mitochondrial Disorders (basic)

Answer 18

MELAS

Elevated lactic acid

Question 19

Phenylketonuria (PKU)

Answer 19

Normal neonate, developmental delay beginning around 3-4 months, essential amino acid can’t be metabolized.

Enzyme deficiency: phenylalanine hydroxylase (PAH)
Phenylalanine to tyrosine is blocked

Elevated phenylalanine on plasma amino acid quantitation (buildup is neurotoxic)

Treated by diet low in phenylalanine (protein)

*Autosomal Recessive

Question 20

Methylmalonic Aciduria (MMA)- Organic Acid Disorder

Answer 20

Severe acidosis in first week of life

Lack of enzyme activity: methylmalonyl-CoA mutase
Methylmalonyl-CoA to succinyl CoA blocked (Krebs cycle)
*Methylmalonyl-CoA from catabolism of certain a.a, cholesterol and odd-chain fatty acids

Methylmalonic acid elevated on urine organic acid quantitation

Treated by diet low in protein

*Autosomal Recessive

Question 21

Urea Cycle Defects

Answer 21

Severe neurological damage if not treated rapidly

Enzyme defects converting toxic ammonia to non-toxic urea (if defects early in the cycle, there is severe hyperammonemia in the neonate)
NAGS, CPS, OTC, ASA, AS, Arginase
OTC-ornithine transcarbamylase deficiency; low levels of citrulline

Elevations of diagnostic a.a except for OTC deficiency (low citrulline) on plasma amino acid quantitation

Treated by diet low in protein and ammonia scavenger medications

*X-linked recessive

Question 22

Hereditary Fructose Intolerance

Answer 22

Ingestion of fructose leads to vomiting and hypoglycemia acutely; chronic ingestion causes hepatomegaly and renal dysfunction. Ex. When babies have juice

Fructoaldolase (Aldolase B) metabolizes fructose (component of sucrose) to glucose in gluconeogenesis.
Fructose (fructokinase) to Fructose 1-phosphate.
Fructose 1-phosphate (fructoaldolase) to DHA-P blocked, elevated fructose 1-phosphate toxic.

Clinical suspicion and molecular analysis aldolase B

Treatment is restricting fruit, vegetables, corn syrups, table sugar to prevent symptoms (diet on slides)

*Autosomal recessive

Question 23

Lesch-Nyhan Disease

Answer 23

Neurologic dysfunction and self-mutilation behavior (can get gout)

Disorder of purine reclamation, defect in hypoxanthine-guanine phosphoribosyltransferase activity (HGPRT)

Clinical suspicion, elevated uric acid and molecular analysis of HGPRT

Treated with low purine diet, allopurinol and medications for treatment of neurologic signs and symptoms

*X-linked recessive

Question 24

Fatty Acid Oxygenation Disorders

VLCAD, LCAD, MCAD, SCAD, LCHAD, SCHAD

Answer 24

Child: lethargy and vomiting following fasting, classically presents with hypoketotic hypoglycemia (low ketones and glucose).

Other disorders have cardiac and/or hepatic involvement

Most common is medium chain acyl-CoA dehydrogenase deficiency (MCAD)

Elevations of fatty acid oxidation intermediates on urine organic acid quantitation and acylcarnitine analysis

Treatment: avoid fasting and rapid treatment of hypoglycemia

*Autosomal recessive

Question 25

Vitamins: Biotinidase

Answer 25

Alopecia, dermatitis, deafness, seizures, neurologic deterioration starting at 4-6 months.

Biotinidase defect: reclamation or recycling of biotin problem (biotin deficiency; biotin important for carboxylation reactions), can’t be broken down into lysine lysylpeptides

Diagnosis by enzyme assay of biotinidase

Treated by biotin supplementation

*Autosomal Recessive

Question 26

Menke Disease (Mineral Disorder)

Answer 26

Severe neurodegenerative disorder beginning in first few months, can’t absorb copper across intestinal epithelium, results in severe copper deficiency
Bald with kinky hair syndrome

Problem with ATP7A gene (transporter for copper)- helps get copper from intestine to blood

Diagnosis suspected by low blood copper and ceruloplasmin, molecular analysis of ATP7A gene

Treatment: none, copper histidinate infusion under investigation

*X-linked Recessive

Question 27

Hunter Syndrome (Lysosomal storage disease)

Answer 27

Accumulate mucopolysaccharides like dermatan and heparin sulfate

a-iduronidase sulfatase defect

Diagnosed by enzyme assay of a-iduronidase sulfatase, urine mucopolysaccharides

Treatment: enzyme replacement therapy (ERT)- i.e. Elaprase

*X-linked Recessive

Question 28

Zellweger Syndrome (Peroxisomal Disorder)

Answer 28

Hypotonic, small face
Defects in formation of peroxisomes or an isolated peroxisomal enzyme defect
-Zellweger syndrome: no peroxisomes formed
-severe , fatal disease

Diagnosis by elevation of very long chain fatty acids

Treatment: none

*Autosomal Recessive

Question 29

Peroxisomes

Answer 29

Cytoplasmic organelles

Functions:
Peroxide metabolism
Catabolism of very long chain fatty acids
Catabolism of bile acids
Synthesis of complex lipids

Question 30

Biochemical Laboratory Tests (list)

Answer 30

Amino acid quantitation
Urine organic acid quantitation
Carnitine levels and acylcarnitine analysis
Ammonia
Lactic Acid
Urine mucopolysaccharides
Very long chain fatty acids

Question 31

Newborn Screening

Answer 31

24 hours get blood sample, fill blood spot

Mailed to Oregon to do biochemical tests

Get another one done between 1 week and 2 weeks old

Variety of lab techniques used to analyze analytes, enzymes or ptoreins

• Tandem Mass spectrometry
• Enzyme analysis
• Electrophoresis
• DNA analysis

Question 32

Tandem Mass Spectrometer

Answer 32

Metabolite assay