1. Biochemical Genetics And Newborn Screening Flashcards
List the groups of biochemical disorders (objective)
Answer later
Explain the clinical laboratory findings suggestive for each of the presented biochemical disorders (objective)
Answer later
Give the treatment regimen for each of the presented biochemical disorders (objective)
Answer later
Discuss the NM newborn screening process (objective)
Answer later
Biochemical Genetics (overview)
“Metabolic diseases”
Products of genes are usually proteins (mostly loss of function)
Amino/organic acids, fatty acid oxidation, nucleic acids, vitamins and minerals
Metabolic Diseases (frequency)
Each individual disease is rare
If protein is enzyme, typically autosomal recessive
If protein is structural, typically autosomal dominant
Biochemical Classification
Amino Acids Organic Acids Urea Cycle Carbohydrates Purines/pyrimidines Lipids Minerals Vitamins Mitochondria Peroxisomes Lysosomal disorders Membrane Transport
Amino Acid Disorders (basic)
Phenylketonuria (PKU)
Elevation of diagnostic amino acids on amino acid quantitation
Organic Acid Disorders (basic)
Methylmalonic Aciduria
Elevation of diagnostic organic acid in urine
Urea Cycle Defects (basic)
Ornithine Transcarbamylase (OTC)
Elevation of ammonia and diagnostic amino acid
Carbohydrate Disorders (basic)
Hereditary fructose intolerance (HFI)
Clinical Suspicion
Purines/Pyrimidines Disorders (basic)
Lesch-Nyhan syndrome
Hyperuricemia
Lipids Disorders (basic)
Medium acyl-CoA dehydrogenase (MCAD)
Diagnostic intermediates on urine organic acid quantitation
Vitamins Disorders (basic)
Biotinidase
Clinical suspicion and relevant laboratory studies
Mineral Disorders (basic)
Menke disease
Relevant laboratory studies: low ceruloplasmin and copper
Lysosomal Storage Disorders (basic)
Hunter syndrome
Clinical and radiologic signs and symptoms
Relevant laboratory studies for disorder
Peroxisomal Disorders (basic)
Zellweger Syndrome
Elevated very long chain fatty acids and phytanic acid
Mitochondrial Disorders (basic)
MELAS
Elevated lactic acid
Phenylketonuria (PKU)
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
Methylmalonic Aciduria (MMA)- Organic Acid Disorder
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
Urea Cycle Defects
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
Hereditary Fructose Intolerance
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
Lesch-Nyhan Disease
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
Fatty Acid Oxygenation Disorders
VLCAD, LCAD, MCAD, SCAD, LCHAD, SCHAD
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
Vitamins: Biotinidase
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
Menke Disease (Mineral Disorder)
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
Hunter Syndrome (Lysosomal storage disease)
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
Zellweger Syndrome (Peroxisomal Disorder)
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
Peroxisomes
Cytoplasmic organelles
Functions: Peroxide metabolism Catabolism of very long chain fatty acids Catabolism of bile acids Synthesis of complex lipids
Biochemical Laboratory Tests (list)
Amino acid quantitation Urine organic acid quantitation Carnitine levels and acylcarnitine analysis Ammonia Lactic Acid Urine mucopolysaccharides Very long chain fatty acids
Newborn Screening
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
Tandem Mass Spectrometer
Metabolite assay
