Biochemical/Metabolic Genetics Flashcards
Newborn Screening
- heel prick done 24-48 hours after birth
- RUSP contains 34 core and 26 secondary conditions
- conditions added based on Wilson and Jungner criteria
- each state free to choose own NBS panels
- consent follows opt-out model
- storage of dried blood spot cards varies from state to state; federally funded research requires parental consent
- screen positive result = repeat test
- actionable result = immediate care initiated
Inborn Errors of Metabolism
- deficiency of enzyme prevents something from being broken down/made
- vast majority are each rare AR conditions; consider consanguinity
- some more common in certain ethnic groups
- can be classified as disorders of intoxication, disorders of energy metabolism (including mitochondrial defects), or disorders involving complex molecules
Errors of Protein Metabolism (DI)
- aminoacidopathies
- organic acidemias
- urea cycle defects
Aminoacidopathies
- phenylketonuria
- hyperphenylalaninemia
- maternal PKU
- tetrahydrobiopterin deficiency
- MSUD
- homocystinuria
- tyrosinemia
Features of Aminoacidopathies
- elevated amino acid level and/or immediately preceding intermediate before defect
- neurological and behavioral impact due to build up in brain
- vomiting, coma, liver failure, thromboembolic complications, FTT, DD, ectopia lentis, cardiomyopathy
- symptom-free interval
Testing for Aminoacidopathies
- plasma/serum/urine amino acid levels (high)
- enzyme activity tests (little to no activity)
Treatment for Aminoacidopathies
- restrict substrate
- low protein diet
- supplement product
- supplement cofactor
- substitute enzyme
Organic Acidemias
- propionic acidemia
- methylmalonic acidemia
- cobalamin deficiencies
- isovaleric acidemia
- 3-MCC deficiency
Features of Organic Acidemias
- low blood pH levels due to build up of organic acids
- vomiting, altered mental status, lethargic, ill appearance, metabolic acidosis, hyperammonemia
Testing for Organic Acidemias
- plasma ammonia (high)
- venous blood gas (severe metabolic acidosis)
- urine organic acids (acid metabolites present)
Treatment for Organic Acidemias
- restrict amino acids preceding the organic acid
- low protein diet
- provide cofactor
- provide carnitine for alternate route of elimination
- pH stabilizer
Urea Cycle Defects
- OTC deficiency
- arginosuccinate lyase deficiency
- argininemia
- later-onset UCDs
Features of Urea Cycle Defects
- neonatal onset
- lethargy, poor feeding, vomiting, seizures, bleeding, hyperventilation, coma, death, hyperammonemia
Testing for Urea Cycle Defects
- ammonia levels (high)
- arginine levels (low)
- blood pH (no acidosis)
Treatment for Urea Cycle Defects
- restrict substrate (essentially no protein); essential amino acid formulas
- provide product (arginine or citrulline)
- replace enzyme (liver transplant)
- ammonia scavengers
- treat secondary effects
Glycogen Storage Diseases
- Hepatic GSDs: GSD 1a (von Gierke), GSD 1b, GSD 3, GSD 4, GSD 6, GSD 9a
- Muscular GSDs: GSD 2 (Pompe), GSD 5 (McArdle’s), GSD 7 (Tarui)
Features of GSDs
- glycogen stored in liver and in some muscles; some disorders affect one or other
- accumulation of glycogen, poor feeding, lethargy, hypoglycemia
Testing for GSDs
- not on NBS, except Pompe
- pyruvate/lactate levels (high)
- blood glucose (low)
- triglycerides (high)
- uric acid (high)
- enzyme analysis
- genetic testing
Treatment for GSDs
- feed every 3 hours to prevent brain damage from lack of glucose
- provide sugar to exercising muscle when heavily used
- boost WBC count
- ERT
Disorders of Sugar Metabolism
- galactosemia (emergency)
- hereditary fructose intolerance
- fructose 1,6 bisphosphatase deficiency
Features of Sugar Metabolism Disorders
- depends on condition
Testing for Sugar Metabolism Disorders
- fructose metabolism conditions not on NBS
- enzyme analysis
- genetic testing
Treatment for Sugar Metabolism Disorders
- restrict intake of offending sugar
Features of CDGs
- infantile onset, DD, heart disease, multiorgan dysfunction, hypoglycemia, protein-losing enteropathy, skin abnormalities (peaux d’orange), neurological abnormalities (stroke-like episodes), abnormal fat distribution, death
Testing for CDGs
- enzyme analysis
- genetic testing
Treatment for CDGs
- none
Fatty Oxidation Defects
- MCAD
- LCHAD
- VLCAD
- SCAD
- maternal HELLP syndrome
Features of FAODs
- lethargy, coma, hypoglycemia, kypoketosis
Testing for FAODs
- acylcarnitine profile (accumulation of fatty acid chains of different sizes)
Treatment for FAODs
- no fasting
- high carb/low fat diet
- supplement with carnitine if low
Disorders of the Carnitine Cycle
- carnitine uptake deficiency
- CPT-1
- translocase deficiency
- CPT-2
Features of Carnitine Cycle Disorders
- muscular weakness, cardiomyopathy, exercise intolerance. rhabdomyolysis, hypoglycemia
Testing for Carnitine Cycle Disorders
- acylcarnitine profile (build-up of long chain fatty acids)
Treatment for Carnitine Cycle Disorders
- provide levocarnitine
- no fasting
- low fat diet
Features of Peroxisomal Disorders
- elevated VLCFA
Testing for Peroxisomal Disorders
- not on NBS, except ALD
- acylcarnitine profile (elevated VLCFA)
- plasmalogen analysis (low)
Treatment for Peroxisomal Disorders
- management of symptoms
- BMT, hydrocortisone (ALD)
Muccopolysaccharidoses
- MPS I (Hurler/Scheie)
- MPS II (Hunter)
- MPS III (Sanfilippo)
- MPS IV (Morquio)
- MPS VI (Maroteaux-Lamy)
- MPS VII (Sly)
- MPS IX (Natowicz)
- Multiple sulfatase deficiency
Features of MPS
- dysfunction in degradation of glycosaminoglycans (GAGs)
- heparan sulfate found in ECM and has neurological effects
- keratan sulfate found in bones, collagen, corneas, connective tissue
- dermatan sulfate found in skin, valves, blood vessels
- coarse facial features, organomegaly (hepatosplenomegaly), skeletal dysplasia, short stature, cognitive decline, progressive
Testing for MPS
- urine GAGs (total GAGs elevated)
- enzyme analysis
- genetic testing
Treatment for MPS
- BMT
- ERT
- supportive treatment
Sphingolipidoses
- GM1 gangliosidosis
- GM2 gangliosidosis (Tay-Sachs)
- Niemann-Pick A/B
- Metachromic leukodystrophy
- Krabbe disease
- Gaucher disease
- Fabry disease
Features of Sphingolipidoses
- defects in sphingolipid metabolism (important for neuronal cell functioning)
- several AJ founder mutations
- progressive neurological/cognitive decline
Testing for Sphingolipidoses
- not on NBS, except Krabbe
- enzyme analysis (beware pseudodeficiency alleles)
- urine analysis (high sulfatides for MLD)
- genetic testing
Treatment for Sphingolipidoses
- supportive treatment
- BMT (Krabbe)
- ERT (Gaucher and Fabry)
Porphyrias
- Acute hepatic: AIP, HCP, VP, ADP
- Cutaneous: PCT (cutaneous and hepatic), CEP, EPP, XLP
Features of Porphyrias
- Acute hepatic: low penetrance (10-20%), women more commonly affected (80% vs 20%), abdominal pain, nausea, vomiting, pain in extremities/back, muscle weakness, anxiety, depression, dark/reddish urine, hepatocellular carcinoma, photosensitivity
- Cutaneous: skin blistering, severe photosensitivity, deposition of porphyrin in skin, bones, teeth
Testing for Porphyrias
- urine ALA and PBG (high)
- urine/plasma/fecal porphyrin levels (results depend on type)
- erythrocyte protoporphyrin levels (elevated in EPP and XLP)
- free:zinc-chelated erthyrocyte protoporphyrin levels (EPP, XLP)
- genetic testing
Treatment for Porphyrias
- Acute hepatic: intravenous hemin, symptomatic relief, liver transplant, sun protection, siRNA and RNAi, avoid triggers (alcohol, smoking, stress, drugs)
- Cutaneous: serial phlebotomies/hydroxychloroquinone, blood transfusions, sun/UV protection, BMT/liver transplant, melanin-producing drugs, symptomatic relief, avoid triggers
Conditions Involving Purine Salvage/Synthesis
- Lesch-Nyhan disease
Conditions Involving Cholesterol
- Niemann-Pick C
- Antley-Bixler syndrome
- Smith-Lemli-Opitz syndrome
Disorders of Carbohydrate Metabolism (DI, DEM)
- glygocen storage disorders
- sugar intolerances
- congenital disorders of glycosylation
Disorders of Fat Metabolism (DEM)
- FAODs
- carnitine cycle defects
Disorders of Peroxisomal Metabolism (DCM)
- peroxisomal biogenesis disorders
- adrenoleukodystrophy
Lysosomal Storage Disorders (DCM)
- mucopolysaccharidoses
- sphingolipidoses
Conditions Involving Copper Metabolism
- Menkes syndrome
- Wilson disease
Conditions Involving Biotin
- biotinidase deficiency
Neurodegeneration with Brain Iron Accumulation
- PKAN (pantothenate kinase-associated neurodegeneration)
- PLAN/INAD
- MPAN
- BPAN
- FAHN
- CoPAN
- KRS
- ACP
- NF (not neurofibromatosis)
Wilson and Jungner Criteria
- accurate screening test
- regular review of scientific and medical rationale
- significant life-challenging risk of morbidity if disorder is untreated
- total costs of system from diagnosis to follow-up must be reasonably priced
- significant prevalence of disorder
- natural history of disease understood
- consumer involvement, physician and public health acceptance in the decision to mandate screening
- positive health benefits must outweigh risks and burdens
- disorder must be treatable and require early treatment
- resources for and access to confirmatory testing, treatment, and counseling
Congenital Disorders of Glycosylation
- CDG 1a
