1
Q
Clinical manifestations of Mitochondrial Disease
A
- Stroke
- Basal ganglia lesions
- Encephalopathy - hepatopathy
- Epilepsy
- Cognitive decline
- Ataxia
- Ocular signs (ptosis, optic nerve atrophy, retinopathy)
- Sensorineural hearing loss
2
Q
Genetic of mitochondrial disease
A
37 genes encode 13 proteins and 24 RNAS
More than 200 nDNA-encoded mito genes - encode over 1500 proteins
Circular mitome
100 known mito disease genes
Defects affect the ETC (electron transport chain/respiratory chain)
3
Q
mtDNA syndromes
A
MELAS - Mitochondrial encephalopathy with lactic acidosis and stroke-like episodes
MERRF - Myoclonic epilepsy with ragged red fibers
NARP - neuropathy, ataxia, retinitis pigmentosa
MILS - maternally inherited Leighs syndrome
LHON - Leber’s hereditary optic neuropathy
KSS/Pearson - sideroblastic anemia, pancreatitis (caused by mtDNA deletions)
4
Q
Heteroplasmy
A
Percentage of affected mitochondria determines severity of phenotype
High percentage - more severe phenotype
Low percentage - may not exhibit any phenotype
ex. T8993G mutation-carrying individuals appear normal from 0-60% affected DNA, have retinitis pigmentosa from 60-75%, have NARP from 75-90%, and have Leighs syndrome if 90% or more of the mitochondria is affected
5
Q
Fission and Fusion (mitochondria dynamics)
A
Mitochondria replicate by fission, require fusion to operate
Several genes regulate this and gene defects lead to mitochondrial disease
- OPA1 - AD Optic Atrophy
- MFN2 - AD axonal variant Charcot-Marie-Tooth
- KIF5A - AD HSP
6
Q
Coenzyme Q10 Deficiency
A
6 Major clinical phenotypes
- Encephalomyopathic form with seizuers and ataxia
- Multisystem infantile form with encephalopathy, cardiomyopathy, and renal failure
- Predominantly cerebellar form with ataxia and cerebellar atrophy
- Leigh syndrome with growth retardation
- Isolated myopathy
- Steroid resistant nephrotic syndrome
May respond dramatically to Coenzyme Q10 treatment
7
Q
mtDNA depletion syndrome symptoms
A
- Lactic acidosis in neonatal/childhood period
- Failure to thrive
- Hyoptonia
- Muscle weakness in childhood and adulthood
- Ataxia in adulthood
- Polyneuropathy in adulthood
- Liver impairment in childhood
- Epilepsy
- Migrane-like headaches in juvenile period
- Developmental delay/cognitive impairment
- Psychiatric symptoms in teens and adulthood
- GI symptoms in adulthood
8
Q
Defects of intergenomic communication
A
Mitochondrial neuro gastrointestinal encephalomyopathy
- pstosis and opthalmoplegia
- GI dysmotility
- cachexia
- peripheral neuropathy
- leukoencephalopathy
9
Q
Mitochondrial Disease Therapeutics
A
- Therapy based on specific pathway of respiratory chain affected
- Three parent children - Mitochondrial genome transfer to avoid mitochondrial diseases
- Gene therapy to reduce mutant mtDNA
10
Q
Ammonia excretion - non-hepatic tissues
A
- Glutamate dehydrogenase and glutamine synthetase remove 2 ammonia molecules from tissues to rid them of nitrogen waste
- Glutamine deposits ammonia in kidney for excretion
11
Q
Urea excretion - hepatic tissues
A
Requires water
Nitrogen waste ends up in urea
Goes into urea cycle
Amino acids derived either from breakdown of protein in tissues or from what is synthesized in those tissues
12
Q
Hyperammonemias
A
Acquired - liver disease leads to portal systemic shunting
Inherited - Urea cycle enzyme defects of CPS1 (carbonyl phosphate synthetase 1) or ornithine transcarbamylase lead to severe hypoammonemia
13
Q
Metabolic functions of the liver
A
- Production and storage of glycogen
- Catabolism of glycogen to glucose
- Conversion of excess glucose to fat
- Transport of lipids/glucose to other tissues
- Conversion of ammonia to urea
14
Q
Deammination as a source of ammonia production
A
Removal of an amino group from amino acids results in the production of an ammonia molecule
15
Q
Non-IEM causes of Hyperammonemias
A
- Drug-related (valproate)
- Acute liver failure
- Reye syndrome
- Massive tissue necrosis
- Chronic UTIs with urine retention
- Overgrowth of bowel flora
- Portocaval shunts
- Transient hyperammonemia in newborns
16
Q
Urea cycle functions
A
- Prevents the accumulation of toxic nitrogenous compounds by removing nitrogen through urea
- Contains several biochemical reactions for the de novo synthesis of arginine
17
Q
Urea Cycle Disorders
A
- Carbamyl phosphate synthetase deficiency
- Ornithine transcarbamylase deficiency (most common)
- Argininosuccinic acid synthetase deficiency
- Argininosuccinic acid lyase deficiency
- Arginase deficiency (lease common)
Characterized by hyperammonemia, encephalopathy (due to accumulation of glutamine in the astrocyte), respiratory alkalosis
18
Q
N-Acetylglutamate Synthase deficiency (NAGS)
A
- Autosomal recessive
- Lethargy, persistent vomiting, poor feeding, hyperventilation, enlarged liver, seizures
- Total deficiency - symptoms appear immediately following birth
- Partial deficiency - may occur later in life following a stressful event such as infection
- Low cirtulline levels, normal orotic acid levels
19
Q
Carbamyl phosphate synthetase deficiency (CPS)
A
- Autosomal recessive
- Lethargy, coma, seizures, vomiting, poor feeding, hyperventilation, heptaomegaly
- Total deficiency - symptoms appear immediately following birth
- Partial deficiency - symptoms appear in childhood
- Low citrulline levels, normal orotic acid levels
20
Q
Ornithine transcarbamylase deficiency
A
- X-linked
- Most common
- Lethargy, coma, seizures, vomiting, poor feeding, hyperventilation, hepatomegaly
- Hemizygote males - onset immediately after birth
- Hemizygote females - 10% are symptomatic
- Low citrulline levels, high orotic acid levels
21
Q
Argininosuccinic acid synthetase deficiency (ASS)
A
- Autosomal recessive
- Lethargy, coma, seizures, vomiting, hyperventilation, poor feeding, hepatomegaly
- Total deficiency - symptoms appear immediately following birth
- Partial deficiency - symptoms appear in childhood
- High citrulline levels, high orotic acid levels
22
Q
Argininiosuccinic acid lyase deficiency (ASL)
A
- Autosomal recessive
- Lethargy, coma, seizures, vomiting, hyperventilation, poor feeding, hepatomegaly
- Total deficiency - symptoms appear immediately following birth
- Partial deficiency - symptoms appear in childhood
- High citrulline levels, high orotic acid levels
23
Q
Arginase Deficiency (ARG)
A
- Autosomal recessive
- Delayed development, protein intolerance, spasticity, seizures, irritability, vomiting, poor appetite
- Slower onset, often present with symptoms of muscle weakness, hyperammonemia is rare
- High citrulline levels, high orotic acid levels
24
Q
Treatment of Urea Cycle Defects
A
- Goal is to maintain plasma glutamine levels at or near normal (Glutamine represents a storage form of nitrogen that can buffer ammonium)
- Measure of plasma glutamine levels may be single best guide to therapy (levels can predict hyperammonemia)
- Restricted intake of dietary protein
- Activation of other waste nitrogen pathways - CPS, OT, ASS - sodium phenylbutyrate activates phenylacetylglutamine - new vehicle for removal of waste nitrogen
- Arginine supplementation in ASS and ASL
- Ammonul medication
- Liver transplant in severe phenotypes
25
Functions of the lymphatic system
- Anatomic organization
- Fluid homeostasis
- Local tissue inflammation and edema
- Infection management
- Cancer
- Nutrition
- Organ rejection
26
Lymphatic development
1. Embryonic veins express high levels of VEGFR-3 while a subpopulation of endothelial cells in large central veins express LYVE-1
2. SOX-18 transcription factor is induced in LYVE-1 positive cells
3. VEGFR-3 is downregulated in veins but remains high in lymphatic endothelial cell (LEC) precursors
4. LEC precursors express neutrophilin-2 which makes them more responsive to VEGF-C, required to form lymph sacs
5. LECs express proteins that lead to platelet aggregation to prevent lymphatico-venous connections
6. LECs differentiate into lymphatic capillaries and vessels
27
Clinical manifestations of lymphedema
- Abnormal accumulation of fluid (possibly lymph) in the interstitial spaces (often extremities)
- Abnormality in the structure or function of the lymph system
- Swollen extremities
- Phenotype is imprecise and penetrance is incomplete
28
Primary Lymphedema (PL)
- AD w/ reduced penetrance (80%)
- Disabling and disfiguring swelling of the limbs
- Variable expression
- Variable age of onset
- Genetic heterogeneity
- VEGFR-3 and SOX-18 mutations
29
VEGFR-3
Expressed in vascular endothelium - lymphatic precursor cell line
- prominent at lymphatic points of origin
- VEGFR3 KO mice showed enlarged pericardial lymphocytes, enlarged paws
- Causes is PL
30
Lymphedema-Distichiasis
- AD
- Lymphedema, predominantly of lower limbs
- onset around puberty
- Distichiasis (double row of eyelashes)
- Varicose veins
- Cleft lip/palate (4%)
- Congenital heart defect (7%)
- FOXC2 mutations
31
Hypotrichosis-Lymphedema-Telangiectasia
- SOX18 mutations
| - AR or AD
32
Galctosemias
- GALK - Galactokinase deficiency
- GALT - Galactose uridyl transferase deficiency
- GALE - Uridine diphosphotase deficiency
33
Fructose diseases
- Fructokinase deficiency
- Hereditary fructose intolerance
- Fructose 1,6-bisphosphotase deficiency
34
Glutamate-Glutamine conversion as ammonia buffer
- Glutamine is a storage form of nitrogen that can provide a short-term buffering of ammonia
- Gluatamate dehydrogenase and gluatmine synthase remove two ammonia molecules from tissues to remove excess nitrogen waste
35
Population-Specific Galactosemia Mutations
S135L - GALT gene mutations - common in African Americans
Q188R - GALT gene mutations - most common mutation in Caucasians
N314D - Duarte allele
36
Clinical Manifestations of GALK
- High galactose, low galactitol, low Gal1P
| - Cataracts only
37
Clinical Manifestations of GALT
- High galactose, high galactitol, high Gal1P
- Cataracts, kidney failure, cerebral consequences, ovarian failure irrespective of diet, hepatomegaly, liver failure, sepsis, bulging fontanelle (pseudotumor cerebri), failure to thrive, leukodystrophy, developmental delay (verbal apraxia), motor difficulties
-NEVER DEVELOP AN AVERSION TO GALACTOSE-CONTAINING FOODS
38
Clinical Manifestations of GALE
- High galactose, high galactitol, high Gal1P
- Normal galactose uridyl transferase activity
- Cataracts, kidney failure, cerebral consequences, ovarian failure, psychomotor retardation
39
Nutritional treatments for galactosemias
- Lactose (glucose + galactose) restriction for life
- Supplement with soy protein
- Calcium supplements
- Monitory Gal1P and urinary galactitol levels
40
Polyols and cataract formation
- Galactose accumulates in the lens
- Converts to galactitol which cannot be degraded by the enzyme polyol dehydrogenase
- Galactitol remains in the lens, favoring osmotic movement of water into the lens
- Water retainment in the lens leads to formation of cataracts
41
Golgi apparatus and sorting of lysosomal enzymes
- Golgi apparatus processes and sorts proteins
- Primary lysosomes bud from trans face of golgi complex - go on to undergo exocytosis and fuse with vesicles to digest contents
- Lysosomal hydrolases covalently modified by mannose-6-phosphate groups on cis face of golgi complex
- Mannose-binding transport vesicles segregate these modified compounds
- Vesicles fuse with late endosomes
42
Gaucher disease and glucocerebrosidase function
Gaucher - most common LSD, AR, chromosome 1
Glucocerebrosidase - normally converts glucocerebroside into its core components glucose and ceramide
-deficiency leads to buildup of glucocerebroside
Gaucher patients exhibit increased glucocerebroside and decreased cholesterol
43
Type 1 Gaucher
Non-neuronopathic
- panethnic, but common in AJ pop
- Onset at any age
- 10-30% of normal enzyme activity
- Hepatosplenomegaly, bone disease, thrombocytopenia, anemia, growth retardation, bone pain/bone crisis, fatigue, abdominal pain
44
Type 2 Gaucher
Acute Neuronopathic - most severe
- panethnic
- onset in infancy
- lifespan 2-3 years
- strabismus, retroflexion of neck, cortical thumbs, visceromegaly, failure to thrive, cachexia (wasting syndrome), early death
45
Type 3 Gaucher
Chronic Neuronopathic
- panethnic
- onset in infancy/childhood
- Less than 10% normal enzyme activity
- Severe early onset, progressive developmental delay, oculomotor apraxia, anemia, thrombocytopenia, visceromegaly, bone disease, bone pain/bone crisis
46
Non-specific Gaucher treatments
- Iron and vitamin supplementation
- Blood transufsions
- Partial or total splenectomy
- Pain management
- Calcium supplementation
47
Specific Gaucher treatments
- ERT for type 1 - Cerezyme
| - Bone marrow transplantation (risky, ethically debated)
48
ERT for Gaucher
- Targeted lysosomal enzyme delivery to site where enzyme is needed
- 50% increase in platelets in patients with thrombocytopenia
- 45% decrease in splenic volume in patients with intact spleens after 9 months
- 15% of patients develop IgG antibodies against enzyme
- only 1 patient reported that developed IgE against enzyme
49
Fabry Genetics
- X-linked LSD
- Deficiency of alpha-galactosidase
- Leads to accumulation of glycosphingolipids in body tissues
50
Clinical Manifestations of Fabry
- Renal failure, cardiomyopathy, GI problems, cerebrovascular problems, chronic pain (usually in extremities), Fabry crises (episodes of extreme pain), angiokeratomas (non-blanching lesions), hypohidrosis, heat or cold intolerance, exercise intolerance, corneal whorl, neurological complications (vertigo, tinnitus)
- Presents in childhood but may be unrecognized into adulthood
- Females can exhibit signs and symptoms to varying degrees
- Males usually have <1% enzyme levels, females may exhibit anywhere from 0-100% enzyme levels
51
ERT for Fabry
- Fabrazyme
- Provides exogenous source of alpha galactosidase
- Significant reduction of GL-3 in kidney, heart, and skin (major glycosphingolipid that builds up due to Fabry)
- GL-3 still present in vascular smooth cell muscles
- Creatinine levels remained normal up to 30 months after starting treatment
- Kidney function remained normal
52
Function of Glycogen in Energy Storage
- glucose is stored as glycogen for later use in energy uptake during fasting
- glyocgen is rapidly depleted during fasting and rapidly replaced upon feeding
- buffers glucose levels in the blood in liver
- provides glucose for energy during exercise/survival reactions in muslce
53
Regulation of glycogen synthase in fasting and feeding
Active form - dephosphorylated
Inactive form - phosporylated
Fasting - Glucagon or epinephrine increases cAMP production which activates protein kinase A to phosphorylate glycogen synthase - inactivates the enzyme to prevent glycogen from being made
Feeding - Insulin reduces cAMP, induces and activates protein phosphatase-1 which activates glycogen synthase by dephosphorylating it resulting in increased production of glycogen
54
Key steps of glycogen degredation
Glycogen phosphorylase - hydrolyzes glucose unites from glycogen, producing glucose-1-phosphate in the process
Debranching enzyme complex - removes branch points to break down glycogen
55
Regulation of glycogen phosphorylase during fasting and feeding
Fasting - glucagon or epinephrine increases cAMP which activates protein kinase A which phosphorylates and activates glycogen phosphorylase resulting in increased glycogenolysis
Feeding - insulin reduces cAMP and induces activation of protein phosphatase-1 which inactivates glycogen phosphorylase and decreases glycogenolysis
56
Type-1a "von Gierke" Glycogen storage disease
- Glucose-6-phosphatase deficiency (first step in glycogen breakdown)
- Glycogen accumulates in cytoplasm
- Glycogen and fat accumulate in liver and kidneys
- Hepatomegaly, hypoglycemia, renomegaly, failure to thrive, growth retardation, lactic acidemia, hyperuricemia (increased production of and decreased renal clearance of uric acid), hyperlipidemia, neutropenia
- Autosomal Recessive
- 50% mortality
57
Management and Treatment of Type 1 Glycogen Storage Disease
- Glucose infusion
- Cornstarch
- Liver transplant
- Prevent hypoglycemia - frequent carb-rich meals throughout day
- Glycosade medical food
58
Fatty acid transport and activation
- Fatty acids are transported bound to albumin and are the primary source of energy during fasting via oxidation in the liver, cardiac muscle, and skeletal muscle
- A series of acyl co-A synthetases activate fatty acids to form CoA thioesters
- Carnitine cycle is required to transport long-chain fatty acids into the mitochondria for beta-oxidation
59
Carnitine Cycle
-Consists of many carnitine transporter enzymes that convert acyl Co-As to acylcarnitines in order to cross the mitochondrial membrane
60
Beta-Oxidation spiral
- Acyl Co-A esters enter beta-oxidation spiral and with each "turn" of the spiral acyl-CoA ester chain is shortened by two carbons in a saturated fatty acid
- Two carbon acetyl-CoA compounds are released as a result
61
Carnitine defects
- Coma
- Seizures
- Hepatomegaly
- Hypoglycemia with fasting
62
Key steps of beta-oxidation
- Occurs in mitochondria
- Each step mediated by enzymes specific to the link of the fatty-acid chain
- Acyl-CoA dehydrogenase mediates the first step of oxidation
- Enzymes insert double bonds into carbons, transfer electrons into ETF
- Acyl-CoA dehydrogenase utilizes electron transfer flavoprotein (ETF) as final protein acceptor
63
ETF dehydrogenase and multiple Acyl-CoA dehydrogenase (ACAD) deficiency
- Deficiencies in ETF dehydrogenase result in secondary deficiencies of all primary dehydrogenase enzymes
- Multiple ACAD deficiency can result in severity ranging from severe lethal neonatal disease to adult onset myopathy
64
Ketone Body Metabolism
- The liver can channel acetyl-CoA into ketone body formation
- Ketogenesis is increased during fasting to provide an alternative source of oxidation to glucose and to prevent proteolysis
- Ketone body metabolism catalyzed by three enzymes:
- HMG-CoA synthetase
- HMG-CoA lyase
- D-3-hydroxybutyrate dehydrogenase
65
Metabolic impairments in ACAD deficiency
- Hypoglycemia
- Less reducing equivalent to oxidative phosphorylation
- No ketone bodies to extrahepatic tissues
- Depletion of the tricarboxcylic acid cycle (Kreb's cycle)
66
Symptoms of ACAD deficiences
- Hypoketotic hypolgycemia
- Reye syndrome (rash, vomiting, liver damage)
- Hypotonia and/or myopathy
- Liver failure
- Peripheral neuropathy
- Failure to thrive
- Coma
- Sudden death
67
Treatment of ACAD deficiences
- Avoid fasting
- Low fat diet (25-35% diet from fat)
- MCT (medium chain triglycerides) oil for long chain defects
- High caloric intake when ill or stressed to avoid fasting
- Nighttime nasogastric feedings
- Carnitine for transporter defects
68
Triheptanoin as a treatment for long-chain fatty acid disorders
- Triheptanoin is composed of three seven-carbon fatty acids
- Able to provide a substrate for the TCA cycle
- Can replace missing substrates in LCAD deficiencies
- Reduced episodes of hypoglycemia, hospitalizations, and rhabdomyolysis
- Improved cardiomyopathy
69
Public Health Significance of congenital heart defects (CHD)
- Most common birth defect (1% of all births)
- Estimated 1 million adults in the US with CHD
- Leading cause of birth-defect associated infant illness and death
- 1.4 billion spent in one year on hospitalizations for individuals with CHD
- Over 40,000 deaths contributed to CHD in 10 years
70
Ventriculoseptal Defects (VSD)
-hole between two ventricles affects flow
71
Atrial-septal defects (ASD)
-hole between two atria affects flow
72
Patent-ductus arteriosus (PDA)
-ductus arteriosis fails to close, leaves an open connection between pulmonary artery and aortic arch
73
Pulmonary-valve stenosis (PVS)
- Narrowing of the pulmonary valve
| - Leads to reduction in blood flow to lungs, thickening of ventricular septal walls
74
Aortic stenosis (AS)
Narrowing of the aortic valve leading to reduction of blood flow to the body
75
Coarctation
Narrowing of the aorta at the ductus arteriosis, left ventricular thickening as it must work harder to pump blood, decreased blood flow to the body
76
Transposition of the great artery (TGA)
Arteries are transposed in abnormal arrangement
-two separate pathways result wherein oxygenated blood continuously pumps to the lungs while deoxygenated blood continuously pumps to the body
77
Tetralogy of Fallot (TOF)
Involves four anatomical abnormalities of the heart
- VSD
- Obstruction to flow through pulmonary valve
- Oxygen poor blood circulated through body
- Blue babies
78
Aneuploidy and microdeletion syndromes
All viable trisomies (13, 18, 21) have CHD associated
-ASD, VSD, PDA, TOF
Turner, Kleinfelter, DiGeorge and William Syndrome all have CHD
```
Syndromic CHD found in deletions
Isolated CHD (nonsyndromic) tends to be due to duplications
```
79
Forward genetic screens to identify CHD genes
- Completely phenotype driven
- No genotype bias
- Saturation level can provide a complex genetic landscape
- Suggests multigenic cause of CHD
- Interactome of CHD genes
80
Mechanism by which ciliary dysfunction results in CHD
-Motile cilia required for flow
- Primary cilia mediate signal transduction
- Cilia regulated cell signaling pathways contribute to CHD
-SHARPEI mutants have immotile cilia and result in CHD phenotypes
81
Neonatal hyperbilirubinemia
Most common medical condition in newborn period
- occurs because RBCs have a shorter lifespan in neonates
- there are more RBCs in neonates than in adults
- there is diminished capacity to conjugate the bilirubin in neonates
- there is increased enterohepatic circulation in neonates
Causes jaundice
Breastmilk feeding my enhance risk for neonatal hyperbilirubinemia
82
Bilirubin Metabolism
1. Heme from red blood cells is converted to CO and biliverdin by heme oxygenase
2. Biliverdin is converted to unconjugated bilirubin by biliverdin reductase
3. Bilirubin-albumin compound transported to the liver
4. UGT1A1 conjugates toxic unconjugated bilirubin into non-toxic conjugated bilirubin
5. Liver excretes conjugated bilirubin
6. Entero-hepatic circulation
83
Kernicterus
Hyperbilirubinemia may develop into kernicterus
1. Movement disorder of the choreoathetoid cerebral palsy
2. Central neural hearing loss
3. Paresis of the vertical gaze
4. Dental enamel hypoplasia
84
G6PD (glucose-6-phosphate dehydrogenase) deficiency
Accounts for 22% of all kernicterus cases
-Regenerates NADPH which in turn reduces oxidized glutathione in RBC antioxidant defense system
X-linked
Four major variants
- G6PD A and G6PD Mediterranean confer advantage to malaria
- G6PD Canton and G6PD Kaiping found in Asian populations
85
G6PD deficiency and hyperbilirubinemia
Two modes of hyperbilirubinemia:
-Acute, often severe hemolytic episodes triggered by oxidant stress and resultant hyperbilirubinemia
-Low-grade hemolysis coupled with genetic polymorphisms of UGT1A1 that limits hepatic bilirubin conjugation
86
Immune-mediated hemolysis
- Major ABO blood group - mother O, infant A or B
- Rh blood group - mother Rh negative, infant positive
- Minor blood groups
87
Red cell membrane defects
Hereditary spherocytosis
| Eliptocytosis
88
UGT1A1 and Gilbert syndrome
Wildtype promoter region contains 6 TA repeats
Gilbert syndrome (G71R variant):
- Number of repeats exceeds 6
- Affinity of TATAA binding protein for promoter weakens
- Decreased UGT1A1 activity
- Hyperbilirubinemia in absence of liver disease and clinically overt hemolysis
Combination of Gilbert genotype with G6PD deficiency, other hemolytic issues (ABO bloodtype, hereditary spherocytosis) leads to dose-dependent interaction enhancing severity of neonatal hyperbilirubinemia
89
Crigler-Najjar Syndrome Type I
Autosomal recessive
Familial non-hemolytic jaundice associated with hyperbilirubinemia and kernicterus
Premature truncation or frameshift of UGT1A1
90
Crigler-Najjar Syndrome Type II
Autosomal recessive
Significant hyperbilirubinemia but low risk for kernicterus
UGT1A1 mutation resulting in markedly reduced enzyme activity
Almost all CN-2 patients carry one allele for Gilbert promoter
91
Co-inheritance and compound heterozygotes in hyperbilirubinemia
Compound heterozygotes experience more severe phenotypes - 10-15% of enzyme activity (Gilbert and CN-1)
Co-inheritance of polymorphisms increases the severity of hyperbilirubinemia in neonates
Inherited Diseases
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