Metabolic insight from genetic diseases Flashcards
What is the effect of most inherited metabolic diseases?
Alter key enzymes that catalyse important reactions in metabolism
genetically alter proteins that regulate the function of these enzymes (co-factors)
Which heritable metabolic diseases can new borns be screened for?
Phenylketonuria (PKU)
Medium-chain acyl-CoA dehydrogenase Deficiency (MCADD)
Maple syrup urine disease (MSUD)
Isovaleric acidaemia (IVA)
Glutaric aciduria type 1 (GA1)
Homocystinuria (pyridoxine unresponsive) (HCU)
How are inherited metabolic disorders identified?
- New born screening
- Screening of blood for abnormal levels of specific metabolites
- Genetic screening of family members to identify known genetic mutations
- Identification of specific symptoms
What is Von gierke’s disease (type 1 glycogen storage disease)?
Deficiency in glucose – 6- phosphatase
Autosomal recessive
Name genetic mutation for type 1 glycogen storage disease?
GSD Ia results from mutations ofG6PC, thegenefor glucose-6-phosphatase(17q21)
What are the consequences and symptoms of 1 glycogen storage disease? What is the treatment?
Can not produce glucose from liver glycogen stores
Prevents gluconeogenesis in liver and kidney from other sources
Symptoms- hypoglycaemia, lactic acidosis, enlarged liver
Treatment: regular food intake low in starch to prevent accumulation of glycogen
What is Hers disease (type vi glycogen storage disease)?
autosomal recessive
Deficiency in liver glycogen phosphorylase (PYGL gene – 14q21)
What are the consequences, symptoms, diagnosis and treatment of Hers disease?
Consequence- reduction in the ability of the liver to break down glycogen
Symptoms- enlarged liver, mild hypoglycaemia, growth retardation, hyperlipidaemia.
Diagnosis- Elevated lactate and transaminase enzymes in blood. Liver biopsy shows reduced PYGL activity.
Treatment- regulation of diet to high glucose foods eaten regularly to avoid hypoglycaemia
What is Mc ardle’s disease (type V glycogen storage disease)?
Deficiency in muscle glycogen phosphorylase
What are the consequences, symptoms, diagnosis and treatment of Mc ardle’s disease?
Consequence- Exercise causes immediate depletion of energy stores since they cannot access energy stored in glycogen.
Symptoms- muscle damage (rhombolysis), inability to perform constant exercise, get “second wind”
Diagnosis: increased levels of myoglobin and creatine in blood (muscle damage)
Dark urine
Biopsy
What is Galactosaemia type 1
Autosomal recessive disease
Deficiency in galactose-1-phosphate uridyl transferase.
What are the consequences, symptoms and treatment of Galactosaemia type 1 ?
Consequence- Causes accumulation of galactose and galactose – 1- phosphate. (hypergalactosaemia)
Symptoms- infants-lethargy, failure to gain weight, jaundice, liver damage, abnormal bleeding, several neurological complications (mental retardation)
Treatment- strict diet control – galactose free diet.
What is Hereditary Fructose intolerance?
deficiency in aldolase B-
which converts fructose -1-phosphate to dihydroxyacetone phosphate and glyceraldehyde (step 4 of glycolysis
What are the consequences, symptoms and treatment of Hereditary Fructose intolerance ?
Consequence-Accumulation of fructose-1-phosphate in liver and kidneys (liver and kidney failure)
Inhibits glucogenolysis and gluconeogenesis leading to hypoglycaemia.
Symptoms- nausea, bloating, abdominal pain, chronic fatigue, malabsorption
Treatment- dietary control of fructose intake.
What is Pyruvate dehydrogenase deficiency?
Caused by mutations in any of the genes coding for the PDC
X-linked (PDHA1) or autosomal recessive
What are the symptoms and treatment for Pyruvate dehydrogenase deficiency?
Symptoms- build up of lactic acid leads to several neurological problems mental retardation, seizures, hypotonia, brain wasting), lactic acidosis, vomiting, breathing problems, abnormal heart beat; fatal if untreated.
Treatment: lipoic acid, ketogenic diet, thiamine.
What is Phenylketonuria?
deficiency in the enzyme: phenylalanine hydroxylase
What are the consequences, symptoms and treatment of Phenylketonuria?
Consequence- phenylalanine and its by products is toxic in the brains of children
Symptoms- developmental delay, mental retardation, albinism, hyperactivity
Treatment: diet low in phenylalanine
What is alkaptonuria?
deficiency in the enzyme homogentisate-1,2-dioxygenase (HGD gene)
What are the consequences, symptoms and treatment of alkaptonuria?
Consequence- accumulation of homogentisic acid
Dark urine
Bluish black discoloration of connective tissue
Symptoms- Joint and cardiac problems (adulthood- clinically silent during childhood)
Treatment- diet low in phenylalanine and high on vitamin C; pain management of joints
What is Maple syrup urine disease?
Rare autosomal recessive disease
deficiency in enzymes that make up the branched chain alpha-keto acid dehydrogenase complex which is essential for breaking down branched chain amino acids leucine, valine and isoleucine.
What are the consequences, symptoms, diagnosis and treatment of Maple syrup urine disease?
Consequence- Accumulation of leucine, valine and isoleucine and there by products (toxic to the brain)
Symptom- smelly urine
Diagnosis: mass spectrometry of blood to detect levels of specific amino acids
Treatment:strict diet control to remove intake of branched chain amino acids.
What is MCAD (Medium chain acyl-coenzyme A dehydrogenase )?
Inability to breakdown medium chain fatty acids due to deficiency in enzyme.
What are the symptoms and treatment of MCAD?
Symptoms- hypoketotic hypoglycaemia, hepatomegaly, diarrhoea, hyperammonemia, sudden infant death is possible.
Treatment- diet low in medium chain fatty acids and supplemented with frequent input of sugar to prevent need to rely on B-oxidation of fats
What is Familial hypercholesterolemia?
defects in low-density lipoprotein break down or uptake into cells (LDL receptor defects)
What are the consequences, symptoms, diagnosis and treatment of Familial hypercholesterolemia?
Consequence- build up of LDL in blood = increased risk of plaque formation and CHD.
Diagnosis: high LDL levels and high cholesterol
Treatment: diet control, statins.
How are inherited metabolic diseases identified?
Newborn screening (hell prick)
Screening of blood for abnormal levels of specific metabolites
Genetic screening of family members to identify known genetic mutations known to cause specific disorders
Which metabolic disorder causes cataracts?
Galactosemia
Which metabolic disorder causes Neurological dysfunction?
Urea cycle defects (build up of ammonia in blood)
