Metabolic insight from genetic diseases

Question 1

What is the effect of most inherited metabolic diseases?

Answer 1

Alter key enzymes that catalyse important reactions in metabolism

genetically alter proteins that regulate the function of these enzymes (co-factors)

Question 2

Which heritable metabolic diseases can new borns be screened for?

Answer 2

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)

Question 3

How are inherited metabolic disorders identified?

Answer 3

• 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

Question 4

What is Von gierke’s disease (type 1 glycogen storage disease)?

Answer 4

Deficiency in glucose – 6- phosphatase

Autosomal recessive

Question 5

Name genetic mutation for type 1 glycogen storage disease?

Answer 5

GSD Ia results from mutations ofG6PC, thegenefor glucose-6-phosphatase(17q21)

Question 6

What are the consequences and symptoms of 1 glycogen storage disease? What is the treatment?

Answer 6

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

Question 7

What is Hers disease (type vi glycogen storage disease)?

Answer 7

autosomal recessive

Deficiency in liver glycogen phosphorylase (PYGL gene – 14q21)

Question 8

What are the consequences, symptoms, diagnosis and treatment of Hers disease?

Answer 8

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

Question 9

What is Mc ardle’s disease (type V glycogen storage disease)?

Answer 9

Deficiency in muscle glycogen phosphorylase

Question 10

What are the consequences, symptoms, diagnosis and treatment of Mc ardle’s disease?

Answer 10

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

Question 11

What is Galactosaemia type 1

Answer 11

Autosomal recessive disease

Deficiency in galactose-1-phosphate uridyl transferase.

Question 12

What are the consequences, symptoms and treatment of Galactosaemia type 1 ?

Answer 12

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.

Question 13

What is Hereditary Fructose intolerance?

Answer 13

deficiency in aldolase B-

which converts fructose -1-phosphate to dihydroxyacetone phosphate and glyceraldehyde (step 4 of glycolysis

Question 14

What are the consequences, symptoms and treatment of Hereditary Fructose intolerance ?

Answer 14

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.

Question 15

What is Pyruvate dehydrogenase deficiency?

Answer 15

Caused by mutations in any of the genes coding for the PDC

X-linked (PDHA1) or autosomal recessive

Question 16

What are the symptoms and treatment for Pyruvate dehydrogenase deficiency?

Answer 16

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.

Question 17

What is Phenylketonuria?

Answer 17

deficiency in the enzyme: phenylalanine hydroxylase

Question 18

What are the consequences, symptoms and treatment of Phenylketonuria?

Answer 18

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

Question 19

What is alkaptonuria?

Answer 19

deficiency in the enzyme homogentisate-1,2-dioxygenase (HGD gene)

Question 20

What are the consequences, symptoms and treatment of alkaptonuria?

Answer 20

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

Question 21

What is Maple syrup urine disease?

Answer 21

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.

Question 22

What are the consequences, symptoms, diagnosis and treatment of Maple syrup urine disease?

Answer 22

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.

Question 23

What is MCAD (Medium chain acyl-coenzyme A dehydrogenase )?

Answer 23

Inability to breakdown medium chain fatty acids due to deficiency in enzyme.

Question 24

What are the symptoms and treatment of MCAD?

Answer 24

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

Question 25

What is Familial hypercholesterolemia?

Answer 25

defects in low-density lipoprotein break down or uptake into cells (LDL receptor defects)

Question 26

What are the consequences, symptoms, diagnosis and treatment of Familial hypercholesterolemia?

Answer 26

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.

Question 27

How are inherited metabolic diseases identified?

Answer 27

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

Question 28

Which metabolic disorder causes cataracts?

Answer 28

Galactosemia

Question 29

Which metabolic disorder causes Neurological dysfunction?

Answer 29

Urea cycle defects (build up of ammonia in blood)