Inborn errors of metabolism: Disorders of Protein and Lipid Metabolism

Question 1

What are inborn errors of metabolism?

Answer 1

Genetic disorders of metabolism, mostly involving single genes which code for enzymes involved in metabolic pathways or transport proteins.

Question 2

What are the clinical presentations of impaired enzyme activity?

Answer 2

1. Accumulation of toxic substances which interfere with normal function.
2. Deficiency of product of a metabolic pathway

Question 3

What are the classifications of IEMs?

Answer 3

1. Disorders causing intoxication
2. Disorders of energy metabolism
3. Disorders involving complex molecules

Question 4

Describe disorders causing intoxication.

Answer 4

• Lead to progressive accumulation of toxic compound.
• PKU, MSUD, organic acidurias

Question 5

Describe disorders of energy metabolism.

Answer 5

• IEM of intermediary metabolism, symptoms due
  in part to energy deficiency
• Mitochondrial disorders or cytoplasmic energy defects

Question 6

Describe disorders involving complex molecules.

Answer 6

• Involves cellular organelles including diseases associated with disturbed synthesis or catabolism of complex molecules.
• Lysosomal storage disorders, peroxisomal disorders, intracellular trafficking disorders

Question 7

Describe newborn screening to detect inborn errors.

Answer 7

• It is a heel prick test done at 3-5 days old and allows for early detection of IEM before clinical signs and symptoms present.
• Early diagnosis allows for the early treatment.
• Reduces morbidity or premature mortality

Question 8

Discuss disorders of amino acid metabolism: Phenylketonuria (PKU).

Answer 8

• Autosomal recessive disorder.
• 97% Incidence due to phenylalanine hydroxylase enzyme defect & 3% due to defective synthesis of the cofactor, tetrahydrobiopterin.

Question 9

What are the symptoms of PKU.

Answer 9

• Irritability
• Vomiting
• Seizures
• Mental retardation by 4 - 6 months
• Reduced melanin production
• Frequently generalised eczema

Question 10

What is the management of PKU?

Answer 10

• Diet low in Phenylalanine; supplemented with Tyrosine
• Cofactor related form: Neurotransmitter supplementation

Question 11

Discuss disorders of amino acid metabolism: Tyrosinaemia type 1.

Answer 11

• Deficiency in fumarylacetoacetate hydrolase
• Accumulation of fumarylacetoacetate and its metabolites in the urine particularly succinyl acetone (Potentially fatal).

Question 12

What are the symptoms of Tyrosinaemia type 1.

Answer 12

• Characteristic cabbage like odour.
• Liver failure and renal tubular acidosis.

Question 13

What is the treatment of Tyrosinaemia type 1.

Answer 13

• Dietary restriction of Phenylalanine and Tyrosine.
• Drug: Nitisinone.

Question 14

Where does Nitisinone act?

Answer 14

It inhibits 4-hydroxyphenylpyruvic acid oxidase, used in treatment of tyrosinaemia type 1

Question 15

Discuss disorders of amino acid metabolism: Organic aciduria.

Answer 15

• Autosomal recessive
• Defective metabolism of lysine, hydroxylysine, and tryptophan (deficiency in glutaryl CoA dehydrogenase)
• Causes accumulation of organic acids in blood and urine (carboxylic acids, hydroxyl)

Question 16

Discuss disorders of amino acid metabolism: Alkaptonuria.

Answer 16

• Its a homogentisic acid oxidase deficiency.
• Causes dark urine and pigmentation phenotype called ochronosis (pigmentation of ears and eyes).
• Arthritis associated with calcification of joints.

Question 17

Discuss disorders of amino acid metabolism: Maple syrup urine disease.

Answer 17

• Its a defect in metabolism of leucine, isoleucine & valine.
• A deficiency in α-keto acid dehydrogenase.

Question 18

What are the symptoms of Maple syrup urine disease?

Answer 18

• Normal first few days of life with progressive lethargy, weight loss, episodes of hypertonia & hypotonia.
• Maple syrup odour to the urine.
• Ketosis, coma and death if not treated.

Question 19

What is the treatment of maple syrup urine disease?

Answer 19

• Dietary restriction of branched chain amino acids

Question 20

Discuss disorders of amino acid transport: Cystinuria

Answer 20

• A heritable disorder of amino acid transport in which large amounts of cystine, and dibasic AA (arginine, lysine and ornithine) are excreted in urine.

-Leads to cystine reals stones.

-Tx: ^fluid intake, alkalisation of urine with sodium bicarbonate.

Question 21

Discuss disorders of amino acid transport: Homocystinuria

Answer 21

• An IEM in which a defective activity of cystathionine synthetase causes an increase in urinary excretion of homocystine.
• Methionine and metabolites are elevated in the blood
• Leads to Cardiovascular disease, DVT, stroke, mental retardation, osteoporosis and dislocation of the lens.

Question 22

Discuss disorders of amino acid transport: Lysinuric protein intolerance (LPI)

Answer 22

• Absorption of dibasic amino acids (Lys, Arg, Orn), leading to impaired function of urea cycle and lysine deficiency.

Question 23

What are the symptoms of LPI?

Answer 23

• Failure to thrive
• Poor appetite
• Protein aversion
• Hyperammonaemia with progressive encephalopathy
• Renal failure
• Osteoporosis

Question 23

What is the treatment of LPI?

Answer 23

• Protein restriction with citrulline replacement to enhance Urea cycle

Question 24

What is hyperammonaemia?

Answer 24

• High levels of ammonia in the blood, which is neurotoxic to CNS.
• Intoxications result in tremors, slurred speech, somnolence, vomiting, cerebral oedema and blurred vision.

Question 25

What are the causes of hyperammonaemia?

Answer 25

1. Acquired: Liver insufficiency, Transient hyperammonaemia of newborn THAN)
2. Congenital hyperammonaemia: Urea cycle disorders, transport defects of urea cycle intermediates

Question 26

Discuss disorders of lipid metabolism: MCADD.

Answer 26

• Medium chain acyl co-enzyme A dehydrogenase deficiency.
• Disorder of fatty acid oxidation due to impaired break down medium chain fatty acids into acetyl-CoA.

Question 26

What are the symptoms of MCADD?

Answer 26

• Intolerance to fasting, hypoketotic hypoglycaemia, liver dysfunction, SIDS, lethargy, seizures and coma.

Question 27

What is the biochemistry of MCAD?

Answer 27

• MCAD is responsible for the dehydrogenation step of fatty acids with chain lengths between 6 and 12 carbons as they undergo beta-oxidation in the mitochondria.
• Beta-oxidation of long chain fatty acids produces two carbon units, acetyl-CoA and the reducing equivalents NADH and FADH2.

Question 28

What are the lysosomal storage disorders?

Answer 28

• Lysosomal storage diseases are inherited metabolic diseases that are characterised by an abnormal build-up of various toxic materials in the body’s cells as a result of enzyme deficiencies.

-There are 50 in total and affect different parts of the body.

• Caused by mutations in the genes encoding a lysosomal enzyme.

Question 29

What are peroxisomal disorders?

Answer 29

• Peroxisomal disorders are a heterogeneous group of inborn errors of metabolism that result in impairment of peroxisome function. In most cases, this results in neurologic dysfunction of varying extent.
• Caused by defects in any of at least 14 different PEX (or peroxin) genes.

Question 30

What are peroxisomes?

Answer 30

Membrane enclosed organelle that contain enzymes involved in a variety of metabolic reactions, including several aspects of energy metabolism.

Question 31

What are congenital disorders of glycosylation?

Answer 31

• A group of inherited metabolic disorders that affect a process called glycosylation.
• Glycosylation is the attachment of long sugar chains to proteins, to create glycoproteins.
• It is caused by aused by mutations in the PMM2 gene.