Inborn errors of metabolism: Disorders of Protein and Lipid Metabolism Flashcards
What are inborn errors of metabolism?
Genetic disorders of metabolism, mostly involving single genes which code for enzymes involved in metabolic pathways or transport proteins.
What are the clinical presentations of impaired enzyme activity?
- Accumulation of toxic substances which interfere with normal function.
- Deficiency of product of a metabolic pathway
What are the classifications of IEMs?
- Disorders causing intoxication
- Disorders of energy metabolism
- Disorders involving complex molecules
Describe disorders causing intoxication.
- Lead to progressive accumulation of toxic compound.
- PKU, MSUD, organic acidurias
Describe disorders of energy metabolism.
- IEM of intermediary metabolism, symptoms due
in part to energy deficiency - Mitochondrial disorders or cytoplasmic energy defects
Describe disorders involving complex molecules.
- Involves cellular organelles including diseases associated with disturbed synthesis or catabolism of complex molecules.
- Lysosomal storage disorders, peroxisomal disorders, intracellular trafficking disorders
Describe newborn screening to detect inborn errors.
- 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
Discuss disorders of amino acid metabolism: Phenylketonuria (PKU).
- Autosomal recessive disorder.
- 97% Incidence due to phenylalanine hydroxylase enzyme defect & 3% due to defective synthesis of the cofactor, tetrahydrobiopterin.
What are the symptoms of PKU.
- Irritability
- Vomiting
- Seizures
- Mental retardation by 4 - 6 months
- Reduced melanin production
- Frequently generalised eczema
What is the management of PKU?
- Diet low in Phenylalanine; supplemented with Tyrosine
- Cofactor related form: Neurotransmitter supplementation
Discuss disorders of amino acid metabolism: Tyrosinaemia type 1.
- Deficiency in fumarylacetoacetate hydrolase
- Accumulation of fumarylacetoacetate and its metabolites in the urine particularly succinyl acetone (Potentially fatal).
What are the symptoms of Tyrosinaemia type 1.
- Characteristic cabbage like odour.
- Liver failure and renal tubular acidosis.
What is the treatment of Tyrosinaemia type 1.
- Dietary restriction of Phenylalanine and Tyrosine.
- Drug: Nitisinone.
Where does Nitisinone act?
It inhibits 4-hydroxyphenylpyruvic acid oxidase, used in treatment of tyrosinaemia type 1
Discuss disorders of amino acid metabolism: Organic aciduria.
- 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)
Discuss disorders of amino acid metabolism: Alkaptonuria.
- 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.
Discuss disorders of amino acid metabolism: Maple syrup urine disease.
- Its a defect in metabolism of leucine, isoleucine & valine.
- A deficiency in α-keto acid dehydrogenase.
What are the symptoms of Maple syrup urine disease?
- 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.
What is the treatment of maple syrup urine disease?
- Dietary restriction of branched chain amino acids
Discuss disorders of amino acid transport: Cystinuria
- 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.
Discuss disorders of amino acid transport: Homocystinuria
- 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.
Discuss disorders of amino acid transport: Lysinuric protein intolerance (LPI)
- Absorption of dibasic amino acids (Lys, Arg, Orn), leading to impaired function of urea cycle and lysine deficiency.
What are the symptoms of LPI?
- Failure to thrive
- Poor appetite
- Protein aversion
- Hyperammonaemia with progressive encephalopathy
- Renal failure
- Osteoporosis
What is the treatment of LPI?
- Protein restriction with citrulline replacement to enhance Urea cycle
