Inborn Metabolic Errors – Genetics

Inborn Errors of Metabolism

• Metabolic disease, also known as enzymopathy or genotropic disease, arises because of an inborn error of metabolism.
• It is inherited and results from a mutation.
• Metabolism involves catabolism and anabolism
• Enzymes, acting as catalysts, are important in facilitating metabolic processes.

Definition of Inborn Errors

• A genetically determined biochemical disorder where a specific enzyme defect produces a metabolic block, leading to pathological consequences.
• It can manifest at birth, like in phenylketonuria, or later in life, like diabetes mellitus.
• An enzyme defect can lead to a buildup of toxic metabolites because the product is not being made.

About Inborn Errors of Metabolism

• Genetic deficiencies affect the production of enzymes, transport proteins, receptor proteins, and subcellular organelles.
• Subcellular organelles include lysosomes, mitochondria, and peroxisomes.
• It also affects structural, assembly, and chaperone proteins.
• Macromolecule diseases involve carbohydrates, lipids, proteins, and nucleic acids.

Types of Inborn Errors

• Carbohydrate disorders include galactose, glucose, glycogen, and fructose issues.
• Protein disorders include amino acid, organic acid, urea cycle, hemoglobin, and connective tissue problems.
• Lipid disorders involve synthesis, degradation, storage, and transport issues.
• Nucleic acid disorders include purines and pyrimidines problems.

Genetic Basis of Disease: Alkaptonuria

• Ingestion of phenylalanine or tyrosine leads to homogentisic acid, but cannot metabolized, leading to carbon dioxide and water.
• The liver lacks homogentisic acid oxidase.
• Homogentisic acid accumulates and is excreted in urine.
• Urine turns black, and arthritis develops later in life.

Genetic Basis of Disease: Phenylketonuria

• Ingestion of phenylalanine causes accumulation of phenylpyruvate in urine, (phenylalanine hydroxylase OR tetrahydrobiopterin)
• Tyrosine is metabolized normally.
• Minor pathways become significant when metabolic blockages occur.

Patterns of Inheritance: Mendelian Inheritance

• New mutations in germ cells are passed onto succeeding generations.
• New somatic cell mutations are not passed but may contribute to diseases like cancer.
• Mutant genes can be recessive or dominant, located on an autosome or a sex chromosome.
• These include autosomal disorders, X-linked disorders and codominance.

Patterns of Inheritance: Autosomal Dominant

• Only one mutated copy of a gene causes the expression of a disease.
• Only one affected parent is necessary to pass on the trait.
• Males and females are equally affected.
• There is a 50% chance of passing the defect to offspring.
• Incomplete penetrance can occur.
• Mutation can occur in egg/sperm cells, leading to conditions like acute intermittent porphyria.
• Examples include Huntington's chorea, Tuberous sclerosis, and familial hypercholesterolemia.

Patterns of Inheritance: Autosomal Recessive

• Two mutated copies of the gene must be present in each cell for a person to be affected.
• Both parents are carriers.
• Both sexes are equally affected.
• There is a 25% chance of offspring being affected if both parents are carriers.
• Examples include alkaptonuria, cystic fibrosis, Tay-Sachs disease, Friedreich's ataxia, and phenylketonuria.

Patterns of Inheritance: X-Linked Dominant

• Females are more frequently affected
• There is no male-to-male transmission.
• An example if Coffin-Lowry syndrome
• Males and females are both affected.
• Affected female has 50% of passing the disorder to sons and her daughters.
• An affected male will pass the condition on to all his daughters, but not to his sons.

Patterns of Inheritance: X-Linked Recessive

• Sons have a 50% chance of inheritance.
• Daughters have a 50% chance of inheritance, but are usually carriers.
• A father cannot pass X-linked traits to his son; but daughters will be carriers.
• Examples include Duchenne muscular dystrophy, hemophilia, and Hunter's disease.
• Fragile X syndrome exists.

Patterns of Inheritance: Codominant

• Single gene has more than just one dominant allele.
• Two different versions of a gene can be expressed.
• An example is AB blood types.

Mechanisms of Disease

• Accumulation of substrate, with an increase of A.
• Reduced product, with a decrease of D.
• Accumulation of intermediates, with the increase of B and C.
• Diversion of intermediates through minor side-pathways, with the increase of X and Y.
• Failure of feedback mechanisms, with the increase of C.
• Failure of transport mechanisms.

Accumulation of Substrate

• Example: Fructose intolerance, where fructose is not converted.

Reduced Product

• Example: Albinism, where the body can not produce melanin.

Accumulation of Intermediates

• This is typical of the storage diseases.
• Types include Sphingolipidoses (accumulate in lysosomes), Mucopolysaccharidoses, Mucolipidoses, and Glycogen storage disease (affects liver, skeletal muscle).
• Causes include lack of synthesis of an enzyme, synthesis of abnormal enzyme, inability to transport the enzyme to the lysosome, synthesis of enzymes that are inactive, and absence or inactivity of activator enzymes.

Loss of Feedback Mechanism

• Example: Lesch-Nyhann Syndrome
• The result is Hypoxanthine-guanine phosphoribosyl transferase deficiency.
• Causes Gout and overproduction of uric acid.
• It can lead to choreoasthetosis, spasticity, variable degrees of mental retardation, and compulsive self-mutilation.
• It can be detected prenatally.

Use of Minor Pathways

• Example: Phenylketonuria
• Phenylketonuria involves an essential amino acid.
• In phenylketonuria, phenylalanine cannot be turned into tyrosine.
• Leading to deficiencies of Phenylalanine hydroxylase and Tetrahydrobiopterin.
• Accumulation of phenylalanine and phenylpyruvate in body fluids can result.
• Early detection is valuable.

Diagnosis of Inborn Errors

• Symptoms are usually nonspecific.
• Useful clues include consanguinity, history of unexplained premature death in older sibling, onset of symptoms following a change in feeding regimen, dysmorphic features like course facies, hepatomegaly, cherry red spots, abnormal kinky hair, decreased pigmentation, cataracts, and retinitis pigmentosa.
• Clinical diagnosis can be aided with an unusual smell
• Maple syrup indicates Maple Syrup Urine Disease.
• Mousy/Musty indicates Phenylketonuria
• Sweaty feet or cheese indicates Isovaleric acidaemia, Type II Glutaric acidaemia
• Rotting fish indicates Trimethylaminuria
• Boiled cabbage indicates Hypermethioninaemia and Tyrosinaemia.
• ?? indicates Diabetes

Laboratory Diagnosis

• Investigations guided by clinical presentation such as suspecting galactosaemia with cataracts.
• The routine tests are for Galactose-1-phosphate uridyl transferase in red blood cells
• Routine investigations: Plasma ammonia, Organic acids (urine) and amino acids (urine & plasma), Plasma lactate, Galactose-1-phosphate uridyl transferase
• Other biochemical investigations are available

Laboratory Diagnosis: Urinalysis and Blood Tests

• Urinalysis tests for Reducing substances, Ketones, and pH.
• Blood tests include Anion gap, Metabolic acidosis, Hypoglycaemia, Hyponatraemia, Respiratory alkalosis, Abnormal liver function tests, and Hyperammonaemia

Role of Nutrition in Treatment

• Protein metabolism disorders:
• Phenylketonuria, requires a diet low in phenylalanine, i.e. no milk, eggs or nutrasweet.
• Maple syrup urine disease, requires a diet low in branched chain amino acids.
• Carbohydrate metabolism disorders:
• Fructose intolerance requires a diet of no fruit, fruit juices, sucrose, honey or starch.
• Galactosaemia requires the avoidance of milk and milk products.
• Co-factor replacement is achieved by diet that is vitamin responsive.
• Eg biotin, vitamin B12, thiamine, vitamin B6

Treatment for Inborn Errors

• Primary treatment is restore child to health.
• Use dietary Modification to achieve this.
• Enzyme replacement therapy can enable reactions that can not take place.
• Supplement with Co-factors to help where the enzyme is deficient.
• Aim is also to decrease formation of toxic metabolites, produce adequate calories and to enhance excretion of toxic metabolites.

Screening the Newborn for Disease

• Screening determination factors: disease with a relatively high incidence, disease can be detected within days of birth , a biochemical marker can easily be measured, the disease is missed clinically causing irreversible damage, treatable with the results being available before irreversible damage occurs
• Testing varies in different countries.
• Hypothyroidism (1:3500) and Phenylketonuria (1:10000) is not carried out in many countries.
• Congenital adrenal hyperplasia 1:500 can be tested for.