Metabolic insights from genetic diseases_RF2025

METABOLIC INSIGHTS FROM GENETIC DISEASES

Presentation by Dr. Robert Formosa, Queen Mary University of London, Malta Campus.

Define inherited metabolic disorders and recognize common examples.
Outline the metabolic impact of Von Gierke's disease.
Summarize the biochemical basis and consequences of galactosaemia.
Distinguish between the biochemical basis and consequences of Hers & McArdle's disease.
Describe the consequences of deficiency in liver fructokinase or fructose 1-phosphate aldolase.
Identify the inherited metabolic disorders of amino acids.
Discuss the impacts of phenylketonuria.
List genetic causes of dyslipidaemia and describe familial hypercholesterolaemia.

Sir Archibald Edward Garrod was a pioneer in this field, discovered alkaptonuria and its inheritance.

Over 7000 biochemical metabolic reactions require approximately 20,000 proteins (mostly enzymes).
These reactions are regulated by about 2000 genes (10% of the genome).
A single genetic change can lead to significant metabolic disruptions.

Genetic defects can result in:
- Changes in protein sequences affecting structure and function.
- Alterations in gene expression (more or less protein production).
- Complete loss of genes leading to the absence of certain proteins.
Many inherited metabolic diseases affect essential enzymes in metabolic processes and can involve regulatory proteins.

Methods include newborn screening via heel prick, blood metabolite screening, and family genetic testing.
Symptoms linked to specific disorders include:
- Hypoglycaemia (Glycogen storage diseases, e.g., Von Gierke’s)
- Cataracts (Galactosaemia)
- Metabolic acidosis (organic acid defects)
- Unusual urine odors (amino acid defects)
- Neurological dysfunction (urea cycle defects)

Screening for inherited metabolic diseases typically occurs within the first 5 days of life; prevalence ranges from 1 in 1000 to 10,000 births.
The UK screens for specific inheritable metabolic conditions.

Carbohydrate metabolism: Example - Von Gierke’s (deficiency in glucose-6-phosphatase).
Amino acid metabolism: Examples include phenylketonuria and maple syrup urine disease.
Organic acid metabolism: Example - Alkaptonuria (deficiency in homogentisate 1,2-dioxygenase).
Fatty acid metabolism: Examples include Medium-chain acyl-CoA dehydrogenase deficiency and familial hypercholesterolaemia.

Incidence: 1 in approx. 43,000 births.
Genetic basis: Autosomal recessive disorder due to mutations in the G6PC gene.
Symptoms include:
- Hypoglycaemia
- Lactic acidosis
- Enlarged liver
- Growth delay.
Management involves regular food intake to prevent glycogen accumulation and may require liver transplant.

Incidence: 1 in 25,000 live births; autosomal recessive.
Caused by insufficient liver glycogen phosphorylase activity.
Symptoms: Enlarged liver, mild hypoglycaemia, growth delay.
Diagnosis via elevated lactate and liver biopsy showing reduced activity of PYGL enzyme.

Similar genetic involvement as Hers Disease but with muscle glycogen phosphorylase deficiency.
Symptoms: Muscle damage, inability to sustain exercise, increased creatine kinase levels, and dark urine.

Incidence: 1 in 30 to 60,000 births; autosomal recessive deficiency in galactose-1-phosphate uridyl transferase.
Symptoms in infants include:
- Lethargy
- Weight gain failure
- Jaundice
- Possible neurological defects.
Treatment: strict lactose-free diet and possible liver transplantation.

Caused by a deficiency in aldolase B.
Symptoms include nausea, abdominal pain, and chronic fatigue due to fructose accumulation.
Management through dietary control to restrict fructose intake.

Rarely reported; associated with mutations affecting PDC enzymes and cofactor deficiencies.
Symptoms: neurological issues and lactic acidosis.
Treatment includes a ketogenic diet.

Incidence: 1 in 15,000 births, common in Ireland and Scotland.
Caused by phenylalanine hydroxylase deficiency, leading to toxic accumulation in children’s brains.
Symptoms: Developmental delay, irritability, and albinism.
Treatment: diet low in phenylalanine.

Deficiency of homogentisate-1,2-dioxygenase causing dark urine and joint problems.
Symptoms appear later in life; treatment involves dietary management.

Autosomal recessive; symptoms include distinctive urine odor and toxic metabolic crisis.
Treatment is a strict diet low in branched-chain amino acids.

Inherited metabolic disorders can manifest early and may be fatal; neonatal screening is crucial.
Most conditions are rare and typically autosomal recessive.
Diseases affect major metabolic pathways, leading to various clinical presentations.
Effective management often requires strict dietary control.
Important disorders: GSD, PKU, alkaptonuria, MSUD, MCAD, and familial hypercholesterolemia.