Metabolic insights from genetic diseases_RF2025

METABOLIC INSIGHTS FROM GENETIC DISEASES

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

TOPICS TO BE COVERED

• Inherited metabolic disorders - overview

• Detecting an inherited metabolic disorder

• Inherited disorders of carbohydrate metabolism

• Inherited disorders of amino acid metabolism

• Inherited disorders of lipid metabolism

• Summary

LEARNING OBJECTIVES

• 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.

INBORN ERRORS OF METABOLISM

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

METABOLIC REACTIONS

• 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.

EFFECTS OF GENETIC ALTERATIONS

• 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.

IDENTIFICATION OF INHERITED METABOLIC DISORDERS

• 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)

NEW-BORN SCREENING

• 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.

CATEGORIES OF INHERITED METABOLIC DISEASES

• 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.

VON GIERKE'S DISEASE (TYPE 1 Glycogen Storage Disease)

• 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.

HERS DISEASE (TYPE VI Glycogen Storage Disease)

• 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.

MC ARDLE’S DISEASE (TYPE V Glycogen Storage Disease)

• 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.

GALACTOSAEMIA TYPE 1

• 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.

HEREDITARY FRUCTOSE INTOLERANCE

• 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.

PYRUVATE DEHYDROGENASE DEFICIENCY

• Rarely reported; associated with mutations affecting PDC enzymes and cofactor deficiencies.

• Symptoms: neurological issues and lactic acidosis.

• Treatment includes a ketogenic diet.

PHENYLKETONURIA (PKU)

• 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.

ALKAPTONURIA

• Deficiency of homogentisate-1,2-dioxygenase causing dark urine and joint problems.

• Symptoms appear later in life; treatment involves dietary management.

MAPLE SYRUP URINE DISEASE (MSUD)

• Autosomal recessive; symptoms include distinctive urine odor and toxic metabolic crisis.

• Treatment is a strict diet low in branched-chain amino acids.

FATTY ACID-RELATED SYNDROME: MCAD

• Incidence: 1 in 5000 births.

• Symptoms include hypoketotic hypoglycaemia and hepatomegaly.

• Treatment involves dietary restrictions on medium-chain fatty acids.

LIPOPROTEIN HANDLING-RELATED SYNDROME: FAMILIAL HYPERCHOLESTEROLEMIA

• Common incidence of 1 in 500 births due to defects in LDL receptor function.

• Treatment includes diet control and statins.

KEY LEARNING POINTS

• 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.

CONCLUSION

• Thank you for listening!