Metabolic Insights from Genetic Diseases Notes

Inherited Metabolic Disorders - Overview

Topics 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 list common inherited metabolic disorders.
  • Outline the metabolic impact of Von Gierke's disease.
  • Outline the biochemical basis and consequences of galactosaemia.
  • Outline the biochemical basis and consequences of McArdle's disease
  • Describe the consequences of a deficiency of liver fructokinase or fructose 1-phosphate aldolase.
  • Outline the inherited metabolic disorders of amino acid metabolism
  • Describe the consequences of phenylketonuria.
  • List the genetic causes of dyslipidaemia.
  • Describe the consequences of familial hypercholesterolaemia.

Inborn Errors of Metabolism

Sir Archibald Edward Garrod (1857-1936) pioneered the field of inborn errors of metabolism and discovered alkaptonuria, understanding its inheritance.

Biochemical Metabolic Reactions

  • Over 7000 biochemical metabolic reactions.
  • Require around 20,000 proteins (mostly enzymes).
  • Regulated by approximately 2000 genes (10%) in the genome.
  • One small genetic change can have vast effects.

Effects of Genetic Alterations

Genetic defects can cause:

  • Changes in protein sequence (affecting protein structure and function).
  • Changes in gene expression (less/more protein produced).
  • Gene could be completely lost (protein lost).
  • Most inherited metabolic diseases alter key enzymes that catalyse important reactions in metabolism.
  • Can also have genetic changes in proteins that regulate the function of these enzymes (co-factors).
  • Generally have clinically apparent inheritance patterns, being among the first disease to be associated with a genetic pattern of inheritance.

Identifying Inherited Metabolic Disorders

  • Newborn screening (heel prick): Screening of blood for abnormal levels of specific metabolites (biochemical screen).
  • Genetic screening of family members to identify known genetic mutations known to cause specific disorders.
  • Identification of specific symptoms can also be sometimes related to particular defects
    • Hypoglycaemia: Glycogen storage diseases (e.g., Von Gierke’s).
    • Cataracts: Galactosemia.
    • Metabolic acidosis: Organic acid defects (e.g., PDC deficiency).
    • Unusual urine odor: Amino acid and organic acid defects.
    • Neurological dysfunction: Urea cycle defects (build up of ammonia in blood).

New-Born Screening

  • These diseases are generally rare (between 1-1000 to 10,000 or more births).
  • Most of these can be screened for at birth (5 days old).
  • Screening for new-borns in the UK is carried out for inheritable metabolic diseases.

More Screening

Clinical suspicion of IEM (Inborn Errors of Metabolism) can lead to various tests:

  • Carbohydrates Metabolism Defects: Galactose, Fructose, Glycogen tests, Specific enzyme assays
  • Organicoacidurias: Urine organic acid assay (TIC or TIC/SIM)
  • Aminoacidopathies: Pyruvate / lactate / ketone body tests, Specific enzyme assays
  • Urea Cycle Defects: Erlich test/Dihydropteridine reductase assay / Bratton-Marshall reaction
  • Mitocondriopathies: Derivation of samples to additional studies whenever needed
  • Peroxisomal Defects: Plasma VLCFA assay, Molecular investigation when appropriate
  • Cholesterol Biosynthesis Defects: Plasma sterols assay
  • Lysosomal Storage Diseases: GAGS, OLS, SOLS, Sialic acid assay, chitotriosidase
  • Porphyrins / Pterins / Purine metabolism Defects
  • Strong clinical suspicion (even with above tests normal)

Target IEM of the CIEM newborn screening programme

Categories include Amino acid disorders, Organic acid disorders, and Fatty acid oxidation disorders.

Specific Target IEMs:
  • Phenylketonuria
  • Maple syrup urine disease
  • Citrullinaemia type 1
  • Argininosuccinic aciduria
  • Homocystinuria
  • Tyrosinaemia type 1
  • Arginase deficiency
  • Defects of biopterin cofactor biosynthesis and regeneration citrullinaemia type 2
  • Hypermethioninaemia
  • Propionic aciduria
  • Methylmalonic aciduria (MUT, cbIA, cbIB)
  • Isovaleric aciduria
  • Beta-ketothiolase deficiency
  • Glutaric aciduria type 1
  • 3-Hydroxy-3-methylglutaryl-CoA lyase deficiency
  • Multiple carboxylase deficiency
  • 3-Methylcrotonyl-CoA carboxylase deficiency
  • 2-Methyl-3-hydroxybutyric aciduria
  • Malonic aciduria
  • 3-Methylglutaconic aciduria type I
  • Isobutyryl-CoA dehydrogenase deficiency
  • 2-Methylbutyryl-CoA dehydrogenase deficiency
  • cbl C and cbl D
  • Carnitine uptake defect
  • Medium-chain acyl-CoA dehydrogenase deficiency
  • Very long-chain acyl-CoA dehydrogenase deficiency
  • Long-chain hydroxyacyl-CoA dehydrogenase deficiency
  • Trifunctional protein deficiency
  • Short-chain acyl-CoA dehydrogenase deficiency
  • Carnitine palmitoyltransferase I deficiency
  • Carnitine palmitoyltransferase II deficiency
  • Carnitine-acylcarnitine translocase deficiency
  • Multiple acyl-CoA dehydrogenase deficiency
  • Medium-/short-chain hydroxyacyl-CoA dehydrogenase deficiency

Overview of Inherited Metabolic Diseases

Categorized by system affected:

  • Carbohydrate metabolism
    • Disorder: Glycogen storage disease (Von Gierke’s type I)
    • Defect: Deficiency in glucose-6-phosphatase
  • Amino acid metabolism
    • Disorder: Phenylketonuria (PKU)
    • Defect: Deficiency in phenylalanine hydroxylase
  • Organic acid metabolism
    • Disorder: Alcaptonuria (AKU)
    • Defect: Deficiency in homogentisate 1,2-dioxygenase
  • Fatty acid metabolism (mitochondrial defects)
    • Disorder: Medium-chain acyl-CoA dehydrogenase (MCAD) deficiency
    • Defect: Deficiency in medium-chain acyl-CoA dehydrogenase altering FA metabolism
  • Disorder: Familial hypercholesterolemia

Carbohydrate-Related Syndromes: Von Gierke’s Disease (Type 1 GSD)

  • Incidence: 1 in approximately 43,000 births.
  • Autosomal recessive disorder resulting from gene defects in either:
    GSD IA results from mutations of G6PC, the gene for glucose-6-phosphatase (17q21)
    GSD IB & 1C mutations in G6P transporters
  • Deficiency in glucose-6-phosphatase:
    • Renders glycogenolysis from the liver useless.
    • Renders gluconeogenesis in the liver and kidney useless.
  • Symptoms: Hypoglycaemia, lactic acidosis (nausea, vomiting), enlarged liver, growth delay.
  • Management: Regular food intake (cornstarch), prevent accumulation of glycogen, liver transplant.

Hers Disease (Type VI Glycogen Storage Disease)

  • Affects 1-25,000 live births; autosomal recessive
  • Deficiency in liver glycogen phosphorylase (PYGL gene – 14q21)
  • Causes reduction in the ability of the liver to break down glycogen
  • Symptoms: Enlarged liver, mild hypoglycaemia, growth delay, hyperlipidaemia, lactic acidosis
  • Diagnosis: Elevated lactate and transaminase enzymes in blood. Liver biopsy shows reduced PYGL activity.
  • Treatment: Regulation of diet to high glucose foods eaten regularly to avoid hypoglycaemia, liver transplant

McArdle’s Disease (Type V Glycogen Storage Disease)

  • Same gene affected as Hers disease, except it is a deficiency in muscle glycogen phosphorylase (not liver)
  • Exercise causes immediate depletion of energy stores since they cannot access energy stored in glycogen.
  • Symptoms: Muscle damage (rhabdomyolysis), inability to perform constant exercise, get “second wind” (tolerate aerobic exercise after 8-10 minutes)
  • Diagnosis: Increased levels of myoglobin and creatine kinase in blood (due to muscle damage); dark urine; biopsy

Galactosaemia Type 1

  • 1 in 30 to 60,000 births
  • Autosomal recessive diseases caused by deficiency in galactose-1-phosphate uridyl transferase (type 1).
  • Causes accumulation of galactose and galactose-1-phosphate (hypergalactosaemia)
  • Symptoms (in infants): lethargy, failure to gain weight, jaundice, liver damage, abnormal bleeding, several neurological complications (mental retardation), possibly death unless treated (due to sepsis and shock).
  • Treatment: strict diet control – lactose/galactose free diet, liver transplant
  • high galactose --> galactitol (via Aldose Reductase)

Hereditary Fructose Intolerance

  • Caused by deficiency in aldolase B, which converts fructose-1-phosphate to dihydroxyacetone phosphate and glyceraldehyde (step 4 of glycolysis).
  • Accumulation of fructose-1-phosphate in liver and kidneys causes liver and kidney failure if untreated
  • Inhibits glycogenolysis and gluconeogenesis leading to hypoglycaemia.
  • Symptoms: Nausea, bloating, abdominal pain, chronic fatigue, malabsorption
  • Treatment: Dietary control of fructose intake.

Pyruvate Dehydrogenase Deficiency

  • Rare condition with the exact prevalence unknown
  • Caused by mutations in any of the genes coding for the PDC (PDHA1, PDHB, DLAT, PDP1) & thiamine, lipoic acid deficiencies
  • X-linked (PDHA1) or autosomal recessive mode of inheritance
  • Symptoms: Build up of lactic acid leads to several neurological problems (mental delay, seizures, hypotonia, brain wasting), lactic acidosis, vomiting, breathing problems, abnormal heart beat; fatal if untreated.
  • Treatment: Ketogenic diet

Amino Acid Syndromes: Phenylketonuria (PKU)

  • 1 in 15,000 births (more common in Ireland and Scotland)
  • Caused by a deficiency in the enzyme: phenylalanine hydroxylase (or less commonly in the enzyme dihydrobiopterin reductase which recycles a co-factor for this reaction)
  • Accumulation of phenylalanine and its by products is toxic in the brains of children (not as much in adults)
  • Symptoms: Developmental delay, mental retardation, albinism, hyperactivity, aminoaciduria, irritability, vomiting.
  • Treatment: Diet low in phenylalanine

Alkaptonuria

  • Caused by a deficiency in the enzyme homogentisate-1,2-dioxygenase (HGD gene)
  • Results in accumulation of homogentisic acid; have dark urine or urine that turns dark on contact with air.
  • May remain clinically silent during childhood, appears as bluish-black discoloration of connective tissue in the body.
  • Symptoms: Joint and cardiac problems which develop in adulthood, Ochronosis
  • Treatment: Diet low in phenylalanine and high in vitamin C; pain management of joints

Maple Syrup Urine Disease (MSUD)

  • Rare autosomal recessive disease (1 in 150,000 births)
  • Gets its name from the particular smell of urine in babies with the disorder
  • Causes by deficiency in enzymes that make up the branched chain alpha-keto-acid dehydrogenase complex which is essential for breaking down branched chain amino acids leucine, valine and isoleucine.
  • As a result these amino acids and their by products accumulate and become toxic to the brain (ketoacidosis) and other organs.
  • Symptoms: Ketoacidosis, lethargy, seizures, , developmental delay, distinctive rash
  • Diagnosis: Mass spectrometry of blood to detect levels of specific amino acids
  • Treatment: Strict diet control to remove intake of branched chain amino acids.

Isovaleric Acidaemia (IVA)

  • 1 in 250000 births
  • Deficit of isovaleryl CoA dehydrogenase
  • Impaired Leucine metabolism
  • Accumulation of highly toxic isovaleric acid
  • Symptoms: Metabolic Crises: vomiting, poor feeding, lethargy, and a "sweaty feet" odor. Neurological Symptoms: developmental delays, hypotonia, seizures, coma
  • Diagnosis: Biochemical Testing: Blood and urine samples are analyzed for elevated levels of isovaleric acid and its derivatives Genetic Testing: mutations in the IVD
  • Treatment: Diet, no leucine or other BCAA, high carbs, liver transplant. Isovaleric acid and its metabolites

Fatty Acid-Related Syndrome: Medium Chain Acyl-Coenzyme A Dehydrogenase (MCAD)

  • Disease of fatty acid metabolism (B-oxidation)
  • Caused by inability to breakdown medium chain fatty acids due to deficiency in enzyme.
  • Clinical features: hypoketotic hypoglycaemia, hepatomegaly, diarrhoea, hyperammonemia, sudden infant death is possible.
  • 1 in 5000 births; autosomal recessive
  • Treatment: Diet low in medium chain fatty acids and supplemented with frequent input of sugar to prevent need to rely on B-oxidation of fats

Lipoprotein Handling-Related Syndrome: Familial Hypercholesterolemia

  • Common: 1 in 500 births
  • Caused by defects in low-density lipoprotein break down or uptake into cells (LDL receptor defects)
  • Results in build up of LDL in blood = increased risk of plaque formation and CHD. Can also be caused by defects in SREBP2 gene.
  • Diagnosis: High LDL levels and high cholesterol
  • Treatment: Diet control, statins.

Key Learning Points

  • Inherited/inborn errors of metabolism show early in life and can be fatal – neonatal screening
  • Most are autosomal recessive and therefore very rare diseases that affect early developmental stages
  • Disease affects all major metabolic pathways – glycolysis, glycogen metabolism, gluconeogenesis, amino acid metabolism, fatty acid metabolism.
  • Diseases always have variable symptoms which are related metabolically to the accumulation of the substrates and/or its derivatives and/or deficiency of the products.
  • Can generally be controlled by strict dietary restrictions.
  • Important one’s to remember: GSD, PKU, alkaptonuria, MSUD, MCAD, Familial Hypercholesterolemia.