IMED1003 - Inborn Errors of Metabolism 1 and 2 (L27 and 28)

IEM

- Sir Archibald Garrod pioneered this field

- Inborn errors not just enzyme defects. Might be transport proteins, receptors or structural components

- Mechanisms of disease: accumulation of a toxin; energy deficiency; deficient production of essential metabolite/srtuctural component

Inherited Disorders

- All feature a genetic defect (often a result of single base substitution or deletion), reduced synthesis or absence of particular protein or change in primary structure

- More than 4000 disorders involving single genes

- Most inherited disorders are autosomal recessive, heterozygotes usually normal. E.g sickle cell anaemia - haemoglobin. some autosomal dominant - hypercholesterolaemia

- many diseases have defective enzyme that cause metabolic disorder

Inherited disorders may be detected at different stages of life:

- heterozygote carriers, often found during screening family members of affected indivdual

- prenatal diagnosis e.g cystic fibrosis

- neonatal screening. e.g phenylketonuria

- neonate developing symptoms in first few weeks

- adult onset. e.g huntingtons disease

Enzyme Deficiencies

- some enzymes require cofactors for activity, and often require modification before use

Classical inborn errors of metabolism ("metabolic disorders")

- involve a missing or defective enzyme, causing block in metabolic pathway and often production of toxic metabolites

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- metabolic imbalance secondary to enzyme deficiency. Three distinct sequelae of a lack of enzyme 3

1. decreased formation of product, D

DIAGRAM ON SLIDE 7

1. decreased formation of product, D

DIAGRAM ON SLIDE 7

DIAGRAM ON SLIDE 7

2. Accumulation of metabolite, C

DIAGRAM ON SLIDE 8

3. Increased formation of other metabolites, e.g E

- other things that can happen if enzyme 3 is defective: if there is feedback inhibition it is interuptted

Inherited disorders diagnosed in first weeks of life often involve central metabolic pathways, AA and CH2O metabolism and storage, urea cycle ect.

- Frequently display non-specific symptoms: vomiting, lethargy, failure to thrive, feeding difficulties, respiratory distress, hypotonia, seizures, hypothermia (especially neonates)

- other telling signs: ocular findings, hepatosplenomegaly, cardiomyopathy, abnormal odour, colour, unusual skin and/or hair

Recognising Metabolic Disorders

- IEM are mainly autosomal recessive

- Some are X-linked recessive

- few autosomal dominant e.g hyperlipidaemia

- DNA analysis useful

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Test for: glucose, electrolytes, gas, ketones, blood urea, nitrogen, creatinine, lactate, ammonia, bilirubin, amino acids, organic acids, and more

Carbohydrates

- most carbohydrates fit into the glycolytic pathway

- glycosidic bond is important

Lactose Intolerance

- lack lactase (primary genetic defect)

- primary genetic defect: enzyme they produce doesn't fold properly due to a mutation or isnt produced in adequate amounts due to some sort of mutation

- these people would have a consequence of not being able to break the glycosidic bond, which means lactose is accumulated

Three ways to metabolise galactose

1. Galactose Dehydrogenase:

- minor pathway, not harmful if GalDH defective

- oxidises galactose to galactonate (requires NAD+ to be reduced to NADH and galactonate can enter PPP

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2. Aldose reductase

- forms galactitol

- when it accumulates it causes cataracts

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3. Galactokinase:

- forms galactose-1-Phosphate

- that can enter glycolytic pathway if we can process it through to glucose-1-phosphate and then glucose-6-phosphate

- UDP-glucose: galactose-1-P uridyltransferase

- this enzyme transfers from a UDP glucose onto galactose-1-P, the UDP, the uridyl thats attached to UDP glucose

- we hence produce glucose-1-phosphate and we add galactose to the UDP forming UDP galactose

- this needs to be recycled so we can continue the reaction

Classical Galactosaemia

- Inborn Error Carbohydrate metabolism, lack of hepatic enzyme

- UDP-glucose: galactose 1-P uridyltransferase

- Galactose-1-P accumulation leads to intellectual disability, jaundice, hepatomegaly, cirrhosis, infantile cataracts, hepatic failure and death

- treatment: galactose-free diet, ophthamology and developmental follow up

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- Consequences: pre-block metabolite increases, post-block metabolite decreases

- if Galactose-1-P builds up it can feed back to galactose which can accumulate

Galactokinase Deficiency Galactosaemia

- Aldose reductase is physiologically unimportant, but excess galactose

- with galactokinase stopped the galactose takes an alternative pathway through aldose reductase, which causes build up of galactitol, which causes galactosuria and galactosaemia. Elevated galactitol can cause cataracts

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Consequences:

- increase in pre-block metabolite and decrease in post-block metabolite

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- classical galactosaemia is miuch more com,mon then galactokinase deficiency

Type Ia Glycogen-Storage Disease

- most common glycogen storage disorder, 25% of total, causes excessive glycogen and fat accumulation (liver, kidney)

- initial symptoms = neonatal hypoglycaemia

- other symptoms include: hepatomegaly, tremors, irritability, seizures, apnoea, coma

- Glucose-6P converted to glucose (glucose 6 phosphotase defective)

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- glucose 6 phosphotase - liver, kidney

Amino Acid as Precursors

DIAGRAM ON SLIDE 24

Tyrosine Related Disorders (NO LEARNING OUTCOME)

DIAGRAM ON SLIDE 25

- it is ketogenic and glucogenic (both aromatic aa are ketogenic and glucogenic)

Albinism

- absence of melanin pigment

- tyrosine is a melanin precursor

Alkaptonuria

- absence of homogentisate oxidase activity

- homogentisate accumulates - can damage cartilage (osteoarthritis), heart valves, precipitate in kidney (kidney stones), usually after age 30

- pigmentation = ochronosis (this word is in the formative exam)

- any enzyme in the pathway can be affected

Maple Syrup Urine Disease

- From early infancy, symptoms include poor feeding, vomiting, dehydration, lethargy, hypotonia, seizures, hypoglycaemia, ketoacidosis, pancreatitis, coma and neurological decline

- branched-chain alpha-ketoacid dehydrogenase is the enzymes thats defective in this disease

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- liver does not have the enzymes to process branched chain amino acids and the liver cannot use ketone bodies as fuel source

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Maple Syrup urine Disease other info

- lack of branch-chain dehydrogenase activity

- leads to elevation of branched-chain amino acids and alpha-keto acids in urine. Urine smells like maple syrup

- neurological symptoms - unless very early intervention via restricting dietary intake of valine, isoleucine, leucine

Phenylalanine Usually converted to Tyrosine

- PKU - lack phenylalanine hydroxylase

- Classical Phenylketonuria (PKU)

- treat PKU by restricting Phe in diet

- Consequences: increase in preblock metabolites (Phenylalanine) and decrease in post block metabolites (Tyrosine) due to the defective enzyme

- phenylalanine cant be excreted and so is excreted to phenylketones

Accumulated Phe is converted into

phenylpyruvate, then phenylacetate and phenyllactate, which are phenylketone derivatives

- these are excreted in urine, hence the name phenylketonuria

PKU Diagram at the main recation

DIAGRAM ON SLIDE 32

Phenylalanine Hydroxylase Reaction

DIAGRAM ON SLIDE 33

- need to be able to recognise and draw phenylalanine and tyrosine

- make sure you know this reaction well

- should be able to tell the enzyme that converts phenylalanine to tyrosine (it is hydroxylating the phenylalanine, hence its oxidising)

- thats why tetrahydrobiopterin is being reduced to dihydrobiopterin

- NADH is converted to NAD+

Disorders of Carnitine Metabolism

- Carnitine transports long chain FA into mitochondria

- Carnitine deficiency - primary or secondary

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PRIMARY:

- caused by abnormal transport of carnitine into cells = carnitine uptake disorder, AKA systemic carnitine deficiency

- Variably associated with hepatomegaly, liver disease, hypertrophic cardiomyopathy and potential arrhythmia

- autosomal recessive

Urea Cycle Disorders

- Appear unaffected at birth

- within days - vomiting, respiratory distress, coma

- symptoms mimic other illnesses

- untreated: results in death

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non-functioning enzyme results in:

- infant: progressive loss of motor and cognitive skills

- pre-school: non-responsive state

- adolesence: death

The Urea Cycle

DIAGRAM ON SLIDE 36

Disorders of Urea Cycle DAIGRAM

- Ornithine Transcarbamoylase (OTC) is the most common deficiency

- next most common is argininosuccinaste lyase (argininosuccinase) (accumulates argininosuccinate)

- results in increased NH3 and decreased urea output

OTC deficiency

- X-linked

- Males (and females homozygotes) severely affected

- females heterozygotes are variably affected due to random X inactivation

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- 12-72 hours

- lethargy, poor feeding, abnormal respiration, vomiting, seizures, decreasing conscious level

- if untreated - death

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- management: early intervention. Restrict dietary intake of proteins, liver transplant, medication (benzoate/phenylacetate) can assist by removing excess ammonia (bypassing urea cycle)

Disorders of Nucleotide Metabolism

Lesch-Nyhan Syndrome: X-linked, lack HGPRT

- impaired kidney function, acute gouty arthritis, self-mutilating behaviour such as lip and finger biting, and or head banging, involuntary muscle movements, neurological impairment

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- results in elevated levles of PRPP if we cant salvage our purine and pyrimidne bases

Disorders of Nucleotide metabolism

- HGPRT deficiency

Summary

DIAGRAM ON SLIDE 41 and 42