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Molecular Basis Of Disease > Inborn Errors Of Metabolism > Flashcards

Inborn Errors Of Metabolism Flashcards

1
Q

What are inborn errors of metabolism?

A

Single gene defects resulting in disruption to metabolic pathways

Can vary in age of onset and clinical severity

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2
Q

What are the effects of inborn errors of metabolism

A

Toxic accumulation of substrates

Toxic accumulation of intermediates from alternative metabolic pathways

Defects in energy production/use due to deficiency of products

Combination of above

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3
Q

What is Alkaptonuria?

A

Autosomal recessive disease

Congenital

Urine turns black on standing

Black ochrontic pigmentation of cartilage and collagen out tissue - ears and eye

Caused by Homogentisic acid oxidase deficiency

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4
Q

What is the molecular disease concept?

A

Inborn errors of metabolism are caused by mutations in genes which then produce abnormal proteins whose functional activities are altered

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5
Q

What are the mechanisms of inheritance for inborn metabolic disease genes?

A

Autosomal recessive - most common

Autosomal dominant - rare in IEMs

X-linked

Mitochondrial

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6
Q

Describe the AUTOSOMAL RECESSIVE mechanism of inheritance.

A

Both parents carry mutation effecting the same gene

1 in 4 risk in pregnancy

Consanguinity (parents are blood related) increases risk of autosomal recessive conditions

Eg. Alkaptonuria

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7
Q

Describe the X LINKED mechanism of inheritance.

A

Passed through the maternal line

  • condition appears in males
  • condition carried in females
  • lyonisation can occur (female carriers can express gene and manifest condition)

Eg. Fabry’s disease

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8
Q

Describe the MITOCHONDRIAL inheritance pathway.

A

Mitochondrial gene mutation

Inherited exclusively from mother
- only egg contributes mitochondria in developing embryo
- fathers do NOT pass on these disorders

Affects both make and female offspring

Eg. MERFF, MELAS

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9
Q

What is heteroplasmy?

A

Cell contains varying amounts of normal mtDNA and also mutated mtDNA.

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10
Q

How is the severity of mitochondrial disease determined?

A

the distribution of affected mitochondria determines presentation

Mitochondrial disease can vary in symptoms, severity, age of onset

High energy-requiring organs ore frequently effected

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11
Q

How common are inborn errors of metabolism?

A

Induvidually rare:

Collectively common:
- high mortality within first year of life
- significant contribution to children of school, age with physical handicap and severe learning difficulties

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12
Q

What are treat,emits available for inborn errors of metabolism?

A

Dietary control/restrictions

Compound supplementation

New drug/enzyme replacement.

Organ transplant

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13
Q

How is IEM classified into toxic accumulation?

A

Protein metabolism
- amino acids
- organic acids
- urea cycle disorders

Carbohydrate intolerance

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14
Q

How can IEM be classified into deficiency in energy production/utilisation?

A

Fatty acid oxidation

Carbohydrate utilisation/production

Mitochondrial disorders

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15
Q

How can IEM be classified into disorders of complex molecules involving organelles?

A

Lysosomal storage disorders

Peroxisomes disorders

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16
Q

How is IEM presented in Neonatal patients?

A

Often acute

Often caused by defects in carbohydrate intolerance and energy metabolism

17
Q

How is IEM presented in late onset patients?

A

Due to accumulation of toxic molecules

  • Patients have residual enzyme activity allowing slower accumulation of toxins
  • symptoms appear at adulthood
  • present with organ Faliure,seizures, encephalopathy
18
Q

How is IEM detected in neonates?

A

Born at term with normal birth weight and no abnormal features.

Symptoms present frequently in the first week of life when starting full milk feeds.

Clues:
- consanguinity
- FH of similar illness in siblings or unexplained deaths
- infant who was well at birth and starts to deteriorate with no obvious reason.

19
Q

Define consanguinity

A

Being from the same ancestor or being related

20
Q

What are the clinical symptoms of neonatal IEM?

A

Poor feeding, lethargy, vomiting

Epileptic encephalopathy

Profound hypotonia (floppy baby)

Organmegaly

Dysmorphic features

Sudden unexpected death in infancy (SUDI)

21
Q

What are the biological symptoms of neonatal IEM?

A

Hypoglycemia

Hyperammonaemia

Unexplained metabolic acidosis

Lactic acidosis

22
Q

What are routine laboratory investigations to detect IEM?

A

Blood gas analysis

Blood glucose and lactate

Plasma ammonia

23
Q

What are specialist investigations to detect IEM?

A

Plasma amino acids

Urinary organic acids + orotic acid

Blood acrylic carnitines

Urinary glycosaminoglycans

Plasma very long chain fatty acids

CSF tests

24
Q

What confirmatory investigations can be done to confirm someone has IEM?

A

Enzymology

Biopsy (muscle, liver)

Fibroblast studies

Mutation analysis - whole genome sequencing

25
Q

What is newborn screening?

A

Early identification of life threatening disease in pre-symptomatic babies

earlier initiation of medical treatment

Reduction of morbidity and mortality

26
Q

What is the criteria for screening?

A

Must be important health problem

Must know Incidence or prevalence in screening population

Natural history of the condition should be understood

Availability of a screening test that is easy to perform and interpret

Availability of an accepted treatment for the condition

Diagnosis and treatment of condition should be cost effective.

27
Q

How is a new born blood sport screening obtained?

A

Samples should be taken on day 5 from heal prick

All four circles on “Guthrie” card red to be completely filled with a single drop of blood which soaks through to the back of the card

Require a good quality bloodspot for analysis

28
Q

What is Tyrosinaemia Type 1?

A

Genetic deficiency in FAH

FAH catalyses the final step in tyrosine metabolism

Increased byproduct succinylacetone leads to significant organ toxicity (liver and kidney)

29
Q

How is Tyrosinaemia Type 1 treated?

A

Nitisinone (NTBC)

  • inhibits an earlier step in the pathway to prevent accumulation of toxic metabolites
  • early treatment achieves 90%> survival rate with normal growth.

Side effects: accumulation of tyrosine and Requires daily dietary restriction of tyrosine and precursor phenylalanine

30
Q

What is ornithischians transcarbamylase deficiency? (OTC)

A

Urea cycle disorder

Symptoms range from mild to profound neuropschiatric manifestations
Eg. Seizures, ataxia

31
Q

What can OTC cause?

A

Factors can trigger hyperammonaemic encephalopathy

  • increased endogenous protein catabolism (eg. Fasting, trauma, infection)
  • high protein

Molecular Basis Of Disease (32 decks)

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