27- Inborn Errors of Metabolism

Question 1

what are inborn errors of metabolism (IEMs)?

Answer 1

rare genetic disorders characterized by disruptions in metabolic pathways due to deficient or absent enzyme activity

arise from single gene defects

Question 2

how do IEMs manifest in the body?

Answer 2

1. toxic accumulation of substrates
2. toxic accumulation of intermediates from alternative metabolic pathways
3. deficiencies in energy production from the lack of essential metabolic products

can manifest as a combination of all three

Question 3

what factors influence the variability in age of onset and clinical severity of IEMs?

Answer 3

• specific metabolic pathway affected
• extent of enzymatic deficiency
• accumulation of toxic substances and their effect on tissues/organs

Question 4

what 4 genetic disorders did Garrod study, and what did he conclude from this?

Answer 4

alkaptonuria, cystinuria, albinism, pentosuria

concluded that these disorders were congenital, inborn and followed Mendel’s laws of inheritance

these disorders were a result of a block in normal metabolism, affecting enzymatic activity controlled by different genes

Question 5

what is alkaptonuria?

Answer 5

• rare genetic disorder
• characterised by a deficiency of the homogentisic acid oxidase enzyme = leads to accumulation of homogentisic acid in the body

Question 6

how is alkaptonuria inherited?

Answer 6

autosomal recessive = both copies of the gene must be mutated

Question 7

key clinical features of alkaptonuria and the pathophysiology behind it

Answer 7

• presence of black urine = caused by homogentisic oxidase deficiency, leading to accumulation of homogentisic acid
• elderly patients may develop black-blue discoloration of the ear cartilage
• ochronosis = widespread deposits of black material in articular cartilage and ligaments

Question 8

how is alkaptonuria diagnosed?

Answer 8

labatory tests, urine samples to detect homogentisic acid

Question 9

what does the one gene-one enzyme concept propose?

Answer 9

suggests that all biochemical processes in organisms are under genetic control

each step in a biochemical pathway is catalysed by a specific enzyme encoded by a single gene

Question 10

what is the molecular disease concept?

Answer 10

suggests that genetic mutations can lead to abnormal proteins with altered structure and functional activities, contributing to disease development

Question 11

how was the molecular disease concept supported by research on SCD?

Answer 11

SCD research showed that a single amino acid substitution in the beta-globin chain of haemoglobin led to changes in protein structure = caused the sickling process seen in SCD patients

Question 12

What are the common inheritance patterns observed in IEMs?

Answer 12

autosomal dominant
autosomal recessive
X-linked
mitochondrial inheritance

Question 13

how does the inheritance pattern vary depending on the location of the gene involved in IEMs?

Answer 13

varies depending on:
- whether the gene involved is autosomal or a sex chromosome (e.g. X-linked)
- whether one or two copies of the gene are needed for the disease phenotype to manifest

Question 14

why is an accurate family history important in establishing the pattern of inheritance of an IEM?

Answer 14

• helps identify carriers of the mutated gene
• can estimate the risk of the disease in other family members
• provides information for genetic counselling and managing the condition

Question 15

What is the most common mode of inheritance for IEMs?

Answer 15

autosomal recessive

Question 16

how does autosomal recessive inheritance occur?

Answer 16

homozygous individuals inherit two copies of the mutated gene

heterozygous individuals are carriers with one mutated gene, typically show no symptoms

Question 17

what is the risk of passing on an autosomal recessive disease if both parents are carriers of a mutation in the same gene?

Answer 17

25% chance of having an affected child = inherits two copies of the mutated gene

50% chance of a carrier child

25% of the child not inheriting either copy of the defective gene

Question 18

What factor affects the risk of autosomal recessive conditions?

Answer 18

consanguinity/ blood relation between parents = higher chance of inheriting the same mutated gene from both parents

Question 19

examples of IEMs inherited through autosomal recessive inheritance

Answer 19

phenylketonuria/ PKU
alkaptonuria
MCADD

Question 20

how does autosomal dominant inheritance differ from autosomal recessive inheritance in IEMs?

Answer 20

autosomal dominance = affected individuals have one affected parent and carry one copy of the mutated gene, enough to manifest the disease

autosomal recessive = need to inherit two copies of the mutated gene to manifest the disease

Question 21

what is the likelihood of passing on an autosomal dominant disease to offspring if one parent is affected?

Answer 21

50% chance the child will inherit the affected gene and manifest the disease

Question 22

do carriers exist in autosomal dominant inheritance?

Answer 22

no - individuals carrying one copy of the mutated gene usually manifest the disease phenotype

Question 23

examples of IEMs inherited through autosomal dominant inheritance

Answer 23

Marfan syndrome
acute intermittent porphyria

Question 24

what is X-linked inheritance?

Answer 24

involves genetic mutations located on the X-chromosome

passed on by females, tends to affect males due to their hemizygous nature (have only one X chromosome inherited from mothers)

Question 25

how do recessive X-linked conditions manifest in males?

Answer 25

manifest in males as they inherit one mutated X chromosome from carrier mothers

as males only have one X chromosome, they are more frequently affected per generation

Question 26

how can recessive X-linked disorders manifest in females?

Answer 26

through lyonization - random inactivation of one of the X chromosomes in female carriers

Question 27

is there male-to-male transmission in X-linked inheritance?

Answer 27

no - males only pass the Y chromosome to their sons

Question 28

describe the inheritance pattern and transmission of recessive X-linked disorders

Answer 28

transmission:
- no male-to-male transmission
- carrier mothers can transmit the disease to sons, daughters become carriers

inheritance pattern:
- males affected more as they’re hemizygous for X chromosome, inherited from mother
- females carriers can manifest the disease through lyonization = random inactivation of one of the X chromosomes

Question 29

examples of diseases inherited through X-linked inheritance?

Answer 29

Fabry’s disease
ornithine carbamoyl transferase deficiency

Question 30

what is mitochondrial inheritance? how are mitochondrial disorders inherited?

Answer 30

the transmission of genetic disorders caused by mutations in mitochondrial DNA

maternally inherited as only the egg contributes mitochondria to the developing embryo

Question 31

what is heteroplasmy in the context of mitochondrial disorders?

Answer 31

heteroplasmy = the presence of both normal and mutated mtDNA within a cell

mitochondrial replication can result in heteroplasmy - wild-type and mutated mtDNA within cells

the proportion and pattern of heteroplasmy affect the severity, presentation, symptoms, and age of onset of mitochondrial disorders

Question 32

why are mitochondrial disorders hard to diagnose?

Answer 32

because of variation in symptoms and presentation caused by heteroplasmy

affected tissues that require more energy are more severely affected - complicates diagnosis and management

Question 33

what triggers disease presentation in mitochondrial disorders?

Answer 33

occurs when the proportion of mutated mtDNA surpasses a certain threshold within affected tissues

threshold varies between tissues = tissues that need more energy are more susceptible to dysfunction

Question 34

describe the prevalence and effects of IEMs

Answer 34

individually rare, collectively common as there are up to 7000 identified disorders

significant implications for mortality and morbidity, especially in children and infants = can result in physical handicaps and severe learning difficulties in children

Question 35

list some treatment strategies for IEMs

Answer 35

dietary control or restrictions
compound supplementation
drug therapy
enzyme replacement therapy
organ transplantation

Question 36

how have advances in genetics contributed to the management of IEMs?

Answer 36

helped to characterize causal genes and underlying metabolic pathways

allowed for targeted disease treatment and personalized medicine approaches

Question 37

what are the three main classifications of IEMs?

Answer 37

1. toxic accumulation
2. deficiency in energy production/utilization
3. disorders of complex molecules involving organelles

Question 38

describe the toxic accumulation classification of IEMs

Answer 38

the accumulation of toxic substances due to deficiencies in enzymes responsible for metabolizing specific compounds

disorders affecting protein metabolism, urea cycle disorders and carbohydrate intolerance

Question 39

types and examples of toxic accumulation IEMs

Answer 39

affecting protein metabolism - e.g. phenylketonuria

urea cycle - e.g. OTCD

carbohydrate intolerance - e.g. galactosemia

Question 40

explain the deficiency in energy production/utilization classification of IEMs

Answer 40

characterized by impaired energy production or use, leading to metabolic dysfunction

disorders affecting fatty acid oxidation, carbohydrate production/utilisation and mitochondrial disorders

Question 41

types and examples of IEMs classified as deficiencies in energy production/utilization

Answer 41

affecting fatty acid oxidation - e.g. MCADD

affecting carbohydrate production/utilisation - glycogen storage disease

mitochondrial disorders - e.g. MELAS, MERFF

Question 42

what are IEM disorders of complex molecules involving organelles?

Answer 42

these affect the metabolism of complex molecules within cellular organelles, leads to their accumulation

disorders such as lysosomal storage disorders and peroxisomal disorders

Question 43

examples of disorders of complex molecules involving organelles