Inborn errors of metabolism Flashcards
Inborn errors of metabolism
Single gene defects resulting in disruption to metabolic pathways
Consequence of IEM
- Toxic accumulation of substrates
- Toxic accumulation of intermediates from alternative metabolic pathways
- Defects in energy production/use due to deficiency of products
Alkaptonuria
Deficiency in homogentisic acid oxidase:
· Autosomal recessive disorder
· Urine turns black on standing (and alkalinisation)
· Black ochrontic pigmentation of cartilage & collagenous tissue (ochronosis)
· Congenital
Cystinuria
Mutations of SLC3A1 amino acid transporter gene (chromosome 2p) & SLC7A9 (Chromosome 19), causing defective transport of cysteine and other dibasic amino acids through epithelial cells of renal tubule and intestinal tract
· Autosomal recessive disorder
· Cysteine has low solubility in urine→formation of calculi in renal tract
Mechanisms of Inheritance
Autosomal Recessive Autosomal Dominant X-linked Co-dominant Mitochondrial
Autosomal recessive inheritance
- Both parents carry a mutation affecting the same gene
- 1 in 4 risk each pregnancy
- Consanguinity increases risk of autosomal recessive conditions
- Examples: cystic fibrosis, sickle cell disease
Autosomal dominant inheritance
- Rare in IEMs
- Examples: Huntington disease, Marfan’s, Familial hypercholesterolemia
X-linked inheritance
Recessive X linked conditions are passed through the maternal line
- Condition does appear in males
- Condition carried in females, but not usually expressed (because females have two copies of X chromosome). Female carriers may manifest condition→Lyonisation (random inactivation of one of the X chromosomes)
- Example: Haemophilia A, Duchenne, Muscular Dystrophy, Fabry’s Disease, Ornithine Carbomyl Transferase Deficiency
Dominant X linked conditions are passed on from either affected parent
-Affected father will only pass the condition to his daughters
-Affected mother can pass the condition to sons and daughters
-Example: Fragile X
There is no male to male transmission
Co-dominant inheritance
· Two different alleles of a gene are expressed, and each allele makes a slightly different protein. Both alleles influence the genetic trait or determine the characteristics of the genetic condition
Example: ABO blood group, ⍺1AT deficiency
Mitochondrial inheritance
· Mitochondrial gene mutation
· Inherited exclusively from mother:
-Only the egg contributes mitochondria to the developing embryo
· Affects both male and female offspring
· E.g. MERRF- Myoclonic epilepsy and ragged red fibre disease: deafness, dementia, seizures
· E.g. MELAS- Mitochondrial encephalopathy with lactic acidosis and stroke-like episodes
What is heteroplasmy?
presence of both normal and mutated mtDNA resulting in mitochondrial inherited disease
How does heteroplasmy arise?
When the mitochondria replicates, it is separate from the nucleus replicating. The mitochondria RANDOMLY segregates in the cells, and sometimes they will segregate with all wildtype, sometimes they will have a combination of wildtype and mutant, and sometimes they will contain all mutant mitochondria.
What does level of heteroplasmy determine?
· Distribution of the affected mitochondria, and thus level of heteroplasmy, determines presentation.
· Mitochondrial disease can vary in symptoms, severity, and age of onset.
Which organs are more commonly affected in mitochondrial diseases?
· High energy-requiring organs (e.g. brain, liver, kidneys) which are more frequently affected
Prevalence of inborn errors of metabolism
Individually rare
Collectively common
- cumulative frequency accounting for high mortality within the first year of life
significant contribution to the 1% of children of school age with physical handicap and the 0.3% with severe learning difficulties
