Inborn Errors of Inheritance Flashcards
1
Q
Inborn errors of metabolism
A
- Any rare disorder caused by an inherited genetic defect in metabolism
- Usually autosomal recessive
- Can result in injury to any tissue, but most damage to developing brain
Mainly represent as reduced activity/ complete absence of enzymes in biochemical pathways: o Amino acid metabolism o Carbohydrate metabolism o Lipid metabolism o Protein metabolism o Pigment metabolism o Other biochemical defects
2
Q
encephalopathy
A
- Overarching term for accumulation of an otherwise normal metabolite that becomes toxic when present in excess concentration in the brain
- Treatment: Diet therapy, or the purposeful interdiction of a potentially injurious nutrient -> often attenuates or even prevents brain injury and permits normal neurological development
3
Q
inborn errors of AA metabolism (PKU)
A
Phenylketonuria (PKU)
- Autosomal recessive, Chromosome 12
- Liver enzyme phenylalanine hydroxylase missing
- ~1:5,000 - 10,000 births
- Phnylalanine is obtained through the diet (mainly proteins)
- Conversion of amino acid phenylalanine to tyrosine is disrupted
- If untreated built up of phenylalanine in the blood & harm central nervous system –> leads untreated to mental retardation and seizures
- Treatment: phenylalanine restricted diet
4
Q
inborn errors of CHO metabolism (Galactosemia type I)
A
- Autosomal recessive
- Mutations in the GALT gene –> Body unable to metabolize the simple sugar galactose -> inability to use galactose to produce energy
- Affects 1:30,000 to 60,000 newborns
- Small amount of galactose present in many foods i.e. makes up half of lactose
5
Q
inborn errors of CHO metabolism (diabetes mellitus)
A
- Absence or insufficient production of insulin causes hyperglycemia
- type I diabetes mellitus: insulin is missing (loss of insulin-producing beta cells)
- type II diabetes mellitus: insulin resistance (cells don’t respond to insulin present)
6
Q
inborn errors of lipid metabolism (tay-sachs)
A
- Autosomal recessive
- Enzyme Hexoaminidase A missing
- Mutation in HEXA gene on chromosome 15
- Lipid storage disorder
- Symptoms: hearing loss, seizures, physical and mental retardation, dementia, red dots on retina
7
Q
inborn errors of protein metabolism (haemophilia)
A
- X-linked recessive
- Absence of clotting factors in plasma
- 1 in 5,000 live male births
- Blood clotting occurs in a cascade
- Any factor insufficiency in the cascade can lead to insufficient blood clotting
8
Q
inborn errors of pigment metabolism (albinism)
A
- Autosomal recessive
- Defective enzyme: tyrosinase
- Complete absence of melanin synthesis
- 1:20,000 births
- Hair white, blue eyes, skin UV sensitive
- Abnormal development of the retina and abnormal patterns of nerve connections between the eye and the brain – vision problems
9
Q
mutant genes (Achondroplasia)
A
- Form of short-limbed dwarfism
- Most common form of short limb dwarfism:
o occurs in 1 : 15,000 to 40,000 newborns
o affects > 250 000 individuals worldwide - Autosomal dominant
- ~80 percent have average-size parents; these cases result from new mutations
- Two specific mutations in the FGFR3 gene are responsible for almost all cases
10
Q
mutant genes (polydactyly)
A
- Person born with extra fingers or toes
- Polydactyly is common
- Results from defective patterning of the anterior-posterior axis of the developing limb
- Full range of Mendelian inheritance patterns
- Small finger duplication is often hereditary
- 100 genes identified that can lead to polydactyly
11
Q
karyotype
A
- Number and visual appearance of metaphase chromosomes ordered by size and location of centromers
- Diploid chromosome set:
o 1 maternal (from the mother via egg)
o 1 paternal (from the father via sperm)
o Humans 2n = 46
12
Q
genetic terminology
gene, alleles, dominant, recessive, homozygote, heterozygote, genotype, phenotype
A
- Gene: e.g. eye colour
- Alleles: different expressions of a gene = forms of a characteristic: individual eye colour: blue/brown
- Dominant: only one copy necessary to express the phenotype (brown allele B)
- Recessive: two copies necessary to express the phenotype (blue allele b)
- Homozygote: two of the same alleles (BB, bb)
- Heterozygote: two different alleles (Bb)
- Genotype: genetic makeup of an organism / which types of genes (alleles) are present
- Phenotype: observable manifestation of these genetic differences/visible expression of a gene(s)
13
Q
human monogenic diseases
A
- Follow a simple Mendelian inheritance
- Result from modifications in the DNA of a single gene
- Estimated ≥10,000 of human diseases monogenic
- The single-gene or monogenic diseases can be classified into:
o Autosomal vs X-linked
o Dominant vs Recessive
14
Q
autosomal dominant disorders
A
- Autosomal: sexes equally affected
- Each child has a 50% chance of inheriting the condition
- Dominant: allele cannot skip generations
- Autosomal –> all forms of transmission present: male to female, male to male, female to male and female to female
- Examples: Huntington disease, Familial Hypercholesterolaemia, Marfan syndrome
15
Q
huntington’s disease (auto dominant)
A
- chromosome 4
- Expansion of a cytosine-adenine-guanine (CAG) triplet within Huntingtin gene -> altered expression of the protein huntingtin
- Mutated protein increases decay rate of certain types of neurons -> death of brain cells
- Symptoms: Jerky, random, and uncontrollable movements called chorea
