Congenital Defects and Inborn Errors Flashcards
What are congenital defects and causes
- Inborn abnormalities, morphological or biochemical at birth
- Measurable effect on physical, intellectual and social well being
- Environmental factors 7% (infectious agents, chemical & pharmacological, radiation), genetic defects (chromosomal 10% and monogenic 8%), idiopathic 25% and unknown 50%
What are environmental factors / teratogens
- Any agent that can harm an embryo or foetus, infectious agents, chemical and pharmacological, radiation
What are environmental agents (infectious)
Rubella:
- Rubella virus
- Mild infection in adults, miscarriage or birth defects in foetus
- Heart defects, deafness, brain damage, cardiac abnormalities
- 1st trimester (40-60% chance of affected foetus)
Toxoplasmosis:
- Zoonotic intracellular parasitic infection caused by toxoplasma gondii
- Carrier by mammals
- Avoid undercooked / contaminated meats, cat faeces
- Affect brain / vision during 1st trimester, miscarriage later
Zika:
- Zika virus via insect bites
- Mother (rash, fever, conjunctivitis, joint pain)
- Foetus (microcephaly, congenital malformation, miscarriage / still birth)
Listeriosis:
- Listeria bacteria
- Uncooked mould ripened cheese, raw seafood
- Miscarriage, still birth, severe illness
Salmonella:
- Salmonella bacteria
- Raw undercooked eggs / reheated chicken
- Gastroenteritis / food poisoning
What are environmental agents (chemical and pharmacological)
- Thalidomide: Prevent nausea, malformation of ears, nose, eyes, heart, phocomelia and ectromelia
- Alcohol: Compromises functioning of placenta, FAS
- FAS: Microcephaly, malformation of heart, limbs, joints, face, seizures, learning difficulties
- Cigarettes: Cleft lip, miscarriage, low birth weight, ectopic pregnancy, SIDS
- Radiation: Death, mental retardation, significant damage during organogenesis
What are genetic defects (structural chromosomal)
Deletions:
- Deletion of part of or an entire chromosome
- Cri du Chat: Chromosome 5, mental impairment, small head
Duplications:
- Addition of parts of a chromosome
- Fragile X Syndrome: Expansion of CGG repeat, intellectual disability, normal (29), affected (700)
Translocations:
- Fragment moved from one chromosome to another
- Transcription altered, can cause cancer
- Acute Myeloid Leukaemia: Rapid growth of poorly differentiated WBC, inadequate production of RBC / platelets
Inversions:
- Chromosome breaks in 2 places, flips and reinserts back to front
- Affects protein expression
- Inversion of 9 is common but doesn’t cause disease
- 40% of mutations in haemophilia A
What are monogenic inherited genetic defects of metabolism and encephalopathy
- Monogenic Diseases: Mendelian inheritance, result from modifications in DNA of a single gene
- Autosomal recessive
- Types: AA, carbohydrate, lipid, protein, pigment, biochemical defects
- Encephalopathy: Accumulation of otherwise normal metabolite that becomes toxic in excess concentration in the brain
What are defects of AA metabolism
- Phenylketonuria (PKU)
- Autosomal recessive
- Chromosome 12
- Liver enzyme phenylalanine hydroxylase missing
- Conversion of phenylalanine (diet) to tyrosine disrupted
- Build up can harm CNS, mental retardation and seizures
- Treatment via phenylalanine restricted diet
What are defects of carbohydrate metabolism
Diabetes Mellitus:
- Absence of insufficient production of insulin causes hyperglycaemia
- 1: Insulin missing, no beta cells, autoimmune, weight loss, increased urination / thirst / hunger
- 2: Insulin resistance, cells don’t respond, obesity, unhealthy lifestyle
What are defects of lipid metabolism
- Tay Sachs
- Autosomal recessive
- Enzyme hexoaminodase A missing
- Mutation in HEXA gene on chromosome 15
- Lipid storage disorder, build-up / toxicity
- Hearing loss, seizures, physical / mental retardation, dementia, red dots on retina
What are defects of protein metabolism
- Haemophilia
- X linked recessive
- Absence of clotting factors in plasma
- Blood clotting occurs in cascade, any factor insufficiency can lead to insufficient clotting
- Internal / external bleeding, bruising, swelling
What are defects of pigment metabolism
- Albinism
- Autosomal recessive
- Defective enzyme tyrosinase
- Complete absence of melanin synthesis
- White hair, blue eyes, skin UV sensitive
- Abnormal development of retina / nerve connections to eye and brain (vision problems)
What are biochemical defects of metabolism
Achondroplasia: - Short limbed dwarfism - M (131) and F (124) - Autosomal dominant - 2 specific mutations in FGFR3 gene - 80% have normal sized parents Polydactyly: - Extra fingers / toes - Autosomal dominant - Defective patterning of anterior-posterior axis of limb - 100 genes identified can lead to this
Define the following related to genetic terminology (10)
- Karyotype: Number and visual appearance of metaphase chromosomes ordered by size / location of centromeres, diploid chromosome set (2n 46), 1 maternal and 1 paternal
- Gene: Biological units of heredity located in chromatin; transmits hereditary information
- Alleles: Genes coding for same trait and found at same locus on homologous chromosomes
- Dominant (D): One allele masks or suppresses expression of its partner
- Recessive (d): Allele that is not expressed in presence of other alleles that generate traits dominant to it
- Homozygote: Identical allelic genes
- Heterozygote: Different allelic genes
- Genotype: Genetic makeup of an organism, types of genes (alleles) present
- Phenotype: Observable manifestation / expression of genotype / genetic differences
- Pedigrees: Traces a particular genetic trait through several generations and helps predict the genotype of future offspring
What is autosome vs X-linked and dominant vs recessive genetic disorders
- Autosomal vs X-Linked: Gene located on autosome or sex chromosome
- Dominant vs Recessive: Number of alleles necessary to express particular phenotype
What are autosomal dominant disorders
- Autosomal: Sexes equally affected, each child has a 50% chance of inheriting condition, all forms of transmission present
- Dominant: Allele cannot skip generations
- Examples: Huntington disease (4), Familial Hypercholesterolaemia, Marfan syndrome
