Lecture 15- Autosomal Dominant and recessive disorders

Question 1

Achondroplasia features

Answer 1

autosomal dominant
shortening of proximal limbs, prominent forehead, depressed nasal bridge
altered ossification of bone
Mutation in the fibroblast growth factor receptor 3 (FGFR3) gene

Question 2

Achondroplasia mutant gene

Answer 2

Mutation in FGFR3 (fibroblast growth factor receptor) gene
• Mutations result in gain of function/premature differentiation of
chrondrocytes into bone
• The wild type allele cannot compensate for / reduce the mutant alleles activity
• These incidence of these mutations increases with paternal age since FGFR3 contains a nucleotide with a predisposition to mutate. thus why 80% of mutations are ‘new’
• Mutations sometimes occur during spermatogenesis
• Potential for prenatal diagnosis
only 20% is genetic based. if two affected parents have a homozygous dominant baby it won’t survive past utero or will die shortly after birth, therefore 2/3 will have condition

Question 3

potential therapy for achondroplasia

Answer 3

soluble form of FGFR3 that reduces the effects of the FGFR3, not signalling cell membrane
vosoritide, a drug with a prolonged 1/2 life to allow normal formation of growing bones

Question 4

Marfan Syndrome

Answer 4

autosomal dominant
due to mutation in fibrillin 1 gene
the protein binds to and stables normal fibrin- a dominant negative effect leading to excessive elasticity of fibrillin.
several hundred alleles (allelic heterogeneity)
affects several organ systems (pleiotropy)
different features may be seen in different membered of the same family (variable expression

Question 5

Phenylketonuria

Answer 5

autosomal recessive disorder due to deficiency (caused by mutation) in phenylalanine hydroxylase gene necessary for conversion of phenylalanine to tyrosine. phenylalanine accumulates in the blood.
homozygous typically fair haird with blue eyes. without treatment children have vommiting, convulsions and develop mental retardation
allelic heterogeneity

management
low phenylalanine diet and supplements

Question 6

newborn metabolic screening programme

Answer 6

heel prick blood from all new borns is analysed. 28 conditions are currently looked for including PKU.

Question 7

hereditary haemochromotosis

Answer 7

autosomal recessive disorder of iron metabolism resulting in iron overload due to increased absorption and excess accumulation. can cause organ and tissue damage over time.
late onset of clinical symptoms
non specific symptoms of lethargy
hepatomegaly and cirrhosis
diabetes
locus heterogeneoty- although 90% of patients have classical HFE mutation

Question 8

diagnosis of Haemochromotosis

Answer 8

based on abnormal iron studies and HFE gene testing; liver biopsy usually not required
Liver biopsy done if HFE gene testing negative or concern about cirrhosis