BLGY1232 Screening, treatment and therapies for inherited disease
Can they be cured?
We can’t change our genes but can monitor what we pass on to the next generation
Genetic counselling provides information and options for carriers of alleles causing
disorders
Diagnosis by genetic testing is available for newborns for some conditions
Pre-natal diagnosis of embryos is also possible
Screening enables us to identify at-risk individuals
Screening of newborns
Condition screened for should be relatively common
Condition should be treatable with early intervention producing positive outcomes
Test should be accurate
Phenylketonuria; autosomal recessive, 1 in 15,000 (but 1 in 4500 in Ireland and 1 in
2500 in Turkey), mutation in Phenylalanine hydroxylase if untreated can lead to
progressive mental retardation and early diagnosis and implementation of low-
phenylalanine diet prevents this
In the UK the NHS universal screening of all infants at 5 days of age is offered for;
Phenylketonuria (PKU) - an inability to convert phenylalanine to tyrosine
results in a buildup of Phe in the blood. This is converted to phenylketons. If
undetected, there is a progressive mental deterioration. Diagnosis soon after
childbirth allows the condition to be managed by a low phenylalanine diet
Congenital hypothyroidism (CHT) - low levels of thyroid hormone result in
stunted growth & mental retardation. Affects about 1 in 4000. Easily treated
by daily thyroxine tablet.
Sickle cell disease (SCD)
Cystic fibrosis (CF)
Medium-chain acyl-CoA dehydrogenase deficiency (MCADD) - Defect in lipid
metabolism, a possible cause of Sudden Infant Death Syndrome. May not be
too harmful except under food deprivation (>10-12 hr) in which case sudden
collapse is possible.
Duchenne Muscular Dystrophy (boys in Wales)
Homocystinuria (N. Ire) - Defect in methionine metabolism causes buildup of
homocystine in blood, leading to cardiovascular conditions. Treated by
Vitamin B6 supplementation and low methionine diet.
Tyrosinaemia (N. Ire) - Inability to break down tyrosine leading to liver
failure. Treated with low-protein diet and drug Nitisinone
Prenatal genetic screening
Amniocentesis samples amniotic fluid to collect foetal cells for analysis at 14-20
weeks
Chorionic villus sampling collects placental cells at 10-15 weeks
Commonly used for screening for chromosomal abnormalities like Down syndrome
(chromosome 21 trisomy), but other conditions also detectable
Invasive: some risk to foetus
Enables intervention at or before birth
, Provides parents with information so they can choose to terminate pregnancy or
make appropriate preparations
Preimplantation genetic diagnosis
Associated with IVF - Typically multiple egg cells are fertilised, and the resultant
embryos can be screened by collecting a single cell from the blastocyst for genetic
analysis
A single cell can be removed from an early embryo and DNA genotyped by PCR assay
Used to screen for alleles of single-gene disorders
Also used to check embryos generated by IVF to ensure no chromosomal
abnormalities
Ethical issues; IVF generates multiple embryos so what happens to unwanted ones?
What traits should one be allowed to choose?
Therapies for many disorders could be developed if we knew more about their
progression in affected individuals. For many conditions, the first inkling the medical
profession has is when a patient turns up in the doctor’s surgery. By this time, it may
be too late.
Saviour sibling
Charlie Whitaker was born with Diamond Blackfan Anaemia (DBA), which prevents
his body making red blood cells In the short term, this can be managed by
repeated blood transfusion It can be permanently cured by a bone marrow
transplant, but this requires a tissue-matched donor Charlie’s parents and sister
did not carry the compatible antigens In 2003, the UK HFEA refused permission
for a “designer baby” – an embryo produced by IVF and selected for it’s
transplantation antigen genotype The Whitakers flew to the US to have IVF and
select an embryo with a compatible genotype: Jamie Whitaker from whose umbilical
cord stem cells were collected for the transplant.
Megan Matthews was born with Fanconi Anaemia – a DNA repair defect causing
bone marrow failure Megan was the first child to be cured by a “saviour Sibling”
in the UK Following IVF, 3-day-old embryos were tested for a genetic match
Megan’s mother had 2 embryos implanted. One – Megan’s brother Max – was born
in 2009, and provided umbilical cord blood and bone marrow for a successful
transplant Note: Fanconi Anaemia is a general DNA repair disorder: Megan may
suffer from other consequences of the disorder, in other tissues that are not
replaced by bone-marrow transplant
Developing effective treatments for human disorders
We have to know how a condition develops thought the life of the affected
individual
In many cases we lack knowledge of the early stages, since these may be
asymptomatic, and the affected person is not medically assessed until symptoms
appear
Now we can make transgenic mice that have been genetically engineered to contain
defective genes and monitor progress throughout development – although mice and
Can they be cured?
We can’t change our genes but can monitor what we pass on to the next generation
Genetic counselling provides information and options for carriers of alleles causing
disorders
Diagnosis by genetic testing is available for newborns for some conditions
Pre-natal diagnosis of embryos is also possible
Screening enables us to identify at-risk individuals
Screening of newborns
Condition screened for should be relatively common
Condition should be treatable with early intervention producing positive outcomes
Test should be accurate
Phenylketonuria; autosomal recessive, 1 in 15,000 (but 1 in 4500 in Ireland and 1 in
2500 in Turkey), mutation in Phenylalanine hydroxylase if untreated can lead to
progressive mental retardation and early diagnosis and implementation of low-
phenylalanine diet prevents this
In the UK the NHS universal screening of all infants at 5 days of age is offered for;
Phenylketonuria (PKU) - an inability to convert phenylalanine to tyrosine
results in a buildup of Phe in the blood. This is converted to phenylketons. If
undetected, there is a progressive mental deterioration. Diagnosis soon after
childbirth allows the condition to be managed by a low phenylalanine diet
Congenital hypothyroidism (CHT) - low levels of thyroid hormone result in
stunted growth & mental retardation. Affects about 1 in 4000. Easily treated
by daily thyroxine tablet.
Sickle cell disease (SCD)
Cystic fibrosis (CF)
Medium-chain acyl-CoA dehydrogenase deficiency (MCADD) - Defect in lipid
metabolism, a possible cause of Sudden Infant Death Syndrome. May not be
too harmful except under food deprivation (>10-12 hr) in which case sudden
collapse is possible.
Duchenne Muscular Dystrophy (boys in Wales)
Homocystinuria (N. Ire) - Defect in methionine metabolism causes buildup of
homocystine in blood, leading to cardiovascular conditions. Treated by
Vitamin B6 supplementation and low methionine diet.
Tyrosinaemia (N. Ire) - Inability to break down tyrosine leading to liver
failure. Treated with low-protein diet and drug Nitisinone
Prenatal genetic screening
Amniocentesis samples amniotic fluid to collect foetal cells for analysis at 14-20
weeks
Chorionic villus sampling collects placental cells at 10-15 weeks
Commonly used for screening for chromosomal abnormalities like Down syndrome
(chromosome 21 trisomy), but other conditions also detectable
Invasive: some risk to foetus
Enables intervention at or before birth
, Provides parents with information so they can choose to terminate pregnancy or
make appropriate preparations
Preimplantation genetic diagnosis
Associated with IVF - Typically multiple egg cells are fertilised, and the resultant
embryos can be screened by collecting a single cell from the blastocyst for genetic
analysis
A single cell can be removed from an early embryo and DNA genotyped by PCR assay
Used to screen for alleles of single-gene disorders
Also used to check embryos generated by IVF to ensure no chromosomal
abnormalities
Ethical issues; IVF generates multiple embryos so what happens to unwanted ones?
What traits should one be allowed to choose?
Therapies for many disorders could be developed if we knew more about their
progression in affected individuals. For many conditions, the first inkling the medical
profession has is when a patient turns up in the doctor’s surgery. By this time, it may
be too late.
Saviour sibling
Charlie Whitaker was born with Diamond Blackfan Anaemia (DBA), which prevents
his body making red blood cells In the short term, this can be managed by
repeated blood transfusion It can be permanently cured by a bone marrow
transplant, but this requires a tissue-matched donor Charlie’s parents and sister
did not carry the compatible antigens In 2003, the UK HFEA refused permission
for a “designer baby” – an embryo produced by IVF and selected for it’s
transplantation antigen genotype The Whitakers flew to the US to have IVF and
select an embryo with a compatible genotype: Jamie Whitaker from whose umbilical
cord stem cells were collected for the transplant.
Megan Matthews was born with Fanconi Anaemia – a DNA repair defect causing
bone marrow failure Megan was the first child to be cured by a “saviour Sibling”
in the UK Following IVF, 3-day-old embryos were tested for a genetic match
Megan’s mother had 2 embryos implanted. One – Megan’s brother Max – was born
in 2009, and provided umbilical cord blood and bone marrow for a successful
transplant Note: Fanconi Anaemia is a general DNA repair disorder: Megan may
suffer from other consequences of the disorder, in other tissues that are not
replaced by bone-marrow transplant
Developing effective treatments for human disorders
We have to know how a condition develops thought the life of the affected
individual
In many cases we lack knowledge of the early stages, since these may be
asymptomatic, and the affected person is not medically assessed until symptoms
appear
Now we can make transgenic mice that have been genetically engineered to contain
defective genes and monitor progress throughout development – although mice and
