Lecture 19 - Prenatal Diagnosis In Thalassemia Flashcards
1
Q
Haemoglobinopathies = inherited disorders of globin (a2b2)
A
1) thalassaemia syndromes - ratio of a/b proteins
2) Variant haemoglobins - abnormal a or b proteins
2
Q
Facts about haemogloninopathies
A
- inherited ones have been positively selected for by malaria - found in regions where malaria is/was endemic
- important ones are a thalassemia, b thalassemia, HbS, HbE
- risk populations: SEA, southern chinese, mediterranean, middle eastern, black africans
3
Q
Difference between thalassemias and variant haemoglobins
A
- Thalassemia: positive family history, almost always inherited, MCV/MCH low
- Variant Hb: Spontaneous or inherited, MCV/MCH normal (HbS) or low (HbE)
4
Q
Inheritance patterns in thalassemia
A
- autosomal recessive
- autosomal co-dominant if carrier has low MCV and in large penetrance
- autosomal dominant b thalassemia: rare
- compound states: HbH
- gene-gene interactions (a and b thalassemia: inheritance of a thalassemia reduces severity of phenotype of b thalassemia due to reduced a chain)
5
Q
Pathogenesis - thalassemia syndromes
A
- a/b globin chain imbalance
- iron overload
- hypersplenism
- complications blood transfusions
- gene/gene interactions
6
Q
Diagnosis of b thalassemia
A
- non deletional gene disorder, usually single nucleotide polymorophism
- microcytic hypochromic anemia
- blood film
- increase HbA2 in heterozygous or intermedia
- b/a biosynthesis ratio (0.5/0.7)
- DNA analysis: point mutation
- Family studies
7
Q
A thalassemia
A
- mostly a deletional disorder
- a+ deletions: 3.7 or 4.2 kbp deletion
- a0 deletions: specific for some regions of the world
8
Q
A thalassemia genotype and phenotype
A
- aa/aa: normal
- a-/aa: a+ normal
- a-/a-: a+, decreased MCV/MCH
- –/aa: a0: decreased MCV/MCH
- a-/–: HbH
- –/–: HbBarts hydrops fetalis
9
Q
Diagnosis of a thalassemia
A
- normal haematology
- microcytic, hypochromic RBC - anemia
- blood film
- HbH inclusions
- a/b biosynthesis ratio
- DNA analysis for deletions
- Family studies
10
Q
Pathophysiologic consequences of switch from HbF to HbA
A
- predominant circulating hemoglobin at the moment of birth is hbF
- infants do not depend on normal amounts and function of HbA until they are 4-6mo
- a-chain hemolobinopathies tend to be symptomatic in utero and at birth
- b chain abnormalities are asymptomatic until 4-6mo
- a chains are needed to form HbF and HbA, but b-chains are required only for HbA
11
Q
Options for prenatal diagnosis
A
- ultrasound: not very sensitive
- chromosome analysis
- biochemical screen
- fetal sampling
- DNA testing
12
Q
Prenatal diagnosis of b-thal
A
- routinely and reliably diagnosed using fetal DNA obtained between 8 and 18 weeks of gestation
- most reliable methods are based on direct DNA analysis: amniocentesis and CVS. Preferable to obtain DNA ealry on
- new techniques: DNA directly from maternal plasma or isolate fetal nucleated RBC from maternal peripheral blood
13
Q
Sources of Fetal DNA
A
- CVS: 11 weeks, aim is in 1st semester
- amniocentesis: 15 weeks, 2nd trimester
- Fetal blood: 18 weeks - not ideal
14
Q
Heterogeneity of b-thalassemia mutations complicates the approach to prenatal diagnosis BUT
A
- 15 b-thal mutations account for more than 90% of individuals affected worldwide
- 3-6 mutations usually account for the vast majority of severe cases in any ethnic group
15
Q
Prenatal diagnosis of a-thalassemia
A
- amniocentesis in pregnancies at risk of homozygous a-thal and the hydrops fetalis syndrome
- molecular hybridization
- detect complete absence of a globin genes in fetal fibroblasts
- ultrasonography detects hydrobs fetalis
- DNA studies or globin synthesis evaluation may be used to confirm the diagnosis in utero
