Lecture 19 - Prenatal Diagnosis In Thalassemia Flashcards Preview

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Haemoglobinopathies = inherited disorders of globin (a2b2)

1) thalassaemia syndromes - ratio of a/b proteins

2) Variant haemoglobins - abnormal a or b proteins


Facts about haemogloninopathies

- 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


Difference between thalassemias and variant haemoglobins

- Thalassemia: positive family history, almost always inherited, MCV/MCH low

- Variant Hb: Spontaneous or inherited, MCV/MCH normal (HbS) or low (HbE)


Inheritance patterns in thalassemia

- 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)


Pathogenesis - thalassemia syndromes

- a/b globin chain imbalance
- iron overload
- hypersplenism
- complications blood transfusions
- gene/gene interactions


Diagnosis of b thalassemia

- 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


A thalassemia

- mostly a deletional disorder
- a+ deletions: 3.7 or 4.2 kbp deletion
- a0 deletions: specific for some regions of the world


A thalassemia genotype and phenotype

- aa/aa: normal
- a-/aa: a+ normal
- a-/a-: a+, decreased MCV/MCH
- --/aa: a0: decreased MCV/MCH
- a-/--: HbH
- --/--: HbBarts hydrops fetalis


Diagnosis of a thalassemia

- normal haematology
- microcytic, hypochromic RBC - anemia
- blood film
- HbH inclusions
- a/b biosynthesis ratio
- DNA analysis for deletions
- Family studies


Pathophysiologic consequences of switch from HbF to HbA

- 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


Options for prenatal diagnosis

- ultrasound: not very sensitive
- chromosome analysis
- biochemical screen
- fetal sampling
- DNA testing


Prenatal diagnosis of b-thal

- 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


Sources of Fetal DNA

- CVS: 11 weeks, aim is in 1st semester
- amniocentesis: 15 weeks, 2nd trimester
- Fetal blood: 18 weeks - not ideal


Heterogeneity of b-thalassemia mutations complicates the approach to prenatal diagnosis BUT

- 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


Prenatal diagnosis of a-thalassemia

- 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


Options after prenatal diagnosis

- termination of pregnancy up to 20 weeks
- nothing
- intrauterine blood transfusion, bone/SCT


Homozygous a thalassemia

- HbH, hydrop fetalis
- usually die in utero
- some infants have had successful blood exchange transfusion immediately after birth
- also possible to salvage affected fetuses by in utero blood transfusions
- limb and urogenital defects are present in a substantial portion of infants
- developmental delay or other neurologic abnormalities


Infications for PND

- HbBarts hydrops fetalis: a0 in each partnet
- b thalassemia major: trait in each patner
- HbH disease: a0 in one and a+ in the other
- various Hb variant combination: HbSS or HbS, HbE with b thalassemia


Preimplantation genetic diagnosis

- involves IVF
- biopsy taken of dividing blastomere
- in theory, useful for a wide number of genetic disorder
- limited by technology
- required confirmation by amniocentesis or CVS
- sexing and simple genetic tests feasible