Transcript Anti-B or not anti-B, that is the question

Phosphoglycerate Kinase
Deficiency
Phosphoglycerate Kinase
In the glycolytic pathway PGK catalyses the
reversible reaction of 1,3-phosphoglycerate to
produce 3-phosphoglycerate and ATP.
Glucose
ATP
HK
ADP
Glucose-6-P
HMP
PGI
Fructose-6-P
ATP
PFK
ADP
Fructose-1,6 di P
TPI
Dihydroxyacelone
P1
Glyceraldehyde-3-P
GAPD
NAD+
NADH
1,3 diphosphoglycerate
DGPM
ADP
PGK
2,3-diphosphoglycerate
ATP
3-phosphoglycerate
MPGM
2-phosphoglycerate
ATP
LDH
Lactate
ADP
Pyruvate
2-phosphoenolpyruvate
PK
NADH
NAD+
Enolase
P1
Phosphoglycerate Kinase
There are 2 human isoenzymes: PGK1 and
PGK2 encoded by 2 distinct genes.
PGK1 is ubiquitously expressed in all somatic cells.
Its gene maps to Xq13.3.
PGK2 is uniquely expressed on meiotic/postmeiotic
spermatogenic cells and the gene maps to 6p12-21.
Phosphoglycerate Kinase
PGK 1 Deficiency: x-linked disorder
characterised by various combintions of
non-spherocytic haemolytic anaemia, mental
retardation, rhabdomyolysis, and various
neurological disfunctions.
• Pleomorphic disease – some patients with
very low levels have no haemolysis
• Some patients have haemolysis at higher
levels
• Disparity may be due to lesions in
different portions of the molecule having
different clinical effect
In a study carried out by Chiarelli et al links
have been made between some of the mutations
and the clinical phenotype. Clinical
manifestations may also depend on intervening
factors such as pharmacological, nutritional and
the environment.
Family studies
• 26 families reported – varying
combinations of haemolytic anaemia,
mental retardation and myopathies
• 20/26 mutations known
• 18 different mutations reported in
severely affected families
• Mostly missense mutations
• Most families have unique mutation
Of the 26 families described
• 18 families had haemolytic anaemia
• 10 families had myopathies - 7 without
anaemia
• Clinical phenotype is similar within
families
• Varying degrees of mental retardation
common
• Severe neonatal jaundice in 1 patient
• 15-20% cases display neonatal anaemia
History:
Baby OP born 8/02/07
On admission: Hepatosplenomegaly,
cardiomegaly, petechiae.
FBC: Hb 66, plt 40, wcc 19.3, retics 33%,
polychromasia, no spherocytes, left shift,
19% myelocytes. Bilirubin 325, conjugated 225.
Group B pos, DAT negative.
Family History
Mum: O positive, no antibodies detected.
P/H: 1 stillborn hydropic baby with
hepatosplenomegaly. 2 miscarriages.
IgG anti-B titre: 32,768.
Chemiluminescence assay: 62.5%.
Investigation of Haemolysis
Osmotic fragility: negative
Ham’s test: negative
AMA: negative
G6PD normal
DAT: negative x 3
CD55, 58, 59 expression abnormal
Phosphoglycerate kinase reduced
OP’s results
Sample sent to Scripps Institute for further
testing. PGK 63.2IU (NR 247-392).
Hemizygous mutation at cDNA 734 giving
a T>C substitution and a predicted Leu245Pro.
Mutation found in OP’s mother and post mortem
tissue of his brother but not his 2 maternal aunts.
OP’s progress
OP continues to be transfusion dependant.
He has neurological abnormalities and
developmental delays.
References
Chiarelli et al. Molecular Insights on Pathogenic
Effects of Mutations causing Phosphoglycerate
Kinase Deficiency. www.plosone. Feb 2012 7:2.
Beutler E. PGK deficiency. 2006. BJH :136, 3-11.