Transcript The Clinical Aspects of Enzyme Deficiencies in Haematology

The Clinical Aspects of
Enzyme Deficiencies in
Haematology
Dr Pasquale Barbaro
Paediatric Haematologist
The Children’s Hospital at Westmead
Summary
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Red cell enzyme deficiencies
Enzyme deficiencies in platelet function defects
Enzyme deficiencies implicated in Neutropenia
Enzyme deficiencies implicated in Bone Marrow failure
Red Cell Enzyme deficiencies
• Red Cell Metabolism
• During maturation, RCs lose their nucleus, organelles and mitochondria
• Require cellular metabolic pathways to ensure red cell membrane and haemoglobin integrity
• Require ATP to drive K/Na pump essential for membrane integrity
• Require NADH to protect from oxidative stress
• Require 2,3 bisphophoglycerate to regulate oxygen affinity
• Red cell enzyme deficiencies lead to non-spheroctyic haemolytic anaemia
• Chronic or intermittent haemolysis
• Pallor, jaundice
• Anaemia, reticulocytosis, hyperbilirubinaemia
• Splenomegaly
• Gall stone production
• Iron overload
Source of NADPH
• Ensures adequate reduced
glutathione
• Protects from oxidative stress
Source of ATP
• Required to drive K/Na Pump
• Essential for Red cell
membrane flexibility and
integrity
Involved in ATP production
Embden-Meyerhof pathway
• ATP production
• Enzyme deficiencies lead to chronic non spherocytic haemolysis of various severities
• Many also have non haematological manifestations
• Neurological
• Myopathy
• Most common:
• Pyruvate Kinase deficiency
• Glucose-6-phosphate isomerase deficiency
• Phosphofructokinase deficiency
• All have autosomal recessive inheritance
• Except Phosphoglycerate kinase deficiency – X-Linked
Pyruvate Kinase deficiency
• Frequency is approximately 1:20,000 in the general white population
• Intracellular
• Lack of ATP
• Excess production of 2,3-bisphosphoglycerate
• Clinical manifestations
• Chronic non-spherocytic haemolytic anaemia
• Stabilises in adulthood, and post-splenectomy
• Pallor, jaundice
• Splenomegaly
• Iron overload
• Treatment
• Supportive – Transfusions
• Splenectomy
• Iron chelation therapy
Glucose phosphate isomerase (GPI) deficiency
• More than 50 cases described
• Second most common enzyme defect in the red cell anaerobic glycolysis
• Clinical features
• More severe haemolysis
• Hydrops foetalis is more common than in other enzymopathies
• May be associated with neurological complications
• Granulocyte dysfunction has also been described
Others
• Phosphofructokinase
• Mild or fully compensated haemolytic anaemia
• Myopathy may be more pronounced symptom
• Aldolase
• Moderate to severe haemolysis
• Neurological and muscle dysfunction
• Recurrent rhabdomyolysis
• Triose-phosphate
• Most severe enzyme defect in EM pathway
• Hydrops foetalis or death in early childhood are common
• Severe neurological complications
Oxidative pathway deficiencies
• RCs continuously exposed to oxidative stress
• Iron is required to be maintained in its active, reduced state
• Oxidised Haemoglobin denatures, and deposits on the red cell membrane
leading to damage.
• Damaged Red cells are then removed in the spleen.
• Deficiencies in these enzymes lead to acute intermittent
haemolysis when there is increased oxidative stress
• Glucose-6-phosphate dehydrogenase deficiency most common
• Glutathione reductase deficiency
• Very rare (2 families reported to date)
• Symptoms are similar to that seen in G6PD deficiency
Nucleotide metabolism disorders
• Purine metabolism is important in RCs to
maintain adequate ATP within red cells
• Pyrimidine-5’-nucleotidase deficiency is the third
most prevalent red cell enzymopathy
• >60 families have been described
• Leads to build up of pyrimidine nucleotides which are
visible as insoluble aggregates (basophilic stippling)
• Mild to moderate chronic haemolysis, splenomegaly
and jaundice
• Deficiencies in adenylate kinase and adenosine
deaminase have been described associated with
haemolysis.
Platelet enzyme defects
• Platelets rely on a number of enzymes to ensure adequate supply of agonists in
granules to ensure platelet aggregation occurs
• Thromboxame pathway
• Cyclo-oxygenase -1
• Thromboxane synthase
• Cytosolic phospholipase A2
• Bleeding phenotype is mild
in almost all cases.
Enzyme defects causing Congenital
Neutropenia
• Marked neutropenia (<0.2x10^9/L)
• Presents in the first year of life with recurrent infections and neutropenia
• May be isolated or syndromic
• Isolated forms are associated with mutations in Neutrophil Elastase (ELANE), HAX1, GFI1.
• Many syndromic forms associated with chronic neutropenia
• Glycogen storage disease Type 1b - Glucose-6-phosphate translocase
• Glucose-6-phosphatase catalytic subunit 3 (G6PC3) deficiency
• Barth Syndrome – tafazzin (a mitochondrial phopspholipid transacylase) deficiency
Enzyme deficiencies causing Aplastic
Anaemia
• Telomere defects
• Ends of linear chromosomes
• Cap the chromosome, forming a buffer, so
that Genomic DNA is not lost during each cell
division.
• When telomeres reach a critically short
length, the DNA Damage response
mechanisms are initiated leading to cellular
senescence or apoptosis.
TELOMERASE
DNA DAMAGE RESPONSE
T-LOOP
APOPTOSIS / SENESCENCE
GENETIC INSTABILITY
Short telomere syndromes
• Dyskeratosis congenita
• Mucocutaneous triad
• Nail dystrophy
• Oral leukoplakia
• Skin pigmentation abnormalities
• Bone Marrow failure
• Lung fibrosis
• Predisposition to malignancy
Short telomere syndromes
• Deficiencies in the specialised polymerase, Telomerase is found in the majority of
cases
• Telomerase is a multiunit holoenzyme made up of Telomerase Reverse Transcriptase
(TERT), Telomerase RNA component (TERC) and Dyskerin.
• Deficiencies in the helicase RTEL1 is also found in a minority of cases of DC
• RTEL1 catalyses the unfolding of the T-loop so that the telomere can be elongated.
Enzyme deficiencies causing Aplastic
Anaemia
• Fanconi Anaemia
• Inherited bone marrow failure syndrome caused by defective DNA break repair mechanisms
• Other congenital anomalies
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Typical facies
Short stature
Café-au-lait
Radial ray abnormalities
Renal
Cardiac
Predisposition to cancer
Fanconi Anaemia
Conclusion
• Enzymes are essential for function of all haematopoietic cell lineages
• Defects in enzymes can lead to a large variety of haematological conditions
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Haemolytic anaemias
Bleeding disorders
Neutropenia
Bone marrow failure
• Treatment is mostly supportive, with bone marrow transplantation able to cure
defect in more severe cases.