Membranopathies Flashcards
The lipid bilayer comprises approximately _____% of the membrane mass
50%
Contains unesterified cholesterol and phospholipids in approximately equal amounts, with small amounts of glycolipids and phosphoinositides
TRUE OR FALSE
Mature erythrocytes are unable to synthesize fatty acids, phospholipids, or cholesterol de novo, and they depend on lipid exchange and limited phospholipid repair.
TRUE
Mature erythrocytes are unable to synthesize fatty acids, phospholipids, or cholesterol de novo, and they depend on lipid exchange and limited phospholipid repair.
lt regulates the fluidity of the membrane and is present in both leaflets
Cholesterol
Phospholipids are asymmetrically distributed
Located in the outer leaflet and play a role in plasma lipid exchange and renewal of membrane phospholipids
Phosphatidylcholine and sphingomyelin
choline phospholipids
Location in the lipid bilayer
Red cell antigens (A, B, H, and P): ________
Aminophospholipids: phosphatidylserine and phosphatidylethanolamine: ___________
Red cell antigens (A, B, H, and P): EXTERNAL
Aminophospholipids: phosphatidylserine and phosphatidylethanolamine: INTERNAL
The asymmetric distribution of phospholipids is maintained by a dynamic process involving ________that translocate the aminophospholipids to the inner and outer leaflets, respectively
Flippase (ATP11C) and Floppase enzymes
A missense mutation in the ATP11C gene on the X chromosome causes mild hemolytic anemia.
Asymmetry of the phospholipids is important for the survival of the erythrocyte because exposure of _________on the cell surface, as found in sickle cell disease and thalassemia, has several deleterious consequences
Phosphatidylserine
- It activates the coagulation cascade and may contribute to thromboses;
- it facilitates adhesion to the vascular endothelium;
- it provides a recognition signal for macrophages to phagocytose these cells; and
- it decreases the interaction of skeletal proteins with the bilayer, which destabilizes the membrane.
A calcium-dependent enzyme that mediates ATP-independent bidirectional movement of phospholipids down their concentration gradient and contributes to the maintenance of phosphatidylserine on the inner leaflet of the membrane.
Scramblase (PLSCR1)
Lipid rafts are anchored to ________ and play a role in signaling and invasion of malaria parasites
Associated with several proteins, including stomatin, flotillin-1 and flotillin-2.
Spectrin
2 classifications of membane proteins:
- Integral
- Peripheral
Embedded in the lipid bilayer, functions as transport proteins, receptors, signaling molecules, and carriers of red cell antigens
Require detergents to extract them
Integral or transmembrane proteins
Constitute the membrane skeleton and are loosely attached to the cytoplasmic face of the lipid bilayer and can be extracted by high or low salt concentrations or by high pH
Function either as structural proteins and form part of the membrane skeleton or they serve as linker proteins attaching the skeleton to the bilayer
Peripheral proteins
The most abundant and important erythrocyte transmembrane proteins
- Anion exchanger-1 (AE1)
- Glycophorins (GPs)
Other Integral Membrane Proteins:
* Rh-RhAG group of proteins
* Ion pumps and channels: omatin, aquaporin, glucose transporter-1 (GLUT-1)
* Cation and anion transporters
Encompasses 13 α-helical transmembrane segments and 1 nonhelicalsegment, all connected by hydrophilic loops.
Anion exchanger-1 (AE1)
- The short cytoplasmic tail binds cytosolic carbonic anhydrase II to form a metabolon with the transmembrane domain, enabling the exchange of HCO3− and Cl− anions
- The external surface of the transmembrane domain of AE1 carries several antigens, including Diego, I/i, and Wright blood groups.
- The N-terminal phosphorylated cytoplasmic domain serves as a major hub for protein-protein interactions; serves as the primary anchor of the glycolytic enzymemetabolon.
- Serves as the major attachment site of the membrane to the underlying skeleton through its interaction with ankyrin, which binds to spectrin
Gene ecoding anion exchanger-1 (AE1)
SLC4A1 gene previously known as band 3
The erythroid isoform is controlled by a promoter upstream of exon 1, whereas transcription of the kidney isoform is initiated from a promoter in intron 3
Responsible for most of the external negative charge of red cells glycophorins, which prevents the adherence of cells to each other and the vascular endothelium
Sialic acid
Function as receptors for Plasmodium falciparum, the most virulent malaria parasite
Glycophorins
- Carry a large number of blood group antigens, including MN, SsU, Miltenberger, En(a−), MK, and Gerbich
- GPA interacts with AE1 as part of a macromolecular complex
- GPC associates with protein 4.1R and p55, thereby providing an additional contact site between the membrane and the skeleton.
Plays a critical role in maintaining the shape and integrity of the red cell
Peripheral Membrane Proteins
SAAAP-iiinnnn
spectrin, actin, adducin, ankyrin, proteins 4.1R, 4.2, 4.9, p55
Major proteins of the erythrocyte membrane skeleton which interact in a horizontal plane
Spectrin, actin, proteins 4.1R, 4.2, 4.9, p55, and the adducins
Mediate the vertical attachment of the skeleton to integral membrane proteins in the lipid bilayer
Linker proteins
* Ankyrin
* Protein 4.1R
The primary connecting protein which links β- spectrin to the cytoplasmic domain of AE1, as well as to the Rh/RhAG complex
Ankyrin
Protein 4.1R binds to GPC and AE1, which serves as a secondary attachment site of the skeleton to integral membrane proteins
Major constituent of the erythrocyte membrane skeleton
Spectrin
Provides the red cell with elasticity and durability to withstand the shear stress encountered in the circulation
Other functions:
* Maintain the biconcave disk shape of the red cell
* Regulate the lateral mobility of integral membrane proteins, and
* Provide structural support for the lipid bilayer
Spectrin
Composed of 2 homologous, but structurally distinct, subunits, α and β, encoded by separate genes, SPTA1 and SPTB, respectively
Behaves like a reversible spring, which may contribute to the elasticity of the membrane
Ankyrin
- Bind to AE1 and the Rh–RhAG macromolecular complex
- Encoded by the ANK1 gene
Responsible for binding to the cytoplasmic domains of AE1 and GPC, as well as to p55, thereby linking the skeleton to the lipid bilayer
Protein 4.1R
Encoded by EPB41
Form of protein 4.1R that is predominating in young erythrocytes
Two forms of protein 4.1R, a and b
Protein 4.1b
A member of the transglutaminase family of proteins, but it has no enzyme activity because it lacks the critical triad of residues that form the active transglutaminase site
Protein 4.2
A calcium/calmodulin-binding phosphoprotein located at the spectrin–actin junctional complex
Also bind AE1 and GLUT-1, and thus form part of the macromolecular junctional complex linking the spectrin skeleton to the lipid bilaye
Adducin
A trimeric phosphoprotein that acts as a linker molecule by binding to the transmembrane GLUT-1
Dematin or protein 4.9
Composition of the ankyrin complex
AE1, GPA, Rh, and RhAG complex proteins
Ankyrin, protein 4.2, and several glycolytic enzymes
Composition of the distal junctional complex
AE1, GPC, GLUT-1, Rh, Kell, and XK proteins
Proteins 4.1R, actin, dematin, adducin, tropomyosin, tropomodulin, and p55.5
The membrane skeleton resembles a lattice-like network, with approximately ______% of the lipid bilayer directly laminated to the underlying skeleton
60%
The (horizontal or vertical) protein interactions are important in the maintenance of the structural integrity of the cell, accounting for the high tensile strength of the erythrocyte
Horizontal
The (horizontal or vertical) protein–protein interactions are critical in the stabilization of the lipid bilayer, preventing loss of microvesicles from the cells
Vertical
Average life span of RBCs
120 days
3 features that regulate the deformability of RBCs:
(a) the biconcave disk shape (a high ratio of surface area to cellular volume)
(b) the viscoelastic properties of the membrane (spectrin)
(c) the cytoplasmic viscosity
Characteristic of RBC that provides a high ratio of surface area to cellular volume and this excess of membrane is critical for survival of the cell
Biconcave disk shape
To prevent fragmentation of the membrane and loss of the biconcave disk shape, the structural integrity of the membrane skeleton is critical.
The horizontal interactions of the peripheral proteins of the junctional complex, mainly protein 4.1R and actin, which link the tail ends of the spectrin tetramers together, is a major determinant of membrane stability.
Cytoplasmic viscosity is determined primarily by the ____________
Intracellular hemoglobin concentration
As the mean cell hemoglobin concentration rises above _________, the viscosity increases exponentially
370 g/L
The hemoglobin concentration is critically dependent on red cell volume, which is primarily determined by the ___________
Total cation content of the cell
The red cell membrane maintains a _______ potassium, ________ sodium, and________calcium content within the cell.
High potassium
Low sodium
Very-low calcium
Extrudes 3 sodium ions in exchange for 2 potassium ions entering the red cell
Na+K+ ATPase
Calcium is pumped out of the cell by this channel
Protects the cell from deleterious effects of calcium, such as echinocytosis, membrane vesiculation, calpain activation, membrane proteolysis, and cellular dehydration
Calmodulin-activated Ca2+ ATPase
The Ca2+-activated K+ channel, also called the _____________
It causes selective loss of K+ in response to increased intracellular Ca2+
Gardos channel
Chloride and bicarbonate anions are readily exchanged through ____
AE1
Water is transported by
Aquaporin-1 (AQP1)
Vertical or Horizontal proteins
Result in destabilization of the bilayer, loss of membrane microvesicles and spherocyte formation
Vertical
Vertical or Horizontal proteins
Disrupt the skeleton resulting in defective shape recovery and elliptocytes
Horizontal
The most common cause of HE
and HPP
Functional self-association defect in α-Spectrin
Protein defect that cause “Acanthocytic” spherocytes present on blood film presplenectomy
β-Spectrin
Deficiency of _________ is the most common cause of HS in North America
Ankyrin
Deficiency is the most common cause of HS in parts of Europe and South Africa
“Pincered” spherocytes are common on blood film presplenectomy
AE1
Deficiency primarily found in Japanese patients with HS
Protein 4.2
The most common mutation is protein 4.2 Nippon, and patients may be homozygous for this mutation or compound heterozygotes with a second mutation on the other allele.
Protein defect in Ankyrin and Protein 4.2 cause
HS recessive
The stabilizing effect of the transmembrane section of AE1 on the lipid bilayer is lost, facilitating the formation of AE1-free microvesicles
SAO is caused by defect in what protein
AE1
Defect in this protein cause spiculated cells (acanthocytes and echinocytes) in addition to spherocytes.
Autosomal dominant HS
Beta spectrin
Defect in this protein cause “pincered” spherocytes
AE1
The hallmark of HS erythrocytes
Loss of membrane surface area relative to intracellular volume
TRUE OR FALSE
The spleen plays a secondary, but important, role in the pathophysiology of HS.
TRUE
The spleen plays a secondary, but important, role in the pathophysiology of HS.
Spherocytes are retained and ultimately destroyed in the spleen and this is the primary cause of the chronic hemolysis experienced by HS patients
The degree of splenic retention correlated with the reduction in the surface-area-to-volume ratio.
In approximately 75% of HS patients, inheritance is _________________
Autosomal dominant
Mutations of these genes are associated with recessive HS
α-spectrin or protein 4.2
Approximately _________ of HS patients have moderate disease
60% to 70%
The most frequent finding (50% of cases) of HS among children
No comparable data exist for adults.
Anemia
Followed by splenomegaly, jaundice, or a positive family history
TRUE OR FALSE
Jaundice may be intermittent and is seen in approximately half of patients, usually in association with viral infections
TRUE
Jaundice may be intermittent and is seen in approximately half of patients, usually in association with viral infections
When present, jaundice is acholuric, characterized by unconjugated hyperbilirubinemia without detectable bilirubinuria.
Palpable splenomegaly is evident in most (>_____%) older children and adults.
> 75%
No proven correlation exists between the spleen size and the severity of HS.
Approximately 20% to 30% of HS
Splenomegaly is mild, reticulocyte counts are generally less than 6%, and spherocytes on the blood film may be minimal
Bilirubin 1-2
Inherritance: Autosomal dominant
Mild Hereditary Spherocytosis
Approximately________ of HS patients have moderately severe disease, as evidenced by indicators of anemia that are more pronounced than in typical moderate HS, and an intermittent requirement for transfusions
Bilirubin 2-3
Inherritance: Autosomal dominant; de novo
5% to 10%
A small number (________%) of patients have severe disease with life-threatening anemia and are transfusion dependent.
<5%
- They almost always have recessive HS.
- Most have severe spectrin deficiency; defects in ankyrin or AE1 have also been identified
Characteristics of patients with severe HS
- Recessive HS
- Severe spectrin deficiency (α-spectrin)
- Irregularly contoured or budding spherocytes or bizarre poikilocytes
Most common finding in neonates with HS
Jaundice
It may be accentuated by coinheritance of Gilbert syndrome, caused by homozygosity for a polymorphism in the promoter of the UGT1 gene
Most frequently reported complication in as many as half of HS patients
Bilirubinate gallstones
Coinheritance of Gilbert syndrome markedly increases the risk of gallstone formation.
The most common crisis in HS, which is usually associated with viral illnesses. Generally mild and characterized by jaundice, splenomegaly, anemia, and reticulocytosis
Hemolytic crisis
Others:
Aplastic crises
Megaloblastic crises
The most common etiologic agent in aplastic crisis
Parvovirus
Aplastic crises usually last for 10–14 days and may bring asymptomatic, undiagnosed HS patients with compensated hemolysis to medical attention
May occur in HS patients with increased folate demands, such as pregnant patients, growing children, or patients recovering from an aplastic crisis
Megaloblastic crises
TRUE OR FALSE
Leg ulcers, chronic dermatitis on the legs and gout are rare manifestations of HS, which usually do not heal even after splenectomy.
FALSE
Leg ulcers, chronic dermatitis on the legs and gout are rare manifestations of HS, which usually heal rapidly after splenectomy.
Most patients have mild to moderate anemia with hemoglobin in the _________range
90–120 g/L
TRUE OR FALSE
Mean corpuscular volume is increased because of relative cellular dehydration in approximately half of patients, but all HS patients have some hydrated cells
FALSE
Mean corpuscular hemoglobin concentration (MCHC) is increased (>36 g/dL) because of relative cellular dehydration in approximately half of patients, but all HS patients have some dehydrated cells
Can be useful as a screening test for HS, especially when combined with an increased red cell distribution width.
TRUE OR FALSE
Mean corpuscular volume (MCV) is usually normal except in cases of severe HS, when MCV is slightly decreased.
TRUE
Mean corpuscular volume (MCV) is usually normal except in cases of severe HS, when MCV is slightly decreased.
Markers of hemolysis
- Reticulocytosis
- Increased lactate dehydrogenase
- Increased urinary and fecal urobilinogen
- Unconjugated hyperbilirubinemia
- Decreased serum haptoglobin
TRUE OR FALSE
Spherocytes typically swell and burst at lower sodium chloride concentrations than do normal biconcave disk-shaped red cells.
FALSE
Spherocytes typically swell and burst at HIGHER sodium chloride concentrations than do normal biconcave disk-shaped red cells.
Tests for hemolysis with poor sensitivity and do not detect all cases of mild HS or those with small numbers of spherocytes, including patients who had recent blood transfusions.
Glycerol lysis test and the acidified glycerol lysis test
- Unreliable and give normal results in the presence of iron deficiency, obstructive jaundice, or, during the recovery phase, of an aplastic crisis
- Do not differentiate HS from other disorders with secondary spherocytosis
A fluorescent dye that binds to the transmembrane proteins, AE1, Rh protein, Rh glycoprotein, and CD47
Eosin 5′-maleimide (EMA)
Expected finding of HS in Eosin 5′-Maleimide Flow Cytometry Test
Decreased fluorescence compared to controls
Also may be observed in patients with HE, HPP, some red cell enzymopathies, and other abnormalities of AE1, such as congenital dyserythropoietic anemia type II (CDAII)
This useful test monitors red cell deformability under a continuous osmotic gradient and a known shear stress, which generates a deformability index profile.
Osmotic Gradient Ektacytometry
Expected finding of HS in Osmotic Gradient Ektacytometry
Decreased maximum deformability index combined with an increased minimum osmotic (Omin) gradient
This test identifies the underlying defective protein after separation of the red cell membrane proteins
Sodium Dodecyl Sulfate Polyacrylamide Gel Electrophoresis SDS-PAGE
TRUE OR FALSE
All the laboratories used at least 2 tests to make a final diagnosis of HS, as none of the currently available methods have 100% sensitivity.
TRUE
All the laboratories used at least 2 tests to make a final diagnosis of HS, as none of the currently available methods have 100% sensitivity.
In neonatal HS, HS ratio (MCHC divided by MCV) of greater than_______has a very high sensitivity and specificity
0.36
The primary determinant of erythrocyte survival in HS patients
Splenic sequestration
TRUE OR FALSE
Postsplenectomy, spherocytosis, and altered osmotic fragility persist, but the “tail” of the osmotic fragility curve, created by conditioning of a subpopulation of spherocytes by the spleen, disappears.
TRUE
Postsplenectomy, spherocytosis, and altered osmotic fragility persist, but the“tail” of the osmotic fragility curve, created by conditioning of a subpopulation of spherocytes by the spleen, disappears.
HS patients candidate for splenectomy
- Transfusion-dependent severe spherocytosis
- Significant signs or symptoms of anemia: growth failure, skeletal changes, leg ulcers, and extramedullary hematopoietic tumors
- patients suffering from vascular compromise of vital organs
Laparoscopic splenectomy has become the method of choice
Because the risk of postsplenectomy sepsis is very high during infancy and early childhood, splenectomy should be delayed until age ______ years if possible and to at least ______years if feasible
5 to 9 years
3 years
Postsplenectomy prophylactic antibiotics
- Penicillin V 125 mg orally twice daily for patients younger than 7 years or
- Penicillin V 250 mg orally twice daily for those older than 7 years, including adults
For at least 5 years postsplenectomy by some and for life by others
Presplenectomy and, in severe cases, post-splenectomy, HS patients should take folic acid (______mg/day orally) to prevent folate deficiency.
Folic acid (1 mg/day orally)
Reasons for splenectomy failure:
- Missed accessory spleen
- Development of splenunculi as a consequence of autotransplantation of splenic tissue during surgery
- Another intrinsic red cell defect, such as pyruvate kinase deficiency
Accessory spleens occur in ____% to ____% of patients and must always be sought.
15% to 40%
Definitive confirmation of ectopic splenic tissue
Radiocolloid liver– spleen scan or
Scan using 51Cr-labeled, heat-damaged red cells
Characterized by the presence of elliptical or oval erythrocytes on the blood films
HEREDITARY ELLIPTOCYTOSIS
The erythrocytes from these patients exhibited increased thermal sensitivity. Seen in patients suffering from severe burns
HEREDITARY PYROPOIKILOCYTOSIS
The primary abnormality in HE erythrocytes
Defective HORIZONTAL interactions between components of the membrane skeleton
The most common defects in HE and HPP
Spectrin
Mutations that affect spectrin heterodimer self-association are found in the majority of HE patients and in all patients with HPP.
This functional defect results in an increased percentage of spectrin dimers relative to tetramers
The primary abnormality in HPP erythrocytes
Combination of HORIZONTAL (impaired spectrin tetramer formation) and VERTICAL (spectrin deficiency) defects
The most important determinants of the severity of hemolysis in HE
Percentage of spectrin dimers and the spectrin content of the membrane skeleton
The most common polymorphism affecting spectrin content and clinical severity
αLELY, the low-expression Lyon α-spectrin allele
HE is typically inherited as an _________ disorder.
Autosomal dominant
TRUE OR FALSE
HPP is an autosomal recessive disorder and a strong genetic relationship exists between HE and HPP, whereby parents or siblings of patients with HPP often have typical HE.
TRUE
HPP is an autosomal recessive disorder and a strong genetic relationship exists between HE and HPP, whereby parents or siblings of patients with HPP often have typical HE.
TRUE OR FALSE (Clinical presentation)
The overwhelming majority of patients with HPP are asymptomatic and are diagnosed incidentally
HE patients present in infancy or early childhood with severe hemolytic anemia
FALSE
The overwhelming majority of patients with HE are asymptomatic and are diagnosed incidentally
HPP patients present in infancy or early childhood with severe hemolytic anemia
Hereditary Elliptocytosis and Pyropoikilocytosis in Infancy
Typically, elliptocytes do not appear on the blood film until the patient is _________
4–6 months old
- These patients may require red cell transfusion, phototherapy, or exchange transfusion.
- Usually, even in severely affected patients, the hemolysis abates between 9 and 12 months of age, and the patient progresses to typical HE with mild anemia.
The hallmark of HE
Presence of cigar-shaped elliptocytes on blood films
TRUE OR FALSE
The degree of hemolysis does not correlate with the number of elliptocytes present.
TRUE
The degree of hemolysis does not correlate with the number of elliptocytes present.
Blood smear features of HPP
Extreme poikilocytosis, some bizarre-shaped cells with fragmentation or budding, and often only very few or no elliptocytes
Microspherocytosis is common and MCV is usually low, ranging between 50 fL and 70 fL.
The thermal instability of erythrocytes, originally reported as diagnostic of HPP, is not unique to this disorder as it is also commonly found in HE erythrocytes.
Prominent cells on blood films of neonates with HPP
Pyknocytes
Causes of acquired elliptocytosis
Megaloblastic anemias, hypochromic microcytic anemias (iron-deficiency anemia and thalassemia), myelodysplastic syndromes, and myelofibrosis
Acquired elliptocytosis generally represents less than _______ of red cells seen on the blood film.
25%
An artifact of blood film preparation and these cells are found only in certain areas of the film, usually near its tail. The long axes of are parallel
Pseudoelliptocytosis
Other name for SOUTH-EAST ASIAN OVALOCYTOSIS
Melanesian elliptocytosis or stomatocytic elliptocytosis
SAO is characterized by the presence of large oval red cells, many of which contain ____________
- 1 or 2 transverse ridges or a longitudinal slit
- At least 20% ovalocytic red cells
- Notable absence of clinical and laboratory evidence of hemolysis
Sturctural abnormality in SAO
AE1(SLC4A1 gene )
Autosomal dominant
Spiculated red cells are classified into 2 types:
A.Acanthocytes
B. Echinocytes
What cell is being described:
Contracted, dense cells with irregular projections from the red cell surface that vary in width and length
Acanthocytes
What cell is being described:
Small, uniform projections spread evenly over the circumference of the red cell
Echinocytes
Normal adults may have as many as____% of spiculated erythrocytes
3%
Conditions where spiculated cells are seen
After transfusion with stored blood
Ingestion of alcohol and certain drugs
Exposure to ionizing radiation or certain venoms
Hemodialysis
Functional or actual splenectomy
Severe liver disease
Severe uremia
Abetalipoproteinemia
Inherited neurologic disorders
Abnormalities of the Kell blood group
Glycolytic enzyme defects
Myelodysplasia
Hypothyroidism
Anorexia nervosa
Vitamin E deficiency
Premature infants
Suppressed expression of Lua and Lub
The anemia in patients with liver disease is often called
Spur-cell anemia
Pathogenesis of spur cell anemia
Accumulation of free (nonesterified) cholesterol in the red cell membrane
Remodeling of abnormally shaped red cells by the spleen
Clinical features of spur cell anemia
Rapidly progressive hemolytic anemia with large numbers of acanthocytes on the blood film
Spur-cell anemia is most common in patients with _______________,
Alcoholic liver disease
TRUE OR FALSE
Splenectomy for spur cell anemia is a dangerous and potentially fatal procedure in these critically ill patients and is recommended
FALSE
Splenectomy is a dangerous and potentially fatal procedure in these critically ill patients and is not recommended
The prognosis for patients with alcoholic liver disease and more than ____% spur cells is very poor.
5%
Only effective treatment option for spur cell anemia
A liver transplant combined with alcohol abstinence
Common features are a degeneration of neurons and abnormal acanthocytic erythrocyte morphology
NEUROACANTHOCYTOSIS
Types of neuroacanthocytosis syndromes:
(a) lipoprotein abnormalities (abetalipoproteinemia and hypobetalipoproteinemia)
(b) neural degeneration of the basal ganglia (chorea-acanthocytosis and McLeod syndrome)
(c) movement abnormalities (Huntington disease-like 2 (HDL2) and pantothenate kinase-associated neurodegeneration)
Very rare autosomal recessive disorder characterized by progressive ataxic neurologic disease, malabsorption of dietary fat and lipid-soluble vitamins (A, D, E, and K), retinal degradation, and acanthocytosis
Absent or extremely low low-density lipoprotein cholesterol, triglyceride, and apoB levels.
Abetalipoproteinemia / Bassen-Kornzweig syndrome
The primary molecular defect in abetalipoproteinemia
Lack of the microsomal triglyceride transfer protein (MTTP)
An essential cofactor for the assembly and secretion of lipoprotein particles that contain apolipoprotein B (apoB)
The altered plasma lipid profile affects in Abetalipoproteinemia: phosphatidylcholine content is __________ with a corresponding ___________ in sphingomyelin.
Phosphatidylcholine: decreased
Sphingomyelin: increased
Primary cause of the neuropathy in Abetalipoproteinemia
Marked vitamin E deficiency
Coagulopathy related to vitamin K deficiency may be observed.
Therapy for Abetalipoproteinemia
Lifelong treatment with a low-fat diet and supplementation with high oral doses of vitamins A, K, D, and E
Do not survive beyond the third decade of life.
Rare autosomal-recessive movement disorder characterized by atrophy of the basal ganglia and progressive neurodegenerative disease with onset in adolescence or early adult life.
The lipoproteins are normal.
Patients are not anemic, and red cell survival is only slightly decreased.
Chorea-Acanthocytosis Syndrome
Causative gene in Chorea-Acanthocytosis Syndrome
VPS13A (vacuolar protein sorting 13 homologue A) codes for chorein
Expression of _________ is restricted to the brain and hematopoietic tissues, which corresponds to the main areas of pathology in chorea-acanthocytosis patients.
β-adducin
Rare X-linked disorder of the Kell blood group system, whereby cells react poorly with Kell antisera, with cardiomyopathy
McLeod Syndrome
Causative gene in McLeod Syndrome
XK protein
Rare disorder caused by expanded CGT/CAG trinucleotide repeats in exon 2A of the Junctophilin-3 (JPH3) gene on chromosome 16q24.3
Features encompass involuntary movements, neuropsychiatric symptoms, and cognitive defect; autosomal dominant and Africa ancestry
No anemia and acanthocytes (>30%
Autosomal dominant
HDL2
Characterized by progressive dystonia, and cognitive impairment in childhood, but no anemia
Mutations in the PANK2 gene on chromosome 20p.13 coding for pantothenate kinase 2
Pantothenate kinase-associated neurodegeneration (Hallervorden-Spatz syndrome)
Cup-shaped red cells characterized by a central hemoglobin-free area
Stomatocytes
Cells which are formed when there is net loss of cations dehydrates the cells
Xerocytes
Causative genes in:
Over-hydration syndromes:
Dehydration syndromes:
Over-hydration syndromes: RHAG, SLC4A1, and GLUT1
Dehydration syndromes: PIEZO1 and KCNN4
The most common form of the cation permeability defects.
Characterized by an efflux of K+
May also exhibit pseudohyperkalemia and perinatal edema
Strong tendency to iron overload regardless of transfusion history
Hereditary xerocytosis, also known as dehydrated hereditary stomatocytosis
Defective gene in Hereditary xerocytosis
PIEZO1
KCNN4 (minority): Gardos channel, a calcium-activated K+ channel
Bigyan ng Piezo KC XerO
Laboratory Features of Hereditary xerocytosis
- Mild to moderate compensated hemolytic anemia with an elevated reticulocyte count
- K+ content is decreased and the Na+ content is increased, but the total monovalent cation content may be slightly reduced
- MCHC is increased
- Erythrocytes are resistant to osmotic lysis and the osmotic gradient ektacytometry curve is shifted to the left
- Stomatocytes are not a prominent feature on blood films, but occasional target cells are seen
- Hemoglobin is concentrated (“puddled”) in discrete areas on the cell periphery
TRUE OR FALSE
Splenectomy does not significantly improve the anemia in Hereditary Xerocytosis
TRUE
Splenectomy does not significantly improve the anemia, which suggests that xerocytes are detected and eliminated in other areas of the reticuloendothelial system.
Markedly high risk of hypercoagulability and life-threatening thrombotic episodes after splenectomy, the procedure is contraindicated
Very rare heterogeneous disorder characterized by a marked passive sodium leak, which increases the water content of the cell and causes macrocytosis
OVERHYDRATED HEREDITARY STOMATOCYTOSIS
Pathogenesis of Hereditary hydrocytosis
Lack of stomatin
Less often, very low levels of this 31-kDa integral membrane protein
Gene mutations associated with Hereditary hydrocytosis
NO gene mutations have been found, which implies that the absence of the protein is a secondary phenomenon.
RhAG
SLC4A1
Exhibits as mild cation leak that is markedly enhanced at low temperatures
Associated with mild to moderate hemolytic anemia, and splenectomy appears to have little or no effect
Cryohydrocytosis
Gene mutations associated with Cryohydrocytosis
GLUT1 gene
Exercise GLUTs u’ll CRY
Are very rare cases where the clinical phenotype and biochemical features of some patients with stomatocytes are intermediate between the extremes of hereditary hydrocytosis and hereditary xerocytosis.
Intermediate syndromes
Mutations have been noted in the PIEZO1 gene, but the defect is unknown in other instances.
A rare condition that leads to accumulation of cholesteryl esters in many tissues, resulting in clinical findings of large orange tonsils and hepatosplenomegaly.
Familial deficiency of high-density lipoproteins
Causes of scquired stomatocytosis
- Acute alcoholism
- Vinca alkaloids
- Long-distance runners immediately after a race
The molecular basis of acquired stomato-cytosis is unknown.
