Clinical Correlations Flashcards
Sickle cell anemia
Individuals with sickle-cell anemia. the Hb content of their blood is about half the normal value, resulting in a chronic short supply of red blood cells and anemia. Caused by a single mutation at the 6th position of the Hb beta chain from Glu to Val (exchange of a surface hydrophillic aa for a hydrophobic one. HbS polymerizes into fibers that change the shape of the RBC and blocks blood capillaries when oxygen levels are low.
The information regarding pKa of a molecule is important in predicting the molecule’s solubility in aqueous environment. Why?
The solubility of a molecule in aqueous phase will increase if the molecule is more polar and thus increases its interaction with water molecules. (ie polar and/or charged molecules will be more soluble in water) (need to look at pKa of molecule, and usually look at the pH in the environment it is)
The information regarding pKa of a molecule is important in predicting its absorption via biological membranes. Why?
The absorption or membrane permeability of a molecule via diffusion will only be possible if the molecule is able to cross through a non-polar environment, ie. only non-polar and small uncharged molecules will be able to diffuse through membranes.
If a person has a disorder in which he cannot absorb galactose, why may he be fine?
Galactose is a C4 epimer to glucose, and we have an enzyme called C4 epimerase. although the patient may not be able to absorb galactose, he can make galactose from glucose
Clinical notes on glycation
the increased level of glycation on a protein is typically associated with a decreased function of the protein; it in chronic hyperglycemia seen in poorly controlled diabetes results in increased levels of glycation on vascular tissues which are strongly suggested to be the cause of kidney damage, and peripheral vascular and cardiovascular insufficiency.
Refsum disease
Refsum disease is caused
by a deficiency in alpha-hydroxylase.
pathology: accumulation of phytanic acid
in the plasma and tissues, causing neuronal Treatment: a diet low in phytanic acid and the phytanic acid precursor
Congenital Disorders of Glycosylation (CDG)
Defects in the glycosylation pathway lead to aberrant glycolcalyces on the cell membrane proteins. CDG type I occurs as a result of missing oligosaccharide chains while CDG type II is characterized by abnormal oligosaccharide chains. CDGs manifest as developmental disorders, autoimmune diseases, sporadic cancers, and metabolic stress
sphingolipidoses
In addition to Niemann-Pick disease, the other main members of this group are, Fabry disease, Krabbe disease, Gaucher disease, Tay-Sachs disease and Metachromatic leukodystrophy. They are generally inherited in an autosomal recessive fashion, but Fabry disease is notably X-linked. Altogether, sphingolipidoses have an incidence of approximately 1 in 10,000, but substantially more in certain populations such as Ashkenazi Jews. Enzyme replacement therapy is available for treating Fabry disease and Gaucher disease, and people with these types of sphingolipidoses may live well into adulthood. The infantile forms of sphingolipidoses are generally fatal by age 1 to 5 years, but progression may be mild for juvenile- or adult-onset forms.
Niemann-Pick Disease
Sphingomyelin can accumulate in a rare hereditary disease called Niemann-Pick Disease (types A and B). It is a genetically-inherited disease caused by a deficiency in the enzyme sphingomyelinase, which results in the accumulation of sphingomyelin in the spleen, liver, lungs, bone marrow, and brain, causing irreversible neurological damage. Of the two types involving sphingomyelinase, type A occurs in infants. It is characterized by jaundice, an enlarged liver, and profound brain damage. Children with this type rarely live beyond 18 months. Type B involves an enlarged liver and spleen, which usually occurs in the pre-teen years. The brain is not affected. Most type B patients present with <1% normal levels of the enzyme in comparison to normal levels. Nieman-Pick type C is associated with a different mutation, and manifests as a buildup of cholesterol and glycolipids in liver, spleen and neural cells.
Multiple Sclerosis (MS)
The myelin sheath, which insulates nerve cell axons, is rich in both sphingomyelin and galactocerebrosides. In multiple sclerosis (MS), an autoimmune response leads to the destruction of the cells which produce myelin. As myelin disappears (demyelinization), nerve cells lose the ability to transmit electrical signals. MS can affect vision, sensation, coordination, movement, and bladder/bowel control. Typically, symptoms initially appear as episodic attacks but may gradually worsen over time.
Epidermolysis bullosa simplex (EBS)
Epidermolysis bullosa simplex (EBS) is caused by mutations in keratin genes resulting in abnormal assembly of keratin filaments in the epidermis. As a result, the skin is highly vulnerable to mechanical injury and even a gentle pressure can rupture its cells, causing the skin to blister. a sheet of epithelial lacking intermediate filaments; under the
mechanical stress, the cell sheet becomes damaged.
Amyotrophic lateral sclerosis (ALS, known as Lou Gehrig’s disease)
Amyotrophic lateral sclerosis (ALS, known as Lou Gehrig’s disease) has been suggested to be result of mutations in neurofilaments. Abnormal accumulation and assembly of neurofilaments cause progressive loss of motor neurons, which in turn leads to muscle atrophy, paralysis, and eventual death. Although the mechanism involved remained to be understood, current research data suggests the involvement of neurofiliaments in pathogenesis of motor neuron disease including ALS.
Kartagener syndrome
Kartagener syndrome – absence of axonemal dynein in flagella and cilia results in their immotility and leads to male sterility and chronic respiratory infection.
I-cell disease
I-cell disease (inclusion body) is caused by
a deficiency of the enzyme (FYI: Phospho Nacetylglucosamine transferase) that modifies the M-6-P moiety to the lysosomal proteins. As a result, lysosomal hydrolases are not marked with the target signal mannose- 6-P. Instead, they are secreted to the outside of the cell. This enzyme deficiency manifests itself by the appearance of huge inclusion bodies in cells and exceptionally high levels of hydrolases in the circulation. The secretion of these hydrolases accounts for the high levels found in the body. I-cell disease primarily affects connective tissue, and patients usually die by the age of 5.
Lysosomal storage diseases
Lysosomal storage diseases comprise a group of more than 50 different genetic diseases. The mostly involve the dysfunction of lysosomal hydrolases, which result in impaired substrate degradation (i.e. accumulation of undegraded substrates in the lysosomes). However, proteins involved in vesicular traffic and the biogenesis of lysosomes have also been shown to cause storage disorder phenotype (such as I-cell disease)
