Glycobiology in Human Disease II Flashcards
Patients with Mucopolysaccharidoses suffer from
Skeletal and extracellular matrix deformities
Clinical diagnosis of a mucopolysaccharidosis is confirmed by measuring the patient’s levels of
Lysosomal hydrolases
The mucopolysaccharidoses are hereditary diseases caused by a deficiency of any one of the lysosomal hydrolases normally involved in the degradation of
Heparin sulfate and/or Dermatan sulfate
Progressive disorders characterized by accumulation of glycosaminoglycans in various tissues, causing a range of symptoms, such as skeletal and extracellular matrix deformities, and mental retardation
Mucopolysaccharidoses
Children who are homozygous for any one of these diseases are apparently normal at birth, and then
Gradually deteriorate
All mucopolysaccharidoses are autosomal recessive diseases except
Hunter Syndrome (X-linked)
Incomplete lysosomal degradation of glycosaminoglycans results in the presence of oligosaccharides in the
Urine
These fragments can be used to diagnose the specific mucopolysaccharidosis by identifying the structure present on the nonreducing end of the
Oligosaccharide
That is because the residue at the nonreducing end would have been the substrate for the
Missing enzyme
Bone marrow and cord blood transplants have been used to treat
Hurler and Hunter syndromes
Caused by a defect in alpha-L-iduronidase
-an inherited autosomal recessive disorder
Hurler syndrome
Characteristic features of this disease including coarsening of the facial features, corneal clouding, and hepatosplenomegaly appear around age 2 in affected individuals
Hurler syndrome
Due to thickening of respiratory secretions, individuals with Hurler syndrome are prone to
Recurrent infections
Patients with Hurler syndrome have a markedly shortened lifespan, often dying before the age of
10
Caused by a defect in iduronate sulfatase
Hunter Syndrome
In contrast to Hurler syndrome, Hunter syndrome is inherited in an
X-linked recessive pattern
Additionally, Hunter syndrome typically occurs
Later in life
Additionally, Hunter syndrome typically occurs later in life that Hurler syndrome and does not have the cardinal feature of
Corneal clouding
Has the key features of intellectual disability, coarse facial features, and short stature
Hunter Syndrome
Results from failure of the body to be able to cleave the alpha 1,4 linkage
Pompe Disease
The defective degradation of glycogen in the lysosomes seen in Pompe disease is caused by the lack of which enzyme?
Lysosomal acid alpha-glucosidase (acid maltase)
The classic infantile form of Pompe disease causes
Cardiomegaly, hypotonia, hepatomegaly, and death before 2 due to cardiorespiratory failure
A heterogeneous group of molecules that are hydrophobic
Lipids
Allow for fats to be transported both extracellularly and intracellularly
Lipoproteins
The main constituent of body fat in the human body
TAGs
Serve as a major source of energy for the body
Lipids
Lipids can be classified as either
-Depending on their structural backbone
Glycerolipids or Sphingolipids
The major consitituents of all cell membranes
Glycerophospholipids
Serve to help anchor proteins in the membrane and can play a role in intracellular signaling (e.g., epinephrine activates phospholipase –C)
Glycerophospholipids
Other unique functions of glycerophospholipids include playing a role in the composition of
Bile, lipoproteins, and lung surfactant
What are the three most abundant glycerophospholipids?
-primary function is structural role in membranes
Phosphatidylethanolamine, phosphatidylcholine, and phosphatidylserine
Glycerophospholipids are synthesized in all cells except for
Mature erythrocytes
Synthesized in the smooth ER and transported to the Golgi body to be sent to membranes or secreted
Glycerophospholipids
This compound can be synthesized de novo from preexisting choline; however, this de novo synthesis is not sufficient for our body’s needs
Phosphatidylcholine (Lecithin)
Can be obtained as an essential dietary nutrient in foods such as fish, eggs, broccoli, peanut butter, and milk chocolate
Phosphatidylcholine (Lecithin)
Serves as a structural component of membranes, a mild detergent in bile, and as part of a surfactant in the small alveoli of the lungs
Lecithin
Impaired production of lecithin can allow for solubilization of hydrophobic compounds in bile, leading to
Gallstones
Inadequate production of lecithin allows for alveoli to collapse in the lungs due to too much
Surface tension
This collapse is commonly seen in premature infants who are born before there is enough
Lecithin produced
Inadequate production of lecithin allows for alveoli to collapse, this is referred to as
Respiratory distress syndrome
Exogenous administration of cortisol to a mother can help increase
Surfactant (Lecithin) production
Used to assess for adequate levels of surfactant
-Can be obtained by amniocentesis
Lecithin : Sphingomyelin ratio (L:S)
What is an adequate L:S?
Greater than 2
What L:S value indicates risk for respiratory distress?
Less than 1.5
Serves as the structural backbone of sphingolipids
Sphingosine
An example of a sphingophospholipids in the body that plays an integral role in the nervous system
Sphingomyelin
As evidenced by its name, sphingomyelin is an important component of the myelin nerve fibers that allow for quick conduction of
Electrical signals
The immediate precursor to sphingomyelin is
Ceramide
Catalyzes the breakdown of sphingomyelin into ceramide and phosphatidylcholine
Sphingomyelinase
Catalyzes the breakdown of ceramide into sphingosine and FFA
Ceramidase
If there is a deficiency of the enzyme sphingomyelinase. As a result, sphingomyelin will build up at toxic levels resulting in a clinical syndrome manifested by
Severe neurological damage, liver enlargement, and premature death
Deficiency of the enzyme sphingomyelinase. As a result, sphingomyelin will build up at toxic levels resulting in a clinical syndrome manifested by severe neurological damage, liver enlargement, and premature death
Niemann-Pick disease
Very severe disease with <1% sphingomyelinase activity
-more frequent in Ashkenazi Jewish population, death during infanthood
Type A Neimann Pick
Less severe form of the disease with 5% or more sphingomyelinase activity
-Life extended to adulthood
Type B Neimann Pick
A type of sphingolipid that contains both carbohydrates and lipids
Glycolipid
A key component in the production of glycolipids
Ceramide
Can be combined with UDP-sugars to form various glycolipid precursors
Ceramide
The degradation of glycolipids follows the classic format of
Last on, first off
A type of lipid molecule that function to provide stability and protection to the plasma membrane lipid bilayer
Sphingolipids
In a normal individual, synthesis and degradation of glycosphingolipids are balanced, so that the amount of these compounds present in membranes is
Constant
Sphingolipidoses typically have an effect on
-due to accumulation of toxic biochemical entities
Neuronal function
A specific lysosomal hydrolytic enzyme is deficient in each
Sphingolipidoses
Each sphingolipidoses is characterized by the accumulation of a single
-Dependent on which enzyme is deficient
Sphingolipid
The disorders are progressive and, although many are fatal in childhood, extensive phenotypic variability is seen leading to the designation of different clinical types
Sphingolipidoses
The sphingolipidoses are autosomal recessive diseases, except for
Fabry disease (X-linked)
The incidence of the sphingolipidoses is low in most populations, except for
-Like Niemann-Pick disease, show a high frequency in the Ashkenazi Jewish population
Gaucher and Tay-Sachs diseases
A specific sphingolipidosis can be diagnosed by measuring enzyme activity in cultured fibroblasts or peripheral leukocytes, or by analysis of
DNA
Shell-like inclusion bodies are seen in histological examination of
Tay-Sachs
A wrinkled tissue paper appearance of the cytosol is seen in
Gaucher disease
In Gaucher disease, macrophages become engorged with
Glucocerebroside
Globosides accumulate in the vascular endothelial lysosomes of the brain, heart, kidneys, and skin in
Fabry Disease
Treated by recombinant human enzyme replacement therapy
Gaucher and Fabry disease
Has also been treated by bone marrow transplantation, and by substrate reduction therapy through pharmacological reduction of glucosylceramide, the substrate for the deficient enzyme
Gaucher DIsease
This disease state is commonly found in Jewish populations of Eastern European decent
Tay-Sachs
The pathogenesis of Tay-Sachs involves an accumulation of ganglionucleosides secondary to a deficient enzyme important for normal breakdown. The deficient enzyme is
B-Hexosaminidase A
A lack of this important enzyme in the breakdown pathway leads to an accumulation of toxic
Gangliosides
This accumulation of gangliosides results in the progressive deterioration of
Nerve Cells
Over time, patients develop progressive neurological dysfunction including poor muscle tone, seizures, nystagmus, ataxia, hyperreflexia, pathological reflexes, and loss of vision
Tay-Sachs
A “cherry-red spot” (although not diagnostic) can be seen on eye examination with
Tay-Sachs
This disease state is a group of inherited metabolic disorders characterized by an autosomal recessive pattern
Niemann-Pick Disease
The disease involves defective breakdown of sphingolipids resulting in toxic accumulations of sphingomyelin
Niemann-Pick Disease
Sphingomyelin is a component of the cell membrane that is typically broken down in
Lysosomes
Sphingomyelin accumulates in lysosomes when we are missing the enzyme
Sphingomyelinase
Characterized by cells with a “foamy” appearance, due to the accumulation of lipids (fat) within the lysosome
Niemann-Pick Disease
In Niemann-Pick disease, sphingomyelin buildup is especially prominant in macrophages in the
Spleen and liver (results in hepatosplenomegaly)
Many of the neurological findings in Niemann-Pick disease are similar to those of
Tay-Sachs
Also shows the cherry-red spot
Niemann-Pick disease
The prototype of macrophage storage disorder is
Gaucher disease
An autosomal recessive disease caused by a deficiency in glucocerebrocidase
Gaucher disease
Tissues most affected by Gaucher disease are those whose lysosomes store the
Glucocerebroside
Lysosomes are critical to the function of
Macrophages
Bone marrow, the liver, lungs, spleen, and brain are affected by
Gaucher disease
Also affected by Gaucher disease since lysosome activity is critical to their function
-bone cells
Osteoclasts
Symptoms include hepatosplenomegaly, pancytopenia, severe pain in bones and joints (particularly in the hips and knees), osteoporosis, avascular necrosis of bones, and potential neurological dysfunction
Gaucher Disease
Diagnosis can be made with measurement of glucocerebrosidase activity in peripheral leukocytes
Gaucher disease
Treatment for Gaucher disease is available with
Intravenous recombinant glucocerebrosidase
Yet another rare, autosomal recessive neurodegenerative disorder. The hallmark features involve myelin loss and the presence of globoid bodies within the white matter
Krabbe Disease
The structural changes seen in Krabbe disease occur due to an inherited deficiency of the lysosomal enzyme
B-galactocerebrosidase
Without this enzyme, the body cannot break down myelin successfully, which gives rise to a host of neurological symptoms
B-galactocerebrosidase
From gross neurological deficits to optic atrophy, there is no single presentation of
Krabbe Disease
