Metabolic Disease & the Maxillofacial Complex Flashcards
What is metabolic disease?
any disruption of the ability to the cell to perform critical biochemical reactions involved in the converting food to energy on a cellular level
Thousands of enzymes participate in dozens of _________ metabolic pathways
interdependent
Are metabolic disease heritable?
typically yes
Do all metabolic diseases present the same?
no, they differ and in some cases appear only when the body is stressed
What is typically affected by metabolic disease?
bone/mineralized tissue and cartilage
what stages of life are affected by metabolic disease?
all!
infancy–> reflects an impact on embryo/fetus
adolescence–> hormonal influence
adult–> can be due to lifestyle
What are some factors that can influence metabolic disease?
genetics, nutrition, gender, age, environment, cultural, occupation, and other diseases/co-morbidities
how do genetics influence metabolic disease?
genes encode for the enzymes that regulate the pathways
how does nutrition influence metabolic disease?
vitamins form precursors to metabolic pathways
What are some of the things that can be screened for in newborn screening?
Phenylketonuria (PKU), hypothyroidism, galactosemia, sickle cell disease, and cystic fibrosis
What is a benefit for newborn screening?
allow for early treatment or dietary intervention to prevent/manage/delay symptoms
What is protein glycosylation?
sugar trees (glycans) are created, altered, and chemically attached to certain proteins or fats
-one of the major post-translational modification
-impacts protein folding, distribution, stability, and activity
How many genes are in the human genome?
20,000-25,000
How many tRNAs can be made with modifications?
over 100,000
*due to large variability in pattern of glycosylation
What are 5 types of protein glycosylation?
N-glycosylation**
O-glycosylation**
Glypiation
C-glycosylation
Phosphoglycosylation
What determines the pattern of glycosylation?
the cell type or tissue type
Why does glycosylation change based on the tissue type?
Different genes are active in different tissues
N-linked glycosylation
amide bond formed between N-acetylglucosamine and the Asparagine (N)
*typically see attached to two blue boxes
Where does N-linked glycosylation occur?
endoplasmic reticulum
O-linked glycosylation
carbs bind to protein backbone by N-acetylgalactosamine and the free hydroxy residue on serine, threonine, and tyrosine on the protein
Where does O-linked glycosylation occur?
ER and golgi
How many congenital disorders of glycosylation (CDG) are there?
around 130
What are some of the dysmorphic features of CDGs?
prominent forehead, dysplastic ears, thin upper lip, long philtrum, and prominent jaw
How many genes are responsible for O-linked glycosylation?
12 genes
Do all mutations in N-glycosylation present the same phenotype?
No, disorders shown will differ based on where the mutation occurs and what sugars are added in what order
*group in clusters
Do all mutations in O-glycosylation present the same phenotype?
yes- similar phenotypes
What is a new tool that has been able to use to try and determine is there metabolic diseases?
AI has been used to scan and compare features of different diseases to see the possibility of having the disease
-not a diagnostic tool, but can give good insight
What does the PMM2 gene encode for?
enzyme that generates mannose-1-phosphate from mannose-6-phosphate
-creates a sugar that can be added
What are some possible clinical testing for CDG?
-simple blood test
-isoelectric focusing: separate molecules based upon electrical charge
-electrospray ionization-mass spectrometry
-enzyme activity assay
-molecular genetic testing
simple blood test for CDGs
analyzes the glycosylation status of transferrin (normally heavily glycosylated)
What are glycosaminoglycans? (GAGs)
highly sulfated, complex linear polysaccharides
have repeating disaccharide units
What are some examples of GAGs?
heparan sulfate, chondroitin sulfate, dermatan sulfate, keratan sulfate, and hyaluronan (hyaluronic acid)
how do GAGs differ?
have different repeating disaccharide combinations
How much water can GAGs bind to?
1000x their weight
Where are GAGs sulfonated?
in the golgi
Which GAG is not sulfated?
hyaluronan
what is the function of GAGs extracellularly?
form extracellular “gel” which gives the extracellular matrix:
-tensile strength and elasticity
-resist compressive force
Roles of GAGs:
strutural properties are critical for modulating receptor/ligand binding, affecting cell function and tissue morphogenesis
-determine how cells respond to growth factors and extracellular stress
What are mucopolysaccharidoses?
-group of 7 disorders
-deficiency in 1 of 11 enzymes involved with the breakdown of GAGs
-causes excessive lysosomal storage of GAGs
Prevalence of MPS
1.9-4.5 of 100,000 live births
*very rare
What do MPSs cause?
over accumulation of GAGs
-result in skeletal abnormalities, poor joint mobility, severe growth deficit, coarse facial features, and enlarge organs
MPSs have _____ features, but _______ variability
common; inter-individual
MPS I and MPS II (Hurlers syndrome)
gingival hyperplasia, delayed tooth eruption, malocclusion, mandicular dysplasia, radiolucent lesion in the jaw, and condylar defects
MPS III (sanfilippo syndrome)
obliteration of pulp chambers and irregular root canals
MPS IV (Morquio syndrome)
enamel defects with generalized loss of tooth structure
MPS VI (Marateaux-Lamy syndrome)
multiple dentigerous cysts, macroglossia, fibrous gingival hyperplasia, generalized bone rarefractions, expanded marrow spaces, cortical wear, impairment of TMJ, impacted teeth, and morphological alterations in nasal cavity and maxillary sinuses
Smith-Lemli-Optitz syndrome
disorder of cholesterol metabolism
-mutation in DHCR7 gene
-one of the final steps in cholesterol formation
-mental retardation, autism, epilepsy, agression, self-mutilation
-if found early, symptoms can be improved with cholesterol supplementation
Functions of cholesterol:
cell membrane, Myelin, bile acids, steroid hormones, and SHH signaling
