Metabolic Disease Flashcards
what is a metabolic disease?
any disruption of the ability of the cell to perform critical biochemical reactions involved in the processes of converting food to energy on a cellular level (ex. metabolism)
metabolic disease can involve
the processing, transport or absorption of proteins (amino acids), carbohydrates (sugars and stretches), or lipids (fatty acids)
thousands of enzymes participate is dozens of
interdependent metabolic pahtways
is metabolic disease heritable?
typically yes
level of robustness with “feedback” mechanisms to help regulate
pathway activities
variable in presentation, in many cases only appearing when the body is
stressed
many affect (3)
bone, mineralized tissue, cartilage
impact on maxillofacial complex can be variable and affect all stages of life
infant, reflecting an impact on the embryo/fetus
adolescence
adult
influencing factors include (8)
genetics nutrition gender age environment cultural occupation other diseases/co-morbidities
in severe cases, — — is done
prenatal screening
newborn metabolic screening (non standardized) in all states allows for
early treatment or dietary intervention to prevent/manage/delay symptoms
examples of newborn metabolic screening (non standardized) in all states (5)
PKU, hypothyroidism, galactosemia, sickle cell disease, CF
glycoslyation
process by which sugar trees (glycans) are created, altered and chemically attached to certain proteins or fats (lipids)
one of the major post translational modifications
glycoslylation
CDG
congenital disorders of glycolsylation
~— subtypes of CDG
130
CDG is characterized by variably dysmorphic features such as
Prominent forehead, dysplastic ears and large ear lobules, thin upper lip, long philtrum, prominent jaw (develops with age as mandible can start as retrognathic), narrow/short palpebral fissures, prominent nose and anteverted nares, high-arched palate, long and slender fingers and toes, peau d’orange (skin of an orange), strabismus, inverted nipples, abnormal fat distribution, cardiac defects, liver and bile duct abnormalities, urogenital malformations
simple monosaccharide modifications of
nuclear transcription factors
complex branched polysaccharides (GAGs) on
cell surface receptors
what does protein glycosylation impact?
protein folding, distribution, stability and activity
the pattern of glycoslation is often
cell type specific
due to differential expression of the genes encoding the
respective enzymes
large variation in pattern because of the difference in
sugar moieties added
N linked glycosylation
efers to amide bond (beta-conformation) formed between GlcNAc (acetylglucosamine) and the amino acid,Asparagine (Asn:N), in a protein.Occurs within the endoplasmic reticulum (ER).▸O-linked
O linked glycosylation
carbohydrates bound to a protein backbone through hydroxyl residues (eg. on Ser, Thr, Tyr). Occurs mostly in ER & Golgi.
mutations in any of the 12 genes responsible for O linked glycoslation all lead to a similar
phenotype
mutations in each gene required for N linked glycolylation do not all give the same phenotype rather, they
group in clusters
distinct clustering of phenotypes is dependent on
defective enzyme in the process of assembly
clinical presentation is partly dictated by the specific function of the
polysaccharide configuration
Face2Gene technology
assessment of craniofacial dysmorphic features (pattern recognition)
what do you input into Face2Gene?
facial frontal photos from 50 unaffected controls and 18 from patients with confirmed PMM2-CDG (most common form)
If a CDG suspected (based on symptoms, patient history and clinical evaluation), testing options include (4)
Simple blood test to analyze the glycosylation status of transferrin (a circulating glycoprotein essential for iron transport)
Electrospray ionization-mass spectrometry can also be used to detect abnormal transferrin - more specific (subtype detection)
Enzyme activity assay for some subtypes
Molecular genetic testing is needed for confirmation.
isoelectric focusing (IEF)
separate molecules such as proteins or enzymes based upon their electrical charge
glycosaminoclgycans (GAGs)
A family of highly sulfated, complex linear polysaccharides(typically of repeating polysaccharide units) having a variety of biological roles
what are the roles of GAGs (4)
Heparin/heparan sulfate
Chondroitin sulfate/dermatan sulfate
Keratan sulfate
Hyaluronan
GAGs can bind as much as —-x their weight in water
1000x
up to – sugars linked to protein (proteoglycan) in the ER and Golgi
80
subsequently — in the Golgi, further modulating properties of the protein
sulfated
what GAG is the exception?
Hyaluronan
hyaluronan
non-sulfated, free (not protein-linked) poly-saccharide synthesized at the plasma membrane
purpose of extracellular gel (2)
tensile strength and elasticity
resists compressive force
the diverse structural properties of GAGs are critical for (3)
modulating receptor / ligand binding, affecting cell function & tissue morphogenesis
MPS
mucopolysaccharidoses
how many MPS disorders are there
7
MPS is the deficiency in
1 of the 11 enzymes involved in the breakdown of GAGs
overall prevalence of MPS
1.9-4.5 per 100,000 live births
MPS is characterized by
lysosomal storage of GAGs
The progressive accumulation of GAGs results in (5)
skeletal deformities poor joint mobility severe growth deficit coarse facial features enlarged organs
MPS 1 (hurler syndrome) and MPS 2 (hunter syndrome)
Gingival hyperplasia, delayed tooth eruption, malocclusion, mandibular dysplasia, radiolucent lesions in the jaws, and condylar defects
MPS 3 (sanfillippo syndrome)
Obliteration of pulp chambers and irregular root canals
MPS 4 (mosquito syndrome)
Enamel defects (1 ̊ & 2 ̊ dentition), with generalized loss of tooth structure
MPS 6 (marateaux-lamy syndrome
Multiple dentigerous cysts, macroglossia, fibrous gingival hyperplasia, generalized bone rarefactions, expanded marrow spaces, cortical wear, osteosclerosis, root resorption, demineralization of the symphysis region, impairment of TMJ, impacted teeth, and morphologic alterations in nasal cavity and maxillary sinuses.
MPS1 and 2 are
lysosomal storage disorders
MPS 1, MPS 2, and smith-lemi opitz syndrome are
metabolic disorders
smith-lemi opitz syndrome
disorder of cholesterol metabolism
smith-lemi opitz syndrome is caused by a mutation in the
DHCR7 gene
DHCR7 gene encodes for
dehydrocholesterol delta reductase
smith-lemi opitz syndrome and cholesterol levels
high cholesterol precursors, low cholesterol
functions of cholesterol (5)
cell membranes myelin (axonal) bile acids steroid hormones SHH signaling
symptoms associated with smith-lemi opitz syndrome (7)
Multiple anomalies (cardiac, urogenital, digit, renal, pulmonary), dysmorphic face, growth deficiency, mental retardation, including autism, epilepsy, aggression, self-mutilation
dental symptoms associated with smith-lemi opitz syndrome
crowded teeth, widely spaced incisors, oligodontia, polydontia, premature tooth eruption, enamel hypoplasia, bifid uvula, broad alveolar ridges, bifid tongue, and Pierre-Robin sequence (glossoptosis, retrognathia and cleft palate) (Rojare et al 2019)
early detection may improve
patient outcomes, as cholesterol supplementation can improve symptoms
Metabolic diseases can have significant impact on the
maxillofacial complex at all ages (embryonic and postnatal)
Important to recognize early as treatments and/or dietary modulations may have a
profound effect on the individual in the long term
Dentists can be at the forefront of recognizing such diseases because of
dental involvement
