Metabolic Disease

Question 1

what is a metabolic disease?

Answer 1

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)

Question 2

metabolic disease can involve

Answer 2

the processing, transport or absorption of proteins (amino acids), carbohydrates (sugars and stretches), or lipids (fatty acids)

Question 3

thousands of enzymes participate is dozens of

Answer 3

interdependent metabolic pahtways

Question 4

is metabolic disease heritable?

Answer 4

typically yes

Question 5

level of robustness with “feedback” mechanisms to help regulate

Answer 5

pathway activities

Question 6

variable in presentation, in many cases only appearing when the body is

Answer 6

stressed

Question 7

many affect (3)

Answer 7

bone, mineralized tissue, cartilage

Question 8

impact on maxillofacial complex can be variable and affect all stages of life

Answer 8

infant, reflecting an impact on the embryo/fetus
adolescence
adult

Question 9

influencing factors include (8)

Answer 9

genetics 
nutrition
gender 
age
environment 
cultural
occupation
other diseases/co-morbidities

Question 10

in severe cases, — — is done

Answer 10

prenatal screening

Question 11

newborn metabolic screening (non standardized) in all states allows for

Answer 11

early treatment or dietary intervention to prevent/manage/delay symptoms

Question 12

examples of newborn metabolic screening (non standardized) in all states (5)

Answer 12

PKU, hypothyroidism, galactosemia, sickle cell disease, CF

Question 13

glycoslyation

Answer 13

process by which sugar trees (glycans) are created, altered and chemically attached to certain proteins or fats (lipids)

Question 14

one of the major post translational modifications

Answer 14

glycoslylation

Question 15

CDG

Answer 15

congenital disorders of glycolsylation

Question 16

~— subtypes of CDG

Answer 16

130

Question 17

CDG is characterized by variably dysmorphic features such as

Answer 17

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

Question 18

simple monosaccharide modifications of

Answer 18

nuclear transcription factors

Question 19

complex branched polysaccharides (GAGs) on

Answer 19

cell surface receptors

Question 20

what does protein glycosylation impact?

Answer 20

protein folding, distribution, stability and activity

Question 21

the pattern of glycoslation is often

Answer 21

cell type specific

Question 22

due to differential expression of the genes encoding the

Answer 22

respective enzymes

Question 23

large variation in pattern because of the difference in

Answer 23

sugar moieties added

Question 24

N linked glycosylation

Answer 24

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

Question 25

O linked glycosylation

Answer 25

carbohydrates bound to a protein backbone through hydroxyl residues (eg. on Ser, Thr, Tyr). Occurs mostly in ER & Golgi.

Question 26

mutations in any of the 12 genes responsible for O linked glycoslation all lead to a similar

Answer 26

phenotype

Question 27

mutations in each gene required for N linked glycolylation do not all give the same phenotype rather, they

Answer 27

group in clusters

Question 28

distinct clustering of phenotypes is dependent on

Answer 28

defective enzyme in the process of assembly

Question 29

clinical presentation is partly dictated by the specific function of the

Answer 29

polysaccharide configuration

Question 30

Face2Gene technology

Answer 30

assessment of craniofacial dysmorphic features (pattern recognition)

Question 31

what do you input into Face2Gene?

Answer 31

facial frontal photos from 50 unaffected controls and 18 from patients with confirmed PMM2-CDG (most common form)

Question 32

If a CDG suspected (based on symptoms, patient history and clinical evaluation), testing options include (4)

Answer 32

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.

Question 33

isoelectric focusing (IEF)

Answer 33

separate molecules such as proteins or enzymes based upon their electrical charge

Question 34

glycosaminoclgycans (GAGs)

Answer 34

A family of highly sulfated, complex linear polysaccharides(typically of repeating polysaccharide units) having a variety of biological roles

Question 35

what are the roles of GAGs (4)

Answer 35

Heparin/heparan sulfate Chondroitin sulfate/dermatan sulfate Keratan sulfate Hyaluronan

Question 36

GAGs can bind as much as ----x their weight in water

Answer 36

1000x

Question 37

up to -- sugars linked to protein (proteoglycan) in the ER and Golgi

Answer 37

80

Question 38

subsequently --- in the Golgi, further modulating properties of the protein

Answer 38

sulfated

Question 39

what GAG is the exception?

Answer 39

Hyaluronan

Question 40

hyaluronan

Answer 40

non-sulfated, free (not protein-linked) poly-saccharide synthesized at the plasma membrane

Question 41

purpose of extracellular gel (2)

Answer 41

tensile strength and elasticity | resists compressive force

Question 42

the diverse structural properties of GAGs are critical for (3)

Answer 42

modulating receptor / ligand binding, affecting cell function & tissue morphogenesis

Question 43

MPS

Answer 43

mucopolysaccharidoses

Question 44

how many MPS disorders are there

Answer 44

7

Question 45

MPS is the deficiency in

Answer 45

1 of the 11 enzymes involved in the breakdown of GAGs

Question 46

overall prevalence of MPS

Answer 46

1.9-4.5 per 100,000 live births

Question 47

MPS is characterized by

Answer 47

lysosomal storage of GAGs

Question 48

The progressive accumulation of GAGs results in (5)

Answer 48

``` skeletal deformities poor joint mobility severe growth deficit coarse facial features enlarged organs ```

Question 49

MPS 1 (hurler syndrome) and MPS 2 (hunter syndrome)

Answer 49

Gingival hyperplasia, delayed tooth eruption, malocclusion, mandibular dysplasia, radiolucent lesions in the jaws, and condylar defects

Question 50

MPS 3 (sanfillippo syndrome)

Answer 50

Obliteration of pulp chambers and irregular root canals

Question 51

MPS 4 (mosquito syndrome)

Answer 51

Enamel defects (1 ̊ & 2 ̊ dentition), with generalized loss of tooth structure

Question 52

MPS 6 (marateaux-lamy syndrome

Answer 52

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.

Question 53

MPS1 and 2 are

Answer 53

lysosomal storage disorders

Question 54

MPS 1, MPS 2, and smith-lemi opitz syndrome are

Answer 54

metabolic disorders

Question 55

smith-lemi opitz syndrome

Answer 55

disorder of cholesterol metabolism

Question 56

smith-lemi opitz syndrome is caused by a mutation in the

Answer 56

DHCR7 gene

Question 57

DHCR7 gene encodes for

Answer 57

dehydrocholesterol delta reductase

Question 58

smith-lemi opitz syndrome and cholesterol levels

Answer 58

high cholesterol precursors, low cholesterol

Question 59

functions of cholesterol (5)

Answer 59

``` cell membranes myelin (axonal) bile acids steroid hormones SHH signaling ```

Question 60

symptoms associated with smith-lemi opitz syndrome (7)

Answer 60

Multiple anomalies (cardiac, urogenital, digit, renal, pulmonary), dysmorphic face, growth deficiency, mental retardation, including autism, epilepsy, aggression, self-mutilation

Question 61

dental symptoms associated with smith-lemi opitz syndrome

Answer 61

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)

Question 62

early detection may improve

Answer 62

patient outcomes, as cholesterol supplementation can improve symptoms

Question 63

Metabolic diseases can have significant impact on the

Answer 63

maxillofacial complex at all ages (embryonic and postnatal)

Question 64

Important to recognize early as treatments and/or dietary modulations may have a

Answer 64

profound effect on the individual in the long term

Question 65

Dentists can be at the forefront of recognizing such diseases because of

Answer 65

dental involvement