Congenital Disorders of Glycosylation Flashcards

1
Q

Name the two types of glycosylation.

A

N-glycosylation

O-glycosylation

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2
Q

What is N-glycosylation?

A

glycosylation of proteins via the amide group of asparagine in the ER (begins assembly on ER wall in cytoplasm and “flips” into ER when chain gets long/heavy enough) –> when 14 sugars are achieved it exports to the ribosome complex –> terminal glucose and manose removed –> transfer to the Golgi for pruning

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3
Q

What are the functions of N-glycan proteins?

A
protein folding and stability
protein-protein complex formation
imparting protease resistance
signaling
cell-cell recognition
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4
Q

What are COGs?

A

Concerved Oligomeric Golgi Complex
permanent Golgi proteins that are involved in retrograde vesicle tethering
8 subunits organized into two lobes

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5
Q

What is O-glycosylation?

A

glycosylation of proteins via OH group of serine or threonine

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6
Q

What are the functions of O-glycan proteins?

A

antibacterial agent in saliva
defines ABO blood type
involved in sperm motility, sperm-egg binding, and preventing of polyspermia
cell adhesion and migration
lymphocyte targeting and inflammatory response

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7
Q

Which conditions cause abnormal processing in the Golgi?

A
CDG-IIa (MGAT2)
CDG-IIb (GCS1)
CDG-IIc (SLC35C1)
CDG-IId (B4GALT1)
CDG-IIe (COG7)
CDG-IIf (LEC2)
CDG-IIg (COG1)
CDG-IIh (COG8)
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8
Q

Describe the inheritance of CDGs.

A

X-linked: MAGT1-CDG, SSR4-CDG, PIGA-CDG, and SLC35A2-CDG
AD (disorders due to loss of function –> haploinsufficiency): EXT1-CDG and EXT2-CDG
All the rest are AR
(De novo mutations normally cause AD XL ALG13-CDG and SLC35A2-CDG

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9
Q

What is CDT testing?

A

carbohydrate deficient transferrin testing
transferrin is glycosylated by N-glycosylation
Type I defects caused by sialic acid not added to the carbohydrate chain (increased bands of disialotransferrin and asialotransferrin on isoelectric focusing)
Type II defects caused by carbohydrate chains that are too broken up (increased bands of trisialotransferrin and monosialotransferrin on isoelectric focusing)
cannot pick up O-glycosylation defects

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10
Q

What is tandem mass spec testing used for in errors of glycosylation?

A

divides particles by charge and mass to give you a picture of the structure of the protein
if you do not have a peak at the normal places you will see which parts are missing/affected by the mutation

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11
Q

What testing options are available for the diagnostic workup of a patient suspected to have an error of glycosylation?

A

abnormal glycosylation testing pattern (transferrin for patients older than three weeks and Apo-C)
enzyme analysis
DNA testing (NGS, WES, WGS)

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12
Q

What is PMM2-CDG?

A

phosphomannomutase deficiency caused by defects in the CDGIa gene
neonatal presentation (ususal): inverted nipples, poor feeding, abnormal fat distribution, hypotonia, cardiac, manifestations (pleurocardial effusion), strabismus (lazy eyes)
later organ involvement: hepatic fibrosis with hepatomegally, nephrosis, gonadal failure
thrombotic events may be seen with reduced factor XI, protein C, and ATIII
neurodevelopmental issues and seizures with abnormal brain findings
abnormal transferrin testing (Type I)
symptomatic treatment

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13
Q

What is PMI-CDG?

A

mannose-6-P isomerase deficiency caused by defects in the CDGIb gene
main manifestations: GI (emesis, chronic diarrhea, protein losing enteropathy, FTT, hepatic fibrosis), may develop hyperinsulinemia, hypoglycemia, and coagulation disturbances
no dysmorphism or neuro manifestations unless there is a stroke
treat with mannose (large amounts)

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14
Q

What is ATP6V0A2-CDG?

A

AR cutis laxa
mainly presents with loose wrinkly skin and large fontanelles
elastin fibers are not glycosylated, so the connective tissue is weakened
can be detected on CDT testing (Type II)

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15
Q

What is COG7-CDG?

A

alters golgi trafficking –> glycosyltransferase activity

presents with microcephally, failure to thrive, adducted thumbs, VSD, hyperthermia

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16
Q

What are O-mannosylation defects?

A

Walker Warburg DS
Muscle-Eye-Brain DS
Fukuyama DS

17
Q

Describe O-mannosylation defects.

A

decrease in o-mannosylation of dystroglycans leads clinically to type of congenital muscular dystrophy that also involves abnormal brain and eye development

18
Q

What are clinical presentations of Dolichol synthesis pathway disorders?

A

midfacial hypoplasia with epicanthal folds, ichthyosis (scaly skin) on lateral sides of hands and feet, decreased visual function with glaucoma

19
Q

Name the Dolichol synthesis pathway disorders.

A

DHDDS, SRD5A3, and DK1 deficiency

20
Q

What are defects in GP1 anchors?

A

GP1 is a membrane bound glycolipid that can be attached post-translationally to anchor protein to anchor protein to the cellular membrane
PIGA (X-linked) result sin paroxysmal nocturnal hemoglobinuria
PIGM (AR) results in GP1 mannosyltransferrase deficiency resulting in venous thrombosis, hepatomegally, and seizures

21
Q

What is NGLY1-CDG?

A

disorder of deglycosylation (first of its kind recently found)
cleaves glycoprotein from oligosaccharide normally, but when deficient ENGase cleaves the glycan to create N-GlcNAc proteins that cannot undergo degradation in the proteosome leading to aggregates and/or impairment of O-GlcNAc signaling
clinically presents with microcephally, high arched palate, and hypolacrima