Osteogenesis imperfecta

Question 1

Osteogenesis imperfecta

Answer 1

Genetic bone disorder characterized by fragile bones which break easily. Most caused by type I collagen mutations (most common type of collagen in bone). Mutation could be in alpha 1 or alpha 2 genes.

Question 2

OI type I

Answer 2

Least severe and most common type. Autosomal dominant inheritance. Blue sclerae, mild-moderate bone fragility, less fractures in adults, rarely fractures in utero, normal or near normal height, half have hearing loss, mitral valve prolapse, bruising, hyperextensibility. OA type IA has no dentinogenesis imperfecta but OA type IB does.

Question 3

OI type II

Answer 3

Most severe type. Leads to death in utero or in preinatal period due to respiratory failure. Caused by new dominant mutations. Severe bone deformity, multiple fractures, very short, bluish-grey sclera, large triangular face, deformed thorax.

Question 4

OI type III

Answer 4

Second most severe type. Progressively deforming and most severe that is compatible with life beyond infancy. Most caused by dominant mutations. Long bone fractures and clavical abnormalities, spine deformities, bluish sclera, short height, triangular face. Many die in childhood or adulthood due to respiratory, cardiac, or neurological problems.

Question 5

OI type IV

Answer 5

Third most severe type and most variable type. Variety of moderately severe forms of dominantly inherited disorders. Mild to moderate bone fragility, some prenatal bowing/fractures, osteoporosis, several fractures per year, osteoporosis and scoliosis, grayish to normal sclerae. OI type IVA have no dentinogenesis imperfecta and OI type IVB do have it.

Question 6

Order of OI severity

Answer 6

II > III > IV > I

Question 7

Null allele mutations in OI

Answer 7

Deletion or insertion causes frameshift, incorrect mRNA and truncated non-functional alpha chain (only half normal amount of type I collagen produced). Primary cause of OI type I. Null allele in alpha2 chain leads to increased levels of alpha1(I)-homotrimers resulting in rare recessive forms of OI.

Question 8

Genes mutated in OI

Answer 8

> 90% caused by mutations in COL1A1 and COL1A2 genes coding for alpha1 and alpha2 chains of type I collagen

Question 9

Structural mutations in OI

Answer 9

Produce abnormal type I collagen with AA substitutions, deletions, and insertions causing OI types II, III, or IV. Most common structural mutation is single nt change in codon for Gly generating new AA. Make non-helical molecules which are readily degraded.

Question 10

Prolylhydroxylase

Answer 10

Hydroxylates prolines and requires molecular oxygen, vitamin C, and alpha-ketoglutarate. Only active when collagen chain NOT in triple helical conformation.

Question 11

Direction of triple helix formation

Answer 11

Nucleation for 3 chains to wrap up occurs at carboxyl end and proceeds like a zipper to amino terminal end. More severe disease if mutation near carboxyl end.

Question 12

Quality control of collagen

Answer 12

If inaccurately formed triple helix gets secreted from cell and degraded

Question 13

Denaturing temp of collagen

Answer 13

42 degrees C (only 5 degrees above body temp) breaks H-bonds that stabilize helix

Question 14

Is it worse to have mutation in alpha1 or alpha2?

Answer 14

Since two alpha1 chains in triple helix only 25% of helices would be bad vs. in alpha2 50% of helices would be bad

Question 15

Diagnosis of OI

Answer 15

Clinical presentation, electrophoresis

Question 16

Treatment of OI

Answer 16

Help with gross motor skills, ambulation, maximize independence. Physical therapy, splinting, surgery to realign bones, medication. Team with orthopedic surgeon, physical therapist.

Question 17

Biphosphates and cyclic pamindromate infusions in OI

Answer 17

Biphosphates sually used to treat osteoporosis. Pamindromate shown to increase height, BMD, decrease fractures. Both drugs cause loss of osteoclast activity (prevents bone remodeling). Would not affect synthesis and deposition of normal or abnormal collagen, but would decrease resorption of bone by osteoclasts.