Achondroplaisa (intergrative)

Question 1

What are the general characteristics of achondroplasia?

Answer 1

Severe inhibition of Cartlidge proliferation at growth plates

Endochondral ossification is affected

Dwarfism is disproportionate (limbs affected more than trunk)

Appositional growth occurs normally

Intermembranous ossification occurs normally

Question 2

Impact of Achondroplasia on intramembranous ossification?

Answer 2

(Parts of the skull)

These all develop normally in achondroplasia as cranial vault has normal capcity and no deficit brain function

Question 3

Impact of Achondroplasia on endochondral ossification?

Answer 3

Sphenoid, temporal and inferior occipital bones ARE AFFECTED:

Midface hypoplasia (airway obstruction)

Narrowing of foramen magnum (spinal cord impingement, quadriplegia or death

Question 4

How is the foramen magnum impacted in Achondroplassia?

Answer 4

Compression of medulla = quadriparesis, sleep apnoea and death

interruption to normal CSF flow = hydrocephalus

Question 5

Lumbar spinal lordosis and stenosis affect from Achondroplasia

Answer 5

Narrowing of vertebral canal in lumbar region

Accentuated lumbar curve anteriorly

= paraplegia

Question 6

Mutation and gene of achondroplasia

Answer 6

FGFR3 (Fibroblast Growth Factor Receptor 3)

Homozygous = lethal

99% = Gly380Arg FGFR3 mutation

Question 7

What type of mutation occurs in Achondroplasia and what is the consequence of this?

Answer 7

Gain of function –> decreased endochondral ossification, inhibited chondrocyte proliferation in growth plate and decerased cartlidge matrix production

Question 8

what receptor does achondroplasia affect?

Answer 8

TK

Question 9

clinical features of achondroplasia

Answer 9

Short stature

Sitting height = normal

Avg trunk length but short arms and legs and disproportionately short upper arm/ thigh

Shortened fingers

Increased head size and prominent forehead

Marked curvature of spine

Waddling gait

Question 10

current therapies for achondroplasia

Answer 10

Distraction osteogenesis
Gives better result
BUT limits quality of life
High rate of complications, infections, stiffness of adj joints and fractures
Breaking of patient’s bone and slowly increasing over time

Orthopedic procedure

Growth Hormone
Minimal effect
Aggravates body disproportion as is (not specific in effect)

Question 11

How does the FGFR3 isoform decoy receptor act as an emerging therapy for achondropladia?

Answer 11

Adding a FGF ligand

Acts like a decoy, binds to FGF isoform and prevents FGF from binding to mutated FGFR3

Reduces FGFR3 signalling

Question 12

TK Inhibitor as a emerging therapy for Achondroplasia

Answer 12

Infigratinib = selective TK inhibitor

Counteracts hyperactivity of FGFR3 by inhibiting phosphorylation of FGFR

Question 13

Meclozine as a emerging therapy for Achondroplasia

Answer 13

Antihistamine and motion sickness drug

Suppresses FGFR3 signaling via downregulating phosphorylation of ERK

Question 14

What is the aim of the orphan Drug Designation Program

Answer 14

Aims to ensure availability of greater range of treatments for rare diseases

Question 15

What is the intended use of the Orphan Drug Designation Progarm?

Answer 15

Drugs that treat diseases that affect fewer than 5 in 10 000 individuals in Australia

Drugs that are not commercially viable when used in the patient population