Osteogenesis imperfecta

People with osteogenesis imperfecta (OI) have bones that fracture easily, low muscle mass,
and joint and ligament laxity

Osteogenesis Imperfecta (OI and sometimes known as Brittle Bone Disease, or "Lobstein
syndrome"[1]) is a genetic bone disorder. People with OI are born with defective connective
tissue, or without the ability to make it, usually because of a deficiency of Type-I collagen.[2]
This deficiency arises from an amino acid substitution of glycine to bulkier amino acids in
the collagen triple helix structure. The larger amino acid side-chains create steric hindrance
that creates a bulge in the collagen complex, which in turn influences both the molecular
nanomechanics as well as the interaction between molecules, which are both compromised.[3]
As a result, the body may respond by hydrolyzing the improper collagen structure. If the
body does not destroy the improper collagen, the relationship between the collagen fibrils and
hydroxyapatite crystals to form bone is altered, causing brittleness.[4] Another suggested
disease mechanism is that the stress state within collagen fibrils is altered at the locations of
mutations, where locally larger shear forces lead to rapid failure of fibrils even at moderate
loads as the homogeneous stress state found in healthy collagen fibrils is lost.[3] These recent
works suggest that OI must be understood as a multi-scale phenomenon, which involves
mechanisms at the genetic, nano-, micro- and macro-level of tissues.

As a genetic disorder, OI is an autosomal dominant defect. Most people with OI receive it

from a parent but it can be an individual (de novo or "sporadic") mutation.

Type I

Blue sclera in osteogenesis imperfecta.

Collagen is of normal quality but is produced in insufficient quantities:

 Bones fracture easily

 Slight spinal curvature
 Loose joints
 Poor muscle tone
  Discoloration of the sclera (whites of the eyes), usually giving them a blue-gray color. The
blue-gray color of the sclera is due to the underlying choroidal veins which show through.
This is due to the sclera being thinner than normal because of the defective Type I collagen
not forming correctly.
 Early loss of hearing in some children
 Slight protrusion of the eyes

IA and IB are defined to be distinguished by the absence/presence of dentinogenesis

imperfecta (characterized by opalescent teeth; absent in IA, present in IB). Life expectancy is
slightly reduced compared to the general population due to the possibility of fatal bone
fractures and complications related to OI Type I such as basilar invagination

Basilar invagination occurs when the top of the C2 vertebrae migrates upward. It can cause
the opening in the skull where the spinal cord passes through to the brain (the foramen
magnum) to narrow. It also may press on the lower brainstem.[1]

There are eight different types of OI, Type I being the most common, though the symptoms
vary from person to person.

Type Description Gene OMIM

COL1A1, 166240 (IA),
I mild
COL1A2 166200 (IB)
COL1A1, 166210 (IIA),
II severe and usually lethal in the perinatal period
COL1A2, CRTAP 610854 (IIB)
COL1A1,
III considered progressive and deforming 259420
COL1A2
COL1A1,
IV deforming, but with normal scleras 166220
COL1A2
shares the same clinical features of IV, but has
V unknown 610967
unique histologic findings ("mesh-like")
shares the same clinical features of IV, but has
VI unknown 610968
unique histologic findings ("fish scale")
VII associated with cartilage associated protein CRTAP 610682
VIII associated with the protein leprecan LEPRE1 610915

Treatment
At present there is no cure for OI. Treatment is aimed at increasing overall bone strength to
prevent fracture and maintain mobility.

There have been many clinical trials performed with Fosamax (Alendronate), a drug used to
treat women experiencing brittleness of bones due to osteoporosis. Higher levels of
effectiveness apparently are to be seen in the pill form versus the IV form, but results seem
inconclusive.[citation needed] The U.S. Food and Drug Administration (FDA) will not approve
Fosamax as a treatment for OI because long term effects of the drug have not been studied,
although it is often used in preteens, instead of Pamidronate.[citation needed]
Bone infections are treated as and when they occur with the appropriate antibiotics and
antiseptics.

[edit] Physiotherapy

Physiotherapy used to strengthen muscles and improve motility in a gentle manner, while
minimizing the risk of fracture. This often involves hydrotherapy and the use of support
cushions to improve posture. Individuals are encouraged to change positions regularly
throughout the day in order to balance the muscles which are being used and the bones which
are under pressure.

Children often develop a fear of trying new ways of moving due to movement being
associated with pain. This can make physiotherapy difficult to administer to young children.

[edit] Physical aids

With adaptive equipment such as crutches, wheelchairs, splints, grabbing arms, and/or
modifications to the home many individuals with OI can obtain a significant degree of
autonomy.

[edit] Bisphosphonates

Bisphosphonates (BPs), particularly those containing nitrogen, are being increasingly

administered to increase bone mass and reduce the incidence of fracture. BPs can be dosed
orally (e.g. alendronate) or by intravenous injection/infusion (e.g. pamidronate,[7] zoledronic
acid).

BP therapy is being used increasingly for the treatment of OI. It has proven efficiency in
reducing fracture rates in children,[8] however only a trend towards decreased fracture was
seen in a small randomized study in adults.[9] While decreasing fracture rates, there is some
concern that prolonged BP treatment may delay the healing of OI fractures, although this has
not been conclusively demonstrated.

Pamidronate is used in USA, UK and Canada. Some hospitals, such as most Shriners, provide
it to children. Some children are under a study of pamidronate. Marketed under the brand
name Aredia, Pamidronate is usually administered as an intravenous infusion, lasting about
three hours. The therapy is repeated every three to six months, and lasts for the life of the
patient. Common side effects include bone pain, low calcium levels, nausea, and dizziness.
According to recent results, extended periods of pamidrinate, (i.e.;6 years) can actually
weaken bones, so patients are recommended to get bone densities every 6 months-1 year, to
monitor bone strength.

[edit] Surgery

Metal rods can be surgically inserted in the long bones to improve strength, a procedure
developed by Harold A. Sofield, MD, at Shriners Hospitals for Children in Chicago. During
the late 1940s, Sofield, Chief of Staff at Shriners Hospitals in Chicago, worked there with
large numbers of children with OI and experimented with various methods to strengthen the
bones in these children.[10] In 1959, with Edward A. Miller, MD, Sofield wrote a seminal
article describing a solution that seemed radical at the time: the placement of stainless steel
rods into the intramedullary canals of the long bones to stabilize and strengthen them. His
treatment proved extremely useful in the rehabilitation and prevention of fractures; it was
adopted throughout the world and still forms the basis for orthopedic treatment of OI.

Spinal fusion can be performed to correct scoliosis, although the inherent bone fragility
makes this operation more complex in OI patients. Surgery for basilar impressions can be
carried out if pressure being exerted on the spinal cord and brain stem is causing neurological
problems.

Osteopenia is a condition where bone mineral density is lower than normal. It is considered by many
doctors to be a precursor to osteoporosis. However, not every person diagnosed with osteopenia
will develop osteoporosis. More specifically, osteopenia is defined as a bone mineral density T-score
between -1.0 and -2.5.

Osteoporosis is a disease of bones that leads to an increased risk of fracture. Osteoporosis literally
means 'porous bones'. In osteoporosis the bone mineral density (BMD) is reduced, bone
microarchitecture is disrupted, and the amount and variety of proteins in bone is altered.

Leading to fragility fractions.

Grey/brown discolouration of the teeth (Dentinogenesis imperfect

OI is usually classified into 4 main types:

   

o       Type 1 – mildest end of range.

o       Type 2 – perinatal lethal.
o       Type 3 – most severe survivable form.
o       Type 4 – intermediate severity.
        Features may include:
o       Fractures with minimal trauma
o       Grey/brown discolouration of the teeth (Dentinogenesis imperfecta: DI)
o       Blue sclerae
o       Progressive hearing loss from young adulthood
o       Characteristic radiological findings
        OI is inherited in an autosomal dominant manner, but new mutations are common, so
lack of family history does not rule out the diagnosis.

Overview

Osteogenesis imperfecta (OI) is a group of inherited disorders of connective tissue (collagen

type 1). It includes a spectrum of disorders of the bones with features ranging from a mild
predisposition to fractures to perinatal lethality.  Osteogenesis Imperfecta has been classified
into 4 main types according to clinical and radiological features.  With emerging molecular
delineation, the classification becomes more complex. 

Inheritance

        Osteogenesis Imperfecta is usually inherited in an autosomal dominant manner

        Osteogenesis Imperfecta usually occurs due to mutations in the COL1A1 and COL1A2
genes, which code for the two peptides of collagen type 1, the principle organic
component of bone.
        An affected first degree relative (parent, sibling or child) strongly supports a suspected
diagnosis in an individual.
        There is a high rate of de novo mutations (60% in mild OI and 100% in lethal OI) so
absence of family history does not exclude the diagnosis.
        The offspring risk to an affected individual is 50%.
 

Features

Apart from fractures of any bone, following minimal trauma, the other features of OI are
variable, but tend to be similar within families.

Classical radiological findings may be seen, but especially milder forms may not be reliable
in excluding the diagnosis. They include old fractures, Wormian bones, osteopaenia,
protrusio acetabuli (deepened hip sockets) and “codfish” vertebrae (crush fractures of the
spine found in adults).

Classification

Type Prevalence Lifetime Bone deformity Stature Sclerae

/100,000 fractures
(approx.)
1 3-4 Few to Rarely Normal/ mild Blue
20’s shortening
2 1-2 (Lethal) Severe Severe short Blue/black
stature
3 1-2 >100 Common – long Short stature Blue
bones & spine.
Often wheelchair
users.
4 3-4 20-100 Mild/moderate. Variable short Usually
stature normal

Testing
The diagnosis of Osteogenesis Imperfecta is based on the family history, clinical and
radiological findings.  Molecular and biochemical testing may be indicated in certain cases
but these tests are not wholly sensitive or specific; results may be equivocal. Test results may
take several months to become available due to the large size of the collagen 1 genes.

Negative results do not exclude a diagnosis of OI – mutations are typically found in about 80-
90% of cases of clinically unambiguous cases. With less certain clinical features the mutation
pick-up rate drops off. Mutation analysis cannot therefore be used to exclude OI in cases of
unexplained fractures with no other features suggestive of OI.

Lymphocytes (from a blood specimen) and cultures fibroblasts (from a skin biopsy) may be
required for analysis.

Poor development of musculo-skeltal system: CT.

http://www.youtube.com/watch?v=KJeLdnZOJF8

Collagen, type I, alpha 1, also known as COL1A1, is a human gene that encodes the major
component of type I collagen, the fibrillar collagen found in most connective tissues,
including cartilage.

Collagen is a protein that strengthens and supports many tissues in the body, including
cartilage, bone, tendon, skin and the white part of the eye (sclera). The COL1A1 gene
produces a component of type I collagen, called the pro-alpha1(I) chain. This chain combines
with another pro-alpha1(I) chain and also with a pro-alpha2(I) chain (produced by the
COL1A2 gene) to make a molecule of type I procollagen. These triple-stranded, rope-like
procollagen molecules must be processed by enzymes outside the cell. Once these molecules
are processed, they arrange themselves into long, thin fibrils that cross-link to one another in
the spaces around cells. The cross-links result in the formation of very strong mature type I
collagen fibers.

The COL1A1 gene is located on the long (q) arm of chromosome 17 between positions 21.3
and 22.1, from base pair 45,616,455 to base pair 45,633,991.

Collagen alpha-2(I) chain is a protein that in humans is encoded by the COL1A2 gene.[1][2]

This gene encodes one of the chains for type I collagen, the fibrillar collagen found in most
connective tissues. Mutations in this gene are associated with osteogenesis imperfecta
Osteogenesis imperfect tarda (type 1)

(fragilitas ossium, brittle bone syndrome)

 Hetereogenous group of mainly autosomally dominant inherited disorders

 Genes encoding the chains in the Type 1 collagen: COL1A1 & COL1A2.

 Normal lifespan: I & IV.

 V.fragile and brittle bone.

 Other collagen containing tissues are also involved e.g. tendons, skin and the eyes.

Type 1:

 Mild bony deformities

 Blue sclera

 Defective dentive

 Early-onset deafness

 Hypermobility of joints
(great flexibility than normal): double jointed, easily dislocated, linked to
development of osteoarthritis which is the degradation of joints.

 Heart valve disorders

Treatment:

Bisphosphonates  enhances bone cortical thickness.

Prognosis  slightly reduced life-span. (depends on severity of disease)

Consult lecture handouts... mutations and how they are detected etc.