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Osteogenesis Imperfecta

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Definition
Osteogenesis imperfecta (OI) is a genetic disorder characterized by bones that break easily, often from little or no apparent cause. A classification system of different types of OI is commonly used to help describe how severely a person with OI is affected. For example, a person may have just a few or as many as several hundred fractures in a lifetime.

Prevalence
While the number of people affected with OI in the United States is unknown, the best estimate suggests a minimum of 20,000 and possibly as many as 50,000.

Diagnosis
OI is caused by genetic defects that affect the body’s ability to make strong bones. In dominant (classical) OI, a person has too little type I collagen or a poor quality of type I collagen due to a mutation in one of the type I collagen genes. Collagen is the major protein of the body’s connective tissue. It is part of the framework that bones are formed around. In recessive OI, mutations in other genes interfere with collagen production. The result in all cases is fragile bones that break easily.

It is often, though not always, possible to diagnose OI based solely on clinical features. Clinical geneticists can also perform biochemical (collagen) or molecular (DNA) tests that can help confirm a diagnosis of OI in some situations. These tests generally require several weeks before results are known. Both the collagen biopsy test and DNA test are thought to detect almost 90% of all type I collagen mutations.

A positive type I collagen study confirms the diagnosis of dominant OI, but a negative result could mean that either a collagen type I mutation is present but was not detected or the patient has a form of the disorder that is not associated with type 1 collagen mutations or the patient has a recessive form of OI. Therefore, a negative type I collagen study does not rule out OI. When a type I collagen mutation is not found, other DNA tests to check for recessive forms are available.

Clinical Features
The characteristic features of OI vary greatly from person to person, even among people with the same type of OI, and even within the same family. Not all characteristics are evident in each case. The majority of cases of OI (possibly 85-90 %) are caused by a dominant mutation in a gene coding for type I collagen (Types I, II, III, and IV in the following list). Types VII and VIII are newly identified forms that are inherited in a recessive manner. The genes causing these two types have been identified. Types V and VI do not have a type 1 collagen mutation, but the genes causing them have not yet been identified. The general features of each known type of OI are as follows:

Type I

  • Most common and mildest type of OI.
  • Bones fracture easily. Most fractures occur before puberty.
  • Normal or near-normal stature.
  • Loose joints and muscle weakness.
  • Sclera (whites of the eyes) usually have a blue, purple, or gray tint.
  •  Triangular face.
  • Tendency toward spinal curvature.
  • Bone deformity absent or minimal.
  • Brittle teeth possible.
  • Hearing loss possible, often beginning in early 20s or 30s.
  • Collagen structure is normal, but the amount is less than normal.

Type II

  • Most severe form.
  • Frequently lethal at or shortly after birth, often due to respiratory problems.
  • Numerous fractures and severe bone deformity.
  • Small stature with underdeveloped lungs.
  • Tinted sclera.
  • Collagen improperly formed.

Type III

  • Bones fracture easily. Fractures often present at birth, and x-rays may reveal healed fractures that occurred before birth.
  • Short stature.
  • Sclera have a blue, purple, or gray tint.
  • Loose joints and poor muscle development in arms and legs.
  • Barrel-shaped rib cage.
  • Triangular face.
  • Spinal curvature.
  • Respiratory problems possible.
  • Bone deformity, often severe.
  • Brittle teeth possible.
  • Hearing loss possible.
  • Collagen improperly formed.

Type IV

  • Between Type I and Type III in severity.
  • Bones fracture easily. Most fractures occur before puberty.
  • Shorter than average stature.
  • Sclera are white or near-white (i.e. normal in color).
  • Mild to moderate bone deformity.
  • Tendency toward spinal curvature.
  • Barrel-shaped rib cage.
  • Triangular face.
  • Brittle teeth possible.
  • Hearing loss possible.
  • Collagen improperly formed.

By studying the appearance of OI bone under the microscope, investigators noticed that some people who are clinically within the Type IV group had a distinct pattern to their bone. When they reviewed the full medical history of these people, they found that groups had other features in common. They named these groups Types V and VI OI. The mutations causing these forms of OI have not been identified, but people in these two groups do not have mutations in the type I collagen genes.

Type V

  • Clinically similar to Type IV in appearance and symptoms of OI.
  • A dense band seen on x-rays adjacent to the growth plate of the long bones.
  • Unusually large calluses (hypertrophic calluses) at the sites of fractures or surgical procedures. (A callus is an area of new bone that is laid down at the fracture site as part of the healing process.)
  • Calcification of the membrane between the radius and ulna (the bones of the forearm). This leads to restriction of forearm rotation.
  • White sclera.
  • Normal teeth.
  • Bone has a “mesh-like” appearance when viewed under the microscope.
  • Dominant inheritance pattern

Type VI

  • Clinically similar to Type IV in appearance and symptoms of OI.
  • The alkaline phosphatase (an enzyme linked to bone formation) activity level is slightly elevated in OI Type VI. This can be determined by a blood test.
  • Bone has a distinctive “fish-scale” appearance when viewed under the microscope.
  • Diagnosed by bone biopsy.
  • Whether this form is inherited in a dominant or recessive manner is unknown, but researchers believe the mode of inheritance is most likely recessive.
  • Eight people with this type of OI have been identified.

Recessive Forms of OI
After years of research, two forms of OI that are inherited in a recessive manner were discovered in 2006. Both types are caused by genes that affect collagen formation. These forms provide information for people who have severe or moderately severe OI but who do not have a primary collagen mutation.

Type VII

  • The first described cases resemble Type IV OI in many aspects of appearance and symptoms.
  • In other instances the appearance and symptoms are similar to Type II lethal OI, except infants had white sclera, a small head and a round face.
  • Short stature.
  • Short humerus (arm bone) and short femur (upper leg bone)
  • Coxa vera is common (the acutely angled femur head affects the hip socket).
  • Results from recessive inheritance of a mutation to the CRTAP (cartilage-associated protein) gene. Partial function of CRTAP leads to moderate symptoms while total absence of CRTAP was lethal in all 4 identified cases.

Type VIII

  • Resembles lethal Type II or Type III OI in appearance and symptoms except that infants have white sclera.
  • Severe growth deficiency.
  • Extreme skeletal under mineralization.
  • Caused by a deficiency of P3H1 (Prolyl 3-hydroxylase 1) due to a mutation to the LEPRE1 gene.

Inheritance Factors
Most cases of OI (85-90%) are caused by a dominant genetic defect. This means that only one copy of the mutation carrying gene is necessary for the child to have OI. Children who have the dominant form of OI have either inherited it from a parent or, when the parent does not have OI, as a spontaneous mutation.

Approximately 10-15 percent of cases of OI are the result of a recessive mutation. In this situation, the parents do not have OI, but both carry the mutation in their genes. To inherit recessive OI the child must receive a copy of the mutation from both parents.

When a child has recessive OI, there is a 25 percent chance per pregnancy that the parents will have another child with OI. Siblings of a person with a recessive form of OI have a 50 percent chance of being a carrier of the recessive gene. DNA testing is available to help parents and siblings determine if they are carriers of this type of gene mutation.

A person with a form of OI caused by a dominant mutation has a 50 percent chance of passing on the disorder to each of his or her children. If one parent has OI because of a recessive mutation, 100 percent of their children will be carriers of the recessive OI mutation. Whether any of these children will have OI will depend on their inheritance from the other parent. Genetic counselors can help people with OI and their family members further understand OI genetics and the possibility of recurrence, and assist in prenatal diagnosis for those who wish to exercise that option. For more information on OI inheritance, see the OI Foundation fact sheet titled “Genetics.”

Treatment
There is not yet a cure for OI. Treatment is directed toward preventing or controlling the symptoms, maximizing independent mobility, and developing optimal bone mass and muscle strength. Care of fractures, extensive surgical and dental procedures, and physical therapy are often recommended for people with OI. Use of wheelchairs, braces, and other mobility aids is common, particularly (although not exclusively) among people with more severe types of OI.

People with OI are encouraged to exercise as much as possible to promote muscle and bone strength, which can help prevent fractures. Swimming and water therapy are common exercise choices for people with OI, as water allows independent movement with little risk of fracture. For those who are able, walking (with or without mobility aids) is excellent exercise. People with OI should consult their physician and/or physical therapist to discuss appropriate and safe exercise.

Children and adults with OI will also benefit from maintaining a healthy weight, eating a nutritious diet, and avoiding activities such as smoking, excessive alcohol and caffeine consumption, and taking steroid medications — all of which may deplete bone and make bones more fragile. For more information on nutrition, see the OI Foundation fact sheet titled “Nutrition.”

A surgical procedure called “rodding” is frequently considered for people with OI. This treatment involves inserting metal rods through the length of the long bones to strengthen them and prevent and/or correct deformities. For more information, see the OI Foundation’s fact sheet on “Rodding Surgery.”

Several medications and other treatments are being explored for their potential use to treat OI. These include growth hormone treatment, treatment with intravenous and oral drugs called bisphosphonates, an injected drug called teriparatide (for adults only) and gene therapies. It is not clear if people with recessive OI will respond in the same manner as people with dominant OI to these treatments. The OI Foundation provides current information on research studies, as well as information about participating in clinical trials.

Prognosis
The prognosis for a person with OI varies greatly depending on the number and severity of symptoms. Respiratory failure is the most frequent cause of death for people with OI, followed by accidental trauma. Despite numerous fractures, restricted physical activity, and short stature, most adults and children with OI lead productive and successful lives. They attend school, develop friendships and other relationships, have careers, raise families, participate in sports and other recreational activities and are active members of their communities.

Coast Guard Day

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Flag of the United States Coast Guard

August 4 is celebrated as Coast Guard Day to honor the establishment on that day in 1790 of the Revenue Cutter Service, forebear of today’s Coast Guard, by the Treasury Department. On that date, Congress, guided by Secretary of the Treasury Alexander Hamilton, authorized the building of a fleet of ten cutters, whose responsibility would be enforcement of the first tariff laws enacted by Congress under the Constitution.

The Coast Guard has been continuously at sea since its inception, although the name Coast Guard didn’t come about until 1915 when the Revenue Cutter Service was merged with the Lifesaving Service. The Lighthouse Service joined the Coast Guard in 1939, followed in 1946 by the Bureau of Navigation and Steamboat Inspection. Finally, in 1967, after 177 years in the Treasury Department, the Coast Guard was transferred to the newly formed Department of Transportation.

Coast Guard Day is primarily an internal activity for active duty Coast Guard personnel, civilian members, reservists, retirees, auxiliarists, and dependents, but it does have a significant share of interest outside the Service. Grand Haven, Michigan, also known as Coast Guard City, USA, annually sponsors the Coast Guard Festival around August 4. Typically it is the largest community celebration of a branch of the Armed Forces in the nation.

In addition to celebrating their own day every year, Coast Guard members also participate as equal partners in Armed Forces Day activities.

Adaptive Q&A

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With such a wide variety of adaptive vehicle equipment available, selecting the appropriate features or modifications can become big task. In an effort to facilitate this process, here are the responses to some of the most frequently asked mobility equipment questions.

Are ramps difficult to operate?
Most vans equipped with side-entry mobility equipment are fully automatic. The seamless loading and unloading process can be as simple as pushing a button. Vans can be converted to automatically open their doors, lower to the curb and deploy or stow a ramp without the driver or passengers needing to work with any equipment. Manual options are also available, however these are also very easy to use. Built with springs that carry most of the ramp’s weight, manual ramp options are also quick, safe and simple to use solutions.

Can I drive from my wheelchair?
In many cases, it is possible for drivers with disabilities and the need for a wheelchair to avoid transferring by properly securing their chair and themselves within the vehicle. With the use of both a wheelchair tie-down system and occupant restraints, driving from a wheelchair can be a safe and convenient option.

Can I drive from my scooter?
Operating or riding a vehicle from scooter is not recommended. In order to remain safe while traveling, passengers or drivers in scooters should always transfer into vehicle seating. Turning or swivel seats can make the transfer process easier and less demanding on those with limited mobility or access to caregiver assistance. Scooters should also be properly secured with a tie-down system to prevent movement in case of a sudden stop or turn.

Side entry vs. rear entry – which is best for me?
There are a few things to consider when deciding between a side entry and a rear entry vehicle. Passengers who are not going to be driving the vehicle typically use rear entry vehicles. Side entry vehicles work well for drivers and co-pilots getting in to the front of the vehicle, as well as passengers. Depending on the parking conditions of your regularly visited establishments, your vehicle’s entry points may need to be redefined. If you often need to parallel park or live in a region that experiences recurring inclement weather, a side-entry vehicle will prove to be a better option for your needs. These are only a few of the deciding factors when it comes to choosing between side and rear-entry.

Can someone else drive my vehicle if I install hand controls?
In most cases, both able-bodied drivers and those with disabilities can comfortably operate vehicles adapted with hand controls. Most hand controls do not interfere with the way a manufacturer intended the vehicle to be driven.

August is SMA Awareness Month

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August is SMA Awareness month and families and friends around the country are joining together to help increase awareness—not only of SMA, but also of our hope for a treatment and cure.

What is Spinal Muscular Atrophy?
Spinal Muscular Atrophy (SMA) Types I, II, and III belong to a group of hereditary diseases that cause weakness and wasting of the voluntary muscles in the arms and legs of infants and children. The disorders are caused by an abnormal or missing gene known as the survival motor neuron gene 1 (SMN1), which is responsible for the production of a protein essential to motor neurons. Without this protein, lower motor neurons in the spinal cord degenerate and die. The type of SMA (I, II, or III) is determined by the age of onset and the severity of symptoms. Type I (also known as Werdnig-Hoffman disease, or infantile-onset SMA) is evident at birth or within the first few months. Symptoms include floppy limbs and trunk, feeble movements of the arms and legs, swallowing and feeding difficulties, and impaired breathing. Type II (the intermediate form) usually begins 6 and 18 months of age. Legs tend to be more impaired than arms. Children with Type II may able to sit and some may be able to stand or walk with help. Symptoms of Type III (also called Kugelberg-Welander disease) appear between 2 and 17 years of age and include difficulty running, climbing steps, or rising from a chair.  The lower extremities are most often affected.  Complications include scoliosis and chronic shortening of muscles or tendons around joints.

Is there any treatment?
There is no cure for SMA. Treatment consists of managing the symptoms and preventing complications.

What is the prognosis?
The prognosis is poor for babies with SMA Type I. Most die within the first two years. For children with SMA Type II, the prognosis for life expectancy or for independent standing or walking roughly correlates with how old they are when they first begin to experience symptoms – older children tend to have less severe symptoms  Life expectancy is reduced but some individuals live into adolescence or young adulthood.  Individuals with SMA type III may be prone to respiratory infections but with care may have a normal lifespan.

What research is being done?
Between 2003 and 2012, the NINDS piloted the Spinal Muscular Atrophy Project to expedite therapeutics development for this hereditary neurodegenerative disease. The Project was designed to accelerate the research process by identifying drugs that increase the level of SMN protein in cultured cells, so that they could be used as potential leads for further drug discovery and clinical testing. Read more about the history of this pioneering effort and how it led to collaboration with several pharmaceutical and biotechnology companies.