“Extraordinary Measures” – A Movie about Pompe’s Disease


 

Extraordinary Measures is a 2010 film about parents trying to save their children affected by Pompe Disease, A Glycogen Storage Disease produced by mutations on a gen that makes the enzyme acid alpha Glycosidase (GAA), a lysosomal hydrolase.

 Pompe disease is a rare (estimated at 1 in every 40,000 births), inherited and often fatal disorder that disables the heart and muscles.

The movie is based on the true story of John and Aileen Crowley, whose two youngest children were affected with Pompe Disease.

The real John Crowley

As you know Glycogen storage diseases are genetic enzyme deficiencies that result in excessive glycogen accumulation within cells. Additional symptoms depend on the particular enzyme that is deficient.

There are different forms of Glycogen Storage Diseases (aka Glycogenoses), including the Type Ia GSD or Von Gierke’s disease, caused by hepatic deficiency of Glucose 6 Phosphatase, the Type IV or Andersen’s Disease, caused by deficit of branching enzyme in various organs, including the liver, and the GSD Type V or McArdle’s Disease (caused by muscle deficiency of Glycogen Phosphorylase), among others.

GSD Type II or Pompe’s Disease was described by Pompe in 1932, when he studied a girl who suffered from a cardiopathy caused by glycogen accumulation.

The National Institute of Neurological Disorders and Stroke (NINDS), an Institute of the National Institutes of Health System, describe the disease in these terms:

 

“Early onset (or infantile Pompe disease is the result of complete or near complete deficiency of GAA.  Symptoms begin in the first months of life, with feeding problems, poor weight gain, muscle weakness, floppiness, and head lag. Respiratory difficulties are often complicated by lung infections.  The heart is grossly enlarged. More than half of all infants with Pompe disease also have enlarged tongues.  Most babies with Pompe disease die from cardiac or respiratory complications before their first birthday. 

 

Late onset (or juvenile/adult) Pompe disease is the result of a partial deficiency of GAA.  The onset can be as early as the first decade of childhood or as late as the sixth decade of adulthood.  The primary symptom is muscle weakness progressing to respiratory weakness and death from respiratory failure after a course lasting several years.  The heart may be involved but it will not be grossly enlarged.  A diagnosis of Pompe disease can be confirmed by screening for the common genetic mutations or measuring the level of GAA enzyme activity in a blood sample — a test that has 100 percent accuracy.  Once Pompe disease is diagnosed, testing of all family members and consultation with a professional geneticist is recommended.  Carriers are most reliably identified via genetic mutation analysis.

A diagnosis of Pompe disease can be confirmed by screening for the common genetic mutations or measuring the level of GAA enzyme activity in a blood sample — a test that has 100 percent accuracy.  Once Pompe disease is diagnosed, testing of all family members and consultation with a professional geneticist is recommended.  Carriers are most reliably identified via genetic mutation analysis.”

“…Individuals with Pompe disease are best treated by a team of specialists (such as cardiologist, neurologist, and respiratory therapist) knowledgeable about the disease, who can offer supportive and symptomatic care.  The discovery of the GAA gene has led to rapid progress in understanding the biological mechanisms and properties of the GAA enzyme.  As a result, an enzyme replacement therapy has been developed that has shown, in clinical trials with infantile-onset patients, to decrease heart size, maintain normal heart function, improve muscle function, tone, and strength, and reduce glycogen accumulation.  A drug called alglucosidase alfa (Myozyme©), has received FDA approval for the treatment of infants and children with Pompe disease.  Another alglucosidase alfa drug, Lumizyme©, has been approved for late-onset (non-infantile) Pompe disease. ..”

“…Without enzyme replacement therapy, the hearts of babies with infantile onset Pompe disease progressively thicken and enlarge.  These babies die before the age of one year from either cardiorespiratory failure or respiratory infection.  For individuals with late onset Pompe disease, the prognosis is dependent upon the age of onset.  In general, the later the age of onset, the slower the progression of the disease.  Ultimately, the prognosis is dependent upon the extent of respiratory muscle involvement. …”

 It is interesting that even when the Acid Alpha-glycosidase is only involved in the degradation of about 3 % of the Glycogen, its deficit provokes such important damages. Since this enzyme is not related to the main pathways of degradation of glycogen, its deficit does not produce hypoglycemia or a direct lack of metabolic energy. Cellular damage is caused mainly by accumulation of glycogen in the cytoplasm and the lysosomes.

As describe above, nowadays the treatment is based on the use of a recombinant human acid Glycosidase as a replacement of the normal enzyme.  “Extraordinary Measures” describes, in fact, the events that triggered the development of the enzyme for the treatment of this disease.

My favorite quotes of this movie:

John Crowley (Looking at the college-aged kids hired to work under Dr. Stonehill):

-These guys make me feel old.
Dr. Robert Stonehill:

– Scientists get all sensible & careful when they get old. Young ones like risk, not afraid of new ideas… and you can pay ’em less.

 

John Crowley (talking with Dr. Stonehill after an argument):

–  “Fine, spend the rest of your life dreaming up great ideas that don’t get funded. Draw your diagrams on the wall that cure diseases in theory but never help a single human being in reality.”

 

John Crowley (arguing with a corporate executive about drug research):

–  “This is not about a return on an investment, it’s about kids. Kids with names, dreams, families that love them.”

 

Recommended articles and links:

NINDS Pompe Disease Information Page

Ibrahim, J.; McGovern, M. M.

Glycogen Storage Disease Type II

Some pictures of the Crowley family

GATTACA


 

After Vincent genetic test:

Vincent: What about the interview?

Dr. Lamar: That was it.

 

Basically GATTACA  is a movie about a future where your DNA becomes your Curriculum Vitae.

What does “GATTACA” means?

In the movie, it is the name of the facility where the action occurs, and apparently, it was the better way that was found by the creators of the movie for arranging the four “bases”  in the DNA (Adenine, Guanine, Cytosine and Thymine) in such a way that it sounds like a name.

The title sequences highlight these letters that represent the nitrogen bases in the DNA:

 

 

GATTACA main message is:

“There is no gen for the human spirit”

 

 

For additional information about this movie, please visit the Moviecular Biology page.

Moviecular Biology Page Updated: Jurassic Park


 

 

John Hammonds: “- All major theme parks have had delays. When they opened Disneyland in 1956, nothing worked, nothing!”

 

Dr. Ian Malcolm– “But John, but if the Pirates of the Caribbean breaks down, the Pirates do not eat the tourists.”

 

 

 

  

 

 

“If there is one thing the history of evolution has taught us it’s that life will not be contained. Life breaks free, expands to new territory, and crashes through barriers, painfully, maybe even dangerously.”

 

 

 

Is the premise of the dinosaur’s DNA obtained from the mosquito possible?

 

What is the Lysine Contingency?

 

Visit the updated Moviecular Biology page!

 

 

Polygamy, Endogamy and Fumarase deficiency.


 

 

 

Original Question

 

Q ( B-08 ) ¨ The deficit of enzymes of the TCA cycle is rare, indicating the importance of this pathway for survival. Several cases, however, are on record in which there is a severe deficiency of the enzyme that catalyzes the interconversion between fumarate and malate.  The patient is characterized by severe neurological impairment, encephalomyopathy, and dystonia developing soon after birth. Urine contains abnormal amounts of fumarate and other metabolites of Krebs Cycle. Which of the above enzymes would be deficient?

 

 

A ( B-08 ): (d) fumarase (aka fumarate hydratase deficiency)

 

 

The twin border communities of Hildale, Utah, and Colorado City, Arizona, have the highest prevalence of known fumarase deficiency cases. And around half the world population of known fumarase deficiency patients have been found in Arizona (Birth Defect is plaguing children in FLDS towns)

 

Hildale, Utah:

  

 

 

Colorado City, Arizona:

 

 

 

  

Why?

 

Because of the existence of two closed communities in this area, founded by fundamental polygamist whose families are very inbreeded. In fact, it should be noted that it was not the polygamy which produces this high prevalence of the fumarase deficiency, as could be understood from some press reports, but the fact that this polygamy occurred in a closed population and with a high endogamic behavior. Apparently the founders had a recessive gen for the fumarate deficiency and the marriage among relatives of these two families, or among relatives in the same family, produced the high prevalence of this genetic  disease.

 

For more information about the history of these communities and the prevalence of fumarase deficiency in them, follow these links:

 

Polygamist community faces rare genetic disorder

 

 

Tracing the Polygamist’s Family Tree

 

 

 

 

 

More information about Fumarase deficiency:

 

Kerrigan, J.F. et al: Fumaric aciduria: clinical and imaging features.

 

Genetics Home reference: Fumarase deficiency