“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

Q: About GSD and Glycogen structure (C-09)


 

Andersen’s Disease is a rare disease caused by the deficit of the Branching enzyme, responsible for the formation of branches in glycogen structure. This results in an abnormal glycogen with few branching points and long peripheral chains. Clinically, hepatoesplenomegaly, cirrhosis of the liver and hepatic failure are major concerns. As the problem is located in the branching points, it is obvious that there is a defect in the formation of:

 

a)     Alpha 1,4 -O-glycosidic linkages

 

b)     Alpha 1,6 -O-glycosidic linkages

 

c)      Alpha 1 ,Beta 2 -O-glycosidic linkages

 

d)     Beta1,3 -O-glycosidic linkages

 

e)     Beta1,4 -O-glycosidic linkages

 

f)       Beta1,6 -O-glycosidic linkages

 

About Muscle Glycogen Phosphorylase Deficiency (GSD V)


Answer to CM-02

 

Original Question

Answer: (c)

                                    https://i2.wp.com/www.gfmer.ch/International_activities_En/Images/Leonardo/Muscles1.jpg

An important energy source for exercising muscle is anaerobic glycolysis, using glucose from the blood, that is converted to glucose 6 (P) inside the muscle cells, and glucose 6 (P) formed from glycogen stored in the muscle. The final product of anaerobic glycolysis is lactate.

The lactate diffuses from the muscle to the blood and then is transported to the liver where it is converted in pyruvate.

This patient is not able to use the glycogen stored in his muscle to obtain energy, since he lacks muscle glycogen phosphorylase, which degrades glycogen to glucose 1 (P). Normally this glucose 1 (P) becomes glucose 6 (P) in a reaction catalyzed by phosphoglucomutase and then glucose 6 (P) enters glycolysis. Due to this patient inability to degrade glycogen, it accumulates in the muscle fiber (it is called Glycogen Storage Disease Type V or McArdle Disease), the patient present fatigue very early in the test and the concentration of lactate in blood drawn from the forearm is lower than in a normal person.

Glucose in blood is not affected since muscle glycogen does not buffer blood glucose.

 

For more information about McArdle Disease, click on these links

Cupler, E.J.: Glycogen Storage Disease Type V

Stojanov, L.:Glycogen Storage Diseases Type I-VII

Association for Glycogen Storage Disease

The association for Glycogen Storage Disease UK

                        Leonardo anatomy muscle drawing

Q: About glycogen phosphorylase deficiency (CM-02)


In the study of a 14 year-old male patient who you suspect has a deficiency of muscle glycogen phosphorylase, you indicate a test based in exercising his forearm by squeezing a rubber ball. Compared with the normal person performing the same exercise, this patient would exhibit which of the following?

 

a)     Exercise for a longer time without fatigue

b)      increased glucose levels in blood drawn from his forearm

c)      decreased lactate levels in blood drawn from his forearm

d)     lower levels of glycogen in biopsy specimens from his forearm muscle

e)     Hyperglycemia

f)       Hypoglycemia

  

 Answer