“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


About Tea and Toasts


A 70 year-old English lady that lives alone is admitted to the hospital for evaluation of a leg wound that is not healing properly. The patient also complains of pain in muscle and bones. On the examination, you find some hemorrhagic lesions in the skin, including ecchymosis in buttocks and both legs and petechiaes in other areas of the skin. The nails show splinter hemorrhages. When asked about her dietetic habits, the patient refers that she is too old to eat so much, so she has a very frugal lunch and dinners based mainly in tea and toasts.

Laboratory examinations show normal blood coagulation tests and Hemoglobin of 9.8 g/dL


The treatment for the condition described above should consist mainly in the administration of the following vitamin:


a)     Ascorbic Acid

b)     Biotin

c)      Folic Acid

d)     Pantothenic acid

e)     Niacin

f)       Vitamin B1

g)     Vitamin B2

h)    Vitamin B6

i)       Vitamin B12

j)       Vitamin D

k)     Vitamin E

l)       Vitamin K

About Residency Match 2009

The largest match in History!


                   “Almost once” (aka “The Big Match”), Domain Sculpture Walk, Sidney, Australia.


According to a press release  of the NRMP, this was the largest match in History.


Active applicants:


15 638 seniors from US Med schools

10 874 graduates from International Schools

  2 015   from Osteopathic schools

  1 222 previously graduated



Total:  29 890 active applicants


PGY-1 Positions offered: 22 427 (the most ever offered by the NRMP)


Which active applicants matched in Post Graduate Year I (PGY-1)?


I have used the numbers in the tables of the NRMP for organizing this “gradient”  that illustrates the percentage of each population of graduates that matched. 


a) 93.1 % of active applicants of seniors of US allopathic medical schools.


b) 71.4 % of active applicants from Canadian Medical Schools matched


c) 69.9 % of active applicants of osteopathic medical schools matched


d) 61.3 % of active applicants of Fifth Pathway programs


e) 47.8 % of US citizens active applicants of International Medical Schools


f) 44.6 % of active applicants previously graduated of US allopathic medical schools


g) 41.6 % of Non-US citizens active applicants of International Medical Schools.


In total:



71,4 % of the active applicants for PGY-1 matched.


95.2 % of the positions were filled during the match.


64.9 % of the offered positions were filled by US Seniors, and 30.3 by other applicants.


A complete information, including all the tables can be found at the site of the NRMP


Advance Data Tables.

2009 Main Residence Match


                                                       Artist Brett Whitely, 1991; photo: Lyn Jones




Q: About Micronutrients and pregnancy


A very anxious 30 year-old female patient goes  to your office because she is late 10 days.  The patient tells you that she is trying to have a baby,  since in a former pregnancy, two years ago, she lost a baby that was born with anencephaly. You indicate pregnancy tests but they do not confirm pregnancy.

Even when the pregnancy test were negatives, which of the following micronutrients you should prescribe to this patient?


a)     Ascorbate


b)     Calcium


c)      Cianocobalamine


d)     Folate


e)     Iron


f)       Niacin


g)     Riboflavin


h)    Vitamin A


i)       Vitamin D


j)       Vitamin E


k)     Vitamin K


Q: About dry eyes, dry skin…


A 45-year-old, overweight male patient  presents to his physician complaining of dry skin with rash episodes, a sensation of dry eyes and lost of vision, mainly at night.  During  questioning,  he says he lost 60 lbs. during the previous year, following a very strict fat-free diet that he modified from some readings.


Which of the following liposoluble vitamins could be deficient in the patient and causing the above described symptoms?


a)     Vitamin A


b)     Vitamin D


c)      Vitamin E


d)     Vitamin F


e)     Vitamin K


Biochemistry Question CM-22


A 15 year-old patient complains of painful muscle cramps when performing physical exercise, followed by stiffness and weakness, and excretion of wined colored urine. A muscle biopsy indicates a muscle glycogen concentration much higher than normal. Deficit of which of the following enzymes is most likely causing these problems in this patient?


a) Creatin kinase


b) ATP synthase


c) Glycogen phosphorylase


d) Glycogen synthase


e) Glucose 6 phosphatase


Cataracts and Biochemistry of the Lens


Original questions:






The light should pass through the cornea, aqueous humor, lens and vitreous humor before reaching the retina for triggering the process of vision. These structures should be transparent in order to allow the path of light.



The lens (m in the figure) is bathed in its anterior side by the aqueous humor (i) and in its posterior side by the vitreous humor (o). It has no blood capillaries (that would interfere with light path), so the aqueous humor is responsible of the nutrition of the lens and the disposal of metabolic products.


The energy necessary for the lens is provided mainly through anaerobic glicolysis; the Krebs cycle, located in peripheral cells, only provide about 5 % of the necessary energy. Pentose phosphate cycle is also another important metabolic pathway in lens since it provides NADPH necessary for the maintenance of the redox status of the lens proteins.


The majority of the proteins in the lens are alpha, beta and gamma crystallines. They should maintain a transparent environment, so they should be in a native, non aggregate state. Some disturbances, as changes in the redox states of these proteins or changes in osmolarity in the lens can produce lost of the native state and aggregation of these proteins.


Cataracts results from changes in solubility and aggregation of the crystallin proteins.

The most frequent kinds of cataracts are those that appear as result of aging (senile cataracts) or as a result of Diabetes Mellitus (diabetic cataracts). Other conditions can also result in cataracts: cataracts that appear in galactosemia are very similar in the way of production to the cataracts that appear in Diabetes.


Aldose reductase is an enzyme that usually reduce aldehyde group of aldoses to a primary alcohol, so the aldose becomes a polyalcohol. The enzyme uses NADPH as hydrogen donor.


Typical reactions catalyzed by aldose reductase are the formation of sorbitol (glucitol) and the formation of dulcitol (galactitol):


Glucose +NADPH —à Glucitol (Sorbitol) + NADP+


Galactose +NADPH —à Galactitol (Dulcitol) + NADP+

Sorbitol (Glucitol)

Sorbitol (Glucitol)



Aldehyde reductase function is mainly in the conversion of glucose to fructose.

Dulcitol (Galactitol)

Dulcitol (Galactitol)





The sequence of reactions is:


1. – Reaction of Aldehyde reductase:

Consist in the reduction of the aldehyde group of glucose to a primary alcohol group, with the conversion of the aldohexose glucose to a polyalcohol.


Glucose + NADPH.H+ —à Sorbitol + NADP+


2. – Reaction of Sorbitol dehydrogenase (SORD):

      Consist in the oxidation of the secondary alcohol group of Carbon 2 of Sorbitol to

       a ketone group. It results in the conversion of Sorbitol in Fructose, a ketohexose.


      Sorbitol + NAD+ –à Fructose + NADH.H+


This sequence of reactions is particularly important in the formation of fructose in the seminal vesicles and the liver, and it has the advantage over the use of the sequence in glycolysis for obtaining fructose – Glucose 6 (P) to Fructose 6 (P) – that this polyalcohol pathway does not require the expending of ATP.


Lens contains aldehyde reductase and also a very low activity of sorbitol dehydrogenase, so some of the glucose that enter in the lens is converted in fructose. This quantity is usually very low since the enzyme aldehyde reductase has a very high Km for glucose.


In conditions of hyperglycemia, since the concentration of aldehyde reductase substrate (glucose) is high, this enzyme becomes very active, and a high quantity of sorbitol is formed. Unfortunately for diabetic patients, the activity of sorbitol dehydrogenase in lens is very low (enough for normal conditions, but not for this abnormal situation) and for complicating more the problem, sorbitol formed in the lens diffuse with difficulty out of it.


As a result, Sorbitol accumulates and increases the osmotic effects producing cell swelling and structural damage (this effect would explain also the neuropathy and vascular problems present in Diabetic patients).


In the lens, these changes in osmolarity will affect the native conformation of the crystalline proteins, in such a way that they aggregate and form structures that scatter the light: Cataracts are being formed.


In patients with galactosemia, a congenital disease in which the patient can not metabolize galactose and this sugar accumulates, the physiopathology of cataracts formation and nerve damage apparently is similar to the mechanism described for diabetes:


Through the reaction of Aldehyde reductase occurs the reduction of the aldehyde group of galactose to a primary alcohol group, with the conversion of the aldohexose galactose to its corresponding polyalcohol, galactitol:


Galactose + NADPH.H+ —à Galactitol + NADP+


Galactitol accumulates increasing the osmotic pressure with similar results to those found in sorbitol accumulation in Diabetes Mellitus.



For more information, please visit the following links:


About Cataracts


Sorbitol: A hazard to diabetes


About side effects of Sorbitol


About Polyol pathway and arterioral dysfunction in hyperglicemia


About galactitol and cataracts formation in galactosemia