8/27/2012

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ALD and LORENZO’S OIL-How much do you know?| By:N. BAFAZINI;Student #:2009078425

BOC 344 TURNING MYSTERY INTO VICTORY; MAKING A MARK IN THE MEDICAL HISTORY ;

LEAVING NO ROOM FOR ERROR .-

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2 INTRODUCT ION :

To introduce this study on a very rare genetic disorder disease known as

Adrenoleukodystrophy (ALD), I would first like to refer to the movie

Lorenzo’s Oil. This movie gives a clear perspective and understanding of the

journey people afflicted by ALD goes through, the sufferings, the impacts on

family, on societies etc. and how it all changes and all they ever had fades

into nothing.

In this movie, Lorenzo is portrayed first as a normal boy with a normal

childhood; doing everything a child of his age did until it all changed in a

split second. He moved from hero to zero. First he showed signs of aggression

towards other students which bothered teachers. They explained this radical

behavior as hyper activeness and disorientation. However, the parents-Augusto

(father) and Michaela (mother)-could not understand all that as they had

never seen him so, until they did. Taking him to a doctor, that is where

after a number of tests which ruled out a lot of diseases, it was discovered

that he has ALD. As the severity of the disease and how long its victims get

to live-two years at most- was explained to them, they refused to accept such

a “curse” rather, however devastated and torn they were; they devoted their

time, lives, energy and all to standing up and fighting back. They took it

upon themselves to find a way to “beat” the disease proclaimed as a dead-end

type of ailment with no cure nor hope.

It is every one’s fear to watch our loved ones suffer to death knowing that

there’s nothing we can do to help. Even when given zero chances and no how

much of a hopeless situation we seem to be swamped in, we all do try all we

can so that at the end of the day we can at least be able to say,” I tried, I

did what I could, when I could up to the limit of my knowledge and when I

knew better I did better, therefore if I knew best, I could have done more;

either way, I tried!” I know this very well because I know it from first

hand. Last year March; those were my words at the end of it all. Even though

I still lost her-my little sister-only at the age of nine after going through

hell in hope that she would make it, I still know even today that I did all I

could, even overstepped my rank, but.... However, Lorenzo’s parents did all

the research and regardless of their lack of neither biological nor medical

health knowledge, they did, with their unstoppable determination and devotion

find a way to help all the children with ALD by manipulating the biochemical

pathway of the disease. This proves that it’s not always about how much one

knows, but about how bad they want something and how far they are willing to

go, that their hard work will pay back.

At the end, Lorenzo’s oil is developed of which as a result of it, Lorenzo

started showing signs of improvement such as ways of communication, which

meant that his levels of VLCSFAs were back to normal. At this moment, it

certainly did not matter how many friends and/or family they lost, how much

rejection they encountered, how much criticism on their lack of knowledge was

thrown at them in the process, finally; they conquered and their son would

see more years-which he did give that his mother even died before him, who

would have guessed??

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3 EP ISODE 1

SHORT HISTORY...

A great interest in the disease has was just recently, maybe due to what a

medical breakthrough Lorenzo became, but it has been around for quite long.

Moser et. al (1997), the disease was first seen in 1910 by Haberfeld and

Spieler in a boy who lost whole body function at the age of six and died

around the age of 8. At that time, the biochemical pathways leading to the

disease were not know even though it was obvious that the myelin was been

degraded in children cerebral hemisphere, which was discovered 3 years later.

It presented itself as multiple sclerosis and so for some time it was treated

as one of those yet with distinct differences, until then and it was grouped

under X-linked genetic disorder. Finally the symptom of the disease was

discovered in 1953 by Powers and Schaumburg. With some advancement in

technology then, they were able to realize cholesterol deposit in the brain

which prompted a conclusion that it is lipid/fatty acid based especially very

long chains of saturated fatty acids. Then followed the finding of the

location at which the reactions occur as well as enzyme(s) responsible. Then

finding that it’s an oxidative reaction that’s at fault, it dragged along the

fact that fatty acid beta-oxidation occurs in the peroxisome (Sigh et al

1984a, b). mostly with inhibitory disorders, if the first step in the

reaction is inhibited due default enzyme, then the rest of the steps do not

happen and so this was the believe; that fatty acyl coA synthase is the

inactive enzyme until it was discovered that the faulty gene actually codes

for a membrane associated transporter protein called ALD-Protein, which

facilitates their transportation across the membrane to the peroxisome for

their beta-oxidation. The saturated very long chains of fatty acids (VLCSFA)

accumulation were then treated through assign a dietary protocol of combined

mono unsaturated fatty acids, oleic (4): erucic (1) acids which are a form of

enzyme biochemical pathway manipulation strategy. However, some therapeutic

strategies such as bone marrow transplants and Immunosuppressions were

brought into use and bone marrow transplantation seemed better... regardless,

the breakthrough of the disease was the development of Lorenzo’s oil...

EP ISODE 2

.....BUT REALLY, WHAT IS ALD?

The acronym ALD stands for Adrenoleukodystrophy; a genetically inherited

disorder resulting from the degradation of the lipid myelin sheath

surrounding the neurons; which intern is caused by the over accumulation of

Long Chain of Saturated Fatty Acids in the brain. This brings up and

important question though, what is MYELIN?

Myelin is produced by plasma cell of Schwann cells and is highly composed of

a type of sphingolipids called sphingomyelin. This sheath is in actual fact a

mound of membrane layers surrounding the cells of the central and peripheral

nervous system-(neurons). Its function is to insulate-has high lipid content

than of protein-, protect as well as prevent conduction across the membrane.

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4 Within this type of lipid, (sphingolipids); there is a continuing metabolic

turnover in both synthesis and degradation. The latter occurs in lysozomes

through the action of hydrolytic enzymes. These pathways however, appear to

be massively connect to “congenital” diseases named lipid storage diseases,

(sphingolipodoses), i.e. highly severe diseases associated with incompetence

and/or deficiency in any of the degradative enzymes leading to an

accumulation of the substrate. This therefore imposes severe malfunctioning

of the central nervous system as they-sphingolipids- are in large amounts in

nervous tissue. The efficiency in neural impulse transmission, i.e.

movements, thinking, speech, etc. all depends on the amount of insulation

around them by the myelin hence why upon its degradation; serious symptoms

are observed on those inflicted such as ALD.

There is however different forms of the disorder. There is

Adrenomyeloneropathy (AMN). It presents itself as multiple sclerosis-meaning

there is gradual but progressive loss of body function yet there is no great

damage to the brain. It has the occurrence percentage of 40%-45% and affects

males of middle age. It can in some people appear as Addison’s disease and/or

adrenal gland disorder as a start. This is mainly due to its mechanisms of

attack,-damages the adrenal gland-and any children of 2 year and above

diagnosed with Addison’s have to be tested for ALD. The most adverse of them

all is the type that destroys the nervous system, the entire body’s control

center; childhood cerebral type administering progressive deterioration of

the myelin in the cerebral cortex, spinal cord, white matter and brain

inflammation. The first diagnosis can be made at the ages of four to eight

with immediate disability, loss of cognition and shut down, finally death

mostly even before the first decade; and this is of course the type Lorenzo

had.

EP ISODE 3

THE GENETICS BEHIND ALD- IT’S ACTUAL CAUSE...

ALD is an autosomal recessive X-linked genetic disorder affecting males only.

What does this mean and why is that??

For every phenotype, there is a gene that codes for it which intern is coded

for by a pair of alleles. The genetic makeup of an individual is such that in

each pair, one is maternal while the other is paternal. Within them, there

are recessive and dominant forms where the latter actually fully overrides

the expression of the former when both in an individual. That is for example,

if in a flower red color is encoded by a dominant allele and white by a

recessive one, then the flower color is going to be red if they both co-

exist. However, it is not just this simple, genetics deals with

probabilities. There is three ways in which the genetic makeup can be

acquired, homozygous dominant (AA), homozygous recessive (aa) or heterozygous

(Aa). When speaking in X-linked/ sex linked genetics terms, there is also

hemizygosity- dominant and recessive- which refers to males as they only have

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5 one X chromosome-see sex determination- they receive maternally and then the

sex determining Y chromosome (XAY or XaY) while females have both Xes (XAXA,

XaXa or XAXa). This therefore means that in X-linked disorders, males will

always be inflicted if the mother is inflicted, again it’s a probability.

SEX DETERMINATION:

NB: XX=FEMALE ANF XY=MALE

With ALD, the disorder coding allele is recessive meaning the son will only

be inflicted if by chance he receives the recessive allele other than the

dominant one,(unfortunate lottery, so they call it.) giving him XaY genotype.

However, the mother in this case shows no signs or symptoms of the disorder

yet the son receives the disease from her, how is that? Well, since its

recessive, the mother has the dominant allele that tramps the expression of

the recessive one and is

therefore just a carrier of the

disorder but not affected while

sons carry a 50% chance of

having the disorder and girls a

50% chance of being carriers. -

X-LINKED RECESSIVE:

GENOTYPES:

Mom=XAXa

Dad=XAY

Results: Sons: 50% Unaffected

50% affected.

Daughters: 50% unaffected

50% carrier

As explained in GEN 216,

pedigrees.

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6 There is a very slight chance though; of having affected female give how rare

the disease is (1 in 100,000 occurrence frequency. allelic frequencies) and

its motility rate. If Lorenzo per say, married a carrier wife:

GENOTYPES:

Lorenzo= XaY

Wife= XAXa

XA Xa

Xa XAXa XaXa

Y XAY XaY

RSULTS: OUT OF ½ GILS AND ½ BOYS

½ AFFECTED AND ½ UNAFFECTED in both sexes but the female is a carrier.

With non-sex linked inheritance such as mitochondrial either dominant or

recessive but in this case focusing on the recessive form, the faulty gene/

allele need not to be carried specifically on the X chromosome- (see ALD

chromosome mapping- mapped as Xq28, terminal segment of the X chromosome arm

(Moser et. Al 1981). For example:

PARENTAL GENOTYPES: Parent 1= AA (homozygous dominant)

Parent 2= Aa (heterozygous)

PUNETTE SQUARE:

A A

A AA AA

a Aa Aa

RESULTS: ALL UNAFFECTED; 50% homozygous dorminant And 50% heterozygous/

carriers

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7

But if both parents are carriers- heterozygous- Aa X Aa

A a

A AA Aa

a Aa aa

RESULTS: ¾ UNAFFECTED with 2/4=carriers and ¼ homozygous dominant. In this

case, there are ¼ chances of having an affected child even though it cannot said for certain whether its boys or girl. This means both parents have to be

carriers of the diseases and are not affected.

X-ALD CHROMOSOME MAP:

ALLELIC FREQUENCIES CULCULATIONS: - just for interest sake:

Calculations are done using the Hardy-Weinberg law equation. This law works

under a number of assumptions such as no change in gene frequency from

generation to generation, no mutation, migration, genetic drift, inbreeding

and selection, large population with random mating. ALD (ignoring that it’s

X-linked) has an incidence of 1/100,000= 0.00001 (aa) hence the frequency of

individuals with it in a population is represented by q2; its recessive.

Equation: p2 + 2pq + q2 =1

Frequency of recessive gene:

q= √q2= √0.00001 = 0.00316 (a)

p + q = 1; therefore p frequency = 1-q

= 1-0.00316 = 0.997 (A)

P2 = (AA) = (0.997)2 = o.994.

Frequency of carriers (Aa): 2pq = 2(0.997) (0.00316) =0.00631.

All should add up to 1; (0.997)2 + 2(0.997*0.00316) + (0.00316)2= 1

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8 NB: IN X-LINKED DISORDERS: X-linked gene in question will equal the frequency

of males (XY) expressing the X-linked trait. For females (XX), the frequency

of having the gene will be = q2 if only the gene frequency = q.

EP ISODE 4

.......ANY SYMPTOMS AND CAUSE

As it is with every disease, there are of course symptoms ALD imposes.

However, let me speak in particular about those Lorenzo showed. He first

showed aggression, hyperactivity and disorientation which were followed by

severe symptoms such as loss of vision, hearing, movement, difficulty in

swallowing, fatigue, loss of coordination and more. The progression is due to

the inability of the body to re-build its myelin like it can with dead tissue

leading to increased destruction of the sheath with time. With each form of

the disorder, there is symptoms associated and the rate of progression differ

greatly in accordance to onset age, length of survival and neuropathology and

so the rate of progression is slower in AMN. However, the prime biochemical

basis of the disease remains unvarying; i.e. the increased levels of un-

branched saturated VLCFAs.

All the symptoms mentioned above are a visual projection of internal

biochemical reaction causing the disease.

Mostly, genetic disorders are associated with enzyme malfunction due to a

faulty gene that codes for it. For instance, if the mutated enzyme is

catabolic and catalyzes glucose metabolism, there will be glucose build up in

the body, no glycolysis, hence no intermediates for Krebs cycle or any other

metabolic pathways which are necessary for cellular functions and survival as

they yield energy to facilitate all that. This will consequently result in a

number of severe problems.

Nonetheless, default in transporter proteins that facilitate substrate or

enzyme transportation across the membrane to their precise location of

catalysis, can also pose similar inconveniences. In the case of ALD, the

patient has an impaired ability to metabolize saturated VLCFA, resulting in

their excessive accumulation; in particular tetracosanoic acid (lignoceric,

C24:0) and Hexacosanoate (cerotic C26:0). It was discovered that it is not

about the enzyme responsible for their catabolism rather the ALD-Protein, a

form of ATP- Binding cassette, responsible for their transportation to the

peroxisome where they are broken down through beta-oxidation; (or peripheral

tissue or mitochondrial matrix for short fatty acids). This process provides

the cell with a lot of intermediate giving it of energy (ATP) essential for

all cellular reactions.- (it yield acyl coA, FADH2, NADH and CO2 + H2O-all

release a lot of energy upon oxidation.-see reaction 1.)

Before the gene was isolated by positional cloning (Moser et. al. 1993); it

was assumed that the problem was failure in fatty acyl- coA synthase

activation thereby unable to carry out the very first step in fatty acid

beta-oxidation- cycles of dehydrogenation, hydration, dehydrogenation and

thiolytic cleavage-; consequently putting at halt all reactions that follow

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9 thereof. However, it was discovered that in animals, the peroxisomal

oxidation only goes up to C4 and C6-acyl-coA which are not very to transport

throughout the body or even to excrete along with urine. The products are

thereby transported to the mitochondria-now that they are shorter- where

further oxidation is bound to occur.

Reaction 1 :( Matthews, Van Holde, Ahern, Biochemistry 3rd Edition, page 646)

E + FAD + R-CH2-CH2-C=0-S-CoA R-CH=CH-C=O-S-CoA +E-FADH2

E-FADH2 + O2 E-FADH + H2O2

H202 H2O + 1/2O2

ENERGY YEILD FROM OXIDATION:

Acyl-CoA 12 ATPs

FADH2 2 ATPs

NADH2 3 ATPs

NB: this is per mole of a cofactor.

EP ISODE 4

WHAT ARE FATTY ACIDS??

These are amphipathic molecules made of a fatty-acyl group and a hydrocarbon

chain. They consist of a polar (hydrophilic) carboxylic head group and a non-

polar (hydrophobic) hydrocarbon chain tail, project different structures,

degree of unsaturation, length and more. There are two main forms though,

saturated and unsaturated and in both, they are either long-(>24 carbons) or

short (1, 16 or 18 carbons). Their relationship with water is the fundamental

bases of membranes structure- the hydrophobic tails are converge towards one

another inward while the hydrophilic heads get in contact with water.

Health wise, the unsaturated form is preferred over unsaturated. This is

mainly due to the fact that the double bonds form bents within the molecule

hence are easily broken down and the more the double bonds the less the

energy (temperature) required to degrade them; especially the cis double bond

since trans bond tend to mimic the saturated fatty acid make-up therefore

still not good. However most fatty acids synthesized by the body have cis

double bonds and are unsaturated, e.g. oleic acid (see fig1). Saturated fatty

acids in one hand, they form a very tightly packed and rigid structure,

therefore the more saturated and longer the chain, the more the energy the

body expends to break them down -10,000 times slower deterioration (Ito et.al

1995) see fig.2.However, unsaturated fatty acids can be converted to

saturated fatty acids through addition of Hydrogen- hydrogenation- thereby

breaking the double bond; e.g., vegetable oil to margarine.

CATALASE

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10

Figure 1 Oleic acid Figure 2 Cerotic acid

With ALD, be in context; C24 and C26 are the saturated very long chains of

fatty acid that seem to be of very high levels in the blood, in nervous

tissue, adrenal cortex etc. Even though Lorenzo was placed on a certain diet

that restricted his consumption of foods that contained VLCFAs meat, fish,

cheese, peanut butter etc., his levels kept increasing, as the body continues

their biosynthesis. These are the two ways in which the body acquires them.

EFFECTS OF THEIR EXCESSIVE ACCUMULATION –VLCFA- IN THE BODY/BRAIN...

Fatty acids are efficient in energy storage, heat production and insulation

due to the carbon in the head group being fully reduced leading to production

of a lot of energy upon its oxidation. The myelin sheath is in actual fact

responsible for neuron insulation. In a person with ALD cells with normal

cDNA, there is a smooth distribution of VLCFAs within respective tissues and

the opposite is true for ALD. Their continued accumulation, especially in the

brain; results in their coiling around the myelin sheath and degrading

it.(fig.3) The mechanism in which this happens is not very clear though, but

speculation is based on their structure. The fact that they have no kinks

prompts their ability to associate themselves with the myelin, making it

soluble and liquefying it leading to its wash away from the neurons. It does

this by surrounding the myelin with the hydrocarbon head with the hydrophilic

heads sticking out- forming some kind of a micelle around it.

Figure 3 .DESTROYED NYELINE SHEATH AROUND NEURONS; & HEALTHY MYELIN

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11 EP ISOD E 5

DIAGNOSIS AND TREATMENT

DIAGNOSIS:

ALD patients show very high levels of VLCSFAs in their bodies to an a point

where they are reflected in body fluids and this aids the diagnosis using

blood plasma and skin fibroblasts (Moser et. al 1983a). Culturing of the

tissues/cell and checking their level of VLCSFA can therefore give doctors a

definite answer of whether the person has the disorder and even the level the

disease severity given the levels. There is however, a room for error, i.e.

there can be found false negatives, as a result other advanced techniques

such as biochemical methods and gene mutational analysis of the ALD-Protein;

are employed especially for the diagnosis of less adverse forms of ALD like

AMN in grown-ups and women heterozygous for the disease. Brain scans-MRIs- of

patients will also display abnormalities on the region of white matter. (See

fig.5)

Figure 5 BRAIN SCANS SHOWING DETORIORATION IN MYELIN

TREATMENT AND CURE:

There is no cure for the disorder, unfortunately but there are proposed forms

of treatment. To design treatment for any disease, its mechanisms of attack,

biochemical pathways as well as its causes have to be investigated and

manipulated. This is exactly what the “Odones” did. Augusto tried to find the

easier and everyday life experience way of explaining the problem so as to

find the treatment and that was when he came up with “the kitchen sink

model.” PLEASE REFER TO THE HARD COPY; SAME PAGE!

In the model, the sink is representative of the blood, the two taps, one for

VLCSFAs acquired form food and the other for those acquired though natural

biosynthesis. The opening to the drain represents excretory or degradative

ways while water represents the VLCSFAs. Logically, as both taps are open

with the drain opening closed, the water fill up the sink until the opening

is opened and as a certain volume of water comes in, a certain volume is

released to avoid overflow. However if just one tap is open, the volume of

water coming definitely goes down and so is one that released. With ALD, it

did not seem to be the case in Lorenzo’s blood. Even though the fatty acids

[2009078425]

12 from foods were eliminated, there seemed to be no difference, the levels

remained high, and this was a paradox he had to understand how it was

happening as it helped him realize that the problem is in their biosynthesis.

It took him a lot of research but he finally found the source of the problem.

He formulated yet another model in which two different types of paper clips

were used. One kind represented the VLCSFA-“bad guys” and the other

unsaturated long chain fatty acids-“good guys”. One clip represents two

carbons and Deirdre and him the enzymes each facilitating its own reaction.

Assuming that the enzymes add the carbon in more or less the same rate in

either form when elongating fatty acid during their biosynthesis, what could

cause the good guys decrease as the good guys increase? This stipulated that

there has to be so kind of a relationship between the two enzymes because

that would be the only explanation to the product of one inhibiting another.

This is the “paper clip model” To his surprise; the answer to this paradox

came to him in a form of a dream.

Up to here; he realized that the whole process is enzyme controlled but could

not yet tell how many enzymes were involved. In his dream, both chains of

paper clips were moving at the same time but they were both pulled by one

person; Lorenzo. In this scene, Lorenzo as well represents an enzyme and he

pulling both chains alone implicated that there is only one enzyme

responsible for the biosynthesis of both forms of fatty acids and this was

the solution to both paradoxes.

Enzyme activity is a very complex mechanism but it can be manipulated if

understood. In ALD, looking at the paradoxes, the biosynthesis is at equal

rate but the degradation rates differ, the VLCSFAs are not metabolized at all

hence only they accumulate. This brought up

the competitive inhibition mechanism of

enzyme activity. In the mechanism, the

principle is the substrate of higher

concentrations will be of preferential over

the other since it can cover up more

environments thereby increasing its chances

of coming in contact with the enzyme. The

end result volume-Vmax is similar the only

difference is the concentrations of the two

competing substrates taken up. As a result,

if an ALD patient was to be stuffed with high concentrations of mono

unsaturated fatty acid in the triglyceride form such as oleic acid, then the

rate at which the enzyme associates with the fatty acid would increase

greatly in contrast to saturated fatty acids. Consequently, the enzyme would

be using the un-harmful fatty acid producing long unsaturated fatty acid

instead of long saturated fatty acid chains. Finally, the biochemical pathway

ADL utilizes was manipulated and treatment was found-oleic acid as part of

the recommended diet. Lorenzo’s levels lowered.

However, oleic acid appeared to be partly effective. This became evident when

the VLCSFAs in Lorenzo’s blood increased again and a second alternative had

[2009078425]

13 to be made. Discovering that oleic acid cis double bond is very low in the

chain and to stop the synthesis of the “bad” guys the chains have to be

blocked a bit higher in the chain between C22 and C24, the doctor’s opinion

was only the mono unsaturated C22 Erucic (glyceryl trierucate) acid could be

an additional competitor against the saturated fatty acids. It is longer that

oleic acid (cis-9-Octadecinoic, C18:1). Regardless, it was considered

inconsumable to humans because it caused cardiac arrests in rats, damage to

the adrenal gland etc there was therefore no way it could be approved for

human drug trials by the Human Studies Review Committee. However, Augusto and

Michaela found it their own way and administered it to Lorenzo either way, in

conjunction with oleic acid. This is LORENZO’S OIL, in 4:1 oleic: erucic acid

concentrations and with is monitored daily administration, Lorenzo’s levels

of VLCSFAs (C24 and C26) dropped down to normal and signs of development in

his condition showed, he could swallow on his own; for starters, then gained

vision and the rest followed .However; the oil could not repair the destroyed

myelin, but could stop its further degradation. The side effect reflected

from the treatment appeared to be reduction of platelet count in the blood.

Platelets play a crucial role in blood clotting. They are the basis of

bleeding control and without them a person can bleed to death. This condition

is known thrombocytopenia.

Apart from Lorenzo’s oil and dietary suggestions, there are other therapeutic

ways of treating the disease. Even so, it is highly vital to be careful of

when the treatment is administered to a patient. For positive results, it has

to be started off at early stages before the disease takes a much more severe

course, or else the rate at which the disease progresses to terminal point

may even increase. There is bone-marrow transplant. The transplantation of

normal bone-marrow cells with the correct code for ALD-Protein into a patient

proved to increase the capacity at which VLCSFAs are degraded thereby proving

to have the ability to correct the mutation somehow. Immuno suppression is

yet another way. However, it is not as effective since its main aim is to

convert the severe form into a milder form like AMN in trial to lower the

rate of inflammatory response observed in the brain as the disease worsens.

Yet to be put into functioning and use is Gene therapy. The gene has been

isolated and proved to refract the deficiency in the metabolism of VLCSFA in

ALD cell cultured (Cartier et. al 1995). Of all these, parental genetic

counseling and family history is still the best in my opinion because it

prepares the parents, even gives them the opportunity to make a choice of not

having children give their chances, as well as allow earlier treatment

administration.

EPISODE 6

[2009078425]

14 LET’S TALK VIEWS...

With every drug development, there is a set of steps to follow especially the

drug trials step. Trials are first done with animals- rats- and if only

proven safe, the drug can then be approved for human clinical trials. It is

not an easy decision to approve drugs and sometimes that alone is a problem.

Use of Erucic acid for human consumption was not approved as it fail in

animal trials but given the pressure the Odone family felt, they went beyond

measures and used it without approval on Lorenzo. This became a problem as

there was no allowed usage and they had to be his guinea pig regardless of

any reasonable risks they were warned about such as the fact that there is no

specific set daily consumption per serving/day. This would result in over

consumption leading to even further complications such as cardiac arrests and

others. It was also argued that there is no knowledge as of to how much

Lorenzo could digest fatty acids which would in return relate to the amount

to consume and more. Their behavior proved the code,” desperate times,

desperate measures!” they were desperate and took every chance they found.

This could have been really gone badly if this was a different case or if one

was highly allergic to it. However in using the aunt as a “rat” seemed highly

justifiable and appropriate as this was the final product and she was an ALD

carrier as well.

Human disorder are really hard to break because every step in drug

development goes against every ethical amendment, there is a lot of paper

work to handle, there cannot be a control group therefore no way to correlate

progress. I remember Prof. Bragg; he was talking about HIV/ any other virus.

He emphasized on the fact that there cannot be a volunteer to be injected

with the virus and live to surfer just for the sake of a medical

breakthrough, which is true and also the opposite would be unethical and feel

like murder and I argued that that’s him justifying why he specializes with

animals. However, it is true. Doctors have protocols and rule to follow and

they cannot take certain risks with patients hence why sometimes the parents

and society should throw in here and there a little incentive into pushing

them to the extremes like Augusto did. He actually worked hard to bring

together a group of doctors who had never worked together before, each

bringing their specialties to try finding a solution to the shaking dogs’

problem. The dogs were born without myelin and the task was to find a way to

remyelinate them. Their working together led to a fast finding of the answer

and the dogs were remyelinated and stopped shaking, subsequently so were

human trials initiated. Not only that, he also release an article which they

pushed for its publication so as to spread word and initiate interest and

curiosity in doctors which would result in their interest in the disease,

even though such researches are really expensive and require funding. This is

not a matter of ethics it’s a matter of demand, supply and profit and that

is; the reluctance in funding such researches based on facts like, they are

very rare; so does that mean they can die it’s an acceptable loss anyway?

Where are their ethics now?

LET’S TALK MY VIEWS...

[2009078425]

15 Putting myself in Michaela’s shoes, being told that I left the window open

and so were robbed scares me and I make sure that I never do it again; what

more of being told that my son is sick and dying rapidly with every passing

minute and it’s all because of me? I understand how she was feeling and so

she expected everyone to feel what she was feeling- the need to try correct a

mistake yet unfortunately this one could not be refracted, because it was not

a mistake, but nature. She was under pressure and so she released it to

nurses, family and pretty much everything that that everything that didn’t

agree with her. The advancements present now in medicine were not available

then and even knowledge and care about family histories and genetic

counseling were not of concern. What am I saying? I am saying with all I know

right now, I would have a child either being a boy or girl because there is a

chance that I may not have an affected son or even not have a son at all,

just have daughters and so I think no law or doctor should stand in my way. I

somehow think it’s about time the ministries of health take into

consideration investing in the investigations and researches of diseases like

ALD as much as they did and still do with HIV- no wonder so many people are

infected-. I intend to be a medical microbiologist focusing on human

pandemics and concentrate on researches on diseases like ALD. I know is not

viral, but been that as it may, it still remains part of the medical

breakthroughs history.

EP ISODE 7

*****CONCLUSION: *****

[2009078425]

16 All in all, ALD is genetically inherited and cannot be controlled like an

infectious disease and even so, carrier women should not be burnt from having

children. X-linked disorders such are quite rare and their occurrence is

quite slim as well especially with recessive form. All the forms of treatment

derived for ALD focuses mainly on refracting the VLCSFA which accumulate in

the brain due a default ALD-Protein (745 amino acid long)- responsible for

their metabolism; and take back their levels to normal, and each in their own

way yet the end game is the same. This is a very severe disease even though

rare and therefore needs to be taken into consideration. There are different

forms but, childhood cerebral form is the most fast progressive form

resulting in retardation. This is due to the rapid degradation of brain

myelin sheath with time. The brain is like a computer CPU, its destruction,

there is no computer, and so this is the very same case with ALD, it destroys

first the brain and the rest is history. The general knowledge about the

disease was that its patients do not live to see even the first decade but

that was until LORENZO’s OIL, a combination of two mono unsaturated long

chain fatty acids; erucic and oleic acid; was developed by Augusto and

Michaela Odone. The oil initiates competitive inhibition which is the basis

of ALD treatment and it is based on the biochemical properties of the

disease. Given everything, it is still necessary for further researches to be

carried out and bring in new advancements on how to deal with other disorders

like ALD. Parents of affected children will always have a disagreement with

doctors whenever they try protesting any initiation of treatment. Support

groups such as ALD foundation are really important and play a vital role in

helping the parents cope emotionally in knowing that they are not alone and

by sharing ideas that may be of help for both the sick child and the parents

too.

In a nut shell; this is one of the successful researches in medical history,

only because someone was willing to go beyond and because of that lives can

be saved. All going over board and taking no consideration none whatsoever

about any ethical law finally paid up, it was not all for nothing.

NB: VLCFAs in plasma: C22:0, C22:1, C24:0, C22:1, C26:0 and C26:1

“All great and honorable actions have been accomplished with great

difficulties and both must be enterprise and overcome with answerable

courage”

- William Bradford

REFERENCES :

TH E L AST CH PTER…

[2009078425]

17 Moser, H.W. (1997) Adrenoleukodystrophy: phenotype, genetics, pathogenesis

and therapy. Brain 120, 1485-1505

Rosen, F.S. (1993) Precious treatment Nature 695

Rizzo, W.B. (1993) Lorenzo’s Oil-hope and disappointment. New England Journal

of Medicine 801-802

Mathews, Van Holde, Ahern, Biochemistry, third edition (2000)640-651

Lorenzo’s Oil movie

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http://clasfaculty.ucdenver.edu/bstith/loren.htm-31/07/2012 @ 10:56

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