Re: Question re: MELAS diagnosis

[Guest guest]

Dear Mitoldies.

I have a question regarding a diagnosis. I am confirmed with MELAS as are

my children. My mother, now deceased, is presumed to have had MELAS, likewise

her mother, based on their medical histories. My brother was recently

tested for MELAS and the results were negative. This does not make sense. I

can

only imagine a clerical error, a lab error, an error in handling the lab

sample, which was blood, or a lack of test sensitivity. He has a life-long

learning disability, cardiomyopathy, muscle weakness, prediabetic, no hearing

loss

yet, but has sleep apnea for which he uses a CPAP.

My brother is currently applying for SSI based on his clinical signs. The

MELAS diagnosis would provide the evidence to make his temporary supplement

permanent. Besides retesting, do you have any suggestions? If retesting, then

with whom and where? The rest of us have the A3243G mtDNA mutation albeit at

less than 10% heteroplasy. This mutation can be determined with only a

blood test if honing in on this specific defect.

Thank you for your help.

a

[Guest guest]

a

I'm not sure about where to have it tested, but would think that one

of the mito labs would be the best place - Dr. Hoppel, Dr. Shoffner,

Dr. Damouro.

If you have a mtDNA defect and he has the same mother, than he would

have to carry the defective gene. Maybe a mito doc would diagnosis him

based on this.

laurie

> Dear Mitoldies.

>

> I have a question regarding a diagnosis. I am confirmed with MELAS as are

> my children. My mother, now deceased, is presumed to have had MELAS,

likewise

> her mother, based on their medical histories. My brother was recently

> tested for MELAS and the results were negative. This does not make sense. I

can

> only imagine a clerical error, a lab error, an error in handling the lab

> sample, which was blood, or a lack of test sensitivity. He has a life-long

> learning disability, cardiomyopathy, muscle weakness, prediabetic, no hearing

loss

> yet, but has sleep apnea for which he uses a CPAP.

>

> My brother is currently applying for SSI based on his clinical signs. The

> MELAS diagnosis would provide the evidence to make his temporary supplement

> permanent. Besides retesting, do you have any suggestions? If retesting,

then

> with whom and where? The rest of us have the A3243G mtDNA mutation albeit at

> less than 10% heteroplasy. This mutation can be determined with only a

> blood test if honing in on this specific defect.

>

> Thank you for your help.

>

> a

>

>

>

>

[Guest guest]

I vote for retesting too, especially if the initial screening was done by a

commercial lab like Athena.

UCSD has an online searchable database of biochemical genetic laboratories

with lists of the genetic tests performed at each. Unfortunately the way the

database is set up I can't link you directly. Go to

http://biochemgen.ucsd.edu/index.htm and click on Biochemical Genetics

Laboratory Services. Use the drop down menu or try searching on specific

terms.

It does not appear that the database has been updated recently, so the

listings may not be current. I haven't been on the site for several years.

Also, their search engine is not very smart. A search for A3243G found

nothing, but it was there. I found it under mitochondrial mutation screening

on the drop-down menu.

Labs that say they can test for the MELAS A3243G point mutation include

UCSD, Columbia University Myopathy DNA Diagnostics Laboratory, Willink

Biochemical Genetics Unit and Emory. The database provides links to each lab

with specific information on testing, time turnaround, specimen

requirements, etc.

Here is another link to a lab which tests for this mutation. Scroll down to

#7.

http://www.medicine.uiowa.edu/otolaryngology/MorlLab/SendSample.htm

Barbara

[Guest guest]

a,

Myself and my son were both confirmed with MELAS via a blood test. Mine was

tested in 1997 based on my sisters confirmed bloodtest and biopsy of 1996. My

sons was collected 11/19/02 and report date was 1/8/03. The doc who diagnosed

my sister (who had many seizures and went into comas) diagnosed all of us.

We sent his test out to University Childrens Genetics Laboratory in Los Angeles

CA from Milwaukee WI. We opted for only one test and paid out of our pocket at

that time because even though he was having problems with sleeping 18 or so

hours per day every few months when he got sick we did not want to jeoperdize

his chance at life insurance later in life. He was 10 at the time.

His test for 3243A>G mutation came back with " 17.5% of mutant genome in this

specimen "

I do not remember my percentage but remember the doctor saying my sisters was

much, much higher. I myself basically get tired easily, and have diabetes with

blood sugar that goes up with physical exercise and occasional constipation and

pain in legs and muscle spasms. My sons problems are the sleeping problem when

he is sick or over does things physically. I have that problem also. He has

dysmobility which if he does not take the Qgel on a daily basis gets severly

constipated which laxatives just make him cramp, not relieve it.

Anyway, my mother more than likely had MELAS also. She died at age 49 in 1988

of a seizure. She supposedly had epilipsy but we now suspect MELAS. My aunt

died at age 58 after fainting. But, my grandmother lived to be 95.

Not sure why the one test would have come back negative. The mutation gene

should be there. It is how severe the mutation is that cause the severity of

the problems and where the mutated genes are.

I am not sure if the mutations can be in just say the muscle in a certain part

of the body and not the blood.

Hopes this helps a little bit. I have the phone number and complete address for

that lab in California from the 2002 report if you would like it to give to your

doctor. Also, I do know that the blood has to be collected without a torniquet

I believe but was taken from mine and my sons upper part of our hand, not our

arms. You can call me if you need more info on the lab or the doc we used in

Milwaukee.

Janet Sample

Re: Re: Question re: MELAS diagnosis

a

I'm not sure about where to have it tested, but would think that one

of the mito labs would be the best place - Dr. Hoppel, Dr. Shoffner,

Dr. Damouro.

If you have a mtDNA defect and he has the same mother, than he would

have to carry the defective gene. Maybe a mito doc would diagnosis him

based on this.

laurie

> Dear Mitoldies.

>

> I have a question regarding a diagnosis. I am confirmed with MELAS as are

> my children. My mother, now deceased, is presumed to have had MELAS,

likewise

> her mother, based on their medical histories. My brother was recently

> tested for MELAS and the results were negative. This does not make sense.

I can

> only imagine a clerical error, a lab error, an error in handling the lab

> sample, which was blood, or a lack of test sensitivity. He has a life-long

> learning disability, cardiomyopathy, muscle weakness, prediabetic, no

hearing loss

> yet, but has sleep apnea for which he uses a CPAP.

>

> My brother is currently applying for SSI based on his clinical signs. The

> MELAS diagnosis would provide the evidence to make his temporary supplement

> permanent. Besides retesting, do you have any suggestions? If retesting,

then

> with whom and where? The rest of us have the A3243G mtDNA mutation albeit

at

> less than 10% heteroplasy. This mutation can be determined with only a

> blood test if honing in on this specific defect.

>

> Thank you for your help.

>

> a

>

>

>

>

[Guest guest]

Thanks, Joanne, for this information on blood re MELAS mutations and

answering my question to Pamela on blood vs. urine. After reading

your post, I found something similar online at this site.

This information may also be relevant to the other person in the

group (was it a?) who asked recently about retesting for her

brother for MELAS.

http://leedsdna.info/tests/mito.htm

" Levels of mutations in different tissues can vary, for example,

with increasing age MELAS mutations disappear from blood but remain

in muscle.

" Deletions of the mtDNA molecules persists in muscle fibres, the

number of which does not increase significantly after early foetal

life. The frequent cell division of leukocyte precursors could

select against the survival of cells containing defective

mitochondria.

" If mitochondrial DNA analysis of blood shows no mutation in cases

where clinicians are convinced of a diagnosis, it is recommended

that muscle tissue is then tested. This is particularly the case

with the mitochondrial myopathies. "

Barbara

> Mitochondrial DNA mutation analysis on blood, skeletal muscle, or

hair follicles: 1) Individuals with more severe clinical

manifestations of MELAS generally have greater than 80% mutant mtDNA

in stable tissues such as muscle. 2) In rapidly dividing cells,

such as the components of the hematopoietic lineages, A3243G

mutation may segregate to extremely low levels, making genetic

diagnosis from blood difficult. 3) Confirming the presence or

absence of mutation MAY require a muscle biopsy with analysis of

skeletal muscle.

[Guest guest]

Again, remember that we are talking about known MELAS mutations,

there are people who have MELAS, but do not have any known genetic

mutations. Mitochondrial diseases are lumped together, and not

having a specific defect doesn't necessarily rule out a specific type

of mito. (kind of like liver diseases are lumped together, but there

are many)

I have had a fresh muscle biopsy, and it was negative for any

specific known MELAS genetic defects, but I am still considered (by

Dr. Shoffner) to have a " MELAS type " mitochondrial disease.

Testing someone for MELAS, that is in a blood or urine sample, might

be a first step, but certainly (according to my info) one can have

all the signs and symptoms of MELAS without an identified genetic

defect. The hard part is identifying it.

As someone who is a scientist in the general area of biochemistry, I

don't suggest " waiting for the technology to catch up " to proper

diagnosis of genetic defects. IMHO you or your loved one are missing

out on treatment options that have minor risks (such as

supplementation or a changed diet) and can improve your/their

condition tremendously. Certainly although I am frustrated at not

having a genetic defect identified, especially because I have an

affected child who has suspected mito, but I have to say components

of the mito cocktail, and an adjusted diet, have helped me

TREMENDOUSLY.

Take care,

RH

>

> > Mitochondrial DNA mutation analysis on blood, skeletal muscle, or

> hair follicles: 1) Individuals with more severe clinical

> manifestations of MELAS generally have greater than 80% mutant

mtDNA

> in stable tissues such as muscle. 2) In rapidly dividing cells,

> such as the components of the hematopoietic lineages, A3243G

> mutation may segregate to extremely low levels, making genetic

> diagnosis from blood difficult. 3) Confirming the presence or

> absence of mutation MAY require a muscle biopsy with analysis of

> skeletal muscle.

>

[Guest guest]

I did wonder reading and following this thread....I was told ragged red

fibers in the muscle tissue was necessary for diagnosis of MELAS. Other

symptoms I

exhibeted (including red streaks at the back of my eyes which no one has

mentioned) were insufficient. I had my biopsy sent to Shoffner who not only

found

the ragged red fibers but did the dna sampling and found the point

mutation...has this changed? I realize it is quite some time since my

diagnosis.....Vivian

[Guest guest]

I don't have ragged red fibers, when I first was looking into

mitochondrial disease (per my new MDA neuro's suggestion at the

time), it looked like *all* mitochondrial disease had ragged red

fibers. Then it began to look like that MERRF definitely had them,

but others may or may not. I actually don't have any microscopic

(cell or mitochondria appearance related) signs of mito, but the

signficant Complex I defect is there nonetheless.

Shoffner is the one who dx'd me with " MELAS phenotype " , based on

symptoms (stroke-like episodes was a strong indicator) and my Complex

I defect shown by the fresh muscle biopsy, 2 years ago.

Take care,

RH

>

> I did wonder reading and following this thread....I was told ragged

red

> fibers in the muscle tissue was necessary for diagnosis of MELAS.

Other symptoms I

> exhibeted (including red streaks at the back of my eyes which no

one has

> mentioned) were insufficient. I had my biopsy sent to Shoffner who

not only found

> the ragged red fibers but did the dna sampling and found the point

> mutation...has this changed? I realize it is quite some time since

my

> diagnosis.....Vivian

>

>

>

[Guest guest]

I forgot I was also going to mention or ask, I also read by articles in the

UMDF site that a negative gene screen for MELAS cannot rule it out as there

are still so many unknown mutations.

also that muslce is more reliable than blood for MtDna screening.

true or false??

[Guest guest]

I was told the same thing by the lab In NY that did my biopsy and UCSD told

me that it is like finding a needle in a haystack and generally a waste of

time and money unless a specific defect is found that they can look for.

[Guest guest]

When I spoke to Cohen when our mtDNA results came back from Shoffner he told

me that mutations are only found in a very small percentage of cases. I

" think " he said something like only 3%.

He said that the fact that a mutation is not found does not rule out Mito.

Hugs,

Marie

_____

From: [mailto: ] On Behalf

Of MitomomX3@...

Sent: Thursday, October 20, 2005 8:24 AM

To:

Subject: Re: Re: Question re: MELAS diagnosis

I forgot I was also going to mention or ask, I also read by articles in the

UMDF site that a negative gene screen for MELAS cannot rule it out as there

are still so many unknown mutations.

also that muslce is more reliable than blood for MtDna screening.

true or false??

[Guest guest]

,

True, the consensus is that muscle is more reliable than blood. Joanne

posted some info from emedicine to this effect.

http://www.emedicine.com/ped/topic1406.htm

MELAS Syndrome Last Updated: October 26, 2004

(Requires free registration to view.)

Similar info at this UK site: http://leedsdna.info/tests/mito.htm

" Levels of mutations in different tissues can vary, for example, with

increasing age MELAS mutations disappear from blood but remain in muscle.

" Deletions of the mtDNA molecules persists in muscle fibres, the number of

which does not increase significantly after early foetal life. The frequent

cell division of leukocyte precursors could select against the survival of

cells containing defective mitochondria.

" If mitochondrial DNA analysis of blood shows no mutation in cases where

clinicians are convinced of a diagnosis, it is recommended that muscle

tissue is then tested. This is particularly the case with the mitochondrial

myopathies. "

Barbara

> I forgot I was also going to mention or ask, I also read by articles in

the

> UMDF site that a negative gene screen for MELAS cannot rule it out as

there

> are still so many unknown mutations.

> also that muslce is more reliable than blood for MtDna screening.

> true or false??

>

[Guest guest]

> -----Original Message-----

> From: [mailto: ] On

Yes, the experts also agree on this, though the success % quoted varies.

http://www.rgbgl.org/research/respiratorychain.htm

" I predict that only in a minority of cases will we be fortunate enough to

find a single gene defect (mitochondrial DNA or nuclear DNA) that is

causative. In fact, in a published study of 2,000 specimens referred for

mtDNA mutation analysis, Dr. Lee-Jun Wong's laboratory found a causative

mutation in under 7%. This ballpark yield in large-scale studies has been

echoed in at least 2 other laboratories. "

Dr. Wong's study:

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ui

ds=9632169&dopt=Abstract Yield of mtDNA mutation analysis in 2,000

patients

Barbara

> I was told the same thing by the lab In NY that did my biopsy and UCSD

told

> me that it is like finding a needle in a haystack and generally a waste

of

> time and money unless a specific defect is found that they can look for.

[Guest guest]

ok this is what I was asking the other day....so muscle biopsy is definately

the best way to go? Vivian

[Guest guest]

> Thanks so much, Barbara. Right now, I haven't started any testing myself,

but my

> sis has had a muscle biopsy, which showed some abnormal mitochondria. She

is

> going through the genetic testing right now, and that's what the muscle

biopsy was

> for. Now, the neurologist is sending some of that tissue to the Cleveland

clinic, to

> see if they can further identify the proteins that are missing, etc. I

guess that is to

> see which area of the respiratory chain is affected? So, can I assume

that with the

> abnormal mitochondria in my sis, that we do have the mito diagnosis?

Some doctors might call this likely mito or presumed mito, but there can be

secondary damage to mitochondria in other kinds of disorders. Certainly it

would point in the direction of a mitochondrial disorder of some sort,

whether primary or secondary. It sounds like they have a two-prong strategy,

both genetic screening for known mutations and assays for the enzymes in the

respiratory chain complexes. This is good, and the results should be very

helpful. I hope so!

Barbara

[Guest guest]

Hi Barbara- no she (Assoc Prof Caroline Sue at Royal North Shore Hospital in

Sydney) didn't say why and I didn't get a chance to pursue this. But she did

say the mutant loadings (mine was only 13% in urine) can fluctuate. (ps Joanne

did you mention urine or just blood as being unstable?? )

After reading all the other interesting comments since this post, I will add

that my first test was muscle biopsy which showed ragged red fibres but I don't

think it showed Complex I deficiency. Prof Sue (a mito expert) confirmed mito

and said she suspected Melas based on history ie sensorineural deafness, an

earlier seizure, and diabetes and spasm (and family history of epilepsy and

such). Then she went on to do the urine test which confirmed the MELAS A3423G

mutation, which was a real stroke of luck apparently. I do not sound nearly as

severe as some eg RH has been, at this stage anyway. As it is only 13% I am

assuming I am mild, however I have not had Melas looked for in skeletal muscle

tissue so don't know what it would be there. One thing I have noticed, the docs

don't really know the answers yet.... my doc says things like " one would hope

so... " More research to do and I think we are part of that...

RE: Re: Question re: MELAS diagnosis

Pamela, Did your doctor give any reason for why he believes urine cells are

more reliable than blood? I was under the impression that any good source of

DNA, whether the defect is in nDNA or mtDNA, would produce the same results

since specific mutations such as A3243G can only be confirmed through

genetic screening. This is a new twist to me, so I'm curious about his

reasoning.

Thanks.

Barbara

> I just thought it worth mentioning that I have just been diagnosed with

MELAS

> A3243G via urine cells. My mito doc in Sydney believes that this is a

more reliable

> source than blood test. pamela

[Guest guest]

<(ps Joanne did you mention urine or just blood as being unstable?? ) >

I know without question that blood is NOT a reliable measure of mitochondrial

disease genetics. Soem individuals are fortunate and they do obtain a diagnosis

via blood testing but that number is quite small. I've read studies that

indicate the diagnosis rate via blood runs between 3% and 7%. Muscle or liver

biopsy (in patients that have liver involvement) seem to be the best diagnostic

tools. Skin fibroblast studies are catching up, but the reproducibility semms

variable.

Even muscle biopsies have mixed results. The most reliable tends to be fresh

muscle biopsies. The downside is so few centers have the capability to actually

do fresh analysis of the RTC and the expense is great. It is also a " crap

shoot " whether or not the tissue sample evaluated will have affected

mitochondria. Example: every biopsy my girls have had (muscle and/or skin) has

yielded different results. Almost all positive, but different. The only

definitely negative result was a frozen muscle biopsy (tissue sent to Athena for

analysis).

Joanne Kocourek (mom to , lies, and )

visit us at: http://www.caringbridge.org/il/annakris

[Guest guest]

Thanks, Pamela. Just curious--do you happen to know if Dr.

Christodoulou is still prominent in the Sydney mito community? I know

several patients who have seen him in the past. I believe he was at the

Children's Hospital of Westmead but also held an academic position in

genetics at U of Sydney.

Barbara

> Hi Barbara- no she (Assoc Prof Caroline Sue at Royal North Shore Hospital

in

> Sydney) didn't say why and I didn't get a chance to pursue this. But she

did say the

> mutant loadings (mine was only 13% in urine) can fluctuate.

[Guest guest]

Vivian,

My sister was diagnosed with MELAS first thru a blood test but the diagnosis did

not come back before she had a stroke and went into 10 hrs of uncontrolled

seizures. Thus when she was put into a medically induced coma they did a muscle

biopsy. I am not sure where the test was sent but the biopsy was done at the

medical college of WI and Froedtert. They took her by ambulance from Manitowoc

(two hrs) after they induced the comas after failing to get the seizures under

control. At the time she was on anti-seizure medication since going into a 4

day coma in February. This was May.

Anyway, they first heard of the " mito " doc in Milwaukee in late March and he had

the blood sent to California to be tested. When this other happened and she was

in a coma they did the muscle biopsy and confirmed the MELAS. she was then

given experimental DCA which did bring her out of the coma and she was up,

walking slightly, and cutting strawberries for a meal on her birthday in August.

Anyway, the point of this is that I was told later after I started reading about

the ragged red fibers on this group shortly after I joined that she had no

ragged red fibers. The doc also to me that the bad cells in her blood that was

tested were considerably higher than mine.

Joanne:

That is a good point about the blood testing and the percentage of people it is

found in. I had been told that also. At the time I had the testing done it was

before my symptoms really were a problem. Granted they had always been there

but the tiredness, getting very fatiqued after doing just a little physical

exercise was not. Also my blood sugar that goes up with physical exercise was

not recognized. So now, in 2005 vs 1997 my symptoms are much worse and I

probably would opt for the surer method of diagnosis.

I believe it depends on what your reasons to get a diagnosis to decide which to

do, a muscle biopsy or blood test and how much you want to put yourself through.

A fresh muscle biopsy cannot be done just anywhere. But a mito blood collection

can be performed in almost any doc office. (although the doc in Milwaukee does

not trust the ones up here in Green Bay. Yet he comes up here to work twice a

month)

Janet Sample

Re: Re: Question re: MELAS diagnosis

I did wonder reading and following this thread....I was told ragged red

fibers in the muscle tissue was necessary for diagnosis of MELAS. Other

symptoms I

exhibeted (including red streaks at the back of my eyes which no one has

mentioned) were insufficient. I had my biopsy sent to Shoffner who not only

found

the ragged red fibers but did the dna sampling and found the point

mutation...has this changed? I realize it is quite some time since my

diagnosis.....Vivian

[Guest guest]

Oh it is so confusing isn't it? There just doesn't seem to be a definite

route to go. Of course your sister was " lucky " in the sense that she had such

dramatic symptoms (same for myself) and was diagnosed rapidly. But from what we

see on this list that is quite often not the case and pursuing diagnosis and

finding help must be arduous. So what is the solution mtDNA ? Vivian

[Guest guest]

I haven't come across him Barbara (only found out I had mito 6 mths ago) but

checked as I didn't know there were any other mito experts in Sydney. Looks as

though he is still active in genetics incl mito at Westmead Childrens

http://www.chw.edu.au/research/groups/wsgp.htm .

RE: Re: Question re: MELAS diagnosis

Thanks, Pamela. Just curious--do you happen to know if Dr.

Christodoulou is still prominent in the Sydney mito community? I know

several patients who have seen him in the past. I believe he was at the

Children's Hospital of Westmead but also held an academic position in

genetics at U of Sydney.

Barbara

> Hi Barbara- no she (Assoc Prof Caroline Sue at Royal North Shore Hospital

in

> Sydney) didn't say why and I didn't get a chance to pursue this. But she

did say the

> mutant loadings (mine was only 13% in urine) can fluctuate.

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