Re: Paternal Inheritance?????

September 10, 2005

Dolores,

Mitochondrial diseases can originate either from defects in:

1. nuclear DNA or 2. mitochondrial DNA.

If the defect is in nuclear DNA, then inheritance can be maternal OR

paternal.

If the defect is in mitochondrial DNA, then inheritance is maternal.

This happens because some mitochondrial proteins are encoded in

mitochondrial DNA and others are encoded in nuclear DNA. Very confusing, I

know.

Just a couple of other points.

1. According to a paper by Drs Cohen and Gold, the majority of mitochondrial

diseases actually originate from nuclear DNA, not mitochondrial DNA. They

say it is a myth that most mitochondrial disease is maternally inherited and

there is good scientific evidence to support this statement.

2. There have been one or two rare cases where it appears that a defect in

mitochondrial DNA was inherited paternally. I can't find the citations at

the moment, but these reports have appeared within the last few years and

caused a stir among geneticists.

But the general rule is: mitochondrial disease that originates from a

nuclear DNA defect can be maternally OR paternally inherited, while

mitochondrial disease that originates from a defect in mitochondrial DNA is

maternally inherited.

Barbara

> Paternal Inheritance?????

>

> The more I read and the more ?? I have. Is there actually Paternal

Inheritance and

> is there a site I can go into for clarification, also what does anyone

know about

> Maternal/Paternal iheritance as I have read somewhere at sometime about

this, but

> mainly it explains about just Maternal inheritance ? I have all these

neat papers to

> fill out to take with me to KU in November and there is a Mother's name,

the name

> of all known illness', cause of death then they go Father's name,

Grandparents etc.

> I do know that I am getting more confused by the day. Thanks, Dolores

>

September 10, 2005

If you do run across a website etc please let me know, please send it on.

Thanks again,

Dolores

Barbara Seaman wheatchild@...> wrote:Dolores,

Mitochondrial diseases can originate either from defects in:

1. nuclear DNA or 2. mitochondrial DNA.

If the defect is in nuclear DNA, then inheritance can be maternal OR

paternal.

If the defect is in mitochondrial DNA, then inheritance is maternal.

This happens because some mitochondrial proteins are encoded in

mitochondrial DNA and others are encoded in nuclear DNA. Very confusing, I

know.

Just a couple of other points.

1. According to a paper by Drs Cohen and Gold, the majority of mitochondrial

diseases actually originate from nuclear DNA, not mitochondrial DNA. They

say it is a myth that most mitochondrial disease is maternally inherited and

there is good scientific evidence to support this statement.

2. There have been one or two rare cases where it appears that a defect in

mitochondrial DNA was inherited paternally. I can't find the citations at

the moment, but these reports have appeared within the last few years and

caused a stir among geneticists.

But the general rule is: mitochondrial disease that originates from a

nuclear DNA defect can be maternally OR paternally inherited, while

mitochondrial disease that originates from a defect in mitochondrial DNA is

maternally inherited.

Barbara

> Paternal Inheritance?????

>

> The more I read and the more ?? I have. Is there actually Paternal

Inheritance and

> is there a site I can go into for clarification, also what does anyone

know about

> Maternal/Paternal iheritance as I have read somewhere at sometime about

this, but

> mainly it explains about just Maternal inheritance ? I have all these

neat papers to

> fill out to take with me to KU in November and there is a Mother's name,

the name

> of all known illness', cause of death then they go Father's name,

Grandparents etc.

> I do know that I am getting more confused by the day. Thanks, Dolores

>

September 10, 2005

Go to www.umdf.org and look in their newsletters online. They have a copy of

the Cohen and Gold article called " The Genetics of Mitochondrial Disorders. "

It's the feature article in Volume 8, Issue 3, Summer 2003.

The way the site is built, I can't send you a link. Sorry.

Barbara

> Paternal Inheritance?????

> >

> > The more I read and the more ?? I have. Is there actually Paternal

> Inheritance and

> > is there a site I can go into for clarification, also what does anyone

> know about

> > Maternal/Paternal iheritance as I have read somewhere at sometime about

> this, but

> > mainly it explains about just Maternal inheritance ? I have all these

> neat papers to

> > fill out to take with me to KU in November and there is a Mother's name,

> the name

> > of all known illness', cause of death then they go Father's name,

> Grandparents etc.

> > I do know that I am getting more confused by the day. Thanks, Dolores

>

> >

September 10, 2005

This is from MDA that may help some.

THE MITOCHONDRIAL GENETICS MAZE

The inheritance patterns of the mitochondrial encephalomyopathies can be

quite complicated. The mutations that cause these diseases can be in the

chromosomes; this is what's usually meant when people talk about a

genetic or inherited disease.

But mitochondrial encephalomyopathies have a unique situation. People

can also inherit one of these diseases through mutations in the

mitochondrial DNA (mtDNA), which comes from the mother only.

Mitochondria are the only parts of the cells that have their own DNA,

separate from that of the chromosomes in the cell's nucleus, called

nuclear DNA.

This situation occurs because the mitochondrial respiratory chain, which

is the final step in the energy-making process, is made up of proteins

that come from both nuclear and mtDNA (see illustration

http://www.mdausa.org/publications/Quest/q64mito.html#gowrong>).

Although only 13 of roughly 100 respiratory chain proteins come from the

mtDNA, these 13 proteins contribute to every part of the respiratory

chain except complex II, and 24 other mitochondrial genes are required

just to manufacture those 13 proteins. Thus, a defect in either a

nuclear gene or one of the 37 mitochondrial genes can cause the

respiratory chain to break down. (This respiratory chain has nothing to

do with breathing.)

When mitochondrial disease is caused by defects in the nuclear DNA, the

inheritance follows a " Mendelian " pattern, just as other inherited

disorders do (named for Gregor Mendel, the 19th-century scientist who

first explained inheritance). These inheritance patterns include

autosomal dominant, autosomal recessive and X-linked. Leigh syndrome

(caused by defects in complexes I and IV) is one of the most common

forms of mitochondrial encephalomyopathy inherited in this fashion. It's

usually autosomal recessive, meaning that two copies of the defective

gene, one from each parent, are required to produce the disease.

Although nuclear DNA defects are relatively straightforward, when a

disease is caused by defects in the mtDNA, it gets more complex.

Mitochondrial genetics are made thornier by the fact that, instead of

inheriting two copies of each mitochondrial gene (one from the father

and one from the mother) in the way that nuclear genes are inherited,

you inherit from your mother literally hundreds of thousands of copies

of the 37 mitochondrial genes, while you inherit no mtDNA from your

father. (Each of the roughly 100,000 mitochondria in the mother's egg

cell may contain between two and 10 copies of the mtDNA genes.)

Also, when a mutation occurs in the mtDNA, only some of the many copies

of mtDNA distributed within the mitochondria of each cell will carry the

mutation -- a situation known as heteroplasmy (see illustration below).

The ratio of mutant to normal mtDNA in each tissue, along with other

factors, may determine the severity of the disease in an individual.

*HETEROPLASMY* [normal mitochondria icon] Normal mitochondria with

normal DNA [mutant mitochondria icon] Mitochondria with mutant DNA

Picture of homoplasmic cell, containing only normal mitochondria with

normal DNA.

" Homoplasmic Cell "

70% mutant mitochondria

=severe symptoms? 30% mutant mitochondria

=mild symptoms?

Picture of heteroplasmic cell, containing both normal and mutant

mitochondria and DNA. Picture of heteroplasmic cell, containing both

normal and mutant mitochondria and DNA.

" Heteroplasmic Cells "

all normal mitochondria some mutant and some normal mitochondria

Most healthy people have homoplasmic cells -- that is, each cell has

normal mitochondrial DNA. People with mitochondrial DNA mutations have

heteroplasmic cells. Each cell has a mixture of good and bad mitochondria.

" And therefore the nice rules that Mendel introduced over a century ago

to explain autosomal recessive, dominant and X-linked inheritance do not

apply, " says Salvatore DiMauro, an MDA researcher at Columbia University

in New York, who has studied mitochondrial disorders for over 30 years.

The only " rules " for inheritance of mtDNA mutations that can be counted

on are that a father can't pass on mtDNA mutations and a mother will

pass on mtDNA mutations to 100 percent of her offspring. This pattern is

known as maternal inheritance.

But, even though all of a woman's children will inherit her mtDNA

mutations, that doesn't make it easy to predict how severe the disease

will be in each child. This is because the ratio of mutant to normal

mtDNA passed from mother to child can vary dramatically and

unpredictably with each pregnancy. Thus a mother with very mild symptoms

of mitochondrial disease, perhaps not even diagnosed as such, may give

birth to one child with a very severe disease and a second child with no

disease symptoms at all. Some researchers believe this is caused by a

" bottleneck " effect during the maturation of the mother's egg cells (see

chart below).

MATERNAL INHERITANCE OF MITOCHONDRIAL DNA MUTATIONS

Diagram: Maternal inheritance. Shows possible outcomes resulting when

mother's egg cells contain varying amounts of mutant mitochondria.

Some mitochondrial encephalomyopathies that may be caused by mtDNA

mutations and are subject to the rules of maternal inheritance are

MERFF, MELAS, NARP, PEO and MILS.

In some syndromes, mtDNA mutations tend to occur spontaneously -- that

is, the mutation isn't present in the mother or the father but has,

instead, occurred very early in the development of the embryo. This is

often the case for KSS, PEO and Pearson, three diseases that result from

a type of mtDNA mutation called a deletion (specific portions of the DNA

are missing) or mtDNA depletion (a general shortage of mtDNA). These

types of spontaneously acquired mutations aren't usually passed to the

next generation.

A third kind of mitochondrial disease inheritance is a combination of

nuclear and mtDNA defects. This type of disease is inherited in a

Mendelian fashion, indicating the involvement of a nuclear gene, but is

also characterized by mtDNA deletions. In this case, the mtDNA deletions

occur because there's a " breakdown in communication " between the nuclear

and mitochondrial DNA.

An example of this type of disease is MNGIE. Recently, Columbia

University researcher Michio Hirano and colleagues identified the

nuclear gene involved in MNGIE. The gene codes for a protein called

thymidine phosphorylase that may be involved in regulating the building

blocks of mitochondrial DNA.

------------------------------------------------------------------------

SYMPTOM VARIABILITY, THE " THRESHOLD EFFECT "

When mitochondrial disease is caused by nuclear DNA mutations, the

symptoms and their severity are very consistent within families. But

symptoms can vary widely even within the same family if the disease is

caused by an mtDNA mutation.

No one knows this better than the Haas family of Charlotte, N.C.

, 11; , 9; and their mother, , all have a

mitochondrial encephalomyopathy with maternal inheritance.

[Photo of the Haas family]

The Haas Family

Haas never knew that she had a mitochondrial disorder until the

disease was diagnosed in her first biological son, . Now she can

make sense of symptoms she only vaguely understood before.

" It's hard to explain, " she says, " but I have a hard time if I walk a

distance, like if I'm trying to go through the airport. If I push

myself, I just have to totally stop or my legs are just going to go out

from under me. "

In contrast, has more severe muscle weakness in his legs. He

uses a wheelchair to travel more than a short distance, and he gets

muscle cramps at night when he has overexerted himself during the day.

In , on the other hand, the disease seems to have affected his

brain more than his muscles.

" is very bright and personable, " says Haas. " He's never met a

stranger. And he can hear a song and sing it, or he can watch something

on TV and tell you exactly what was said. But in school he just can't

get the simple things like the ABCs. "

Heteroplasmy -- the variation of mutations among copies of mtDNA within

a cell -- may account for the very different symptoms in members of the

same family.

DiMauro explains that when you have a mutation in mtDNA, all cells in

the body will contain the mutated DNA, and, in theory, all tissues

should be affected.

" But, " says DiMauro, " the trick is in the percentage of mutant

mitochondria in each tissue. Because different tissues have different

energy needs, the percentage of the mutation needed to cause problems

varies. " This phenomenon is called the threshold effect.

" For example, if 70 percent of the mtDNA in the liver is mutated, that

liver may still function pretty well without causing any symptoms. But

the same percent in brain, or in muscle, may cause problems, " he says.

Thus, brain and muscle can be said to have a low threshold for

tolerating mitochondrial mutations.

The idea of an energy threshold explains the variability in clinical

presentation of people with mitochondrial diseases, even in the same

family. It also explains why these diseases are multisystemic syndromes,

DiMauro says.

In other words, even though the two Haas boys got exactly the same mtDNA

mutation from their mother, they may have gotten different doses of

normal vs. mutant mtDNA, and the mutant DNA may have distributed itself

differently in their tissues.

DiMauro says that many doctors once discounted the idea that mutations

in the mtDNA could cause disease. Then, in 1988, it was discovered that

mutations in mtDNA can lead to disease and a torrential amount of

research opened up. Recently, interest in mitochondria has redoubled as

scientists find that mitochondrial dysfunction may be involved in

phenomena as diverse as diabetes, amyotrophic lateral sclerosis (ALS)

and aging.

There's no doubt that the resurgence of interest will yield new

information about mitochondrial disorders and their management. .

Dolores wrote:

>The more I read and the more ?? I have. Is there actually Paternal Inheritance

and is there a site I can go into for clarification, also what does anyone know

about Maternal/Paternal iheritance as I have read somewhere at sometime about

this, but mainly it explains about just Maternal inheritance ? I have all these

neat papers to fill out to take with me to KU in November and there is a

Mother's name, the name of all known illness', cause of death then they go

Father's name, Grandparents etc. I do know that I am getting more confused by

the day. Thanks, Dolores

>

September 10, 2005

Thanks and I'll not get repetitive this time I have to remember when I am

changing wording to be sure and delete before I change it. Dolores

Barbara Seaman wheatchild@...> wrote:Go to www.umdf.org and look

in their newsletters online. They have a copy of

the Cohen and Gold article called " The Genetics of Mitochondrial Disorders. "

It's the feature article in Volume 8, Issue 3, Summer 2003.

The way the site is built, I can't send you a link. Sorry.

Barbara

> Paternal Inheritance?????

> >

> > The more I read and the more ?? I have. Is there actually Paternal

> Inheritance and

> > is there a site I can go into for clarification, also what does anyone

> know about

> > Maternal/Paternal iheritance as I have read somewhere at sometime about

> this, but

> > mainly it explains about just Maternal inheritance ? I have all these

> neat papers to

> > fill out to take with me to KU in November and there is a Mother's name,

> the name

> > of all known illness', cause of death then they go Father's name,

> Grandparents etc.

> > I do know that I am getting more confused by the day. Thanks, Dolores

>

> >

September 10, 2005

I have many symptomatic individuals on both sides of my family, but

stronger on my paternal side. I am thought to have a nDNA genetic

defect, I had mtDNA sequencing and that was negative, in addition to

the standard genetic blood testing for specific errors.

The person with most similar symptoms to me was my uncle, who was my

dad's brother - neuropathy, stroke-like episodes but no evidence of

a " real " stroke, episodic confusion...

Take care,

RH

> The more I read and the more ?? I have. Is there actually Paternal

Inheritance and is there a site I can go into for clarification, also

what does anyone know about Maternal/Paternal iheritance as I have

read somewhere at sometime about this, but mainly it explains about

just Maternal inheritance ? I have all these neat papers to fill out

to take with me to KU in November and there is a Mother's name, the

name of all known illness', cause of death then they go Father's

name, Grandparents etc. I do know that I am getting more confused by

the day. Thanks, Dolores

>

September 10, 2005

I have a lot of strange sympotamic relatives on both side of the family but it

appears that I have more on my Dad's side of the family. About all of my

Mother's sisters and other relatives have had thyroid and had to have surgery

for goiters (sp), I can remember that my Great-grandmother had a huge throat and

neck area. My maternal Grandmother died of " harden arteries to the brain " as it

was called in the early 1960's plus Mother had Alzheimer's as does her one

sister, one Aunt (I raised her daughter) was in and out of mental hospitals

after her husband left her for a neighbor woman. There are a lot of strange

symptoms on Daddy's side of the family as my Grandmother would have what I

called " little strokes " times when her mouth would draw to one side and I would

have to put her to bed again, she died of leukemia in 1957 one week after my

Grandfather passed away of cancer. Daddy had been on dialysis for 15 months as

well as having had several strokes prior to that plus my cousin,

Daddy and my Grandfather all had severe tremors, one Aunt fell straight at a

back in San Diego in the mid-1950's and they never did did know what caused her

death?? When I start trying to fill out " family history " for KU I think I need

an extra page if they want every little detail? Thanks, Dolores

ohgminion rakshasis@...> wrote: