Mitoland:
A guide to mitochondrial diseasefor patients and parents
Sumit Parikh, MD

Table of Contents
Mitochondrial Disease . . . . . . . . . . . . . . . . . . . . . . . . . . 1
At Peak Production: Cells and Energy . . . . . . . . . . . . . 2
A Production Breakdown . . . . . . . . . . . . . . . . . . . . . . . . 3
Unhealthy Mitochondria: Examining the Causes . . . 5
Autosomal Recessive Inheritance . . . . . . . . . . . . . 7
Autosomal Dominant Inheritance . . . . . . . . . . . . 8
Mitochondrial Inheritance . . . . . . . . . . . . . . . . . . . 9
Looking at the Symptoms . . . . . . . . . . . . . . . . . . . . . . 10
Getting to the Diagnosis . . . . . . . . . . . . . . . . . . . . . . . . 11
More Invasive Tests . . . . . . . . . . . . . . . . . . . . . . . . 12
Testing the Tissue: Skin Biopsy . . . . . . . . . . . . . . 14
Testing the Tissue: Muscle Biopsy . . . . . . . . . . . 15
Treating the Problem . . . . . . . . . . . . . . . . . . . . . . . . . . 16
Moving Forward . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 17
Mitochondrial Disease Organizations . . . . . . . . . . . . 18

Inner membrane

Outer
membraneMatrix

Inside the mitochondrion

Mitochondrial Disease
Like a car that stalls and comes to a stop, certain diseases can make the bodyfeel like it has “run out of gas,” too. But while it’s easy to get a car going byfilling up the tank, getting the body running again is a lot more complicated.
Our bodies are fueled by oxygen and the nutrients we get from food. The
protein, fats, and carbohydrates we consume go
through a chemical process that converts themto energy, which in turn fuels our cells andkeeps us moving and growing.
It’s an automatic process thatworks around the clock – until
there’s a breakdown. That
breakdown andthe problems
that come withit are known as
mitochondrial
disease.

Like a car that’s fueled bygasoline, our bodies are fueledby the energy we get from food.

1

At Peak Production: Cells and Energy

At Peak Production
For most of us, eating is easy; it’s the part where our bodies convert thefood to energy that’s a lot more complex. Fortunately, the mitochondria
do all that work for us.

• Each of us is born with trillions of cells, and each cell comes with several
thousand mitochondria—all of which we initially inherited from ourmothers.

• Mitochondria are the “power plants” or batteries of the cell. They are living,breathing production factories whose job is to convert food molecules
into chemical energy. Our cells use that energy to keep us going.

Mitochondria are the “powerplants” of the cell. They convert
food molecules into chemicalenergy, which our cells use tokeep us going.

2

A Production Breakdown• The number of mitochondria in a cell depends on how much energythat cell needs to do its job.

Our cells use energy to keep our bodies
going. The bigger the job a cell has to do,
the more energy it needs to get it done.

Cells in the brain or nervous
system need a lot more mitochondria to function than the skin cells
do, just as a semi needs more gas in its tank than a MINI Cooper does.

A Production Breakdown
When there are so many mitochondria at work, not all of them can be top
performers. In fact, at birth, a very small number of our mitochondria may
not work well, but as we get older that number increases. This is one of thereasons we age.
3

A Production Breakdown

As we get older, the number ofmitochondria that don't work
well increases. This is one ofthe reasons why we age.

Certain diseases can also increase the number of unhealthy mitochondria
over a person’s lifetime. They include:• Diabetes• Huntington’s disease• Alzheimer’s disease• Amyotrophic lateral sclerosis (ALS)
However, some people are born with or develop too many unhealthy
mitochondria, cannot make enough mitochondria, or are unable to keepsome or all of their mitochondria running at full speed.
Having too many unhealthy mitochondria, or not making enough, keeps thecell from generating enough energy to work properly. The cell may even die.
Having too many low-functioning mitochondria results in mitochondrial
disease.

4

Unhealthy Mitochondria: Examining the Causes

Examining the Causes
In a large percentage of patients, unhealthy mitochondria can develop
when they are damaged by a number of things, including:• Other diseases and disorders that affect the body (several listed on theprevious page)• Viruses and toxins(poisons), including
certain medicines
In these circumstances, themitochondrial
disease is secondary
to that otherproblem.
Mitochondrial diseases
can also be primary – meaning
genetic – in that the problem
is in the blueprints (DNA) involvedin building mitochondria or providing
the tools to keep them running.

Mitochondrial
disease can develop
when the mitochondria aredamaged by diseases,
viruses, and toxins.

While some genetic diseases are inherited, meaning that they are passed
down from parent to child through DNA, some changes in the DNA canoccur spontaneously in the child and do not exist in the parents. Thesechanges in the child’s DNA occur very early in the pregnancy (typicallythe first two weeks).
5Unhealthy Mitochondria: Examining the Causes• Genes are the substances that give us our physicaltraits and characteristics, like our mother’s browneyes or our dad’s ability to roll his tongue. Each
person receives two copies of each gene: one
from the mother and one from the father.

• Genes contain DNA, which hold the genetic instructions, or “blueprints,” for building a human being.
The DNA lives in the cell’s nucleus (nDNA). The
nucleus is the control center of the cell.

• Mitochondria are unique because they containtheir own DNA (mtDNA for short),
inherited from only the person’s
mother. This is in contrast tonDNA, which is inherited fromboth parents.

• More than 80% of primary
mitochondrial disease is caused
by nDNA mutations (changes).

• Less than 20% of primary mitochondrial disease is caused by mtDNAmutations.
If mitochondrial disease is inherited, it is important to find out which
type of inheritance it is. This can predict the risk of the disease being
inherited by future children or the risk of the child’s siblings, parents,
uncles, and aunts of having and passing on the disease.

6Autosomal Recessive Inheritance

When inherited, the types of mitochondrial disease inheritance include:
nDNA inheritance (also called autosomal inheritance):• If the gene is recessive (one gene from each parent), there is a 25% chancethat each child will inherit the disease.

Autosomal Recessive Inheritance

Unaffected son

Carrier daughter

Carrier father

Carrier son

Carrier motherAffected daughter

7Autosomal Dominant Inheritance• If the gene is dominant (a gene from either parent), there is a 50% chancethat each child will inherit the disease.

Autosomal Dominant Inheritance

Affected son

Unaffected daughter

Unaffected motherAffected father
Unaffected son

Affected daughter

8•Mitochondrial Inheritance

mtDNA inheritance:• mtDNA are maternally inherited, so if the problem is here, there is a
100% chance that each child will inherit the disease, although symptoms might be markedly different and either more or less severe. But,
remember that mtDNA mutations only cause 20% or less of primary
mitochondrial disease since most of the blueprints involved in building
them come from regular DNA.

Mitochondrial Inheritance
Affectedmother

Unaffectedfather

Affectedchildren

Unaffectedmother

UnaffectedchildrenAffectedfather9Looking at the Symptoms

Combination of mtDNA and nDNA defects:• The complete relationship between nDNA and mtDNA and their correlation in mitochondrial formation isn’t known.

Looking at theSymptoms

Brain
Eyes

Because mitochondria
are in nearly every cell inthe body, mitochondrial
disease can affect one or
all organs, including thefollowing:

Ears

HeartStomach• Brain• Nerves (including theMuscles

nerves to the stomachand intestines)• Muscles• Kidneys• Heart• Liver• Eyes• Ears• Pancreas
Mitochondrial disease can affect one or all organs.

In some patients, only
one organ is affected, whilein other patients many of the organs are involved.

10Getting to the Diagnosis

Depending on which cells of the body are affected, symptoms might include:• Poor growth• Loss of muscle coordination,muscle weakness• Visual and/or hearing problems• Developmental delays, learning
disabilities• Intellectual disability• Heart, liver, or kidney disease• Gastrointestinal disorders,severe constipation• Respiratory disorders• Diabetes• Neurological problems,seizures• Thyroid dysfunction• Dementia (mental disordercharacterized by confusion,disorientation, and memoryloss)

The type of symptoms a person has depends
on which cells of the body are affected.

Getting to the Diagnosis
Because mitochondrial disease can affect so many different parts ofthe body, resulting in many different symptoms, it can be difficult todiagnose.

11More Invasive Tests

To diagnose the condition, the doctor will start with a series ofexaminations and tests that may include the following:• Evaluating a patient’s family history• A complete physical examination• A neurological examination• A metabolic examination that involves testing the blood and urine,
and, if needed, doing a cerebral spinal fluid test (spinal tap)
• Genetic DNA tests in blood• Other tests, depending on the patient’s symptoms and the areasof the body that are affected, might include:• Magnetic resonance imaging (MRI) or spectroscopy (MRS) for
neurological symptoms• Retinal exam or electroretinogram (ERG) for vision symptoms• Electrocardiogram (EKG) or echocardiogram for symptoms of heartdisease• Audiogram or Auditory-Brainstem Evoked Responses (ABER) for
hearing symptoms• Blood test to detect thyroid dysfunction if the patient has thyroid
problems

More Invasive Tests
If the first series of tests to diagnose mitochondrial disease doesn’t provide
any useful results, more tests may be needed. Your doctor may want to test
chemical markers in the body’s fluid and tissues. This procedure, calledbiochemical testing, looks for changes in the body’s chemistry. Some of thesetests, such as tissue analysis, may be invasive (meaning that they involve
making a puncture or incision on a part of the body).

12More Invasive Tests

Testing Body Fluids
When mitochondria are unhealthy,
they can’t properly do their job ofprocessing body chemicals
involved inmakingenergy.

When mitochondria can't process chemicals properly, some of the chemicals hit
a roadblock that causes a pileup, spilling them into blood, urine, and spinal fluid.

Instead of continuing into the mitochondria for processing, some of thechemicals essentially hit a roadblock, resulting in a pileup. This chemical
accumulation spills over and can be measured in the blood, urine, and spinal fluid.
These chemicals include:• Lactate• Pyruvate• Alanine• Products of the Krebs cycle (also called the citric acid cycle)
13

Testing the Tissue: Skin Biopsy

Testing the Tissue: Skin Biopsy
A skin biopsy is a procedure in which the doctor removes a small sample
of skin to have it tested. The skin sample may be removed with a punch
biopsy, a type of biopsy that uses an instrument similar to a pencil witha sharp, round, hollow opening where the eraser should be.

During the biopsy:• The doctor will clean the biopsy site.
• He or she will then numb the skin with an anesthetic spray, cream,or injection.
• Next, the doctor will remove two small (3 mm) pieces of skin.
• A nurse may apply pressure to the area to stop the bleeding.
• The doctor will then close the incision, using adhesive strips thatlook like small pieces of tape.
The entire biopsy procedure lasts about 15 minutes.
After the biopsy:• You will need to stay in the treatment area for a short time forobservation.
• You may have some soreness around the biopsied area for oneto two weeks.
• Ask your doctor when you should come back for a follow-up visit.
• You may have a small scar at the biopsy site.

14

Testing the Tissue: Muscle Biopsy

Testing the skin sample:
The skin sample is sent to a lab and the mitochondria are examined with
an electron microscope. Because skin tissue is different from muscle,
brain, heart, and liver tissue, the test results are not always helpful indiagnosing a disease.

Testing the Tissue: Muscle Biopsy
A muscle biopsy is a surgical procedure in which small samples of muscle
tissue are removed for testing. Because a muscle biopsy is an invasive,
expensive test that requires the use of general anesthesia for children, you
and your doctor may want to compare the risks and costs of the test withany benefits that could result from a diagnosis.
Before the biopsy:• You (or your child) will be given general anesthesia. This will make you
very relaxed and you will then be sedated (in a sleep-like state) for theprocedure.
During the biopsy:• The surgeon will clean the biopsy site.
• He or she will then make a small incision (1- to 2-inch cut), usually in the
top of the thigh, and remove up to three one-cubic centimeter samples
from the muscle.
• The doctor will close the incision, usually with stitches.
The entire biopsy procedure lasts about 30 minutes.

15

Treating the Problem

After the biopsy:• You will stay in the treatment area for a short time for observation.
• There will be some muscle soreness (similar to a pulled muscle
or a muscle strain) around the biopsied area for one to twoweeks.

• Your doctor may prescribe medication to relieve pain for a few days
after the procedure.

• Keep the incision area as clean and as dry as possible. The doctor
will tell you when the stitches should be removed.

• Ask your doctor when you should come back for a follow-up visit.
• You may have a 1- to 2-inch scar from the biopsy.
Testing the muscle sample:
Muscle removed for biopsy can be tested in many ways. Muscle isstudied under the microscope to see how the mitochondria appear.
Some of the enzymes that work in the mitochondria can also bemeasured.
While these test results can show signs of mitochondrial disease orthat the mitochondria are not healthy, this only confirms that there
is a problem, and not necessarily what the problem is.
Muscle should also be sent for specialized genetic which cannot be
performed accurately in blood.

16

Moving Forward

Treating the Problem
There is no cure for mitochondrial disease, but treatment can help reduce
symptoms, or delay or prevent the progression of the disease.
However, each person needs a treatment that is individually tailored tohim or her. Because people are “biochemically different,” no two people
will respond to a treatment in the exact way, even if they have the same
condition.
Treatments for mitochondrial disease may include:• Screening test to see if any other body systems are affected• Special medical precautions when sick or needing medical proceduresor surgeries• Physical, speech and occupational therapy• Vitamins and supplements, including:• Coenzyme Q10• B complex vitamins: thiamine (B1), riboflavin (B2), niacin (B3), B6,folate, B12, biotin, pantothenic acid
• Increasing the doses of these supplements during illness• Diet changes prescribed by a doctor along with a registered dietitianMoving Forward
Once a person has been diagnosed with a specific mitochondrial disease,
work on treating it can begin. However, there is no way to predict how thedisease will affect a person in the long run. It might progress quickly orslowly, even over decades. It might also appear stable for years.
Your doctor can help you figure out what course your condition might takeand provide you with the proper treatment.

17

Mitochondrial Disease Organizations

Mitochondrial Disease Organizations
United Mitochondrial Disease Foundation (UMDF)
8085 Saltsburg Road, Suite 201
Pittsburgh, PA 15239
Phone: 1.888.317.UMDF (8633)
E-mail: info@umdf.org
www.umdf.org
Mitochondrial Medicine Society (MMS)
www.mitosoc.org
Organic Acidemia Association
9040 Duluth Street
Golden Valley, MN 55427
Phone: 763.559.1797 (Central Time)
Fax: 866.539.4060 (Toll-free)E-mail: mkstagni@gmail.com
www.oaanews.org
Fatty Oxidation Disorder Support GroupPO Box 54
Okemos, MI 48805-0054
Phone: 517.381.1940 (8 am-8 pm EST)Fax: 866.290.4060 (Toll-free)E-mail: deb@fodsupport.org
www.FODsupport.org
Cleveland Clinic
Neurological Institute
Pediatric Neurology & Neurosurgery
http://my.clevelandclinic.org/departments/neurological18

Sumit Parikh, MD, is a neurometabolic and neurogenetics
Staff Clinician at Cleveland Clinic. He specializes in theevaluation, diagnosis, and treatment of developmental delay,neurodegeneration, and metabolic disease. Dr. Parikh is theCo-Director of the Cleveland Clinic Mitochondrial Clinic andthe Cyclic Vomiting Syndrome Clinic.
Sumit Parikh, MD

This information is not intended to replace the medical advice ofyour doctor or health care provider. Please consult your health careprovider for advice about a specific medical condition.

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