expanding genetic horizons...

Mitochondrial Disease

Mitochondrial disorders are a group of diseases that alter the body’s ability to adequately convert food into the energy needed for bodily functions. These diseases impactup to 1 in 4,000 individuals and can result in widespread clinical problems including vision and hearing loss, seizures, low muscle tone, muscle weakness, migraines, chronic fatigue, developmental delays, AUTISM (ASD or autistic features), kidney and liver disease, diabetes and other endocrine problems and alterations in blood pressure, heart rate and temperature regulation. Affected individuals can have some or many of these symptoms and problems. Often, but not always, these disorders show progressive symptoms worsening over time, particularly with stressors such as illness or surgery. 

The mitochondria are located inside our body’s cells and create energy, known as ATP, through a complex series ofbiochemical reactions in the electron transport chain. The electron transport chain, also known as the respiratory chain, is composed of five complexes (Complex I-V) or groups of chemicals whose sole purpose is to create energy from the breakdown products of food using phosphate and oxygen. There are hundreds of different genes (37 inherited from mom in the form of the mitochondrial DNA and over 850 inherited from both parents in the nuclear DNA) that encode for various proteins that come together like jigsaw puzzle pieces ultimately to create energy.

Mitochondrial disorders are diseases that alter one or more of these genes and proteins resulting in decreased or ineffective energy production and subsequent malfunctioning of our body’s energy-producing processes. Although some forms of mitochondrial disease are sporadic only affecting one person in an extended family, most types are inherited creating a greater impact on families at large.

Poor mitochondrial functioning has also been linked to the onset of many other disease processes including Alzheimer’s, Parkinson’s disease, schizophrenia and bipolar disorder.  Some medications such as the HIV anti-viral drugs are also known to affect the mitochondria resulting in poor energy production and mitochondrial disease symptoms.  This secondary mitochondrial dysfunction is due to the mitochondria becoming “sick” or “toxic” due to changes in the cells.


Mitochondial Disease & Autism

Click the image to the right to listen to
Dr Kendall's MitoAction 2011 lecture on
Mito-Autism - diagnoses, testing, and treatment

Click the image
to read Dr Kendall's article
as it was published in
Autism Science Digest April 2011

Article on Bridging the Gap Between Autism (ASD) and Mitochondrial Disease by Dr Fran Kendall with Virtual Medical Practice

Click the image
for a PDF of our handout
on Autism and Mito Disorders

3 panel brochure on Mitochondrial Disorders and Autism (ASD) by Dr Fran Kendall
Click the image
for a PDF list of possible Mito symptoms
with a list of genetic testing for ASD patients
List of possible Mitochondrial symptoms aith a list of genetic testing for Autism (ASD) patients by Dr Fran Kendall with Virtual Medical Practice

Many recent studies have linked Autism Spectrum Disorder (ASD) to poor mitochondrial functioning. Understanding these disorders, their symptoms and evaluation may help ASD families determine if further testing is important for their child.

Mitochondrial dysfunction has already been linked to many neurological conditions. Its association with ASD is a topic of recent interest, research and discussion. ASD, a complex neurobiological disease, affects 1 in 110 individuals and impacts their ability to communicate and relate to others while predisposing them to rigid routines and repetitive behaviors.

Although several studies completed by a group in Portugal in 2005 & 2007 suggested that 4.1% of patients with autism had underlying mitochondrial disease, rendering it a rare but definable cause of ASD, a recent study out of UC Davispublished in the Journal of the American Medical Association (JAMA) in November 2010, suggests a much stronger link between autism and mitochondrial dysfunction.  The authors report that children with autism are far more likely to have defects in their bodies’ ability to produce energy than typically developing children. The study discovered widespread reduced mitochondrial enzyme function among the autistic children. Complex I was the site of the most common deficiency, found in 60% of the autistic patients, and occurred five out of six times in combination with Complex V. Other children had problems in Complexes III and IV. In addition, the autistic children showed other signs of mitochondrial impairment. Although many questions remain to be answered, the study results point to a stronger link between mitochondrial dysfunction and autism than was previously believed to exist. Importantly, this association was established utilizing a cell population (lymphocytes, a type of white blood cell) that is easily obtainable via a blood draw.

Most recently in January 2011, a review in Molecular Psychiatry reported findings that suggest children with ASD have a spectrum of mitochondrial dysfunction of varying severity.  This article, like the JAMA report, also indicates that more research is needed to understand this association but emphasized the need for ASD children to be screened for possible mitochondrial dysfunction citing improvement in a number of children with ASD and mitochondrial abnormalities following the institution of mitochondrial disease management.
Which ASD patients should be evaluated for mitochondrial disease or other genetic disorders?
In our opinion, ALL ASD spectrum patients should undergo a basic genetics work-up (see table 2). While some of the first tier tests in table 2 can be obtained without a sub-specialist’s input, the interpretation of the data may be difficult without a genetics specialist.  Deciding if a given patient requires a more in depth investigation for mitochondrial or other rare metabolic or genetic diseases should be undertaken by a mitochondrial expert and/or a biochemical geneticist and is based on a number of factors including screening laboratory testing, family history, physical findings and clinical features.  In general, the genetics work-up and ongoing management of an ASD patient (should a genetics diagnosis be made) is best completed by someone trained in genetics with mitochondrial and metabolic disease experience and expertise.
Why is it important to know if an ASD patient has mitochondrial disease?
Most people or families seek a diagnosis for two general reasons: 1) to improve the life and health of the affected person; and 2) to determine the risks to other family members. Although mitochondrial disease is not yet curable, an affected person’s quality and duration of life can be improved by aggressive metabolic management by a mitochondrial expert.Knowing that a patient has a mito disorder is important, for example, to ER staff and other healthcare professionals as certain protocols should be followed to prevent the adverse affects that can occur particularly at times of illness and stress.  Having a clear diagnosis can also assist families with future pregnancy planning as well as understanding risks for other family members. In addition, mitochondrial medicine is rapidly changing with a number of clinical trials underway. Enrollment and participation in ongoing treatment trials and research protocols requires that a patient be definitively diagnosed with a mitochondrial disease (for example, identification of the mito gene defect).
How is mitochondrial disease diagnosed?

Some patients present with a collection of clinical features and findings that enable them to be diagnosed by a comprehensive history, examination and minimal testing such as blood lactate level and brain MRI. (See Table 1 for a comprehensive list of mito related clinical symptoms.) Such is typically the case in patients affected by Leigh disease, a particularly aggressive form of mito disease. These individuals have very specific brain MRI changes and often have elevated lactate levels. In this case, diagnosis can be made on clinical and laboratory findings alone.

In other cases, patients present with findings that are clearly seen in several of the commonly described mitochondrial disease known to be associated with very specific gene changes. An example is a patient who presents with elevated lactate levels, stroke-like episodes and progressive problems who is found to have the common tRNAmtDNA 3243 mutation seen with MELAS (Mitochondrial Encehalomyopathy Lactic Acidosis and Stroke-Like episodes). This diagnosis is confirmed using a simple blood test.

In the past,for many others, definitive diagnosis of a mitochondrial disease required the completion of special studies on a tissue rich in mitochondria. The tissues in the body that house the most mitochondria are the brain, kidney, liver, heart, and skeletal muscle. Since collection of brain and heart tissue was impractical and attainment of kidney or liver tissue for analysis is very invasive, potentially damaging and very dangerous, muscle tissue became the tissue of choice for investigation. Once collected, mitochondria are removed from the muscle tissue and studied using special instruments such as a spectrophotometer. By using these special instruments in the laboratory the physician is able to interpret whether or not a specific person appears to be making energy at normal levels. Unfortunately, biopsies have always carried a risk of false positives and false negatives.  However, the recent development of non-invasive enzyme testing utilizing tissues other than muscle (buccal swabs, lymphocytes) as well as the expansion of gene testing from a simple blood draw to include over 700 mito related genes opens the door to widespread access of mitochondrial testing to a large patient population without the risk, cost and invasiveness of traditional muscle biopsies.
  • Developmental delays
  • Migraines
  • Seizures
  • Dementia
  • Autistic Features
  • Strokes
  • Neuro-psychiatric disturbances
  • Mental retardation
  • Atypical cerebral palsy
  • Absent reflexes
  • Fainting
  • Neuropathic pain
  • Weakness (may be intermittent)
  • Dysautonomia - temperature instability & other dysautonomic problems
  • Weakness
  • Dysmotility
  • Gastroesophogeal reflux
  • Cramping
  • Hypotonia
  • Diarrhea or constipation
  • Gastrointestinal problems
  • Muscle pain
  • Pseudo-obstruction
  • Irritable bowel syndrome

  • Renal tubular acidosis or wasting
  • Cardiomyopathy
  • Cardiac conduction defects (heart blocks)
  • Liver failure
  • Hypoglycemia (low blood sugar)
Ears & Eyes
  • Visual loss and blindness
  • Optic atrophy
  • Acquired strabismus
  • Ptosis
  • Ophthalmoplegia
  • Retinitis pigmentosa
  • Hearing loss and deafness


Pancreas & Other Glands
  • Diabetes and exocrine pancreatic failure (inability to make digestive enzymes)
  • Parathyroid failure (low calcium
  • Failure to gain weight
  • Unexplained vomiting
  • Respiratory problems
  • Fatigue
  • Short stature

Genetic Testing for Autistic Spectrum Disorder (ASD) Patients
Tier 1 - basic work-up recommended for all patients. While some of these first tier tests can be obtained without a sub-specialist’s input, the interpretation of the data may be difficult without a genetics specialist.
  • Chromosome microarray studies
  • Complete metabolic panel, cbc, cpk
  • Ammonia level
  • Lactate and pyruvate levels
  • Carnitine, plasma total and free
  • Coenzyme q10 level
  • Plasma and urine amino acids
  • Urine organic acids
  • Plasma acylcarnitines
  • Thyroid function tests
Tier 2 - depends on clinical features and results of Tier 1 testing. These tests should be undertaken by a mitochondrial expert and/or a biochemical geneticist.
  • Mitochondrial enzyme and/or dna testing
  • Rett syndrome dna testing
  • PTEN mutational analysis
  • Nlgn3, nlgn4x, shank3, snrpn gene testing
  • Lysosomal enzyme testing
  • Peroxisome disease testing (vlcfas)
  • Csf studies for lactate and pyruvate, amino acids and neurotransmitters
  • Brain MRI

Navigating the road of complex medical problems can be confusing and overwhelming.  Many parents and families find themselves alone and sometimes bewildered as they try to determine the best course of action for their loved one.  Understanding the facts and options, and what constitutes an appropriate evaluation and work-up, will empower families to obtain the best care for their child or loved one and help provide them with the best possible outcome and quality of life. Utilizing resources such as foundations, other support organizations and chat rooms particularly to seek opinions about the subspecialists you are considering for care will alleviate much of the stress of the process, avoid potential conflicts of interest with some providers and guarantee the best care for your family.


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