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RSDSA and American RSDHope Jointly Award Research Grant to the Children’s Hospital of Los Angeles  

Lynne Orsini, Executive Director of American RSDHope, and James W. Broatch, MSW, executive director of the Reflex Sympathetic Dystrophy Association of America (RSDSA ) awarded a $50,000 research grant to Richard Boles, MD, Director, Center for Metabolic and Mitochondrial Disorders at the Childrens Hospital Los Angeles. 

Dr. Boles and his team, Essam A. Zaki, Ph.D. Post-doctoral Student, Erin E. Baldwin, MS Genetic Counselor, and Katherine R. U. Heisner, BS, Research Assistant will study Maternally inherited mitochondrial DNA sequence variants and CRPS-I.

Their hypothesis is that is that a brain/nerve energy deficiency that can be caused by maternally inherited changes in the mtDNA code plays an important role in the development of many functional disorders, including CRPS-I. The team will study up to 300 individuals who have been diagnosed with CRPS-I By a physician or other health care providers.

Dr. Boles explains his interest in this subject: “I am a practicing pediatric geneticist/metabolic specialist, as well as a medical researcher in mitochondrial genetics. In my clinical practice, hundreds of families are followed in which multiple matrilineal relatives suffer from neurological disorders, especially intermittent functional conditions. Our interest in complex regional pain syndrome type 1 (CRPS-I) stems from the observation that, in addition to other functional conditions, 12 of my patients have symptoms that meet all of the international diagnostic criteria for CRPS-I. Examples include a 9-year-old girl with severe pain, allodynia (touch perceived as severe pain), swelling and color change to the whole arm and hand for several weeks following an arm bone fracture, and a 14-year-old girl with a change in sensation and color in a stocking-like distribution, with full disability secondary to allodynia following a fall during gymnastics without noted fracture.

“All of those 12 children meet established clinical criteria for the diagnosis of a mitochondrial disorder, and almost all of the family histories are highly suggestive of maternal inheritance. Beyond these 12 children, many more of my patients with mitochondrial disease from families demonstrating maternal-inheritance have frequent episodes of localized extremity pain that doesn’t quite meet the CRPS-I diagnostic criteria. Many of their brothers, sisters and mothers have these episodes of pain as well.

Final Progress Report: RSDSA and AMERICAN RSDhope Grant

Researcher’s Name: Richard G. Boles, M.D.
E-mail Address: [email protected]
Institution: Childrens Hospital Los Angeles
Project Title: Maternally inherited mitochondrial DNA sequence variants and CRPS-I
Date: June 30, 2010

1. What were the (specific) original objectives of this study?

a. To determine the degree of maternal inheritance in CRPS-I.
b. To determine the prevalence of specific functional-disorder-related mitochondrial DNA (mtDNA) polymorphisms in CRPS-I.

2/3. Which objectives have been accomplished – summarize these accomplishments

a. The manuscript of the case series of 8 children with CRPS-I and maternally inherited mitochondrial dysfunction is now published in Archives of Diseases in Childhood.
b. We have further developed and validated our Quantitative Pedigree Analysis methodology (see previous Progress Report).
c. We have found that the same mtDNA polymorphisms associated with cyclic vomiting syndrome are also associated with CRPS-I and multiple additional functional disorders (see attached manuscripts, including a manuscript submitted to Lancet).
d. Co-enzyme Q10 is effective and well tolerated in the treatment of cyclic vomiting syndrome, (published in BMC Neurology). This suggests that “co-Q” may be helpful in the treatment of CRPS-I, which is indeed my anecdotal clinical observation in several cases, especially combined with mega-dosages of B vitamins and high-dosage amitriptyline.
e. We have preliminary data demonstrating probable maternal inheritance in 9/40 (22%) of CRPS-I cases referred through RSDSA/RSDHope, versus 1/40 (2%) of controls (P = 0.004) (see attached abstract presented at Mitochondria 2009 in the Washington D.C. area). 
f. We have data demonstrating an association of mtDNA polymorphism 16519T with CRPS-I cases referred through RSDSA/RSDHope (21/49 = 43% of mtDNA haplogroup H CRPS-I subjects versus in 63/231 = 27% of HgH population controls; P = 0.031; odds ratio 2.0, 95% CI 1.1-3.8) (see attached abstract presented at Mitochondria 2009 in the Washington D.C. area). 16519T is also associated with other functional disorders (see attached manuscripts and published articles) and thus this project provides supporting molecular data that CRPS-I is fundamentally related to the other functional disorders.
g. Clinical data from the CRPS-I cases referred through RSDSA/RSDHope reveals that virtually all subjects suffer from multiple functional disorders in addition to CRPS-I. Many patients suffer from more than ten different functional disorders, frequently including the same as the ones that our group found are associated with 16519T.

4. Which objectives have not been accomplished?

None. However, the clinical data is voluminous and a statistician is still analyzing it to see if any additional findings of the study can be found within.

5. Describe any problems in meeting these objectives

The study was delayed because of personnel issues as discussed in the previous Progress Report.

6. Any budgetary questions


7. Future plans for this project

The attached manuscript was recently submitted to Lancet. Some of the CRPS-I data from this study are included in that manuscript. Recently, the P.I. received a good score on the first submission of an NIH grant application to sequence the full mtDNA in large numbers of subjects with cyclic vomiting syndrome and migraine. If funded, any disease-associated mtDNA sequence variants found as part of that study will be assayed for in the current bank of CRPS-I DNA samples.

Once the clinical data has been fully analyzed, likely a manuscript related to CRPS-I will be drafted for publication. This manuscript will probably focus on the high co-morbid functional disease burden in CRPS-I patients, as well as the finding of probable maternal inheritance in a sizable minority.

8. Publications or scientific presentations resulting from this project

Publications Resulting From This Project:

Boles RG, Kerr JR, Zaki EA, Das K, Biswas S, Gardner A. “Functional” and dysautonomic-related conditions: Are we but blind men feeling different parts of an energy-depleted elephant? Submitted to Lancet.

Related Publications:

Higashimoto T, Baldwin E, Gold JI, Boles RG (2008): Reflex sympathetic dystrophy: Complex regional pain syndrome type I in children with mitochondrial disease and maternal inheritance. Arch Dis Child 93:390-7.

Camilleri M, Carlson P, Zinsmeister AR, McKinzie S, Busciglio I, Burton D, Zaki EA, Boles RG (2009): Mitochondrial DNA Polymorphisms, Functional Gastrointestinal Disorders and Gastrointestinal Motor and Sensory Functions. Am J Physiol – Gastrointest Liver Physiol. Am J Physiol Gastrointest Liver Physiol 296:G510-6.

Zaki EA, Freilinger T, Klopstock T, Baldwin EE, Heisner K, Adams K, Dichgans M, Wagler S, Boles RG (2009): Two Common Mitochondrial DNA Polymorphisms Are Highly Associated With Migraine Headache and Cyclic Vomiting Syndrome. Cephalalgia 29:719-28.

Boles RG, Zaki EA, Lavenbarg T, Hejazi R, Foran P, Freeborn J, Trilokekar S, McCallum R (2009): Are pediatric and adult-onset cyclic vomiting syndrome (CVS) biologically different conditions? Relationship of adult-onset CVS with the migraine and pediatric CVS-associated common mtDNA polymorphisms 16519T and 3010A. Neurogastroenterol Motil. Epub ahead of print.

Boles RG, Lovett-Barr MR, Preston A, Li BU, Adams K (2010): Treatment of cyclic vomiting syndrome with co-enzyme Q10 and amitriptyline, a retrospective study. BMC Neurology 10:10.

9. Statement written for the general public summarizing the highlights of this report The term “functional disorders” refers to conditions that cause symptoms, but no abnormal findings on testing, such as from blood or imaging scans. Examples include migraine, cyclic vomiting syndrome (CVS), chronic fatigue syndrome, fibromyalgia, and irritable bowel, as well as CRPS-I (RDS). The first finding of this RSDSA and RSDHope-funded study is that CRPS-I patients usually suffer from multiple functional disorders, including the ones listed above.Second, in this study the Boles group found that disease is primarily inherited in the mother’s family in 22% of CRPS-I families. Maternal inheritance suggests that the genetic mutation causing disease is encoded on the mitochondrial DNA (mtDNA), because the mtDNA is inherited exclusively from the mother.

Third, in this study the Boles group found that the mtDNA sequence variant called 16519T is common in CRPS-I patients. Previously, they had found that 16519T is common in CVS and in migraine patients. The data implies that 16519 doubles the risk that a person will develop CRPS-I. Overall, their data suggests that a sizable minority of CRPS-I patients have disease in part due to mitochondrial dysfunction (low cellular energy levels), which in turn is in part due to DNA sequences inherited from the mother.

UPDATE – (October 2012)  – See additional information below on Cyclic Vomiting Syndrome and DNA/CRPS Connection?

What is mitochondrial DNA?

In this section from the NIH website, they explain what exactly it is;

Mitochondria are structures within cells that convert the energy from food into a form that cells can use. Although most DNA is packaged in chromosomes within the nucleus, mitochondria also have a small amount of their own DNA. This genetic material is known as mitochondrial DNA or mtDNA. In humans, mitochondrial DNA spans about 16,500 DNA building blocks (base pairs), representing a small fraction of the total DNA in cells.

Mitochondrial DNA contains 37 genes, all of which are essential for normal mitochondrial function. Thirteen of these genes provide instructions for making enzymes involved in oxidative phosphorylation. Oxidative phosphorylation is a process that uses oxygen and simple sugars to create adenosine triphosphate (ATP), the cell’s main energy source. The remaining genes provide instructions for making molecules called transfer RNA (tRNA) and ribosomal RNA (rRNA), which are chemical cousins of DNA. These types of RNA help assemble protein building blocks (amino acids) into functioning proteins.

Mitochondrial genes are among the estimated 20,000 to 25,000 total genes in the human genome.

How are changes in mitochondrial DNA related to health conditions?Many genetic conditions are related to changes in particular mitochondrial genes. This list of disorders associated with mitochondrial genes provides links to additional information.

The following conditions are related to changes in the structure of mitochondrial DNA.

cancersMitochondrial DNA is prone to somatic mutations, which are a type of noninherited mutation. Somatic mutations occur in the DNA of certain cells during a person’s lifetime and typically are not passed to future generations. There is limited evidence linking somatic mutations in mitochondrial DNA with certain cancers, including breast, colon, stomach, liver, and kidney tumors. These mutations might also be associated with cancer of blood-forming tissue (leukemia) and cancer of immune system cells (lymphoma).

It is possible that somatic mutations in mitochondrial DNA increase the production of potentially harmful molecules called reactive oxygen species. Mitochondrial DNA is particularly vulnerable to the effects of these molecules and has a limited ability to repair itself. As a result, reactive oxygen species easily damage mitochondrial DNA, causing a buildup of additional somatic mutations. Researchers are investigating how these mutations could be related to uncontrolled cell division and the growth of cancerous tumors.

Cyclic vomiting syndrome

Cyclic vomiting syndrome may be related to genetic changes in mitochondrial DNA. Some of these changes alter single DNA building blocks (nucleotides), whereas others rearrange larger segments of mitochondrial DNA. These changes likely impair the ability of mitochondria to produce energy. Defects in energy production may lead to symptoms during periods when the body requires more energy, such as when the immune system is fighting an infection. However, it remains unclear how changes in mitochondrial function are related to recurrent episodes of nausea and vomiting.