A PHYSICIAN’S PERSPECTIVE ON
MITOCHONDRIAL DISORDERS
Abigail Collins, M.D.
Director of Pediatric Movement Disorders
Assistant Professor of Neurology and Pediatrics
University of Colorado, School of Medicine, Denver
OBJECTIVES
Mitochondrial physiology
 Genetic complexities of mitochondrial disorders
 Challenges of making the diagnosis
 Treatments
 Frontiers
 Resources and advocacy

CELLS
MITOCHONDRIAL FUNCTION
MITOCHONDRIAL ANATOMY
MITOCHONDRIAL NETWORK
RESPIRATORY CHAIN
MITOCHONDRIAL ENERGY PRODUCTION
MITOCHONDRIAL EVOLUTION
GENETICS: MITOCHONDRIAL DNA (MTDNA)
GENETICS: NUCLEAR DNA (NDNA)
GENETICS: MTDNA + NDNA
RESPIRATORY CHAIN: MTDNA+ NDNA
AUTOSOMAL RECESSIVE VS DOMINANT
MITOCHONDRIAL DNA INHERITANCE
MITOCHONDRIAL DISEASES
100s of different diseases genetically
 Even in individuals with the same mutation,
there are different symptoms
 Change over time
 Challenging to diagnose
 Challenging to treat

DIAGNOSIS: SYMPTOMS
DIAGNOSIS: ASSESSING INVOLVEMENT
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Brain MRI
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EEG
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Sleep Study
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PFTs
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Echocardiogram
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EKG
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Abdominal Ultrasound
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Swallow Evaluation
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Nutrition Assessment
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Developmental Assessment
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Vision Test
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Ophthalmologic Examination
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Hearing Test
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Labs:
 LFTs
 Fasting Serum Glucose
 Ammonia
 Amino Acids (for
glutamine and tyrosine)
 Albumin
 Cholesterol
 PT/PTT
 Lactic Acid
 Free/Total Carnitine
 UOA
 UA
DIAGNOSIS: GENETICS AND TISSUE
SYMPTOM REVIEW: BRAIN
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Seizures
Myoclonus
Ataxia
Hypotonia
Spasticity
Dystonia
Tremor
Other movement disorder
"stroke-like" episodes
Hemiparesis
Migraine
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Central Apnea
Developmental Delays
Developmental Regression
Dementia
Learning Disabilities
Autism or autistic-like
features
Behavioral Concerns
Psychiatric Conditions
Coma
Sudden Death
SYMPTOM REVIEW: PERIPHERAL AND
AUTONOMIC NERVOUS SYSTEMS
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PNS:
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Numbness
Paresthesias
Pain
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ANS:
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Heat or Cold
Intolerance
Temperature
Dysregulation (low
baseline temp)
Abnormal Sweating
(decreased in hot,
increased in cold)
Pallor, Blotching or
Mottling of Skin
without provocation
Dizziness
Fainting
SYMPTOM REVIEW: MUSCLE, VISION,
HEARING
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Muscle:
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Fatigue
Exercise Intolerance
Pain
Spasms
Tenderness
Myoglobinuria
Hearing:
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Hearing Loss
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Eyes:
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Blurry Vision
Double Vision
Ptosis
Ophthalmoplegia
Optic Atrophy
Pigmentary
Retinopathy
SYMPTOM REVIEW: HEART, LUNGS,
KIDNEYS, BLADDER, ENDOCRINE
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Pulmonary:
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Dyspnea
 Obstructive Sleep
Apnea
Urinary Retention
 Incomplete Emptying
 UTI
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Heart:
Cardiomyopathy
 Arrhythmia
 Heart Block
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Kidney:
Renal Tubular
Acidosis
 Renal Failure
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Bladder:
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Endocrine:
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Short Stature
Diabetes Mellitus
Hypothyroidism
Hypoparathyroidism
Adrenal Insufficiency
SYMPTOM REVIEW: GI
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GI:
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Anorexia
Early Satiety
Failure to Thrive
Abdominal Pain
Gastroesophageal
Reflux
Bloating
Abdominal Distention
Pseudo-Obstruction
Constipation
Cyclic Vomiting
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Liver:
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Hepatomegaly
Dysfunction
Fatty Liver
Cirrhosis
Coagulopathy
Pancreas:
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Pancreatic dysfunction
SYMPTOM REVIEW: SKIN, BLOOD, LABS
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Skin:
Pallor, Blotchiness,
Mottling without
Provocation
 Erythromyalgia
 Easy Bruising
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Blood:
Anemia
 Sideroblastic Anemia
 Neutropenia
 Thrombocytopenia
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Metabolic:
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Metabolic Acidosis
Lactic Acidosis
Hyperammonemia
Hypoglycemia
Low Carnitine
Fatty Acid betaOxidation Dysfunction
Post-prandial Ketosis
Secondary
Neurotransmitter
Abnormality
TREATMENT: DAILY TO DO LIST TO
SUPPORT YOUR MITOCHONDRIAL
FUNCTION
Conserve energy
 Stay cool
 Get adequate nutrition
 Prevent infections
 Hydrate
 Supplement
 Exercise
 Avoid toxins
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Medications
 Anesthetics
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Educate providers for concerning symptoms
TREATMENT: EXERCISE
TREATMENT: ANTIOXIDANTS THEORY
TREATMENT: CO ENZYME Q10 (COQ10)
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Made in human cells
Important for a host of functions
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Shuttling electrons in the respiratory chain
Shuttling electrons when fat is broken down
Signaling in cell
Falls as we age (70 yo has 50% levels of a 20 yo)
Only stored in body for about 2 weeks and ½ life about 36
hours
Insoluble in water (powder formulations have poor absorption)
Ubiquinol or ubiquinone absorbed better
Dosing: (debated)
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CoQ10 as Ubiquinol: (preferred)
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2-8 mg/kg/day in 2 divided doses
50-600 mg once daily
Co Q 10 as Ubiquinone:
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Pediatric:
Adult:
Pediatric:
Adult:
5-30 mg/kg/day in 2 divided doses
300-2400 mg in 2-3 divided doses
Contraindications: none
Side Effects: sleep disruption, wakefulness
TREATMENT: RIBOFLAVIN (VITAMIN B2)
Water soluble vitamin
 Building block for complex I & II
 Cofactor for enzymes in breaking down glucose
(Krebs Cycle) and fat (Fatty Acid Oxidation) in
mitochondria
 Dosing: 50-400 mg per day
 Contraindications: none
 Side Effects: anorexia &/or nausea at high doses,
bright yellow-orange urine
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TREATMENT: L-CREATINE
Binds phosphate groups in cell to buffer them
and shuttle them around
 Phosphate groups are a component of the energy
currency of the cell (ADP and ATP)
 Obtained through diet and made in cells
 Highest concentrations in high energy need
organs (skeletal muscles and brain)
 Dosing:
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Pediatric:
0.1 g/kg/day in 2 divided doses
 Adult:
10 g/d in 2 divided doses
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Contraindications: kidney or liver disease
 Side Effects: upset stomach, diarrhea
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TREATMENT: L-CARNITINE
Shuttles long fats into mitochondria and helps
processing of fats to be broken down into energy
(via Krebs cycle)
 75% obtained from diet, 25% made in body
(majority in skeletal muscles)
 Muscle, heart and liver (NOT brain) depend on
fat for majority of their energy production
 Oral Dosing:
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Pediatric:
20-100 mg/kg/d in 2-3 divided doses
 Adult:
330-990 mg/dose 2-3 times per day
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Contraindications: allergy to carnitine
 Side Effects: body odor (related to dosing),
stomach upset , dirrhea
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MEDICATIONS TO AVOID
AMINOGLYCOSIDES
Amikacin
 Kanamycin
 Neomycin
 Streptomycin
 Gancyclovir (systemic for VZV, HIV, CMV)
 Gentamicin (infection in newborns)
 Tobramycin (systemic, oral inhalation)
 Tobramycin (ophthalmic)
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STEM CELLS: THEORY
STEM CELLS AND MITOCHONDRIAL
DISEASE
•
Location
Direct transplantation into affected organ
– Localized Delivery
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Arterial into vascular distribution
Fluid space around organ
Systemic Delivery
Types of Cells
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Undifferentiated Pluripotent Stem Cells
Early Progenitor Cells
Neuronal Progenitor Cells
Neurons
Support Cells
STEM CELLS: MAKING THEORY INTO
REALITY
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Requirements for Feasible Stem Cell Therapy
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Post-transplant cellular survival
Host organ integration
Cellular connections
Correct differentiation to replace lost cells
Timing of transplant in disease process
Functional Improvement
STEM CELLS: RECOMMENDATIONS
•
•
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Not ready for prime-time
Get reliable
information(www.stemcells.nih.gov)
Weigh risks and benefits
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Financial
Infectious Diseases
Worsening of Symptoms
Lack of Benefit
Consider treatment differences
Consider enrolling in a research study
Consider waiting until demonstrated to be
more effective
Have realistic expectations of degree of
benefit
FRONTIERS

Functional Assessment:
Complex V testing
 Single mitochondrial respiratory chain analysis

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Genetic Diagnosis
nDNA arrays
 Whole exome sequencing
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Biomarkers
FGF-21 as possible reliable biomarker for
mitochondrial disease involving muscle
 13-C methionine breath test for mitochondrial liver
disease
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Treatment
ADVOCACY
Providers may not be familiar with symptoms or
diagnosis
 Providers have 1000s of patients they care for
 Educated caregivers are the best advocate for a
person with mitochondrial disease

Schools/Work
 Health Care Providers
 Insurance Companies
 Legislators
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Awareness
 Research Funding
 Supplement and Medical Foods Insurance Coverage
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MITOACTION WEBSITE
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A Clinician’s Guide to Symptoms
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Overview of mitochondrial disease
Finding the right provider
Care during wellness
Care during illness
Protocols and Letters
School Advocacy and Educational Support
Suggested accommodations
 How to get an aide
 IEPS, 504s, IFSP
 School nurse protocol
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“Energy for Education” Video
SUGGESTED PROTOCOLS AND LETTERS
Protocol for School (describes symptoms and
management/accomodations in depth)
 Mitochondrial Debilitating Fatigue for School
 Suggested Mitochondrial Protocol to be Shared
with School Nurse
 Protocol for Fever and Infection
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PCP Office
 ED
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Protocol for Vomiting
 Protocol for General Surgery
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Eating Disrupted
 Eating Not Disrupted
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ADVOCACY: SCHOOL PROTOCOL
ADVOCACY: INFECTION AT PCP’S OFFICE
ADVOCACY: PROCEDURE WITH FASTING
OTHER RESOURCES
www.umdf.org
 www.clinicaltrials.gov
 www.rarediseases.org
 Staff at Children’s Mitochondrial Clinic for
medical information for other providers
 Patient and Provider Support
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In-person
 On-line
 Phone: Mito-411 (1-888-MITO-411)
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Consider signing up on patient registry (will be
contacted for possible clinical trials)
MY RECOMMENDATIONS FOR WHAT
CAREGIVERS AND PATIENTS SHOULD DO
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Educate themselves as much as possible about their
disease
Advocate in school, in public, at work, in your community,
&/or with your legislators
Demand supplements be covered by insurance companies
Print out protocols and letters, bring them to your provider
to fill out, keep them with you at all times and give copies
to others
Spend a lot of time on the mitoaction website
Make sure your health care providers are willing to learn
about mitochondrial disorders
Find providers who play well together
Exercise
Do OT/PT/ST to support function
CHILDREN’S MITOCHONDRIAL CLINIC
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Patients of any Age (yes, we see adults)
Diagnosed or Suspected Mitochondrial Disorders
Staff:
Metabolic Physician = Dr. Johan Van Hove
Neurologist = Dr. Abbie Collins
 Genetic Counselors*
 Social Worker
 Associated Staff
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Cardiology
Gastroenterology
Pulmonology
Neuromuscular Neurologist
Epileptologists
Nutritionists
Meets once per month currently on the first Tuesday
morning of the month
Scheduled through Metabolics: 303-724-2338
QUESTIONS?