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

Brain MRI EEG Sleep Study PFTs Echocardiogram EKG Abdominal Ultrasound Swallow Evaluation Nutrition Assessment Developmental Assessment Vision Test Ophthalmologic

Examination Hearing Test

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

Seizures Myoclonus Ataxia Hypotonia Spasticity Dystonia Tremor Other movement

disorder "stroke-like" episodes Hemiparesis Migraine

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

PNS: Numbness Paresthesias Pain

ANS: 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

Muscle: Fatigue Exercise Intolerance Pain Spasms Tenderness Myoglobinuria

Hearing: Hearing Loss

Eyes: Blurry Vision Double Vision Ptosis Ophthalmoplegia Optic Atrophy Pigmentary

Retinopathy

SYMPTOM REVIEW: HEART, LUNGS, KIDNEYS, BLADDER, ENDOCRINE

Pulmonary: Dyspnea Obstructive Sleep

Apnea Heart:

Cardiomyopathy Arrhythmia Heart Block

Kidney: Renal Tubular

Acidosis Renal Failure

Bladder: Urinary Retention Incomplete

Emptying UTI

Endocrine: Short Stature Diabetes Mellitus Hypothyroidism Hypoparathyroidism Adrenal Insufficiency

SYMPTOM REVIEW: GI

GI: Anorexia Early Satiety Failure to Thrive Abdominal Pain Gastroesophageal

Reflux Bloating Abdominal Distention Pseudo-Obstruction Constipation Cyclic Vomiting

Liver: Hepatomegaly Dysfunction Fatty Liver Cirrhosis Coagulopathy

Pancreas: Pancreatic

dysfunction

SYMPTOM REVIEW: SKIN, BLOOD, LABS

Skin: Pallor, Blotchiness,

Mottling without Provocation

Erythromyalgia Easy Bruising

Blood: Anemia Sideroblastic Anemia Neutropenia Thrombocytopenia

Metabolic: Metabolic Acidosis Lactic Acidosis Hyperammonemia Hypoglycemia Low Carnitine Fatty Acid beta-

Oxidation 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

Medications Anesthetics

Educate providers for concerning symptoms

TREATMENT: EXERCISE

TREATMENT: ANTIOXIDANTS THEORY

TREATMENT: CO ENZYME Q10 (COQ10)

Made in human cells Important for a host of functions

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)

CoQ10 as Ubiquinol: (preferred) Pediatric: 2-8 mg/kg/day in 2 divided doses Adult: 50-600 mg once daily

Co Q 10 as Ubiquinone: Pediatric: 5-30 mg/kg/day in 2 divided doses Adult: 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

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:

Pediatric: 0.1 g/kg/day in 2 divided doses Adult: 10 g/d in 2 divided doses

Contraindications: kidney or liver disease Side Effects: upset stomach, diarrhea

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: Pediatric: 20-100 mg/kg/d in 2-3 divided

doses Adult: 330-990 mg/dose 2-3 times per day

Contraindications: allergy to carnitine Side Effects: body odor (related to dosing),

stomach upset , dirrhea

MEDICATIONS TO AVOID

AMINOGLYCOSIDES

Amikacin Kanamycin Neomycin Streptomycin Gancyclovir (systemic for VZV, HIV, CMV) Gentamicin (infection in newborns) Tobramycin (systemic, oral inhalation) Tobramycin (ophthalmic)

STEM CELLS: THEORY

STEM CELLS AND MITOCHONDRIAL DISEASE

• Location – Direct transplantation into affected organ– Localized Delivery

• Arterial into vascular distribution• Fluid space around organ

– Systemic Delivery• Types of Cells

– Undifferentiated Pluripotent Stem Cells– Early Progenitor Cells– Neuronal Progenitor Cells– Neurons– Support Cells

STEM CELLS: MAKING THEORY INTO REALITY

Requirements for Feasible Stem Cell Therapy 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

• Not ready for prime-time• Get reliable information(

www.stemcells.nih.gov)• Weigh risks and benefits

– 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

Genetic Diagnosis nDNA arrays Whole exome sequencing

Biomarkers FGF-21 as possible reliable biomarker for

mitochondrial disease involving muscle 13-C methionine breath test for mitochondrial

liver disease 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

Awareness Research Funding Supplement and Medical Foods Insurance Coverage

MITOACTION WEBSITE

A Clinician’s Guide to Symptoms 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

“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

PCP Office ED

Protocol for Vomiting Protocol for General Surgery

Eating Disrupted Eating Not Disrupted

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

In-person On-line Phone: Mito-411 (1-888-MITO-411)

Consider signing up on patient registry (will be contacted for possible clinical trials)

MY RECOMMENDATIONS FOR WHAT CAREGIVERS AND PATIENTS SHOULD DO

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 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

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?