The North American Mitochondrial Disease Survey (2012) and - PowerPoint PPT Presentation

The North American Mitochondrial Disease Survey (2012) and Consensus Project (2013) Practice Patterns and Challenges Mitochondrion 2013 Sumit Parikh Md Genetics in Medicine 2015

How is mitochondrial medicine practiced in North America? Is there consensus? Is there a need for consensus criteria?

Invitations sent to CNS, SIMD, MMS, metab-l and Child Neurology list-serv members 37 initial volunteers 5 stopped participating 32 completed all surveys

Practice Locations Little Rock, Arkansas San Diego, California Stanford, California Vancouver, BC, Canada Hamilton, Ontario, Canada Aurora, Colorado Washington, DC Atlanta, Georgia Indianapolis, Indiana New Orleans, Louisiana Baltimore, Maryland Bethesda, Maryland Boston, Massachusetts Detroit, Michigan Rochester, Minnesota Akron, Ohio Cleveland, Ohio Columbus, Ohio Nashville, Tennessee Houston, Texas Philadelphia, Pennsylvania Pittsburgh, Pennsylvania Seattle, Washington Milwaukee, Wisconsin

Biochemical genetics Neurometabolism/Neurogenetics Child Neurology Clinical Genetics Neuromuscular Other 6% 31% 9% 9% 16% 28%

81% of physicians surveyed, while pediatric trained, see both adults and pediatric patients

New Patient Consult Visit Time 50 minutes Average time of a follow-up < 60 minutes visit 25% 60-90 minutes 50% 90-120 minutes 25%

New Patient Preparation Time < 30 minutes 16% 60-90 minutes 19% 30-60 minutes 38% 90-120 minutes 13% Variable 16%

Mitochondrial clinics require Time !!! Prescreening of patients 66% Advance review of records 94% Multiple specialty appointments 69% Additional preparation time > 30 minutes 69% Physician Extenders 90% Case Review with colleagues 88% 50% cancel visit if no records received

Biochemical studies obtained 100% Lactate Organic Acids, urine 100% 94% CMP 91% Amino Acids, plasma 84% Acylcarnitines CBC 54% 47% Urinalysis 38% Pyruvate Amino Acids, urine 31% 28% CK 6% MMA 3% Carnitine, urine 32 38% 0 8 16 24 Physicians surveyed 38%

Genetic studies obtained 28% 50% mtDNA point mutation first Perceived pressure to perform mtDNA 34% mtDNA genome first sequencing 63% Nuclear Gene Panel, Selective 38% Nuclear Gene Panel, 100 genes 15% Nuclear Gene Panel, > 100 genes 59% Exome, if needed 0 8 16 24 32 84% 38% 100% Physicians surveyed 38%

Perception of various laboratories that perform mitochondrial testing bit.ly/mms paper supplement 38% 38%

53% 46% 97% obtain a muscle wait until a child is at biopsy when faced least a year old prior prefer the quadricep with normal to obtaining a muscle muscle biochemical screening biopsy (if not longer) 84% Only 31% Only 43% obtain at least ETC establish whether an enzymology, ETC abnormality is measure muscle histology and electron significant via Coenzyme Q10 levels microscopy diagnostic criteria Only 48% 78% 81% obtain mtDNA feel mitochondrial obtain liver biopsy if sequencing, deletion testing in skin is of there is hepatic and duplication limited value disease analysis

63% of physicians surveyed use diagnostic criteria 60% 20% 20% Modified Bernier Nijmegen NAMDC

37% of physicians surveyed require a genetic diagnosis

100% believe in secondary mitochondrial dysfunction 34% need to treat secondary dysfunction

88% unsure if Autism related mitochondrial dysfunction is a primary or secondary phenomenon 78% unsure what symptoms represents mitochondrial autism

28 28% % of physicians surveyed 19% 19% 16% 16% 14 0 < 5% 5-10% 10-20% >20% Unable to assess Perceived Muscle Biopsy False-Positive Rate

30 28% % of physicians surveyed 22% 22% 19% 15 6% 3% 0 < 5% 5-20% 20-30% 30-50% >50% Unable to assess Perceived Muscle Biopsy False-Negative Rate

50 % of physicians surveyed 50% 25 28% 16% 0% 3% 3% 0 < 5% 5-10% 10-20% 20-40% >40% Unable to assess Perceived Skin Biopsy False-Negative Rate

Part 2 Treatment and Preventative Care 38% 38%

Supplement used most commonly 75% Creatine 94% Levo-Carnitine 100% 100% CoQ10 100% L-Arginine for strokes 0 8 16 24 32 84% Physicians surveyed

Start cocktail Start individual supplement 50% 50%

Ubiquinol vs Ubiquinone Ubiqunol Ubiquinone Does not matter 42% 48% 10%

Following CoQ10 levels Follow levels Do not follow levels 47% 53%

Following CoQ10 levels Leukocyte levels Serum levels 12% No preference 47% 41%

Use of exercise as a treatment Recommend exercise No recommendation 22% 78%

Type of exercise recommended Land, water and resistance Land and resistance Per therapist 12% 40% 48%

Lab work checked preventatively 100% Electrolytes 100% Transaminases HgbA1C 84% 72% Thyroid function 68% Amino acids, urine 56% 80% CoQ10 obtain screening 52% Lipids every 1-2 years 28% Adrenal function 38% 0 6.25 12.5 18.75 25 Physicians surveyed 38%

Preventative Testing obtained routinely 81% EKG Echo 81% 81% Ophthalmology Cardiology Consultaton 69% Audiograms 63% Sleep studies, if fatigue 47% 38% Immnologic tests 22% Repeat MRI 13% Repeat CSF 6% Stress test 6% Resting metabolic rate 0 8 16 24 32 Physicians surveyed

Clinician Participation Levels Educational talks to families 69% Advisory Board 60% Educational talks to physicians 50% 47% Fundraising Political Advocacy 34% 28% Walkathon participation 0 8 16 24 32 38% Physicians surveyed 38%

Similarities in practice but a general lack of consensus

Agreement in care Clinic structures and organization Physician perceptions of various diagnostic laboratories Care requires significantly more time Shortage of adult trained experts

Variability in care Diagnostic approaches used Extent of testing sent Interpretation of test results How a diagnosis of mitochondrial disease is arrived upon Treatment variability

Officers of the MMS, 2012-2014 Amy Goldstein Sumit Parikh Greg Enns Mary Kay Koenig Russ Saneto Fernando Scaglia

Methods to develop consensus borrowed from Georgianne Arnold ✤ Evidence-based ✤ Eminence based (grey heads in the room) ✤ Committee based (may the strongest personality win) ✤ NIH style consensus (non-experts decide) ✤ Individual (I’ll decide)

Oxford Levels of Evidence

Delphi Method “Pooled intelligence enhances individual judgement and captures the collective opinion of a group of experts” Developing consensus in the absence of sufficient evidence utilizing a committee of 15-25 content experts

Delphi Method “Pooled intelligence enhances individual judgement and captures the collective opinion of a group of experts” Committee Literature Survey forms Consensus? review and data summary subgroups Survey with Items Face-to-face group’s without Consensus? responses discussion consensus revealed

Delphi Method The Good borrowed from Georgianne Arnold ✤ Quantifiable consensus ✤ Less personality based; results driven to the group mean ✤ Leaves room for dissent ✤ Panel size allows for functional and geographic diversity

Delphi Method The Bad borrowed from Georgianne Arnold ✤ The “Mean” is not Scientific Truth ✤ Panel selection is a source of bias (having people who all agree) ✤ Consensus not always reached ✤ Managing groups of physicians is like “herding a group of cats”

Consensus Criteria Working Group Irina Anselm Bruce Cohen Salvatore DiMauro Marni Falk Carol Greene Richard Haas Michio Hirano Andrea Gropman Phil Morgan Mark Tarnopolsky Kathie Simms Johan Van Hove Lynne Wolfe

Neurometabolism/Neurogenetics Neurology Biochemical genetics Clinical Genetics Anesthesia Nurse Practioner 5% 32% 5% 11% 16% 32%

Consensus Criteria ✤ Biochemical Testing in Blood, ✤ Anesthesia Urine and Spinal fluid ✤ Treatment During Illness ✤ Genetic Testing ✤ Treatment with vitamins and ✤ Pathology and Biochemical xenobiotics Testing of Tissue ✤ Neuroimaging ✤ Treatment of Acute Stroke ✤ Exercise

Next? ✤ Preventative Care Guidelines?