Optimized Nutrition in Mitochondrial Disease Correlates to Improved Muscle Fatigue, Strength, and Quality of Life

We sought to prospectively characterize the nutritional status of adults ≥ 19 years (n = 22, 27% males) and children (n = 38, 61% male) with genetically-confirmed primary mitochondrial disease (PMD) to guide development of precision nutritional support strategies to be tested in future clinical trials. We excluded subjects who were exclusively tube-fed. Daily caloric requirements were estimated using World Health Organization (WHO) equations to predict resting energy expenditure (REE) multiplied by an activity factor (AF) based on individual activity levels. We developed a Mitochondrial Disease Activity Factors (MOTIVATOR) score to encompass the impact of muscle fatigue typical of PMD on physical activity levels. PMD cohort daily diet intake was estimated to be 1,143 ± 104.1 kcal in adults (mean ± SEM, 76.2% of WHO-MOTIVATOR predicted requirement), and 1,114 ± 62.3 kcal in children (86.4% predicted). A total of 11/22 (50%) adults and 18/38 (47.4%) children with PMD consumed ≤ 75% predicted daily Kcal needs. Malnutrition was identified in 16/60 (26.7%) PMD subjects. Increased protein and fat intake correlated with improved muscle strength in those with insufficient daily Kcal intake (≤ 75% predicted); higher protein and fat intake correlated with decreased muscle fatigue; and higher protein, fat, and carbohydrate intake correlated with improved quality of life (QoL). These data demonstrate the frequent occurrence of malnutrition in PMD and emphasize the critical need to devise nutritional interventions to optimize clinical outcomes. Supplementary Information The online version contains supplementary material available at 10.1007/s13311-023-01418-9.

Overweight (BMI 25-29.9),and Obese (BMI 30 and above) [1] ^BMI scores < 5th percentile were classified as Underweight, 5th-84th percentile were Appropriate, 85th-97th percentile were Overweight, and > 97th percentile were Obese Abbreviation(s): BMI -Body Mass Index    <0.0001 c a Intake goal for CHO and PRO (g/day) is based on the DRI which is sex and age based.Population reference for Fat (g/day) intake is based on the CSFII, 1998 survey, reported in the DRI [6].
b Comparison of individual macronutrient intake vs. standard DRI macronutrient intake goal by unpaired parametric-test: significant difference is p<0.05 c Comparison of individual macronutrient intake vs individual macronutrient intake goal by paired parametric-test d Two subjects (n=2) under 1 year of age had CHO intake goal of 95 g/day, PRO intake of 11 g/day, and fat intake of 39.5g/day     a Malnutrition classification following GLIM (Global Leadership Initiative on Malnutrition) guidelines were only applied to the adult cohort (n =23) [9].^Levels of Severity were only applied to the pediatric cohort following the pediatric ASPEN malnutrition criteria [2].

Table e -4. Comparison of Daily Kcal Intake using Conventional World Health Organization [3] (WHO) vs. Harris Benedict (HB) [4] vs Mifflin-St. Jeor [5] Resting Energy Expenditure Equations in adult subjects*
Predicted Kcal intake calculation: Resting Energy Expenditure value x ASPEN/RDA Activity Factor ^Comparison by paired parametric t-test of Predicted Kcal intake vs.Estimated daily Kcal intake: significant difference is p<0.05 # One-way ANOVA comparison of predicted Kcal intake and percent (%) predicted Kcal intake using WHO vs HB vs MSJ equations Abbreviation(s): ASPEN -American Society for Parenteral and Enteral Nutrition, RDA -Recommended Daily Allowance, WHO -World Health Organization, HB -Harris Benedict, MSJ -Mifflin-St.Jeor

Table e -6. Mitochondrial Activity Factors (MOTIVATOR)
Instructions for Estimation of Total Energy Needs in Individuals with Primary Mitochondrial Disease:* Total Calculated Energy Needs= Resting Energy Expenditure [3]** x

Table e -7. Pediatric (age 1 through 18 years) Mitochondrial Activity Factors (MOTIVATOR) AF Activity Level Motor Function and Fatigue Characterization Description
Use of wheelchair or adapted stroller • May drive power wheelchair Unable to climb stairs.Able to sit in a stair glide chair to be transported up steps • Swinging at Playground o Parent/caregiver places in age-appropriate swing, able to hold onto swing and kick legs but unable to "pump" swing, needs to be pushed by parent/caregiver • Swimming o Requires a flotation device or support of parent/caregiver but can kick and move arms and legs in the water, but does not propel across water, remains in place (treading water), may stand without support in chest deep water and take steps with hand-held assist or holding edge of pool 1.3-1.4Level 3: Light • Walks independently using assistive device (walker, crutches, gait trainer) or hand-held assistance from caregiver, or short distances unsupported indoors • When seated, hands are free to play • Able to move into and out of sitting independently • Crawls independently around room • Cruises along furniture • Some physical assistance required for difficult transfers such as getting up off the floor • Physical assistance required for stair climbing • Requires use of wheelchair, stroller, or scooter for community level distances and requires adapted equipment for sports Parent places in age-appropriate swing, able to hold onto swing and move trunk and leg in pumping motion but unable to start swing without assistance, able to maintain balance and sustain swinging, while being pushed by parents intermittently for at least 5 minutes • Swimming o May need minimal flotation device such as a tube, "swimmies" (inflatable arm bands), a pool noodle, kick board, or swim vest, but able to kick and propel across short distances (10 ft or less), may be able to stand without support and take steps in chest deep water at least 10 steps without support.In general plays in small area of pool o Needs to be pushed in a fully supportive adapted stroller or wheelchair (head and trunk supports, tilt-in-space, or reclined).• Stair Climbing o Unable to climb stairs or use stair glide.Carried by caregiver or stairs avoided.• Swinging at Playground o Parent/caregiver places in fully supportive adapted swing and parent/caregiver pushes swing.• Swimming o Requires fully supportive adapted swimming flotation devices and full assistance by parent/caregiver, minimal movement of extremities in water.Transported in manual wheelchair or adapted stroller 1.1-1.3Level 2: Very Light • Unable to walk • Sits independently but not able to move into or out of this position • Rolling, or crawling on belly, or creeping on all fours less than 10 ft • Physical assistance required for transfers or transitions • Able to weight bear, may take 5-10 steps with physical assistance or support with walker or gait trainer • o

•
Able to stand and walk independently indoors and outdoors including home and school • No assistive devices needed/may wear orthotics Limited by fatigue: • Able to walk 1/4 mile (5 city blocks) but requires rests • Able to walk up one full flight but not 2 flights of steps without rest • Able to run < 1 minute before requiring rest • Able to sit independently and play with arms free but requires rest or leans on support in < 10 minutes.Able to transition in and out of sitting, crawling, and pulls to stand independently • Able to crawl throughout house, requires rest after ≤ 10 minutes of activity Able to enter and exit pool independently (age-appropriate assistance for younger toddler/child), able to move independently walking in chest deep water or swimming with minimal (age appropriate) or no flotation device.Able to propel him/herself across the pool at least 20 ft.Able to sustain activity in the water <=10 minutes before requires rest.Able to stand and walk independently indoors and outdoors including home and school • No assistive devices needed/may wear orthotics • Able to walk 1/4 mile (5 city blocks) without rest • Able to walk up 2 flights of steps without rest • Able to run > 1 minute without rest • Able to sit independently and play with arms free without leaning on support >=10 minutes Younger children (developmental age 1-2 years): • Able to transition in and out of sitting, crawling, and pulls to stand independently • Able to crawl reciprocally throughout house > 10 minutes without rests Able to enter and exit pool independently (age-appropriate assistance for younger toddler/child), able to move independently walking in chest deep water or swimming with minimal (age appropriate) or no flotation device.Able to propel him/herself across the pool at least 20 ft.Able to sustain activity in the water 11-29 minutes before requires rest.Able to walk, run, play, and participate in activities or sports independently without limitations.Able to run and jump and walk on uneven terrain.Keeps up with peers.Able to walk independently throughout community on all surfaces and uneven terrain without limitations.May wear orthotics.Able to keep up with peers, no rests needed.• Stair Climbing o Able to walk up multiple (>2) flights of steps at home, in school, and in the community without any limitations or rests needed • Swinging at Playground o Child attains sitting on swing independently (younger child may be assisted by parent/caregiver age appropriately), able to pump independently without assistance and sustain swinging >10 minutes.• Swimming o Able to enter and exit pool independently (age-appropriate assistance for younger toddler/child), able to move independently walking in chest deep water or swimming with minimal (age appropriate) or no flotation device.Able to propel him/herself across full length of standard sized pool (25 yards/75 feet) and swim laps without flotation device.Able to sustain activity in the water >30 minutes without rest.Able to keep up with peers. o

Table e -8. Adult (age ≥ 19 years) Mitochondrial Activity Factors MOTIVATOR
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Table e -12. Macronutrient Intake (g/day) across Kcal intake groups
[6]sumption goal for CHO and PRO (g/day) is based on the DRI which is sex and age based.Population reference consumption for Fat (g/day) is based on the CSFII, 1989 survey, reported in the DRI[6].B Estimated Maintenance Fluid Needs was based on the Holliday Segar Equation, which is weight based. A

Table e -13. Comparison of BMI and daily Kcal consumption with presence of GI symptoms (n=22 adult subjects*)
Individual subjects within BMI classification and Kcal classification reporting multiple GI symptoms A/B/C/D

Primary Mitochondrial Disease Genetic Etiologies Genetic Etiologies, n Adult Malnutrition GLIM
and ASPEN (n=2)

Table e -17. Adult Malnutrition
BMI Classifications; U= Underweight, A= Appropriate, O= Overweight/Obese b ASPEN Malnutrition requires both weight loss and inadequate food criteria to be met c ASPEN criteria requires a weight loss of 5% in 1 month, 7.5% in 3 months, 10% over 6 months or 20% in 12 months d GLIM Malnutrition requires both a physiological criterion (at least 1) and an etiological criterion to be met e GLIM Low BMI index <20 if < 70 years f GLIM weight loss of >5% within past 6 months, or >10% beyond 6 months a