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Diet, Motor Activity & Daily Activity Limitations in Individuals with SELENON (SEPN1) - Related Myopathy

J.M. Prystupa1, R. Alvarez2, C. A. Genetti1, E. Weller3, S. Liu4, E.C. Troiano1, B. Moghadaszadeh1 & A.H. Beggs1

1Boston Children's Hospital (BCH), Genetics & Genomics, Boston, USA, 2Cure CMD, Lakewood, USA, 3BCH, Hematology Oncology, Biostatistics, ICCTR, Boston, USA, 4BCH, Biostatistics, ICCTR, Boston, USA

 

Poster

  • See below poster for further details.

Abstract

Introduction

  • Mutations in the SELENON (SEPN1) gene result in a group of rare congenital myopathies called SELENON-related myopathies (SELENON-RM)1-5
  • SELENON-RM affected individuals typically present early in life with hypotonia and axial weakness, with evolving spinal rigidity, scoliosis, decreased stamina, low body mass, & respiratory insufficiency which in turn can affect an individual's stamina & ability to walk, run, climb stairs, & rise from floor or seated position1,3-7
  • The severity of these symptoms varies widely between patients1,3-5 including those with identical mutations6
  • An online patient reported outcomes survey was developed to evaluate whether diet can help explain some of this variation

Methods

  • 29 participants (21 males, 8 females) with genetically-confirmed SELENON-RM completed a modified version of the EPIC-Food Frequency Questionnaire (EPIC-FFQ)
  • Average daily intakes (ADI) were calculated using the FFQ EPIC Tool for Analysis (FETA) software8
  • Participants were then asked 24 activity-related questions
    (Answer range: 6 = ‘Very Easy’ to 1 = ‘Not Able’ to complete & 0 = ‘Unknown’)
  • Statistics (correlation, regression) were performed using Microsoft Excel9 & SAS 9.410

Results & Discussion

  • All participants answered questions about completing 21 daily activities (DAS)
  • 23 participants (79.3%; 18 men, 5 women) answered an additional 3 questions about walking ability (WLS) over short (100ft; flat/inclined) & long (660ft) distances
  • See the supplementary information section for details regarding DAS & WLS scoring
  • Table 1 contains the descriptive statistics of the categories of interest for the 29 survey participants

Table 1. Summary statistics (DAS = Daily Activity Score, WLS = Walking Scores, ADI = Average Daily Intake). Additional summary statistics for individual daily tasks are provided in Supplementary Tables 1 & 2.

 

Category		 Median (Range)
All (n=29)		 Median (Range)
Females (n=8)		 Median (Range)
Males (n=21)		  
p-value
Age 23.0 (7 - 56) 30.5 (7 - 56) 15.0 (8 - 56) 0.3139
DAS 74 (25 -105) 61 (25 - 92) 81 (26 - 105) 0.0251
WLS 16 (3 - 18) 10 (3 - 15) 17 (7 - 18) 0.0106
ADI - Energy (kcal) 1334 (654 - 4378) 1537 (654 - 2527) 1334 (772 - 4378) 0.9999
ADI - Protein (g) 70 (26 -133) 61 (26 - 118) 73 (42 - 133) 0.1611
ADI - Fat (g) 64 (27 - 255) 67 (30 - 163) 63 (27 - 255) 0.8466
ADI - Carbohydrate (g) 134 (73 -414) 140 (75 - 227) 132 (73 - 414) 0.6466
ADI - Sugars (g) 61 (19 - 209) 86 (19 - 131) 61 (20 - 209) 0.6815
  • Males had significantly higher activity scores (DAS & WLS) compared to females
    • This is despite consuming a similar amount of total calories, macronutrients & sugars
    • Biological differences between genders may help explain some of these observed differences
      • Men have increased muscle fiber size & strength compared to women11
      • When fat-free mass is considered, women have a higher caloric cost for walking & running compared to men12
  • Activity scores were negatively correlated with age (DAS = -0.6333, p = 0.0012; WLS = -0.6640, p = <0.0001 using Spearman Correlation)
  • Age & gender is associated with activity scores in a multivariable model  (Table 2)
    • Age is negatively associated with activity scores
    • Males have higher activity scores compared to females
    • This is in contrast with previously published data in SELENON-KO animal models, which notes males “having a comparable or more marked phenotype”1 and illustrates that observations in the animal models may not reflect the SELENON-RM human phenotype completely3

 

 

Table 2. Multivariable model analysis results for WLS and DAS.

 

Variable		 WLS
β (95%)		 WLS
p-value		 DAS
β (95%)		 DAS
p-value
Age (1 y increase) -0.2 (-0.2 , -0.1) <0.0001 -0.8 (-1.2 , -0.5) <0.0001
Gender (M v F) 5.5 (3.3 , 7.7) <0.0001 15.0 (2.7 , 27.2) 0.0168

Conclusions & Future Research

  • The findings from our research here suggests that both age and gender are significant for influencing perceived activity scores in SELENON-RM affected individuals
  • Sample size must be increased before dietary influences can be adequately assessed
    • Nevertheless, total calories, macronutrients or sugar intakes do not appear to have any influence on perceived activity scores
  • Future research will include expansion of the cohort & further analysis of the survey modules, including investigating associations between specific nutrient intakes & perceived daily activity, walking, & running scores for both males & females, along with age & body mass index & pulmonary information, which could provide additional insight on the variation of symptom severity observed in SELENON-RM affected individuals

Acknowledgements

  • We would like to thank the many SELENON-RM affected individuals who took the time to complete the survey. Funding for this project was provided by the Lee & Penny Anderson Family Foundation and utilized the resources of Cure CMD

References

  1. Filipe, A., A. Chernorudskiy, S. Arbogast, E. Varone, R-N. Villar-Quiles, D. Pozzer, M. Moulin, S. Fumagalli, E. Cabet, S. Dudhal, M-G. De Simoni, R. Denis, N. Vadrot, C. Dill, M. Giovarelli, L. Szweda, C. De Palma, P. Pinton, C. Giorgi, C. Viscomi, E. Clementi, S. Missiroli, S. Boncompagni, E. Zito, and A. Ferreiro. 2020. Defective endoplasmic reticulum-mitochondria contacts and bioenergetics in SEPN1-related myopathy, Cell Death Differ. doi: 10.1038/s41418-020-0587-z.
  2. Moghadaszadeh, B., B. E. Rider, M. W. Lawlor, M. K. Childers, R. W. Grange, K. Gupta, S. S. Boukedes, C. A. Owen, and A. H. Beggs. 2013. Selenoprotein N Deficiency in Mice Is Associated with Abnormal Lung Development. FASEB J. 27(4): 1585-99.
  3. Rederstorff, M., P. Castets, S. Arbogast, J. Lainé, S. Vassilopoulos, M. Beuvin, O. Dubourg, A. Vignaud, A. Ferry, A. Krol, V. Allamand, P. Guicheney, A. Ferreiro, and A. Lescure. 2011. Increased Muscle Stress-Sensitivity Induced by Selenoprotein N Inactivation in Mouse: A Mammalian Model for SEPN1-Related Myopathy, PLOS ONE. 6: e23094.
  4. Scoto, M., S. Cirak, R. Mein, L. Feng, A. Y. Manzur, S. Robb, A. M. Childs, R. M. Quinlivan, H. Roper, D. H. Jones, C. Longman, G. Chow, M. Pane, M. Main, M. G. Hanna, K. Bushby, C. Sewry, S. Abbs, E. Mercuri & F. Muntoni. 2011. SEPN1-Related Myopathies: Clinical Course in a Large Cohort of Patients. Neurology. 76(24): 2073-8.
  5. Schara, U., W. Kress, C.G. Bönnemann, N. Breitbach-Faller, C.G. Korenke, G. Schreiber, M. Stoetter, A. Ferreiro, & M. von der Hagen. 2008. The Phenotype and Long-Term Follow-up in 11 Patients with Juvenile Selenoprotein N1-Related Myopathy. Eur J Paediatr Neurol. 12(3): 224-30.
  6. Clarke, N. F., W. Kidson, S. Quijano-Roy, B. Estournet, A. Ferreiro, P. Guicheney, J.I Manson, A.J. Kornberg, L.K. Shield & K.N. North. 2006. SEPN1: Associated with Congenital Fiber-Type Disproportion and Insulin Resistance. Ann Neurol. 59(3): 546-52.
  7. Ferreiro, A., S. Quijano-Roy, C. Pichereau, B. Moghadaszadeh, N. Goemans, C. Bonnemann, H. Jungbluth, V. Straub, M. Villanova, J. P. Leroy, N. B. Romero, J. J. Martin, F. Muntoni, T. Voit, B. Estournet, P. Richard, M. Fardeau, and P. Guicheney. 2002. Mutations of the Selenoprotein N Gene, Which Is Implicated in Rigid Spine Muscular Dystrophy, Cause the Classical Phenotype of Multiminicore Disease: Reassessing the Nosology of Early-Onset Myopathies. Am J Hum Genet. 71(4): 739-49.
  8. Mulligan A, Luben R, Bhaniani A, Parry-Smith D, O’Connor L, Khawaja A, Forouhi NG, Khaw KT. 2014. A new tool for converting food frequency questionnaire data into nutrient and food group values: FETA research methods and availability. BMJ Open. 4(3):e004503.
  9. Microsoft Corporation. 2018. Microsoft Excel. Available at: https://office.microsoft.com/excel.
  10. SAS Institute. 2014.SAS: SAS 9.4. Cary, NC.
  11. Miller, A. E., J. D. MacDougall, M. A. Tarnopolsky, and D. G. Sale.1993. Gender Differences in Strength and Muscle Fiber Characteristics. Eur J Appl Physiol Occup Physiol. 66(3): 254-62.
  12. Pauley, A., C.B Dixon, E. S. Rawson, T. R. McConnell, and J. L. Andreacci. 2016. The impact of body composition on energy expenditure during walking and running in young adults. J. Exerc. Physiol. Online. 19: 66+.

Supplemental Material 

Activity Information

  • Each survey respondent was asked 24 activity questions (see Supplementary Table 1 for details)
  • Survey respondents then chose one of the following answers which had a corresponding score (displayed in brackets)

“Very Easy” (6)
“Moderately Easy” (5)
“Not Easy or Hard” (4)
“Moderately Difficult” (3)
“Very Difficult” (2)
“Not Able” (1)
“Unknown” (0)

  • Daily Activity Scores (DAS) were calculated from the sum of the 21 (DA1 – DA21) individual daily activity questions (for a maximum score of 126)
  • Walking Scores (WLS) were calculated from the sum of the 3 (WL1-WL3) individual walking questions (for a maximum score of 18)
  • Supplementary Table 2 shows which activities had the highest and lowest median values for the survey respondents

 

Supplementary Table 1. The summary statistics for the individual activity related questions 

 

Question
Number  
Activity		 Median
(Range)
All		   Median
(Range)
Females		 Median
(Range)
Males
DA1 Unbutton/button a shirt 6 (3-6) 6 (3-6) 6 (3-6)
DA2 Pull a T shirt over head 5 (1-6) 4 (2-6) 5 (1-6)
DA3 Shampoo hair in a standing position 5 (1-6) 4 (1-6) 5 (1-6)
DA4 Put on socks 5 (1-6) 3 (1-6) 5 (1-6)
DA5 Put on pants while standing without the use of a chair or wall to help with balance 2 (1-6) 1 (1-3) 2 (1-6)
DA6 Open a twist cap bottle 5 (1-6) 4.5 (1-6) 5 (3-6)
DA7 Blow up a balloon 2 (1-5) 1 (1-5) 2 (1-5)
DA8 Lift a small 2 lb (0.91 kg) weight to an overhead shelf 4 (1-6) 2.5 (1-5) 5 (1-6)
DA9 Pick up a tennis ball from the ground from a standing position 4 (1-6) 3.5 (1-5) 5 (1-6)
DA10 Sit in a crossed legged position 5 (1-6) 4.5 (1-6) 5 (1-6)
DA11 When standing; tuck chin to chest 3 (1-6) 2 (1-6) 4 (1-6)
DA12 Balance on one leg only for 10 seconds 5 (1-6) 3.5 (1-6) 5 (1-6)
DA13 Ride a bicycle 3 (1-6) 2 (1-4) 3 (1-6)
DA14 Perform a squat 2 (1-6) 2 (1-4) 3 (1-6)
DA15 Stand from a chair (of average height) 4 (1-6) 3 (1-4) 5 (1-6)
DA16 Stand up from floor 3 (1-6) 2 (1-3) 3 (1-6)
DA17 When laying on back; tuck chin to chest 2 (1-6) 2 (1-6) 2 (1-6)
DA18 When laying on back; roll onto stomach 4 (1-6) 3 (1-6) 5 (1-6)
DA19 When laying on stomach; roll onto back 4 (1-6) 3.5 (1-6) 5 (1-6)
DA20 Do a sit-up 1 (1-6) 1 (1-2) 1 (1-6)
DA21 Do a push up 1 (1-4) 1 (1-3) 1 (1-4)
WL1 Walk a short (100 ft; 30.5 m ) distance on a flat surface 6 (1-6) 4 (1-6) 6 (3-6)
WL2 Walk a short (100 ft; 30.5 m) distance on an incline 5 (1-6) 3 (1-5) 5 (2-6)
WL3 Walk a long (660 ft; 201 m) distance on a flat surface 5 (1-6) 3 (1-4) 6 (2-6)

 

Supplementary Table 2. The individual activities listed by their median value

 
Median
Value
All
Females
Males

6

“Very Easy”

 • Unbutton/button a shirt
• Walk a short (100 ft; 30.5 m) distance on a flat surface		 • Unbutton/button a shirt • Unbutton/button a shirt
• Walk a long (660 ft; 201 m) distance on a flat surface
• Walk a short (100 ft; 30.5 m) distance on a flat surface

5

“Moderately Easy”

 • Balance on one leg only for 10 seconds
• Open a twist cap bottle
• Pull a T shirt over head
• Put on socks
• Shampoo hair in a standing position
• Sit in a crossed legged position
• Walk a long (660 ft; 201 m) distance on a flat surface
• Walk a short (100 ft; 30.5 m) distance on an incline		   • Balance on one leg only for 10 seconds
• Lift a small 2 lb (0.91 kg) weight to an overhead shelf
• Open a twist cap bottle
• Pick up a tennis ball from the ground from a standing position
• Pull a T shirt over head
• Put on socks
• Shampoo hair in a standing position
• Sit in a crossed legged position
• Stand from a chair (of average height)
• When laying on back; roll onto stomach
• Walk a short (100 ft; 30.5 m) distance on an incline
• When laying on stomach; roll onto back
4.5   • Open a twist cap bottle
• Sit in a crossed legged position		  

4

“Not Easy
or Hard”

 • Lift a small 2 lb (0.91 kg) weight to an overhead shelf
• Pick up a tennis ball from the ground from a standing position
• Stand from a chair (of average height)
• When laying on back; roll onto stomach
• When laying on stomach; roll onto back		 • Pull a T shirt over head
• Shampoo hair in a standing position
• Walk a short (100 ft; 30.5 m) distance on a flat surface		 • When standing; tuck chin to chest
3.5   • Balance on one leg only for 10 seconds
• Pick up a tennis ball from the ground from a standing position
• When laying on stomach; roll onto back		  

3

“Moderately Difficult”

 • Ride a bicycle
• Stand up from floor
• When standing; tuck chin to chest		 • Put on socks
• Stand from a chair (of average height)
• Walk a long (660 ft; 201 m) distance on a flat surface
• When laying on back; roll onto stomach		 • Perform a squat
• Ride a bicycle
• Stand up from floor
2.5   • Lift a small 2 lb (0.91 kg) weight to an overhead shelf  

2

“Very Difficult”

 • Blow up a balloon
• Perform a squat
• Put on pants while standing without the use of a chair or wall to help with balance
• When laying on back; tuck chin to chest		 • Perform a squat
• Ride a bicycle
• Stand up from floor
• When laying on back; tuck chin to chest
• When standing; tuck chin to chest		 • Blow up a balloon
• Put on pants while standing without the use of a chair or wall to help with balance
• When laying on back; tuck chin to chest

1

“Not Able”

 • Do a push up
• Do a sit-up		 • Blow up a balloon
• Do a push up
• Do a sit-up
• Put on pants while standing without the use of a chair or wall to help with balance		 • Do a sit-up
• Do a push up

 

 

This page was last updated October 20, 2020.