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
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.
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.
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