Individualized Assessment of Exercise Capacity in Response to Acute and Long-Term Enzyme Replacement Therapy in Pediatric Pompe Disease
Abstract
:1. Introduction
2. Materials and Methods
2.1. Study Measures
2.1.1. Spirometry
2.1.2. CPET
2.1.3. Six-Minute Walking Test
2.1.4. Motor Function
2.1.5. Evaluation of Alpha-Glucosidase Activity in Dried Blood Spots
2.2. Statistics
3. Results
3.1. Paired Evaluation before and Two Days after Enzyme Administration
3.2. Long-Term Effect of ERT
4. Discussion
5. Conclusions
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Conflicts of Interest
References
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Patient 1 | Patient 2 | Patient 3 | Patient 4 | |
---|---|---|---|---|
Age (years)/sex | 5.5/Female | 6/Male | 11/Male | 10/Male |
Study duration (years) | 1.2 | 1.3 | 5.3 | 6 |
Height (cm) | 112.5 | 113 | 139 | 145 |
Weight (kg) | 21.2 | 26.5 | 37.2 | 44.1 |
BMI (%) | 16.8 (83) | 20.8 (99) | 19.3 (78) | 21 (92) |
GAA mutation | R854X/L355P | L355P/D404N | L355P/L355P | L355P/D404N |
CRIM status | Positive | Positive | Positive | Positive |
Ethnicity | Muslim | Druze | Druze | Druze |
Onset | Infantile | Infantile | Infantile | Infantile |
ERT onset age (months) | 5 | 3 | 7 | 1 |
Cardiomyopathy at infancy | Yes | Yes | Yes | Yes |
Current echo | Normal | Normal | Normal | Normal |
Drop foot | No | Yes | Yes | Yes |
Gastrostomy | No | Yes | No | No |
First Evaluation | Second Evaluation (+7 Months) | Third Evaluation (+14 Months) | ||||
---|---|---|---|---|---|---|
Post-ERT | Pre-ERT | Post-ERT | Pre-ERT | Post-ERT | Pre-ERT | |
Age at test (years) | 5.5 | 5.5 | 6.2 | 6.2 | 6.7 | 6.7 |
Height (cm) | 112.5 | 112.5 | 116.5 | 116.5 | 119 | 119 |
BMI percentile | 83 | 83 | 73 | 73 | 84 | 84 |
ERT dose (mg/kg) | 40/EOW | 40/EOW | 40/EOW | 40/EOW | 40/EOW | 40/EOW |
Enzyme level (μmol/L/h) | 34.85 | 1.22 | N/A | 1.24 | 49.87 | 0.83 |
FEV1 (L/s) | 1.12 | 1.07 | 1.22 | 1.17 | 1.4 | 1.29 |
FEV1 (% of the predicted value) | 99 | 94 | 100 | 96 | 109 | 101 |
FVC (L) | 1.19 | 1.42 | 1.26 | 1.25 | 1.46 | 1.34 |
FVC (% of the predicted value) | 97 | 115 | 94 | 93 | 103 | 94 |
Peak HR (bpm) | 198 | 197 | 199 | 195 | 208 | 199 |
Absolute peak VO2 (mL/min) | 615 | 647 | 698 | 626 | 731 | 695 |
Specific peak VO2 (mL/kg/min) | 29 | 30.5 | 31.6 | 28.3 | 30 | 28.5 |
Peak VO2 (% of the predicted value) | 62 | 65 | 68 | 61 | 67 | 64 |
VE/VCO2 slope | 38.7 | 37.8 | 41.7 | 32 | 42.4 | 33.5 |
O2 pulse (% of the predicted value) | 64 | 68 | 70 | 64 | 65 | 65 |
Breathing reserve | L | N | L | N | L | N |
6MWD (meters) | 495 | 495 | 576 | 527 | 555 | 534 |
Walking %, running (%), jumping (%) GMFM-88) | 100 | 100 | 100 | 100 | 100 | 100 |
Total score (%) (GMFM-88) | 98.5 | 99.6 | 98.4 | 98.8 | 100 | 100 |
First Evaluation | Second Evaluation (+7 Months) | Third Evaluation (+15 Months) | ||||
---|---|---|---|---|---|---|
Post-ERT | Pre-ERT | Post-ERT | Pre-ERT | Post-ERT | Pre-ERT | |
Age at test (years) | 6.2 | 6.2 | 6.9 | 6.9 | 7.5 | 7.5 |
Height (cm) | 113 | 113 | 118 | 118 | 123 | 123 |
BMI percentile | 99 | 99 | 97 | 97 | 97 | 97 |
ERT dose (mg/kg) | 20/EOW | 20/EOW | 40/EOW | 40/EOW | 40/EOW | 40/EOW |
Enzyme level (μmol/L/h) | 14.68 | 1.34 | 9.35 | 0.95 | 6.45 | 1.35 |
FEV1 (L/s) | 1.03 | 1.29 | 1.16 | 1.2 | 1.12 | 1.06 |
FEV1 (% of the predicted value) | 87 | 104 | 88 | 91 | 77 | 73 |
FVC (L) | 1.15 | 1.47 | 1.33 | 1.38 | 1.32 | 1.24 |
FVC (% of the predicted value) | 87 | 107 | 90 | 94 | 80 | 76 |
Peak HR (bpm) | 202 | 204 | 190 | 172 | 170 | 185 |
Absolute peak VO2 (mL/min) | 751 | 721 | 726 | 644 | 736 | 590 |
Specific peak VO2 (mL/kg/min) | 28.3 | 27.2 | 25.9 | 23 | 23.6 | 18.9 |
Peak VO2 (% of the predicted value) | 65 | 59 | 56 | 49 | 49 | 40 |
VE/VCO2 slope | 39.9 | 32.3 | 40 | 42.4 | 38 | 43.2 |
O2 pulse (% of the predicted value) | 65 | 59 | 60 | 58 | 59 | 43 |
Breathing reserve | L | N | N | N | N | N |
6MWD (meters) | 306 | 306 | 324 | 315 | 288 | 263 |
Walking (%), running (%), jumping (%) (GMFM-88) | 54.1 | 58.3 | 61.1 | 54.1 | 50 | 50 |
Total score (%) (GMFM-88) | 83.4 | 84.3 | 85.4 | 81.8 | 80.2 | 79.88 |
First Evaluation | Second Evaluation (+1 Month) | Third Evaluation (+55 Months) | Fourth Evaluation (+63 Months) | |||||
---|---|---|---|---|---|---|---|---|
Post-ERT | Pre-ERT | Post-ERT | Pre-ERT | Post-ERT | Pre-ERT | Post-ERT | Pre-ERT | |
Age at test (years) | 11.2 | 11.2 | 11.3 | 11.3 | 15.9 | 15.9 | 16.5 | 16.5 |
Height (cm) | 139 | 139 | 139 | 139 | 165 | 165 | 166 | 166 |
BMI percentile | 78 | 78 | 78 | 78 | 65 | 65 | 57 | 57 |
ERT dose (mg/kg) | 20/EOW | 20/EOW | 40/EOW | 40/EOW | 20/W | 20/W | 20/W | 20/W |
Enzyme level (μmol/L/h) | 8.7 | 0.55 | 9.35 | 2 | N/A | 2.85 | 10.15 | 3.55 |
FEV1 (L/s) | 1.64 | 1.7 | 1.8 | 1.78 | 2.9 | 2.93 | 2.77 | 2.84 |
FEV1 (% of the predicted value) | 81 | 85 | 89 | 88 | 80 | 80 | 73 | 75 |
FVC (L) | 1.72 | 1.78 | 2.03 | 1.93 | 2.96 | 2.98 | 2.8 | 3.08 |
FVC (% of the predicted value) | 75 | 78 | 88 | 84 | 71 | 71 | 64 | 71 |
Peak HR (bpm) | 172 | 166 | 189 | 166 | 175 | 130 | 168 | 157 |
Absolute peak VO2 (mL/min) | 1400 | 1308 | 1610 | 1346 | 1197 | 1117 | 1147 | 1119 |
Specific peak VO2 (mL/kg/min) | 37.6 | 35.2 | 43.3 | 36.2 | 20.3 | 18.9 | 19.4 | 19 |
Peak VO2 (% of the predicted value) | 84 | 79 | 97 | 81 | 43 | 40 | 41 | 40 |
VE/VCO2 slope | 37.9 | 24.6 | 41.1 | 30.4 | 36.7 | 23.4 | 32.7 | 32.5 |
O2 pulse (% of the predicted value) | 8.4 | 7.9 | 8.5 | 8.1 | 6.8 | 8.6 | 6.8 | 7.1 |
Breathing reserve | N | N | L | N | N | N | N | N |
6MWD (meters) | 620 | 450 | 570 | 580 | 457 | 495 | 468 | 442 |
Walking (%), running (%), jumping (%) (GMFM-88) | 98.6 | 97.2 | 100 | 97 | 77.7 | 77.7 | 70.8 | 65.2 |
Total score (%) (GMFM-88) | 98 | 97.2 | 97.8 | 97.2 | 89.5 | 89.5 | 91.6 | 87.1 |
First Evaluation | Second Evaluation (+32 Months) | Third Evaluation (+33 Months) | Fourth Evaluation (+55 Months) | Fifth Evaluation (+59 Months) | Sixth Evaluation (+62 Months) | Seventh Evaluation (+74 Months) | ||||||||
---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
Post-ERT | Pre-ERT | Post-ERT | Pre-ERT | Post-ERT | Pre-ERT | Post-ERT | Pre-ERT | Post-ERT | Pre-ERT | Post-ERT | Pre-ERT | Post-ERT | Pre-ERT | |
Age at test (years) | 10 | 10 | 12.8 | 12.8 | 12.9 | 12.9 | 14.7 | 14.7 | 15.1 | 15.1 | 15.4 | 15.4 | 16.4 | 16.4 |
Height (cm) | 145 | 145 | 167 | 167 | 167 | 167 | 177 | 177 | 177 | 178 | 178 | 178 | 186 | 186 |
BMI percentiles | 92 | 92 | 94 | 92 | 83 | 83 | 97 | 97 | 98 | 98 | 98 | 98 | 95 | 95 |
ERT dose (mg/kg) EOW | 20 | 20 | 20 | 20 | 40 | 40 | 40 | 40 | 20 | 20 | 40 | 40 | 40 | 40 |
Enzyme level (μmol/L/h) | N/A | N/A | 13.4 | 0.85 | N/A | N/A | 27.5 | 1.43 | 8.45 | 0.34 | N/A | N/A | N/A | N/A |
FEV1 (L/s) | 1.99 | 2.01 | 2.51 | 2.29 | 2.74 | 2.62 | 3.09 | 3.12 | 3.3 | 3.41 | 3.39 | 3.23 | 3.45 | 3.45 |
FEV1 (% of the predicted value) | 89 | 90 | 74 | 67 | 80 | 77 | 77 | 78 | 80 | 82 | 81 | 77 | 74 | 74 |
FVC (L) | 2.44 | 2.38 | 2.82 | 2.73 | 3.1 | 2.95 | 3.69 | 3.44 | 3.65 | 4.01 | 3.85 | 3.8 | 3.94 | 3.95 |
FVC (% of the predicted value) | 95 | 92 | 71 | 69 | 78 | 74 | 78 | 73 | 76 | 82 | 78 | 77 | 72 | 72 |
Peak HR (bpm) | 190 | 186 | 206 | 200 | 197 | 198 | 203 | 205 | 207 | 204 | 201 | 191 | 198 | 201 |
Absolute peak VO2 (mL/min) | 1764 | 1733 | 2000 | 1908 | 2165 | 1950 | 2320 | 2440 | 2151 | 2274 | 2261 | 2134 | 1838 | 2163 |
Specific peak VO2 (mL/kg/min) | 40 | 40.2 | 30.3 | 28.9 | 33.31 | 30 | 26.4 | 27.7 | 22.96 | 23.99 | 23.93 | 22.58 | 19.5 | 23.01 |
Peak VO2 (% of the predicted value) | 86 | 88 | 63 | 60 | 69 | 62 | 63 | 67 | 59 | 62 | 61 | 58 | 48 | 57 |
VE/VCO2 slope | 36 | 31.1 | 30.5 | 29.5 | 26.8 | 28.5 | 29.3 | 27.3 | 31.8 | 30.6 | 28.8 | 30 | 27.9 | 28.4 |
O2 pulse (% of the predicted value) | 91 | 95 | 61 | 60 | 70 | 63 | 69 | 71 | 56 | 60 | 60 | 60 | 48 | 56 |
Breathing reserve | N | N | N | N | N | N | N | N | N | N | N | N | N | N |
6MWD (meters) | 635 | 660 | 550 | 564 | 554 | 504 | 549 | 531 | 531 | 522 | 508 | 508 | 504 | 496 |
Walking (%), running (%), jumping (%) (GMFM-88) | 100 | 100 | 95.8 | 94.4 | 98.6 | 97.2 | 98.6 | 93 | 94.4 | 93 | 90.2 | 90.2 | 91.6 | 87.5 |
Total Score %-GMFM-88 | 100 | 100 | 96.58 | 96.9 | 98.2 | 96.58 | 98.1 | 97.5 | 97.84 | 97.56 | 95.9 | 96.5 | 97.2 | 95.4 |
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Bar-Yoseph, R.; Tal, G.; Dumin, E.; Hanna, M.; Mainzer, G.; Zucker-Toledano, M.; Shallufi, G.; Jahshan, M.; Mandel, H.; Bentur, L. Individualized Assessment of Exercise Capacity in Response to Acute and Long-Term Enzyme Replacement Therapy in Pediatric Pompe Disease. J. Pers. Med. 2021, 11, 1105. https://doi.org/10.3390/jpm11111105
Bar-Yoseph R, Tal G, Dumin E, Hanna M, Mainzer G, Zucker-Toledano M, Shallufi G, Jahshan M, Mandel H, Bentur L. Individualized Assessment of Exercise Capacity in Response to Acute and Long-Term Enzyme Replacement Therapy in Pediatric Pompe Disease. Journal of Personalized Medicine. 2021; 11(11):1105. https://doi.org/10.3390/jpm11111105
Chicago/Turabian StyleBar-Yoseph, Ronen, Galit Tal, Elena Dumin, Moneera Hanna, Gur Mainzer, Merav Zucker-Toledano, George Shallufi, Mira Jahshan, Hanna Mandel, and Lea Bentur. 2021. "Individualized Assessment of Exercise Capacity in Response to Acute and Long-Term Enzyme Replacement Therapy in Pediatric Pompe Disease" Journal of Personalized Medicine 11, no. 11: 1105. https://doi.org/10.3390/jpm11111105