A 24-year-old male patient with BH4 deficiency since childhood with a PTPS gene mutations (exon 5 c.259C > T, p.P87S/c.155A > G, p.N52S) was stable in pediatric outpatient follow-up for > 20 years while taking sapropterin, L-Dopa, and 5-HTP regularly. He was referred to the rehabilitation clinic for a pulmonary function test (PFT) and CPET due to obesity and exercise intolerance. Physical assessment revealed a height of 186.8 cm and a weight of 104.4 kg. The patients underwent PFT and CPET with informed consent and without any contraindications, following the recommendations of the American College of Sports Medicine’s Guidelines for Exercise Testing and Prescriptions (ACSM guidelines), 10th edition [10].
PFTs are performed by spirometry, collecting forced vital capacity (FVC), forced expiratory volume in one second (FEV1) and maximal voluntary ventilation. The CPET equipment consists of a flywheel, a flow module, a gas analyzer and an electrocardiogram (ECG) monitor. A detailed demonstration was given before the test, and the patient was in normal health and was able to understand and follow the doctor’s instructions. Then, we performed symptom-limited exercise tests using a 20-watts-per-minute bicycle protocol. HR, BP, minute ventilation (VE), oxygen uptake (VO2), carbon dioxide output (VCO2), respiratory exchange ratio (RER) and partial pressure of end-tidal carbon dioxide (PETCO2) were collected. The predicted maximum HR (HRmax) was 196 beats/min, which was derived from the prediction formula 216.6 − (0.84 × age) [11]. VO2 (ml/kg/min) was recorded sequentially during the test and divided by 3.5 to present exercise capacity as the metabolic equivalent of tasks (MET). The predicted maximum VO2 (VO2 max pred) was determined by age, sex, and body weight. HR recovery (HRR) is the difference between the HR 1 min after the test and the peak HR (peak HR). The anaerobic threshold (AT) was determined by the VE/VO2 and VE/VCO2 methods.
The VO2 max was determined if any of the following criteria were met: 1) VO2 was maintained at a plateau with the increase of power; 2) HR failed to increase with the increase of power; 3) peak RER of ≥ 1.10. The test was terminated following the patient’s request due to severe fatigue and leg soreness. The maximum effort was considered to have been reached when the peak RER exceeds 1.10. Angina, cyanosis, or dizziness were not observed during the examination, with no ST elevation or displacement on the ECG monitor. HR and BP rose steadily as the workload increased. Benchmark values and test results are presented in Tables 1 and 2.
Table 1
Baseline characteristics before the cardiopulmonary exercise test
Weight (kg)
|
104.4
|
BMI (kg/m²)
|
29.9
|
Body fat percentage (%)
|
28%
|
SBP at rest (mmHg)
|
152
|
DBP at rest (mmHg)
|
91
|
HR at rest (bpm)
|
75
|
FVC (L)
|
5.90
|
FVC, % of predicted
|
111.3%
|
FEV1(L)
|
4.76
|
FEV1, % of predicted
|
108.2%
|
FEV1/FVC
|
80.68%
|
MVV(L)
|
107.7
|
PETCO2 (L)
|
37
|
Height (cm)
|
186.8
|
BMI: body mass index, SBP: systolic blood pressure, DBP: diastolic blood pressure, HR: heart rate, FVC: forced vital capacity, FEV1: forced expiratory volume in one second, MVV: maximal voluntary ventilation, PETCO2: end-tidal carbon dioxide
|
Table 2
Cardiopulmonary exercise test results
OUES
|
2.5
|
VE/VCO2 slope
|
28.8
|
VO2/WR slope (mL/min/watt)
|
8.9
|
Anaerobic threshold
|
|
AT HR (bpm)
|
113
|
AT VO2 (mL/min)
|
15.1
|
AT MET
|
4.3
|
AT VE (L)
|
40.8
|
AT RER
|
0.9
|
AT PETCO2 (L)
|
41
|
Peak exercise
|
|
Peak HR (bpm)
|
160
|
Peak HR, % of predicted
|
81.6%
|
Peak SBP (mmHg)
|
165
|
Peak DBP (mmHg)
|
65
|
Peak VO2 (mL/min)
|
27.3
|
Peak MET
|
7.8
|
Peak MET, % of predicted
|
64.38%
|
Peak VE (L)
|
98.8
|
BR, % of MVV
|
8.26%
|
Peak RER
|
1.14
|
Peak PETCO2 (L)
|
42
|
HRR (beats)
|
28
|
HRR: heart rate recovery, OUES: oxygen uptake efficiency slope, VO2: oxygen consumption, WR: work rate, PETCO2: end-tidal carbon dioxide, MET: metabolic equivalent of task, VE: minute ventilation, BR: breathing reserve, RER: respiratory exchange ratio
|
The peak HR was 81.6% of the predicted value of HRmax with the patient’s best efforts, suggesting a lesser risk of chronotropic insufficiency in the patient. The 20-watt cycling exercise test revealed an HRR of 28 and a maximum exercise capacity of 7.8 METs (maximum oxygen uptake: 27.3 ml/kg/min), which is 64.83% of the predicted value, indicating moderate functional impairment. The 6-min walk test was 621 meters. FVC and FEV1 were within the normal range, with FEV1/FVC of 80.68%, and breathing reserve was 8.26%. Lung function demonstrated no obvious abnormalities, with no signs of lung disease [12]. The slope of VE/VCO2 was 28.8, indicating sufficient ventilation efficiency. No myocardial ischemia and arrhythmia were found during exercise, and the maximum oxygen consumption standard defined by ACSM guidelines was reached. The resting HR was 75 beats/min, and the maximum HR during exercise was 160 beats/min. The test reached 81% of the target HR and 70% of the reserve HR, indicating no obvious abnormality in the heart performance. However, the patient has obesity, with a body fat rate of 28%, a body mass index of 29.9, a high resting metabolic rate and resting oxygen uptake. The need for oxygen uptake was more prominent during high-intensity exercise. Therefore, we concluded that his lower maximum predicted oxygen uptake and functional impairment were caused by obesity.
The CPET results revealed that the patient can engage in low-to-moderate activities in daily life, such as performing housework (e.g., mopping the floor, sweeping the floor, shopping) and engaging in leisure sports (e.g., walking, jogging, playing table tennis, playing badminton) with no obstacles. He should be careful when engaging in strenuous activities such as diving, fast running, fast cycling, etc. [13]. The ACSM guidelines recommend the use of the principle of “FITT-VP” to set exercise prescriptions, including frequency, intensity, time, type, volume, and progression, to improve physical fitness and maintain health. We recommend an aerobic exercise program of at least 30 min per day, at least 5 days per week, at a moderate intensity. Intensity is calculated using the oxygen uptake reserve method [14]. The target VO2 (ml/kg/min) is (27.3 − 3.5 × (40%~60%) + 3.5, i.e., 13.02 ~ 17.78 ml/ kg/min). Specifically, it is equivalent to 2.9 ~ 5.8 km/h for jogging on flat ground. The exercise time can then be increased to 60 min a day or 250–300 min a week [10].
Moreover, proper weight loss can help. Some patients with obesity have an increased basal metabolic rate at rest and a more significant increase in energy demand during exercise to support heavier physical activity, requiring an increased cardiopulmonary response to complete an exercise, and decrease cardiac output reserve, thereby limiting maximum exercise performance [15]. Resistance training has no significant effect on weight loss and cannot prevent fat-free mass reduction, but it can reduce energy consumption at rest, enhance muscle strength, and physical function and reduce risk factors. Therefore, 2–4 groups of 2–3 days a week, 8–12 times per group of resistance training programs are also recommended, targeting the main muscle group training, with approximately 60–70% of 1-RM intensity, which can be gradually increased. Either mechanical training or free weight training is fine. The weight loss goal can be set to reduce the body weight by 3–10% within 3–6 months, and the energy intake can be reduced by 500–1000 calories per day to achieve the goal of 0.5–0.9 kg of weight loss per week [10].