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Review
. 2020 Jun 15;16(6):977-982.
doi: 10.5664/jcsm.8434.

TECPR2 mutation-associated respiratory dysregulation: more than central apnea

Pallavi P Patwari  1 , Lisa F Wolfe  2 , Girish D Sharma  1 , Elizabeth Berry-Kravis  1
Affiliations
Review

TECPR2 mutation-associated respiratory dysregulation: more than central apnea

Pallavi P Patwari et al. J Clin Sleep Med. .

Abstract

Children with rare genetic diseases that cause respiratory dysregulation are at particularly high mortality risk due to development of respiratory failure. The tectonin β-propeller-containing protein 2 (TECPR2) mutations are proposed to cause autophagy defect affecting axonal integrity and development of progressive neurodegenerative and neuromuscular disease. Published TECPR2 mutation cases have described a high prevalence of respiratory failure. We review respiratory pathology in previously published cases and a new case of a 5-year-old girl with previously undescribed TECPR2 mutation demonstrating progressive central apnea due to respiratory cycle dysregulation. This is the first TECPR2 mutation case to demonstrate an ataxic (Biot's) breathing pattern with consistently inconsistent inspiratory and expiratory times and with relatively intact chemoreception during sleep. Therefore, we propose that the central apnea index alone may not be the appropriate marker for mortality risk. Rather, the morbidity and mortality associated with TECPR2 mutations are multisystem in nature and this burden complicates the ultimate needs for ventilation support and prognosis.

Keywords: Biot’s breathing; ataxic breathing; central apnea; circadian rhythm disturbance; respiratory and autonomic dysregulation.

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Conflict of interest statement

All authors approved the final manuscript as submitted and agree to be accountable for all aspects of the work. The patient’s parents provided written consent to publication of this de-identified case report. The authors report no conflicts of interest.

Figures

Figure 1
Figure 1. Simplified pathway for respiratory control.
In the midbrain, the pre-Bötzinger complex is considered the pacemaker responsible for rhythm generation (setting breathing frequency) and a proposed pattern generator is responsible for the respiratory cycle (duration of breath and tidal volume); together, this is referred to as the CPG. Input to the CPG comes from central chemoreceptors (in response to hypercarbia), peripheral chemoreceptors (in response to hypoxia), and other peripheral sensory receptors. The integration of this input also occurs at multiple levels. The output then drives the motor response that manifests as minute ventilation (alveolar ventilation). To further fine-tune control of breathing, multiple feedback loops are simultaneously in play, of which some are well established (chemoreflex or loop gain) and others are yet to be defined. During wakefulness, simplistically, volitional control of breathing can override CPG to allow for speaking and eating (although, in normal conditions, also maintaining appropriate gas exchange). During NREM sleep, breathing drive is predominantly influenced by chemoreception and absent behavioral influences, resulting in a stable (monotonous) respiratory pattern. CCHS = congenital central hypoventilation syndrome; CPG = central pattern generator; DMD = Duchenne muscular dystrophy; MSA = multiple system atrophy; NREM = non–rapid eye movement; pCO2 = partial pressure of carbon dioxide; pFRG = parafacial respiratory group; pO2 = partial pressure of oxygen; PreBötzC = pre-Bötzinger complex; REM = rapid eye movement; RTN = retrotrapezoid nucleus.
Figure 2
Figure 2. Polysomnogram demonstrating respiratory cycle variability in NREM sleep.
Images are of a 2-minute segment from baseline polysomnogram comparing an age-matched, relatively healthy child with the patient at 3.8 years and 5 years of age. The respiratory cycle values to the right note the average and standard deviation of total cycle time, inspiratory time, and expiratory time for the breaths in the first 30 seconds of the 2-minute segment. (A) A 4-year-old girl with mild pediatric OSA. Note the normal (monotonous) respiratory pattern and stable respiratory cycle times. (B) Our patient at 3.8 years of age. The ETCO2 waveform is manually shifted 3 seconds earlier to account for recording delay compared to flow and respiratory effort bands (RIP). The vertical yellow bars indicate the expiratory component of each respiratory cycle. Note the wide variability and absent pattern. (C) Our patient at 5 years of age. The start of inhalation is noted by a red arrow and dashed line. The purple arrows are of fixed length and indicate the start of exhalation. Again, note the absence of distinct pattern and wide variability in both inspiratory time and expiratory time with slower respiratory rate at 6–10 breaths per minute. ETCO2 = end-tidal carbon dioxide; NREM = non–rapid eye movement; OSA = obstructive sleep apnea; RIP = respiratory inductance plethysmography.
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