肺胞低換気症候群

BACKGROUND: Pompe disease is an autosomal recessive disorder caused by a deficiency of acid α-glucosidase (GAA) enzyme. This deficiency induces progressive glycogen accumulation, leading to weakness of the respiratory muscle, including the diaphragm. As established enzyme replacement therapy is available for Pompe disease, earlier detection of potential Late-Onset Pompe Disease (LOPD) and subsequent intervention would have a significant clinical impact. PURPOSE: Our hypothesis was that sleep problems, including sleep-disordered breathing (SDB) and clinical symptoms, may indicate an early stage of LOPD, since decreased respiratory muscle activity often presents initially during sleep. The primary aim of the PSSAP-J study was to demonstrate a higher prevalence of LOPD in a sleep-laboratory-based population. Secondary aims included identifying predictive factors for LOPD from diagnostic polysomnography (PSG) findings and clinical symptoms. METHODS: This prospective multicenter observational cohort study enrolled consecutive patients presenting to sleep laboratories for overnight PSG due to suspected SDB. All patients underwent a Dried Blood Spot (DBS) screening for GAA activity. Genetic analysis of the GAA gene was performed for confirmatory testing when indicated. RESULT: A total of 724 participants were analyzed, although the COVID-19 pandemic prevented reaching the target sample size (n = 1,500). No definitive LOPD cases were confirmed among those who completed the confirmatory testing (prevalence 0%; 95% confidence interval [CI], 0.00%-0.51%). However, seven screen-positive patients declined confirmatory testing and were classified as indeterminate cases. Consequently, we could not definitively establish a higher prevalence or identify predictive factors for LOPD in this population. CONCLUSION: Although the primary study aims could not be confirmed due to the sample size shortfall and the presence of indeterminate cases, our findings highlight the importance for sleep physicians to maintain a high index of suspicion for underlying myopathies, such as LOPD, in clinical practice. CLINICAL TRIAL REGISTRATION: UMIN000039191, UMIN Clinical Trials Registry ( http://www.umin.ac.jp/ctr ).

PURPOSE OF REVIEW: Sleep-disordered breathing (SDB) is an increasingly recognized contributor to WHO Group 3 pulmonary hypertension (PH). This review examines the epidemiology and pathophysiology linking SDB to PH, evaluates the evidence base for sleep-directed therapies in modifying pulmonary hemodynamics, and highlights emerging treatment modalities that may be able to alter disease course. RECENT FINDINGS: The mechanisms underlying SDB-related PH are multifactorial, including recurrent nocturnal hypoxemia, altered intrathoracic pressures, and obesity-driven metabolic and inflammatory dysregulation. Positive airway pressure therapy remains the cornerstone of treatment of SDB-related PH, though mandibular advancement devices and hypoglossal nerve stimulation offer viable alternatives. Hypoxic burden, rather than apnea-hypopnea index alone, is increasingly recognized as a better predictor for cardiovascular and pulmonary vascular outcomes in SDB. Long-term oxygen therapy provides hemodynamic benefit in patients with resting hypoxemia, though evidence is limited in those with isolated nocturnal desaturation. SUMMARY: SDB is an underdiagnosed and clinically important contributor to PH. Early identification and treatment, particularly with positive airway pressure therapy when indicated, can meaningfully reduce pulmonary arterial pressures. Future research should prioritize prospective trials examining the direct impact of glucagon-like peptide-1 receptor agonists and bariatric surgery on pulmonary hemodynamics and standardize the use of hypoxic burden as a clinical endpoint.

Congenital central hypoventilation syndrome (CCHS) is a genetic disorder caused by mutations in the PHOX2B gene, characterized by impaired autonomic control of breathing and systemic consequences that may affect gut homeostasis. This study provides the first integrated multi-omics analysis in a CCHS group and matched controls, combining fecal DNA-based gut taxonomic profiling with targeted quantification of fatty acids and aromatic carboxylic acids. While overall microbial diversity and community structure remained largely preserved, significant alterations were observed in specific taxa within the CCHS group. Notably, the control group exhibited an enrichment of short-chain fatty acid (SCFA)-producing genera, which are associated with eubiotic gut ecosystems, whereas the CCHS group showed higher abundance of taxa commonly linked to inflammatory contexts. Consistently, fecal levels of beneficial SCFAs-particularly valeric acid, and to a lesser extent butyric acid-were reduced in CCHS group. These findings point to a dysbiotic gut microbiota in patients with CCHS, likely supporting putative inflammatory processes that would further worsen overall health status if confirmed. Furthermore, this work provides exploratory functional signatures for future studies aimed at understanding systemic consequences, guiding mechanistic investigations, and informing strategies to improve supportive care and long-term health outcomes in this rare patient population.

Breathing movements driven by the brainstem rhythmogenic neural networks rely on chemosensory inputs to produce a motor output that is homeostatically adjusted to the prevailing metabolic demand. The central CO2 chemoreflex is a critical component of respiratory neural circuitry, as defects in these sensors cause hypoventilation syndromes, which are typically difficult to manage pharmacologically. Progesterone has long been known to stimulate breathing in both sexes, and remarkably, a potent progestin drug, etonogestrel (ETO), has been shown to enhance CO2-chemosensitivity in animal models and in a subset of female patients affected by congenital central hypoventilation syndrome. Our recent work shows that systemic chronic ETO treatment recovered the CO2 chemoreflex in female rats in which <80% of neurons of the key CO2 chemosensory structure of the retrotrapezoid nucleus (RTN) were eliminated, whereas male rats with similar lesions and ETO serum levels did not show recovery of the CO2 chemoreflex. Interestingly, female respiratory recovery was associated with increased expression of the pH sensors Task2 and Gpr4 mRNA in the surviving RTN neurons, suggesting that progestin drugs may recover the CO2 chemoreflex responses in a sex-specific fashion.

A 63-year-old female with metastatic breast cancer presented with acute hypercapnic respiratory failure secondary to severe diaphragmatic dysfunction and mixed upper and lower motor neuron signs. Serum onconeural and neural surface antibody panels were negative, and initial cerebrospinal fluid analysis revealed albuminocytologic dissociation. Immunotherapy with intravenous immunoglobulin (IVIG) produced no clinical improvement, necessitating invasive mechanical ventilation and gastrostomy. Applying the 2021 PNS-Care consensus criteria, the case fulfills criteria for possible paraneoplastic amyotrophic lateral sclerosis (ALS), although coincidental sporadic disease cannot be excluded. A markedly elevated erythrocyte sedimentation rate (ESR) was observed, largely attributable to skeletal metastases and localized pulmonary collapse. Clinicians must maintain a high index of suspicion for motor neuron disease in cancer patients with unexplained hypoventilation.