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Background:
Congenital central hypoventilation syndrome (CCHS) is a rare disorder characterized by respiratory system abnormalities, including alveolar hypoventilation and autonomic nervous system dysregulation. CCHS is associated with compromised brain development and neurocognitive functioning. Studies that evaluate cognitive skills in CCHS are...
Contexts in source publication
Context 1
... composite = 83.25, and non-verbal composite = 82.0). Caregiver ratings of executive functions from the BRIEF (available for five patients), reported in Table 6, demonstrated scores within the average range (T-scores for the Global Executive Composite; M = 54.6, SD = 14.32); however, at-risk levels of working memory difficulties were noted. ...Context 2
... composite = 83.25, and non-verbal composite = 82.0). Caregiver ratings of executive functions from the BRIEF (available for five patients), reported in Table 6, demonstrated scores within the average range (T-scores for the Global Executive Composite; M = 54.6, SD = 14.32); however, at-risk levels of working memory difficulties were noted. ...Similar publications
Background: 22q11.2 deletion syndrome (22q11DS) is a common recurrent neurogenetic condition associated with elevated risk for developmental neuropsychiatric disorders and intellectual disability. Children and adults with 22q11DS often exhibit marked social impairment as well as neurocognitive deficits, and have elevated rates of both autism spectr...
Citations
... Neurodevelopmental disorders (developmental delays, formal diagnosis of learning disabilities, attention deficit hyperactivity disorder) were observed in a survey of 196 patients with CCHS [3]. Several studies have described neurocognition in this particular population [4][5][6]. One case report described a severe developmental delay with autism spectrum disorder (ASD) [7], and three patients were reported with ASD or pervasive developmental disorder [3]. ...
Background
Congenital central hypoventilation syndrome (CCHS) is a rare condition characterized by alveolar hypoventilation and autonomic nervous system (ANS) dysfunction requiring long-term ventilation. CCHS could constitute a risk factor of autism spectrum disorder (ASD) due to birth injury related to respiratory failure, which remains to be determined. ANS dysfunction has also been described in ASD and there are indications for altered contribution of ANS-central nervous system interaction in processing of social information; thus, CCHS could be a risk factor for ASD based on pathophysiological background also. Our study aimed to determine the prevalence of ASD among CCHS patients, identify risk factors, and explore the relationship between the ANS, evaluated by heart rate variability indices, and adaptative functioning.
Results
Our retrospective study, based on the analysis of records of a French national center of patients with CCHS under 20 years of age, determined that the prevalence of ASD (diagnosed by a psychiatrist, following the criteria of DSM-4 or DSM-5) was 6/69 patients, 8.7% (95% confidence interval: 3.3–18.0%). In a case (CCHS with ASD, n = 6) – control (CCHS without ASD, n = 12) study with matching on sex, longer neonatal hospitalization stay and glycemic dysfunction were associated with ASD. Adaptative functioning was assessed using Vineland Adaptative behavioral scales (VABS) and heart rate variability indices (including daytime RMSSD as an index of parasympathetic modulation) were obtained from ECG Holter performed the same day. In 19 young subjects with CCHS who had both ECG Holter and VABS, significant positive correlations were observed between RMSSD and three of four sub-domains of the VABS (communication: R = 0.50, p = 0.028; daily living skills: R = 0.60, p = 0.006; socialization: R = 0.52, p = 0.021).
Conclusion
Our study suggests a high prevalence of ASD in patients with CCHS. Glycemic dysfunction and longer initial hospitalization stays were associated with ASD development. A defect in parasympathetic modulation was associated with worse adaptative functioning.
... The increase in CCHS awareness over the last decade has resulted in earlier screening and interventions for patients with CCHS [7]. Therefore, recent studies have focused not only on patient survival but also on neurodevelopment and cognitive skills [8]. In 2017, the Korean Ministry of Health and Welfare designated CCHS as a rare disease, which means that medical care is covered by the national insurance copayment system, and awareness of CCHS has increased. ...
... Owing to the potential for repeated hypoxic brain damage, neurocognitive functioning is often impaired. Comprehensive neuropsychological assessment is recommended for patients with CCHS to improve their quality of life [8]. In our cohort, almost all patients had some form of developmental delay. ...
Congenital central hypoventilation syndrome (CCHS) is a rare genetic disorder characterized by hypoventilation due to impaired breathing control by the central nervous system and other symptoms of autonomic dysfunction. Mutations in paired-like homeobox 2 B (PHOX2B) are responsible for most cases of CCHS. Patients with CCHS have various phenotypes and severities, making the diagnosis difficult. This study aimed to present a comprehensive single-center experience of patients with CCHS, including key clinical features, treatment strategies, and outcomes. A retrospective chart review was performed for patients diagnosed with CCHS between January 2001 and July 2023 at Seoul National University Children’s Hospital. Finally, we selected 24 patients and collected their demographic data, genotypes, ventilation methods, and clinical features related to autonomic dysfunction. The relationship between the clinical manifestations and genotypes was also examined. All patients used home ventilators, and tracheostomy was performed in 87.5% of patients. Fifteen (62.5%) patients had constipation and nine (37.5%) were diagnosed with Hirschsprung disease. Arrhythmia, endocrine dysfunction, and subclinical hypothyroidism were present in nine (37.5%), six patients (25.0%), and two patients (16.7%), respectively. A significant number of patients exhibited neurodevelopmental delays (19 patients, 79.2%). There was a correlation between the phenotype and genotype of PHOX2B in patients with CCHS. (r = 0.71, p < 0.001).
Conclusion: There was a positive correlation between paired-like homeobox 2 B mutations (especially the number of GCN repeats in the polyalanine repeat mutations sequence) and clinical manifestations. This study also demonstrated how initial treatment for hypoventilation affects neurodevelopmental outcomes in patients with CCHS. What is Known:
• Congenital central hypoventilation syndrome is a rare genetic disorder characterized by hypoventilation and dysfunction of autonomic nervous system.
• The disease-defining gene of CCHS isPHOX2Bgene – most of the cases have heterozygous PARMs and the number of GCN triplets varies among the patients(20/24 – 20/33).
What is New:
• We have noted in the Korean patients with CCHS that there is a correlation between genotype (number of GCN repeats) and severity of phenotype.
• National support for rare diseases allowed for a prompter diagnosis of patients with CCHS in Korean population.
... CCHS can impact the autonomic nervous system, and individuals with this syndrome may experience poor neurocognitive outcomes due to the potential for repeated episodes of hypoxemia and hypercarbia (Zelko et al., 2018). Working memory has been identified as a potential weakness in individuals with CCHS (Macdonald et al., 2020). ...
Breathing plays a crucial role in shaping perceptual and cognitive processes by regulating the strength and synchronisation of neural oscillations. Numerous studies have demonstrated that respiratory rhythms govern a wide range of behavioural effects across cognitive, affective, and perceptual domains. Additionally, respiratory-modulated brain oscillations have been observed in various mammalian models and across diverse frequency spectra. However, a comprehensive framework to elucidate these disparate phenomena remains elusive. In this review, we synthesise existing findings to propose a neural gradient of respiratory-modulated brain oscillations and examine recent computational models of neural oscillations to map this gradient onto a hierarchical cascade of precision-weighted prediction errors. By deciphering the computational mechanisms underlying respiratory control of these processes, we can potentially uncover innovative pathways for understanding hidden links between respiratory-brain coupling and psychiatric disorders.
... СВЦГВ также следует рассматривать в случаях внезапного апноэ в любом возрасте, судорог, внезапной смерти [8]. Дети с большим количеством полиаланиновых повторов имеют более низкие показатели психомоторного и когнитивного развития [25,26]. ...
The article provides a brief review of the etiopathogenetic aspects of congenital central hypoventilation syndrome with an emphasis on genotype-phenotypic correlations, and highlights approaches to ventilatory support. Based on the data of the local register, the experience of Almazov National Medical Research Centre is summarised. A systematic multidisciplinary approach to the treatment and rehabilitation of children with congenital central hypoventilation syndrome that has been implemented provides the most favorable results in preserving neurological and intellectual potential and quality of life.
... [4][5][6][7] Overall intellectual functioning in CCHS varies broadly, ranging from below average to superior, and several areas of cognitive vulnerability have been identified. [8][9][10][11][12][13][14][15] Differences have been noted in cognitive subdomains such as fluid reasoning, visuoperceptual reasoning, clerical/processing speed, working memory, sequential processing, and verbal ability. Variables found to be related to cognitive outcomes have included PHOX2B genotype, 13,14 age at assessment (i.e., preschool vs. school-age), 10 introduction of positive pressure ventilation via tracheostomy in the first 3 months of life 15,16 and compliance with recommended ventilatory support and limitations on strenuous activities. 1 The broad spectrum of cognitive outcomes in CCHS underscores the need for longitudinal neurocognitive testing, with the aim to personalize management and optimize cognitive functioning. ...
... [8][9][10][11][12][13][14][15] Differences have been noted in cognitive subdomains such as fluid reasoning, visuoperceptual reasoning, clerical/processing speed, working memory, sequential processing, and verbal ability. Variables found to be related to cognitive outcomes have included PHOX2B genotype, 13,14 age at assessment (i.e., preschool vs. school-age), 10 introduction of positive pressure ventilation via tracheostomy in the first 3 months of life 15,16 and compliance with recommended ventilatory support and limitations on strenuous activities. 1 The broad spectrum of cognitive outcomes in CCHS underscores the need for longitudinal neurocognitive testing, with the aim to personalize management and optimize cognitive functioning. ...
Congenital central hypoventilation syndrome (CCHS) is a rare neurocristopathy, caused by mutations in the paired‐like homeobox gene PHOX2B, which alters control of breathing and autonomic nervous system regulation, necessitating artificial ventilation as life‐support. A broad range of neurocognitive performance has been reported in CCHS, including an array of cognitive deficits. We administered the NIH ToolboxⓇ Cognition Battery (NTCB), a novel technology comprised of seven tasks presented via an interactive computer tablet application, to a CCHS cohort and studied its convergent and divergent validity relative to traditional clinical neurocognitive measures. The NTCB was administered to 51 CCHS participants, including a sub‐cohort of 24 who also received traditional clinical neurocognitive testing (Wechsler Intelligence Scales). Age‐corrected NTCB scores from the overall sample and sub‐cohort were compared to population norms. Associations between NTCB indices and Wechsler Intelligence scores were studied to determine the convergent and divergent validity of the NTCB. NTCB test results indicated reduced Fluid Cognition, which measures new learning and speeded information processing (p<0.001), but intact Crystallized Cognition, which measures past learning, in CCHS relative to population norms. Moderate to strong associations (r > 0.60) were found between age‐corrected NTCB Fluid and Crystallized indices and comparable Wechsler indices, supporting the convergent and discriminant validity of the NTCB. Results reveal deficits of Fluid Cognition in individuals with CCHS and indicate that the NTCB is a valid and sensitive measure of cognitive outcomes in this population. Our findings suggest that the NTCB may play a useful role in tracking neurocognition in CCHS. This article is protected by copyright. All rights reserved.
... Such problems include developmental delays (45%), learning disabilities (29.6%), attention deficit disorder (12.8%), speech delay (51%), and delays in motor development (45.4%) as discussed by Ruof et al. [4]. In the handful of studies that have been conducted, neurocognitive deficits are often present for patients with CCHS as well as impaired psychosocial functioning [10]. Although the symptoms and resulting impairments caused by CCHS may lead to significant anxiety, few published reports exist of this association. ...
... Emerging research supports the need for comprehensive neuropsychological evaluation in patients with CCHS [10]. On average, patients with CCHS have demonstrated intellectual functioning scores that are estimated to be in the borderline impaired range. ...
... On average, patients with CCHS have demonstrated intellectual functioning scores that are estimated to be in the borderline impaired range. However, previous work also shows there can be a wide range of IQ scores [10]. Several studies have demonstrated that individuals with CCHS demonstrate average coping skills and behavioral difficulties-suggesting that many individuals with CCHS are resilient and have the ability to cope with stressors [13]. ...
Congenital central hypoventilation syndrome (CCHS) is a life-threatening disorder characterized by respiratory symptoms such as hypoventilation during sleep, significantly reduced ventilatory and arousal responses, and sustained hypoxia. Patients with CCHS exhibit neurocognitive deficits due to structural abnormalities in the brainstem, cerebellum, and forebrain. Due to the potential for repeated hypoxemia and hypercarbia among patients with CCHS, neurocognitive functioning is often impaired. This is the first described report in which a patient with CCHS and specific phobia has been reported and highlights the importance of neuropsychological testing in directing treatment approaches. We report a case of a 26-year-old male, diagnosed with CCHS and specific phobia. This patient was overdue for a needed bronchoscopy to check his airway for abnormalities (recommended every 12-24 months). The patient had developed a specific phobia to procedures involving anesthesia. It was determined in the initial phase of treatment that the patient’s neurocognitive status was impacting his ability to engage in psychiatric and psychosocial treatment. This patient’s care consisted of neuropsychological testing, with medication consultation, and cognitive behavioral psychotherapy. Treatment involved consistent collaboration among the patient’s treating clinicians as well as collaboration with the patient’s family and team of nurses. At the conclusion of treatment, the patient had successfully completed his bronchoscopy and future treatment goals were identified. This case emphasizes the importance of a neuropsychological evaluation when there is a disconnect in a patient’s information processing, as the results may be highly informative in directing treatment for patients with CCHS and specific phobia. The collaborative care we provided offers insights which may direct future interventions for patients with CCHS and improve their quality of life. Our case adds support to the recommendation that patients with CCHS and impaired psychosocial functioning should receive neuropsychological testing to best direct treatment.
1. Introduction
Congenital central hypoventilation syndrome (CCHS) is a rare genetic condition characterized by hypoventilation with progressive hypoxemia and hypercarbia during sleep but with normal ventilation while awake [1, 2]. These patients experience extreme sleep-related hypoventilation which sometimes extends to wakefulness [3]. CCHS is related to mutations of the PHOX2B gene and involves multiple autonomic nervous system disorders marked by impaired ventilatory function [3]. Respiratory arrest during sleep is a constant threat for these patients, and the majority are on long-term ventilatory support via tracheostomy. This disease has an overall high mortality rate with only 50 of 70 patients living beyond 1 year of age [4]. Additional comorbidities include cardiac conduction disorders, gastroesophageal reflux, constipation with Hirschsprung’s disease, thermal dysregulation, orthostatic hypotension, ophthalmologic disorders, or neural crest tumors [5]. Patients with CCHS require ventilatory support, and a bronchoscopy is recommended every 12-24 months to examine for abnormalities in the airway [6].
In addition to the medical comorbidities, a number of neurocognitive abnormalities are present in patients with CCHS [2]. Functional magnetic resonance imaging (fMRI) studies show structural differences in the brainstem and cerebellum to the forebrain [7]. What is not clear is whether these abnormalities are caused directly by the pathology or the result of the disease-causing mutation [2]. A study conducted with children with CCHS demonstrated reduced corpus callosum fibers in motor, cognitive, speech, and ophthalmologic regulatory areas [8]. As patients advance in age, patients with CCHS evidenced decreases in the volume of gray matter in autonomic, respiratory, and cognitive regulatory areas. This change in gray matter may be a contributing factor to the functional cognitive deterioration noted in patients with CCHS [9].
Based on cross-sectional study data of 196 patients with CCHS (age range 0.4-38 years), we know that children and young adults with CCHS report a broad range of developmental, psychological, and neurocognitive problems [4]. Such problems include developmental delays (45%), learning disabilities (29.6%), attention deficit disorder (12.8%), speech delay (51%), and delays in motor development (45.4%) as discussed by Ruof et al. [4]. In the handful of studies that have been conducted, neurocognitive deficits are often present for patients with CCHS as well as impaired psychosocial functioning [10]. Although the symptoms and resulting impairments caused by CCHS may lead to significant anxiety, few published reports exist of this association. Even fewer published studies discuss treatment options for psychiatric management of cognitive and psychiatric symptoms for patients with CCHS. Due to the rarity of CCHS, many physicians are unaware of this diagnosis and may only treat one of these highly specialized patients over the course of their professional work [11]. The role of neuropsychological evaluation was critical in our understanding this patient’s current functioning and to direct our treatment approach. Therefore, we provide the details of this case as well as the highly collaborative nature (see Figure 1) of the care provided in an effort to both increase awareness about this syndrome and share key components of treatment that may be applied to other individuals with CCHS and psychiatric comorbidities.
... This effect has been already demonstrated in other breathing disorders characterized by intermittent hypoxia such as sudden infant death syndrome (SIDS), obstructive sleep apnea syndrome (OSAS), and Rett syndrome (Prandota, 2004;Lavie, 2015;Bebensee et al., 2017). According to the American Thoracic Society (ATS) recommendations, neuropsychological status should be assessed in all CCHS patients in order to early identify and treat those individuals that would benefit from early interventions to ameliorate their cognitive abilities (Macdonald et al., 2020). ...
Congenital central hypoventilation syndrome (CCHS) is a genetic disorder of neurodevelopment, with an autosomal dominant transmission, caused by heterozygous mutations in the PHOX2B gene. CCHS is a rare disorder characterized by hypoventilation due to the failure of autonomic control of breathing. Until now no curative treatment has been found. PHOX2B is a transcription factor that plays a crucial role in the development (and maintenance) of the autonomic nervous system, and in particular the neuronal structures involved in respiratory reflexes. The underlying pathogenetic mechanism is still unclear, although studies in vivo and in CCHS patients indicate that some neuronal structures may be damaged. Moreover, in vitro experimental data suggest that transcriptional dysregulation and protein misfolding may be key pathogenic mechanisms. This review summarizes latest researches that improved the comprehension of the molecular pathogenetic mechanisms responsible for CCHS and discusses the search for therapeutic intervention in light of the current knowledge about PHOX2B function.
... Zalecają również zastosowanie bardziej dogłębnych testów poznawczych, szczególnie badających pamięć roboczą i funkcje wykonawcze, w celu lepszego zrozumienia specyficznych deficytów, które są powszechne u tej grupy chorych. W przyszłych badaniach warto by również rozważyć uwzględnienie testów przesiewowych dotyczących takich sfer jak czytanie czy matematyka (MacDonald et al., 2020). ...
... Funkcjonowanie psychospołeczne osób z Zespołem Wrodzonej Centralnej Hipowentylacji (CCHS)W najnowszych badaniach dotyczących psychospołecznych i kognitywnych aspektów funkcjonowania osób z CCHS(MacDonald et al., 2020) wykazano, że istnieje związek między zaburzeniem funkcji neuropoznawczych mierzonych odpowiednimi testami a niektórymi rodzajami ekspansji powtórzeń polialaninowych (PARMS), występującymi w zespole Klątwy Ondyny. W badaniu wzięło udział siedmiu pacjentów z CCHS w wieku od 1 roku do 20 lat, którzy poddani zostali badaniom testowym w warunkach klinicznych. ...
Congenital Central Hypoventilation Syndrome (CCHS) is a rare, life-threatening disease. CCHS affects the central and autonomic nervous system, which controls many of the body’s automatic functions. The most recognizable symptom of CCHS is the inability to control
breathing to varying degrees, which results in the need to support ventilation throughout the day or only during sleep. It is estimated that there are 1200 cases of CCHS worldwide. In Poland, only 18 children have been affected by this disease, and the disease began to be talked
about only quite recently in our country. Despite this, there are only few articles in Polish that could provide parents and patients with a source of knowledge and support in coping with this disease.
Purpose
Congenital central hypoventilation syndrome (CCHS) is a rare genetic disorder characterized by hypoventilation due to impaired breathing control by the central nervous system and other symptoms of autonomic dysfunction. Mutations in paired-like homeobox 2 B (PHOX2B) are responsible for most cases of CCHS. Patients with CCHS have various phenotypes and severities, making the diagnosis difficult. This study aimed to present a comprehensive single-center experience of patients with CCHS, including key clinical features, treatment strategies, and outcomes.
Methods
A retrospective chart review was performed for patients diagnosed with CCHS between January 2001 and July 2023 at Seoul National University Children’s Hospital. Finally, we selected 24 patients and collected their demographic data, genotypes, ventilation methods, and clinical features related to autonomic dysfunction. The relationship between the clinical manifestations and genotypes was also examined.
Results
All patients used home ventilators, and tracheostomy was performed in 87.5% of patients. Fifteen (62.5%) patients had constipation and nine (37.5%) were diagnosed with Hirschsprung disease. Arrhythmia, endocrine dysfunction, and subclinical hypothyroidism were present in nine (37.5%), six patients (25.0%), and two patients (16.7%), respectively. A significant number of patients exhibited neurodevelopmental delays (19 patients, 79.2%). There was a correlation between the phenotype and genotype of PHOX2B in patients with CCHS. (r = 0.71, p < 0.001)
Conclusions
There was a positive correlation between paired-like homeobox 2 B mutations (especially the number of GCN repeats in the polyalanine repeat mutations sequence) and clinical manifestations. This study also demonstrated how initial treatment for hypoventilation affects neurodevelopmental outcomes in patients with CCHS.
