Search

Rett syndrome (RTT) is a neurodevelopmental disorder caused mostly by mutations in the MECP2 gene. RTT patients show periodical hypoventilation attacks. The breathing disorder contributing to the high incidence of sudden death is thought to be due to depressed central inspiratory (I) activity via unknown cellular processes. Demonstration of such processes may lead to targets for pharmacological control of the RTT-type hypoventilation. We performed in vivo recordings from medullary respiratory neurons on the RTT rat model. To our surprise, both I and expiratory (E) neurons in the ventral respiratory column (VRC) increased their firing activity in Mecp2-null rats with severe hypoventilation. These I neurons including E-I phase-spanning and other I neurons remained active during apneas. Consistent with enhanced central I drive, ectopic phrenic discharges during expiration as well as apnea were observed in the Mecp2-null rats. Considering the increased I neuronal firing and ectopic phrenic activity, the RTT-type hypoventilation does not seem to be caused by depression in central I activity, neither reduced medullary I premotor output. This as well as excessive E neuronal firing as shown in our previous studies suggests inadequate synaptic inhibition for phase transition. We found that the abnormal respiratory neuronal firing, ectopic phrenic discharge as well as RTT-type hypoventilation all can be corrected by enhancing GABAergic inhibition. More strikingly, Mecp2-null rats reaching humane endpoints with severe hypoventilation can be rescued by GABAergic augmentation. Thus, defective GABAergic inhibition among respiratory neurons is likely to play a role in the RTT-type hypoventilation, which can be effectively controlled with pharmacological agents., (© 2021 Wiley Periodicals LLC.)

Perry disease (Perry syndrome) is a rare, rapidly progressive, autosomal dominant neurodegenerative disease characterized by parkinsonism, depression/apathy, weight loss, and respiratory symptoms including central hypoventilation. It is caused by missense mutations (e.g. p.G71A) in the DCTN1 gene. We previously generated transgenic mice that expressed human DCTN1 G71A mutant protein under the control of Thy1 promoter. These mice exhibited apathy-like behavior and parkinsonism. However, it is possible that this phenotype was due to a gene-dosage imbalance or transgene insertion position. To circumvent these potential caveats, we have generated a knock-in mouse model carrying a p.G71A mutation in Dctn1. Heterozygous Dctn1 G71A and wild-type littermates were subjected to a battery of behavioral analyses. Furthermore, immunohistochemistry for tyrosine hydroxylase (TH) was performed on brain sections of these mice, and TH signal intensity in substantia nigral neurons was quantified. Dctn1 G71A mice were immobile for longer than wild-type mice of the same age and sex in the tail-suspension test, revealing depressive characteristics. In addition, the beam-walking test and pole test detected motor deficits in Dctn1 G71A female mice. Finally, immunostaining revealed a decrease in TH immunoreactivity in neurons of the substantia nigra in the Dctn1 G71A mice. Collectively, heterozygous Dctn1 G71A mice showed depression-like behavior, motor deficits, and a functional reduction in substantia nigral neurons, as judged by TH immunostaining, thereby exhibiting multiple features of Perry disease. Hence, this mouse model will be useful in elucidating pathological mechanisms of Perry disease and for developing novel therapeutic strategies against it., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Rapid onset Obesity, Hypothalamic dysfunction, Hypoventilation, and Autonomic Dysregulation (ROHHAD) is a rare syndrome whose underlying pathophysiology and etiology remain elusive. We present the case of a 36-month-old boy with the classic symptoms of ROHHAD and a neuroendocrine tumor, who progressed rapidly and subsequently succumbed to cardiorespiratory arrest because of hypoventilation. His magnetic resonance imaging findings at the initial diagnosis and the brain autopsy results are detailed. The literature was reviewed to summarize the current understanding of the underlying mechanism of this rare disorder., Competing Interests: The authors declare no conflict of interest., (Copyright © 2020 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Mutations in the PHOX2B gene cause congenital central hypoventilation syndrome (CCHS), a rare autonomic nervous system dysfunction disorder characterized by a decreased ventilatory response to hypercapnia. Affected subjects develop alveolar hypoventilation requiring ventilatory support particularly during the non-REM phase of sleep. In more severe cases, hypoventilation may extend into wakefulness. CCHS is associated with disorders characterized by the defective migration/differentiation of neural crest derivatives, including aganglionic megacolon or milder gastrointestinal phenotypes, such as constipation. Most cases of CCHS are de novo, caused by heterozygosity for polyalanine repeat expansion mutations (PARMs) in exon 3. About 10% of cases are due to heterozygous non-PARM missense, nonsense or frameshift mutations., Methods: We describe a three-generation Maltese-Caucasian family with a variable respiratory/Hirschsprung phenotype, characterized by chronic constipation, three siblings with Hirschsprung disease necessitating surgery, chronic hypoxia, and alveolar hypoventilation requiring non-invasive ventilation., Results: The sequencing of PHOX2B revealed a novel heterozygous c.241+2delT splice variant in exon 1 that segregates with the CCHS/Hirschsprung phenotype in the family. The mutation generates a non-functional splice site with a deleterious effect on protein structure and is pathogenic according to ACMG P VS1, PM2, and PP1 criteria., Conclusion: This report is significant as no PHOX2B splice-site mutations have been reported. Additionally, it highlights the variability in clinical expression and disease severity of non-PARM mutations., (© 2020 The Authors. Molecular Genetics & Genomic Medicine published by Wiley Periodicals LLC.)

Recently, the genetic cause of HIDEA syndrome (hypotonia, hypoventilation, intellectual disability, dysautonomia, epilepsy, and eye abnormalities) was identified as biallelic pathogenic variants in P4HTM, which encodes an atypical member of the prolyl 4-hydroxylases (P4Hs) family of enzymes. We report seven patients from four new families in whom HIDEA was only diagnosed after whole-exome sequencing (WES) revealed novel disease-causing variants in P4HTM. We note the variable phenotypic expressivity of the syndrome except for cognitive impairment/developmental delay, and hypotonia, which seem to be consistent findings. One patient only presented with hypotonia, developmental delay, and abnormal eye movements, which highlights the challenge in diagnosing milder cases with this new syndrome. Other notable features include mild facial dysmorphism, obesity, and brain dysmyelination and atrophy. We conclude that HIDEA is a highly variable syndrome and suspect that a large fraction of patients will be diagnosed via reverse phenotyping after recessive P4HTM variants are identified by agnostic genomic sequencing assays., (© 2020 Wiley Periodicals LLC.)

Introduction: Perry syndrome, also recognized as Perry disease, is a rare autosomal dominant disorder characterized by midlife-onset atypical parkinsonism, apathy or depression, respiratory failure and weight loss caused by a mutation in the Dynactin (DCTN1) gene., Case Description: A fifty-six years-old adopted male presented with atypical parkinsonism with bradykinesia and postural instability, apathy, weight loss, and recurrent respiratory failure due to central hypoventilation requiring tracheostomy., Methods and Results: Clinical workup revealed a novel DCTN1 p.Tyr78His variant. Using bioinformatic protein structure modeling, we compare our patient's variant to known DCTN1 mutations and predict protein stability of each variant at the CAP-Gly domain of p150 Glued . All eight variants causing Perry syndrome, as well as Tyr78His, are located at site expected to interact with MAPRE1 tail and are predicted to be destabilizing. Variants causing atypical parkinsonism with incomplete Perry syndrome phenotype (K56R and K68E) are not significantly destabilizing in silico., Conclusion: We propose p.Tyr78His as the ninth pathogenic DCTN1 variant causing Perry syndrome. Bioinformatic protein modeling may provide additional window to understand and interpret DCTN1 variants, as we observed non-destabilizing variants to have different phenotype than destabilizing variants., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Objective: The Korean patient with Perry syndrome (PS) was the first to come to autopsy. We report a pathologically confirmed patient with PS, and compare to pathological findings of previous literatures., Materials and Methods: The patient had a family history of parkinsonism and had a mutation in the DCTN1 gene. After death an autopsy was performed. We analyzed macroscopic and microscopic findings of the patient., Results: There was no prominent cortical atrophy, but microscopy showed severe neuronal loss, microvacuolation, and gliosis in the substantia nigra (SN). We identified transactive response DNA-binding protein 43 (TDP-43)-positive neuronal cytoplasmic inclusions, dystrophic neurites, and glial cytoplasmic inclusions in surviving SN neurons. In addition, some neurofibrillary tangles (NFTs) were also seen in the parahippocampal gyrus., Conclusion: The neuropathology, including TDP-43 proteinopathy, is comparable to that reported previously in Caucasian populations. In addition to the stereotypic features of PS, our patient had NFTs in the parahippocampal gyrus, the pathology similar to that is described as primary age-related tauopathy (PART). These observations suggest that comorbid age-related neuropathologic change may also contribute to cognitive impairment in PS.

Paired Like homeobox 2B (PHOX2B) is a gene crucial for the differentiation of the neural lineages of the autonomic nervous system (ANS), whose coding mutations cause congenital central hypoventilation syndrome (CCHS). The vast majority of PHOX2B mutations in CCHS is represented by expansions of a polyalanine region in exon 3, collectively defined PARMs (PolyAlanine Repeat Mutations), the minority being frameshift, missense and nonsense mutations, defined as NPARMs (Non-PARMs). While PARMs are nearly exclusively associated with isolated CCHS, most of NPARMs is detected in syndromic CCHS, presenting with neuroblastoma and/or Hirschsprung disease. More recently, evidence of a complex role of PHOX2B in the pathogenesis of a wider spectrum of ANS disorders has emerged. Indeed, common and hypomorphic PHOX2B variants, including synonymous, polyalanine-contractions, gene deletions may influence the occurrence of either apparent life-threatening event (ALTE), Sudden Infant Death Syndrome (SIDS), neuroblastoma, or isolated HSCR, likely through small effects on PHOX2B expression levels. After an introduction to the role of PHOX2B in the ANS development, causative mutations, common variants, and gene expression deregulation of the PHOX2B gene are discussed, though the involvement of synonymous variants and contractions requires further confirmations with respect to ANS disorders and molecular mechanisms underlying the PHOX2B phenotypic heterogeneity., (© 2019 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Congenital central hypoventilation syndrome is a disorder of respiratory control caused by mutations in the paired-like homeobox 2B gene. Mutations in the paired-like homeobox 2B gene are also responsible for Hirschsprung's disease. Variant Hirschsprung's disease is a rarer disorder that does not meet the diagnostic criteria of Hirschsprung's disease, although severe functional bowel obstruction persists. We present a case of an extremely low birth weight infant with congenital central hypoventilation syndrome and variant Hirschsprung's disease. A male infant who was diagnosed to have fetal growth restriction and polyhydramnios was delivered by emergency cesarean section at 30 weeks and 3 days of gestational age due to non-reassuring fetal status. The birth weight was 979 g, and intensive care was started immediately following delivery. The patient exhibited refractory apnea and was diagnosed with congenital central hypoventilation syndrome by genetic testing of the paired-like homeobox 2B gene. The patient also exhibited refractory functional bowel obstruction and was diagnosed to have variant Hirschsprung's disease through pathological examination of his intestinal specimens. The patient grew slowly but surely with intensive care including mechanical ventilation and parenteral nutrition. However, the patient repeatedly suffered from sepsis and died of fungemia at 197 days of age. This is the first congenital central hypoventilation syndrome case that was accompanied with variant Hirschsprung's disease, and the paired-like homeobox 2B mutation detected in this case (NM_003924.3: c.441G > C; p.(Gln147His)) is novel. This case suggests that the paired-like homeobox 2B mutation causes not only congenital central hypoventilation syndrome and Hirschsprung's disease, but also variant Hirschsprung's disease in humans. It also highlights the extreme difficulty in treating premature infants with severe and prolonged functional bowel obstruction., (Copyright © 2018 Elsevier Masson SAS. All rights reserved.)

The respiratory rhythm is generated by the preBötzinger complex in the medulla oblongata, and is modulated by neurons in the retrotrapezoid nucleus (RTN), which are essential for accelerating respiration in response to high CO 2 Here we identify a LBX1 frameshift ( LBX1 FS ) mutation in patients with congenital central hypoventilation. The mutation alters the C-terminal but not the DNA-binding domain of LBX1 Mice with the analogous mutation recapitulate the breathing deficits found in humans. Furthermore, the mutation only interferes with a small subset of Lbx1 functions, and in particular with development of RTN neurons that coexpress Lbx1 and Phox2b. Genome-wide analyses in a cell culture model show that Lbx1 FS and wild-type Lbx1 proteins are mostly bound to similar sites, but that Lbx1 FS is unable to cooperate with Phox2b. Thus, our analyses on Lbx1 FS (dys)function reveals an unusual pathomechanism; that is, a mutation that selectively interferes with the ability of Lbx1 to cooperate with Phox2b, and thus impairs the development of a small subpopulation of neurons essential for respiratory control., Competing Interests: The authors declare no conflict of interest., (Copyright © 2018 the Author(s). Published by PNAS.)

Congenital central hypoventilation syndrome (CCHS) is a disorder of ventilatory control and autonomic dysregulation that can be caused by mutations in the paired-like homeobox 2B (PHOX2B) gene. The majority of CCHS cases are caused by polyalanine repeat mutations (PARMs) in PHOX2B; however, in rare cases, non-polyalanine repeat mutations (NPARMs) have been identified. Here, we report two patients with NPARMs in PHOX2B. Patient 1 has a mild CCHS phenotype seen only on polysomnogram, which was performed for desaturations and stridor following a bronchiolitis episode, and characterized by night-time hypoventilation and a history of ganglioneuroblastoma. She carried a novel de novo missense variant, p.R102S (c.304C > A), in exon 2. Patient 2 has an atypical CCHS phenotype including micrognathia, gastroesophageal reflux, stridor, hypopnea, and intermittent desaturations. Sleep study demonstrated that Patient 2 had daytime and night-time hypercarbia with obstructive sleep apnea, requiring tracheostomy. On PHOX2B sequencing, she carried a recently identified nonsense variant, p.Y78* (c.234C > G), in exon 1. In summary, we present two patients with CCHS and identified NPARMs in PHOX2B who have distinct differences in phenotype severity, further elucidating the range of clinical outcomes in CCHS and illustrating the necessity of considering PHOX2B mutations when encountering atypical CCHS presentations., (© 2018 Wiley Periodicals, Inc.)

Introduction: Perry syndrome is a rapidly progressive, autosomal dominant parkinsonism characterized by central hypoventilation, depression and severe weight loss. To date, eight DCTN1 mutations have been identified associated with Perry syndrome. A novel F52L DCTN1 mutation case of Perry syndrome is characterized by late-onset parkinsonism and frontotemporal atrophy., Methods: A Japanese woman suffered from slowly progressing parkinsonism since age 48. At age 59, she developed central hypoventilation, and required breathing assistance. Gene analysis identified a p.F52L mutation in DCTN1 and she was diagnosed with Perry syndrome. She died of aspiration pneumonia at age 74., Results: Postmortem examination revealed severe neuronal loss in the substantia nigra and the putamen. Immunohistochemistry for DCTN1 revealed many abnormal aggregates, mainly in neurons in the brainstem and basal ganglia. Additionally, numerous abnormal phosphorylated tau deposits including neurofibrillary tangles, tuft-shaped astrocytes and coiled bodies were observed mainly in the basal ganglia, brainstem and cerebellum. These correspond with the neuropathologic criteria for progressive supranuclear palsy. Colocalization of DCTN1 and tau were occasionally seen. Colocalization of phosphorylated α-synuclein and DCTN1 were also observed in Lewy body-like structures in oculomotor nuclei. Phosphorylated TARDBP-positive neuronal cytoplasmic inclusions were few., Conclusion: In conjunction with long disease duration and aging, our findings suggest that the F52L DCTN1 mutation may evoke severe tauopathy and moderate α-synucleinopathy., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Objective: To establish international diagnostic criteria for Perry syndrome, a disorder characterised by clinical signs of parkinsonism, depression/apathy, weight loss, respiratory symptoms, mutations in the DCTN1 gene and TAR DNA-binding protein 43 (TDP-43) pathology., Methods: Data from the published literature and newly identified patients were gathered and analysed during and after the International Symposium on Perry syndrome in Tokyo to identify diagnostic criteria for Perry syndrome., Results: Eighty-seven patients with Perry syndrome carrying DCTN1 mutations from 20 families were included in this study, and common signs of the disorder were identified, including parkinsonism (95.2% of patients), depression/apathy (71.4%), respiratory symptoms (66.7%) and weight loss (49.2%)., Conclusions: Based on our findings, we propose the following definitive diagnostic criteria for Perry syndrome: the presence of four cardinal signs of Perry syndrome, accompanied by a mutation in DCTN1; or a family history of the disease, parkinsonism and a mutation in DCTN1 ; or the presence of four cardinal signs and pathological findings that include nigral neuronal loss and TDP-43 pathology. As patients with Perry syndrome present with uniform clinical, genetic and pathological features, we further propose the disorder be termed 'Perry disease.', Competing Interests: Competing interests: None declared., (© Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2018. All rights reserved. No commercial use is permitted unless otherwise expressly granted.)

Introduction: Congenital central hypoventilation syndrome (CCHS) syndrome is a rare disease caused by mutations in the PHOX2B gene. Patients show a reduced response to hypercapnia and hypoxia accompanied by diffuse disturbances of the autonomic nervous system and occasionaly also disturbances in neuroimaging. A specific neuropsychological profile has not been described in children and adolescents with CCHS., Case Reports: We describe three cases (aged between 4 and 19 years) with different profiles of affectation in cognitive and functionality. These profiles are compared with the features described in the literature about neuropsychology in CCHS., Conclusions: The profile of functional impairment in the CCHS is variable: in case 1, a severe global developmental delay with autistic features and marked functional involvement is described. In case 2, bilateral atrophy of the hippocampus is associated with involvement in social cognition and in executive functions with moderate functional repercussion. Case 3 shows difficulties in some cognitive executive functions (planning and non-verbal fluency), but without functional repercussion. Neuropsychological assessment can help in the clinical management of these patients by determining and guiding the need for rehabilitation treatments.

Anesthetic agents have been implicated in the causation of neurological and cognitive deficits after surgery, the exacerbation of chronic neurodegenerative disease, and were recently reported to promote the onset of the neurologic respiratory disease Congenital Central Hypoventilation Syndrome (CCHS), related to misfolding of the transcription factor Phox2B. To study how anesthetic agents could affect neuronal function through alterations to protein folding, we created neuronal cell models emulating the graded disease severity of CCHS. We found that the gas anesthetic isoflurane and the opiate morphine potentiated aggregation and mislocalization of Phox2B variants, similar to that seen in CCHS, and observed transcript and protein level changes consistent with activation of the endoplasmic reticulum (ER) unfolded protein response. Attenuation of ER stress pathways did not result in a correction of Phox2B misfolding, indicating a primary effect of isoflurane on protein structure. We also observed that isoflurane hindered the folding and activity of proteins that rely heavily on ER function, like the CFTR channel. Our results show how anesthetic drugs can alter protein folding and induce ER stress, indicating a mechanism by which these agents may affect neuronal function after surgery.

Congenital central hypoventilation syndrome (CCHS), known colloquially as Ondine's curse, is a rare disorder characterized by impaired autonomic control of breathing during sleep from the loss of vagal input and diminished sensitivity of CO 2 receptors in the medulla. CCHS correlates to the malformation of the neural crest located in the brainstem; this consequently affects the loss of sensitivity of CO 2 chemoreceptors, bringing about hypoventilation during sleep. The primary cause of CCHS is the mutation of the paired-like homeobox PHO2XB gene, found in 90% of the patients. This mutation not only affects breathing but also drives neurological abnormalities such as autonomic and neurocognitive dysfunction. Though typically congenital, there have been late-onset (i.e., acquired) cases reported. It is vital for physicians and clinicians to be able to diagnose CCHS due to its similar presentation to other syndromes and disorders, which may cause it to be misdiagnosed and may account for its deleterious effects. CCHS can lead to a constellation of symptoms, and consideration of diseases that present concomitantly with CCHS affords us a better understanding of the etiology of this illness. Although a rare syndrome, we aim to review the current literature to emphasize the pathogenesis, etiology, clinical presentation, symptoms, diagnosis, and current treatment methods of CCHS for clinicians to better identify and understand this condition., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Introduction: Orexin is a neuropeptide that plays a key role in maintaining a state of arousal, and possibly associates with sleep apnea syndrome (SAS). Reduced orexin immunoreactivity has been reported in various neurologic conditions such as narcolepsy, Alzheimer's disease, Lewy body disease and multiple system atrophy (MSA); however, there has been no report investigating orexin in Perry syndrome, a rare hereditary neurodegenerative disease characterized by four clinical cardinal signs (parkinsonism, depression/apathy, weight loss, and central hypoventilation). Perry syndrome patients frequently have sleep disturbances, including SAS and insomnia., Methods: We evaluated orexin immunoreactivity in Perry syndrome. Using imaging analysis, we quantitatively assessed orexin immunoreactivity in the nucleus basalis of Meynert in three Perry syndrome cases, as well as five cases of frontotemporal lobar degeneration with motor neuron disease, five cases of MSA and five age-matched controls. For these cases, antemortem clinical information on sleep disturbances has been reviewed., Results: In Perry syndrome and MSA, there was reduction of orexin immunoreactivity compared with controls (Perry syndrome: p = 0.020, MSA: p < 0.001). In contrast, FTLD-MND did not have significant reduction of orexin immunoreactivity. Two out of three cases of Perry syndrome had SAS confirmed by polysomnography., Conclusions: This is the first report assessing orexin immunoreactivity in Perry syndrome, and it showed significant reduction, similar to select neurodegenerative diseases, such as MSA. Further analysis with more cases will be needed to elucidate the specific mechanism of orexin loss in these disorders., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Perry syndrome is a rare atypical parkinsonism with depression, apathy, weight loss, and central hypoventilation caused by mutations in dynactin p150glued (DCTN1). A rare distal hereditary motor neuropathy, HMN7B, also has mutations in DCTN1. Perry syndrome has TAR DNA-binding protein of 43 kDa (TDP-43) inclusions as a defining feature. Other TDP-43 proteinopathies include amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD) with and without motor neuron disease (FTLD-MND). TDP-43 forms aggregates in neuronal cytoplasmic inclusions (NCIs), neuronal intranuclear inclusions, dystrophic neurites (DNs), as well as axonal spheroids, oligodendroglial cytoplasmic inclusions, and perivascular astrocytic inclusions (PVIs). We performed semiquantitative assessment of these lesions and presence of dynactin subunit p50 lesions in 3 cases of Perry syndrome and one of HMN7B. We compared them with 3 cases of FTLD-MND, 3 of ALS, and 3 of hippocampal sclerosis (HpScl). Perry syndrome had NCIs, DNs, and frequent PVIs and spheroids. Perry syndrome cases were similar, but different from ALS, FTLD-MND, and HpScl. TDP-43 pathology was not detected in HMN7B. Dynactin p50 inclusions were observed in both Perry syndrome and HMN7B, but not in the other conditions. These results suggest that Perry syndrome may be distinctive type of TDP-43 proteinopathy., (© 2017 American Association of Neuropathologists, Inc. All rights reserved.)

Perry syndrome (PS) is a rare hereditary neurodegenerative disease characterized by autosomal dominant parkinsonism, psychiatric symptoms, weight loss, central hypoventilation, and distinct TDP-43 pathology. The mutated causative gene for PS is DCTN1, which encodes the dynactin subunit p150 Glued . Dynactin is a motor protein involved in axonal transport; the p150 Glued subunit has a critical role in the overall function. Since the discovery of DCTN1 in PS, it has been increasingly recognized that DCTN1 mutations can exhibit more diverse phenotypes than previously thought. Progressive supranuclear palsy- and/or frontotemporal dementia-like phenotypes have been associated with the PS phenotypes. In addition, DCTN1 mutations were identified in a family with motor-neuron disease before the discovery in PS. In this review, we analyze the clinical and genetic aspects of DCTN1-related neurodegeneration and discuss its pathogenesis. We also describe three families with PS, Canadian, Polish, and Brazilian. DCTN1 mutation was newly identified in two of them, the Canadian and Polish families. The Canadian family was first described in late 1970's but was never genetically tested. We recently had the opportunity to evaluate this family and to test the gene status of an affected family member. The Polish family is newly identified and is the first PS family in Poland. Although still rare, DCTN1-related neurodegeneration needs to be considered in a differential diagnosis of parkinsonian disorders, frontotemporal dementia, and motor-neuron diseases, especially if there is family history., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Pathogenic variants in PHOX2B lead to congenital central hypoventilation syndrome (CCHS), a rare disorder of the nervous system characterized by autonomic dysregulation and hypoventilation typically presenting in the neonatal period, although a milder late-onset (LO) presentation has been reported. More than 90% of cases are caused by polyalanine repeat mutations (PARMs) in the C-terminus of the protein; however non-polyalanine repeat mutations (NPARMs) have been reported. Most NPARMs are located in exon 3 of PHOX2B and result in a more severe clinical presentation including Hirschsprung disease (HSCR) and/or peripheral neuroblastic tumors (PNTs). A previously reported nonsense pathogenic variant in exon 1 of a patient with LO-CCHS and no HSCR or PNTs leads to translational reinitiation at a downstream AUG codon producing an N-terminally truncated protein. Here we report additional individuals with nonsense pathogenic variants in exon 1 of PHOX2B. In vitro analyses were used to determine if these and other reported nonsense variants in PHOX2B exon 1 produced N-terminally truncated proteins. We found that all tested nonsense variants in PHOX2B exon 1 produced a truncated protein of the same size. This truncated protein localized to the nucleus and transactivated a target promoter. These data suggest that nonsense pathogenic variants in the first exon of PHOX2B likely escape nonsense mediated decay (NMD) and produce N-terminally truncated proteins functionally distinct from those produced by the more common PARMs., (© 2017 Wiley Periodicals, Inc.)

Background: Perry syndrome is a rare autosomal dominant disorder clinically characterized by parkinsonism with depression/apathy, weight loss, and central hypoventilation. Eight mutations in DCTN1 gene have been reported. A novel disease model is required because the detailed pathogenesis remains unclear., Methods: To develop a novel model, we generated induced pluripotent stem cells (iPSCs) from a Perry syndrome patient with F52L mutation in DCTN1, and describe clinical and neuroimaging investigations. We differentiated iPSCs into tyrosine hydroxylase (TH)-positive neurons. Immunocytochemistry analyses of control and mutant were performed., Results: The patient displayed levodopa responsive parkinsonism. Dopamine transporter single photon emission tomography showed markedly decreased uptake in the striatum, and metaiodobenzylguanidine cardiac scintigraphy also showed decreased uptake. Perry syndrome TH-positive neurons showed dynactin aggregates in cytoplasm., Conclusions: TH-positive neurons from Perry syndrome iPSCs recapitulated an aspect of the disease phenotype of Perry syndrome., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

The developmental lineage of the PHOX2B-expressing neurons in the retrotrapezoid nucleus (RTN) has been extensively studied. These cells are thought to function as central respiratory chemoreceptors, i.e., the mechanism by which brain Pco2 regulates breathing. The molecular and cellular basis of central respiratory chemoreception is based on the detection of CO2 via intrinsic proton receptors (TASK-2, GPR4) as well as synaptic input from peripheral chemoreceptors and other brain regions. Murine models of congenital central hypoventilation syndrome designed with PHOX2B mutations have suggested RTN neuron agenesis. In this review, we examine, through human and experimental animal models, how a restricted number of neurons that express the transcription factor PHOX2B play a crucial role in the control of breathing and autonomic regulation., (Copyright © 2016 the American Physiological Society.)

Fetuses as early as 15 weeks' gestation exhibit rhythmical respiratory movements shown by real-time ultrasonography. The nucleus/tractus solitarius is the principal brainstem respiratory center; other medullary nuclei also participate. The purpose was to determine temporal maturation of synaptogenesis. Delayed synaptic maturation may explain neurogenic apnea or hypoventilation of prematurity and some cases of sudden infant death syndrome. Sections of medulla oblongata were studied from 30 human fetal and neonatal brains 9 to 41 weeks' gestation. Synaptophysin demonstrated the immunocytochemical sequence of synaptogenesis. Other neuronal markers and myelin stain also were applied. The nucleus/tractus solitarius was similarly studied in fetuses with chromosomopathies, metabolic encephalopathies, and brain malformations. Synapse formation in the nucleus solitarius begins at about 12 weeks' gestation and matures by 15 weeks; myelination initiated at 33 weeks. Synaptogenesis was delayed in 3 fetuses with different conditions, but was not specific for only nucleus solitarius. Delayed synaptogenesis or myelination in the nucleus solitarius may play a role in neonatal hypoventilation, especially in preterm infants and in some sudden infant death syndrome cases., (© The Author(s) 2015.)

Rapid-onset obesity with hypothalamic dysfunction, hypoventilation, and autonomic dysregulation (ROHHAD) syndrome is a rare and potentially lethal disorder. The etiology is unclear but paraneoplastic syndrome and autoimmunity secondary to neural crest tumors have been considered, even in patients without any detectable tumor due to their tendency for spontaneous remission. We are presenting a 13-year-old girl with ROHHAD syndrome and celiac disease, which may suggest further evidence for immune-mediated etiology in the pathogenesis of ROHHAD syndrome.

Background: Germline non-polyalanine repeat expansion mutations in PHOX2B (PHOX2B NPARM) predispose to peripheral neuroblastic tumors (PNT), frequently in association with other neurocristopathies: Hirschsprung disease (HSCR) or congenital central hypoventilation syndrome (CCHS). Although PHOX2B polyalanine repeat expansions predispose to a low incidence of benign PNTs, the oncologic phenotype associated with PHOX2B NPARM is still not known in detail., Methods: We analyzed prognostic factors, treatment toxicity, and outcome of patients with PNT and PHOX2B NPARM., Results: Thirteen patients were identified, six of whom also had CCHS and/or HSCR, one also had late-onset hypoventilation with hypothalamic dysfunction (LO-CHS/HD), and six had no other neurocristopathy. Four tumours were "poorly differentiated," and nine were differentiated, including five ganglioneuromas, three ganglioneuroblastomas, and one differentiating neuroblastoma, hence illustrating that PHOX2B NPARM are predominantly associated with differentiating tumors. Nevertheless, three patients had stage 4 and one patient had stage 3 disease. Segmental chromosomal alterations, correlating with poor prognosis, were found in all the six tumors analyzed by array-comparative genomic hybridization. One patient died of tumor progression, one is on palliative care, one died of hypoventilation, and 10 patients are still alive, with median follow-up of 5 years., Conclusions: Based on histological phenotype, our series suggests that heterozygous PHOX2B NPARM do not fully preclude ganglion cell differentiation in tumors. However, this tumor predisposition syndrome may also be associated with poorly differentiated tumors with unfavorable genomic profiles and clinically aggressive behaviors. The intrafamilial variability and the unpredictable tumor prognosis should be considered in genetic counseling., (© 2015 Wiley Periodicals, Inc.)

Human congenital central hypoventilation syndrome (CCHS), resulting from mutations in transcription factor PHOX2B, manifests with impaired responses to hypoxemia and hypercapnia especially during sleep. To identify brainstem structures developmentally affected in CCHS, we analyzed two postmortem neonatal-lethal cases with confirmed polyalanine repeat expansion (PARM) or Non-PARM (PHOX2B∆8) mutation of PHOX2B. Both human cases showed neuronal losses within the locus coeruleus (LC), which is important for central noradrenergic signaling. Using a conditionally active transgenic mouse model of the PHOX2B∆8 mutation, we found that early embryonic expression (

Background: Perry syndrome (PS) caused by DCTN1 gene mutation is clinically characterized by autosomal dominant parkinsonism, depression, severe weight loss, and hypoventilation. Previous pathological studies have reported relative sparing of the cerebral cortex in this syndrome. Here, we characterize novel clinical and neuroimaging features in 3 patients with PS., Methods: (18)F-fluorinated N-3-fluoropropyl-2-ß-carboxymethoxy-3-β-(4-iodophenyl) nortropane ([(18)F]FP-CIT) PET, [(18)F]fluorodeoxyglucose PET, or volumetric MRI was performed in probands, and imaging data were analyzed and compared with those of control subjects., Results: We identified 2 novel mutations of DCTN1. Oculogyric crisis that presented before levodopa treatment was observed in 1 case. One patient had supranuclear gaze palsy. In 2 cases, [(18)F]FP-CIT showed marked loss of dopamine transporter binding with only mild parkinsonism. Areas of hypometabolism or cortical thickness change were observed in dorsolateral frontal, anterior cingulate, lateral temporal, and inferior parietal cortices., Conclusion: Oculomotor manifestations are not uncommon in PS. Neuroimaging studies suggest involvement of the frontotemporoparietal cortex, which may be the clinical correlate of apathy and depression, as well as pathological changes in subcortical structures., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

Modulation in ventilatory settings is one of the approaches and interventions used to treat and prevent secondary brain damage after traumatic brain injury (TBI). Here we investigate the effect of hyperoxia in combination with hypoventilation on brain oxygenation, metabolism and intracranial pressure. Twelve pigs were divided into three groups; group1-100% hyperoxia (n=4), group 2-100% hyperoxia and 20% decrease in minute volume (MV) (n=4) and group 3-100% hyperoxia and 50% decrease in MV (n=4). Neither of the ventilator settings affected the lactate/pyruvate ratio significantly. However, there was a significant decrease of brain lactate (2.6±1.7 to 1.8±1.6mM) and a rapid and marked increase in brain oxygenation (7.9±0.7 to 61.3±17.6mmHg) in group 3. Intracranial pressure (ICP) was not significantly affected in this group, however, the ICP increased significantly in group 2 with 100% hyperoxia plus 20% reduction in minute volume. We conclude that hyperoxia in combination with 50% decrease in MV showed pronounced increase in partial brain oxygen tension (pbrO2) and decrease in brain lactate. The ventilatory modification, used in this study should be considered for further investigation as a possible therapeutic intervention for TBI patients., (Copyright © 2013 Elsevier B.V. All rights reserved.)

Background: Despite advances in critical care, more effective methods of systemic oxygenation in patients with acute lung injury or acute respiratory distress syndrome are needed. The goal of this study was to determine if it is possible to increase systemic oxygenation by transpleural perfusion with oxygenated perfluorocarbon in animals with induced acute lung injury., Methods: Eighteen Sprague-Dawley rats were intubated, and acute lung injury was induced by aspiration of 0.1N HCl (1 mL/kg) through the tracheal tube. Inflow and outflow tubes were placed in the thoracic cavity and connected to a perfusion circuit containing a roller pump, warmer, and oxygenator. Rats in group I were not treated after aspiration of HCl, those in group II were perfused with oxygenated saline, and those in group III were perfused with oxygenated perfluorocarbon. Arterial blood gases were collected every 30 minutes for 180 minutes. At the last step of the experiments, pathological examination of the lungs and parietal pleura was performed., Results: PaO(2) in group III was significantly higher than that in group I or II. PaCO(2) in group III was significantly lower than that in the other two groups. Histological examination showed relatively well-delineated zones of inflammation-free coagulative necrosis of lung parenchyma in all groups., Conclusions: Transpleural perfusion with oxygenated perfluorocarbon in an animal model of induced acute lung injury resulted in a significant increase in systemic oxygenation and depletion of systemic carbon dioxide, and might be a useful method for improving systemic oxygenation in patients with acute lung injury.

The study aims were twofold: 1) identify the localization and the cytoarchitecture of the retrotrapezoid nucleus (RTN) in the human fetus and infant and 2) ascertain if the RTN, given its essential role in animal studies for the maintenance of breathing and chemoreception, showed abnormalities in victims of sudden perinatal and infant death (sudden intrauterine unexplained death/SIUD - and sudden infant death syndrome/SIDS). We examined SIDS and SIUD cases and Controls (n=58) from 34 gestational weeks to 8 months of postnatal age by complete autopsy, in-depth autonomic nervous system histological examination, and immunohistochemical analysis of the PHOX2B gene, a transcriptional factor involved in Congenital Central Hypoventilation Syndrome that has been defined as a marker of rat RTN neurons. We identified a group of PHOX2B-immunopositive neurons within the caudal pons, contiguous to the facial/parafacial complex, in 90% of Controls, likely the homologous human RTN (hRTN). We observed structural and/or PHOX2B-expression abnormalities of the hRTN in 71% of SIUD/SIDS cases vs 10% of Controls (p<0.05). In conclusion we suggest that developmental abnormalities of the hRTN may seriously compromise chemoreception control, playing a critical role in the pathogenesis of both SIUD and SIDS., (Copyright © 2012 Elsevier B.V. All rights reserved.)

Central hypoventilation syndrome (CHS) is a rare condition characterized by hypoventilation during sleep, reduced ventilatory responsiveness to CO(2) and O(2), impaired perception of air hunger, and autonomic abnormalities. Neural impairments accompany the condition, including structural injury, impaired cerebral autoregulation, and dysfunctional autonomic control. The hypoventilation may induce cortical hypoxic injury, additional to consequences of maldevelopment from PHOX2B mutations present in most CHS subjects. We assessed cortical injury in clinically diagnosed CHS using high-resolution magnetic resonance imaging scans, collected from 14 CHS (mean age ± standard deviation [SD] 17.7 ± 5.0 years; 6 female) and 29 control (mean age ± SD, 17.9 ± 4.3 years; 12 female) subjects. We measured group differences in mean cortical thickness and age-thickness correlations using FreeSurfer software, accounting for age and sex (0.1 false discovery rate). Reduced thickness in CHS appeared in the dorsomedial frontal cortex and anterior cingulate; medial prefrontal, parietal, and posterior cingulate cortices; the insular cortex; anterior and lateral temporal lobes; and mid- and accessory motor strips. Normal age-related cortical thinning in multiple regions did not appear in CHS. The cortical thinning may contribute to CHS cardiovascular and memory deficits and may impair affect and perception of breathlessness. Extensive axonal injury in CHS is paralleled by reduced cortical tissue and absence of normal developmental patterns.

We report on a newborn with congenital hypotonia, unilateral facial palsy, sucking and swallowing difficulties, velopalatine incoordination, and unilateral impairment of the auditory brainstem responses, attributable to brainstem dysgenesis. On follow-up, the child manifested developmental delay and central hypoventilation syndrome during sleep. The ventilation abnormality during sleep with insensitivity to hypercapnia, associated with unilateral facial paralysis, indicates a pontine lesion, including the parafacial respiratory group., (Copyright © 2012 Elsevier Inc. All rights reserved.)

In bronchopulmonary dysplasia (BPD), alveolar septae are thickened with collagen and α-smooth muscle actin, transforming growth factor (TGF)-β-positive myofibroblasts. Periostin, a secreted extracellular matrix protein, is involved in TGF-β-mediated fibrosis and myofibroblast differentiation. We hypothesized that periostin expression is required for hypoalveolarization and interstitial fibrosis in hyperoxia-exposed neonatal mice, an animal model for this disease. We also examined periostin expression in neonatal lung mesenchymal stromal cells and lung tissue of hyperoxia-exposed neonatal mice and human infants with BPD. Two-to-three day-old wild-type and periostin null mice were exposed to air or 75% oxygen for 14 days. Mesenchymal stromal cells were isolated from tracheal aspirates of premature infants. Hyperoxic exposure of neonatal mice increased alveolar wall periostin expression, particularly in areas of interstitial thickening. Periostin co-localized with α-smooth muscle actin, suggesting synthesis by myofibroblasts. A similar pattern was found in lung sections of infants dying of BPD. Unlike wild-type mice, hyperoxia-exposed periostin null mice did not show larger air spaces or α-smooth muscle-positive myofibroblasts. Compared to hyperoxia-exposed wild-type mice, hyperoxia-exposed periostin null mice also showed reduced lung mRNA expression of α-smooth muscle actin, elastin, CXCL1, CXCL2 and CCL4. TGF-β treatment increased mesenchymal stromal cell periostin expression, and periostin treatment increased TGF-β-mediated DNA synthesis and myofibroblast differentiation. We conclude that periostin expression is increased in the lungs of hyperoxia-exposed neonatal mice and infants with BPD, and is required for hyperoxia-induced hypoalveolarization and interstitial fibrosis.

Congenital central hypoventilation syndrome (CCHS), a condition associated with mutations in the PHOX2B gene, is characterized by loss of breathing drive during sleep, insensitivity to CO2 and O2, and multiple somatomotor, autonomic, neuropsychological, and ophthalmologic deficits, including impaired intrinsic and extrinsic eye muscle control. Brain structural studies show injury in peri-callosal regions and the corpus callosum (CC), which has the potential to affect functions disturbed in the syndrome; however, the extent of CC injury in CCHS is unclear. Diffusion tensor imaging (DTI)-based fiber tractography procedures display fiber directional information and allow quantification of fiber integrity. We performed DTI in 13 CCHS children (age, 18.2±4.7 years; eight male) and 31 control (17.4±4.9 years; 18 male) subjects using a 3.0-Tesla magnetic resonance imaging scanner; CC fibers were assessed globally and regionally with tractography procedures, and fiber counts and densities compared between groups using analysis-of-covariance (covariates; age and sex). Global CC evaluation showed reduced fiber counts and densities in CCHS over control subjects (CCHS vs. controls; fiber-counts, 4490±854 vs. 5232±777, P<0.001; fiber-density, 10.0±1.5 vs. 10.8±0.9 fibers/mm2, P<0.020), and regional examination revealed that these changes are localized to callosal axons projecting to prefrontal (217±47 vs. 248±32, P<0.005), premotor (201±51 vs. 241±47, P<0.012), parietal (179±64 vs. 238±54, P<0.002), and occipital regions (363±46 vs. 431±82, P<0.004). Corpus callosum fibers in CCHS are compromised in motor, cognitive, speech, and ophthalmologic regulatory areas. The mechanisms of fiber injury are unclear, but may result from hypoxia or perfusion deficits accompanying the syndrome, or from consequences of PHOX2B action., (Copyright © 2011 IBRO. Published by Elsevier Ltd. All rights reserved.)

Background: Cerebral microdialysis, cerebral blood flow, and cerebral oxygenation (PbrO2) measurements using intraparenchymal probes are widely accepted as invasive diagnostic monitoring for early detection of secondary ischemia., Objective: To evaluate a novel PbrO2 probe for continuous and quantitative oxygenation assessment compared with the existing gold standard PbrO2 probe., Methods: In 9 pigs, 2 PbrO2 probes (Neurovent-TO vs Licox) were implanted into the subcortical white matter. An intracranial pressure probe was inserted contralaterally. The PbrO2 probes were tested during (1) baseline measurements followed by (2) hyperoxygenation (fraction of inspired oxygen [Fio2]=1.0), medically induced (3) hypo- and (4) hypertension, (5) hyperventilation, (6) tris-hydroxymethylaminomethane application, and (7) hypoxygenation (Fio2<0.05). For statistical analyses, Bland-Altman plots were used., Results: The Neurovent-TO probe is easy to handle and does not need a specific storage or calibration. Bland-Altman analyses revealed good comparability of both technologies under baseline conditions (meandiff 2.09 mm Hg, standard deviation 0.04 mm Hg, range 1.98-2.20 mm Hg), but measurement dynamics during hyperoxygenation (Fio2=1.0) revealed significantly different profiles, eg Neurovent-TO probe reached up to 1.53-fold higher PbrO2 values than the Licox probe. During hypoxygenation (Fio2<0.05), the Neurovent-TO probe detected the hypoxic level of 8.5 mm Hg 1.5 minutes earlier than did the Licox probe. All other maneuvers showed similar responses in both technologies., Conclusion: The Neurovent-TO PbrO2 device comparably measures PbrO2 under most conditions tested compared with the Licox device. The Neurovent-TO is more sensitive to rapid Fio2 changes. Further studies are necessary to clarify these differences. It is questionable whether existing knowledge of Licox tissue oxygenation, ie, hypoxic threshold, can be directly transferred to the Neurovent-TO.

The paired-like homeobox 2B gene (PHOX2B) is the disease-defining gene for congenital central hypoventilation syndrome (CCHS). Individuals with CCHS typically present in the newborn period with alveolar hypoventilation during sleep and often during wakefulness, altered respiratory control including reduced or absent ventilatory responses to hypercarbia and hypoxemia, and autonomic nervous system (ANS) dysregulation; however, a subset of individuals present well into adulthood. Thermoregulation is altered and perception of shortness of breath is absent, but voluntary breathing is retained. Structural and functional magnetic resonance imaging (MRI) and limited post-mortem studies in subjects with CCHS reveal abnormalities in both forebrain and brainstem. MRI changes appear in the hypothalamus (responsible for thermal drive to breathing), posterior thalamus and midbrain (mediating O(2) and oscillatory motor patterns), caudal raphé and locus coeruleus (regulating serotonergic and noradrenergic systems), the lateral medulla, parabrachial pons, and cerebellum (coordinating chemoreceptor and somatic afferent activity with breathing), and insular and cingulate cortices (mediating shortness of breath perception). Structural and functional alterations in these sites may result from PHOX2B mutations or be secondary to hypoxia/perfusion alterations from suboptimal management/compliance. The study of CCHS, with collaboration between physician-scientists and basic scientists, offers a rare opportunity to investigate control of breathing within the complex physiological network of the ANS., (Copyright © 2010 Elsevier B.V. All rights reserved.)

Perry syndrome is characterized clinically by autosomal dominantly inherited, rapidly progressive parkinsonism, depression, weight loss and hypoventilation. In the seven families reported previously and the two new families presented herein (the Hawaii family and the Fukuoka-4 Japanese family), the mean disease onset age is 48 years (range: 35-61) and the mean disease duration five years (range: 2-10). Histology and immunohistochemistry show severe neuronal loss in the substantia nigra and locus coeruleus, with TDP-43-positive pathology in neurons (intranuclear and cytoplasmic inclusions, dystrophic neurites, axonal spheroids) and glial cells (glial cytoplasmic inclusions). Compared with other TDP-43-proteinopathies (amyotrophic lateral sclerosis and ubiquitin-positive frontotemporal lobar degeneration), the distribution is unique in Perry syndrome with pallidonigral distribution and sparing of the cortex, hippocampus and motor neurons. The genetic cause of Perry syndrome was recently identified with five mutations in the dynactin gene (DCTN1) segregating with disease in eight families. DCTN1 encodes p150(glued), the major subunit of the dynactin protein complex, which plays a crucial role in retrograde axonal and cytoplasmic transport of various cargoes. Evidence suggests the Perry mutations alter the binding of p150(glued) to microtubules. Further studies will examine reasons for the vulnerability of selected neuronal populations in Perry syndrome, and the link between the genetic defect and TDP-43 pathology.

Congenital central hypoventilation syndrome (CCHS) children show cognitive and affective deficits, in addition to state-specific loss of respiratory drive. The caudate nuclei serve motor, cognitive, and affective roles, and show structural deficits in CCHS patients, based on gross voxel-based analytic procedures. However, the magnitude and regional sites of caudate injury in CCHS are unclear. We assessed global caudate nuclei volumes with manual volumetric procedures, and regional volume differences with three-dimensional surface morphometry in 14 CCHS (mean age+/-SD: 15.1+/-2.3 years; 8 male) and 31 control children (15.1+/-2.4 years; 17 male) using brain magnetic resonance imaging (MRI). Two high-resolution T1-weighted image series were collected using a 3.0 Tesla MRI scanner; images were averaged and reoriented (rigid-body transformation) to common space. Both left and right caudate nuclei were outlined in the reoriented images, and global volumes calculated; surface models were derived from manually-outlined caudate structures. Global caudate nuclei volume differences between groups were evaluated using a multivariate analysis of covariance (covariates: age, gender, and total intracranial volume). Both left and right caudate nuclei volumes were significantly reduced in CCHS over control subjects (left, 4293.45+/-549.05 vs. 4626.87+/-593.41 mm(3), P<0.006; right, 4376.29+/-565.42 vs. 4747.81+/-578.13 mm(3), P<0.004). Regional deficits in CCHS caudate volume appeared bilaterally, in the rostral head, ventrolateral mid, and caudal body. Damaged caudate nuclei may contribute to CCHS neuropsychological and motor deficits; hypoxic processes, or maldevelopment in the condition may underlie the injury.

Children with congenital central hypoventilation syndrome (CCHS), a genetic disorder characterized by diminished drive to breathe during sleep and impaired CO(2) sensitivity, show brain structural and functional changes on magnetic resonance imaging (MRI) scans, with impaired responses in specific hippocampal regions, suggesting localized injury.We assessed total volume and regional variation in hippocampal surface morphology to identify areas affected in the syndrome. We studied 18 CCHS (mean age+/-std: 15.1+/-2.2 years; 8 female) and 32 healthy control (age 15.2+/-2.4 years; 14 female) children, and traced hippocampi on 1 mm(3) resolution T1-weighted scans, collected with a 3.0 Tesla MRI scanner. Regional hippocampal volume variations, adjusted for cranial volume, were compared between groups based on t-tests of surface distances to the structure midline, with correction for multiple comparisons. Significant tissue losses emerged in CCHS patients on the left side, with a trend for loss on the right; however, most areas affected on the left also showed equivalent right-sided volume reductions. Reduced regional volumes appeared in the left rostral hippocampus, bilateral areas in mid and mid-to-caudal regions, and a dorsal-caudal region, adjacent to the fimbria.The volume losses may result from hypoxic exposure following hypoventilation during sleep-disordered breathing, or from developmental or vascular consequences of genetic mutations in the syndrome. The sites of change overlap regions of abnormal functional responses to respiratory and autonomic challenges. Affected hippocampal areas have roles associated with memory, mood, and indirectly, autonomic regulation; impairments in these behavioral and physiological functions appear in CCHS.

Objective: Autosomal dominant parkinsonism, hypoventilation, depression and severe weight loss (Perry syndrome) is an early-onset rapidly progressive disease. At autopsy, previous studies have found severe neuronal loss in the substantia nigra without Lewy bodies. Transactive response DNA-binding protein of 43 kDa (TDP-43) has recently been identified as a major ubiquitinated constituent of neuronal and glial inclusions in frontotemporal lobar degeneration with ubiquitin-positive inclusions and in amyotrophic lateral sclerosis. This study reports clinical, genetic and neuropathologic investigations of Perry syndrome., Methods: Clinical data and autopsy brain tissue samples were collected from eight patients from four genealogically unrelated kindreds with Perry syndrome. Brain tissue was studied with immunohistochemistry and biochemistry for TDP-43. Patients were screened for mutations in the progranulin (GRN) and TDP-43 (TARDBP) genes., Results: The mean age at onset was 47 years (range 40-56), and the mean age at death was 52 years (range 44-64). In all patients, we identified TDP-43-positive neuronal inclusions, dystrophic neurites and axonal spheroids in a predominantly pallidonigral distribution, and we demonstrated changes in solubility and electrophoretic mobility of TDP-43 in brain tissue. The inclusions were highly pleomorphic and predominated in the extrapyramidal system, sparing the cortex, hippocampus and motor neurons. There were no mutations in GRN or TARDBP., Interpretation: Perry syndrome displays unique TDP-43 pathology that is selective for the extrapyramidal system and spares the neocortex and motor neurons.

Perry syndrome consists of early-onset parkinsonism, depression, severe weight loss and hypoventilation, with brain pathology characterized by TDP-43 immunostaining. We carried out genome-wide linkage analysis and identified five disease-segregating mutations affecting the CAP-Gly domain of dynactin (encoded by DCTN1) in eight families with Perry syndrome; these mutations diminish microtubule binding and lead to intracytoplasmic inclusions. Our findings show that DCTN1 mutations, previously associated with motor neuron disease, can underlie the selective vulnerability of other neuronal populations in distinct neurodegenerative disorders.

A case of central hypoventilation syndrome was identified in a child with brainstem and cervical cord injury following Haemophilus influenzae type b meningitis and extensive herpes simplex infection. This process resulted in a spastic tetraplegia, and the child continues to require respiratory support. Possible mechanisms of causation are discussed including an evolving, progressive inflammatory or vasculitic process in the setting of transient immunosuppression.

Objective: Oxygen desaturation is common among patients with sleep apnea. This study was designed to evaluate the methods used to express the severity of oxygen desaturation in patients with obstructive sleep apnea hypopnea syndrome., Methods: The oxygen saturation data of 215 patients [suspected of having obstructive sleep apnea (OSA)] studied at the Sleep Centre of Peking Union Medical College Hospital were evaluated. Apnea-hypopnea index (AHI) and the following conventional indices of oxygen desaturation were compared: average oxygen saturation (AO(2)), lowest oxygen saturation (LO(2)), oxygen desaturation index (ODI), average desaturation and the percent of the total time with oxygen saturation level lower than 90% (T < 90%)., Results: There was a significant correlation between the oxygen saturation values measured by any method (AO(2), LO(2), ODI, average desaturation, T < 90%) and the severity of sleep AHI (r = -0.610, 0.983, -0.789, 0.782, 0.821, respectively, P = 0.001)., Conclusions: The best method of expressing the severity of oxygen desaturation in patients with obstructive sleep apnea hypopnea syndrome needs the combination of several conventional indices of oxygen desaturation (lowest oxygen saturation, oxygen desaturation index, and the percent of the total time with oxygen saturation level lower than 90%).

Diaphragm pacing with electrical stimulation of the phrenic nerve is an established treatment for central hypoventilation syndrome. The device, however, is not readily available. We tested the same spinal cord stimulator we use for pain control in phrenic nerve stimulation. We implanted a spinal cord stimulator (Itrel 3 or X-trel, Medtronic, MN) in 6 patients with chronic hypoventilation because of brainstem or high cervical cord dysfunction. The stimulation electrode was placed along the right phrenic nerve in the neck, and the device was implanted in the anterior chest. We used the cyclic mode, and set the parameters at I second ramp up, 2 seconds on, 3 seconds off. The pulse width and the frequency were set at 150 microseconds and 21 Hz, respectively. The amplitude of the output was adjusted to obtain sufficient tidal volume and to maintain PaCO2 at around 40 mm Hg. During a follow-up period up to four years, stable and sufficient ventilation was observed in all patients without any complications. Although further long follow-up is necessary, diaphragm pacing with the spinal cord stimulator is feasible and effective for the treatment of the central hypoventilation syndrome.

Objective: To explore the appropriate study how to properly evaluate the hypoxemia degree in patients with obstructive sleep apnea/hypoventilation syndrome (OSAHS)., Methods: polysomnography was conducted on 108 OSAHS patients and 37 simple snorers to record the minimum oxygen saturation level (MiO(2)) and the total recorded time spent below 90% oxygen saturation (TS90%). The correlation between MiO(2) and the percent of the total recorded time spent below 90% oxygen saturation (TS90%) with the AHI were calculated., Results: The value of TS90% was significantly increased, and the value of MiO(2) was significantly decreased as the severity of OSAHS increased (all P < 0.001). The correlation coefficients of TS90% with AHI and with Epworth sleepiness scale (ESS) were both much higher than those of MiO(2)., Conclusion: TS90% can express the severity of hypoxemia of the OSAHS patients more correctly than MiO(2). TS90% combined with MiO(2) can comprehensively and objectively reflect the severity of hypoxia of the OSAHS patients.

Congenital central hypoventilation syndrome (CCHS) is a rare neurocristopathy characterized by absence of adequate autonomic control of respiration with decreased sensitivity to hypoxia and hypercapnia. Frameshift mutations and polyalanine triplet expansions in the coding region of PHOX2B have been identified in the vast majority of CCHS patients and a correlation between length of the expanded region and severity of CCHS has been reported. In this work, we have undertaken in vitro analyses aimed at identifying the pathogenetic mechanisms which underlie the effects of PHOX2B mutations in CCHS. According to the known role of this gene, a transcription factor expressed during autonomic nervous system development, we have tested the transcriptional activity of WT and mutant PHOX2B expression constructs on the regulatory regions of two target genes, DbetaH and PHOX2A. We observed that the two sets of mutations play different roles in the transcriptional regulation of these genes, showing a correlation between the length of polyalanine expansions and the severity of reduced transcriptional activity. In particular, although reduced transactivation due to polyalanine expansions may be caused by retention of the mutated protein in the cytoplasm or in the nuclear aggregates, frameshift mutations did not impair the PHOX2B nuclear income, suggesting a different mechanism through which they would exert the observed effects on target promoters. Moreover, the frameshift due to deletion of a cytosine residue seems to cause sequestration of the corresponding mutant PHOX2B in the nucleolar compartment.