P083 Sleep disordered breathing in Joubert syndrome

Joubert syndrome (JS) is an autosomal recessive disorder with a distinctive mid-hindbrain malformation known as the "molar tooth sign" which involves the breathing control center and its connections with other structures. Literature has reported significant respiratory abnormalities which included hyperpnea interspersed with apneic episodes during wakefulness. Larger-scale studies looking at polysomnographic findings or subjective reports of sleep problems in this population have not yet been published. The primary objectives were (1) compare a large group of children with JS and their unaffected siblings for caregiver-reported sleep difficulties. Secondary objectives were (1) present new polysomnography (PSG) data on our JS cohort; (2) review sleep disordered breathing (SDB) in other rare congenital hindbrain anatomic abnormalities. We conducted a cross-sectional study on a cohort of 109 families affected by JS. Pediatric Sleep Questionnaire (PSQ) and the Children's Sleep Habits Questionnaire (CSHQ) along with general medical health information focused on respiratory and sleep problems were mailed to all patients and families. Caregivers were asked to complete the survey for both children with JS and unaffected siblings, if any. Baseline diagnostic PSG was retrospectively reviewed for those with available studies, and the sleep parameters were compared to a referent cohort. Study participants with JS were older than their unaffected siblings (p = 0.02). Genetic mutations were available for 41 out of 118 individuals, with the most common mutation being MKS3 (31.4%). Patients with JS had higher scores in the PSQ compared to their unaffected siblings (p < 0.001). PSG data showed severe SDB with apnea-hypopnea index (AHI) of 23 ± 15 events/h in patients with JS. Events were primarily obstructive (obstructive AHI 18 ± 15 events/h vs central AHI 4 ± 4 events/h). Abnormal sleep architecture with increased arousal indices, decreased efficiency, and more time awake and in light sleep or wakefulness when compared to the referent data. SDB is common and severe in patients with JS, and the significantly greater obstructive component reported in this cohort makes it necessary to perform complete PSG studies to address or prevent clinical manifestations in this at-risk population. PSQ could represent a viable method to screen for SDB in JS.

Joubert syndrome is an autosomal-recessive disorder characterized by cerebellar hypoplasia, hypotonia, developmental delay, abnormal respiratory patterns, and abnormal eye movements. The biochemical and genetic basis of Joubert syndrome is unknown and a specific chromosomal locus for this disorder has not been identified. Review of this disorder and related syndromes suggests that (1) hypoplasia of the cerebellar vermis in Joubert syndrome is frequently associated with a complex brain stem malformation represented as the "molar tooth sign" on magnetic resonance imaging, (2) the "molar tooth sign" could be present in association with the Dandy-Walker malformation and occipital encephalocele, (3) cerebellar hypoplasia is present in conditions related to Joubert syndrome such as Arima syndrome; Senior-Loken syndrome; cerebellar vermian hypoplasia, oligophrenia, congenital ataxia, coloboma, and hepatic fibrosis syndrome; and juvenile nephronophthisis due to NPH1 mutations, and (4) the brainstem-vermis malformation spectrum is probably caused by at least two and probably several genetic loci. We have ascertained previously a cohort of 50 patients with a putative diagnosis of Joubert syndrome in order to evaluate the presence of associated malformations, and to initiate studies leading to the identification of genes causing Joubert and related syndromes. Among the associated malformations found in patients ascertained as having Joubert syndrome, 8% of patients had polydactyly, 4% had ocular colobomas, 2% had renal cysts, and 2% had soft-tissue tumors of the tongue. The WNT1 gene has been tested as a candidate gene for Joubert syndrome based on its expression in the developing cerebellum and an associated mutation in the swaying mouse. A search for mutations in WNT1 in a series of patients with Joubert syndrome did not detect mutations at this locus. This analysis suggested that mutations in WNT1 might not have a significant role in Joubert syndrome, and other functional candidate genes related to development of the cerebellum need to be examined. A genome-wide linkage analysis carried out in 10 Joubert syndrome pedigrees did not identify a specific chromosomal locus for this disorder. This observation, along with those from clinical studies, provides further evidence that Joubert and related syndromes are genetically heterogeneous.

Individuals with Duchenne muscular dystrophy (DMD) frequently develop sleep-disordered breathing. Noninvasive ventilation is often prescribed for sleep-disordered breathing treatment based on the American Academy of Sleep Medicine (AASM) criteria. In 2018, DMD disease-specific criteria for sleep-disordered breathing were established. Our study aimed to examine the clinical interpretation differences using these different criteria. We performed a multicenter, retrospective chart review of children with DMD followed at The Hospital for Sick Children, Toronto, Canada, and Rady Children's Hospital, San Diego, California, who underwent polysomnography from August 1, 2012, to February 29, 2020. Baseline characteristics and polysomnography data were summarized using descriptive statistics. Agreement for the diagnosis of sleep-disordered breathing evaluated by kappa statistics and sensitivity/specificity analysis was assessed. One hundred five male children with DMD (mean ± SD age: 12.1 ± 3.8 years; body mass index z score: 0.2 ± 2.3) were included. The proportions of children with DMD that met at least 1 AASM criterion and at least 1 DMD criterion were 45.7% and 67.6%, respectively. We found that 32.4% of children met neither AASM nor DMD criteria. Overall agreement between AASM and DMD criteria was moderate (k = 0.57). There was almost perfect agreement in sleep apnea diagnosis (k = 0.90); however, there was only slight agreement in hypoventilation diagnosis (k = 0.12) between AASM and DMD criteria. There were more children with DMD diagnosed with nocturnal hypoventilation and prescribed noninvasive ventilation using DMD criteria compared with AASM criteria. Future studies should address whether the prescription of noninvasive ventilation for children with DMD based on both criteria is associated with different clinical outcomes. Hurvitz MS, Sunkonkit K, Massicotte C, Li R, Bhattacharjee R, Amin R. Characterization of sleep-disordered breathing in children with Duchenne muscular dystrophy by the American Academy of Sleep Medicine criteria vs disease-specific criteria: what are the differences? J Clin Sleep Med. 2022;18(2):609-615.

Joubert syndrome (JS) is an autosomal recessive or X‐linked congenital cerebellar ataxia characterised by a peculiar hindbrain–midbrain malformation, the ‘molar tooth sign’ (MTS). JS is characterised by neonatal hypotonia which later evolves into ataxia, developmental delay, abnormal eye movements, breathing abnormalities and intellectual disability. This neurological presentation can be variably complicated by the involvement of multiple organs such as the kidneys, retina, liver and skeleton. JS is genetically heterogeneous, with 26 causative genes identified to date. All genes encode for proteins of the primary cilium, a nearly ubiquitous subcellular organelle that plays essential roles in embryonic development and cell functioning. Indeed, JS is part of ciliopathies, an expanding group of disorders that share many clinical and genetic determinants. The marked clinical and genetic heterogeneity of JS and ciliopathies may be explained by oligogenic inheritance and the existence of genetic modifiers. Key Concepts: Joubert syndrome (JS) is a congenital ataxia with autosomal or X‐linked recessive inheritance. The diagnostic hallmark of JS is a peculiar cerebellar and brainstem malformation, the so‐called ‘molar tooth sign’ recognisable on brain imaging. Neurological features of JS include hypotonia, ataxia, developmental delay, intellectual impairment, oculomotor abnormalities and alterations of the breathing pattern in neonatal age. JS may present with variable involvement of the eyes, kidneys, liver, polydactyly and oral‐facial defects. JS is genetically heterogeneous, with 26 genes identified to date, that are overall responsible of about half cases. JS pathogenesis is related to the dysfunction of the primary cilium, making JS part of the expanding group of ‘ciliopathies’. The primary cilium is an immotile organelle, located of the surface of nearly every cell type, that plays key roles in cellular functioning and embryonic development. Ciliopathies are characterised by wide clinical and genetic heterogeneity, and present significant clinical and genetic overlap among distinct conditions. Such complexity has been partly explained by showing oligogenic inheritance and the existence of genetic modifiers of the phenotype.

Chiari malformation Type I (CM-I) has been associated with sleep disordered breathing (SDB). The aim of this study was to evaluate the prevalence of SDB in CM-I and its clinical correlates in a population of children and adolescents. Fifty-three consecutive children and adolescents affected by CM-I were enrolled (27 girls and 26 boys, mean age 10.3 ± 4.3, range: 3-18 years). All patients underwent neurological examination, MRI, and polysomnography (PSG). Otorhinolaryngologic clinical evaluation was performed in patients with polysomnographic evidence of sleep-related upper airway obstruction. Mean size of the herniation was 9.5 ± 5.4 mm. Fourteen patients had syringomyelia, 5 had hydrocephalus, 31 presented neurological signs, 14 had epileptic seizures, and 7 reported poor sleep. PSG revealed SDB in 13 subjects. Patients with SDB, compared to those without SDB, had a higher prevalence hydrocephalus (p = 0.002), syringomyelia (p = 0.001), and neurological symptoms (p = 0.028). No significant difference was observed in age, gender, prevalence of epilepsy, and size of the herniation. Obstructive SDB was associated with syringomyelia (p = 0.004), whereas central SDB was associated with hydrocephalus (p = 0.034). In our population of CM-I patients the prevalence of SDB was 24%, lower than that reported in literature. Moreover, our findings suggest that abnormalities in cerebrospinal fluid dynamics in CM-I, particularly syringomyelia and hydro-cephalus, are associated with SDB.

(1) To assess the predictors for obtaining polysomnography (PSG) in children undergoing adenotonsillectomy (AT) for sleep-disordered breathing, and (2) to estimate the adherence to the American Academy of Otolaryngology-Head and Neck Surgery (AAO-HNS) guideline recommendations for pre-AT PSG. This was a retrospective cohort study of children who were seen in the Pediatric Otolaryngology Clinic and underwent AT for sleep-disordered breathing over a 13-month period at a single tertiary care children's hospital. Patients with and without pre-AT PSG were compared using bivariate and logistic regression analysis to identify predictors for PSG. Electronic medical records were reviewed for demographic variables, medical comorbidities, and PSG data. Adherence to AAO-HNS guideline recommendations was estimated by calculating the proportion of patients who had a PSG among those who met the recommended criteria for pre-AT PSG. Mean age was 6.6 ± 3.6 years with 53% male. A total of 65 of 324 children (20%) underwent PSG prior to AT. The only factor significantly associated with pre-AT PSG was age 1 to 3 years (odds ratio 4.5, 95% confidence interval [2.2, 9.0], P < .001). Among patients who met AAO-HNS criteria for pre-AT PSG, 28 of 128 (20%) underwent PSG compared to 35 of 186 (19%) who did not meet criteria (odds ratio 1.0, 95% confidence interval [0.6, 1.9], P = .87). Among children who underwent AT, the only significant predictor of obtaining pre-AT PSG was age 1 to 3 years. The rate of adherence to the AAO-HNS guideline recommendations was low (20%), which represents an educational opportunity.

The aim of this study was to describe sleep-disordered breathing (SDB) and treatment in children with achondroplasia (ACH). A retrospective longitudinal study was conducted at the Sleep Unit, Hospital de Pediatría Garrahan. Children with ACH, aged 0 to 18 years, referred for SDB due to clinical symptoms or foramen magnum stenosis (FMS) with at least one polysomnography (PSG) between 2002 and 2019 were included in the study. The primary outcomes included SDB typification and therapeutic interventions. We included 89 patients; 79.7% had one PSG, 13.4% had two PSGs, and 5.6% had three PSGs. The first PSG confirmed SDB in 65.16% patients. Obstructive sleep apnea (OSA) was present in 59.6% patients, central sleep apnea (CSA) in 1.72% patients, OSA + CSA in 4.49% patients, and normal PSG in 34.83% patients. OSA was mild in 32.07% patients, moderate in 18.86% patients, and severe in 49.05% patients. Clinical and airway evaluation, central imaging, evoked potentials, and PSG were considered before each therapeutic decision. After the first PSG, patients received one or more treatments as needed: watchful waiting; nasal steroids; ear, nose, and throat surgery; foramen magnum decompression; and noninvasive ventilation. A second PSG was available in 18 patients and 72.22% had SDB. A third PSG was available in 10 patients and 77.8% had SDB. We reconfirm an elevated frequency of SDB in ACH children and underline the need for a multidisciplinary and stepwise longitudinal approach.

Key features of Joubert syndrome include developmental delay, hypotonia, hyperpnea and apnea, oculomotor apraxia, and the presence of the molar tooth sign on axial imaging through the brainstem isthmus--the junction of the pons and mesencephalon. Interestingly, 1 in 10 patients with Joubert syndrome has abnormal cerebrospinal fluid collections misdiagnosed as Dandy-Walker variants. Because of important differences in patient management, genetic counseling, and prognosis between these conditions, we undertook a study to determine if the brainstem isthmus is normal in Dandy-Walker syndrome. Using standard landmarks, we evaluated development of the isthmus in normal subjects and in subjects with Joubert syndrome and Dandy-Walker syndrome. Four of five brainstem measures increased with age in normal subjects. In subjects with Joubert syndrome, the depth and length of the interpeduncular fossa were increased, and the width of the isthmus was decreased. In subjects with Dandy-Walker syndrome, the width of the brainstem isthmus was normal, and the molar tooth sign was absent. Although the pons can be hypoplastic in Dandy-Walker syndrome, we conclude that the pontomesencephalic junction is normal. Thus, the molar tooth sign can effectively distinguish between Joubert and Dandy-Walker syndromes. Genetic heterogeneity or epigenetic factors may account for abnormal cerebrospinal fluid collections in some cases of Joubert syndrome.

Acute and Chronic Respiratory Failure in Patients With Obesity-Hypoventilation Syndrome: A New Challenge for Noninvasive Ventilation

Introduction Joubert syndrome is an autosomal recessive heterogenous ciliopathy characterized by cerebellar vermis hypoplasia resulting in ataxia, hypotonia, developmental delay, neonatal respiratory dysregulation, and abnormal eye movements. It is typically accompanied by the pathognomonic “molar tooth sign” on brain MRI. Primary central sleep apnea has been described in case reports about this condition, however given the rarity of this disease, there are very few studies conducted on these patients. Our goal is to share our treatment approaches for the sleep disturbances seen in these patients. Report of case(s) A 6-year-old female from Kuwait with a history of Joubert syndrome and global development delay presented at UCMC for evaluation of sleep issues. During the history taking, patient’s mother reported that the patient was born with acute respiratory failure shortly and required CPAP therapy in the NICU. She later developed tachypnea and cyanosis during feedings, which prompted further evaluation. A subsequent brain MRI demonstrated a molar tooth sign consistent with Joubert Syndrome. Patient required supplemental oxygenation due to nocturnal desaturations found on pulse oximetry. Due to persistent apneas and chokings during sleep, the patient underwent a repeat diagnostic polysomnogram with an electroencephalogram at our institution demonstrating severe central sleep apnea most predominant during NREM sleep. An extended montage of the EEG did not show any epileptiform discharge. This was followed by a mask de-sensitization and an inpatient PAP titration study during which BPAP therapy ST mode with a backup rate of 8 breath/minute successfully treated the patient’s primary central sleep apnea. Patient also underwent a multidisciplinary consultation with PM&amp;R, speech therapy and ophthalmology due to her ataxia, speech delay, and need to assess for retinal dystrophy, respectively. Conclusion Sleep disordered breathing in the neonatal period is an early presentation in Joubert syndrome with central sleep apnea being the primary sleep disordered breathing. Fortunately, the clinical course of sleep disordered breathing does improve with treatment overtime, as in our case. Treatment options include conservative treatment, oxygen supplementation or PAP therapy. In our case, BPAP with ST mode was the most effective modality despite the need for mask desensitization and initial hesitation with using a PAP device. Support (if any)

The Cerebellum and Cerebellar Disorders

Missense mutations in AHI1 result in the neurodevelopmental ciliopathy called Joubert syndrome. Mutations in AHI1 decrease cilia formation, alter its localization and stability, and change its binding to HAP1 and NPHP1. Mutations in AHI1 affect ciliogenesis, AHI1 protein localization, and AHI1-protein interactions. This study begins to describe how missense mutations in AHI1 can cause Joubert syndrome. Mutations in AHI1 cause Joubert syndrome (JBTS), a neurodevelopmental ciliopathy, characterized by midbrain-hindbrain malformations and motor/cognitive deficits. Here, we show that primary cilia (PC) formation is decreased in fibroblasts from individuals with JBTS and AHI1 mutations. Most missense mutations in AHI1, causing JBTS, occur in known protein domains, however, a common V443D mutation in AHI1 is found in a region with no known protein motifs. We show that cells transfected with AHI1-V443D, or a new JBTS-causing mutation, AHI1-R351L, have aberrant localization of AHI1 at the basal bodies of PC and at cell-cell junctions, likely through decreased binding of mutant AHI1 to NPHP1 (another JBTS-causing protein). The AHI1-V443D mutation causes decreased AHI1 stability because there is a 50% reduction in AHI1-V443D protein levels compared with wild type AHI1. Huntingtin-associated protein-1 (Hap1) is a regulatory protein that binds Ahi1, and Hap1 knock-out mice have been reported to have JBTS-like phenotypes, suggesting a role for Hap1 in ciliogenesis. Fibroblasts and neurons with Hap1 deficiency form PC with normal growth factor-induced ciliary signaling, indicating that the Hap1 JBTS phenotype is likely not through effects at PC. These results also suggest that the binding of Ahi1 and Hap1 may not be critical for ciliary function. However, we show that HAP1 has decreased binding to AHI1-V443D indicating that this altered binding could be responsible for the JBTS-like phenotype through an unknown pathway. Thus, these JBTS-associated missense mutations alter their subcellular distribution and protein interactions, compromising functions of AHI1 in cell polarity and cilium-mediated signaling, thereby contributing to JBTS.

To study the clinical and genetic features of Joubert syndrome (JS) in children. A retrospective analysis was performed on the clinical data, genetic data, and follow-up data of 20 children who were diagnosed with JS in the Department of Children's Rehabilitation, the Third Affiliated Hospital of Zhengzhou University, from January 2017 to July 2022. Among the 20 children with JS, there were 11 boys and 9 girls. The common clinical manifestations were developmental delay (20 children, 100%), abnormal eye movement (19 children, 95%), and hypotonia (16 children, 80%), followed by abnormal respiratory rhythm in 5 children (25%) and unusual facies (including prominent forehead, low-set ears, and triangular mouth) in 3 children (15%), and no limb deformity was observed. All 20 children (100%) had the typical "molar tooth sign" and "midline cleft syndrome" on head images, and 6 children (30%) had abnormal eye examination results. Genetic testing was performed on 7 children and revealed 6 pathogenic genes, i.e., the CPLANE1, RPGRIP1L, MKS1, CC2D2A, CEP120, and AHI1 genes. For children with developmental delay, especially those with abnormal eye movement and hypotonia, it is recommended to perform a head imaging examination to determine the presence or absence of "molar tooth sign" and "midline cleft syndrome", so as to screen for JS to avoid missed diagnosis and misdiagnosis. There are many pathogenic genes for JS, and whole-exome sequencing can assist in the diagnosis of JS.

Joubert syndrome (JBTS) is a clinically and genetically heterogeneous group of ciliopathy with a key diagnostic feature of 'molar tooth sign' in brain MRI. So far, over 20 causative genes have been identified, but only one gene (OFD1) results in X-linked Joubert syndrome 10 (JBTS10). Six mutations in the OFD1 gene have been found to cause JBTS10. In this study, we identified a novel OFD1 mutation of c.2843_2844 delAA (p.Lys948ArgfsX) in a 3-month-old boy with a 'molar tooth sign' and clinical features of JBTS using targeted exome next-generation sequencing. The de-novo OFD1 mutation in exon 21 leads to a frameshift mutation generating a prematurely truncated protein and is predicted to partly reduce the function of the OFD1 protein. Our study expands the genotype-phenotype spectrum in JBTS and will have applications in prenatal and early diagnosis of the disorder. This is the first report of the OFD1 mutation causing JBTS in a Chinese population.

Joubert syndrome (JS) is an autosomal recessive disorder, which is characterized by hypotonia, ataxia, psychomotor delay, and variable occurrences of oculomotor apraxia and neonatal breathing abnormalities. JS is clinically and genetically heterogeneous. The present study investigated a typical JS family. The 'molar tooth sign' was observed in the proband through magnetic resonance imaging. Other symptoms of JS include cerebellar vermis hypoplasia/dysplasia, oculomotor apraxia and intellectual disability. High‑throughput sequencing revealed that JS was caused by coiled‑coil and C2 domain containing 2A (CC2D2A) compound heterozygous mutations. One CC2D2A allele was affected with a missense mutation, c.2581G>A, which led to a p.Asp861Asn amino acid replacement. The other allele was affected with a c.2848C>T nonsense mutation, which resulted in a truncated CC2D2A protein (p.Arg950Ter). Both of these alterations are novel. Further investigation indicated that the proband's father was the c.2581G>A carrier, whereas the mother was the c.2848C>T carrier. These results indicated that JS in the proband was caused by novel compound heterozygous mutations in CC2D2A, which were inherited from both parents. These findings may be used to establish prenatal molecular diagnostic criteria, which may be beneficial in future pregnancies.