CAPOS Syndrome Research Articles

CAPOS Syndrome with Fluctuating Symptoms

AbstractWe report a patient with CAPOS syndrome (Cerebellar ataxia, Areflexia, Pes cavus, Optic atrophy, and Sensorineural hearing loss) with classic features who also exhibited fluctuating vestibulocochlear symptoms that met the criteria for Meniere's disease. A male patient was initially symptomatic at 13 months of age with ataxia and loss of deep tendon reflexes in the setting of fever. This was followed by the development of baseline ataxia with superimposed spells of vertigo and ataxia, progressive hearing loss with episodic fluctuations, optic atrophy, pes cavus, and areflexia. Spells lasted minutes to hours and were frequently triggered by ambient heat and fever. He was diagnosed with a de novo pathogenic variant p.Glu818Lys mutation in ATP1A3. We provide detailed clinical features of this case, a summary of CAPOS cases reported to date, and an overview of allelically related syndromes.

Bilateral sequential cochlear implantation in a patient with the CAPOS syndrome – postsynaptic auditory neuropathy related toa missense mutation within the ATP1A3 gene

ntroduction: This paper presents a boy with CAPOS syndrome (Cerebellar ataxia, Areflexia, Pes calvus, Optic atrophy, Sensorineural hearing loss) and postsynaptic auditory neuropathy who underwent bilateral, sequential cochlear implantation. Aim: The aim of the study is to describe the development of communication skills after bilateral cochlear implantation in a child with multiple disabilities including profound hearing loss and vision impairment. Material and methods: The patient’s medical history, including the results of diagnostic tests is presented. Sequential, bilateral cochlear implantation was performed at the age of 7 (right ear) and 8 years (left ear). Results: The results of audiometric tests confirmed postsynaptic auditory neuropathy. Molecular testing revealed a diseasecausing heterozygous c.3007C>A variant in the ATP1A3 gene encoding the Na+/K+ ATPase. 14 months after surgery, the ability to speak had not been regained, but the patient was able to distinguish the environmental sounds. Conclusions: Cochlear implantation is recommended for patients with CAPOS syndrome. The development of communication skills improved the functioning of the child in the family and school environment. Meaning: The results observed in the presented patient differ from the results achieved by patients with cochlear hearing loss and presynaptic neuropathies, but indicate the validity of bilateral cochlear implantation in patients with postsynaptic neuropathy in the CAPOS syndrome.

ATP1A3-related disorders in the differential diagnosis of acute brainstem and cerebellar dysfunction.

Alternating Hemiplegia of Childhood (AHC), Rapid-onset Dystonia-Parkinsonism (RDP), and CAPOS syndrome (Cerebellar ataxia, Areflexia, Pes cavus, Optic atrophy, and Sensorineural hearing loss) are all caused by mutations in the same gene: ATP1A3. Although initially they were considered separate disorders, recent evidence suggests a continuous clinical spectrum of ATP1A3-related disorders. At onsetall these disorders can present with acute brainstem dysfunction triggered by a febrile illness. An infectious or autoimmune disorder is usually suspected. A genetic disorder is rarely considered in the first acute episode. We present three patients with ATP1A3 mutations: one patient with AHC, one patient with RDP, and one patient with CAPOS syndrome. We describe the acute onset and overlapping clinical features of these three patients with classical phenotypes. These cases highlight ATP1A3-related disorders as a possible cause of acute brainstem dysfunction with normal ancillary testing.

Impact of structured physical therapy intervention on functional recovery in a patient with CAPOS syndrome: a case report

BackgroundCAPOS syndrome (cerebellar ataxia, areflexia, pescavus, optic atrophy, and sensorineural hearing loss) is a rare congenital autosomal dominant disorder. The resulting neurological sequelae of impairments are progressive in nature and may interfere with functional independence, performing activities of daily living (ADL’s), and subsequently, affecting the quality of life (QOL). Since it is an extremely rare disorder, there is a severe dearth in the literature about how specific physiotherapy interventions may affect their functional status. Therefore, our objective was to investigate the effects of proprioceptive neuromuscular facilitation (PNF) and Frenkel’s coordination exercises on functional recovery in a patient with CAPOS syndrome.Case presentationWe herein present a case of a 25-year-old Indian male with complaints of generalized body weakness, difficulty visualizing distant objects, nystagmus, progressive sensorineural deafness, and ataxia. He was rehabilitated with a structured/customized physiotherapy protocol consisting of PNF approach and coordination exercises for 4 weeks, 6 days/week, 60 min daily. An improvement in overall functional performance of patient as per post-intervention scores of manual muscle testing, trunk control measurement scale, functional independence measure (components of self-care, transfers, and locomotion), and decline in severity of ataxia on scale for assessment and rating of ataxia scale was observed.ConclusionPNF and Frenkel’s exercises resulted in an improvement in overall functional performance of the patient. Improvement was observed in post-test scores of Manual Muscle Testing (MMT), Trunk Control Measurement Scale (TCMS), and Functional Independence Measure (FIM) for the components of self-care, transfers, and locomotion. Additionally, results also showed a decline in severity of ataxia on post-test scores of scale for the assessment and rating of ataxia (SARA) scale (i.e., from severe to moderate).

ATP1A3-Related Disorders: An Ever-Expanding Clinical Spectrum.

The Na+/K+ ATPases are Sodium-Potassium exchanging pumps, with a heteromeric α-β-γ protein complex. The α3 isoform is required as a rescue pump, after repeated action potentials, with a distribution predominantly in neurons of the central nervous system. This isoform is encoded by the ATP1A3 gene. Pathogenic variants in this gene have been implicated in several phenotypes in the last decades. Carriers of pathogenic variants in this gene manifest neurological and non-neurological features in many combinations, usually with an acute onset and paroxysmal episodes triggered by fever or other factors. The first three syndromes described were: (1) rapid-onset dystonia parkinsonism; (2) alternating hemiplegia of childhood; and, (3) cerebellar ataxia, pes cavus, optic atrophy, and sensorineural hearing loss (CAPOS syndrome). Since their original description, an expanding number of cases presenting with atypical and overlapping features have been reported. Because of this, ATP1A3-disorders are now beginning to be viewed as a phenotypic continuum representing discrete expressions along a broadly heterogeneous clinical spectrum.

A CAPOS syndrome patient presenting a good clinical course regarding recurrent acute encephalopathy and acute cerebellar ataxia attacks after acetazolamide treatment

A CAPOS syndrome patient presenting a good clinical course regarding recurrent acute encephalopathy and acute cerebellar ataxia attacks after acetazolamide treatment

ATP1A3 mutation presenting as CAPOS syndrome + dystonia phenotype

ATP1A3 mutation presenting as CAPOS syndrome + dystonia phenotype

CAPOS Syndrome: A Rare ATP1A3-Related Disorder.

CAPOS Syndrome: A Rare ATP1A3-Related Disorder.

Fever-related ataxia: a case report of CAPOS syndrome

BackgroundCAPOS (Cerebellar ataxia, Areflexia, Pes cavus, Optic atrophy and Sensorineural hearing loss) syndrome is caused by the heterozygous mutation, c.2452G > A, in the ATP1A3 gene. Other mutations in this gene can cause a spectrum of overlapping phenotypes including alternating hemiplegia of childhood, rapid onset dystonia parkinsonism, early infantile epileptic encephalopathy and fever induced paroxysmal weakness and encephalopathy. The phenotype is still mistaken for mitochondrial/metabolic disorders and follow up studies are scare.Case presentationWe report a 20 year old Norwegian male with ataxia, sensorineural deafness and visual loss. Before the age of five he experienced three fever related episodes of acute neurological deterioration when he temporarily lost his acquired motor skills and developed persistent gait and limb ataxia. In childhood, he developed bilateral optic atrophy and bilateral sensorineural hearing loss. Motor skills improved and at age 20 the patient showed a mild ataxia, hearing loss and reduced vision. A c.2452G > A mutation in the ATP1A3 gene was identified and CAPOS syndrome was confirmed.ConclusionsThis is the first Norwegian patient reported with CAPOS syndrome. Our patient had a de novo, previously identified ATP1A3 mutation. The combination of recurrent episodes of fever related ataxia, loss of motor skills in early childhood, and early onset hearing and vision loss is typical of CAPOS syndrome. Previous reports suggest a gradual progression of the disease after the initial episodes, while this patient showed a good outcome with improvement of motor skills from adolescence long after the last deterioration episode.

Cochlear Implantation in a Case of Auditory Neuropathy Spectrum Disorder with CAPOS Syndrome

Auditory neuropathy spectrum disorder (ANSD) is a hearing disorder which characterized with normal outer hair cell function but disrupted neural synchrony in the afferent auditory pathway. CAPOS (cerebellar ataxia, areflexia, pes cavus, optic atrophy, and sensorineural hearing loss) syndrome can manifest itself with ANSD and this rare situation and audiological rehabilitation outcomes have not well documented in the literature. We aim to present a cochlear implant user subject with CAPOS syndrome and ANSD. A 14-year-old girl diagnosed with ANSD and CAPOS syndrome. She received unilateral cochlear implant (CI). Her hearing sensitivity and speech perception abilities have been improved with CI. Also, she has a good music perception ability measured with the Turkish version of Clinical Assessment of Music Perception Test. After detailed audiological evaluations, CI could be a good option for patients who have ANSD and CAPOS syndrome.

Findings from aetiological investigation of Auditory Neuropathy Spectrum Disorder in children referred to cochlear implant programs

ObjectivesAuditory neuropathy spectrum disorder (ANSD) is an audiological diagnosis characterised by hearing dysfunction in the presence of intact outer hair cell function in the cochlea. ANSD is thought to account for 7–10% of all childhood permanent hearing impairment, and can result from a range of pathological processes. This paper describes the rationale, methods and findings from the aetiological investigation of ANSD. MethodsRetrospective audit of four cochlear implant programmes. Results97 patients were identified. 79% of patients were identified before the age of one. Prematurity and jaundice were the most frequently identified aetiological factors. 33 patients had cochlear nerve deficiency on imaging. Genetic diagnoses identified included otoferlin, SX010 gene, connexin 26 and A1FM1 gene mutations. ANSD was seen in conjunction with syndromes including Kallman syndrome, CHARGE syndrome, X-linked deafness, SOTOS syndrome, Brown Vieletto Van Laere syndrome, and CAPOS syndrome. DiscussionWe present a two-level system of aetiological investigation that is clinically practical. Patients with ANSD sufficiently severe to consider cochlear implantation are generally identified at an early age. Aetiological investigation is important to guide prognosis and identify comorbidity. ConclusionPrematurity and jaundice are the most commonly identified aetiological factors in ANSD. Imaging findings identify crucial factors in a significant minority. An important minority may have genetic and syndromic diagnoses that require further management.

Cerebellar Ataxia with Progressive Optic Atrophy and Deafness (CAPOS Syndrome): A Rare Case Report

CAPOS syndrome (cerebellar ataxia, areflexia, pes cavus, optic atrophy, sensorineural hearing loss) is a rare autosomal dominant disorder caused by ATP1A3 mutation. Fever triggered cerebellar dysfunction along with progressive optic atrophy and sensorineural deafness are typical features. Herein, we report a 20-year-old female with multiple fever induced cerebellar dysfunction with partial improvement. Pendular nystagmus and optic atrophy were prominent which were also present in patient’s younger sister. As there was progressive sensorineural hearing loss and areflexia, CAPOS syndrome was diagnosed. Though specific therapy is yet to be developed, acetazolamide, cochlear implantation, visual aid and family screening may improve quality of life. Bangladesh Journal of Neuroscience 2018; Vol. 34 (2): 110-114

The CAPOS mutation in ATP1A3 alters Na/K-ATPase function and results in auditory neuropathy which has implications for management.

Cerebellar ataxia, areflexia, pes cavus, optic atrophy and sensorineural hearing impairment (CAPOS) is a rare clinically distinct syndrome caused by a single dominant missense mutation, c.2452G>A, p.Glu818Lys, in ATP1A3, encoding the neuron-specific alpha subunit of the Na+/K+-ATPase α3. Allelic mutations cause the neurological diseases rapid dystonia Parkinsonism and alternating hemiplegia of childhood, disorders which do not encompass hearing or visual impairment. We present detailed clinical phenotypic information in 18 genetically confirmed patients from 11 families (10 previously unreported) from Denmark, Sweden, UK and Germany indicating a specific type of hearing impairment-auditory neuropathy (AN). All patients were clinically suspected of CAPOS and had hearing problems. In this retrospective analysis of audiological data, we show for the first time that cochlear outer hair cell activity was preserved as shown by the presence of otoacoustic emissions and cochlear microphonic potentials, but the auditory brainstem responses were grossly abnormal, likely reflecting neural dyssynchrony. Poor speech perception was observed, especially in noise, which was beyond the hearing level obtained in the pure tone audiograms in several of the patients presented here. Molecular modelling and in vitro electrophysiological studies of the specific CAPOS mutation were performed. Heterologous expression studies of α3 with the p.Glu818Lys mutation affects sodium binding to, and release from, the sodium-specific site in the pump, the third ion-binding site. Molecular dynamics simulations confirm that the structure of the C-terminal region is affected. In conclusion, we demonstrate for the first time evidence for auditory neuropathy in CAPOS syndrome, which may reflect impaired propagation of electrical impulses along the spiral ganglion neurons. This has implications for diagnosis and patient management. Auditory neuropathy is difficult to treat with conventional hearing aids, but preliminary improvement in speech perception in some patientssuggests that cochlear implantation may be effectivein CAPOS patients.

ATP1A3-related disorders: An update.

Alternating Hemiplegia of Childhood (AHC), Rapid-onset Dystonia Parkinsonism (RDP) and CAPOS syndrome (cerebellar ataxia, areflexia, pes cavus, optic atrophy, and sensorineural hearing loss) are three distinct, yet partially overlapping clinical syndromes that have long been thought to be allelic disorders. From 2004 to 2012, both autosomal dominant and de novo mutations in ATP1A3 have been detected in patients affected by these three conditions. Growing evidence suggests that AHC, RDP and CAPOS syndrome are part of a large and continuously expanding clinical spectrum and share some recurrent clinical features, such as abrupt-onset, asymmetric anatomical distribution and the presence of triggering factors, which are highly suggestive of ATP1A3 mutations. In this review, we will highlight the main clinical and genetic features of ATP1A3-related disorders focussing on shared and distinct features that can be helpful in clinical practice to individuate mutation carriers.

ATP1A3 mutations can cause progressive auditory neuropathy: a new gene of auditory synaptopathy

The etiologies and prevalence of sporadic, postlingual-onset, progressive auditory neuropathy spectrum disorder (ANSD) have rarely been documented. Thus, we aimed to evaluate the prevalence and molecular etiologies of these cases. Three out of 106 sporadic progressive hearing losses turned out to manifest ANSD. Through whole exome sequencing and subsequent bioinformatics analysis, two out of the three were found to share a de novo variant, p.E818K of ATP1A3, which had been reported to cause exclusively CAPOS (cerebellar ataxia, areflexia, pes cavus, optic atrophy, and sensorineural hearing loss) syndrome. However, hearing loss induced by CAPOS has never been characterized to date. Interestingly, the first proband did not manifest any features of CAPOS, except subclinical areflexia; however, the phenotypes of second proband was compatible with that of CAPOS, making this the first reported CAPOS allele in Koreans. This ANSD phenotype was compatible with known expression of ATP1A3 mainly in the synapse between afferent nerve and inner hair cells. Based on this, cochlear implantation (CI) was performed in the first proband, leading to remarkable benefits. Collectively, the de novo ATP1A3 variant can cause postlingual-onset auditory synaptopathy, making this gene a significant contributor to sporadic progressive ANSD and a biomarker ensuring favorable short-term CI outcomes.

CAPOS-Syndrome: A Rare Differential Diagnosis to Friedreich’s Ataxia

Background: Friedreich’s ataxia is the most common hereditary form of ataxia with an incidence of 1:50,000. Typical symptoms are ataxia, sensory neuropathy, scoliosis with further skeletal deformities, and cardiomyopathy. The disease is caused by a homozygote mutation of the frataxin gene on chromosome 9. A rare differential diagnosis in contrast to the above mentioned is the CAPOS syndrome with an incidence of 1:1,000,000. This syndrome shows likewise a progressive cerebellar ataxia, areflexia, progressive atrophy of the optic nerve, sensory-neural deafness, as well as foot abnormalities. Remarkable is the aggravation of cerebellar ataxia which can be triggered by infections. The etiology of this syndrome is not fully understood yet; few affected families show a mutation in the ATP1A3-gene.

Deficits in social behavioral tests in a mouse model of alternating hemiplegia of childhood

Social behavioral deficits have been observed in patients diagnosed with alternating hemiplegia of childhood (AHC), rapid-onset dystonia-parkinsonism and CAPOS syndrome, in which specific missense mutations in ATP1A3, encoding the Na+, K+-ATPase α3 subunit, have been identified. To test the hypothesis that social behavioral deficits represent part of the phenotype of Na+, K+-ATPase α3 mutations, we assessed the social behavior of the Myshkin mouse model of AHC, which has an I810N mutation identical to that found in an AHC patient with co-morbid autism. Myshkin mice displayed deficits in three tests of social behavior: nest building, pup retrieval and the three-chamber social approach test. Chronic treatment with the mood stabilizer lithium enhanced nest building in wild-type but not Myshkin mice. In light of previous studies revealing a broad profile of neurobehavioral deficits in the Myshkin model – consistent with the complex clinical profile of AHC – our results suggest that Na+, K+-ATPase α3 dysfunction has a deleterious, but nonspecific, effect on social behavior. By better defining the behavioral profile of Myshkin mice, we identify additional ATP1A3-related symptoms for which the Myshkin model could be used as a tool to advance understanding of the underlying neural mechanisms and develop novel therapeutic strategies.

CAPOS syndrome and hemiplegic migraine in a novel pedigree with the specific ATP1A3 mutation

ObjectiveIdentification and characterization of a novel pedigree with ATP1A3 mutations presenting with CAPOS syndrome and hemiplegic migraine. MethodsWe have carried out clinical examinations of a three-generation pedigree with CAPOS syndrome and analyzed the ATP1A3 gene to identify causative mutations. The pedigree is of Slavic origin from Southeastern Europe. ResultsThe clinical phenotype comprised cerebellar ataxia, areflexia, optic atrophy, and sensorineural hearing loss. Pes cavus was present in two of the four patients studied. The symptoms were triggered by fever and varied in severity in family members, exhibiting a chronic progressive course with or without relapses/remissions. The ATP1A3 c.2452G>A mutation was identified in the affected members of the family, while one of the mutation carriers exhibited both CAPOS and hemiplegic migraine. ConclusionsThis study confirms that the specific c.2452G>A mutation in the ATP1A3 gene is associated with the CAPOS syndrome in pedigrees of different ethnic backgrounds. In patients with febrile episodes of ataxic encephalopathy or weakness, or both, genetic analysis of the ATP1A3 gene should be warranted. This is also the first report showing the co-occurrence of hemiplegic migraine and CAPOS syndrome in a patient with ATP1A3 mutations. Migraine has not been previously documented in ATP1A3 mutation carriers.

Intermediate Phenotypes of ATP1A3 Mutations: Phenotype-Genotype Correlations.

BackgroundATP1A3-related disorders include rapid-onset dystonia–parkinsonism (RDP or DYT12), alternating hemiplegia of childhood (AHC), and CAPOS syndrome (Cerebellar ataxia, Areflexia, Pes cavus, Optic atrophy, and Sensorineural hearing loss).Case ReportWe report two cases with intermediate forms between RDP and AHC. Patient 1 initially presented with the AHC phenotype, but the RDP phenotype emerged at age 14 years. The second patient presented with levodopa-responsive paroxysmal oculogyria, a finding never before reported in ATP1A3-related disorders. Genetic testing confirmed heterozygous changes in the ATP1A3 gene in both patients, one of them novel.DiscussionIntermediate phenotypes of RDP and AHC support the concept that these two disorders are part of a spectrum. We add our cases to the phenotype–genotype correlations of ATP1A3-related disorders.

Intermediate Phenotypes of <i>ATP1A3</i> Mutations: Phenotype–Genotype Correlations

<strong>Background:</strong> <em>ATP1A3</em>-related disorders include rapid-onset dystonia–parkinsonism (RDP or DYT12), alternating hemiplegia of childhood (AHC), and CAPOS syndrome (Cerebellar ataxia, Areflexia, Pes cavus, Optic atrophy, and Sensorineural hearing loss). <strong>Case Report:</strong> We report two cases with intermediate forms between RDP and AHC. Patient 1 initially presented with the AHC phenotype, but the RDP phenotype emerged at age 14 years. The second patient presented with levodopa-responsive paroxysmal oculogyria, a finding never before reported in ATP1A3-related disorders. Genetic testing confirmed heterozygous changes in the <em>ATP1A3</em> gene in both patients, one of them novel. <strong>Discussion:</strong> Intermediate phenotypes of RDP and AHC support the concept that these two disorders are part of a spectrum. We add our cases to the phenotype–genotype correlations of <em>ATP1A3</em>-related disorders.