RESUMO
Cerebellar ataxia, areflexia, pes cavus, optic atrophy, and sensorineural hearing loss (CAPOS) syndrome (OMIM# 601338) is a rare autosomal dominant disorder characterized by episodic, fever-induced ataxic encephalopathy in childhood with residual symptoms. All identified patients have the same heterozygous missense variant c.2452G>A (p.Glu818Lys) in the ATP1A3 gene, encoding Na+ /K+ ATPase α3. We describe a large CAPOS pedigree with three generations of affected members, the first ascertained in the United States. Deafness, optic atrophy, and pes cavus were present in all three members of the family evaluated. In addition, one of the affected individuals experienced markedly worsening features during her three pregnancies and in the immediate postpartum period, a potential element of the natural history of CAPOS previously unreported. We conclude that the triggering factors and clinical spectrum of pathogenic ATP1A3 variants may be broader than previously described. Targeted sequencing of ATP1A3 should be considered in any patient presenting with cerebellar ataxia triggered by febrile illness, or pregnancy and delivery, especially in the presence of sensorineural hearing loss, optic atrophy, pes cavus, or early childhood history of acute encephalopathic ataxia. Prophylactic administration of acetazolamide or flunarizine may prevent acute episodes of ataxia or mitigate neurologic symptoms, although their efficacies have not been well studied.
Assuntos
Ataxia Cerebelar/diagnóstico , Ataxia Cerebelar/genética , Deformidades Congênitas do Pé/diagnóstico , Deformidades Congênitas do Pé/genética , Perda Auditiva Neurossensorial/diagnóstico , Perda Auditiva Neurossensorial/genética , Atrofia Óptica/diagnóstico , Atrofia Óptica/genética , Fenótipo , Complicações na Gravidez , Reflexo Anormal/genética , Alelos , Pré-Escolar , Feminino , Estudos de Associação Genética , Genótipo , Humanos , Lactente , Masculino , Linhagem , Gravidez , ATPase Trocadora de Sódio-Potássio/genéticaRESUMO
CAPOS syndrome is an autosomal dominant neurological disorder caused by mutations in the ATP1A3 gene. Initial symptoms, often fever-induced, include recurrent acute ataxic encephalopathy in childhood, featuring cerebellar ataxia, optic atrophy, areflflexia, sensorineural hearing loss, and in some cases, pes cavus. This report details a case of CAPOS syndrome resulting from a maternal ATP1A3 gene mutation. Both the child and her mother exhibited symptoms post-febrile induction,including severe sensorineural hearing loss in both ears, ataxia, areflexia, and decreased vision. Additionally, the patient's mother presented with pes cavus. Genetic testing revealed a c. 2452G>Aï¼Glu818Lysï¼ heterozygous mutation in theATP1A3 gene in the patient . This article aims to enhance clinicians' understanding of CAPOS syndrome, emphasizing the case's clinical characteristics, diagnostic process, treatment, and its correlation with genotypeic findings.
Assuntos
Ataxia Cerebelar , Deformidades Congênitas do Pé , Perda Auditiva Neurossensorial , Atrofia Óptica , Reflexo Anormal , Pé Cavo , Humanos , Criança , Feminino , Ataxia Cerebelar/genética , Ataxia Cerebelar/diagnóstico , Perda Auditiva Neurossensorial/genética , Perda Auditiva Neurossensorial/diagnóstico , Atrofia Óptica/genética , Atrofia Óptica/diagnóstico , Mutação , Fenótipo , ATPase Trocadora de Sódio-Potássio/genéticaRESUMO
CAPOS (cerebellar ataxia, areflexia, pes cavus, optic atrophy, and sensorineural hearing loss) syndrome is a rare genetic disorder caused by the heterozygous mutation, c.2452G > A, in the ATP1A3 gene. CAPOS syndrome involves a characteristic episode in which neuropathy develops after a fever in childhood, and here, we describe the case of a patient with CAPOS syndrome. The patient had repeated episodes of a fever around 74 months of age. Although he could speak at 23 months of age, he presented with hearing difficulty after the fever. Pure-tone audiometry revealed moderate-to-severe bilateral sensorineural hearing loss, and auditory brainstem response (ABR) showed poor response in the both ears. Auditory stead-state response (ASSR) produced relatively consistent results compared to pure-tone audiometry. A mutation in the ATP1A3 gene was detected through genetic testing. In CAPOS syndrome, a genetic mutation leads to desynchronization during neural firing. We believe that this desynchronization in neural firing is responsible for the lack of response in the ABR and the presence of a response in the ASSR. In this patient, we attribute the response detection in ASSR to its greater tolerance for errors in the timing of neural firing compared to ABR.
Assuntos
Audiometria de Tons Puros , Potenciais Evocados Auditivos do Tronco Encefálico , Perda Auditiva Neurossensorial , ATPase Trocadora de Sódio-Potássio , Humanos , Masculino , Perda Auditiva Neurossensorial/genética , ATPase Trocadora de Sódio-Potássio/genética , Febre , Atrofia Óptica/genética , Reflexo Anormal , Ataxia Cerebelar/genética , Ataxia Cerebelar/fisiopatologia , Deformidades Congênitas do Pé/genética , MutaçãoRESUMO
BACKGROUND: ATP1A3-related disorders are rare but increasingly recognized syndromes with overlapping phenotypes. CLINICAL OBSERVATIONS: A male child and his mother with c.2452G>A (p.Glu818Lys) mutation and an unrelated child with c.2428A>T (p.Ile810Phe) mutation in the ATP1A3 gene are reported. RESULTS: The first child presented with fever-induced flaccid unresponsiveness and the diagnosis was made after extensive negative workup except for abnormal EMG showing low amplitude motor responses with acute denervation; his symptomatic mother went undiagnosed for thirty years until his diagnosis. An unrelated male child presented with symptoms most consistent with the rapid-onset dystonia-Parkinsonism (RDP) phenotype but with intermediate features of alternating dystonia with choreoathetoid movements two years after a c.2428A>T (p.Ile810Phe) mutation was found. CONCLUSION: ATP1A3-related disorders have variable manifestations and can remain undiagnosed for decades. Treatment remains mostly supportive. With the increasing use of genetic testing for broad indications, further research into effective therapies is necessary.
Assuntos
Distonia , Distúrbios Distônicos , Humanos , Masculino , Mutação/genética , Fenótipo , ATPase Trocadora de Sódio-Potássio/genéticaRESUMO
Objective: The objective of this study is to analyze the genotype-phenotype correlation of patients with auditory neuropathy (AN), which is a clinical condition featuring normal cochlear responses and abnormal neural responses, and ATP1A3 c.2452 G > A (p.E818K), which has been generally recognized as a genetic cause of cerebellar ataxia, areflexia, pes cavus, optic atrophy, and sensorineural hearing loss (CAPOS) syndrome. Methods: Four patients diagnosed as AN by clinical evaluation and otoacoustic emission and auditory brainstem responses were recruited and analyzed by next-generation sequencing to identify candidate disease-causing variants. Sanger sequencing was performed on the patients and their parents to verify the results, and short tandem repeat-based testing was conducted to confirm the biological relationship between the parents and the patients. Furthermore, cochlear implantation (CI) was performed in one AN patient to reconstruct hearing. Results: Four subjects with AN were identified to share a de novo variant, p.E818K in the ATP1A3 gene. Except for the AN phenotype, patients 1 and 2 exhibited varying degrees of neurological symptoms, implying that they can be diagnosed as CAPOS syndrome. During the 15 years follow-up of patient 1, we observed delayed neurological events and progressive bilateral sensorineural hearing loss in pure tone threshold (pure tone audiometry, PTA). Patient 2 underwent CI on his left ear, and the result was poor. The other two patients (patient 3 and patient 4, who were 8 and 6 years old, respectively) denied any neurological symptoms. Conclusion: ATP1A3 p.E818K has rarely been documented in the Chinese AN population. Our study confirms that p.E818K in the ATP1A3 gene is a multiethnic cause of AN in Chinese individuals. Our study further demonstrates the significance of genetic testing for this specific mutation for identifying the special subtype of AN with somewhat favorable CI outcome and offers a more accurate genetic counseling about the specific de novo mutation.
RESUMO
The Na+/K+ ATPases are Sodium-Potassium exchanging pumps, with a heteromeric α-ß-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.
RESUMO
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 onset all 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.
Assuntos
Ataxia Cerebelar , Distúrbios Distônicos , Tronco Encefálico , Ataxia Cerebelar/diagnóstico , Ataxia Cerebelar/genética , Diagnóstico Diferencial , Distúrbios Distônicos/diagnóstico , Humanos , Mutação/genética , ATPase Trocadora de Sódio-Potássio/genéticaRESUMO
BACKGROUND: CAPOS (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 PRESENTATION: We 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. CONCLUSIONS: This 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.
RESUMO
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.
RESUMO
A 38-year-old female patient experienced recurrent episodes of neurological deterioration during febrile illness at the age of 7 and 8â¯months, and 2, 4, and 37â¯years. Acute symptoms comprised unconsciousness, headache, abnormal ocular movements, flaccid paralysis with areflexia, ataxia, dysphagia, and movement disorders. Each episode of neurological deterioration was followed by partial recovery with residual symptoms of progressive disturbance of visual acuity with optic atrophy and hearing loss, moderate intellectual disability, strabismus, ophthalmoplegia, as well as fluctuating degree of gait ataxia, chorea, tremor, and myoclonus. In addition, electrocardiography revealed incomplete right bundle branch block. The genetic testing revealed a de novo heterozygous mutation of c.2452Gâ¯>â¯A (p.Glu818Lys) in the ATP1A3 gene, which was compatible with the clinical phenotype of CAPOS (cerebellar ataxia, areflexia, pes cavus, optic atrophy, and sensorineural hearing loss)/CAOS syndrome. Here we discuss the significance of clinical features of a patient, overlapping with those of alternating hemiplegia of childhood, along with a literature review.
Assuntos
Ataxia Cerebelar/genética , Deformidades Congênitas do Pé/genética , Perda Auditiva Neurossensorial/genética , Mutação , Atrofia Óptica/genética , Reflexo Anormal/genética , ATPase Trocadora de Sódio-Potássio/genética , Adulto , Encéfalo/diagnóstico por imagem , Encéfalo/fisiopatologia , Ataxia Cerebelar/diagnóstico por imagem , Ataxia Cerebelar/tratamento farmacológico , Ataxia Cerebelar/fisiopatologia , Progressão da Doença , Feminino , Deformidades Congênitas do Pé/diagnóstico por imagem , Deformidades Congênitas do Pé/tratamento farmacológico , Deformidades Congênitas do Pé/fisiopatologia , Perda Auditiva Neurossensorial/diagnóstico por imagem , Perda Auditiva Neurossensorial/tratamento farmacológico , Perda Auditiva Neurossensorial/fisiopatologia , Humanos , Atrofia Óptica/diagnóstico por imagem , Atrofia Óptica/tratamento farmacológico , Atrofia Óptica/fisiopatologia , FenótipoRESUMO
BACKGROUND: CAPOS syndrome (cerebellar ataxia, areflexia, pes cavus, optic atrophy, and sensorineural hearing loss) is a rare disease that has been reported in 22 patients so far. In all cases, the mutation c.2452G>A (p.Glu818Lys) in the ATP1A3 gene was identified. Patients typically present at an early age with an acute-onset fever-induced episode of ataxia frequently associated with encephalopathy and weakness. They usually present one to three episodes. The acute symptoms improve within days, but most patients show slow progression afterward. METHODS: We describe three new patients, a woman and her two sons diagnosed with CAPOS syndrome. A systematic review of literature on previously reported patients was performed. RESULTS: The first son presented with acute-onset ataxia, encephalopathy, and sensorineural hearing loss, induced by febrile illness. The second one developed generalized areflexia and mild instability without an acute episode. The mother had been previously diagnosed with sensorineural hearing loss and optic nerve atrophy. The c.2452G>A mutation in ATP1A3 was found in all three patients. CONCLUSION: Only 25 Individuals with CAPOS syndrome have been reported, including our family. This is the first time a Spanish family has been described. The fact that both siblings were assessed before the first acute-onset episode contributes to the description of early symptoms and signs of the disease, which could aid early diagnosis and management before the onset of acute episodes.
Assuntos
Ataxia Cerebelar/diagnóstico , Deformidades Congênitas do Pé/diagnóstico , Perda Auditiva Neurossensorial/diagnóstico , Atrofia Óptica/diagnóstico , Adulto , Ataxia/diagnóstico , Ataxia/genética , Ataxia/fisiopatologia , Ataxia Cerebelar/genética , Ataxia Cerebelar/fisiopatologia , Criança , Diagnóstico Precoce , Família , Feminino , Deformidades Congênitas do Pé/genética , Deformidades Congênitas do Pé/fisiopatologia , Perda Auditiva Neurossensorial/genética , Perda Auditiva Neurossensorial/fisiopatologia , Humanos , Masculino , Atrofia Óptica/genética , Atrofia Óptica/fisiopatologia , Reflexo Anormal/genéticaRESUMO
BACKGROUND: The clinical syndrome of cerebellar ataxia, areflexia, pes cavus, optic atrophy, and sensorineural hearing loss (CAPOS) was first described 20 years ago, but it was only recently that whole exome sequencing unveiled the causative mutation in the ATP1A3 gene. We present four patients from the seventh and eighth family identified worldwide, provide a critical review of all patients published thus far, and speculate about the pathophysiologic processes underlying the acute neurological manifestations. CLINICAL OBSERVATIONS: The individuals presented here experienced one to three paroxysmal, short-lasting episodes in childhood with cerebellar symptoms and signs, hypotonia, ophthalmoparesis, motor weakness, areflexia, and/or lethargy that were consistently associated with febrile illness. An underlying c.2452G>A mutation in the ATP1A3 gene was found in all four individuals. Besides the persisting CAPOS features, other possibly related sequelae included dystonia, myoclonus, and emotional and behavioral changes. After initiation of acetazolamide in two patients, no further episodes occurred. CONCLUSION: Targeted sequencing of the ATP1A3 gene is recommended in children exhibiting paroxysmal, fever-induced ataxia and in adults with a more or less stationary or slowly progressive cerebellar syndrome since childhood accompanied by mixed combinations of areflexia, pes cavus, profound visual impairment, and/or sensorineural hearing loss. Similar to some other types of episodic ataxia, acetazolamide may be considered in patients with CAPOS syndrome to prevent or attenuate bouts of ataxia, but this requires further study.
Assuntos
Ataxia Cerebelar/genética , Deformidades Congênitas do Pé/genética , Perda Auditiva Neurossensorial/genética , Atrofia Óptica/genética , Mutação Puntual , Reflexo Anormal/genética , ATPase Trocadora de Sódio-Potássio/genética , Adulto , Criança , Pré-Escolar , Família , Feminino , Humanos , MasculinoAssuntos
Ataxia Cerebelar , Distonia , Deformidades Congênitas do Pé , Perda Auditiva Neurossensorial , Atrofia Óptica , Reflexo Anormal , ATPase Trocadora de Sódio-Potássio/genética , Adolescente , Ataxia Cerebelar/complicações , Ataxia Cerebelar/genética , Ataxia Cerebelar/fisiopatologia , Distonia/etiologia , Distonia/genética , Distonia/fisiopatologia , Feminino , Deformidades Congênitas do Pé/complicações , Deformidades Congênitas do Pé/genética , Deformidades Congênitas do Pé/fisiopatologia , Perda Auditiva Neurossensorial/complicações , Perda Auditiva Neurossensorial/genética , Perda Auditiva Neurossensorial/fisiopatologia , Humanos , Atrofia Óptica/complicações , Atrofia Óptica/genética , Atrofia Óptica/fisiopatologia , Fenótipo , Reflexo Anormal/genéticaRESUMO
BACKGROUND: ATP1A3 mutations have now been recognized in infants and children presenting with a diverse group of neurological phenotypes, including Rapid-onset Dystonia-Parkinsonism (RDP), Alternating Hemiplegia of Childhood (AHC), and most recently, Cerebellar ataxia, Areflexia, Pes cavus, Optic atrophy, and Sensorineural hearing loss (CAPOS) syndrome. METHODS: Existing literature on ATP1A3-related disorders in the pediatric population were reviewed, with attention to clinical features and associated genotypes among those with RDP, AHC, or CAPOS syndrome phenotypes. RESULTS: While classically defined phenotypes associated with AHC, RDP, and CAPOS syndromes are distinct, common elements among ATP1A3-related neurological disorders include characteristic episodic neurological symptoms and signs that vary in severity, duration, and frequency of occurrence. Affected children typically present in the context of an acute onset of paroxysmal, episodic neurological symptoms ranging from oculomotor abnormalities, hypotonia, paralysis, dystonia, ataxia, seizure-like episodes, or encephalopathy. Neurodevelopmental delays or persistence of dystonia, chorea, or ataxia after resolution of an initial episode are common, providing important clues for diagnosis. CONCLUSIONS: The phenotypic spectrum of ATP1A3-related neurological disorders continues to expand beyond the distinct yet overlapping phenotypes in patients with AHC, RDP, and CAPOS syndromes. ATP1A3 mutation analysis is appropriate to consider in the diagnostic algorithm for any child presenting with episodic or fluctuating ataxia, weakness or dystonia whether they manifest persistence of neurological symptoms between episodes. Additional work is needed to better identify and classify affected patients and develop targeted treatment approaches.