CAPOS syndrome

Key Points at a Glance

Highlights of This Disease

• CAPOS syndrome is a rare autosomal dominant disorder caused by mutations in the ATP1A3 gene.
• It is defined by five major signs: cerebellar ataxia, areflexia, pes cavus, optic atrophy, and sensorineural hearing loss.
• Acute attacks triggered by fever lead to gait disturbance, muscle weakness, and impaired consciousness.
• Neurological sequelae may persist after attacks and can worsen with each recurrence.
• No curative treatment has been established; management focuses on symptomatic therapy and avoiding triggers of fever.
• It is an ultra-rare disease with an estimated patient population of fewer than 1,000.
• It is important to differentiate from similar diseases caused by other mutations in the ATP1A3 gene (such as RECA/FIPWE).

1. What is CAPOS syndrome?

CAPOS syndrome is a rare neurological disease named after the initials of its five major signs.

• C: Cerebellar ataxia
• A: Areflexia
• P: Pes cavus
• O: Optic atrophy
• S: Sensorineural hearing loss

First reported by Nicolaides et al. in 1996. Three members of one family presented with early-onset cerebellar ataxia, progressive optic atrophy, areflexia, and pes cavus deformity, and it was described as a distinct syndrome. The number of patients worldwide is estimated to be less than 1,000, and as of 2020, only 33 cases have been reported in English literature. Symptoms may appear from infancy.

The causative gene is ATP1A3 (chromosome 19, 19q13), which encodes the α3 subunit of Na⁺/K⁺-ATPase. The disease spectrum due to ATP1A3 mutations includes, in addition to CAPOS, four phenotypes: rapid-onset dystonia-parkinsonism (RDP), alternating hemiplegia of childhood (AHC), and severe infantile epileptic encephalopathy. ¹⁾

Q How many patients have CAPOS syndrome?

A

The number of patients worldwide is estimated to be less than 1,000. As of 2020, only 33 cases have been reported in English literature, making it an extremely rare disease.

2. Main Symptoms and Clinical Findings

Subjective Symptoms

Acute attacks are triggered by fever or infection. The main symptoms during an attack are as follows:

• Gait disturbance (ataxia): Loss of motor coordination due to cerebellar inflammation.
• Muscle weakness: Weakness in the limbs
• Dysarthria: Difficulty speaking or slurred speech
• Dysphagia: Difficulty swallowing
• Impaired consciousness/seizures: In severe cases, may lead to coma
• Vision loss: Progressive decline due to optic atrophy
• Hearing loss: Presents as sensorineural hearing loss

Clinical Findings (5 Major Signs)

The five major signs of CAPOS syndrome are classified into three groups: nervous system, eyes, and ears/feet.

Nervous System

Cerebellar ataxia: Loss of coordination of muscle movements due to inflammation of the cerebellum. It appears paroxysmally and shows partial recovery.

Areflexia: Loss of deep tendon reflexes. It may also appear as hyporeflexia.

Eyes

Optic atrophy: Caused by the death of retinal ganglion cell axons. Leads to progressive vision loss.

Eye movement abnormalities: Nystagmus or strabismus may appear paroxysmally.

Ears and Feet

Sensorineural hearing loss: Hearing loss due to damage to the inner ear or auditory nerve.

Pes cavus: A foot deformity with an abnormally high arch.

Other findings include hypotonia or dystonia, myoclonus, bradykinesia, autistic behavior, intellectual disability, heart conduction block, and cognitive dysfunction.

Q What symptoms should be noted when an attack occurs?

A

If acute ataxia, muscle weakness, dysarthria, or dysphagia appear during fever, it may be an attack. If impaired consciousness or convulsions are also present, it is a severe case and prompt medical attention is necessary. For details, see the “Subjective Symptoms” section.

3. Causes and Risk Factors

CAPOS syndrome is caused by mutations in the ATP1A3 gene on chromosome 19 (19q13). This mutation causes dysfunction of the α3 polypeptide of Na⁺/K⁺-ATPase, distorting the electrochemical gradient across the cell membrane.

The inheritance pattern is autosomal dominant, with a 50% chance of a child inheriting the disease from an affected parent. However, it can also occur as a de novo mutation (new sporadic mutation), so a family history is not essential for diagnosis. Prenatal diagnosis is possible.

The main triggers for onset are as follows:

• Fever associated with infection: the most important trigger
• Childbirth: there are reports of delivery as a trigger

The α3 subunit is concentrated in GABAergic neurons (basal ganglia: striatum, globus pallidus, subthalamic nucleus, substantia nigra) and is involved in important circuits for fine motor control. ¹⁾

Daily Precautions

• Detect fever early and actively manage it with antipyretics.
• Ensure adequate hydration when fever occurs.
• Since neurological sequelae can worsen with each recurrence, it is important to avoid triggers (fever).

Q Can CAPOS syndrome occur even if no family member has it?

A

Yes, it is possible. CAPOS syndrome can occur as a de novo mutation (new sporadic mutation), so the diagnosis cannot be ruled out even without a family history. Although it is an autosomal dominant disorder, sporadic cases have been reported.

4. Diagnosis and Testing Methods

The diagnosis of CAPOS syndrome is based on a combination of clinical diagnosis using the five major signs (CAPOS) and genetic diagnosis by identifying ATP1A3 gene mutations.

Main Tests

• Genetic testing: Identify ATP1A3 mutations using whole exome sequencing (WES), etc. ²⁾
• Brain MRI: Usually normal, but cerebellar atrophy, corpus callosum hypoplasia, and anterior commissure hypoplasia were observed in 4/35 cases (11.4%) ¹⁾
• Cerebrospinal fluid analysis and metabolic screening: Usually normal. Used to rule out other diseases.
• Electroencephalography (EEG): Usually normal ²⁾

Differential Diagnosis

It is important to differentiate within the ATP1A3-related disease spectrum and from other diseases.

The differential diagnosis of the four ATP1A3-related phenotypes is shown below.

Disease	Main features	CAPOS-specific signs
CAPOS	Fever-induced ataxia, optic atrophy, hearing loss, pes cavus	Present (optic atrophy, hearing loss, pes cavus)
RECA/FIPWE (756 residue variant)	Fever-induced ataxia and hypotonia	None1)
AHC	Hemiplegic attacks, improvement with sleep, dystonia	None2)
RDP	Dystonia + parkinsonism, persistent	None2)

Other differential diagnoses include the following:

• Infectious encephalitis: Differentiation from acute neurological symptoms during fever is necessary²⁾
• Fisher syndrome: Triad of ataxia, areflexia, and external ophthalmoplegia. Anti-GQ1b antibody positivity >80%, cerebrospinal fluid albuminocytologic dissociation is characteristic
• Wolfram syndrome (DIDMOAD): juvenile-onset diabetes + optic atrophy + diabetes insipidus + hearing loss. WFS1 gene mutation
• ADOA (autosomal dominant optic atrophy): school-age onset. OPA1 gene mutation, acquired tritanopia

5. Standard treatment

No curative treatment has been established to date. Treatment focuses on symptomatic therapy and prevention of attacks.

Symptomatic therapy

• Physical therapy (PT): rehabilitation for ataxia and muscle weakness
• Occupational therapy (OT): Maintenance and improvement of activities of daily living
• Speech therapy (ST): Management of dysarthria and dysphagia
• Vision loss and hearing loss: Standard medical management (hearing aids, low vision aids, etc.)

Seizure prevention and fever management

• Aggressive fever management: Case reports suggest that regular antipyretic administration and adequate fluid intake may prevent developmental regression²⁾
• Acetazolamide: A carbonic anhydrase inhibitor. It may reduce ion leakage and normalize neuronal excitability by inducing metabolic acidosis. However, its efficacy in case reports is limited.
• Flunarizine: Has a history of use in AHC and may also be used in CAPOS management
• Topiramate and ketogenic diet: Reported in some cases
• Oxcarbazepine: Expected to act on the Na⁺/K⁺-ATPase pump mechanism, but efficacy was not confirmed and was discontinued in some cases²⁾

Treatment considerations

• Preventive treatment to avoid seizure episodes and worsening of neurological outcomes has not been established at present¹⁾.
• Active management during fever may help prevent developmental regression, but evidence is limited to case reports.
• All treatments are symptomatic and do not correct the genetic mutation itself.

Q What measures should be taken during fever?

A

There are case reports that regular antipyretic administration and adequate fluid intake contributed to avoiding developmental regression ²⁾. Early detection and active management of fever are recommended. Consult your primary physician for detailed management.

6. Pathophysiology and Detailed Mechanism of Onset

The ATP1A3 gene encodes the α3 subunit of the Na⁺/K⁺-ATPase pump. This pump transports 3 Na⁺ ions out of the cell and 2 K⁺ ions into the cell, maintaining the electrochemical gradient of the cell membrane. ¹⁾

Expression of the α3 subunit is limited to neurons, particularly GABAergic neurons. It is concentrated in the basal ganglia (striatum, globus pallidus, subthalamic nucleus, substantia nigra), forming important neural circuits for fine motor control. When ATP1A3 mutations cause dysfunction of the α3 polypeptide, the electrochemical gradient is distorted, leading to abnormal neuronal excitability. ¹⁾

A specific mutation for CAPOS syndrome is known: c.2452G>A (p.Glu818Lys). In contrast, the 756 residue mutation (p.Arg756His/Cys/Leu) causes RECA/FIPWE rather than CAPOS, and the important distinguishing point is that it does not show the hearing loss, optic atrophy, and pes cavus characteristic of CAPOS. ¹⁾

The correspondence between ATP1A3 mutations and phenotypes is shown below.

Mutation	Phenotype	Characteristic symptoms
p.Glu818Lys	CAPOS	Optic atrophy, hearing loss, pes cavus present
p.Arg756His (34 cases)	RECA/FIPWE	Optic atrophy, hearing loss, no pes cavus1)
p.Arg756Cys (20 cases)	RECA/FIPWE	Optic atrophy, hearing loss, no pes cavus1)
p.Arg756Leu (3 cases)	RECA/FIPWE	Optic atrophy, hearing loss, no pes cavus1)

Regarding the pathology of optic atrophy, it has been suggested that mechanisms of retinal ganglion cell death similar to those in ADOA (mitochondrial dysfunction due to OPA1 gene mutation) and Wolfram syndrome (endoplasmic reticulum dysfunction due to WFS1 gene mutation) may also be involved in CAPOS syndrome.

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7. Latest Research and Future Perspectives (Research-stage Reports)

For patients: Please read this

The following information is currently at the research or clinical trial stage and is not standard treatment available at general hospitals. It is reference information for professionals regarding future medical developments.

Expanding the ATP1A3 Phenotypic Spectrum

In addition to AHC, RDP, and CAPOS, RECA/FIPWE have been newly proposed, and the genotype-phenotype correlation of the ATP1A3 disease spectrum is being refined. ¹⁾²⁾

Biela et al. (2021) conducted a literature review of 57 cases with residue 756 mutations (34 cases of p.Arg756His, 20 cases of p.Arg756Cys, 3 cases of p.Arg756Leu) ¹⁾. Detailed analysis of 35 cases reported ictal symptoms including severe hypotonia (30/35, 85.7%), ataxia (28/35, 80.0%), dysarthria (26/35, 74.3%), impaired consciousness (22/35, 62.9%), dystonia (21/35, 60.0%), dysphagia (18/35, 51.4%), choreiform movements (9/35, 25.7%), and ocular motor symptoms (8/35, 22.9%). Age at first attack ranged from 8 months to 10 years (median 1.9 years), with 19/35 cases (54.3%) having their first attack before age 2.

Clinical Differences Between Phenotypes

Comparison between the p.Arg756His group and the p.Arg756Cys group showed a difference in the frequency of impaired consciousness (47.4% vs 76.9%). The p.Arg756Cys group had a higher frequency of cognitive developmental delay. ¹⁾

Long-term prognosis and brain imaging follow-up

Since cerebellar atrophy may appear late, long-term brain MRI follow-up is recommended. ¹⁾ It has been reported that disease progression is usually not observed after childhood. There is currently no preventive treatment to prevent seizure episodes and worsening of neurological outcomes. ¹⁾

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8. References

1. Biela M, Rydzanicz M, Szymanska K, et al. Variants of ATP1A3 in residue 756 cause a separate phenotype of relapsing encephalopathy with cerebellar ataxia (RECA)—Report of two cases and literature review. Mol Genet Genomic Med. 2021;9:e1772.
2. Tahir S, Chencheri N, Abdalla AA, et al. A Rare Cause of Recurrent Febrile Encephalopathy in a Child: The Expanding Spectrum of ATP1A3 Mutations. Cureus. 2021;13(12):e20438.
3. Sharawat IK, Kasinathan A, Suthar R, Sankhyan N. CAPOS Syndrome: A Rare ATP1A3-Related Disorder. Ann Indian Acad Neurol. 2020;23(3):397-398. PMID: 32606553.