What is the diagnosis and treatment approach for Cape syndrome presenting with upper arm weakness and paralysis?

CAPOS Syndrome: Diagnosis and Management of Upper Arm Weakness and Paralysis

CAPOS syndrome (Cerebellar Ataxia, Areflexia, Pes cavus, Optic atrophy, and Sensorineural hearing loss) is the most likely diagnosis for upper arm weakness and paralysis with relative preservation of lower extremity strength, caused by a specific c.2452G>A mutation in the ATP1A3 gene. 1, 2

Clinical Presentation

CAPOS syndrome typically presents with:

• Acute-onset episodes of cerebellar ataxia triggered by febrile illness
• Upper extremity weakness/paralysis that is disproportionate to lower extremity involvement
• Generalized areflexia
• Progressive development of:
  • Optic atrophy
  • Sensorineural hearing loss
  • Pes cavus (high-arched feet)

The distinctive pattern of upper arm weakness with relative preservation of lower extremity function is a hallmark feature that differentiates CAPOS syndrome from other neurological disorders 3.

Diagnostic Approach

1. Genetic Testing

   • Targeted sequencing of the ATP1A3 gene to identify the c.2452G>A (p.Glu818Lys) mutation, which has been found in all reported cases of CAPOS syndrome 1, 2

2. Neurological Evaluation

   • Assessment for cerebellar signs (ataxia, dysmetria)
   • Evaluation of deep tendon reflexes (typically absent)
   • Testing of muscle strength with focus on upper vs. lower extremity discrepancy

3. Ophthalmologic Examination

   • Evaluation for optic atrophy

4. Audiologic Assessment

   • Testing for sensorineural hearing loss

5. Neuroimaging

   • Brain MRI to evaluate cerebellar structures and rule out other causes
   • Consider EEG if seizure-like activity is suspected 4

Differential Diagnosis

1. Acute Central Cervical Spinal Cord Injury

   • Similar pattern of upper extremity weakness with preserved lower extremity strength
   • Usually associated with trauma or cervical stenosis 3

2. Cruciate Paralysis

   • Selective weakness of upper extremities
   • Associated with lesions at the cervicomedullary junction 3

3. Cryopyrin-Associated Periodic Syndromes (CAPS)

   • Presents with systemic inflammation, rash, and fever
   • Caused by mutations in NLRP3 gene, not ATP1A3 5, 6

4. Cap Myopathy

   • Congenital myopathy with weakness
   • Caused by mutations in TPM2 gene 7

Management Approach

1. Acute Episode Management

   • Supportive care during fever-induced episodes
   • Acetazolamide may prevent or attenuate acute episodes of ataxia and weakness 2
   • Antipyretics for fever management

2. Long-term Management

   • Regular monitoring of disease progression
   • Audiologic interventions for hearing loss
   • Visual aids for optic atrophy
   • Physical therapy to maintain strength and function
   • Genetic counseling (autosomal dominant inheritance)

3. Monitoring

   • Regular assessment of:
     • Neurological function
     • Hearing
     • Visual acuity
     • Quality of life measures

Prognosis

• Patients typically experience 1-3 acute episodes in childhood
• Symptoms may improve after acute episodes but some neurological deficits persist
• Progressive development of characteristic features (optic atrophy, hearing loss)
• Long-term sequelae may include dystonia, myoclonus, and behavioral changes 2

Important Clinical Pearls

• Early diagnosis before the first acute episode is possible by recognizing early signs like mild instability and areflexia 1
• The mutation is consistently c.2452G>A in the ATP1A3 gene across all reported cases, making genetic testing highly specific 1, 2
• Consider CAPOS syndrome in any child with fever-induced ataxia and upper extremity weakness
• Adults with progressive cerebellar syndrome since childhood accompanied by areflexia, visual impairment, and hearing loss should be evaluated for CAPOS syndrome

CAPOS syndrome represents a rare but distinctive neurological disorder with characteristic clinical features that should prompt targeted genetic testing for early diagnosis and management.