Currently, the ATP1A1-related disorders may be differentiated according to the specific clinical features:
1. Charcot-Marie-Tooth type 2D (CMT2DD; axonal-to-intermediate sensory and motor peripheral neuropathy with variable age of onset, ranging from late childhood to fifties, and slow progression):
• Pes cavus
• Distal muscle weakness and atrophy
• Muscle cramps
• Reduced/absent deep tendon reflexes
• Steppage gait
• Foot drop
• Atrophy of the intrinsic hand muscles
• Lower limbs more affected than upper limbs
• Decreased vibratory sensation
2. Hypomagnesemia, intractable seizures, severe intellectual disability (HOMGSMR2):
• Severe renal magnesium wasting causing hypomagnesemia
• Renal potassium wasting causing hypokalemia
• Polyuria
• Medullary hyperechogenicity compatible with nephrocalcinosis
• Epilepsy with generalized tonic-clonic seizures and episodes of status epilepticus
• Global developmental delay
• Behavioral manifestations (autism spectrum disorder, self-beating, hyperactivity)
• Brain abnormalities at neuroimaging (volume loss, incomplete myelination)
3. Early-onset complex neurodevelopmental syndrome:
• Intellectual disability
• Spasticity/Spastic paraparesis
• Peripheral, motor predominant neuropathy
• Sleep disturbances
• Epilepsy
• Behavioral manifestations (autism spectrum disorder, self-beating, hyperactivity)
ATP1A1