GJA1 Variants Cause Spastic Paraplegia Associated with Cerebral Hypomyelination

Area of Science:

• Genetics and Neurology
• Neurodegenerative Diseases
• Medical Imaging

Background:

• Oculodentodigital dysplasia, an autosomal dominant disorder caused by GJA1 variants, presents with dysmorphic features.
• Neurologic symptoms are noted in some patients, but a distinct neuroimaging pattern has been lacking.

Purpose of the Study:

• To investigate the neuroimaging patterns and pathophysiology of neurologic deficits in patients with GJA1-related hereditary spastic paraplegia.
• To correlate clinical severity with specific neuroimaging findings.

Main Methods:

• Studied 8 consecutive patients with hereditary spastic paraplegia due to GJA1 variants.
• Performed cerebral MRI to assess white matter abnormalities and basal ganglia signals.
• Correlated clinical disease severity with imaging findings.

Main Results:

• Observed variable white matter abnormalities consistent with hypomyelination.
• Detected bilateral basal ganglia hypointense signals on T2-weighted and/or susceptibility sequences.
• Found a correlation between more prominent basal ganglia abnormalities and higher disability.

Conclusions:

• GJA1-related hereditary spastic paraplegia is a complex neurodegenerative disease impacting myelin and basal ganglia.
• GJA1 variants should be considered in hereditary spastic paraplegia with hypomyelination and signs of neurodegeneration/iron accumulation.