Cerebral palsy in siblings caused by compound heterozygous mutations in the gene encoding protein C

Area of Science:

• Neurology
• Genetics
• Pediatrics

Background:

• Cerebral palsy (CP) is a common neurodevelopmental disorder.
• Periventricular haemorrhagic infarction (PVHI) is a type of brain injury that can lead to CP.
• Genetic factors are increasingly recognized as contributing to CP etiology.

Observation:

• Two sisters presented with severe neurological deficits, including cortical visual blindness, epilepsy, and varying degrees of motor impairment (spastic diplegia and quadriplegia).
• Neuroimaging revealed extensive bilateral periventricular haemorrhagic infarction (PVHI) in both siblings, suggestive of cerebral venous thrombosis.
• Both sisters exhibited purpura fulminans and showed reduced protein C activity, with heterozygous compound mutations in the protein C gene (PROC).

Findings:

• This is the first reported family with compound heterozygous PROC mutations identified as the likely cause of familial CP.
• The identified mutations in the protein C gene (PROC) led to both quantitative and qualitative deficiencies in protein C.
• The clinical presentation in both sisters, including PVHI and CP, was strongly associated with the genetic defect in protein C.

Implications:

• This study identifies novel monogenic causes of cerebral palsy, expanding the known genetic landscape of the disorder.
• Understanding the genetic basis of familial CP can aid in diagnosis, genetic counseling, and potentially targeted therapies.
• The findings highlight the critical role of protein C in fetal and neonatal brain development and hemostasis.