Recessive symptomatic focal epilepsy and mutant contactin-associated protein-like 2

Area of Science:

• Neuroscience
• Genetics
• Developmental Biology

Background:

• Contactin-associated protein-like 2 (CASPR2), encoded by CNTNAP2, is crucial for clustering voltage-gated potassium channels at the nodes of Ranvier.
• Proper K(v)1.1 channel function is essential for neuronal signaling and development.

Purpose of the Study:

• To investigate the genetic basis of a severe neurodevelopmental disorder observed in Old Order Amish children.
• To understand the role of CNTNAP2 and CASPR2 in cortical development and neurological function.

Main Methods:

• Genetic analysis to identify mutations in the CNTNAP2 gene.
• Clinical evaluation of affected children, including neurological examinations and behavioral assessments.
• Histopathological examination of temporal lobe specimens.

Main Results:

• Identified a homozygous mutation in the CNTNAP2 gene in affected children.
• Observed a consistent phenotype including cortical dysplasia, intractable focal epilepsy, macrocephaly, and diminished reflexes.
• Clinical presentation included early-onset seizures, language regression, hyperactivity, aggression, and mental retardation.
• Pathological findings revealed neuronal migration abnormalities, astrogliosis, and reduced CASPR2 expression in resected temporal lobes.

Conclusions:

• Homozygous CNTNAP2 mutations cause a severe autosomal recessive neurodevelopmental disorder.
• CASPR2 deficiency disrupts neuronal development and function, leading to epilepsy and cognitive/behavioral deficits.
• This finding underscores the importance of CASPR2 in normal brain development and synaptic function.