The portal for rare diseases and orphan drugs

CNTNAP2-related developmental and epileptic encephalopathy is a very rare disease and to date, 28 affected individuals from 15 families are reported in literature worldwide.

In all affected individuals, moderate to usually severe intellectual disability with speech impairment and seizures is present. Initial motor and cognitive development may be unaffected or only mildly delayed in few cases. Onset of seizures is usually during infancy or early childhood, typically within the first 3.5 years of life. With seizure onset, developmental regression with loss of verbal skills frequently occurs. Subsequently, speech is absent or very limited with only few words in most of the affected individuals. Ataxic gait, muscular hypo- or hypertonia or hyporeflexia can occur. Moreover, behavioral abnormalities such as stereotypic hand movements, teeth grinding, reduced eye contact, self-harm or aggressivity and autistic features are common. Further clinical aspects may include paroxysmal hyperventilation or breathing abnormalities or, rarely, a large head circumference. Focal cortical dysplasia, cerebellar hypoplasia or vermian atrophy may be detected in cerebral magnetic resonance imaging (MRI), but cerebral MRI might also be normal. Minor, but non-specific facial dysmorphism might be noted in few of the affected individuals.

The disorder is caused by bi-allelic intragenic deletions (rarely duplications) or truncating variants in the CNTNAP2 gene (7q35-q36.1). It encodes contactin-associated protein 2 (CASPR2), a transmembrane protein from the neurexin superfamily, which is involved in neural-glia interactions and clustering of potassium channels in myelinated axons.

Diagnosis might be achieved by targeted testing upon clinical suspicion, but in most cases, it is made by untargeted approaches such as chromosomal microarray analysis and/or multigene panel or exome sequencing.

The differential diagnosis includes other developmental and epileptic encephalopathies, such as MEF2C-related neurodevelopmental disorder (5q14.3 microdeletion syndrome), Pitt Hopkins syndrome, Angelman syndrome, Rett syndrome or NRXN1-associated autosomal recessive neurodevelopmental disorder.

Prenatal diagnosis and preimplantation-diagnostics are possible where the pathogenic variant(s) has/have been identified in a family member and/or where carrier status in the parents has been confirmed.

Inheritance is autosomal recessive. For parents who are both carriers of the variant there is a 25% recurrence risk for each pregnancy. Heterozygous carriers of deletions/variants in CNTNAP2 may have an increased risk for variable neuropsychiatric abnormalities.

Management of seizures is required. Ongoing developmental assessments are recommended to tailor educational services to individual needs, e.g. physical, occupational, speech therapies and behavioral management strategies.

There are affected individuals living in their fourth decade. Moderate to severe cognitive impairment is present with dependence on others for help in daily living.