APA (Old Order Amish; Eastern Pennsylvania)

Inheritance: autosomal recessive
Genes: CNTNAP2
CASPR2

CDFE syndrome

Epilepsy
Developmental regression
Hyperactivity
Impulsive behavior
Mental retardation
Cortical dysplasia

Cortical Dysplasia-Focal Epilepsy Syndrome

Clinical Characteristics

General description (for patients):

General activity is diminished in infancy with general reduction on responses to their environment such as imitation of and concentration on others.  Verbal comprehension and language skills seem normal before the onset of seizures, which begin at a median age of 16 months.  Children may walk by themselves by about 2 years of age.  Physical features and growth are normal except for a somewhat enlarged skull in some.  Seizures of various types begin between 14 and 20 months and are severe in a third of patients.  With their onset, behavioral problems become evident, such hyperactivity and impulsive aggression.  Language skills that may have developed tend to regress.

Medical description:  

This is a severe neurological disorder that has an infantile onset with marked developmental regression.  Clinical information is based on a report of nine patients from Amish near Lancaster, PA, aged 2-9 years, in whom mild motor delay was a feature of infancy.  They had limitation of skills requiring imitation, concentration and motor planning.  Some language skills developed but these regressed after the onset of seizures between 14 and 20 months.  Physical growth seemed to follow a normal pattern except for generally large heads.  Deep tendon reflexes were absent or diminished.  At the same time, aberrant behavior consisting of hyperactive, impulsive and aggressive acting out may begin.   Autistic characteristics such as poor eye contact, aloofness and self-stimulation have been described.  What language skills that develop tend to regress.  Intelligence scores were 1-5 years behind chronological ages.  There is general neurological regression from the start.
Seizures are of multiple types, partial and generalized, and can be intractable although improved control has been reported with zonisamide.  EEGs may show normal background rhythms with seizure discharges noted in the parietal and frontal areas.  MRI shows focal malformations and areas of dysplasia in the anterior temporal lobes documented histologically.  Periventricular leukomalacia is also present. Brain biopsies show evidence of abnormal neuronal migration and widespread astrogliosis.

Genetics:

This is an autosomal recessive disorder can be caused by a missense deletion (3709delG) mutation in The CNTNAP2 gene located on chromosome 7 (7q35-q36).  The expression of the protein product, CASPR2, is reduced in brain temporal lobe tissue.  Nine such patients have been reported among the Amish of Eastern Pennsylvania.  Recently, a single related Indiana Amish child has been reported with the same mutation.

Treatment:

There is no known treatment.

Prognosis:

The limited number of patients described so far has shown generalized neurological deterioration to the age of 10 years at least.

Ancillary reatments and support:

General supportive care.

Specialists and specialty centers:

Neurologist, nutritionist, pediatrician.

References:

Strauss, K.A., Puffenberger, E.G., Huentelman, M.J., Gottlieb, S., Dobrin, S.E., Parod, B.S., Stephan, D.A., and Morton, D.H.:  Recessive symptomatic focal epilepsy and mutant contactin-associated protein-like 2.  New Eng. J. Med. 354: 1370-1377, 2006. PubMed ID: 16571880


Jackman, C., Horn, N.D., Molleston, J.P., and Sokol, D.K.:  Gene associated with seizures, autism, and hepatomegaly in an Amish girl.  Pediatr. Neurol. 40: 310-313, 2009.  PubMed: 19302947


Resources:

Focal Cortical Dysplasia