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Amish May Get Autism After All

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Seizure Disorder in Amish Children Points to Autism


By Neil Osterweil, Senior Associate Editor, MedPage Today
Published: March 29, 2006
Reviewed by Zalman S. Agus, MD; Emeritus Professor at the University of Pennsylvania School of Medicine.

STRASBURG, Pa., March 29 - A study of Old Order Amish children has identified the genetic mutation that causes a previously unknown disorder, with seizures that progress to autism and retardation. m.

The recessive disorder, dubbed cortical dysplasia-focal epilepsy syndrome, or CDFE, is marked by relatively normal infancy followed by onset at about 14 to 16 months of age of frequent seizures -- 50 to 90 per week.

The seizure onset is followed by language regression and the development of hyperactivity, aggressive and impulsive behaviors, and mental retardation, reported Kevin A. Strauss, M.D., of the Clinic for Special Children here, and colleagues, The Old Order Amish is a close-knit, genetically homogenous population.

The finding points to a genetic variation in the gene encoding for contactin-associated protein-like 2 (CASPR2) as a possible cause of both epilepsy and autism in the affected children, the investigators wrote in the March 30 issue of the New England Journal of Medicine.

"We were able to unequivocally map the disease gene to chromosome 7 and identify a pathogenic sequence variant in the gene CNTNAP2, which codes for the CASPR2 protein," said co-author Erik G. Puffenberger, Ph.D., laboratory director at the Center for Special Children.

"Although these patients were from an isolated population, we anticipate that CASPR2 mutations will be found in children from other populations with mental retardation, seizures, and autism," he added.

Genetics researchers often find insights into the origins of developmental disorders by studying populations such as the Amish, Mennonites, and Hasidic Jews. Members of these groups tend to have ancestors who came from the same geographic region, live in isolated populations, and intermarry, allowing recessive genetic traits to emerge in their offspring.

Dr. Strauss and colleagues at his center and at the Translational Genomics Research Institute in Phoenix and Center for Human Genetics in Marshfield, Wis., studied nine patients with CDFE to see whether they could narrow in on a specific cause of the epilepsy.

The clinical course in the children consisted of "mild gross motor delay and subtle limitations in skills that required imitation, concentration, or motor planning," the investigators wrote.

The children generally had good language comprehension and eight of the nine had age-appropriate cognitive and social development before the onset of seizures.

The seizures, including simple, partial, and complex partial types, began at a median age of 16 months (range 14-20) and were frequent and intractable when the children were between the ages of two and seven. The seizures did not resolve following resective surgery, but tended to abate spontaneously several years after onset, the authors noted

The seizure onset was followed by deterioration in learning ability and social development, and by age three all patients with CDFE were found to have "language regression, aberrant social interactions, and a restricted behavioral repertoire."

The investigators took DNA samples from four of the children and their six parents, and used DNA microarray analysis to screen for genetic variations.

After narrowing the field of candidates, they then tested all of the children with CDFE, and found that they were homozygous for a single-base deletion at nucleotide 3709 in exon 22 of the CNTNAP2 gene.

An analysis of an additional 105 healthy Old Order Amish controls showed that none was homozygous for the mutation, but that four were carriers. The authors then sequenced the gene in an additional 18 Amish patients with complex partial seizures, and found that nine of these patients were homozygous for the deletion. These patients were all siblings of seven of the children with CDFE.

Their findings provide important insights into a previously unknown developmental role for CASPR2, a protein known to be important for neuronal and glial connections in the mature central nervous system.

"Previous studies on CASPR2 in isolated cell cultures and genetic 'knockout' mice did not predict its fundamental role in human brain development or cortical electrical activity," Dr. Krauss said. "The present findings are compelling evidence for such roles, and open new directions for epilepsy and autism research beyond the index population."

His colleague, D. Holmes Morton, M.D., co-founder and medical director of the Center for Special Children, added that "the identification of the mutation in CASPR2 in our Amish patients has already allowed us to recognize affected newborns before they become symptomatic. Our hope is that early treatment and prevention of prolonged seizures in these infants will lessen the effects of the disorder upon the lives of children and their families."

Primary source: New England Journal of Medicine
Source reference: Strauss KA et al. "Recessive Symptomatic Focal Epilepsy and Mutant Contactin-Associated Protein-like 2" N Engl J Med 2006;354:1370-7.

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