Title of Research Grant

Down Syndrome Disintegrative Disorder: Possible Hashimoto’s Encephalopathy?


Priya Kishnani, MD and Gordon Worley, MD
Applicant’s Primary Department: Pediatrics
Secondary Department: Division of Medical Genetics, Program in Neurodevelopmental Pediatrics

Summary of Proposed Project

The prevalence of autoimmune disease is much higher in Down Syndrome (DS) than in the general population. We have encountered 10 patients in the Duke DS Comprehensive Clinic who developed cognitive regression, autistic characteristics, and insomnia beginning in their early teenage years. These patients all had thyroid autoimmunity without clinical thyroid disease. Cognitive and developmental regression associated with thyroid autoimmunity has not previously been described in children with DS. We are naming this condition DS Disintegrative Disorder (DSDD), because of its similarity to Disintegrative Disorder in three to five year old typical children. Hashimoto’s Encephalopathy (HE) is an autoimmune CNS disease associated with but not caused by thyroid autoimmunity, most commonly reported in adults, but also reported to occur in some children. Cerebral folate deficiency is caused by either autoimmunity to a tissue folate receptor or by abnormalities of folic acid metabolism. In children, cerebral folate deficiency can also lead to autism, regression, and insomnia. Chromosome 21 contains many genes for folate metabolism, folate transport, and for enzymes that require folate for activity (including N6ANTI).

The purpose of the study is to characterize the clinical and laboratory findings in DSDD; evaluate thoroughly all patients with DSDD for known metabolic causes of regression; to test the hypotheses that antibodies to the tissue folate receptor and to alpha enolase are present in some subjects; and to evaluate subjects for evidence of abnormal folate metabolism.

Lay Summary of Proposed Project

The prevalence of autoimmune disease is much higher in Down syndrome (DS) than in the general population. It appears that a subset of adolescent patients in the Duke Comprehensive DS Clinic have experienced significant regression. We would like to systematically evaluate these patients by review of medical records, laboratory evaluations, neuropsychological evaluations, and speech and language testing, and then compare the patients’ data to draw conclusions about their similarities. We are going to test these patients to see if they have a problem using folate correctly, and if they do, our next step in a future study is to treat the patients with folinic acid to see if their symptoms, such as learning, social withdrawal, perseverative thoughts, or trouble sleeping improve with treatment. Describing this subset of patients in the medical literature will help other clinicians caring for people with DS identify this dual diagnosis and monitor or treat these patients appropriately.