Brief Report: Autistic Symptoms, Developmental Regression, Mental Retardation, Epilepsy, and Dyskinesias in CNS Folate Deficiency
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We studied seven children with CNS folate deficiency (CFD). All cases exhibited psychomotor retardation, regression, cognitive delay, and dyskinesia; six had seizures; four demonstrated neurological abnormalities in the neonatal period. Two subjects had profound neurological abnormalities that precluded formal behavioral testing. Five subjects received ADOS and ADI-R testing and met diagnostic criteria for autism or autism spectrum disorders. They exhibited difficulties with transitions, insistence on sameness, unusual sensory interests, and repetitive behaviors. Those with the best language skills largely used repetitive phrases. No mutations were found in folate transporter or folate enzyme genes. These findings demonstrate that autistic features are salient in CFD and suggest that a subset of children with developmental regression, mental retardation, seizures, dyskinesia, and autism may have CNS folate abnormalities.
KeywordsFolic Acid 5-methyltetrahydrofolate 5-MTHF Cerebral folate deficiency Folate transporters Autism
The data were obtained in the course of clinical care and are used with the written permission of the subject’s parents. The authors thank the patients and their families for their cooperation and Arthur L. Beaudet, MD for his support. This study was funded by the Gustavus and Louise Pfeiffer Foundation. P.M. was supported by NIH NS049181 and March of Dimes 5-FY05-38 Basil O’Connor Starter Scholar Research Award.
- Hyland, K., & Surtees, R. (1992). Measurement of 5-methyltetrahydrofolate in cerebrospinal fluid using HPLC with coulometric electrochemical detection. Pteridines, 3, 149–150.Google Scholar
- James, S. J., Melnyk, S., Jernigan, S., Cleves, M. A., Halsted, C. H., Wong, D. H., Cutler, P., Bock, K., Boris, M., Bradstreet, J. J., Baker, S. M., & Gaylor, D. W. (2006). Metabolic endophenotype and related genotypes are associated with oxidative stress in children with autism. American Journal of Medical Genetics. Part B, Neuropsychiatric Genetics, 141(8), 947–956.CrossRefGoogle Scholar
- Moretti, P., Sahoo, T., Hyland, K., Bottiglieri, T., Peters, S., del Gaudio, D., Roa, B., Curry, S., Zhu, H., Finnell, R. H., Neul, J. L., Ramaekers, V. T., Blau, N., Bacino, C. A., Miller, G., & Scaglia, F. (2005). Cerebral folate deficiency with developmental delay, autism, and response to folinic acid. Neurology, 64(6), 1088–1090.PubMedGoogle Scholar
- Pineda, M., Ormazabal, A., Lopez-Gallardo, E., Nascimento, A., Solano, A., Herrero, M. D., Vilaseca, M. A., Briones, P., Ibanez, L., Montoya, J., & Artuch, R. (2006). Cerebral folate deficiency and leukoencephalopathy caused by a mitochondrial DNA deletion. Annals of Neurology, 59, 394–398.CrossRefGoogle Scholar
- Qiu, A., Jansen, M., Sakaris, A., Min, S. H., Chattopadhyay, S., Tsai, E., Sandoval, C., Zhao, R., Akabas, M. H., & Goldman, I. D. (2006). Identification of an intestinal folate transporter and the molecular basis for hereditary folate malabsorption. Cell, 127(5), 917–928.PubMedCrossRefGoogle Scholar
- Ramaekers, V. T., Hausler, M., Opladen, T., Heimann, G., & Blau, N. (2002). Psychomotor retardation, spastic paraplegia, cerebellar ataxia and dyskinesia associated with low 5-methyltetrahydrofolate in cerebrospinal fluid: a novel neurometabolic condition responding to folinic acid substitution. Neuropediatrics, 33(6), 301–308.PubMedCrossRefGoogle Scholar
- Rosenblatt, D. S., & Fenton, W. A. (2000). Inherited disorders of folate and cobalamin transport and metabolism. In C. R. Scriver, et al. (Eds.), The metabolic and molecular bases of inherited disease. New York: McGraw-Hill.Google Scholar
- Wevers, R. A., Hansen, S. I., van Hellenberg Hubar, J. L., Holm, J., Hoier-Madsen, M., & Jongen, P. J. (1994). Folate deficiency in cerebrospinal fluid associated with a defect in folate binding protein in the central nervous system. Journal of Neurology, Neurosurgery, and Psychiatry, 57(2), 223–226.PubMedCrossRefGoogle Scholar