Autism spectrum disorders (ASDs)—which include autistic disorder, Asperger’s Syndrome, and pervasive developmental disorder-not otherwise specified (PDD-NOS)—are defined by behavioral observations and characterized by impairments in communication and social interaction, along with restrictive and repetitive behaviors.
The association of ASD with a number of physiological abnormalities, including immune dysfunction and inflammation, mitochondrial dysfunction, oxidative stress and environmental toxicant exposures, has gained increased attention. An example of a physiological abnormality that might cause ASD is mitochondrial disease.
Recently we reviewed the evidence for children with ASD having abnormal functioning of mitochondria [5].
The mitochondrion is an essential part of each cell, and is responsible for producing energy for the cellular metabolic processes. When this energy engine of the cell does not work correctly, many organs in the body—especially those that require a high amount of energy (like the brain, gastrointestinal tract, and immune system)—may not function correctly, resulting in symptoms seen in mitochondrial disorders.
WHAT IS CFD?
CFD is characterized by below normal levels of the active metabolite of folate known as 5-methyltetrahydrofolate (5MTHF) in the central nervous system (CNS), despite normal levels of folate metabolites in the blood.
5MTHF is normally transported into the CNS through one of two pathways. The CNS folate receptor protein alpha (FRA) transports 5MTHF directly into the CNS in a process that is dependent on mitochondrial function (ATP production). 5MTHF is also transported into the CNS through the reduced folate carrier (RFC). Impaired transport of 5MTHF into the CNS can lead to reduced levels of 5MTHF in the brain and cause CFD.
One study reported a child with ASD who also had mitochondrial disease and CFD. In most of these cases, autoantibodies to FRA were not found, suggesting that it was the lack of ATP availability secondary to mitochondrial dysfunction that resulted in the impaired transportation of 5-MTHF into the CNS.
CFD AND ASD
To date, three studies have reported a connection between CFD and Rett syndrome [25-27], and seven studies have reported an association with ASD [10, 13, 24, 28-31].
FRA AUTOANTIBODY TESTING ADVISABLE?
Because FRA autoantibodies appear to be highly prevalent in children with ASD, we recommend that FRA autoantibody testing should be considered in all patients with ASD. Early identification and treatment is paramount, as younger children generally respond more robustly than older children, with “cure” reported in some children.
The test we run is ONLY $200.00 and done via blood testing, results in 6-12 days.
References:
APA. Diagnostic and statistical manual of mental disorders. 4th edn. American Psychiatric Association: Washington, DC, 1994.
Rice C. Prevalence of autism spectrum disorders – Autism and Developmental Disabilities Monitoring Network, United States, 2006.
MMWR Surveill Summ. 2009;58(10):1-20.
Schaefer GB, Mendelsohn NJ. Genetics evaluation for the etiologic diagnosis of autism spectrum disorders. Genet Med. 2008;10(1):4-12.
Rossignol DA, Frye RE. A review of research trends in physiological abnormalities in autism spectrum disorders: immune dysregulation, inflammation, oxidative stress, mitochondrial dysfunction and environmental toxicant exposures. Mol Psychiatry. 2011.5
Rossignol DA, Frye RE. Mitochondrial dysfunction in autism spectrum disorders: a systematic review and meta- analysis. Mol Psychiatry. 2011.
Frye RE, Rossignol DA. Mitochondrial dysfunction can connect the diverse medical symptoms associated with autism spectrum disorders. Pediatr Res. 2011 May;69(5 Pt 2):41R-7R.
Frye RE, Sequeira JM, Quadros EV, James SJ, Rossignol D. Cerebral folate receptor autoantibodies in autism spectrum disorder. Mol Psychiatry. 2011.
Ramaekers VT, Hausler M, Opladen T, HeimannG , Blau N. 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. 2002;33(6):301-8.
HansenF, Blau N. Cerebralfolatedeficiency: life-changing supplementation with folinic acid. Mol Genet Metab. 2005;84(4):371-3.
Ramaekers VT, Rothenberg SP, Sequeira M, Opladen T, Blau N, Quadros EV et al. Autoantibodies to folate receptors in the cerebral folate deficiency syndrome. N Engl J Med. 2005;352(19):1985-91.
Molloy AM, Quadros EV, Sequeira JM, Troendle JF, Scott JM, Kirke PN et al. Lack of association between folate-receptor autoantibodies and neural-tube defects. N Engl J Med. 2009;361(2):152-60.
Berrocal-Zaragoza MI, Fernandez-Ballart JD, Murphy MM, Cavalle-Busquets P, Sequeira JM, Quadros EV. Association between blocking folate receptor autoantibodies and subfertility. Fertil Steril. 2009;91(4 Suppl):1518-21.
Ramaekers VT, Sequeira JM, Blau N, Quadros EV. Amilk- free diet downregulates folate receptor autoimmunity in cerebral folate deficiency syndrome. Dev Med Child Neurol. 2008;50(5):346-52.
Whiteley P, Haracopos D,Knivsberg AM,Reichelt KL ,Parlar S, Jacobsen J et al. The ScanBrit randomised, controlled, single-blind study of a gluten- and casein-free dietary intervention for children with autism spectrum disorders. Nutr Neurosci. 2010;13(2):87-100.
Afzal N, Murch S, Thirrupathy K ,Berger L ,Fagbemi A, Heuschkel R. Constipation with acquired megarectum in children with autism. Pediatrics. 2003;112(4):939-42.
Kushak RI, Lauwers GY, Winter HS, Buie TM. Intestinal disaccharidase activity in patients with autism: Effect of age, gender, and intestinal inflammation. Autism. 2011.;15(3):285-94.
Shabo Y, Barzel R, Margoulis M, Yagil R.Camel milk for food allergies in children. Isr Med Assoc J. 2005;7(12):796-8.
Shabo Y, Yagil R. Etiology of autism and camel milk as therapy. International Journal on Disability and Human Development. 2005;4(2):67-70.
Pineda M, Ormazabal A, Lopez-Gallardo E, Nascimento A, Solano A, Herrero MD et al. Cerebral folate deficiency and leukoencephalopathy caused by a mitochondrial DNA deletion. Ann Neurol. 2006;59(2):394-8.
Ramaekers VT, Weis J, Sequeira JM, Quadros EV, Blau N. Mitochondrial complex I encephalomyopathy and cerebral 5-methyltetrahydrofolate deficiency. Neuropediatrics. 2007;38(4):184-7.
Hasselmann O, Blau N, Ramaekers VT, Quadros EV, Sequeira JM, Weissert M. Cerebral folate deficiency and CNS inflammatory markers in Alpers disease. Mol Genet Metab. 2010;99(1):58-61.
Frye RE. Complex IV hyperfunction in autism spectrum disorder: a new mitochondrial syndrome. Ped Neurol. 2011.
Garcia-Cazorla A, Quadros EV, Nascimento A, Garcia-Silva MT,BrionesP,MontoyaJetal.Mitochondrialdiseases associated with cerebral folate deficiency. Neurology. 2008;70(16):1360-2.
Shoffner J, Hyams L, Langley GN, Cossette S, Mylacraine L, Dale J et al. Fever plus mitochondrial disease could be risk factors for autistic regression. J Child Neurol. 2010;25(4):429- 34.
Ramaekers VT, Hansen SI, Holm J, Opladen T, Senderek J, Hausler M et al. Reduced folate transport to the CNS in femaleRettpatients.Neurology.2003;61(4):506-15.
Ramaekers VT, Sequeira JM, Artuch R, Blau N, Temudo T, Ormazabal A et al. Folate receptor autoantibodies and spinal fluid 5-methyltetrahydrofolate deficiency in Rett syndrome. Neuropediatrics. 2007;38(4):179-83.
Perez-Duenas B, Ormazabal A, Toma C, Torrico B, Cormand B, Serrano M et al. Cerebral folate deficiency syndromes in childhood: clinical, analytical, and etiologic aspects. Arch Neurol. 2011;68(5):615-21.
Moretti P, Peters SU, Del Gaudio D, Sahoo T, Hyland K, Bottiglieri T et al. Brief report: autistic symptoms, developmental regression, mental retardation, epilepsy, anddyskinesiasinCNSfolatedeficiency.JAutismDev Disord. 2008;38(6):1170-7.
Ramaekers VT, Blau N, Sequeira JM, Nassogne MC, Quadros EV. Folate receptor autoimmunity and cerebral folatedeficiencyinlow-functioningautismwith neurological deficits. Neuropediatrics. 2007;38(6):276-81.
Ramaekers VT, Blau N. Cerebral folate deficiency. Dev Med Child Neurol. 2004;46(12):843-51.
Moretti P, Sahoo T, Hyland K, Bottiglieri T, Peters S, delGaudioDetal.Cerebralfolatedeficiencywith developmental delay, autism, and response to folinic acid. Neurology. 2005;64(6):1088-90.
