Folate Receptor Autoimmunity and Cerebral Folate Deficiency in Low-Functioning Autism with Neurological Deficits

Ramaekers, Vincent; Blau, Nenad; Sequeira, Jeffrey M.; Nassogne, Marie‐Cécile; Quadros, Edward V.

doi:10.1055/s-2008-1065354

Cited by 148 publications

(190 citation statements)

References 18 publications

Supporting

Mentioning

179

Contrasting

Unclassified

Order By: Relevance

“…[184][185][186] Additionally, there may be increased serum folate receptor autoantibodies in children with low-functioning autism with or without neurological deficits relative to control subjects without autism. 187 This suggests that folate transfer to the fetus during pregnancy may be blocked, which may increase risk of neural tube defects. 188 Because these elevated autoantibodies were also present in at least one parent of children with autism, parental antibodies may contribute to autism etiology.…”

Section: Autoimmune Diseasesmentioning

confidence: 99%

Environmental factors associated with autism spectrum disorder: a scoping review for the years 2003–2013

Montigny

Ofner

et al. 2017

Health Promot Chronic Dis Prev Can

View full text Add to dashboard Cite

Introduction: The number of children diagnosed with autism spectrum disorder (ASD) has been rapidly rising in the past decade. The etiology of this disorder, however, is largely unknown, although the environmental relative to the genetic contribution is substantial. We conducted a scoping review to comprehensively assess the current state of knowledge of the environmental factors present from preconception to early life associated with ASD, and to identify research gaps.

show abstract

Section: Autoimmune Diseasesmentioning

confidence: 99%

Environmental factors associated with autism spectrum disorder: a scoping review for the years 2003–2013

Montigny

Ofner

et al. 2017

Health Promot Chronic Dis Prev Can

View full text Add to dashboard Cite

show abstract

“…Intervention with pharmacologic doses of folinic acid normalized the CSF folate levels with clinical improvement [ 12 ]. Because a number of the patients with CFD showed symptoms that were similar to those associated with ASD, we evaluated patients with low functioning autism and identified FR α -blocking antibodies in 76% of these patients [ 14 ]. This analysis was subsequently extended to children with ASD.…”

Section: Discovery Of Fr α Auabsmentioning

confidence: 99%

“…Nevertheless, the prevalence of the FR α AuAb and NTD pregnancy in Ireland remains higher than in the rest of Europe and the USA. These FR α AuAbs are also associated with numerous developmental disorders in children such as cerebral folate deficiency (CFD) syndrome [ 12 ], Rett syndrome [ 13 ], low functioning autism with neurological deficits [ 14 ], and autism spectrum disorders (ASD) [ 15 , 16 ]. The AuAbs could exert their effect either by blocking folate transport or potentially by an antibody-mediated immune reaction.…”

Section: Introductionmentioning

confidence: 99%

The diagnostic utility of folate receptor autoantibodies in blood

Sequeira

Ramaekers

Quadros

2013

Clinical Chemistry and Laboratory Medicine

View full text Add to dashboard Cite

Folate supplementation reduces the risk of neural tube defect (NTD) pregnancy, and folinic acid has been used to correct cerebral folate deficiency (CFD) in children with developmental disorders. In the absence of systemic folate deficiency, the discovery of autoantibodies (AuAbs) to folate receptor α (FR α ) that block the uptake of folate offers one mechanism to explain the response to folate in these disorders. The association of FR α AuAbs with pregnancy-related complications, CFD syndrome, and autism spectrum disorders and response to folate therapy is highly suggestive of the involvement of these AuAbs in the disruption of brain development and function via folate pathways. The two types of antibodies identified in the serum of patients are blocking antibody and binding antibody. The two antibo dies can be measured by the specific assays described and exert their pathological effects either by functional blocking of folate transport as previously shown or hypothetically by disrupting the FR by an antigen-antibody-mediated inflammatory response. We have identified both IgG and IgM AuAbs in these conditions. The predominant antibodies in women with NTD pregnancy belong to the IgG1 and IgG2 isotype and in CFD children, the IgG1 and IgG4 isotype. This review describes the methods used to measure these AuAbs, their binding characteristics, affinity, cross-reactivity, and potential mechanisms by which folate therapy could work. Because these AuAbs are associated with various pathologies during fetal and neonatal development, early detection and intervention could prevent or reverse the consequences of exposure to these AuAbs.

show abstract

“…The third recognized CFD syndrome is infantile autism, frequently associated with three or more neurological deficits encountered in the infantile-onset CFD [ 21 ], but infantile autism without neurological deficits has been increasingly recognized [ 22 ]. In a group of 25 patients with infantile autism associated with neurological deficits, spinal fluid MTHF levels were lowered due to relatively high blocking serum FR autoantibody titers in almost all (24 of 25) patients.…”

Section: Cerebral Folate Deficiency Syndromes Associated With Fr Automentioning

confidence: 99%

Clinical recognition and aspects of the cerebral folate deficiency syndromes

Ramaekers¹,

Sequeira

Quadros

2013

Clinical Chemistry and Laboratory Medicine

View full text Add to dashboard Cite

Abstract:We characterized cerebral folate deficiency (CFD) as any neuro-psychiatric condition associated with low spinal fluid (CSF) N 5 -methyltetrahydrofolate (MTHF) but normal folate status outside the central nervous system (CNS). The commonest cause underlying CFD syndromes is the presence of serum autoantibodies of the blocking type directed against folate receptor-α (FR α ) attached to the plasma-side of choroid plexus epithelial cells. Blocking FR antibodies inhibit MTHF transport across the choroid plexus. Serum titers of FR antibodies may fluctuate significantly over time. Less frequent causes of CFD are FOLR-1 mutations, mitochondrial disorders and inborn errors affecting folate metabolism. Maternal FR antibodies have been associated with neural tube defects while the presence of FR antibodies in either one or both parents increases the risk of an offspring with infantile autism. Recognizable CFD syndromes attributed to FR-antibodies in childhood are infantile-onset CFD presenting 4 -6 months after birth, infantile autism with neurological deficits, and a spastic ataxic syndrome from the age of 1 year, while progressive dystonic or schizophrenic syndromes develop during adolescence. FR autoantibodies are frequently found in autism spectrum disorders, in an Aicardi-Gouti è res variant and in Rett syndrome. The heterogeneous phenotype of CFD syndromes might be determined by different ages of onset and periods when FR autoantibodies are generated with consequent CNS folate deficiency. Folate deficiency during various critical stages of fetal and infantile development affects structural and functional refinement of the brain. Awareness of CFD syndromes should lead to early detection, diagnosis and improved prognosis of these potentially treatable group of autoimmune and genetically determined conditions.

show abstract

Folate Receptor Autoimmunity and Cerebral Folate Deficiency in Low-Functioning Autism with Neurological Deficits

Cited by 148 publications

References 18 publications

Environmental factors associated with autism spectrum disorder: a scoping review for the years 2003–2013

Environmental factors associated with autism spectrum disorder: a scoping review for the years 2003–2013

The diagnostic utility of folate receptor autoantibodies in blood

Clinical recognition and aspects of the cerebral folate deficiency syndromes

Contact Info

Product

Resources

About