Monday, July 11, 2016

Cerebral folate deficiency and neuropsychiatric conditions

Ramaekers VT, Sequeira JM, Quadros EV. The basis for folinic acid treatment in
neuro-psychiatric disorders. Biochimie. 2016 Jul;126:79-90.

Multiple factors such as genetic and extraneous causes (drugs, toxins, adverse psychological events) contribute to neuro-psychiatric conditions. In a subgroup of these disorders, systemic folate deficiency has been associated with macrocytic anemia and neuropsychiatric phenotypes. In some of these, despite normal systemic levels, folate transport to the brain is impaired in the so-called cerebral folate deficiency (CFD) syndromes presenting as developmental and psychiatric disorders. These include infantile-onset CFD syndrome, infantile autism with or without neurologic deficits, a spastic-ataxic syndrome and intractable epilepsy in young children expanding to refractory schizophrenia in adolescents, and finally treatment-resistant major depression in adults. Folate receptor alpha (FRα) autoimmunity with low CSF N(5)-methyl-tetrahydrofolate (MTHF) underlies most CFD syndromes, whereas FRα gene abnormalities and mitochondrial gene defects are rarely found. The age at which FRα antibodies of the blocking type emerge, determines the clinical phenotype. Infantile CFD syndrome and autism with neurological deficits tend to be characterized by elevated FRα antibody titers and low CSF MTHF. In contrast, in infantile autism and intractable schizophrenia, abnormal behavioral signs and symptoms may wax and wane with fluctuating FRα antibody titers over time accompanied by cycling changes in CSF folate, tetrahydrobiopterin (BH4) and neurotransmitter metabolites ranging between low and normal levels. We propose a hypothetical model explaining the pathogenesis of schizophrenia. Based on findings from clinical, genetic, spinal fluid and MRI spectroscopic studies, we discuss the neurochemical changes associated with these disorders, metabolic and regulatory pathways, synthesis and catabolism of neurotransmitters, and the impact of oxidative stress on the pathogenesis of these conditions. A diagnostic algorithm and therapeutic regimens using high dose folinic acid, corticosteroids and milk-free diet is presented which has proven to be beneficial in providing adequate folate to the brain and decreasing the FRα autoantibody titer in those positive for the antibody.

From the article:

The first-described infantile-onset [cerebral folate deficiency]CFD syndrome, attributed to FRα autoantibodies in 90% of cases, is an orphan disease with an estimated prevalence between 1/4000 and 1/6000 children, equal sex distribution and occurrence among all ethnic groups. Since one-third of cases with the infantile-onset CFD syndrome manifest low-functioning autism, the prevalence of low-IQ autism with neurological deficits, where high FRα antibody titers are detected in almost all cases, is considered to represent an extremely rare condition within the group of autism spectrum disorders (ASD). The prevalence of CFD caused by autosomal recessive FRα gene defects remains unknown but is probably even much rarer.

The prevalence of ASD has been estimated at 1.5%, varying between 0.6% and 2.2%, measured in different locations of the US population. In Europe, estimates ranged between 1% up to 2%. About 1/3 of children with ASD have low-functioning autism with an IQ ≤ 70. In the latter group of low-functioning autism our studies identified a prevalence of blocking FR autoantibodies between 55 and 59%. Our findings could be reproduced by Frye et al., who identified blocking type FRα autoantibodies at a rate of 60% in children with ASD.

We conducted a study in 25 patients (mean age 5.6 and range 2–13.9 years), suffering from severe low-functioning autism associated with at least one or more neurological deficits, as encountered in the infantile onset CFD syndrome…

The mean CSF MTHF concentration was significantly decreased in all 25 patients compared to healthy controls (mean ± SD: 22.9 ± 17 nmoL/L versus mean ± SD at 82 ± 31.3 nmoL/L for controls). The results showed that 24 of 25 patients with low CSF MTHF had autoantibodies of the blocking type against the FRα with a mean value of 1.09 pmol FRα blocked/ml serum (range: 0–4.19).

A subsequent study was performed among 59 patients in the same age group who suffered from low-functioning autism without neurological deficits. Compared to autism with neurological deficits and controls, the serum folate in these 59 patients with autism was slightly lower, while their CSF MTHF levels were also moderately diminished compared to the very low levels in the group of patients suffering from autism plus neurological deficits and patients with infantile CFD (Table 1).

The less marked drop of CSF MTHF values in autism without neurological deficits can be explained by the presence of only moderately increased FRα autoantibody titers as compared to autism plus neurological deficits or infantile CFD syndrome in whom much higher antibody titers tend to cause a more pronounced decrease in CSF MTHF levels...

After diagnosis of low-functioning autism in a younger group of 110 children (age mean ± SD: 4.8 ± 3.3 years), the occurrence of serum FRα autoantibodies of the blocking type was assessed among these children and their parents and compared to a control group of 30 families having a child with developmental delay without autistic features. This study was performed as an extension of a preliminary study. In 6 patients with autism (5%) genetic abnormalities were found. The results showed that 55% of all children tested positive for FRα autoantibodies of the blocking type. In 25% of the mothers and 26% of fathers, blocking FRα autoantibodies were found, whereas FRα autoantibodies were found in only 1 child and his parents out of 30 control families. Since in some families FRα autoantibodies were only present in either one or both parents and not in their autistic child, our results established that in 71% of the 110 families, FRα autoantibodies of the blocking type tested positive in the child and/or parents, whereas in 29% of the families FRα autoantibodies were absent in the child and both parents. Among the 110 families, different combinations of positive or negative FRα antibodies in the autistic child and parents have been encountered (Fig. 5). In many families FRα autoantibodies were only found in the autistic child or in autistic siblings while both parents tested negative. However, in one non-consanguineous family of Turkish descent, the healthy mother was found to be a carrier of blocking FRα autoantibodies. She gave birth to three girls who all had FRα autoantibodies and suffered from severe low-IQ autism while additional features of Rett syndrome with intractable epilepsy were present in the youngest girl. Another example is a family where the healthy father carried FRα autoantibodies that were also found in his dizygotic male twins, while their mother tested negative.

When the FRα autoantibody titer drops or becomes negative, folate flux to neurons is re-established, thus restoring folate-dependent neuro-metabolic processes. The consequent sudden rise of dopamine and serotonin could lead to relative overstimulation of their receptors, expressed at low density and form the basis of positive symptoms…

In young children treatment of infantile CFD syndrome, autism with neurologic deficits and the spastic-ataxic CFD syndrome due to FRα autoantibodies used high doses of folinic acid at 0.5–1 mg/kg/day…

Milk products of animal origin contain a soluble FR protein with almost identical structural homology with the human FRα antigen. Exposure to this soluble FR protein among genetically prone individuals elicits the formation of FRα specific autoantibodies reacting with FRα antigen attached to the choroid plexus. Therefore, a strict animal-milk free diet has been shown to reduce FRα antibodies titers significantly, which supports the reported positive response in a subpopulation of autistic children receiving a gluten and milk-free diet…

Outcome after folinic acid treatment for infantile CFD and autism with neurological deficits associated with FRα autoantibodies has been reported to be excellent if diagnosis and treatment are started immediately when the first signs and symptoms begin to manifest. However, if the time between onset of clinical features and diagnosis plus treatment is delayed, outcome and prognosis become less favorable. Therefore, screening for FRα autoantibodies should be advocated at the very onset or with clinical suspicion of a possible CFD syndrome…

Previous publications have defined the evolution of signs and symptoms evolving from the age of 4–6 months, which manifest as salient clinical features for the orphan disease infantile-onset CFD syndrome. For each child suspected to suffer from infantile CFD syndrome, a spinal fluid sample should be examined for the presence of low MTHF levels. After confirmation of low CSF MTHF, further investigation includes analysis of serum FRα autoantibodies, DNA sequencing of the FRα gene and testing for mitochondrial disorders. The earlier the high dose folinic acid therapy can be started, the better the outcome will be. The diagnostic workup, including differential diagnosis and treatment guidelines have been described previously. The high rate of prevalence of blocking FRα autoantibodies among 55–59% of patients with low-functioning autism is an indication to investigate the presence for these FRα autoantibodies, because the majority of patients may benefit from folinic acid treatment and a milk free diet.



  1. Ramaekers VT, Blau N, Sequeira JM, Nassogne MC, Quadros EV. Folate receptor autoimmunity and cerebral folate deficiency in low-functioning autism with neurological deficits. Neuropediatrics. 2007 Dec;38(6):276-81.

    Reduced folate transport to the CNS was identified in two autism spectrum disorders, i.e., Rett syndrome and infantile low-functioning autism with neurological abnormalities. Twenty-five patients with early-onset low-functioning autism with or without neurological deficits, were evaluated for serum folate, cerebrospinal fluid (CSF) 5-methyltetrahydrofolate (5MTHF), and serum FR autoantibodies of the blocking type to determine the significance of folate receptor (FR) autoantibodies with respect to folate transport across the blood-CSF barrier. In spite of normal serum folate, CSF 5MTHF was low in 23 of 25 patients. The reduced CSF folate in 19 of these 23 patients could be explained by serum FR autoantibodies blocking the folate binding site of the membrane-attached FR on the choroid epithelial cells. Oral folinic acid supplements led to normal CSF 5MTHF and partial or complete clinical recovery after 12 months. Serum FR autoimmunity appears to represent an important factor in the pathogenesis of reduced folate transport to the nervous system among children with early-onset low-functioning autism associated with or without neurological deficits. Early detection of FR autoantibodies may be a key factor in the prevention and therapeutic intervention among this subgroup of patients with autism.

  2. Mangold S, Blau N, Opladen T, Steinfeld R, Wessling B, Zerres K, Häusler M. Cerebral folate deficiency: a neurometabolic syndrome? Mol Genet Metab. 2011 Nov;104(3):369-72.

    Cerebral folate deficiency (CFD) is increasingly recognized in various neurological conditions, raising the question of whether it might represent a clear-cut clinical syndrome.
    Retrospective analysis of patients with low cerebral spinal fluid (CSF) 5-methyltetrahydrofolate (5MTHF) values was performed.
    58 pediatric patients with low (-2nd to -3rd standard deviation) and 45 patients with very low 5MTHF values (<3rd standard deviation) were identified, including 22 patients with defined underlying neurological conditions. The leading symptoms were mental retardation (n=84), motor retardation (n=75), epilepsy (n=53), ataxia (n=44) and pyramidal tract signs (n=37). There was no relationship between 5MTHF levels and the severity of clinical disease, the duration of clinical disease, distinct neurological symptoms and antiepileptic drug treatment, respectively. Genetical analysis for mutations in the folate receptor 1 gene proved normal in all 16 children studied.
    For the majority of patients CFD is not a clear-cut neurometabolic syndrome but the common result of different genetic, metabolic or unknown processes. Nevertheless, CFD may represent a treatable disease-modifying factor which should therefore be addressed in prospective studies.

  3. Moretti P, Peters SU, Del Gaudio D, Sahoo T, Hyland K, Bottiglieri T, Hopkin RJ, Peach E, Min SH, Goldman D, Roa B, Bacino CA, Scaglia F. Brief report:autistic symptoms, developmental regression, mental retardation, epilepsy, and dyskinesias in CNS folate deficiency. J Autism Dev Disord. 2008 Jul;38(6):1170-7.

    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.

  4. Frye RE, Sequeira JM, Quadros EV, James SJ, Rossignol DA. Cerebral folate receptor autoantibodies in autism spectrum disorder. Mol Psychiatry. 2013 Mar;18(3):369-81.

    Cerebral folate deficiency (CFD) syndrome is a neurodevelopmental disorder typically caused by folate receptor autoantibodies (FRAs) that interfere with folate transport across the blood-brain barrier. Autism spectrum disorders (ASDs) and improvements in ASD symptoms with leucovorin (folinic acid) treatment have been reported in some children with CFD. In children with ASD, the prevalence of FRAs and the response to leucovorin in FRA-positive children has not been systematically investigated. In this study, serum FRA concentrations were measured in 93 children with ASD and a high prevalence (75.3%) of FRAs was found. In 16 children, the concentration of blocking FRA significantly correlated with cerebrospinal fluid 5-methyltetrahydrofolate concentrations, which were below the normative mean in every case. Children with FRAs were treated with oral leucovorin calcium (2 mg kg(-1) per day; maximum 50 mg per day). Treatment response was measured and compared with a wait-list control group. Compared with controls, significantly higher improvement ratings were observed in treated children over a mean period of 4 months in verbal communication, receptive and expressive language, attention and stereotypical behavior. Approximately one-third of treated children demonstrated moderate to much improvement. The incidence of adverse effects was low. This study suggests that FRAs may be important in ASD and that FRA-positive children with ASD may benefit from leucovorin calcium treatment. Given these results, empirical treatment with leucovorin calcium may be a reasonable and non-invasive approach in FRA-positive children with ASD. Additional studies of folate receptor autoimmunity and leucovorin calcium treatment in children with ASD are warranted.