Thursday, June 23, 2016

CSF 5-methyltetrahydrofolate and autism

Shoffner J, Trommer B, Thurm A, Farmer C, Langley WA 3rd, Soskey L, Rodriguez
AN, D'Souza P, Spence SJ, Hyland K, Swedo SE. CSF concentrations of
5-methyltetrahydrofolate in a cohort of young children with autism. Neurology.
2016 Jun 14;86(24):2258-63.

Abstract
OBJECTIVE:
To examine the association between cerebral folate deficiency and autism, this study examined CSF 5-methyltetrahydrofolate (5-MTHF) concentrations in a group of young children with autism, investigated the natural variation in CSF 5-MTHF over time, and assessed the relationship between CSF 5-MTHF and symptoms.
METHODS:
CSF was collected from 67 children with a diagnosis of DSM-IV-TR autistic disorder (age, mean ± SD 43 ± 11 months), with a second CSF sample obtained 1-3 years later on 31 of these subjects (time to follow-up, 30 ± 8 months).
RESULTS:
At time 1, 7% (5/67) of participants had 5-MTHF <40 nmol/L. At follow-up, 23% (7/31) of participants had 5-MTHF <40 nmol/L (only one of whom had been low at time 1). A moderate correlation with a very wide confidence interval (CI) was observed between time 1 and time 2 CSF 5-MTHF measurements (Pearson r[p] = 0.38 [0.04]; 95% CI 0.02-0.64). Neither the CSF 5-MTHF levels nor changes over time correlated with the clinical features of autism.
CONCLUSIONS:
CSF 5-MTHF levels vary significantly over time in an unpredictable fashion and do not show a significant relationship to typical clinical features of autism. Reduced CSF 5-MTHF levels are a nonspecific finding in autism. Our data do not support the use of lumbar puncture for assessment of CSF 5-MTHF in autism.

4 comments:

  1. From the Shoffner article in the post:

    Three case series report on CFD in autism spectrum disorder (ASD), each concluding that there may be some causal relationship. One study reported some evidence of neurologic improvement associated with CSF 5-MTHF normalization.

    While there is speculation that dysfunctional folate metabolism might play a role in the pathogenesis of autism, these hypotheses are limited by the lack of pediatric CSF controls. Further, there is no systematic documentation of whether low CSF 5-MTHF in ASD is accompanied by the neurologic symptoms of CFD. We obtained repeat CSF 5-MTHF samples from young children with autism participating in a longitudinal phenotyping study, who were not recruited based on neurologic symptoms of CFD. Our objectives were to characterize their CSF 5-MTHF levels, determine variability in CSF 5-MTHF over time, and evaluate the relationship between CSF 5-MTHF levels and symptoms of autism. As folate receptor autoantibodies have been reported to be present in a significant number of children with ASD,19 anti–folate transport protein binding antibodies (immunoglobulin G [IgG] anti-FBP) were also assessed...

    At time 1, 4 (6%) participants had elevated antibodies binding to the folate receptor protein (IgG anti-FBP) (66, 71, 84, and 153 pmol/mL). All of these participants had CSF 5-MTHF above 40 nmol/L (49, 52, 61, and 66 nmol/L). One of the participants with elevated antibodies at time 1 had a second LP, at which time no IgG anti-FBP were detected. However, at time 2, 4 (13%) different participants had elevated IgG anti-FBP (77, 110, 159, and 226 pmol/mL; corresponding 5-MTHF 56, 63, 43, and 56 nmol/L)...

    Overall, the clinical evaluation revealed few abnormalities for any of the children, including the 11 who had 5-MTHF <40 nmol/L at either time point...

    All studies that assess pediatric CSF are limited by the absence of reference values from healthy children as well as the lack of understanding of the natural variability over time of this metabolite. Our results emphasize that the natural variation on CSF 5-MTHF can be large, calling into question the value of single timepoint measurements. Since ethical restrictions preclude LPs from being performed for research studies among healthy, typically developing children, results for the children with autism were compared against a group of children with neurologic problems, including CFD. CSF 5-MTHF values ranged up to 151.2 nmol/L in this comparison group, while the maximum value observed in the autism group at time 1 was only 96.0 nmol/L. The lower bounds of the samples were similar, as were the rates of values less than 40 nmol/L (autism, 7%; comparison, 9%)...

    Existing studies generally converge upon 40 nmol/L as the lower limit of normal CSF 5-MTHF.2,3 Using the limit of 40 nmol/L, 11 children with autism (but without other neurologic abnormalities) were found to have low CSF 5-MTHF concentrations at either time 1 or time 2. The lack of stability across measurements and the failure to find correlation between behavioral measures and CSF 5-MTHF levels are evidence against the role of CSF 5-MTHF in the etiology of autism. In fact, CSF 5-MTHF decreased over time for a subgroup of children with autism, consistent with cross-sectional studies showing decreasing CSF 5-MTHF with age in healthy children...

    This investigation represents the largest collection of CSF from an ASD cohort to date. It is also unique for having longitudinal samples and analyses. Low CSF 5-MTHF levels were found in only a small fraction of children with ASD, and were neither consistent across time nor associated with clinical symptoms or behavioral characteristics.

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  2. Pérez-Dueñas B, Ormazábal A, Toma C, Torrico B, Cormand B, Serrano M, Sierra C, De Grandis E, Marfa MP, García-Cazorla A, Campistol J, Pascual JM, Artuch R. Cerebral folate deficiency syndromes in childhood: clinical, analytical, and etiologic aspects. Arch Neurol. 2011 May;68(5):615-21.

    Abstract
    BACKGROUND:
    Cerebral folate deficiency may be amenable to therapeutic supplementation. Diverse metabolic pathways and unrelated processes can lead to cerebrospinal fluid 5-methyltetrahydrofolate (5-MTHF) depletion, the hallmark of cerebral folate deficiency.
    OBJECTIVE:
    To analyze cerebral folate abundance in a large prospective series of children diagnosed with any neurologic disorder for which a diagnostic lumbar puncture was indicated.
    DESIGN:
    We studied the spectrum and frequency of disorders associated with cerebral folate deficiency by measuring cerebrospinal fluid 5-MTHF, biogenic amines, and pterins. Direct sequencing of the FOLR1 transporter gene was also performed in some patients.
    SETTING:
    Academic pediatric medical center.
    PARTICIPANTS:
    We studied 134 individuals free of neurometabolic disease and 584 patients with any of several diseases of the central nervous system.
    RESULTS:
    Of 584 patients, 71 (12%) exhibited 5-MTHF deficiency. Mild to moderate deficiency (n = 63; range, 19-63 nmol/L) was associated with perinatal asphyxia, central nervous system infection, or diseases of probable genetic origin (inborn errors of metabolism, white matter disorders, Rett syndrome, or epileptic encephalopathies). Severe 5-MTHF depletion (n = 8; range, 0.6-13 nmol/L) was detected in severe MTHF reductase deficiency, Kearns-Sayre syndrome, biotin-responsive striatal necrosis, acute necrotizing encephalitis of Hurst, and FOLR1 defect. A strong correlation was observed between cerebrospinal fluid and plasma folate levels in cerebral folate deficiency.
    CONCLUSIONS:
    Of the 2 main forms of cerebral folate deficiency identified, mild to moderate 5-MTHF deficiency was most commonly associated with disorders bearing no primary relation to folate metabolism, whereas profound 5-MTHF depletion was associated with specific mitochondrial disorders, metabolic and transporter defects, or cerebral degenerations. The results suggest that 5-MTHF can serve either as the hallmark of inborn disorders of folate transport and metabolism or, more frequently, as an indicator of neurologic dysfunction.

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  3. Main PA, Angley MT, Thomas P, O'Doherty CE, Fenech M. Folate and methionine metabolism in autism: a systematic review. Am J Clin Nutr. 2010 Jun;91(6):1598-620.

    Abstract
    BACKGROUND:
    Autism is a complex neurodevelopmental disorder that is increasingly being recognized as a public health issue. Recent evidence has emerged that children with autism may have altered folate or methionine metabolism, which suggests the folate-methionine cycle may play a key role in the etiology of autism.
    OBJECTIVE:
    The objective was to conduct a systematic review to examine the evidence for the involvement of alterations in folate-methionine metabolism in the etiology of autism.
    DESIGN:
    A systematic literature review was conducted of studies reporting data for metabolites, interventions, or genes of the folate-methionine pathway in autism. Eighteen studies met the inclusion criteria, 17 of which provided data on metabolites, 5 on interventions, and 6 on genes and their related polymorphisms.
    RESULTS:
    The findings of the review were conflicting. The variance in results can be attributed to heterogeneity between subjects with autism, sampling issues, and the wide range of analytic techniques used. Most genetic studies were inadequately powered to provide more than an indication of likely genetic relations.
    CONCLUSIONS:
    The review concluded that further research is required with appropriately standardized and adequately powered study designs before any definitive conclusions can be made about the role for a dysfunctional folate-methionine pathway in the etiology of autism. There is also a need to determine whether functional benefits occur when correcting apparent deficits in folate-methionine metabolism in children with autism.

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  4. In 23 of 71 children (32%) with decreased 5-MTHF, no etiologic diagnosis was identified after extensive investigation. Most of these patients exhibited mild to moderate reductions of 5-MTHF and normal CSF to plasma folate ratios, making it unlikely that there was a transport defect across the blood-CSF barrier. These patients manifested diverse clinical phenotypes (mostly infantile spasms, drug-refractory epilepsies of infancy or early childhood, or progressive motor deterioration syndromes), disease courses, and neuroimaging findings, suggesting broad disease heterogeneity. Because CFD is, in principle, amenable to therapeutic supplementation, a trial with folinic acid was attempted in 11 patients with decreased 5-MTHF of unknown cause, to investigate whether decreased CNS folate availability might play a causative or significant role in their encephalopathies. Clinical benefits were limited to 2 patients who experienced only mild transitory improvement in communicative skills and seizure control. These observations agree with poor treatment response observed in patients with mild CSF 5-MTHF deficiencies associated with Rett syndrome. In contrast, favorable clinical responses have been reported in patients with profound CSF 5-MTHF deficiency due to KSS13 and FOLR1 defect. A study (including validated clinical scales for the evaluation of communicative skills, seizures, and other neurologic signs; biochemical monitoring; and assessment of concomitant antiepileptic therapy) is under way to evaluate the efficacy and safety of folinic acid supplementation in CFD syndrome, particularly in mild and moderate deficiencies.

    Pérez-Dueñas B, Ormazábal A, Toma C, Torrico B, Cormand B, Serrano M, Sierra C, De Grandis E, Marfa MP, García-Cazorla A, Campistol J, Pascual JM, Artuch R. Cerebral folate deficiency syndromes in childhood: clinical, analytical, and etiologic aspects. Arch Neurol. 2011 May;68(5):615-21.

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