Talk:Cerebral folate deficiency

Problems

VernaMM, there are some problems with this draft that you should try to fix before submitting for review:

1. In the first sentence, the source you cite does not support the claim that the condition is "common" in ASD.
2. Source pmid:22488256 is a letter. You need a reliable secondary source to support biomedical claims.
3. You can't insert an advert for a testing kit into an encyclopedia article. Nor does the source pmid:23314538 support that.
4. The source pmid:18355335 is a clinical trial, not a secondary source. It says nothing about ASD, and you can't synthesise arguments that something with an effect on cerebral folate deficiency syndrome will have an effect on ASD.
5. The source pmid:27752075 is a small trial. You need a reliable secondary source to support biomedical claims.
6. The source pmid:24224089 is a single trial. You need a reliable secondary source to support biomedical claims.

My opinion is that you don't have sufficient WP:MEDRS-compliant sourcing to write an article on this topic. --RexxS (talk) 14:50, 6 December 2016 (UTC)

Issues raised by soupvector

I quote: "The article doesn't seem neutral with respect to mechanism, e.g. the sources I cited above note that: (i) serum folate levels aren't a reliable measure of total-body folate stores due to wild fluctuations, (ii) response to supplementation suggests that the purported block in transport is at most a relative block. The problem is pervasive in the article, starting with this sentence in the lede, The numerous causes of the syndrome disrupt folate transport via the choroid plexus. Good luck with this!" (Papers mentioned by soupvector)

Soupvector - but according to descriptions, response to supplementation is only efficient when the patient is supplemented with folinic acid, and not with folic acid, so the "transport disruption" mechanism must be true, mustn't it? Or does folic acid also benefit patients, making it a "relative block"? --CopperKettle 03:30, 7 January 2019 (UTC)

We need sources per WP:MEDRS after trimming the primary sources not much was left so I merged it into folate deficiency. Doc James (talk · contribs · email) 13:39, 7 January 2019 (UTC)

Looking further I am finding a fair number of reviews. Enough I think for a stand alone article. Doc James (talk · contribs · email) 14:10, 7 January 2019 (UTC)

References

Thank you! FOLR1 mutations are not the only cause. There is one other gene, and mitochondrial disorders, and the alleged FR1a-antibody caused cases of deficiency. I'll try to find appropriate sources. --CopperKettle 14:47, 7 January 2019 (UTC)

I'd like to have a well-balanced article about this condition, because judging by psychiatric research it might turn out much more common than previously thought, if studies are replicated. I'd like to translate this well-balanced article for RuWiki, with all possible genes\antibodies\other causes mentioned, to Russian, because there is almost nothing about this condition in the Russian Web. I'm afraid I won't have enough time to do all that. I've read a bunch of articles from PubMed but they might turn out to be not acceptable as sources here. Maybe I'll return when and if I have time. For now, I'm glad that the article exists, even with just a single cause mentioned. --CopperKettle 15:08, 7 January 2019 (UTC)

Battlori, Perez and Garcia are primary research David notMD (talk) 16:43, 15 January 2019 (UTC)

Will this count as a good secondary source? I propose adding a mention of Kearns-Sayre syndrome

• Baumgartner MR Vitamin-responsive disorders: cobalamin, folate, biotin, vitamins B1 and E PMID 23622402

I quote:

Secondary cerebral folate deficiency has been shown in patients with Kearns–Sayre syndrome (Garcia-Cazorla et al., 2008), and low CSF folate levels have been found in a number of other disorders such as Rett syndrome, autistic spectrum and mitochondrial disorders, although the causal mechanism is unclear. The importance of these findings lies in the possibility that treatment with folinic acid may improve symptoms. Thus screening the CSF in patients with neurological disorders of unknown origin may be beneficial and have therapeutic consequences.

I propose adding a mention of Kearns-Sayre syndrome, if this paper (which also appears in the book Pediatric Neurology, Volume III (2013) (page 1805) is good enough to count as a creditable secondary source. --CopperKettle 15:08, 8 January 2019 (UTC)

• P.S. Interestingly, in Hereditary folate malabsorption patients also develop cerebral folate deficiency if treatment relies on folic acid only - which fails to pass into the CSF. --CopperKettle 19:08, 8 January 2019 (UTC)

Multiple causes?

This article appears to be expandable to causes other than FOLR1. For this reason I amended text in lead and body of article. If I have gotten ahead of the evidence here, please revert. David notMD (talk) 19:58, 8 January 2019 (UTC)

Yes the one above would count as another mechanism. Have added. Doc James (talk · contribs · email) 21:41, 8 January 2019 (UTC)

Per this bit "low CSF folate levels have been found in a number of other disorders such as Rett syndrome, autistic spectrum and mitochondrial disorders, although the causal mechanism is unclear" I would say not strong enough to list as a cause. Doc James (talk · contribs · email) 21:46, 8 January 2019 (UTC)

Perhaps in these: Hyland 2010 (PMID 20668945), Ramaekers 2013 (PMID 23314531), Desai 2016 (PMID 26924398), Ramaekers (PMID 27068282). David notMD (talk) 21:57, 8 January 2019 (UTC)

I got distracted by reading the basics of folate metabolism, and the history. And I have work to do.. D'oh. I'll try to find reputable secondary sources concerning other mitochondrial disorders, autism spectrum conditions, depression etc. Or if\when such reputable sources appear in the future, I'll add them by and by. --CopperKettle 06:12, 9 January 2019 (UTC)

P.S. I've just found one review, although it was published in a journal of Hindawi Publishing Corporation, which was briefly included in the predatory publishing list in 2010. Here goes: PMID 23984056 (by Agadi, Quach, Haneef) - authors are not related to Ramaekers et al. --CopperKettle 14:42, 9 January 2019 (UTC)

Concerning antibodies as possible cause - are these secondary sources okay?

• From the review cited by David notMD: (2010) (Hyland, Shoffner, Heales) (REVIEW) Cerebral folate deficiency (Journal of Inherited Metabolic Disease) (PMID 20668945):

Sequencing the genes coding for FR1 (FOLR1) and FR2 (FOLR2) in these patients failed to detect any pathogenic mutations, and it was suggested that the mechanism might involve the presence of antagonists or the formation of autoantibodies against the FR1 protein. The latter was, indeed, shown to be the case when 25 of 28 infants with CFD were found to have autoantibodies against the FRs, whereas these were not present in any of the 28 control individuals (Ramaekers et al. 2005).

The authors conclude:

Apart for FR autoantibody formation and mutations in the FOLR1 gene, the mechanisms responsible for causing CFD are often unknown.

--CopperKettle 18:01, 9 January 2019 (UTC)

• From a 2013 review in Epilepsy Research and Treatment (journal went defunct in 2017), (REVIEW) (Agadi, Quach, Haneef) Vitamin-responsive epileptic encephalopathies in children, PMID 23984056:

Folinic acid responsive epilepsies are also commonly known as cerebral folate deficiency syndromes. Although cerebral folate deficiency is associated with diverse neurological conditions, only a few conditions are responsive to treatment with folinic acid. These are usually mediated by either genetic or autoimmune mechanisms and cause low concentration of CSF 5-methyl tetrahydrofolate (MTHF).

4.1. Autoimmune Folate Antibodies

Clinical signs and symptoms typically begin at around 4 months of age with an onset of irritability and sleep disturbance. This is usually followed by the development of psychomotor retardation, seizures, dyskinesia, cerebellar ataxia, and spastic diplegia. Other signs include deceleration of head growth in the early stages of the disorder. In untreated cases, visual disturbances manifest after 3 years of age and sensorineural hearing loss after approximately 6 years of age. About one-third of patients may develop epileptic spasms, recurrent myoclonic-astatic seizures, absence seizures, and generalized tonic-clonic seizures. Thirty-five percent of the patients also have autistic spectrum disorders [46, 47]. CSF MTHF level is typically low. Autoantibodies to folate are often present in serum. Interestingly, erythrocyte folate is usually normal. EEG findings are nonspecific and vary from mild diffuse slowing, multifocal spike-wave discharges, and hypsarrhythmic background pattern to electrical status epilepticus in sleep [48].

--CopperKettle 18:23, 9 January 2019 (UTC)

• From a 2015 review in the Korean Journal of Pediatrics (2015) (Hwang, Kwon) Early-onset epileptic encephalopathies and the diagnostic approach to underlying causes PMID 26692875:

Folinic acid responsive epilepsies are caused by low concentration of 5-methyltetrahydrofolate (MTHF) in the cerebrospinal fluid (CSF), which is associated with various neurological conditions18). Genetic or autoimmune mechanisms cause cerebral folate deficiency and delayed treatment may lead to encephalopathy with severe learning disabilities. EEG may show abnormal background activity with multifocal spike-wave complexes, but typically has no diagnostic features. Neuroimaging results are also usually normal19). Patients either do not respond to pyridoxine at all or exhibit only a temporary improvement. However, such patients show a marked neurological recovery including cessation of seizures upon folinic acid treatment18).

--CopperKettle 18:38, 9 January 2019 (UTC)

• From a 2012 book written by Phillip L. Pearl and titled Inherited Metabolic Epilepsies, page 3:

Cerebral folate deficiency has been associated both with auto-antibodies and gene mutations of the folate FR1 receptor.[..] This disorder is covered in more detail in Chapter 22 by Dr Fernando Scaglia

--CopperKettle 19:04, 9 January 2019 (UTC)

(page 264, chapter summary)

Cerebral folate deficiency (CFD) is a neurometabolic condition associated with low levels of 5-methy-ltetrahydrofolate in the cerebrospinal fluid with normal folate levels in plasma and red blood cells. CFD has been found in diverse neurological conditions and for the majority of patients does not represent a defined neuro-genetic syndrome but the common result of different genetic and metabolic disorders. There seems to be a role for blocking autoantibodies against membrane-associated folate receptors of the choroid plexus in certain cases. Successful treatment of CFD with high doses of folinic acid has been reported in some subjects with CFD.

--CopperKettle 04:33, 10 January 2019 (UTC)

• From the 2017 book "Hematology: Basic Principles and Practice (Hoffman et al.), page 537:

  Cerebral folate deficiency
  
  Cerebral folate deficiency is a broad syndrome whereby several diseases can be accompanied by neurologic findings and low CSF folates but with normal serum folate levels?39'24" The GPI-anchored folate receptor-OC on the basolateral surface of choroid plexus cells is critical to the transport of folate from the blood across the CSF into the brain. Predictably, therefore, mutation of folate receptor-a, or the generation of antibodies to folate binding proteins found in cow’s milk that cross react with choroid plexus folate receptor-a, can perturb folate transport into the brain and lead to cerebral folate deficiency. Indeed, among a group of 14 children with extremely low (<5 nmol/1) levels of 5-methyl-THF in the CSF, mutations in folate receptor-a, which led to a failure in expression of functional folate receptors, were identified in 10 of them (71%).46,47 These patients presented at <3 years with symptoms of developmental delay, movement disturbances, ataxia, myoclonic seizures, infantile spasms, and leukodystrophy that was reversed by folinic acid.42’'241 The finding of two older patients (aged 13 and 15 years) with severe polyneuropathy raises the possibility of other patients who may also have such defects that can present in young adulthood with unexplained neurologic disorders.

  --CopperKettle 08:31, 10 January 2019 (UTC)

• From the 2012 review (2012) (REVIEW) (Serrano M, Pérez-Dueñas B, Montoya J, Ormazabal A, Artuch R.) Genetic causes of cerebral folate deficiency: clinical, biochemical and therapeutic aspects (PMID 22835503):

  CFD is a biochemical abnormality frequently found in children found to have various neurological disorders [17,31]. More than 30 diseases affecting the CNS in association with CFD have been described [32–38]. [...]
  
  FRa autoantibodies
  
  Ramaekers et al. demonstrated the presence of blocking autoantibodies against high-affinity FRa from the choroid plexus in serum from children with CFD [40].

  --CopperKettle 19:04, 10 January 2019 (UTC)

  https://vinuarumugham.substack.com/p/cows-milk-protein-contaminated-vaccines Vinucube (talk) 01:54, 26 October 2022 (UTC)

• Found another article that explains multiple causes of CFD. https://rarediseases.org/rare-diseases/cerebral-folate-deficiency/

Causes include: disruption of the FRA receptor, and mitochondrial disease can cause the disruption. — Preceding unsigned comment added by Sweenetr1951 (talk • contribs) 16:19, 11 March 2021 (UTC)

Autism evidence will need to be very strong

There are many nutrient and non-nutrient dietary supplements being proposed as Autism therapies. I would prefer to see STRONG evidence before CFD is proposed as a diagnostic and folinic acid a treatment. Especially leery of VT Ramaekers, who is of the opinion that CFD is the root cause of many conditions, and folinic acid the treatment. David notMD (talk) 21:04, 9 January 2019 (UTC)

I read the papers of this group (Ramaekers et al) and did not get the impression that they deem it the root cause. Autism, like schizophrenia and depression, is a hodgepodge of different causes, with different gene variations interacting with environment to bring out the symptoms in a particular patient. It would be odd to consider low CSF 5MTHF to be the root cause of it. Thus far, there are studies in which low CSF 5MTHF was found in patients, and there is a study (Shoffner et al., 2016) the authors of which conclude that "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". I think that a mention of the possible contribution of CFD to some cases of autism could be made if there are good secondary sources in which this possibility is deemed strong enough to merit a mention. --CopperKettle 04:03, 10 January 2019 (UTC)

As someone who labored in the dietary supplement industry (recently retired), any glimmer of a nutrient involvement in a disease not sufficiently well treated by medicine leads to egregious marketing as a 'cure.' I recommend not opening that door unless the evidence is far stronger than a possibility. David notMD (talk) 22:21, 10 January 2019 (UTC)

I see! The door has been opened - the only (very meager) sources in Russian that mention CFD online are web-forums created and maintained my relatives of autistic children. I would be glad if even a fraction of patients eventually got better from this. If I had a child with autism, I would also frequent such forums and buy supplements to use "just in case it pans out". But I agree that at Wikipedia we should rely on secondary sources and not tout anything as a cure. Thus far, secondary sources do not mention the autism link with certainty. --CopperKettle 07:30, 11 January 2019 (UTC)

Folinic acid improves verbal communication in children with autism and language impairment: a randomized double-blind placebo-controlled trial

https://www.nature.com/articles/mp2016168 Vinucube (talk) 01:57, 26 October 2022 (UTC)

In the U.S., there are several dietary supplement companies selling folinic acid, usually described as a bioactive form of folate, servings 800 micrograms. Most are vague on health claims, but from one: "...is a highly bioavailable source of folic acid that helps the body build healthy red blood cells. It supports healthy brain and neurological development along with healthy cell division." Just an example of marketing getting ahead of science. David notMD (talk) 15:01, 11 January 2019 (UTC)

Association with dihydrofolate reductase deficiency (secondary source, 2011)

Cerebral folate deficiency has also been reported in dihydrofolate reductase deficiency, with a secondary source (book) dated 2011. Quote (Google Books link):

Deficiency of dihydrofolate reductase (DHFR) leads to depletion of cerebral tetrahydrobiopterin (BH4) which interferes with the formation of dopamine, norepinephrine, and serotonin. Patients with DHFR deficiency have megaloblastic anemia or pancytopenia and severe cerebral folate deficiency. Concentrations of cerebrospinal fluid 5-methyltetrahydrofolate (5-MTHF) and BH4 are markedly decreased. Cerebral manifestations included seizures, profound developmental delay, and cerebral atrophy. Treatment with folinic acid reverses hematologic manifestations.

--CopperKettle 10:33, 13 January 2019 (UTC)

Quote from a primary source (PMID 21310277, Cario et al., 2011):

In patients 2 and 3, CSF 5-MTHF was undetectable despite preceding FA treatment (Table 1). Total red blood cell (RBC) folate was low in all patients. Initially, treatment with folinic acid (5-formyltetrahydrofolate; 5-FTHF) at 1 mg/kg per day resulted in CSF 5-MTHF normalization in patients 2 and 3; patient 1 was not reexamined.

--CopperKettle 10:36, 13 January 2019 (UTC)

References

A fresh article - is it a review?

I've just found one very fresh article, seemingly a review. I'm reading it: The Role of Vitamins in Autism Spectrum Disorder: What Do We Know?. (Bjorklund et al., Journal of Molecular Neuroscence, 2019)

How do I know if it is fit for use as a secondary source? It reads like a review. I'm stashing quotes from it in a Word file just in case. --CopperKettle 17:48, 13 January 2019 (UTC)

It includes a paragraph listing some studies\trials and a short "might improve" conclusion:

Cerebral folate deficiency is a disorder in which the concentrations of folate are low in the cerebrospinal fluid (CSF) but normal in the blood. Treatment with folate has normalized the CSF folate and improved the neurological manifestations (Ramaekers et al. 2002; Ramaekers et al. 2005, Frye et al. 2018). Many studies have demonstrated that patients with ASD usually had a folate deficiency, which was improved after treatment with folinic acid (Moretti et al., 2005; Ramaekers et al. 2005; Ramaekers et al. 2007; Moretti et al. 2008; Frye and Rossignol 2014). However, a study revealed no evidence for an association between early folic acid supplements for reduced risk of ASD in offspring of women compared with women with no supplement use in the same period (Virk et al. 2016). The most recent randomized, double-blind placebocontrolled trial (Frye et al. 2018) on patients with nonsyndromic ASD treatment with high-dose folinic acid for 3 months resulted in improvement in verbal communication as compared with placebo (Frye et al. 2018). Another study revealed that folate receptor α (FRα) autoantibodies (FRAAs) are common in ASD patients. The binding of FRAAs to the FRα could disrupt transport of folate across the blood-brain barrier (Frye et al. 2017). On the other hand, the overexpression of FRα in the early fetal thyroid indicates that maternal FRAAs during fetal and neonatal exposure could affect thyroid development and may contribute to the ASD pathology (Frye et al. 2017).

In conclusion, various studies showed some evidence on the treatment with folinic acid might improve the autistic symptoms and the effect of the periconceptional use of prenatal vitamins.

Comments are welcome. Is this a good source to be cited, and would the mention of this "folinic acid might improve" be okay in the article? --CopperKettle 18:21, 13 January 2019 (UTC)

P.S. The first author of this paper has a Wikipedia article dedicated to him, I've just discovered: Geir Bjørklund --CopperKettle 19:00, 13 January 2019 (UTC)

I still think of this proposed connection as a 'bridge too far.' Worried a but about the low impact factor of the journal in question and the fact that the authors (from many different countries) do not appear to have a past history of research in either folate metabolism or autism spectrum disorder. The causes section could benefit from more detail, but in my opinion premature to add mention of folinic acid as possible treatment for ASD. David notMD (talk) 21:19, 13 January 2019 (UTC)

I will check on the authors' backgrounds, but at least the lead author, Geir Bjørklund, seems to be immersed in autism research. --CopperKettle 06:40, 14 January 2019 (UTC)

There is a strong suspicion that Geir created the Wikipedia article about himself, using many different accounts (sockpuppets) or had other people make entries (meatpuppets). His support of mercury in dental fillings as the cause of many diseases is considered fringe science. David notMD (talk) 11:56, 14 January 2019 (UTC)

But there seems no "controversy" section in his article, so his research must be not getting critique. And he seemingly gets grant funding without problems. Interesting. I'll read up. --CopperKettle 14:19, 14 January 2019 (UTC)

We are getting sidetracked here. The 'review' article is in my opinion not sufficient to support mention of autism as a condition treatable with folinic acid. As for Geir, there is no controversy section in the article about him because he wrote the article. David notMD (talk) 16:41, 14 January 2019 (UTC)

Mention of cow milk as a source of antigens provoking antibody production (secondary source, a 2018 book)

Mined some more info. Mention of cow milk as a culprit and a bovine milk-free diet as part of the therapeutic strategy. Description of cerebral folate deficiency by Asok C. Antony, in Concise Guide to Hematology (2018), in the chapter Vitamin B12 and Folate Deficiency, pages 37-48:

Cerebral folate deficiency:

(a) Caused either by congenital mutations or autoantibodies to folate receptors can perturb folate receptor-mediated folate transport into the brain (via the choroid plexus) and lead to cerebral folate deficiency.

(b) These autoantibodies to human folate receptors develop against closely related folate-binding proteins found in cow’s milk that share common epitopes.

(c) Neonatal presentation (~6 months): agitation/insomnia, deceleration of head growth, psychomotor retardation, hypotonia/ataxia, spasticity, dyskinesias, epilepsy, and even autistic features.

(d) Affected children respond to high-dose folinic acid and a bovine milk-free diet.

--CopperKettle 12:44, 15 January 2019 (UTC)

Interestingly in the 2012 edition of this chapter, the list contained section (e), which apparently went missing later:

(e) Similar auto - antibodies to folate receptors found in two autism spectrum disorders (Rett syndrome and infantile low - functioning autism with neurological abnormalities); some can respond partially or completely to folinic acid. Rett syndrome — which occurs almost exclusively in girls and may be misdiagnosed as autism or cerebral palsy — is a disorder of the nervous system that is clinically silent until 6 – 18 months when it manifests itself by developmental reversals, especially in the areas of expressive language and hand use ( https://health.google.com/health/ref/Rett+syndrome ).

--CopperKettle 12:55, 15 January 2019 (UTC)

References

moderate versus severe

If look back at Perez (PMID 21555636) makes a distinction between moderate and severe CFD. Many diseases for moderate, a few for severe. Begs question whether low cerebral folate concentration is result of many conditions and also a cause of a few. I added Desai as ref in support of folinic acid for autoantibody condition. David notMD (talk) 22:25, 15 January 2019 (UTC)

In my MS Word file where I stashed quotes from CFD-related papers, this is one of the most quoted paper. I have a couple of full pages of quotes from it. Indeed, their patients demonstrated a correlation between serum folate and CSF folate: "A strong correlation was observed between cerebrospinal fluid and plasma folate levels in cerebral folate deficiency". That's probably because many patients were moderately deficient - maybe in such cases the brain deficiency may stem partly from overall deficiency, or generally from the overall diseased state of the organism (leading to poor choroid plexus function?). Another quote:

"Our results illustrate that it is also possible that mild or moderate reductions of CSF 5-MTHF concentration indicate transient biochemical derangement in acquired conditions such as asphyxia or CNS infections. In our experience, 1 patient with benign idiopathic neonatal seizures and reduced 5-MTHF values showed spontaneous normalization of 5-MTHF values 6 months later, whereas 4 patients with initial normal values of 5-MTHF (mean, 58 nmol/L) exhibited a significant drop in 5-MTHF concentrations (mean, 24 nmol/L) after a mean period of 12 months. "

--CopperKettle 05:21, 16 January 2019 (UTC)

Here are my three MS Word files with excerpts from different papers. --CopperKettle 07:59, 16 January 2019 (UTC)

Mentioned in an autism-related article

Cerebral folate deficiency is mentioned in an autism-related article in Wikipedia: Conditions comorbid to autism spectrum disorders. I'm afraid though that this might be deleted because of course there's only one high-quality study of folinic acid in autism thus far. --CopperKettle 16:00, 21 January 2019 (UTC)

Seems like it's a losing battle, trying to keep medical articles in Wikipedia reliant on secondary sources. I find primary sources galore while browsing the articles. --CopperKettle 16:09, 21 January 2019 (UTC)

Excerpts from a 2019 review

• (2019)(REVIEW) (Simon Pope et al.) Cerebral folate deficiency: Analytical tests and differential diagnosis. IN: Journal of Inherited Metabolic Disease (Impact: 3.970, from 1978) PMID 30916789

The authors write that CFD can also be caused by mutations affecting 5-formyltetrahydrofolate cyclo-ligase, but thus far there are only two cases known, with a pioneering publication in 2018. In patients, 5-MTHF is at the low end of normal range, but..

Rodan et al. hypothesise that although extracellular 5-MTHF levels are not low, intracellular levels may be deficient and suggest that accumulation of intracellular 5-formyl-THF polyglutamates may inhibit synthesis of 5,10-methylenetetrahydrofolate by SHMT and in turn lead to inhibition of 5-MTHF production.

Further, the authors of the review write that Serine deficiency syndromes also cause CFD:

Thus, serine deficiency leads to mild to moderate CFD and disorders of serine biosynthesis and transport should be considered in the differential diagnosis of CFD (Molero-Luis et al, 2015).

A quote about CFD in Dihydropteridine reductase deficiency:

Progressive cerebral calcification affecting the basal ganglia and white matter has been reported to result from secondary CFD in patients with DHPR deficiency and can be prevented by folinic acid supplementation (Irons et al, 1987; Woody et al, 1989."

A quote about folate receptor autoantibodies (Ramaekers, Frye, etc.):

These results have not been replicated in other laboratories and it is possible that in some neurological conditions, the observed mildly low CSF 5-MTHF values are an epiphenomenon with no pathophysiological implications. In the authors’ experience, a relatively frequent cause of mild to moderate CFD is a suboptimal blood folate status due to inadequate intake (Perez-Dueñas et al, 2011).

--CopperKettle 17:04, 17 April 2019 (UTC)

GNAO1: two case reports

Interesting:

• Case report 1
• Case report 2

--CopperKettle (talk) 06:07, 20 November 2022 (UTC)

Hyperphosphatasia with mental retardation 3: case report

A case report of cerebral folate deficiency in a 5 yo girl with HPMRS 3. CopperKettle (talk) 07:09, 27 April 2023 (UTC)