Teaching Neuro
            <i>Images</i>
            : White matter hypomyelination and progressive calcifications in cerebral folate deficiency

Nicolai, Joost; Kempen, Marjan J. A. van; Postma, Alida A.

doi:10.1212/wnl.0000000000002805

Cited by 5 publications

(4 citation statements)

References 2 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…3 C). These observations reinforce the role of folate deficiency in SPG56 disease, since brain calcifications are a known feature of cerebral folate deficiency (Nicolai et al, 2016).…”

Section: Extension Of the Pathologic Process To Spg56 Patientssupporting

confidence: 76%

“…The association between the lack of folates and CYP2U1 LoF was further supported by neuroimaging studies. It has previously been reported that folate deficiency may be associated with white matter lesions, cortico-subcortical atrophy, and basal ganglia calcifications ( Nicolai et al, 2016 ). In our cohort, brain magnetic resonance imaging (MRI) revealed white matter lesions at a deep/periventricular level with a radial distribution in 15 patients, similar to earlier studies ( Tesson et al, 2012 ).…”

Section: Resultsmentioning

confidence: 99%

See 1 more Smart Citation

Implication of folate deficiency in CYP2U1 loss of function

Pujol

Legrand

Parodi

et al. 2021

Journal of Experimental Medicine

View full text Add to dashboard Cite

Hereditary spastic paraplegias are heterogeneous neurodegenerative disorders. Understanding of their pathogenic mechanisms remains sparse, and therapeutic options are lacking. We characterized a mouse model lacking the Cyp2u1 gene, loss of which is known to be involved in a complex form of these diseases in humans. We showed that this model partially recapitulated the clinical and biochemical phenotypes of patients. Using electron microscopy, lipidomic, and proteomic studies, we identified vitamin B2 as a substrate of the CYP2U1 enzyme, as well as coenzyme Q, neopterin, and IFN-α levels as putative biomarkers in mice and fluids obtained from the largest series of CYP2U1-mutated patients reported so far. We also confirmed brain calcifications as a potential biomarker in patients. Our results suggest that CYP2U1 deficiency disrupts mitochondrial function and impacts proper neurodevelopment, which could be prevented by folate supplementation in our mouse model, followed by a neurodegenerative process altering multiple neuronal and extraneuronal tissues.

show abstract

“…3 C). These observations reinforce the role of folate deficiency in SPG56 disease, since brain calcifications are a known feature of cerebral folate deficiency (Nicolai et al, 2016).…”

Section: Extension Of the Pathologic Process To Spg56 Patientssupporting

confidence: 76%

Section: Resultsmentioning

confidence: 99%

Implication of folate deficiency in CYP2U1 loss of function

Pujol

Legrand

Parodi

et al. 2021

Journal of Experimental Medicine

View full text Add to dashboard Cite

show abstract

“…The detection of folate in these regions suggests a role for this vitamin in many of the specialized functions of cells and connections in these regions, as evidenced by disruptions in folate metabolism leading to molecular, structural, and behavioral impairments [37]. Evidence of hypomyelination of white matter tracts in folate deficiency and genetic cases of CFD also suggest that folate is required for the development of these regions [38].…”

Section: Discussionmentioning

confidence: 99%

Brain Uptake of Folate Forms in the Presence of Folate Receptor Alpha Antibodies in Young Rats: Folate and Antibody Distribution

2023

View full text Add to dashboard Cite

In a rat model, following exposure to rat folate receptor alpha antibodies (FRαAb) during gestation, FRαAb accumulates in the placenta and the fetus and blocks folate transport to the fetal brain and produces behavioral deficits in the offspring. These deficits could be prevented with folinic acid. Therefore, we sought to evaluate folate transport to the brain in young rat pups and determine what effect FRαAb has on this process, to better understand the folate receptor autoimmune disorder associated with cerebral folate deficiency (CFD) in autism spectrum disorders (ASD). When injected intraperitoneally (IP), FRαAb localizes to the choroid plexus and blood vessels including the capillaries throughout the brain parenchyma. Biotin-tagged folic acid shows distribution in the white matter tracts in the cerebrum and cerebellum. Since these antibodies can block folate transport to the brain, we orally administered various folate forms to identify the form that is better-absorbed and transported to the brain and is most effective in restoring cerebral folate status in the presence of FRαAb. The three forms of folate, namely folic acid, D,L-folinic acid and levofolinate, are converted to methylfolate while L-methylfolate is absorbed as such and all are efficiently distributed to the brain. However, significantly higher folate concentration is seen in the cerebrum and cerebellum with levofolinate in the presence or absence of FRαAb. Our results in the rat model support testing levofolinate to treat CFD in children with ASD.

show abstract

“…At 2 years of follow-up, the neurologic examination and brain MRI performed were stable ( Figure, B ) than a nonprogressive leukoencephalopathy was hypothesized. 2 A further CSF analysis showed reduced 5-MTHF levels (10 nmol/L, normal values: 41–117), and genetic testing with next-generation sequencing of selected genes revealed the heterozygous variation of the FOLR1 double gene (c.45G>T and c.493+2T>C); therefore, CFD was diagnosed. The patient's father, mother, and 2 daughters were also assessed.…”

Section: Introductionmentioning

confidence: 99%

FOLR1 Gene Variation With Adult-Onset Cerebral Folate Deficiency and Stable Clinical and MRI Features up to 2 Years

Manco,

Cortese,

Alberti

et al. 2023

Neurol Genet

View full text Add to dashboard Cite

ObjectivesThe objective of this case report was to describe the first report ofFOLR1variants associated with adult-onset paucisymptomatic leukoencephalopathy associated with cerebral folate deficiency (CFD).MethodsConsidering the patient's symptoms, a nonprogressive leukoencephalopathy was suspected. CSF 5-methyltetrahydrofolate levels were low (10 nmol/L, normal range 41–117). With no other identifiable causes, a genetic analysis was conducted, revealing a compound heterozygousFOLR1variation (c.45G>T and c. 493+2T>C).ResultsA 47-year-old man with a history of drug and alcohol abuse was admitted to the hospital for double vision and postural instability. MRI of the brain was performed, which showed bilateral leukoencephalopathy. Diffusion tensor imaging revealed a diffuse reduction in fractional anisotropy, suggesting microstructural changes. MRI of the brain and overall clinical picture were stable on subsequent serial examinations.DiscussionScientific evidence supports the deleterious effect of c.45G>T and c.493+2T>C variations on the folate receptor-α (FRα) protein structure and function. The weakness of the expression and function of FRα without elimination of its function caused by specific compound heterozygous variations may explain the atypical features observed in our patient. Although rare, CFD should be considered in paucisymptomatic adult patients with stable diffuse MRI white matter changes.

show abstract

Teaching Neuro Images : White matter hypomyelination and progressive calcifications in cerebral folate deficiency

Cited by 5 publications

References 2 publications

Implication of folate deficiency in CYP2U1 loss of function

Implication of folate deficiency in CYP2U1 loss of function

Brain Uptake of Folate Forms in the Presence of Folate Receptor Alpha Antibodies in Young Rats: Folate and Antibody Distribution

FOLR1 Gene Variation With Adult-Onset Cerebral Folate Deficiency and Stable Clinical and MRI Features up to 2 Years

Contact Info

Product

Resources

About