Cerebral folate deficiency

Cerebral folate deficiency
File:File:5-Methyltetrahydrofolate.png
Synonyms	Cerebral folate deficiency syndrome, neurodegeneration due to cerebral folate transport deficiency, cerebral folate transport deficiency, FOLR1 deficiency<ref name=GARD2019> Cerebral folate deficiency(link). rarediseases.info.nih.gov. </ref><ref name=GHR2019/>
Pronounce
Field
Symptoms
Complications
Onset
Duration
Types
Causes	Genetic disorder<ref name=GHR2019/>, autoantibodies
Risks
Diagnosis	Lumbar puncture
Differential diagnosis
Prevention
Treatment
Medication	Folinic acid
Prognosis
Frequency	FOLR1 mutation, <20 described cases<ref name=GHR2019/>
Deaths

Cerebral folate deficiency is a condition in which concentrations of 5-methyltetrahydrofolate are low in the brain as measured in the cerebral spinal fluid despite being normal in the blood.<ref name=Gordon2009>,

 Cerebral folate deficiency., 
 Developmental Medicine and Child Neurology, 
 
 Vol. 51(Issue: 3),
 pp. 180–182,
 DOI: 10.1111/j.1469-8749.2008.03185.x,
 PMID: 19260931,</ref> Symptoms typically appear at about 5 to 24 months of age.<ref name=Gordon2009/><ref name=GHR2019/> Without treatment there may be poor muscle tone, trouble with coordination, trouble talking, and seizures.<ref name=Gordon2009/> 

One cause of cerebral folate deficiency is a mutation in a gene responsible for folate transport, specifically FOLR1.<ref name=GHR2019/><ref name="pmid22835503">,

 Genetic causes of cerebral folate deficiency: clinical, biochemical and therapeutic aspects, 
 Drug Discovery Today, 
 
 Vol. 17(Issue: 23–24),
 pp. 1299–1306,
 DOI: 10.1016/j.drudis.2012.07.008,
 PMID: 22835503,</ref> This is inherited from a person's parents in an autosomal recessive manner.<ref name=GHR2019/> Other causes appear to be Kearns–Sayre syndrome<ref name=Baumgartner2013>, 
  
 Vitamin-responsive disorders: cobalamin, folate, biotin, vitamins B1 and E., 
  
  
  
  
 Volume: 113, 
 ISBN 9780444595652, 
 DOI: 10.1016/B978-0-444-59565-2.00049-6, 
  
  
 Pages: 1799–1810,</ref> and autoantibodies to the folate receptor.<ref name="pmid20668945">, 
 Cerebral folate deficiency, 
 Journal of Inherited Metabolic Disease, 
 
 Vol. 33(Issue: 5),
 pp. 563–570,
 DOI: 10.1007/s10545-010-9159-6,
 PMID: 20668945,</ref><ref name="pmid23984056">, 
 Vitamin-responsive epileptic encephalopathies in children, 
 Epilepsy Research and Treatment, 
 
 Vol. 2013,
 pp. 1–8,
 DOI: 10.1155/2013/510529,
 PMID: 23984056,
 PMC: 3745849,</ref><ref name="MD2012">{{{last}}}, 
 Phillip L. Pearl, MD, 
  
 Inherited Metabolic Epilepsies. online version, 
  
 Demos Medical Publishing, 
  
  
  
 ISBN 978-1-61705-056-5, 
  
  
  
 Pages: 3–,</ref>

For people with the FOLR1 mutation, even when the systemic deficiency is corrected by folate, the cerebral deficiency remains and must be treated with folinic acid. Success depends on early initiation of treatment and treatment for a long period of time.<ref name="pmid27664775">,

 The proton-coupled folate transporter (PCFT-SLC46A1) and the syndrome of systemic and cerebral folate deficiency of infancy: Hereditary folate malabsorption, 
 Molecular Aspects of Medicine, 
 
 Vol. 53,
 pp. 57–72,
 DOI: 10.1016/j.mam.2016.09.002,
 PMID: 27664775,
 PMC: 5253092,</ref><ref name=Gordon2009/> Fewer than 20 people with the FOLR1 defect have been described in the medical literature.<ref name=GHR2019>

Cerebral folate transport deficiency(link). Genetics Home Reference.

</ref>

Signs and symptoms

Children with the FOLR1 mutation are born healthy. Symptoms typically appear at about 5 to 24 months of age. The symptoms get worse with time. Without treatment there may be poor muscle tone, trouble with coordination, trouble talking, and seizures.<ref name=GHR2019/><ref name=Gordon2009/>

Causes

One cause of cerebral folate deficiency is due to a genetic mutation in the FOLR1 gene. It is inherited from a person's parents in an autosomal recessive manner.<ref name=GHR2019/> Other causes appear to be Kearns–Sayre syndrome<ref name=Baumgartner2013 /> and autoantibodies to the folate receptor.<ref name="pmid20668945" /><ref name="pmid23984056" /><ref name="MD2012" />

Furthermore, secondary cerebral folate deficiency can develop in patients suffering from other conditions. For example, it can develop in AADC deficiency through the depletion of methyl donors, such as SAM and 5-MTHF, by O-methylation of the excessive amounts of L-dopa present in patients.<ref name = "pmid28100251">,

 Consensus guideline for the diagnosis and treatment of aromatic l-amino acid decarboxylase (AADC) deficiency, 
 Orphanet J Rare Dis,</ref><ref name="pmid30916789">, 
 Cerebral folate deficiency: Analytical tests and differential diagnosis, 
 Journal of Inherited Metabolic Disease, 
 
 Vol. 42(Issue: 4),
 pp. 655–672,
 DOI: 10.1002/jimd.12092,
 PMID: 30916789,</ref>

Treatment

For people with the FOLR1 mutation, even when the systemic deficiency is corrected by folate, the cerebral deficiency remains, and must be treated with folinic acid. Success depends on early initiation of treatment.<ref name="pmid27664775"/> Treatment requires taking folinic acid for a significant period of time.<ref name=Gordon2009/> Fewer than 20 people with the FOLR1 defect have been described in the medical literature.<ref name=GHR2019/> Treatment with pharmacologic doses of folinic acid has also led to reversal of some symptoms in children diagnosed with cerebral folate deficiency and testing positive for autoantibodies to folate receptor alpha.<ref name=Desai2016>,

 The metabolic basis for developmental disorders due to defective folate transport, 
 Biochimie, 
 
 Vol. 126,
 pp. 31–42,
 DOI: 10.1016/j.biochi.2016.02.012,
 PMID: 26924398,</ref>

See also

• Hereditary folate malabsorption
• Folate deficiency

External links

• Cerebral Folate Deficiency - description (2019) on the website of the National Organization for Rare Disorders (NORD).

References

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