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cerebral folate receptor alpha deficiency

ICD-10 Codes

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Description

Cerebral Folate Receptor Alpha Deficiency: A Treatable Neurodegenerative Disorder

Cerebral folate receptor alpha (FRα) deficiency is a rare neurodevelopmental disorder caused by a shortage of the B-vitamin folate in the brain. This condition affects the transport of 5-methyltetrahydrofolate (5-MTHF), a crucial form of folate, into the brain.

Signs and Symptoms

The symptoms of cerebral folate receptor alpha deficiency can vary from person to person but often include:

  • Movement disturbances
  • Loss of previously acquired mental and movement abilities
  • Poor muscle control (ataxia)
  • Epilepsy
  • Irritability and anxiety
  • Poor sleep
  • Gross motor problems or coordination issues
  • Tics
  • Seizures, including absence seizures, myoclonic fits, and tonic-clonic episodes

Causes and Diagnosis

Cerebral folate receptor alpha deficiency is caused by a defect in the folate receptor alpha gene, leading to impaired transport of 5-MTHF into the brain. This condition can be diagnosed through various tests, including:

  • Measurement of 5-MTHF levels in cerebral spinal fluid
  • Genetic testing for mutations in the folate receptor alpha gene

Treatment and Management

Fortunately, cerebral folate receptor alpha deficiency is a treatable condition. Treatment typically involves supplementation with 5-MTHF, which can help alleviate symptoms and improve cognitive and motor function.

References

  • [1] Cerebral folate transport deficiency is a disorder that develops from a shortage (deficiency) of the B-vitamin folate (also called vitamin B9) in the brain. [2]
  • The cerebral folate receptor alpha (FRα) transports 5-methyltetrahydrofolate (5-MTHF) into the brain; low 5-MTHF in the brain causes cerebral folate deficiency. [3]
  • Folate receptor alpha defect causes cerebral folate transport deficiency: a treatable neurodegenerative disorder associated with disturbed myelin metabolism. [5]
  • Symptoms range from sleep disturbance, irritability, visual disturbance and seizures in the form of absence seizure, myoclonic fits and tonic-clonic episodes. [6]

Additional Characteristics

  • Tics
  • Epilepsy
  • Movement disturbances
  • Loss of previously acquired mental and movement abilities
  • Poor muscle control (ataxia)
  • Irritability and anxiety
  • Poor sleep
  • Gross motor problems or coordination issues
  • Seizures, including absence seizures, myoclonic fits, and tonic-clonic episodes

Signs and Symptoms

Early symptoms of cerebral folate receptor alpha deficiency include intellectual disability, speech difficulties, and recurrent seizures in a third of affected children [1].

Some common signs and symptoms of this condition are:

  • Intellectual disability: Individuals with cerebral folate receptor alpha deficiency may experience significant delays or regression in their cognitive development [4].
  • Speech difficulties: Speech problems, including trouble talking, are also a characteristic feature of this condition [6].
  • Recurrent seizures (epilepsy): Seizures occur in approximately one-third of affected children and can be a recurring issue [1][2].
  • Movement disturbances: Movement problems such as tremors, difficulty with coordination, and poor muscle control (ataxia) are also associated with cerebral folate receptor alpha deficiency [4].
  • Developmental delay or regression: Some individuals may experience delays or regression in their developmental milestones [5].

Without treatment, additional symptoms can include poor muscle tone, trouble with coordination, and seizures [6].

It's essential to note that these symptoms can vary in severity and presentation among affected individuals.

Additional Symptoms

  • Intellectual disability
  • Speech difficulties
  • Developmental delay or regression
  • Movement disturbances
  • Recurrent seizures
  • Poor muscle tone
  • Trouble with coordination

Diagnostic Tests

Diagnostic Tests for Cerebral Folate Receptor Alpha Deficiency

Cerebral folate receptor alpha (CFRA) deficiency, also known as cerebral folate deficiency (CFD), is a rare disorder that affects the brain's ability to absorb folate. Diagnostic tests are essential to confirm this condition.

  • Molecular Genetic Testing: This test identifies biallelic FOLR1 pathogenic variants in individuals with CFRA deficiency [1].
  • Blood Test: A blood test can determine if an individual has Foliate Receptor Autoantibodies (FRAAs), which are associated with CFD [4]. However, this test cannot confirm the presence of CFRA deficiency.
  • Cerebrospinal Fluid (CSF) Analysis: This procedure involves taking a sample of CSF from the brain and spinal cord to detect autoantibodies that interfere with folate transfer [8].
  • Imaging Studies: MRI brain scans may show delayed myelination and demyelinated subcortical and periventricular areas in individuals with untreated CFD [3].

References:

[1] Jan 11, 2024 — The diagnosis of FOLR1-CFTD is established in a proband with biallelic FOLR1 pathogenic variants identified by molecular genetic testing. [3] by VT Ramaekers · 2022 · Cited by 32 — Among half of the untreated CFD cases, MRI brain scans show delayed myelination with demyelinated subcortical and periventricular areas, ... [4] A blood test can determine if your child has FRAAs. It is important to note that a Folate Receptor Autoantibody Test cannot tell you whether or not your child ... [8] by VT Ramaekers · 2005 · Cited by 293 — Cerebral folate deficiency is a disorder in which autoantibodies can prevent the transfer of folate from the plasma to the cerebrospinal fluid.

Additional Diagnostic Tests

  • Blood Test
  • Imaging Studies
  • Cerebrospinal Fluid (CSF) Analysis
  • Molecular Genetic Testing

Treatment

Cerebral folate receptor alpha (FRα) deficiency can be treated with various medications, including:

  • d,l-leucovorin (folinic acid): This is a form of folic acid that can be used to treat FRα deficiency. It works by bypassing the defective FRα protein and directly delivering folate into the brain [3][6].
  • High-dose methyfolate: This medication has been shown to be beneficial in treating FRα deficiency, particularly in children with autism spectrum disorders (ASD) [4][8].
  • Folinic acid supplementation: Daily administration of high-dose folinic acid has been found to be effective in controlling symptoms and improving cognitive function in individuals with FRα deficiency [7].

It's essential to note that these treatments may have varying degrees of success, and individual results may differ. A healthcare professional should be consulted for personalized guidance on medication treatment.

References:

[3] Rossignol DA (2021) - CFD has been associated with autism spectrum disorders (ASD) and is treated with d,l-leucovorin (folinic acid).

[6] Oct 15, 2022 - Folinic acid (tradename Leucovorin) is a form of folic acid that can be used to treat cerebral folate deficiency.

[7] Ramaekers VT (2014) - Daily administration of high-dose folinic acid appears to be beneficial for the control of negative and positive symptoms.

[8] Frye RE (2013) - This study suggests that FRAs may be important in ASD and that FRA-positive children with ASD may benefit from leucovorin calcium treatment.

Recommended Medications

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Differential Diagnosis

Additional Differential Diagnoses

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Additional Information

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DOID:0050719
rdf-schema#label
cerebral folate receptor alpha deficiency
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t332329
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http://www.w3.org/2002/07/owl#Class
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owl#annotatedSource
t332497
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disease_ontology
oboInOwl#created_by
lschriml
oboInOwl#creation_date
2012-06-11T02:58:59Z
oboInOwl#id
DOID:0050719
oboInOwl#hasDbXref
MIM:613068
oboInOwl#hasExactSynonym
Neurodegeneration due to cerebral folate transport deficiency
IAO_0000115
A vitamin metabolic disorder that has_material_basis_in mutations in the folate receptor 1 (FOLR1) gene coding for folate receptor alpha (FRalpha), is located_in the brain and is characterized by progressive movement disturbance, psychomotor decline, and epilepsy.
IDO_0000664
http://purl.obolibrary.org/obo/GENO_0000148
RO_0004026
http://purl.obolibrary.org/obo/UBERON_0001893
relatedICD
http://example.org/icd10/E75.243

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