Cerebral Folate Deficiency via the FOLR1 Gene

Summary and Pricing

Test Method

Sequencing and CNV Detection via NextGen Sequencing using PG-Select Capture Probes
Test Code Test Copy GenesTest CPT Code Gene CPT Codes Copy CPT Codes Base Price
9171 FOLR1 81479 81479,81479 $640 Order Options and Pricing
Test Code Test Copy Genes Test CPT Code Gene CPT Codes Copy CPT Code Base Price
9171FOLR181479 81479 $640 Order Options and Pricing

Pricing Comments

This test is also offered via our exome backbone with CNV detection (click here). The exome-based test may be higher priced, but permits reflex to the entire exome or to any other set of clinically relevant genes.

An additional 25% charge will be applied to STAT orders. STAT orders are prioritized throughout the testing process.

Turnaround Time

18 days on average for standard orders or 14 days on average for STAT orders.

Once a specimen has started the testing process in our lab, the most accurate prediction of TAT will be displayed in the myPrevent portal as an Estimated Report Date (ERD) range. We calculate the ERD for each specimen as testing progresses; therefore the ERD range may differ from our published average TAT. View more about turnaround times here.

Targeted Testing

For ordering sequencing of targeted known variants, go to our Targeted Variants page.

EMAIL CONTACTS

Genetic Counselors

Geneticist

Clinical Features and Genetics

Clinical Features

Cerebral folate deficiency (CFD) is a neurometabolic disorder caused by reduced levels of folate in the brain. CFD patients typically present with global developmental delay around 2 years of age. Common symptoms seen in CFD patients include hypotonia, ataxia, myoclonic seizures, and athetoid movements (Grapp et al. 2012). Moderate to severe psychomotor regression is observed following disease onset. Patients are intellectually disabled, lack language, and have an increased incidence of aggressive behavior. If left untreated, patients develop frequent refractory seizures and are often wheelchair-bound due to worsening motor symptoms. MRI reveals abnormal myelination of the periventricular and subcortical white matter as well as cerebellar atrophy. Metabolite analysis reveals low 5-methyl-tetrahydrofolate levels in cerebrospinal fluid (CSF), but a normal folate metabolism profile in plasma. This CSF-plasma difference helps distinguish CFD from other folate deficiency syndromes (Pérez-Dueñas et al. 2010).

Oral folinic acid supplementation was found to greatly improve symptoms, particularly seizures and motor abnormalities, in affected individuals (Pérez-Dueñas et al. 2010; Grapp et al. 2012). Early folinic acid treatment at first clinical onset was reported to completely reverse CFD symptoms (Steinfeld et al. 2009).

Genetics

Cerebral folate deficiency is inherited in an autosomal recessive manner and can be caused by variants in the FOLR1 gene. Nonsense, missense, and splice site variants as well as small duplications in FOLR1 have been reported to cause cerebral folate deficiency (Grapp et al. 2012). Other reported causes of CFD include: autoantibodies directed against the FOLR1 protein, mitochondrial disorders, and Rett syndrome (Ramaekers et al. 2013).

Folate derivatives are essential cofactors required for many biological processes, including DNA synthesis. Dietary folate is metabolized in the liver to the physiologically active form 5-methyl-tetrahydrofolate (5MTHF) which is then distributed by the bloodstream (Hyland et al. 2010). Humans possess multiple folate receptors, and folate receptor-alpha appears to be the primary receptor responsible for transporting 5MTHF across the blood-CSF barrier in adults (Steinfeld et al. 2009). FOLR1 encodes the cerebral folate receptor-alpha. Loss of FOLR1 results in greatly reduced levels of 5MTHF in the brain. Supplementation with folinic acid increases serum levels of 5MTHF and increases the amount of 5MTHF transported to the CSF via other low affinity folate transporters (Ramaekers et al. 2013).

Clinical Sensitivity - Sequencing with CNV PG-Select

FOLR1 was sequenced in 72 patients with low levels (<40nmol/l) of 5MTHF in cerebrospinal fluid. Pathogenic FOLR1 variants were identified in 10 (~14%) patients (Grapp et al. 2012). The authors noted that of the 14 patients that had extremely low CSF 5MTHF levels (<5nmol/l), 10 (~70%) had pathogenic FOLR1 variants.

Testing Strategy

This test provides full coverage of all coding exons of the FOLR1 gene, plus ~10 bases of flanking noncoding DNA. We define full coverage as >20X NGS reads or Sanger sequencing.

Indications for Test

FOLR1 sequencing should be considered in patients with onset of seizure and developmental regression after two years of age who have normal blood folate levels, but have severely reduced 5MTHF in cerebrospinal fluid. One study suggests that CSF 5MTHF levels < 5 nmol/l are a strong indication for FOLR1 sequencing (Grapp et al. 2012). As mentioned above, FOLR1 variants are not the sole cause of CFD; Ramaekers et al. have published guidelines for molecular diagnosis in suspected CFD patients (Ramaekers et al. 2013). This test may also be considered for the reproductive partners of individuals who carry pathogenic variants in FOLR1.

Gene

Official Gene Symbol OMIM ID
FOLR1 136430
Inheritance Abbreviation
Autosomal Dominant AD
Autosomal Recessive AR
X-Linked XL
Mitochondrial MT

Disease

Name Inheritance OMIM ID
Cerebral Folate Deficiency AR 613068

Related Test

Name
Disorders of Folate Metabolism and Transport Panel

Citations

  • Grapp M, Just IA, Linnankivi T, Wolf P, Lucke T, Hausler M, Gartner J, Steinfeld R. 2012. Molecular characterization of folate receptor 1 mutations delineates cerebral folate transport deficiency. Brain 135: 2022–2031. PubMed ID: 22586289
  • Hyland K, Shoffner J, Heales SJ. 2010. Cerebral folate deficiency. Journal of Inherited Metabolic Disease 33: 563–570. PubMed ID: 20668945
  • Pérez-Dueñas B, Toma C, Ormazábal A, Muchart J, Sanmartí F, Bombau G, Serrano M, García-Cazorla A, Cormand B, Artuch R. 2010. Progressive ataxia and myoclonic epilepsy in a patient with a homozygous mutation in the FOLR1 gene. Journal of Inherited Metabolic Disease 33: 795–802. PubMed ID: 20857335
  • Ramaekers V, Sequeira JM, Quadros EV. 2013. Clinical recognition and aspects of the cerebral folate deficiency syndromes. Clinical Chemistry and Laboratory Medicine 51: PubMed ID: 23314536
  • Steinfeld R, Grapp M, Kraetzner R, Dreha-Kulaczewski S, Helms G, Dechent P, Wevers R, Grosso S, Gärtner J. 2009. Folate Receptor Alpha Defect Causes Cerebral Folate Transport Deficiency: A Treatable Neurodegenerative Disorder Associated with Disturbed Myelin Metabolism. The American Journal of Human Genetics 85: 354–363. PubMed ID: 19732866

Ordering/Specimens

Ordering Options

We offer several options when ordering sequencing tests. For more information on these options, see our Ordering Instructions page. To view available options, click on the Order Options button within the test description.

myPrevent - Online Ordering

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Requisition Form

  • A completed requisition form must accompany all specimens.
  • Billing information along with specimen and shipping instructions are within the requisition form.
  • All testing must be ordered by a qualified healthcare provider.

For Requisition Forms, visit our Forms page


Specimen Types

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