Düzenli T., Demir E., Hırfanoğlu T., Kayhan G.
8. Erciyes Tıp Tıbbi Genetik Kongresi, Kayseri, Türkiye, 21 - 23 Eylül 2023, cilt.1, ss.71-72, (Özet Bildiri)
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Yayın Türü:
Bildiri / Özet Bildiri
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Cilt numarası:
1
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Basıldığı Şehir:
Kayseri
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Basıldığı Ülke:
Türkiye
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Sayfa Sayıları:
ss.71-72
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Gazi Üniversitesi Adresli:
Evet
Özet
Introduction
Cerebral folate deficiency is a progressive neurodegenerative disorder caused by biallelic pathogenic mutations in the FOLR1 gene, which encodes
the alpha subunit of the folate receptor in the choroid plexus. The disease manifests in late infancy with neurodevelopmental regression,
hypomyelinating leukodystrophy, ataxia and epilepsy. Treatment with folinic acid has been reported to improve symptoms, and in some patients,
even complete recovery has been reported.
Case Report
A 14-year-old male patient was referred to our clinic with epilepsy, neuromuscular regression and cerebellar atrophy. It was noted that he had no
previous illness until the age of 7 years and his neurodevelopmental milestones were normal. He developed tremor and ataxia at the age of 7
and generalized tonic-clonic seizures at the age of 11. The seizures were partially controlled with dual antiepileptic treatment. At the age of 12,
strabismus and walking difficulties were added to the patient’s symptoms.
Electroencephalography revealed generalized periodic epileptic discharges, which were considered in favor of neurodegenerative processes. Cranial
magnetic resonance imaging (MRI) showed hyperintense signal changes in the lentiform nuclei, cerebellar atrophy, and areas of no signal in the
bilateral frontoparietal and basal ganglia on the SWI sequence, consistent with Wilson’s disease (Figure 1). ATP7B sequence analysis performed for
Wilson disease was normal. Then, clinical exome sequencing [SOPHiA Genetics Clinical Exome Solution v3 kit (CES; SOPHiA Genetics, Boston, MA) and
sequenced on a NextSeq500 instrument (Illumina, San Diego, CA)] was performed for other possible etiology.
Clinical exome sequencing analysis revealed a homozygous non-sense variant, c.591C>A (p.Tyr197Ter), in the FOLR1 (NM_016729.3) gene, which
was classified as likely pathogenic (Figure 2). Following genetic diagnosis, low 5-methyltetrahydrofolate level in the cerebrospinal fluid supported
the diagnosis. Oral folinic acid treatment was started.
Discussion
Cerebral folate deficiency due to FOLR1 mutations is a very rare disorder, with 33 patients described in the literature to date. This gene encodes
the folate receptor-alpha (FOLRα), which is densely expressed in the choroid plexus and is responsible for the transport of 5-methyltetrahydrofolate
across the blood-brain barrier. Loss of function variants in this gene disrupt folate transport to the brain and cause progressive neurodegeneration.
The homozygous variant of FOLR1 (NM_016729.3) c.591C>A (p.Tyr197Ter) has not been previously reported in the literature. Since this variant is
located in the last exon of the protein, non-sense-mediated decay of the transcript is not clear. Although it has been suggested that this presumed
truncated protein may be responsible for the late onset of symptoms in our patient, even in patients who have variant may cause a longer truncated
protein is compatible with the typical course of the disease (1, 2). The late onset of symptoms in our patient may be related with diet, unknown
modifier genes or obscure initial findings.
Cerebellar atrophy, found in 84% (28/33) of patients, is the most common MRI finding and may be important in the differential diagnosis. In addition,
subcortical and periventricular white matter lesions, demyelination, hypomyelination, cerebral subcortical calcifications, basal ganglia calcifications,
encephalomalacia, laminar necrosis, thin corpus callosum can be considered in the differential diagnosis of many diseases (3).
Conclusion
Early treatment with folinic acid has been shown to stabilize and even reverse neurodegenerative processes in some patients (3). For this reason,
early diagnosis and treatment of this rare disease are of the utmost importance.
References
1. Toelle SP, Wille D, Schmitt B, Scheer I, Thöny B, Plecko B. Sensory stimulus-sensitive drop attacks and basal ganglia calcification: new findings in a patient
with FOLR1 deficiency. Epileptic Disord 2014; 16: 88-92.
2. Dill P, Schneider J, Weber P, Trachsel D, Tekin M, Jakobs C. Pyridoxal phosphate-responsive seizures in a patient with cerebral folate deficiency (CFD) and
congenital deafness with labyrinthine aplasia, microtia and microdontia (LAMM). Mol Genet Metab 2011; 104: 362-368.
3. Potic A, Perrier S, Radovic T, Gavrilovic S, Ostojic J, Tran LT. Hypomyelination caused by a novel homozygous pathogenic variant in FOLR1: complete clinical
and radiological recovery with oral folinic acid therapy and review of the literature. Orphanet J Rare Dis 2023; 18: 187.