Abstracts

Rationale: Folate receptor α (FRα) plays an important role in transporting 5-methyltetrahydrofolate (5-MTHF) from the blood into the cerebrospinal fluid (CSF). Mutations in the folate receptor 1 (FOLR1) gene encoding FRα cause cerebral folate deficiency (CFD). Early initiation of treatment with folinic acid is of paramount importance in CFD. We report two siblings with FOLR1-related CFD. Notably, the older sibling (patient 1) had an atypical presentation with hemiparesis, which delayed the diagnosis. Only after the more typical presentation in the younger sibling (patient 2) was the treatment with folinic acid started in both patients. We investigated patient 1 to find etiologic factors for stroke. We also searched the literature to see if there were patients with CFD due to a FOLR1 mutation who presented with stroke-like symptoms.

Methods: Patient 1 had his first seizure at the age of two years six months (staring, oroalimentary automatisms). CT scan was obtained (parents reported a mild head trauma), which revealed calcifications in basal ganglia. MRI revealed dilated ventricles and slight hypomyelination. Two months later, in the setting of a febrile illness, the child had few right-sided myoclonic seizures followed by short-lasting left-sided hemiclonic seizures, after which left-sided hemiparesis was noted. After a few such seizures, a repeat MRI showed a right-sided parieto-occipital T2 bright region spanning gray and white matter (fig. 1). To exclude hematological and cardiovascular causes, we checked cholesterol and performed echocardiography and coagulogram. To exclude a mitochondrial disorder, glucose and lactate in the blood and CSF were checked. After a few months of intensive rehabilitation physical therapy, the child recovered from hemiparesis but developed ataxia and tremor. Amino and organic acids were checked in blood and urine. Patient 1 continued to deteriorate with loss of speech and ambulation and developed drug-resistant seizures. Clinical exome sequencing revealed a homozygous mutation in FOLR1.

We conducted a literature search for cerebral folate deficiency AND (folate receptor 1 OR folr1 OR folate receptor alpha) AND mutat* NOT autoantibod*. Our search yielded 21 results. Articles with description of clinical presentations were included.

Results: The investigations performed for hemiparesis were within normal limits. Patient 1 recovered from hemiparesis after a few months of intensive rehabilitation therapy, making Todd’s paresis unlikely. Also, the seizures which preceded the hemiparesis were short-lasting, in contrast to longer-lasting seizures that could cause damage to the cortex and explain the hemiparesis. However, continuous EEG was not performed, and we cannot exclude the possibility of subclinical seizures.

From 24 patients presented in 13 articles, no one had stroke-like symptoms. Notably, MRIs of two patients showed laminar necrosis (BMC Med Genet 2020 21:235; Kobayashi Y et al. Severe leukoencephalopathy with cortical involvement and peripheral neuropathy due to FOLR1 deficiency. Brain Dev (2016)).

Conclusions: Patient 1’s presentation may expand the clinical spectrum of FOLR1-related CFD to include stroke-like episodes.

Funding: Please list any funding that was received in support of this abstract.: No funding was received.