Abstract Details

Title Novel Mechanism of Cerebral Folate Deficiency with Compound Heterozygous Variants in Reduced Folate Carrier (SLC19A1) in Two Siblings Manifesting with Acute Brainstem Lesions (Atypical ADEM)

Topic Child Neurology and Developmental Neurology

Presentation(s) P8 - Poster Session 8 (8:00 AM-9:00 AM)

Poster/Presentation
Number 6-006

Objective NA

Background CFD with movement disorders and epilepsy has been linked to three folate mechanisms: Proton-Coupled Folate Transporter (PCFT; SLC46A1), Folate Receptor alpha (FRα; FOLR1), and 5,10 methyl-tetrahydrofolate synthetase deficiency. We report a potentially novel mechanism of Cerebral Folate Deficiency (CFD) due to Reduced Folate Carrier (RFC) in two siblings that presented with acute symmetric brainstem lesions.

Design/Methods Whole exome sequencing (WES) of the siblings and their parents; serial CSF studies including neurotransmitters, 5-MTHF, and anti-FRα antibodies; and MRI imaging of both siblings were done.

Results At four months, the brother had focal seizures that evolved to intractable myoclonic epilepsy, progressive spastic quadriparesis and bulbar weakness when he presented to us at age three. Initial MRI showed signal abnormalities in the midbrain and basal ganglia, mimicking ADEM, which was treated with methylprednisolone and IVIG. Subsequently, WES identified compound heterozygous variants: c.137 G>A (p.S46N) and c.422_424del (p.F141del) in SLC19A1. At age three, CSF 5-MTHF was undetectable, prompting monthly 20mg/kg intravenous (IV) folinic acid. He died at age four years before achieving optimal CSF levels. Sister developed mild oculomotor apraxia and motor dyspraxia at three years. She was diagnosed with CFD at eight years. She was lost to follow up for 6 years , until age 14, when she presented with chronic rashes, subacute tinnitus and vomiting, progressing to acute encephalopathy with cardiac decompensation requiring ECMO. MRI revealed restricted diffusion and symmetric T2 FLAIR lesions in thalami and midbrain. Following treatment with high-dose IV methylprednisolone, IVIG, folinic acid, vitamin B12, and thiamine, her symptoms improved and MRI and CSF 5-MTHF levels normalized.

Conclusions We describe two siblings with heterozygous SLC19A1 variants(RFC) who presented with CFD manifesting as acute metabolic encephalopathy and symmetric brainstem lesions. Their treatment was challenging, possibly due to a novel genetic variant causing defect in folate transport into neurons.

Authors/Disclosures
Sanjit K. Sah, MD (SUNY Upstate Medical University) PRESENTER	Dr. Sah has nothing to disclose.
Ai Sakonju, MD (SUNY Upstate Medical Center)	Dr. Sakonju has nothing to disclose.

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