A Rare and Treatable Cause for Generalized Epilepsy: Biotinidase Deficiency

Biotin is an essential cofactor for four carboxylase enzymes that participate in glucose, amino acid, and fatty acid catabolism [1]. Biotin recycling is essential since humans cannot synthesize this molecule de novo, and it is mediated by the enzyme biotinidase. Deficiency of this enzyme leads to the disturbance of metabolic homeostasis with clinical features including seizures, ataxia, hypotonia, developmental delay, eczema, alopecia, and occasional ophthalmologic and auditory symptoms [2]. Biotinidase deficiency (BD) is an autosomal recessive disorder. Mild BD refers to the form of the disease with 10%–30% of enzyme activity, and these patients can be asymptomatic until triggered by metabolic stress [2]. We describe a teenager with well-controlled generalized epilepsy who was eventually diagnosed with mild BD. This 14-year-old previously healthy girl was diagnosed with idiopathic generalized epilepsy. She had normal development and was noted to be intellectually gifted. She was socially appropriate and participated in competitive cheerleading at school. Her physical examination was normal, including symmetric reflexes in the extremities and a thorough motor and sensory examination. Electroencephalogram indicated generalized, posterior-predominant epileptiform discharges. As part of her epilepsy evaluation, magnetic resonance imaging (MRI) of the brain showed a hyperintense T2-weighted signal in the right cerebral peduncle (Figure 1a) with no abnormal postcontrast enhancement on FLAIR (fluid-attenuated inversion recovery). Whole-exome sequence revealed compound heterozygosity for two pathogenic variants in the BTD gene, confirming a diagnosis of BD. Her regimen included levetiracetam 750 mg twice daily and biotin 5 mg daily. MRI brain at 8 months after initial scan showed interval decrease in signal intensity and size of the right cerebral peduncle lesion (Figure 1b). At 20 months after initial imaging, the lesion was barely detectable on imaging (Figure 1c). No further seizure episodes were observed, although the relationship to her epilepsy is unknown. We are currently evaluating when to stop her antiseizure medication. This report showcases a rare but treatable cause for epilepsy. The vast majority of BD occurs in the first few months of life and usually before 5 years of age [3]. When the deficiency presents late, it most commonly involves the central nervous system and can mimic acquired neuroinflammatory disorders [2, 3]. In one study, neurological problems occurred in 31% of adult-onset BD and 43% of mild BD, with seizures being one of the most frequent symptoms [2]. While MRI of the brain and spinal cord can be normal, both white matter lesions within the brain and spinal cord have been reported. In one study, the most common imaging abnormalities in children with BD included the optic pathway, fornices, mamillary bodies, hippocampus, brainstem, and spinal cord [4]. In patients with generalized epilepsy with unexplained white matter lesions, we encourage consideration of genetic testing of the BTD gene, as newborn screening captures only slightly more than half (51.5%) of the infants with this disorder, and mild deficiency may be missed due to its significant residual enzyme activity [2]. As our patient demonstrates, treatment can reverse identified lesions and prevent further complications [3]. We describe a pediatric patient with atypical clinical presentation of BD and the importance of considering this disorder in the differential diagnosis of generalized epilepsy and unexplained MRI white matter lesions. Clinicians should remain vigilant since early identification through genetic testing and prompt initiation of biotin can lead to significant clinical and radiologic improvements. Sammie Lai: writing – original draft, writing – review and editing, resources, data curation, investigation, validation. Fernando N. Galan: conceptualization, supervision, investigation, writing – review and editing, validation. The authors declare no conflicts of interest.