Hereditary methemoglobinemia presenting as breakthrough seizures: a case letter

Methemoglobinemia is a rare condition characterized by elevated levels of methemoglobin (MetHb), a form of hemoglobin with oxidized ferric iron (Fe3+) instead of ferrous (Fe2+), rendering it unable to bind oxygen. This leads to impaired oxygen delivery to tissues, causing hypoxia and cyanosis despite normal arterial oxygen tension.[1] Methemoglobinemia can be congenital or acquired. Congenital forms result from mutations in genes such as CYB5R3, which encodes NADH-cytochrome b5 reductase (CYB5R), the enzyme responsible for reducing MetHb to functional hemoglobin.[2] There are 2 types of congenital methemoglobinemia. Type I (erythrocytic) is limited to red blood cells and presents with mild cyanosis, while Type II (generalized) affects all tissues and is associated with severe neurological impairment and developmental delay.[3] CYB5R maintains redox balance in erythrocytes by transferring electrons from NADH to cytochrome b5, which reduces MetHb.[4] Mutations such as P144L and L148P in the CYB5R3 gene impair enzyme stability and activity, contributing to congenital methemoglobinemia.[5] The CYB5R enzyme assay evaluates enzyme activity in patient samples. Hall et al.[6] described an antibody-based spot test that sensitively detects CYB5R activity in hemolysates and helps identify patients with congenital CYB5R deficiency. The standard treatment for acquired methemoglobinemia is methylene blue, which acts as an artificial electron acceptor for NADPH-dependent MetHb reductase, restoring hemoglobin to its oxygen-carrying state.[1] We present the case of a 21-year-old woman with a history of epilepsy, attention-deficit/hyperactivity disorder, depression, and anxiety, who presented to the emergency department (ED) with breakthrough seizures. Two weeks earlier, she was seen in the ED for a single generalized tonic-clonic seizure. Computerized tomography brain and chest X-ray were unremarkable, and she was discharged after observation. No arterial blood gas (ABG) was obtained, and methemoglobinemia was not suspected. She returned after experiencing 2 witnessed episodes of generalized tonic-clonic seizures at home. She reported compliance with her antiseizure treatment with levetiracetam (LEV) 750 mg twice daily. In the ED, she was given 1 g of LEV, a computerized tomography brain showed no intracerebral abnormalities or changes since the previous exam, and chest X-ray and electrocardiogram were normal. Her initial vitals were notable for hypoxia with an oxygen saturation in the 80s on room air, which did not improve with supplemental oxygen via nasal cannula. A complete blood count and comprehensive metabolic panel were normal except for total bilirubin 1.6 mg/dL. Urinalysis was unremarkable. ABG on 4 L oxygen showed MetHb 16.9%, above the 5% diagnostic threshold (Table 1). Urine toxicology was positive only for marijuana. Poison control was contacted and recommended methylene blue 1 mg/kg. This resulted in immediate improvement in O2 saturation and she was admitted to the intensive care unit for observation. Table 1 - Arterial Blood Gas Before and After Methylene Blue Administration Parameter 14:27 (Before Methylene Blue) 19:33 (After Methylene Blue) Reference Range ABG HCO3 − (mmol/L) 21.4 ↓ 24.0 22–26 Base excess (BE) −2.2 −0.2 −2 to +2 Temperature (°C) 37.0 37.0 37.0 Corrected pH 7.425 7.418 7.35–7.45 Corrected pCO2 (mm Hg) 33.3 ↓ 38.1 35–45 Corrected pO2 (mm Hg) 228.9 ↑ 100.5 75–100 Total hemoglobin (g/dL) 13.7 13.2 12–16 Deoxyhemoglobin (%) 0.0 2.0 95 O2 saturation (%) 100.0 98.0 >95 O2 delivery device 4 L via nasal cannula Room air – Carboxyhemoglobin (%) 0.3 0.6