Recurrent stroke in a patient with vitamin B ₁₂ deficiency and MTHFR mutation

Abstract

W e report an unusual case of recurrent stroke in a patient with vitamin B 12 deficiency who was also homozygous for the methylene tetrahydrofolate reductase (MTHFR) gene mutation. The patient was a 35-year-old male vegetarian with no known medical history who initially presented with global aphasia, slurred speech, right facial weakness, and right-sided hemiplegia and was found to have a stroke (NIH Stroke Scale score of 25). At that time a CT scan of the head ruled out intracranial hemorrhage and a CT angiogram of the head and neck was done. The patient was found to have occlusion of the M1 segment of the left middle cerebral artery. Because he was within the time frame for thrombolytics, systemic thrombolysis with alteplase was given without improvement. He therefore underwent a cerebral angiogram that demonstrated occlusion of the M1 segment of the left middle cerebral artery and very poor leptomeningeal collaterals from the left anterior and posterior cerebral artery territories (figure 1). He underwent mechanical thrombectomy of the left middle cerebral artery thrombus with Penumbra aspiration device (Penumbra Inc., Alameda, CA) and SOLITAIRE stentriever (Covidien, Irvine, CA) with complete recanalization of the occluded segment (figure 2). He had a remarkable early recovery as the hemiplegia resolved. During the hospital course he was placed on a statin and low-dose aspirin and was later discharged to a rehabilitation unit for treatment of his right-sided hemiparesis and residual expressive aphasia. Workup for secondary stroke prevention, including telemetry and a transesophageal echocardiogram, was unremarkable.On follow-up MRI 3 months later, a small new acute left middle cerebral artery stroke was found. At that time he underwent a workup for a hypercoagulable state. The workup was negative for the following: lupus anticoagulant, anticardiolipin antibody, factor V Leiden mutation, prothrombin gene mutation, protein C and S deficiency, and antithrombin deficiency. However, the patient was found to have a markedly elevated homocysteine level of 55.7 mmol/L (normal 5-15 mmol/L) and relatively low levels of vitamin B 12 and folate at 206 ng/L (normal 180-914 ng/L) and 5.2 mg/L (normal $4 mg/L), respectively. Serum creatinine was 0.98 mg/dL and complete blood count showed hemoglobin of 14.4 g/dL and mean corpuscular volume of 88 fL. Genetic testing revealed the presence of homozygous MTHFR 677 TT genotype.The patient was then treated with supplemental vitamin B 12 1,000 mcg daily, initially IM and then orally. He also received folic acid supplementation. Two months later, the patient's symptoms improved dramatically, with resolution of his expressive aphasia and marked improvement of his right-sided hemiparesis. Laboratory data also showed improvement, as Practical ImplicationsIn certain patients with recurrent stroke, such as those with elevated homocysteine and MTHFR gene mutations, supplemental vitamin B 12 may be beneficial.

Traditional risk factors and combined genetic markers of recurrent ischemic stroke in adults

“…Pezzini et al 6 proved that the TT genotype of MTHFR 677 is a risk factor of recurrence (HR: 3.69). In addition, two cases demonstrate the association between homozygous MTHFR 677 variation and AIS recurrence in adults 27,28 . The second polymorphism of MTHFR (A1298C) has been studied in recurrent pediatric stroke, repeat abortions, and venous thrombosis, but not in recurrent AIS in adults 29,30 .…”

“…In addition, two cases demonstrate the association between homozygous MTHFR 677 variation and AIS recurrence in adults. 27,28 The second polymorphism of MTHFR (A1298C) has been studied in recurrent pediatric stroke, repeat abortions, and venous thrombosis, but not in recurrent AIS in adults. 29,30 This polymorphism was significantly associated with ischemic stroke recurrence in our study.…”

Insight into Crosstalk between Ferroptosis and Necroptosis: Novel Therapeutics in Ischemic Stroke

“…Inducers: erastin [22], sorafenib [23], acrolein [22] Inhibitors: DFO [24], vitamin B12 [25], carvacrol [26], Chinese herbal medicines including naotaifang [27] Inducers: alkylating agents [28], X-rays [29] Inhibitors: Nec-1 [30], infliximab [7], dabrafenib [31], Chinese herbal medicines including curcumin [32] 2 Oxidative Medicine and Cellular Longevity conditions, instead of SLC39A14 which is a member of the solute carrier 39 family mediating cellular uptake of iron, zinc, and manganese [54,55]. However, SLC39A14 functions as the hepatic transporter of NTBI in the absence of TF [54,55].…”

“…Homocysteine has been proven to be an adverse factor in ischemic stroke, because homocysteine activates microglia and induces proinflammatory cytokine release and promotes lipid peroxidation. Therefore, vitamin B12 (cyanocobalamin) reduces oxidative stress and lipid peroxidation by lowering homocysteine levels [ 25 ]. The changes are beneficial to inhibit ferroptosis, protect the integrity of endothelial cells and the BBB, promote neural repair, and improve recovery in ischemic stroke [ 25 , 176 , 177 ].…”

“…Therefore, vitamin B12 (cyanocobalamin) reduces oxidative stress and lipid peroxidation by lowering homocysteine levels [ 25 ]. The changes are beneficial to inhibit ferroptosis, protect the integrity of endothelial cells and the BBB, promote neural repair, and improve recovery in ischemic stroke [ 25 , 176 , 177 ]. In addition to vitamin B12, the most potent compound 2-(1-(4-(4-methylpiperazin-1-yl) phenyl) ethyl)-10H-phenothiazine (51) of promethazine has a good ability to permeate the BBB and good therapeutic effect in MCAO model [ 178 ].…”