Journal of the Neurological Sciences 336 (2014) 257–259 Contents lists available at ScienceDirect Journal of the Neurological Sciences journal homepage: www.elsevier.com/locate/jns Short communication A case of homocystinuria due to CBS gene mutations revealed by cerebral venous thrombosis Mariana Sarov a,b, Adeline Not a, Hélène Ogier de Baulny c, Pascal Masnou a, Katayoun Vahedi d, Marie-Germaine Bousser e, Christian Denier a,b,f,⁎ a Neurology Department, Bicêtre Hospital Assistance Publique — Hôpitaux de Paris (AP-HP), France Paris-Sud University, Le Kremlin Bicêtre, France Pediatry Department, Robert Debré Hospital, AP-HP, France d Neurology Unit, Hôpital Privé d'Antony, France e Neurology Department, Lariboisière Hospital, AP-HP, Paris, France f INSERM U788, Le Kremlin-Bicêtre, France b c a r t i c l e i n f o Article history: Received 16 July 2013 Received in revised form 2 October 2013 Accepted 4 October 2013 Available online 11 October 2013 Keywords: Cerebral venous thrombosis Hyperhomocysteinemia Cystathionine beta synthase (CBS) Methionine Vascular Thromboembolic a b s t r a c t Background: Homocystinuria caused by cystathionine beta synthase (CBS) deficiency is most often diagnosed in childhood and has a variable expressivity. The most frequent abnormalities include intellectual disability, ectopia lentis, myopia, skeletal abnormalities or thromboembolism. Objective: To report a case of homocystinuria unraveled by cerebral venous thrombosis (CVT). Observation: A 17 year old female was admitted in our department of neurology for subacute headache and presented seizures in the emergency room. Cerebral imaging revealed CVT. Severe hyperhomocysteinemia was found and led to the diagnosis of homocystinuria due to composite heterozygous mutations in the CBS gene. Further investigations disclosed lens subluxation in association with myopia, mild scoliosis and osteopenia. The patient was treated by heparin followed by warfarin, vitamin therapy and dietary methionine restriction. Total homocysteine and methionine levels became normal in a few weeks and the patient had a complete recovery. Conclusion: In patients with CVT, plasma total homocysteine measurement as part of the etiologic work up may reveal severe hyperhomocysteinemia due to CBS or remethylation defects that require specific treatment and management including perhaps protein-restricted diet and/or vitamin therapy for life. © 2013 Elsevier B.V. All rights reserved. 1. Introduction Causes, risk factors and predisposing conditions associated with cerebral venous thrombosis (CVT) are multiple [1]. Within the detailed biological work up, plasmatic total homocysteine (tHcy) concentration has to be systematically measured not only to detect frequent mild hyperhomocysteinemia due to C677T MTHFR polymorphism, this factor predisposing to thromboembolism events, but also to allow identification of rare but severe hyperhomocysteinemia due to cystathionine beta synthase (CBS) or remethylation defects (that require specific management, like protein-restricted diet and vitamin therapy for life). Homocystinuria due to defective CBS activity is a rare metabolic disease. In its classic form, it is a recessively inherited disorder of the transsulfuration pathway of methionine metabolism (see Fig. 1). Most often diagnosed in childhood, its worldwide incidence is from 1 in ⁎ Corresponding author at: Department of Neurology, Hôpital de Bicêtre, 78 rue du Général Leclerc, 94275 Le Kremlin-Bicêtre, France. Tel.: + 33 1 45 21 26 18; fax: + 33 1 45 21 31 49. E-mail address: christian.denier@bct.aphp.fr (C. Denier). 0022-510X/$ – see front matter © 2013 Elsevier B.V. All rights reserved. http://dx.doi.org/10.1016/j.jns.2013.10.009 58,000 to 1 in 1,000,000 [2–4]. CBS deficiency incidence varies from region to region. Differences are strongly influenced both by founder effects and by the relative frequencies of B6-responsive and B6-nonresponsive mutations. For example, the relatively high value of 1:58,000 is for Northern Ireland and is due to the frequency of the G307S B6-nonresponsive mutation. A more extreme example is the prevalence of 1:1800 found by molecular screening of newborns in the highly consanguineous population of Qatar, 6/7 of whom were homozygous for the B6-nonresponsive R336C mutation [5]. Common symptoms are developmental delay/intellectual disability, epilepsy, ectopia lentis and/or severe myopia, skeletal abnormalities (“marfanoid” aspect, scoliosis and osteoporosis) and vascular changes, mostly thromboembolic events. Homocystinuria due to CBS deficiency is also sometimes revealed by CVT in adults or teenagers [6–10] as herein reported with details. 2. Case report A 17 year-old female was admitted in our department of neurology for a 2 week history of headaches, nausea and vomiting. She had no 258 M. Sarov et al. / Journal of the Neurological Sciences 336 (2014) 257–259 Fig. 1. Schematic representation of homocysteine and methionine metabolism. Enzymes are represented in bold characters. Cardinal biochemical features of CBS deficiency are markedly increased levels of plasma total homocysteine (tHcy) and its metabolite, methionine, and increased homocystinuria. Hyperhomocysteinemia with a normal methionine level can be caused by metabolic errors that affect homocysteine to methionine conversion or disorders of cobalamin/vitamin B12 metabolism. Adapted from Testai and Gorelick [4]. personal or family medical history. She was in high school studying literature and her global intellectual quotient was 105. Hormonal triphasic low dose estroprogestative contraception had been initiated three weeks before and then suspended because of nausea and abdominal pain. In the emergency room, she presented seizures beyond which neurological examination and standard biology were normal. Brain CT showed a hyperdensity of superior sagittal and right lateral sinuses. MRI confirmed thrombosis, with no associated sign of brain venous infarction. Additional hematological work up showed normal protein C and S, antithrombin III, anticardiolipin and β2GP1 antibodies. Factor II and V and MTHFR polymorphism screenings were negative. Plasmatic total homocystine (tHcy) level was high: 500 μmol/L (normal b 15). Further investigations confirmed homocystinuria with an abnormal level of plasma methionine (548 μmol/L) on plasma aminoacid chromatomatography. Cystathionine beta synthase (CBS) activity was markedly reduced in cultured fibroblasts. Genetic analysis revealed 2 heterozygous nucleotidic variations: c.572 CNT (p. Thr191Met) and c.452-2ANC (p.Gly151Val fsX9), both previously described as pathogenic CBS mutations (CBS mutation database at http://cbs.lf1.cuni.cz/index. php). Except for subluxated lenses (see infra), clinical examination did not reveal the pathognomonic signs of hyperhomocyteinemia. The patient was slender (59 kg weight and 169 cm height) but, did not present the Marfan's morphotype except for long fingers. Ophthalmologic examination revealed bilateral and mild subluxation of the lens most probably responsible for a previously known myopia. Further investigations disclosed mild scoliosis and slight osteopenia of the long bones: osteodensitometry disclosed −1.1 Bone Mineral Density (BMD) (while osteoporosis refers to values below −2.5). Carotid, femoral and aortic vessels as well as cardiac ultrasonography were normal. The patient was treated with low molecular weight heparin followed by oral warfarin. She improved rapidly: headaches disappeared in a few days and no further seizures occurred. Because of identification of initial high plasmatic methionine, and free and total homocysteinemia (respectively 521, 58 and 550 μmol/L (normal reference: b 10–40; b0.1 and b 15 μmol/L)), supplementations were prescribed with vitamins B6 (pyridoxine), B9 (folinic acid), and vitamin B12 (hydroxocobalamine) along with a methionine restricted diet. Dietary treatment reduced methionine intake by restricting natural protein supply and entailed reducing daily methionine amount to approximately 10 mg/kg bodyweight. Following this supplementation and restriction, the plasmatic methionine, and free and total homocysteinemia levels were lowered to 304, 46 and 209 μmol/L on day 7, and 169, 14 and 119 μmol/L on day 15, suggesting a B6-responsiveness in this patient. At 3 months follow up, the plasmatic methionine and free and tHcy levels remained low (i.e. respectively 34, 2 and 25 μmol/L) with diet and vitamin supplementation and the brain MRI showed recanalization of superior sagittal and lateral sinuses. Oral warfarin was then stopped and treatment with aspirin was prescribed. Six months later, no additional neurological event had occurred. 3. Discussion Our patient had superior sagittal sinus and right lateral sinus thromboses, which revealed a molecularly and biochemically proven CBS deficiency homocystinuria. The clinical presentation of a 2 week history of headaches and nausea is a classical sign of CVT, and diagnosis was finally established on MRI. The detailed etiologic work up showed increased levels of plasma total homocysteine (tHcy) and of its metabolite, methionine, and increased homocystinuria, which led to the diagnosis of CBS deficiency. Among biological predisposing conditions, elevated plasmatic levels of tHcy has been shown to be an independent risk factor for CVT (OR around 4) (for fasting tHcy N 90th percentile, OR 4.6 (95% CI 1.6 to 12.8) in Cantu et al., 2004 and 4.2 (2.3 to 7.6) in Martinelli et al., 2007) [11,12]. Factors causing mild or moderate hyperhomocysteinemia (from 15 to 70 μmol/L) include i) methylenetetrahydrofolate reductase (MTHFR) polymorphism C/T at position 677, ii) compounds interfering with the metabolism of folate or cobalamin (methotrexate, anticonvulsivants), iii) deficient nutritional status resulting from inadequate ingestion of vitamins and chronic renal failure or cancer. In rare cases of severe hyperhomocysteinemia (N 100 μmol/L), as in our patient, the diagnosis of homocystinuria with CBS deficiency or remethylation defects has to be considered (see Fig. 1). Very few cases of CVT revealing homocystinuria in adulthood or teenagers patients have been reported [6–10], especially in females in hormonal context, following delivery [6,7] or, as in our case, in M. Sarov et al. / Journal of the Neurological Sciences 336 (2014) 257–259 weeks following introduction of oral contraception. Initial deep vein thrombotic events in CBS deficiency have been previously reported in hormonal context in females with a history of deep venous thrombosis (DVT) and pulmonary embolism (PE). For example, Gaustadnes reported 3 sisters with hyperhomocysteinemia due to CBS mutations with no other known thrombophilic predisposition who presented single or multiple venous thromboses such as DVT and PE (but no CVT) at ages 21–23 y-o, while two of them were on oral contraceptives [13]. In one published case, CVT occurred after each of the patient's 2 pregnancies; CBS deficiency was diagnosed at the second episode [6]. Previously reported inaugural CVT mainly occurred in young women (at 17 and 30 years old) [8]; 16 years old [9] and 19 years old [4]. Additional thrombotic risk factors in these adult cases are rarely noted. When mentioned, associated symptoms are scarce and usually include only slight manifestations such as scoliosis, myopia and lens subluxation as in our case [8]. When noted, long term anticoagulation was prescribed knowing the possible iatrogenic osteoporosis in long term users of coumarins [6,9]. Because of thrombosis extension despite anticoagulation, in situ thrombolysis was performed in one case with superior sagittal thrombosis with subsequent frontal hemorrhage [6]. The prevalence of thrombotic complications in patients with CBS deficiency varies from 25% to 42% according to cohorts which included mainly B6 responsive patients or B6 non responders [2,3]. These complications are the major cause of morbidity and early death. Thrombotic events are mainly peripheral veins thrombosis (51%), and cerebrovascular accidents (32%) [2]. Occurrence of thromboembolic events is age-dependent: the risk for untreated patients is 25% at 16 years old and 50% at 29 years old [2,3]. In 1% of CBS deficiency patients, vascular events are inaugural [2]. Interestingly, recent research on genetic studies suggest that a high proportion, possibly the predominant portion of B6 responsive CBS deficiency patients, may be clinically asymptomatic or ascertained for thromboembolic events occurring as late as during the third decade [14]. Treatment strategies in hyperhomocystinuria aim to maintain the free and total homocyteine levels as close to normal as possible, so as to reduce significantly the cardiovascular risk. Vitamin B6 responsiveness has to be determined by a pyridoxine challenge to enhance the conversion of homocysteine to cysteine (see Fig. 1). Other treatments include folates and vitamin B12 supplementation, protein- and methionine-restricted diets and possibly betaine treatment [3,4]. In contrast to the usual more severely affected B6-nonresponsive CBS deficient patients, our patient had B6-responsive CBS deficiency and a mild phenotype with no associated intellectual disability [2]. 259 4. Conclusion Our case report illustrates a mild B6/pyridoxine responsive homocystinuria revealed by a CVT, emphasizing the importance of systematic total homocysteine (tHcy) measurement as part of the etiological CVT work up. CBS deficiency is rare but leads to important specific prophylactic management including vitamin supplementation, dietary restriction, and counseling for prevention of further thromboembolic events for life. Conflict of interest statement The authors have nothing to disclose. References [1] Bousser MG, Ferro JM. Cerebral venous thrombosis: an update. Lancet Neurol 2007;6:162–70. 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