A case of multiorgan atherosclerotic disease in patient affected by hyperhomocystinemia with multiple heterozygous mutations

Abstract number: CD116

Cortellaro^* M., Gualdoni^* A., Arquati^* M., Porta^* B., Serino^* G., Rossi† E.

†L. Sacco Hospital, Milan, Italy ^*San Donato Hospital, Italy;

Background  

Homocysteine (Hcy) is a sulfur amino-acid, whose metabolism is at the intersection of two metabolic pathways: the first one, transulfuration, which is catalyzed by cystathionine-b synthase (CBS) using vitamin B6 as a cofactor, the second one, remethylation, which is a reaction dependent from activation of methylentetrahydropholate redutase (MTHFR) and catalyzed by vitamin B12 dependent methionine synthase. Impaired enzyme function as a result of genetic mutation or deficiency of the essential B vitamins (pyridoxine and cyanocobalamin) and folic acid can lead to hyperhomocysteinemia. Raised levels of Hcy are independent and dose related risk factor for atherosclerotic vascular disease.

Case report  

Male 31 years old, non smoker presenting marfanoid habitus, at the age of 17 years onset of arterial hypertension (systolic value 170 mmHg; diastolic value 90 mmHg) associated with severe stenosis of right renal artery. The arterial pressure values were normalized after percutaneous transcatheter angioplasty. After two years were diagnosed lower limbs arteriopathy with trofic ulcers and the patient was submitted to gangliectomy without benefit. At the age of 24 years, ectopia lentis has been surgically corrected. At the age of 29 years the patient was sent to our department after acute myocardial infarction with angiographic evidence of significant stenosis of LAD coronary and second diagonal branch. Laboratory findings showed hyperHcy (364 mmol L^-1), reduced MTHFR activity due to double heterozygous mutations C677T and A1298C, CBS heterozygous mutation G919A, and low levels of vitamin B12 (103 pg mL^-1) and folic acid (3.7 ng mL^-1)Thrombophilic screening and genetic assessment for Marfan's syndrome were negative. No evidence of diabetes mellitus and dyslipidemia. From the age of 29 years the patient is receiving vitamin supplementation (50 mg of vitamin B6 and 5 mg of folic acid daily, plus 1000 mg of vitamin B12 montlhy). After 3 years follow-up, the patient appears symptoms-free and presents normal levels of Hcy (mean 12 mmol). Coronary angiography and 2-D B-mode ultrasound scans of lower limbs revealed complete regression of atherosclerotic lesions.

Conclusions  

In this case multiple heterozygous mutations in genes encoding for MTHFR and CBS determined clinical picture typical of single homozygous mutation. Replacement therapy with pyridoxine, cyanocobalamin, and folic acid is able to induce complete regression of documented atherosclerotic disease.