A novel 110-bp insertion in a patient with homocysteinuria.

Abstract

Homocysteinuria is an inherited recessive disorder caused by cystathionine beta-synthase (CBS) deficiency that has a wide spectrum of clinical manifestations, including ocular lens dislocation, skeletal disproportion, osteoporosis, vascular thrombosis, and central nervous system dysfunction [1]. The CBS enzyme catalyzes the synthesis of cystathionine from homocysteine and serine in the methionine pathway. This results in accumulation of homocysteine and methionine in plasma, leading to excretion of excessive urinary homocysteine. CBS deficiency has a worldwide incidence of 1/344,000 live births (range: 1/58,000-1/1000 live births) [2]. Human CBS is located in the cytoplasm of cells and is composed of 4 identical 63-kDa subunits. The CBS gene is located on the long (q) arm of chromosome 21 at position 22.3, encodes a protein consisting of 551 amino acids, and has 16 exons [3]. Herein we report a patient with homocysteinuria that was a carrier of compound heterozygote mutations in the CBS gene, 1 of which is novel, and a discussion of the clinical and molecular findings. A 14-year-old boy was referred to our hospital for evaluation of ocular symptoms that began approximately 1 year earlier. He was the first born of non-consanguineous parents that had lost 1 fetus. Family history of neurologic and thromboembolic disease was negative. Pregnancy and delivery were uneventful. The proband had neuromotor developmental delay. At the age of 10 years he had a clonic seizure of the left side. He had a marfanoid face and neurological examination showed left-sided central facial palsy, and mild left hemiparesis. Complete blood count results were normal. Cranial CT showed an area of low attenuation in the left frontoparietal region consistent with infarction. Prothrombotic work-up results were as follows: serum methionine level: 4.7 mg / dL (normal: 0.09-0.6 mg/dL); free homocysteine concentration: 50 mmol/L (normal: <12.5 mmol/L); urine homocysteine concentration: 360 mmol/L (normal: 5-15 mmol/L). The patient was diagnosed as homocysteinuria, and hydroxy cobalamin injections, vitamin B6, acetyl-salicylic acid, and a low-methionine diet were started and maintained.