Long term follow up of a 21 y/o female with methylcobalamin-treated methionine synthase deficiency. D. Adams1, B. Brooks5, J. Sloan1, J. Filiano2, H. Levy3,4, C. Venditti1 1) NHGRI, NIH, Bethesda, MD; 2) Dept of Pediatrics and Medicine, Dartmouth Medical School, Hanover, NH; 3) Div. of Genetics, Children's Hospital, Boston, MA; 4) Dept of Pediatrics, Harvard Medical School, Boston, MA; 5) NEI, NIH, Bethesda, MD.

   We present a 21 y/o female with methylcobalamin-treated methionine synthase deficiency (cblG). She was diagnosed at 5 m/o after a course marked by failure to thrive, irritability, and megaloblastic anemia. Visual evoked potential (VEP) testing showed impaired visual pathway conduction. Therapy with methylcobalamin was initiated. Shortly after diagnosis she developed infantile spasms with hypsarrythmia. Anti-epileptic medications (AEDs) were trialed without success. The seizures were only controllable by AEDs after a course of ACTH. VEPs gradually returned to normal, presumably due to optic nerve/tract remyelination. However, developmental delay and cognitive impairment persisted. Current therapies include methylcobalamin 500 mcg twice per week, L-methionine 25 mg twice daily, betaine 3 grams per day, folate and leukovorin. Urine organic acid analysis shows minimal excretion of 3-methylglutaconic acid and 3-methylglutaric acid. The total plasma homocysteine level is between 22 and 26 umol/L. The plasma methylmalonic acid level is normal at 0.15 umol/L. Plasma GAA and creatine are normal. Retinal exams are normal bilaterally; there is no evidence of optic atrophy. There is bilateral, asymmetric clonus at the ankles. A brain MRI shows normal brain structure. Magnetic resonance spectroscopy shows decreased NAA in some gray matter areas including the basal ganglia. The young woman described provides an example of the long term outcome of methionine synthase deficiency treated with methylcobalamin. Her overall course appeared to stabilize with the institution of therapy. Open issues include: 1) the contribution of her infantile spasms and hypsarrythmia to her present cognitive delays, 2) the progressivity of her lower extremity spasticity, 3) the metabolic basis of the 3-methylglutaconic and 3-methylglutaric acid excretion, and 4) the course of eye disease in treated cblG given the apparent reversal of visual tract damage.