In an infant with methylmalonic aciduria (613646) detected by newborn screening, Quadros et al. (2010) identified a homozygous 3-bp deletion (262delGAG) in the CD320 gene, resulting in an in-frame deletion of glu88 in the 3-prime end of the first LDLR type A domain. Newborn screening identified increased blood C3-acylcarnitine levels, and urinary analysis showed moderately elevated MMA. Plasma vitamin B12 and total homocysteine levels were normal. Repeat screening on day 14 of life showed normal C3-acylcarnitine levels and increased MMA; vitamin B12 was administered intramuscularly, and MMA returned to normal. All hematologic parameters were normal, and the mother had no laboratory abnormalities. Studies of patient fibroblasts showed increased levels of MMA and homocysteine compared to control cells, but these levels decreased in the presence of high levels of cobalamin. Patient fibroblasts showed low uptake of transcobalamin-bound cobalamin, but normal conversion to adenosylcobalamin and methylcobalamin, suggesting a defect in the receptor. Insertion of the missing codon by site-directed mutagenesis fully restored TCBLR function. Studies of 4 additional cell lines derived from patients with similar features identified the same mutation; 2 of these additional patients had increased serum homocysteine.
Karth et al. (2012) described a 7-week-old male who presented with bilateral central retinal artery occlusions (CRAO) following incision and drainage of an inguinal lymph node abscess 2 days before and short course of clindamycin preoperatively. Laboratory studies showed elevated serum homocysteine and MMA, indicating a functional deficit of vitamin B12 although serum levels of B12 were normal. DNA analysis of patient fibroblasts revealed homozygosity for an in-frame deletion of glu88 (262_264delGAG) of the CD320 gene. After 5 days of treatment with intravenous vitamin B6 and intramuscular B12-hydroxocobalamine, serum homocysteine was nearly normalized and serum MMA was normalized. At follow-up at 4 months of age, the patient's vitamin B12, homocysteine, and MMA levels were within normal limits. Karth et al. (2012) noted that hyperhomocysteinemia is a known risk factor for retinal vascular occlusive disease; the CRAO in this patient resulted in severe vision loss.
