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  1. K. Cusmano-Ozog1,
  2. F. Lorey2,
  3. S. Levine2,
  4. M. Martin3,
  5. E. Nicholas3,
  6. S. Packman3,
  7. D. S. Rosenblatt4,
  8. T. M. Cowan1,5,
  9. G. M. Enns1
  1. 1Department of Pediatrics, Division of Medical Genetics, Stanford University, Stanford, CA
  2. 2California Department of Health Services, Genetic Disease Branch, Sacramento, CA
  3. 3Department of Pediatrics, Division of Medical Genetics, University of California, San Francisco, San Francisco, CA
  4. 4Department of Human Genetics and Division of Medical Genetics, Department of Medicine, McGill University, Montreal, QC
  5. 5Department of Pathology, Stanford University School of Medicine, Stanford, CA.


Cobalamin C (cblC) disease is the most common inborn error of vitamin B12 metabolism. Patients have elevated methylmalonic acid (MMA) and homocysteine and typically have a poor prognosis. Common features include mental retardation, nystagmus, pigmentary retinopathy, and neurodegeneration. Treatment includes protein restriction and hydroxocobalamin, betaine, carnitine, and folic acid supplementation. California initiated expanded newborn screening (NBS) in July 2005. Since that time, there have been 10 cases of cblC disease confirmed by fibroblast complementation analysis and/or biochemical studies, resulting in a surprisingly high estimated prevalence of 1 in 60,000. An additional three newborns have been identified in Northern California in whom confirmatory studies are pending. Because 8 of 10 cases are Hispanic, we estimate the prevalence in the Hispanic population to be 1 in 37,000. In the confirmed cases, initial NBS results showed an elevated C3 level ranging from 6.5 to 13.1 μmol/L and an elevated C3/C2 ratio ranging from 0.29 to 0.45 (reference range < 0.25). The state's initial cutoff level for C3 was 9.25 μmol/L; however, this was lowered to 6.5 μmol/L after one individual was confirmed to have cblC disease whose screen was positive only for an elevated C3/C2 ratio. Follow-up testing in the confirmed cases revealed elevated serum MMA levels of 10.8 to 208 μmol/L (normal < 0.3) and homocysteine levels of 26.8 to 247 μmol/L (normal < 14). At presentation, most patients were asymptomatic, although mild to moderate hypotonia was present in two cases and seizures in one in whom treatment was delayed until age 1 month. Given the ranges of abnormal metabolites and clinical presentations, cblC disease appears to comprise a phenotypic spectrum. Although most patients are still infants, they appear to be developing normally and do not have ophthalmologic abnormalities. Further studies including longitudinal ophthalmologic and developmental evaluations and genotype-phenotype correlation analysis are needed.

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