Ophthalmic Manifestations and Long-Term Visual Outcomes in Patients with Cobalamin C Deficiency

Ophthalmology. 2016 Mar;123(3):571-82. doi: 10.1016/j.ophtha.2015.10.041. Epub 2016 Jan 26.


Purpose: To explore the ocular manifestations of cobalamin C (cblC) deficiency, an inborn error of intracellular vitamin B12 metabolism.

Design: Retrospective, observational case series.

Participants: Twenty-five cblC patients underwent clinical and ophthalmic examination at the National Institutes of Health between August 2004 and September 2012. Patient ages ranged from 2 to 27 years at last ophthalmic visit, and follow-up ranged from 0 to 83 months (median, 37 months; range, 13-83 months) over a total of 69 visits.

Methods: Best-corrected visual acuity, slit-lamp biomicroscopy, dilated fundus examination, wide-field photography, fundus autofluorescence imaging, sedated electroretinography, optical coherence tomography, genetics and metabolite assessment.

Main outcome measures: Visual acuity and presence and degree of retinal degeneration and optic nerve pallor.

Results: Nystagmus (64%), strabismus (52%), macular degeneration (72%), optic nerve pallor (68%), and vascular changes (64%) were present. c.271dupA (p.R91KfsX14) homozygous patients (n = 14) showed early and extensive macular degeneration. Electroretinography showed that scotopic and photopic responses were reduced and delayed, but were preserved remarkably in some patients despite severe degeneration. Optical coherence tomography images through the central macular lesion of a patient with severe retinal degeneration showed extreme thinning, some preservation of retinal lamination, and nearly complete loss of the outer nuclear layer. Despite hyperhomocysteinemia, no patients exhibited lens dislocation.

Conclusions: This longitudinal study reports ocular outcomes in the largest group of patients with cblC deficiency systematically examined at a single center over an extended period. Differences in progression and severity of macular degeneration, optic nerve pallor, and vascular attenuation between homozygous c.271dupA (p.R91KfsX14) patients and compound heterozygotes were noted. The pace and chronicity of ophthalmic manifestations lacked strict correlation to metabolic status as measured during visits. Prenatal or early treatment, or both, may have mitigated ocular disease, leading to better functional acuity, but patients still progressed to severe macular degeneration. The effects of prenatal or early treatment, or both, in siblings; the manifestation of severe disease in infancy; the presence of comorbid developmental abnormalities; and the possible laminar structural defect noted in many patients are findings showing that cblC deficiency displays a developmental as well as a degenerative ocular phenotype.

Publication types

  • Observational Study
  • Research Support, N.I.H., Extramural
  • Research Support, N.I.H., Intramural

MeSH terms

  • Adolescent
  • Adult
  • Carrier Proteins / genetics
  • Child
  • Child, Preschool
  • Disease Progression
  • Electroretinography
  • Follow-Up Studies
  • Homocystinuria / diagnosis*
  • Homocystinuria / drug therapy
  • Homocystinuria / genetics
  • Homocystinuria / physiopathology
  • Humans
  • Hydroxocobalamin / therapeutic use
  • Injections, Intramuscular
  • Macular Degeneration / diagnosis*
  • Macular Degeneration / drug therapy
  • Macular Degeneration / genetics
  • Macular Degeneration / physiopathology
  • Nystagmus, Pathologic / diagnosis*
  • Nystagmus, Pathologic / drug therapy
  • Nystagmus, Pathologic / genetics
  • Nystagmus, Pathologic / physiopathology
  • Optic Nerve Diseases / diagnosis*
  • Optic Nerve Diseases / drug therapy
  • Optic Nerve Diseases / genetics
  • Optic Nerve Diseases / physiopathology
  • Optical Imaging
  • Oxidoreductases
  • Phenotype
  • Retrospective Studies
  • Strabismus / diagnosis*
  • Strabismus / drug therapy
  • Strabismus / genetics
  • Strabismus / physiopathology
  • Tomography, Optical Coherence
  • Visual Acuity / physiology
  • Vitamin B 12 Deficiency / congenital*
  • Vitamin B 12 Deficiency / diagnosis
  • Vitamin B 12 Deficiency / drug therapy
  • Vitamin B 12 Deficiency / genetics
  • Vitamin B 12 Deficiency / physiopathology
  • Vitamin B Complex / therapeutic use


  • Carrier Proteins
  • Vitamin B Complex
  • MMACHC protein, human
  • Oxidoreductases
  • Hydroxocobalamin

Supplementary concepts

  • Methylmalonic acidemia with homocystinuria