Retinal Structure in Cobalamin C Disease: Mechanistic and Therapeutic Implications

Alemán, Tomás S.; Brodie, Frank; Garvin, Christopher; Gewaily, Dina; Fıçıcıoğlu, Can; Mills, Monte D.; Forbes, Brian J.; Maguire, Albert M.; Davidson, Stefanie L.

doi:10.3109/13816810.2014.885059

Cited by 16 publications

(26 citation statements)

References 38 publications

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“…These signs often occur before 1 year of age and include manifest nystagmus (16/21 [76%]), macular degeneration (7/21 [33%]), and irregular macula and reduced ERG results (patient 9 at 3 months of age and patient 11 at 1 month of age). An additional rare and severe early manifestation, first reported recently in a patient in the first year of life, 23 is macular coloboma as seen in patient 3 (3 months of age; Table 1). Although coloboma also is seen in some, but not all, older cblC patients as they progress to end-stage macular degeneration (Table 1; Fig 3A), 18 coloboma seen in the first few months of life could represent either very severe degenerative processes, abnormal ocular development at the time of birth, or both.…”

Section: Discussionmentioning

confidence: 84%

“…25 A role for this enzyme in human ocular development is suggested by the recent documentation, via spectral-domain OCT, of ocular changes from infancy to 13 years of age in one c.271dupA (p.R91KfsX14) homozygous patient in whom photoreceptor outer segment loss, thinning of the outer nuclear layer, and a thickened, delaminated inner retina resembling an immature retina were noted. 23 Other investigators have observed progressive degeneration via OCT imaging performed at 4 and 7 months of age. 18 The fact that we and others also have observed similar changes in retinal structure (Fig 4B, C), 18,23 that patients can demonstrate severe disease in infancy, and that comorbid developmental abnormalities exist reinforces the concept that cblC deficiency comprises a developmental, as well as a degenerative phenotype.…”

Section: Discussionmentioning

confidence: 98%

“…23 Other investigators have observed progressive degeneration via OCT imaging performed at 4 and 7 months of age. 18 The fact that we and others also have observed similar changes in retinal structure (Fig 4B, C), 18,23 that patients can demonstrate severe disease in infancy, and that comorbid developmental abnormalities exist reinforces the concept that cblC deficiency comprises a developmental, as well as a degenerative phenotype.…”

Section: Discussionmentioning

confidence: 98%

“…14,46,47 Compared with our c.271dupA (p.R91KfsX14) homozygous patients, the results for c.271dupA (p.R91KfsX14) homozygous patients in the literature are very similar. 14,23,48–51 …”

Section: Discussionmentioning

confidence: 99%

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

et al. 2016

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Ocular manifestations of cobalamin C deficiency include a developmental as well as a degenerative phenotype and lack strict correlation to metabolic status, but may be mitigated by prenatal or early treatment. Purpose To explore the ocular manifestations of cobalamin C (cblC) deficiency, an inborn error of intracellular vitamin B12 metabolism caused by mutations in the MMACHC gene. Design Retrospective, observational case series. Participants Twenty-five cblC patients underwent clinical and ophthalmic examination at the National Institutes of Health Clinical Center 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, 36 months; range, 13–83 months) over a total of 69 visits. Methods Best-corrected Snellen visual acuity, slit-lamp biomicroscopy, dilated fundus examination, wide-field photography, fundus autofluorescence imaging, sedated electroretinography, spectral-domain optical coherence tomography, 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 (e.g., microcephaly, cardiac noncompaction), 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.

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Section: Discussionmentioning

confidence: 84%

Section: Discussionmentioning

confidence: 98%

Section: Discussionmentioning

confidence: 98%

“…14,46,47 Compared with our c.271dupA (p.R91KfsX14) homozygous patients, the results for c.271dupA (p.R91KfsX14) homozygous patients in the literature are very similar. 14,23,48–51 …”

Section: Discussionmentioning

confidence: 99%

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

et al. 2016

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“…Early diagnosis and treatment can improve outcomes but cannot prevent all complications of CblC disease (Rosenblatt et al 1997;Andersson et al 1999;Boxer et al 2005;Smith et al 2006;Thauvin-Robinet et al 2007;Martinelli et al 2011;Aleman et al 2014). Early therapy may be particularly beneficial for late-onset patients, as it can be started prior to the development of any organ damage .…”

Section: Discussionmentioning

confidence: 99%

Cobalamin C Disease Missed by Newborn Screening in a Patient with Low Carnitine Level

et al. 2015

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Cobalamin C (CblC) disease is the most common inherited disorder of intracellular cobalamin metabolism. It is a multisystemic disorder mainly affecting the eye and brain and characterized biochemically by methylmalonic aciduria, low methionine level, and homocystinuria. We report a patient found to have CblC disease who initially presented with low carnitine and normal propionylcarnitine (C3) levels on newborn screen. Newborn screening likely failed to detect CblC in this patient because of both his low carnitine level and the presence of a mild phenotype.

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Cobalamin D Deficiency Identified Through Newborn Screening

et al. 2018

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Cobalamin D deficiency (cblD) is one of the least common cobalamin metabolism disorders. It may result in isolated homocystinuria, isolated methylmalonic aciduria, or combined methylmalonic aciduria and homocystinuria (cblD-combined). Only seven cases of the combined cblD form have been reported to date. Due to the rarity of this disorder, the presentation and symptoms are not well described. We present an eighth case of the cblD-combined subtype, who had a positive newborn screen (NBS) on day of life 3. She was symptomatic and developed lethargy and poor oral intake at 8 days of life. She was treated with 10% dextrose, folinic acid, intramuscular hydroxocobalamin, and betaine. Despite the early initiation of treatment, she developed complications of the disease and was found to have abnormal brain imaging findings at 17 days of age and macular atrophy at 3 months of age and has global developmental delay. We provide detailed description of her presentation, her treatment, and her complications to aid in the understanding of this rare disorder, which is very similar to the more common cobalamin C disorder (cblC).

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Retinal Structure in Cobalamin C Disease: Mechanistic and Therapeutic Implications

Cited by 16 publications

References 38 publications

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

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

Cobalamin C Disease Missed by Newborn Screening in a Patient with Low Carnitine Level

Cobalamin D Deficiency Identified Through Newborn Screening

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