Ocular disease in the cobalamin C defect: A review of the literature and a suggested framework for clinical surveillance

Weisfeld-Adams, James D.; McCourt, Emily A.; Diaz, George A.; Oliver, Scott C. N.

doi:10.1016/j.ymgme.2015.01.012

Cited by 37 publications

(55 citation statements)

References 89 publications

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“…Our study includes the oldest c.271dupA (p.R91KfsX14) homozygous patients in the literature to date, with 5 patients 18 through 27 years of age at the last ophthalmic visit (Table 1). Previously, the oldest 2 patients who are c.271dupA (p.R91KfsX14) homozygous reported in the literature were 17 and 23 years of age when the ophthalmic findings were made, 14,18 although there may be older patients in the literature without reported genotypes. In the infantile-onset group, patients are severely affected compared with late-onset patients, and neonatal and infantile presentation of systemic symptoms (e.g., failure to thrive, encephalopathy, acute lethargy) also is accompanied by overt ophthalmic signs.…”

Section: Discussionmentioning

confidence: 99%

“…17 However, as noted in a recent comprehensive review of cblC deficiency, 18 publications that detail ophthalmic parameters are sparse. To date, there are fewer than 100 patients described for whom detailed ocular examination results are included (only 61 of these patients are identified by genotype), with the largest studies reporting results from 12 patients.…”

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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: 99%

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confidence: 99%

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

et al. 2016

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“…Other clinical signs include proteinlosing enteropathy, pulmonary hypertension (Iodice et al 2013), acidosis, and hyperammonemia (Fischer et al 2014;Martinelli et al 2011). Although cblC is part of a group of conditions that are accompanied by an elevation of both homocystine and methylmalonic acid in blood and plasma, it is clinically unique because some features are reported only in this defect, such as the distinct maculopathy (Gizicki et al 2014;Weisfeld-Adams et al 2015) and hemolytic-uremic-like syndrome.…”

Section: Introductionmentioning

confidence: 99%

“…Longo and colleagues (2005) also found that 30% of their patients had basal ganglia lesions. Concerning ophthalmological findings, progressive visual deficits such maculopathy, retinopathy, and nystagmus, in addition to abnormal vision, are extremely common in earlyonset cblC and most children will have developed these deficits before school entry, despite early and aggressive biochemical treatment (Gizicki et al 2014;Weisfeld-Adams et al 2015). Strabismus and optic atrophy also affect individuals with the early-onset type relatively frequently (Weisfeld-Adams et al 2015).…”

Section: Introductionmentioning

confidence: 99%

A Highly Diverse Portrait: Heterogeneity of Neuropsychological Profiles in cblC Defect

et al. 2015

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Cobalamin C is a rare inborn disorder of metabolism that results in multisystemic abnormalities, including progressive visual deficits. Although the cellular pathophysiology of cblC is a field of active study, little attention has been dedicated to documenting the cognitive consequences of the defect. The neuropsychological assessment of nine individuals aged between 23 months and 24 years was conducted to establish cognitive profiles. Results reveal a marked heterogeneity, with intellectual functioning ranging from extremely low to average, and cognitive difficulties (e.g., attention) evidenced even in those who are not intellectually disabled. Central nervous system abnormalities and multisystem disease are likely to be major contributing factors to the observed cognitive impairments, with the presence of visual deficits constituting an additional impediment to normal cognitive development. This study underscores the importance of conduct ing in-depth neuropsychological assessments in individuals with cblC, the results of which may be particularly helpful for clinical management, guidance toward rehabilitation services, and educational/vocational planning.

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“…Over 300 cbl-C patients have been reported globally to date. [3] The incidence of this disorder in Chinese patients has not yet been reported. [4] But mutations in the gene of methylmalonic aciduria (cobalamin deficiency) cbl-C type, with homocystinuria (MMACHC) were found as the cause of cbl-C disorder in Chinese patients by impairing intracellular synthesis of adenosylcobalamin and methylcobalamin, which are the cofactors for the methylmalonyl coenzyme A mutase and methionine synthase enzymes.…”

Section: Introductionmentioning

confidence: 99%

Clinical characteristics of hemolytic uremic syndrome secondary to cobalamin C disorder in Chinese children

Song

Peng

et al. 2015

World J Pediatr

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The results of this study demonstrated that cbl-C disorder should be investigated in any child presenting with HUS. The high concentrations of homocysteine and MMA could be used for timely recognization of the disease. Once the high levels of plasma homocystein and/or plasma or urine MMA are detected, the treatment with parenteral hydroxocobalamin should be prescribed immediately. The early diagnosis and treatment would contribute to the good prognosis of the disease.

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Ocular disease in the cobalamin C defect: A review of the literature and a suggested framework for clinical surveillance

Cited by 37 publications

References 89 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

A Highly Diverse Portrait: Heterogeneity of Neuropsychological Profiles in cblC Defect

Clinical characteristics of hemolytic uremic syndrome secondary to cobalamin C disorder in Chinese children

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