Cobalamin C Deficiency Shows a Rapidly Progressing Maculopathy With Severe Photoreceptor and Ganglion Cell Loss

Bonafede, Lucas; Fıçıcıoğlu, Can; Serrano, Leona; Han, Grace; Morgan, Jessica Ijams Wolfing; Mills, Monte D.; Forbes, Brian J.; Davidson, Stefanie L.; Binenbaum, Gil; Kaplan, Paige; Nichols, Charles W.; Verloo, Patrick; Leroy, Bart P.; Maguire, Albert M.; Alemán, Tomás S.

doi:10.1167/iovs.15-17857

Cited by 32 publications

(34 citation statements)

References 69 publications

(151 reference statements)

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“…Comparisons of total plasma homocysteine, methionine, and methylmalonic acid levels in our cohort versus several large published studies 10,11,16–20 demonstrated lower total plasma homocysteine and methylmalonic acid levels in our cohort as compared to these previously published studies (Figures 2a, Figure 2c) whereas methionine levels were comparable (not shown). The high frequency of the c.482G>A(p.Arg161Gln) pathogenic variant in our cohort contributes to this observation as 13/27 (48%) of our individuals are compound heterozygous for this variant compared to 4/86 (5%) individuals in these published studies (combined) 8, 9, 14–18 .…”

Section: Resultssupporting

confidence: 54%

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Milder clinical and biochemical phenotypes associated with the c.482G > A (p.Arg161Gln) pathogenic variant in cobalamin C disease: Implications for management and screening

Almannai

Marom

Divin

et al. 2017

Molecular Genetics and Metabolism

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Introduction Cobalamin C disease is a multisystemic disease with variable manifestations and age of onset. Genotype-phenotype correlations are well-recognized in this disorder. Here, we present a large cohort of individuals with cobalamin C disease, several of whom are heterozygous for the c.482G>A pathogenic variant (p.Arg161Gln). We compared clinical characteristics of individuals with this pathogenic variant to those who do not have this variant. To our knowledge, this study represents the largest single cohort of individuals with the c.482G>A (p.Arg161Gln) pathogenic variant. Methods A retrospective chart review of 27 individuals from 21 families with cobalamin C disease who are followed at our facility was conducted. Results 13 individuals (48%) are compound heterozygous with the c.482G>A (p.Arg161Gln) on one allele and a second pathogenic variant on the other allele. Individuals with the c.482G>A (p.Arg161Gln) pathogenic variant had later onset of symptoms and easier metabolic control. Moreover, they had milder biochemical abnormalities at presentation which likely contributed to the observation that 4 individuals (31%) in this group were missed by newborn screening. Conclusion The c.482G>A (p.Arg161Gln) pathogenic variant is associated with milder disease. These individuals may not receive a timely diagnosis as they may not be identified on newborn screening or because of unrecognized, late onset symptoms. Despite the milder presentation, significant complications can occur, especially if treatment is delayed.

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Section: Resultssupporting

confidence: 54%

“…One of the observations in this study is that those in our cohort have lower total plasma homocysteine and methylmalonic acid levels compared to several published studies 10,11,16–20 . The high frequency of the c.482G>A (p.R161Q) pathogenic variant in this study contributes to this observation.…”

Section: Discussionsupporting

confidence: 50%

Milder clinical and biochemical phenotypes associated with the c.482G > A (p.Arg161Gln) pathogenic variant in cobalamin C disease: Implications for management and screening

Almannai

Marom

Divin

et al. 2017

Molecular Genetics and Metabolism

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“…Neonates typically show lethargy, seizures and muscular hypotonia, often in combination with megaloblastic anaemia or neutropenia/pancytopenia. Up to 50 % of infants exhibit signs of visual impairment such as nystagmus on the background of retinopathy or optic atrophy (Bonafede et al 2015; Weisfeld-Adams et al 2015; Brooks et al 2016). Microangiopathic renal or pulmonary disease mostly manifests early but may also be present in older children or adults (Grangé et al 2015; Kömhoff et al 2013; Sharma et al 2007).…”

Section: Which Clinical Signs Are Characteristic For Remethylation Dementioning

confidence: 99%

Guidelines for diagnosis and management of the cobalamin‐related remethylation disorders cblC, cblD, cblE, cblF, cblG, cblJ and MTHFR deficiency

Huemer

Diodato

Schwahn

et al. 2016

J of Inher Metab Disea

232

368

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BackgroundRemethylation defects are rare inherited disorders in which impaired remethylation of homocysteine to methionine leads to accumulation of homocysteine and perturbation of numerous methylation reactions.ObjectiveTo summarise clinical and biochemical characteristics of these severe disorders and to provide guidelines on diagnosis and management.Data sourcesReview, evaluation and discussion of the medical literature (Medline, Cochrane databases) by a panel of experts on these rare diseases following the GRADE approach.Key recommendationsWe strongly recommend measuring plasma total homocysteine in any patient presenting with the combination of neurological and/or visual and/or haematological symptoms, subacute spinal cord degeneration, atypical haemolytic uraemic syndrome or unexplained vascular thrombosis. We strongly recommend to initiate treatment with parenteral hydroxocobalamin without delay in any suspected remethylation disorder; it significantly improves survival and incidence of severe complications. We strongly recommend betaine treatment in individuals with MTHFR deficiency; it improves the outcome and prevents disease when given early.Electronic supplementary materialThe online version of this article (doi:10.1007/s10545-016-9991-4) contains supplementary material, which is available to authorised users.

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“…11,12 The ocular and cognitive manifestations of the disease seem especially difficult to prevent. 5,6,8,11–13 The mainstay of treatment includes high-dose intramuscular hydroxycobalamin (OHCbl), which can lower serum MMA and homocysteine levels and increase serum methionine levels. 14,15 Betaine can also be used to increase remethylation of homocysteine to methionine.…”

Section: Introductionmentioning

confidence: 99%

Efficacy of early treatment in patients with cobalamin C disease identified by newborn screening: a 16-year experience

Ahrens‐Nicklas

Whitaker

Kaplan

et al. 2017

Genetics in Medicine

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Purpose Despite implementation of newborn screening (NBS), outcomes in cobalamin C disease (cblC) remain poor. Therapy with hydroxycobalamin and betaine is widely used, but dietary recommendations vary among metabolic centers. We present a longitudinal analysis of the relationship between metabolic control, diet, and outcomes in a cohort of cblC patients. Methods We completed a retrospective analysis of 12 patients with cblC referred for abnormal NBS results and followed in our center between 1999 and 2015. Results Of the patients, 87.5% had intellectual disability and 75% had retinopathy; 16.7% had one episode of mild acidosis. However, no patients manifested major metabolic decompensation. Developmental outcomes correlated more closely with initial metabolic abnormalities than with long-term metabolic control. Increased intake of medical foods resulted in better control but also perturbations in the ratios of essential amino acids and lower z-scores for head circumference. We found no relationship between diet and cognitive outcomes. Conclusions Although dietary therapy for cblC patients improves metabolic control, few patients experience metabolic decompensation regardless of diet. Increased incomplete protein intake is not correlated with improvements in outcomes. Overall, outcomes are poor despite early initiation of therapy and regardless of the dietary strategy used.

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Cobalamin C Deficiency Shows a Rapidly Progressing Maculopathy With Severe Photoreceptor and Ganglion Cell Loss

Cited by 32 publications

References 69 publications

Milder clinical and biochemical phenotypes associated with the c.482G > A (p.Arg161Gln) pathogenic variant in cobalamin C disease: Implications for management and screening

Milder clinical and biochemical phenotypes associated with the c.482G > A (p.Arg161Gln) pathogenic variant in cobalamin C disease: Implications for management and screening

Guidelines for diagnosis and management of the cobalamin‐related remethylation disorders cblC, cblD, cblE, cblF, cblG, cblJ and MTHFR deficiency

Efficacy of early treatment in patients with cobalamin C disease identified by newborn screening: a 16-year experience

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