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![Retinal degeneration occurs in cobalamin C deficiency independent of metabolic status and within a variety of genotypes. Metabolite levels (in μM) at the time of examination are listed to the right or left of each panel. A, Fundus photograph showing a macular coloboma in patient 14 at 30 years of age (visual acuity [VA], 1.51 logarithms of the minimum angle of resolution [logMAR]; c.271DupA [p.R91KfsX14] homozygous). Despite the severe degeneration, a small portion of the retina is preserved. B, Wide-field photograph of patient 11 obtained at 17 years of age (VA, 1.51 logMAR; c.271DupA [p.R91KfsX14] homozygous). Note bone spicules and significant progression despite youth. C, Fundus photograph from patient 18 obtained at 22 years of age, whose genotype is the relatively unusual c.271dupA (p.R91KfsX14), c.600G>A (p.W200X). Although the retina is relatively preserved, central nervous system involvement severely affects vision (right-eye VA, 1.2 logMAR). D, Fundus photograph from patient 15 obtained at 14 years of age, with moderate total plasma homocysteine (tHcy) and methylmalonic acid (MMA) concentrations, showing some optic nerve pallor but no clinical macular degeneration (c.271dupA [p.R91KfsX14], c331C→T [p.R111X] genotype). E, Fundus photograph from patient 23 obtained at 7 years of age. This patient with later-onset disease had abnormal tHcy and MMA concentrations and showed no macular degeneration. F, Fundus photograph from patient 24 obtained at 21 years of age. This patient with later-onset disease had normal vision (0 logMAR) and no macular degeneration, but did show drusen-like deposits. Panel inset, Autofluorescence photograph of the same retinal area as in (F). Note the lack of autofluorescence of the drusen-like deposits.](profile/Wadih-Zein-2/publication/292115663/figure/fig1/AS:322827623387146@1453979511350/Retinal-degeneration-occurs-in-cobalamin-C-deficiency-independent-of-metabolic-status-and.png)
Retinal degeneration occurs in cobalamin C deficiency independent of metabolic status and within a variety of genotypes. Metabolite levels (in μM) at the time of examination are listed to the right or left of each panel. A, Fundus photograph showing a macular coloboma in patient 14 at 30 years of age (visual acuity [VA], 1.51 logarithms of the minimum angle of resolution [logMAR]; c.271DupA [p.R91KfsX14] homozygous). Despite the severe degeneration, a small portion of the retina is preserved. B, Wide-field photograph of patient 11 obtained at 17 years of age (VA, 1.51 logMAR; c.271DupA [p.R91KfsX14] homozygous). Note bone spicules and significant progression despite youth. C, Fundus photograph from patient 18 obtained at 22 years of age, whose genotype is the relatively unusual c.271dupA (p.R91KfsX14), c.600G>A (p.W200X). Although the retina is relatively preserved, central nervous system involvement severely affects vision (right-eye VA, 1.2 logMAR). D, Fundus photograph from patient 15 obtained at 14 years of age, with moderate total plasma homocysteine (tHcy) and methylmalonic acid (MMA) concentrations, showing some optic nerve pallor but no clinical macular degeneration (c.271dupA [p.R91KfsX14], c331C→T [p.R111X] genotype). E, Fundus photograph from patient 23 obtained at 7 years of age. This patient with later-onset disease had abnormal tHcy and MMA concentrations and showed no macular degeneration. F, Fundus photograph from patient 24 obtained at 21 years of age. This patient with later-onset disease had normal vision (0 logMAR) and no macular degeneration, but did show drusen-like deposits. Panel inset, Autofluorescence photograph of the same retinal area as in (F). Note the lack of autofluorescence of the drusen-like deposits.
Source publication
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 2...
Contexts in source publication
Context 1
... were not available because of limited cooperation by the patients. However, 3 patients with similarly high plasma tHcy and MMA concentrations are shown in Figure 3AeC Fig 3C) had relatively normal fundus findings despite comparable metabolite profiles as those severely affected. Similarly, patients 15 and 16, with infantile- onset disease and genotype c.271dupA (p.R91KfsX14), c.331C>(p.R111X), had widely variable metabolite levels and no macular atrophy at the last ophthalmic visit (Table 1). ...Context 2
... were not available because of limited cooperation by the patients. However, 3 patients with similarly high plasma tHcy and MMA concentrations are shown in Figure 3AeC Fig 3C) had relatively normal fundus findings despite comparable metabolite profiles as those severely affected. Similarly, patients 15 and 16, with infantile- onset disease and genotype c.271dupA (p.R91KfsX14), c.331C>(p.R111X), had widely variable metabolite levels and no macular atrophy at the last ophthalmic visit (Table 1). ...Context 3
... most cases, these findings track with the severity of the retinal degeneration, but there are exceptions. For example, 4- year-old patient 15 with genotype c.271dupA (p.R91KfsX14), c.331C>T (p.R111X) exhibited no apparent macular degeneration, but showed temporal pallor clinically (Table 1; Fig 3D). However, patient 16 (10 years of age), who shares the same genotype, did not exhibit optic pallor (Table 1). ...Context 4
... of the later-onset patients in our study (patients 22e25) experienced clinical macular degeneration. Two of these patients are pictured in the final panels of Figure 2. Figure 3E shows patient 23 (7 years of age), who was formally diagnosed just before 5 years of age because of behavioral and cognitive changes in school. This patient had increased plasma tHcy and MMA concentrations but showed no macular degeneration. ...Context 5
... patient had increased plasma tHcy and MMA concentrations but showed no macular degeneration. Patient 24 (21 years of age) with late-onset disease showed no functional defect in vision, nystagmus, or strabismus; however, drusen-like deposits were apparent on the fundus examination (Fig 3F). Note the lack of autofluorescence of the deposits in the photograph to the right. ...Context 6
... autofluorescence imaging, ERG, and OCT were used to characterize further the degeneration in 2 c.271dupA (p.R91KfsX14) homozygous patients. Figure 4A is a wide-field autofluorescence photograph from patient 14, a 27-year-old with end-stage degeneration who is also pictured in Figure 3A. Note the significant hyperautofluorescence in the periphery and macula and the hyperautofluorescence in the center. ...Context 7
... 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 patients with cblC deficiency 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. . E, Fundus photograph from patient 23 obtained at 7 years of age. ...Context 8
... patient also showed an accumulation of mucopolysaccharides in the sclera, potentially because of lysosomal dysfunction, and degenerated mitochondria in the iris pigment epithelium. 16 Whether such an accumulation is a factor in the unusual finding of drusen-like deposits on the macula of late-onset patient 24 (Fig 3F)dwhich, like the guttae, has not been seen previously in cblC-deficient patientsdremains unknown but is worthy of exploration in other older cblC- deficient patients. As others have described, we found that most late-onset cblC-deficient patients do not manifest visible retinal pathologic features. ...Similar publications
Background:
Cobalamin C (cblC) defect is the most common inborn error of Vitamin B12 metabolism often causing severe neurological, renal, gastrointestinal and hematological symptoms. Onset with pulmonary hypertension (PAH) and atypical hemolytic-uremic syndrome (aHUS) is rare.
Case presentation:
We describe the case of a 2-years old child, previ...
Citations
... In MMACHC, by contrast, retinal and especially macular changes were observed in many patients. [24][25][26] The largest study to date analyzed 25 MMACHC patients and observed a macular dystrophy / degeneration as the most common ocular abnormality in 72% of patients. 25 Patients with macular dystrophy in our cohort showed a complete atrophy of the outer retina and retinal pigment epithelium, leading to severely impaired BCVA. ...
... [24][25][26] The largest study to date analyzed 25 MMACHC patients and observed a macular dystrophy / degeneration as the most common ocular abnormality in 72% of patients. 25 Patients with macular dystrophy in our cohort showed a complete atrophy of the outer retina and retinal pigment epithelium, leading to severely impaired BCVA. MacTel, on the other hand, is characterized by intraretinal cystoid changes that can extent to outer retinal atrophy over time. ...
... When focusing on metabolic changes, however, macular dystrophy in MMACHC could be considered an extreme phenotype due to the strong metabolic changes caused by a severe genetic mutation, while MacTel patients only show mild changes in metabolite levels and hence mild or delayed morphological changes in the macula. In total, 92% of MMACHC patients showed an ocular abnormality that exceeded the need for corrective lenses, 25 disorders lead to severely elevated systemic Hcy levels, they differ with regards to their effect on Met, Cys, methylmalonic acid and cystathionine levels. 27 MMACHC also differs from the two other disorders because it leads to a functional vitamin B12 deficiency. ...
Purpose
Serine (Ser) and glycine (Gly) levels were reported to differ between Macular telangiectasia type 2 (MacTel) patients compared to healthy controls. Since they are closely related to methylation metabolism, this report investigates methylation-associated metabolite (MAM) levels in MacTel patients and retinal changes in monogenetic methylation disorders.
Methods
Prospective, monocentric study on MacTel patients and healthy controls the underwent a standardized protocol including a blood draw. MAM levels in plasma were determined using targeted quantitative metabolomics. Furthermore, patient records of cystathionine beta-synthase (CBS), methylenetetrahydrofolate reductase (MTHFR), and cobalamin C (MMACHC) deficiency were screened for reported retinal changes.
Results
In total, 29 MacTel patients and 27 healthy controls were included. MacTel patients showed lower plasma Ser (p = 0.02 and p = 0.01) and Gly (p= 0.11 and p = 0.11) levels than controls. Principal component analyses revealed that MAM, especially homocysteine, contributed to a distinct clustering of MacTel patients. No retinal changes were seen in CBS (n=1) and MTHFR (n=2) deficiency, while two patients with MMACHC (n=4) deficiency displayed extensive macular dystrophy.
Conclusions
MacTel patients show distinct clustering of MAM compared to controls. Of the three homocystinurias, only MMACHC resulted in macular dystrophy, possibly due to distinct compensatory pathways.
... Early-onset cases exhibit progressive retinal conditions, ranging from subtle retinal nerve fiber layer loss to advanced optic and macular atrophy with characteristic "bone spicule" pigmentation, accompanied by nystagmus, abnormal vision, and strabismus. Late-onset cases do not consistently show evidence of retinal degeneration or optic atrophy [57][58][59]. Understanding these ocular manifestations is pivotal for ophthalmologists in providing comprehensive care and improving patient outcomes in the context of metabolic disorders affecting Hcy metabolism. ...
Hyperhomocysteinemia (HHcy) is recognized as an independent risk factor for various significant medical conditions, yet controversy persists around its assessment and management. The diagnosis of disorders afffecting homocysteine (Hcy) metabolism faces delays due to insufficient awareness of its clinical presentation and unique biochemical characteristics. In cases of arterial or venous thrombotic vascular events, particularly with other comorbidities, it is crucial to consider moderate to severe HHcy. A nutritional approach to HHcy management involves implementing dietary strategies and targeted supplementation, emphasizing key nutrients like vitamin B6, B12, and folate that are crucial for Hcy conversion. Adequate intake of these vitamins, along with betaine supplementation, supports Hcy remethylation. Lifestyle modifications, such as smoking cessation and regular physical activity, complement the nutritional approach to enhance Hcy metabolism. For individuals with HHcy, maintaining a plasma Hcy concentration below 50 μmol/L consistently is vital to lowering the risk of vascular events. Collaboration with healthcare professionals and dietitians is essential for developing personalized dietary plans addressing the specific needs and underlying health conditions. This integrated approach aims to optimize metabolic processes and reduce the associated health risks.
... This suggests that although patients with the c.482G > A variant may have milder clinical symptoms and progress slowly, many individuals, especially with adult-onset cases, may present insidious and nonspecific symptoms and develop neurological disease in the absence of encephalopathic crises [21]. Interestingly, the incidence of ocular disease in this study is lower than that reported in other research [22]. As previously reported [22][23][24], ophthalmologic manifestations, including maculopathy, progressive retinal dysfunction, and, less frequently, optic atrophy could be seen in most patients with infantile CblC disease. ...
... Interestingly, the incidence of ocular disease in this study is lower than that reported in other research [22]. As previously reported [22][23][24], ophthalmologic manifestations, including maculopathy, progressive retinal dysfunction, and, less frequently, optic atrophy could be seen in most patients with infantile CblC disease. In our cohort, only 11.9% of patients suffered from ocular disease in the nonc.482G ...
Background
The aim of this study was to characterize the variable phenotypes and outcomes associated with the methylmalonic aciduria and homocystinuria type C protein gene ( MMACHC ) c.482G > A mutation in 195 Chinese cases with CblC disease.
Methods
We carried out a national, retrospective multicenter study of 195 Chinese patients with CblC disease attributable to the MMACHC c.482G > A variant either in a homozygous or compound heterozygous state. The control group consisted of 200 patients diagnosed with CblC disease who did not possess the c.482G > A mutation. Clinical features, including disease onset, symptoms, biochemical metabolites, gene mutation, and follow-up outcomes were reviewed and analyzed in detail. The median follow-up period spanned 3 years and 8 months, with a range of 1 year and 2 months to 12 years and 10 months.
Results
Among 195 patients carrying the c.482G > A variant, 125 (64.1%) cases were diagnosed by newborn screening (NBS), 60 (30.8%) cases were detected due to disease onset, and 10 (5.1%) cases were identified from sibling diagnoses. One hundred and seventeen (93.6%) individuals who were diagnosed by NBS, and nine patients who came from sibling diagnoses remained asymptomatic in this study. From 69 symptomatic patients of the c.482G > A group, more patients presented with later onset, and the top six common clinical symptoms at disease onset were developmental delay (59.4%), lower limb weakness and poor exercise tolerance (50.7%), cognitive decline (37.7%), gait instability and abnormal posture (36.2%), seizures (26.1%), and psychiatric and behavioral disturbances (24.6%). In the 159 symptomatic patients lacking c.482G > A variants, the most frequently observed clinical manifestations at disease onset included developmental delay (81.8%), lethargy and feeding difficulty (62.9%), lower limb weakness and poor exercise tolerance (54.7%), prolonged neonatal jaundice (51.6%), vomiting (47.2%), and seizures (32.7%). Before treatment, the levels of blood propionylcarnitine, propionylcarnitine/acetylcarnitine ratio, and homocysteine in the c.482G > A group were significantly lower ( P < 0.05) than those in the non-c.482G > A group, while the concentration of urinary methylmalonic acid was slightly lower ( P > 0.05). The degree of decline in the above metabolites after treatment in different groups significantly differed in both plasma total homocysteine values and urinary methylmalonic acid levels ( P < 0.05). In patients carrying the c.482G > A variant compared with the non-c.428G > A group, there were markedly lower rates of mortality (0.5% vs. 2.0%) and developmental delay (20.5% vs. 65.5%). When compared with individuals diagnosed due to disease onset, those identified through NBS in either group exhibited a reduced proportion of disease onset (6.7% vs. 100% in the c.482G > A group, 54.4% vs. 100% in the non-c.482G > A group), lower mortality (0.0% vs. 1.7% in the c.482G > A group, 0.0% vs. 3.6% in the non-c.482G > A group), and had a higher percentage of patients exhibiting normal psychomotor and language development (99.3% vs. 33.3% in the c.482G > A group, 58.9% vs. 10.9% in the non-c.482G > A group).
Conclusions
The c.482G > A variant in MMACHC is associated with late-onset and milder phenotypes of CblC disease. Patients with this mutation tend to have a relatively better response to hydroxocobalamin, better metabolic control, and more favorable neurological outcomes. NBS and other appropriate pre-symptomatic treatments seem to be helpful in early diagnosis, resulting in favorable clinical outcomes.
... Early-onset cases exhibit progressive retinal conditions, ranging from subtle retinal nerve fiber layer loss to advanced optic and macular atrophy with characteristic "bone spicule" pigmentation, accompanied by nystagmus, abnormal vision, and strabismus. Late-onset cases do not consistently show evidence of retinal degeneration or optic atrophy [40][41][42]. Understanding these ocular manifestations is pivotal for ophthalmologists in providing comprehensive care and improving patient outcomes in the context of metabolic disorders affecting Hcys metabolism. ...
Hyperhomocysteinemia (HHcys) is recognized as an independent risk factor for various significant medical conditions, yet controversy persists around its assessment and management. The diagnosis of disorders affecting homocysteine (Hcys) metabolism faces delays due to insufficient awareness of its clinical presentation and unique biochemical characteristics. In cases of arterial or venous thrombotic vascular events, particularly with other comorbidities, it is crucial to consider moderate to severe HHcys. A nutritional approach to HHcys management involves implementing dietary strategies and targeted supplementation, emphasizing key nutrients like vitamin B6, B12, and folate crucial for Hcys conversion. Adequate intake of these vitamins, along with betaine supplementation, supports Hcys remethylation. Lifestyle modifications, such as smoking cessation and regular physical activity, complement the nutritional approach to enhance Hcys metabolism. For individuals with HHcys, maintaining a plasma Hcys concentration below 50 μmol/L consistently is vital to lower the risk of vascular events. Collaboration with healthcare professionals and dietitians is essential for developing personalized dietary plans addressing specific needs and underlying health conditions. This integrated approach aims to optimize metabolic processes and reduce the associated health risks.
... However complete normalization of the metabolic parameters is rare [5] and the long-term neurological and ophthalmological outcome is poor [6]. Visual manifestations in early-onset patients include lack of eye-tracking or unstable fixation, low visual acuity when measurable and sometimes, reduced light perception [7]. Oculomotor abnormalities are very common with nystagmus and/ or strabismus usually seen at diagnosis [6]. ...
... They include macular degeneration and/or clinically evident retinopathy which can lead to blindness [1,8]. Very few cases of isolated optic atrophy have also been reported in cblC deficiency patients with no maculopathy [7,9]. Some other optic atrophy cases were diagnosed after retinal evolution with maculopathy [10]. ...
... The other cases of optic atrophy published without maculopathy were based on the appearance of the fundi, presenting optic disc pallor in four patients described by Brooks, et al., [7]. In six cblC deficient patients published by Ku, et al., [10] three showed a maculopathy initially and an optic disc pallor later with signs of optic atrophy after few months of evolution. ...
... The current standard of care is OHCbl injection, which usually results in a decrease in HCY and an increase in methionine concentration, implying a restoration and stabilization of metabolic parameters. However, a longitudinal follow-up study of cblG and also of other IECM patients indicate that treatments appear to have little to no effect on the ocular phenotypes which persist and progress despite treatment [4,15,16]. While the underlying pathomechanisms of ocular symptoms remain elusive, there is a lack of studies that specifically address the origin of these symptoms in cblG disorders from a retinal-focused perspective, and this can be attributed largely to the absence of suitable experimental models. ...
... This delay may arise from impaired maturation of the visual system, as evidenced by the downregulation of Pax6 expression; indeed, this latter is a critical transcription factor involved in the embryonic and postnatal stages of visual system development and maturation [19,20]. However, deficient mice also exhibit a slight decrease of visual acuity with some individual variability, similarly to the decreased visual acuity found in some IECM patients [5,15]. In the methylome study, mice exhibiting the most significant decrease in visual acuity, compared to wild type, showed changes in methylation in the promoter regions of genes involved in eye development and retinoid metabolism which is crucial for visual phototransduction pathway [21]. ...
... IECM is also often characterized by severe neurological impairment parallel to ocular symptoms. These neurological defects include brain atrophy, demyelinated area, and EEG abnormality [4,15]. However, studies on rats showed that methyl donor deficiency that is characterized by a drop in SAM/SAH ratio is often linked to neuronal cell death, pro-apoptotic state, metabolic alteration, development and cell differentiation impairment, and synaptic alterations [29][30][31] which could affect visual cortex processing thus participating to the decrease visual acuity as reported in animals' models with altered visual cortex [32][33][34]. ...
Background
MTR gene encodes the cytoplasmic enzyme methionine synthase, which plays a pivotal role in the methionine cycle of one-carbon metabolism. This cycle holds a significant importance in generating S-adenosylmethionine (SAM) and S-adenosylhomocysteine (SAH), the respective universal methyl donor and end-product of epigenetic transmethylation reactions. cblG type of inherited disorders of vitamin B12 metabolism due to mutations in MTR gene exhibits a wide spectrum of symptoms, including a retinopathy unresponsive to conventional therapies.
Methods
To unveil the underlying epigenetic pathological mechanisms, we conducted a comprehensive study of epigenomic-wide alterations of DNA methylation by NGS of bisulfited retinal DNA in an original murine model with conditional Mtr deletion in retinal tissue. Our focus was on postnatal day 21, a critical developmental juncture for ocular structure refinement and functional maturation.
Results
We observed delayed eye opening and impaired visual acuity and alterations in the one-carbon metabolomic profile, with a notable dramatic decline in SAM/SAH ratio predicted to impair DNA methylation. This metabolic disruption led to epigenome-wide changes in genes involved in eye development, synaptic plasticity, and retinoid metabolism, including promoter hypermethylation of Rarα, a regulator of Lrat expression. Consistently, we observed a decline in cone photoreceptor cells and reduced expression of Lrat, Rpe65, and Rdh5, three pivotal genes of eye retinoid metabolism.
Conclusion
We introduced an original in vivo model for studying cblG retinopathy, which highlighted the pivotal role of altered DNA methylation in eye development, cone differentiation, and retinoid metabolism. This model can be used for preclinical studies of novel therapeutic targets.
... The systematic search generated 166 publications of which 52 (Shinnar 1984;Mitchell et al. 1986;Watkin and Rosenblatt 1989;Brandstetter et al. 1990;Traboulsi et al. 1992;Ticho et al. 1992;Wilson et al. 1998;Patton et al. 2000;Powers et al. 2001;Zava et al. 2002;Kind et al. 2002;Suormala et al. 2004;Poloschek et al. 2005;Ricci et al. 2005;Tsina 2005;Schimel and Mets 2006;Thauvin-Robinet et al. 2007;Müller et al. 2007;Sharma et al. 2007;Nogueira et al. 2008;Gaillard et al. 2008;Gerth et al. 2008;Valayannopoulos et al. 2009;Profitlich et al. 2009;Grant et al. 2010;Outteryck et al. 2012;Fuchs et al. 2012;Weisfeld-Adams et al. 2013;Gizicki et al. 2014;Kandula et al. 2014;Huemer et al. 2014;Ahrens-Nicklas et al. 2015;Weisfeld-Adams et al. 2015;Collison et al. 2015;Huemer et al. 2015;Constantinou et al. 2015;Aleman et al. 2015;Bonafede et al. 2015;Brooks et al. 2016;Ku et al. 2016;Wu et al. 2017;Fettelschoss et al. 2017;Bacci et al. 2017;Abu-El-Haija et al. 2018a;Wang et al. 2019;Kvittingen et al. 1997;Pinar-Sueiro et al. 2010;Traber et al. 2011;AlOwain et al. 2019;Martinez Alvarez et al. 2016;Williams et al. 2009;Hörster et al. 2021) appeared to be relevant to the review. Based on these 52 studies, we were able to review the individual data from 163 cbl patients and 24 mut patients with ocular manifestations (Fig. 1). ...
... The spectrum of ocular pathology has been extensively studied in cblC disease (Fuchs et al. 2012;Weisfeld-Adams et al. 2015;Brooks et al. 2016). However, little is known about the ocular phenotype associated with other inherited disorders of intracellular Cbl metabolism. ...
... Eye disease in cbl patients was characterized by a wide range of abnormalities including nystagmus, strabismus, retinal and macular degeneration and optic atrophy with significant differences between groups, suggestive of distinct pathophysiological mechanisms. Nevertheless, consistent with the previous findings in cblC patients (Gaillard et al. 2008;Gerth et al. 2008;Fuchs et al. 2012;Weisfeld-Adams et al. 2013Fischer et al. 2014;Brooks et al. 2016;Huemer et al. 2019), these abnormalities were very uncommon in patients with late-onset disease, regardless of the type of defect. ...
Inherited disorders of cobalamin (cbl) metabolism (cblA-J) result in accumulation of methylmalonic acid (MMA) and/or homocystinuria (HCU). Clinical presentation includes ophthalmological manifestations related to retina, optic nerve and posterior visual alterations, mainly reported in cblC and sporadically in other cbl inborn errors.
We searched MEDLINE EMBASE and Cochrane Library, and analyzed articles reporting ocular manifestations in cbl inborn errors. Out of 166 studies a total of 52 studies reporting 163 cbl and 24 mut cases were included. Ocular manifestations were found in all cbl defects except for cblB and cblD-MMA; cblC was the most frequent disorder affecting 137 (84.0%) patients. The c.271dupA was the most common pathogenic variant, accounting for 70/105 (66.7%) cases. One hundred and thirty-seven out of 154 (88.9%) patients presented with early-onset disease (0–12 months). Nystagmus and strabismus were observed in all groups with the exception of MMA patients while maculopathy and peripheral retinal degeneration were almost exclusively found in MMA-HCU patients. Optic nerve damage ranging from mild temporal disc pallor to complete atrophy was prevalent in MMA-HCU.and MMA groups. Nystagmus was frequent in early-onset patients. Retinal and macular degeneration worsened despite early treatment and stabilized systemic function in these patients. The functional prognosis remains poor with final visual acuity < 20/200 in 55.6% (25/45) of cases. In conclusion, the spectrum of eye disease in Cbl patients depends on metabolic severity and age of onset. The development of visual manifestations over time despite early metabolic treatment point out the need for specific innovative therapies.
... Cbl in its active cofactor forms, adenosylated Cbl (AdoCbl) and methylated Cbl (MeCbl), is required for methylmalonyl-CoA mutase (MMUT) and methionine synthase (MS), respectively [5,6]. Patients with diseasecausing bi-allelic variants in MMACHC often present as infants with a severe multisystem pathology that impairs, inter alia, kidney and liver function as well as visual acuity [7][8][9][10][11][12][13][14]. As cblC deficiency is a rare disease with a heterogeneous phenotype [11,15,16], many aspects about the disease mechanism are unknown [17]. ...
The MMACHC gene encodes for an enzyme involved in intracellular vitamin B12 metabolism, and autosomal recessive defects in MMACHC represent the most common disorder of intracellular vitamin B12 metabolism. Recent studies have identified increased levels of reactive oxygen species in cells and tissues with MMACHC dysfunction, suggesting a role for oxidative stress in disease. To investigate the link between oxidative stress and MMACHC, we exposed mice as well as human and mouse cells to hypoxia, and found significant repression of MMACHC in all investigated tissues (retina, eyecup, liver, kidney) and cell lines (HeLa, ARPE-19, human and mouse fibroblasts, 661 W). Furthermore, in HeLa cells, we found transcriptional repression already at 5% oxygen, which was stable during prolonged hypoxia up to 5 days, and a return of MMACHC transcripts to normal levels only 24 h after reoxygenation. This hypoxia-induced downregulation of MMACHC was not due to altered function of the known MMACHC controlling transcription factor complex HCFC1/THAP11/ZNF143. Using in vitro RNA interference against hypoxia-induced transcription factors (HIF1alpha, HIF2alpha and REST) as well as the microRNA transcription machinery (DROSHA), we observed release of hypoxia-dependent downregulation of MMACHC expression by HIF1alpha and DROSHA, whose combined effect was additive. Together, these results strongly indicate that MMACHC is a hypoxia-regulated gene whose downregulation appears to be partially mediated through both hypoxia-induced transcription factor and microRNA machinery. These findings suggest that oxidative stress could impair vitamin B12 metabolism by repression of MMACHC in healthy as well as in diseased individuals.
... It could be the result of the feedback of ganglion cell dysfunctions. This remains to be elucidated [2,33,35,36]. ...
Introduction
Transcobalamin (TC) transports cobalamin (vitamin B12) from plasma into cells. Its congenital deficiency is a rare autosomal recessive disorder due to mutations in the TCN2 gene. It causes intracellular cobalamin depletion with early onset in the first months of life, failure to thrive with pallor due to megaloblastic anemia. It can be associated with pancytopenia, gastrointestinal symptoms with vomiting, diarrhea, and neurological complications with myelopathy. Aggressive vitamin B12 parenteral therapy must be instituted early and continuously. Retinopathy and maculopathy are rarely associated with this condition.
Subject
We report the electrophysiological results of one TC-deficient patient diagnosed at the age of 4 months immediately and continuosly treated by hydroxocobalamin IM. Her visual function was followed by eight ophthalmological assessments, eight flash-ERG, six EOG, one mf-ERG, and seven P-ERG recordings over a 10-year period, between the age of 2y 9 m and 12y 6 m.
Results
Her ophthalmological assessment including visual acuity, fundi, optical coherent tomography (OCT), and retinal nerve fiber layer (RNFL) remained normal. From the age of 2y 9 m to 5y, dark-adapted and light-adapted flash-ERGs, EOGs and pattern-ERG were normal. From the age of 6y 4 m to 12y 6 m, dark-adapted flash-ERGs and EOGs remained normal. Cone a-wave amplitudes remained normal, whereas cone b-wave and flicker-response amplitudes were decreased. At the age of 12y 6 m, mf-ERG N1P1 amplitudes on the central 30° were decreased. From the age of 7y 4 m to 12y 6 m, P-ERG P50 amplitudes were decreased with no N95.
Comments
While clinical and anatomical assessments remained normal over a 10-year period, patient’s electrophysiological results suggested the progressive onset of a subclinical retinopathy of inner-cone dystrophy type, and a subclinical maculopathy on the central 30° including the ganglion cell layer deficiency on the central 15°, despite continuous intramuscular treatment, RPE and scotopic system remaining normal. The origins of such subclinical retinopathy and maculopathy are unknown and independent of early disease identification and aggressive intramuscular hydroxocobalamin therapy.
... Especially patients with an early disease onset frequently show a number of heterogeneous ophthalmic manifestations such as degeneration of the central retina, bull's eye atrophy, and impaired photopic vision (impaired cone function). Additionally, chorioretinal atrophies, optic nerve pallors, vessel attenuation as well as nystagmus, strabismus, and even optic colobomas have been observed [2,[10][11][12][13][14][15][16][17]. Due to newborn screening programs, patients now have the chance to be diagnosed and treated early after birth. ...
... Compared with cblC patients, those with isolated methylmalonic aciduria caused by mutations in MMUT present with higher plasma and urine concentrations of MMA [13,[34][35][36]; while many patients suffering from classical homocystinuria (caused by dysfunction of cystathionine beta-synthase) have higher plasma total Hcy (tHcy) concentrations [13,37]. Nevertheless, neither of those patient groups displays an ocular phenotype similar to cblC patients. ...
... Compared with cblC patients, those with isolated methylmalonic aciduria caused by mutations in MMUT present with higher plasma and urine concentrations of MMA [13,[34][35][36]; while many patients suffering from classical homocystinuria (caused by dysfunction of cystathionine beta-synthase) have higher plasma total Hcy (tHcy) concentrations [13,37]. Nevertheless, neither of those patient groups displays an ocular phenotype similar to cblC patients. ...
Combined methylmalonic aciduria with homocystinuria (cblC type) is a rare disease caused by mutations in the MMACHC gene. MMACHC encodes an enzyme crucial for intracellular vitamin B12 metabolism, leading to the accumulation of toxic metabolites e.g. methylmalonic acid (MMA) and homocysteine (Hcy), and secondary disturbances in folate and one-carbon metabolism when not fully functional. Patients with cblC deficiency often present in the neonatal or early childhood period with a severe multisystem pathology, which comprises a broad spectrum of treatment-resistant ophthalmological phenotypes, including retinal degeneration, impaired vision, and vascular changes. To examine the potential function of MMACHC in the retina and how its loss may impact disease, we performed gene expression studies in human and mouse, which showed that local expression of MMACHC in the retina and retinal pigment epithelium is relatively stable over time. To study whether functional MMACHC is required for retinal function and tissue integrity, we generated a transgenic mouse lacking Mmachc expression in cells of the peripheral retina. Characterization of this mouse revealed accumulation of cblC disease related metabolites, including MMA and the folate-dependent purine synthesis intermediates AICA-riboside and SAICA-riboside in the retina. Nevertheless, fundus appearance, morphology, vasculature, and cellular composition of the retina, as well as ocular function, remained normal in mice up to 6 or 12 months of age. Our data indicates that peripheral retinal neurons do not require intrinsic expression of Mmachc for survival and function and questions whether a local MMACHC deficiency is responsible for the retinal phenotypes in patients.
