PMC5065014_01
Box-and-whisker plot showing all recorded acuities at all visits. Visual acuity (VA) of many cobalamin C patients deteriorates to legal blindness, often in the first decade of life. Because of limitations in patient cooperation, patients were assessed for either VA or best-corrected VA (BCVA), and those values are reported. The right eye VA and BCVA are reported, because left eye values were consistent within patients. *Outlier. CUSM = central, unsteady, and maintained; DupA homozyg = ; DupA heterzyg = ; FF = fix and follow only; logMAR = logarithm of the minimum angle of resolution; Non-DupA =.
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F1
This degeneration, shown in Figure 1, is variable in pacing and degree. This end stage may occur as early as the first decade (patients 3 and 6), although progression to this point more typically takes place early in the second decade of life or later (Fig 1).
PMC5065014_02
Box-and-whisker plot showing all recorded acuities at all visits. Visual acuity (VA) of many cobalamin C patients deteriorates to legal blindness, often in the first decade of life. Because of limitations in patient cooperation, patients were assessed for either VA or best-corrected VA (BCVA), and those values are reported. The right eye VA and BCVA are reported, because left eye values were consistent within patients. *Outlier. CUSM = central, unsteady, and maintained; DupA homozyg = ; DupA heterzyg = ; FF = fix and follow only; logMAR = logarithm of the minimum angle of resolution; Non-DupA =.
nihms742061f1.jpg
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F1
This degeneration, shown in Figure 1, is variable in pacing and degree. This end stage may occur as early as the first decade (patients 3 and 6), although progression to this point more typically takes place early in the second decade of life or later (Fig 1).
Macular changes in cobalamin C are early and progressive and may include a developmental component. A, Fundus photograph showing macular coloboma in 12-month-old (patient [pt] 2) homozygous for c.271DupA (p.R91KfsX14). Coloboma was documented at 6 months of age or earlier, but photographs were not available from that time point. B-G, Fundus photographs of sibling pairs homozygous for c.271DupA (p.R91KfsX14) showing degeneration and the effect of prenatal or early treatment, or both, on the course of macular degeneration. B, C, Fundus photographs from patient 5 obtained at (B) 5 years of age and (C) 10 years of age (VA, 0.8 logarithm of the minimum angle of resolution [logMAR]), who was treated with hydroxocobalamin injections starting at 5 days of age. D, Fundus photograph of patient 6, older sibling of patient 5, obtained at 9 years of age (VA, 1.6 logMAR). E, F, Fundus photographs of patient 4, diagnosed and treated prenatally, obtained at (E) 5 years of age (VA, 0.7 logMAR) and (F) 10 years of age (BCVA, 1.0 logMAR). G, Fundus photograph of patient 8, who was not treated prenatally and is the older sibling of patient 4, at 10 years of age (VA, fix and follow). The table below the figure reports the plasma total plasma homocysteine (tHcy), serum methylmalonic acid (MMA), and plasma methionine (Meth) concentrations (muM) for the patients at each time point. *Past history of higher MMA levels, with a high of 4.4 at 8 years of age.
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Figure 4C shows OCT images of a cut passing through the central macular lesion of patient 11 (also shown in Fig 2B) and shows extreme thinning, some preservation of retinal lamination, and nearly complete loss of the outer nuclear layer.
PMC5065014_03
Retinal degeneration occurs in cobalamin C independent of metabolic status and within a variety of genotypes. Metabolite levels (in muM) 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 logarithm of the minimum angle of resolution [logMAR] at 27 years of age; 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) levels, 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 levels 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.
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F3
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.
PMC5065014_04
Macular changes in cobalamin C are early and progressive and may include a developmental component. A, Fundus photograph showing macular coloboma in 12-month-old (patient [pt] 2) homozygous for c.271DupA (p.R91KfsX14). Coloboma was documented at 6 months of age or earlier, but photographs were not available from that time point. B-G, Fundus photographs of sibling pairs homozygous for c.271DupA (p.R91KfsX14) showing degeneration and the effect of prenatal or early treatment, or both, on the course of macular degeneration. B, C, Fundus photographs from patient 5 obtained at (B) 5 years of age and (C) 10 years of age (VA, 0.8 logarithm of the minimum angle of resolution [logMAR]), who was treated with hydroxocobalamin injections starting at 5 days of age. D, Fundus photograph of patient 6, older sibling of patient 5, obtained at 9 years of age (VA, 1.6 logMAR). E, F, Fundus photographs of patient 4, diagnosed and treated prenatally, obtained at (E) 5 years of age (VA, 0.7 logMAR) and (F) 10 years of age (BCVA, 1.0 logMAR). G, Fundus photograph of patient 8, who was not treated prenatally and is the older sibling of patient 4, at 10 years of age (VA, fix and follow). The table below the figure reports the plasma total plasma homocysteine (tHcy), serum methylmalonic acid (MMA), and plasma methionine (Meth) concentrations (muM) for the patients at each time point. *Past history of higher MMA levels, with a high of 4.4 at 8 years of age.
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F2
Figure 4C shows OCT images of a cut passing through the central macular lesion of patient 11 (also shown in Fig 2B) and shows extreme thinning, some preservation of retinal lamination, and nearly complete loss of the outer nuclear layer.
Retinal degeneration occurs in cobalamin C independent of metabolic status and within a variety of genotypes. Metabolite levels (in muM) 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 logarithm of the minimum angle of resolution [logMAR] at 27 years of age; 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) levels, 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 levels 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.
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F3
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.
PMC5065014_05
Macular changes in cobalamin C are early and progressive and may include a developmental component. A, Fundus photograph showing macular coloboma in 12-month-old (patient [pt] 2) homozygous for c.271DupA (p.R91KfsX14). Coloboma was documented at 6 months of age or earlier, but photographs were not available from that time point. B-G, Fundus photographs of sibling pairs homozygous for c.271DupA (p.R91KfsX14) showing degeneration and the effect of prenatal or early treatment, or both, on the course of macular degeneration. B, C, Fundus photographs from patient 5 obtained at (B) 5 years of age and (C) 10 years of age (VA, 0.8 logarithm of the minimum angle of resolution [logMAR]), who was treated with hydroxocobalamin injections starting at 5 days of age. D, Fundus photograph of patient 6, older sibling of patient 5, obtained at 9 years of age (VA, 1.6 logMAR). E, F, Fundus photographs of patient 4, diagnosed and treated prenatally, obtained at (E) 5 years of age (VA, 0.7 logMAR) and (F) 10 years of age (BCVA, 1.0 logMAR). G, Fundus photograph of patient 8, who was not treated prenatally and is the older sibling of patient 4, at 10 years of age (VA, fix and follow). The table below the figure reports the plasma total plasma homocysteine (tHcy), serum methylmalonic acid (MMA), and plasma methionine (Meth) concentrations (muM) for the patients at each time point. *Past history of higher MMA levels, with a high of 4.4 at 8 years of age.
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F2
Figure 4C shows OCT images of a cut passing through the central macular lesion of patient 11 (also shown in Fig 2B) and shows extreme thinning, some preservation of retinal lamination, and nearly complete loss of the outer nuclear layer.
Retinal degeneration occurs in cobalamin C independent of metabolic status and within a variety of genotypes. Metabolite levels (in muM) 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 logarithm of the minimum angle of resolution [logMAR] at 27 years of age; 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) levels, 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 levels 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.
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F3
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.
Pathologic and functional analysis of c.271DupA (p.R91KfsX14) homozygotes showing preservation of peripheral retinal structure and function and retinal architecture consistent with a developmental defect. A, Autofluorescence photograph from patient (pt) 14 obtained at 27 years of age showing end-stage degeneration. Note the significant hyperautofluorescence in the periphery and macula and the hyperautofluorescence in the center. Despite widespread macular atrophy, there is a clear zone of peripheral sparing. In addition, there is clear peripapillary sparing around the optic nerve. B, Cirrus high-resolution optical coherence tomography (OCT) raster scan from near the edge of the macular atrophic lesion (inset) showing atrophy and loss of retinal laminar structure extending well beyond the macular atrophic lesion. Note abnormal reflectivity and a pattern consistent with end-stage degeneration and possible indications of developmental abnormalities. C, Cirrus high-resolution OCT raster scan from the center of the macular atrophic lesion (inset) showing loss of the inner segment-outer segment photoreceptor junction within macular lesion. The scan shows relatively normal retinal architecture beyond the macular lesion with an abrupt transition (white arrows are used to depict the boundaries of the lesion on this scan). D, Electroretinography (ERG) results obtained from patient 14 showing both scotopic and photopic responses are reduced and delayed (scotopic>photopic), but remarkably preserved considering the macular condition. E, Electroretinography (ERG) results obtained from patient 11 at 17 years of age showing significant attenuation and delay of both scotopic and photopic responses (wide-field photograph in Fig 3B).
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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. In the OCT image in Figure 4B, from near the edge of the macular lesion, atrophy and loss of laminar structure extend well beyond the lesion. The ERG results obtained from this patient at 27 years of age are displayed in Figure 4D. Figure 4C shows OCT images of a cut passing through the central macular lesion of patient 11 (also shown in Fig 2B) and shows extreme thinning, some preservation of retinal lamination, and nearly complete loss of the outer nuclear layer.