- Email: [email protected]
Ocular manifestations of cobalamin C type methylmalonic aciduria with homocystinuria
Ocular manifestations of cobalamin C type methylmalonic aciduria with homocystinuria Leah R. Fuchs, MD,a Matthieu Robert, MD,b Isabelle Ingster-Moati, MD, PhD,b Lucia Couette, MD,b Jean-Louis Dufier, MD,b Pascale de Lonlay, MD,b and Scott E. Brodie, MD, PhDa PURPOSE
To report the ocular complications of cobalamin-C type methylmalonic aciduria with homocystinuria (cblC) in a large consecutive series of patients.
METHODS
Medical records of patients with genetically diagnosed cblC disease from Mount Sinai Medical Center, New York, and H^ opital Necker, Paris, France, were reviewed. All patients with the diagnosis of cblC seen after January 2008 at Mount Sinai and January 1998 at H^ opital Necker were included.
RESULTS
A total of 9 cases are reported. Age at initial ocular examination ranged from 3.5 months to 10 years of age. All 9 patients had early-onset disease, with manifestation of disease presenting prior to 1 year of age. Two patients had definitive optic nerve pallor. All patients had retinal findings ranging from peripheral pigmentary retinal changes to central macular atrophy with Bull’s eye lesions. Optical coherence tomography was performed on one child and showed retinal thinning in the area of the bull’s eye lesions. Electroretinography was performed in 6 of the 9 patients, three of whom showed decreased scotopic and photopic responses. The other three patients had normal responses on electroretinography.
CONCLUSIONS
Ocular findings in patients with cblC are variable. All patients in the study exhibited earlyonset disease and had noteworthy ophthalmic findings. To the best of our knowledge, this is the first study in the literature correlating optical coherence tomography findings with fundus findings in cblC. ( J AAPOS 2012;16:370-375)
C
obalamin-C type methylmalonic aciduria with homocystinuria (cblC) is a rare autosomal-recessive inborn error of intracellular cobalamin metabolism caused by mutation in the MMACHC gene.1 The conversion of dietary vitamin B12 or cobalamin into an active form is dysfunctional. Systemic findings of the disease include failure to thrive, megaloblastic anemia, and neurologic dysfunction.2 Reported ocular findings include nystagmus, optic atrophy, pigmentary retinopathy, and retinal degeneration with maculopathy.3 Age at onset of disease has been correlated with extent of ocular disease.3-5 Patients with early-onset disease, defined as manifestation of disease within the first 12 months of age, often exhibit both neurological deterioration and progressive retinopathy. Patients with late-onset disease, in which symptoms become manifest after the age of 5 years, have not been shown to develop retinopathy. Author affiliations: aOphthalmology, Mount Sinai School of Medicine, New York, New York; bService d’ophtalmologie, H^opital Necker, Paris, France Presented at the 2011 Annual Meeting of the Association for Research in Vision and Ophthalmology, May 1-5, 2011, Fort Lauderdale, Florida. Submitted July 4, 2011. Revision accepted February 11, 2012. Correspondence: Leah R. Fuchs, MD, Department of Ophthalmology, The Mount Sinai School of Medicine, One Gustave L. Levy Place, Box 1183, New York, NY 10029 (email: [email protected]). Copyright Ó 2012 by the American Association for Pediatric Ophthalmology and Strabismus. 1091-8531/$36.00 http://dx.doi.org/10.1016/j.jaapos.2012.02.019
370
Because both metabolic and biochemical abnormalities are present, the diagnosis of cblC can be made on newborn screening, hopefully allowing for initiation of treatment prior to the development of notable pathology. A total of 22 cases have been reported in the literature of ocular findings of the disease.3,6-11 The purpose of this study is to report the largest series of patients with ocular abnormalities due to cblC.
Subjects and Methods Medical records of patients with the genetic diagnosis of cblC cared for by the senior authors (SEB at Mount Sinai Medical Center, New York, and IIM at H^ opital Necker, Paris, France) were reviewed. All patients with the diagnosis of cblC seen after January 2008, at Mount Sinai, and after January 1998, at H^ opital Necker were included. All patients had genetically confirmed cblC disease. Four of the patients were known to have undergone testing using DNA extraction of peripheral blood leukocytes. The Invader Assay (Third Wave Technologies, Madison, WI) was used to detect the MTHFR C677T and MTHFR A1298C mutations. One patient had genetic sequencing identifying the exact amino acid mutation. The details of the methods of genetic testing of the remaining patients are unavailable, but in each case a notation in the medical record indicated that genetic testing had confirmed the diagnosis. Patients were referred to the ophthalmology departments from the hospital genetics service. Age and sex were recorded, as was visual acuity, when possible. The
Journal of AAPOS
Volume 16 Number 4 / August 2012
Fuchs et al
371
FIG 1. Fundus photographs. A-B, Patient 2 at 9 years of age. Vision at that time was counting fingers at 5 feet in the right eye and 20/70 in the left eye. Retinal examination revealed bilateral bull’s eye macular atrophy. C-D, Patient 3, left eye, a sibling of patient 2, at 10 years of age, with visual acuity of counting fingers at 6 feet in both eyes. Retinal examination revealed retinal pigment epithelial clumping and atrophy. E-F, Patient 9 at 2 years of age: foveal abnormalities are present in both eyes. presence or absence of nystagmus and strabismus was noted. The appearance of the optic nerves and fundi was documented. Electroretinogram (ERG) and visually evoked potentials were recorded for some of the patients. Optical coherence tomography (OCT) was performed if possible. Of the 9 patients, 7 had follow-up examinations (mean, 22 months; range, 3-58 months).
Results The medical records of nine patients (seven boys) were reviewed; no patient diagnosed with cb1C was excluded (see
Journal of AAPOS
e-Supplement 1, available at jaapos.org). Age at initial ophthalmologic examination ranged from 3.5 months to 10 years of age. All children in the study had early-onset disease. As most patients were preverbal at the time of examination, visual acuity was difficult to obtain. Two children had central, steady, and maintained vision in each eye, and 3 children seemed to fix and follow in each eye. Two children had questionable no light perception in both eyes. Visual acuity in a pair of siblings was counting fingers at 6 feet in each eye in one child (aged 10 at presentation) and 20/
372
Fuchs et al
Volume 16 Number 4 / August 2012 Table 1. Results of electroretinogram (ERG) and visual-evoked potential (VEP) testing Patient 1 5 6 7 8 9
ERG
VEP
Reduced scotopic and photopic responses Normal Normal No discernible scotopic responses; decreased photopic responses Decreased photopic and scotopic responses Normal
Primitive, undifferentiated waveforms NA Normal No discernible responses Increased P2 wave culmination latencies NA
NA, not available.
FIG 2. A-B, Macular OCT of Patient 2. The OCT of the right and left eyes in patient at age 9 showed significant retinal thinning is present through the bull’s eye maculopathy.
125 in the right eye and 20/30 in the left eye in the other child (aged 6). Three children had strabismus at presentation, all of whom exhibited an esotropia. Six children had nystagmus. The optic nerves of 6 of the children appeared normal; 2 patients’ optic nerves had definitive pallor, while one had questionable pallor. All patients had retinal findings (Figure 1). Mild changes included peripheral pigmentary changes and mottling, while the most severe findings included central macular atrophy with Bull’s eye lesions (Figure 1A and B). One child showed small abnormalities at the bottom of the foveal depressions in both eyes (Figure 1E and F). The macular OCT from the patient with fundus findings in Figure 1A and B shows retinal thinning (Figure 2).
Electroretinogram and Visually Evoked Potentials Six of the children underwent ERG testing according to International Society for Clinical Electrophysiology of Vision (ISCEV) standards (Table 1). Three children exhibited normal responses (see, for example, Figure 3); 3 children had decreased scotopic and photopic responses. One of these children, examined at 3.5 months of age, exhibited normal photopic and flicker responses but scotopic responses of about 50% of normal (Figure 4A). On repeat ERG at 19 months of age, photopic responses were normal in latency, but reduced in amplitude to about 33% of normal for both single flash and 30-Hz flicker stimulation.
Responses following dark adaptation to the standard ISCEV full-strength flash were greatly attenuated to approximately 20% of normal (Figure 4B). Four children underwent visual-evoked potential testing (Table 1): 1 had normal responses; 1 had no discernable responses; 1 child had primitive, undifferentiated waveforms; and 1 had increased P2 wave culmination latencies. Of the 9 patients, 4 of the children were known to be heterozygous for MTHFR C677T (methylenetetrahydrofolate reductase), and wild type for the MTHFR A1298C mutation. One child was found to have the following mutations: c.dup271A (p.Arg91Lys fsh13X) heterozygous and c.615C . G (p.Tyr205X) heterozygous. The remaining 4 children were known to have MMHAC mutations, but the exact mutations and details of their genetic testing are not available.
Discussion Numerous ocular complications are found in patients with cblC. Findings are variable and can include nystagmus, strabismus, optic nerve pallor, pigmentary retinopathy, and decreased ERG responses. Such ocular manifestations are present very early in life in children with early-onset disease. Maculopathy described in patients with cblC occurs very early and likely develops prior to birth, whereas most other maculopathies do not present until a later age. Similar ocular pathology is found in both transcobalamin II deficiency, which involves defective intestinal absorption of vitamin B12, and cblC. Soueid and colleagues12 describe a case of transcobalamin II deficiency in a 7-month-old patient. Fundus examination remained normal until age 16, when there was a decrease in visual acuity with accompanying pigmentary retinopathy. Fluorescein angiography revealed central hypofluorescence in the macula surrounded by hyperfluorescence. Retinal degeneration did not progress with the administration of high-dose supplementation of hydroxocobalamin in the patient described in the study. In this study, follow-up was not long enough to determine whether or not high-dose supplementation altered progression of ocular disease.
Journal of AAPOS
Volume 16 Number 4 / August 2012
Fuchs et al
373
FIG 3. Normal ERG findings in Patient 5.
The mechanism of retinal degeneration in congenital cblC is not fully elucidated. Although supplementation with hydroxocobalamin and L-methionine improves anemia, it does not stop the progression of retinopathy, especially in children with early onset of the condition7,8; however, two of the children in the series are brothers, with the child diagnosed and treated at an earlier
Journal of AAPOS
developing less retinopathy than the sibling started on treatment later. Accumulation of neither methylmalonic acid nor homocysteine is likely the cause of retinal degeneration. Once the factors responsible for such degeneration are identified, treatment to prevent the onset of macular degeneration can be developed.
374
Fuchs et al
Volume 16 Number 4 / August 2012
FIG 4. Patient 1 ERG findings. A, At 3 months of age, showing normal responses to photopic single flash and 30-Hz flicker stimulation. Responses following dark adaptation to the standard ISCEV full-strength flash were about 50% of normal in amplitude. B, At 19 months of age, showing reduced scotopic and photopic responses.
This study corroborates previously reported ocular findings in cases of cblC. To date, this is the largest series of patients with ocular abnormalities due to cblC. In addition to ERG and visual-evoked potential information, this is the
first study in the literature correlating OCT findings with fundus findings. The study also supports previous reports of patients with early-onset disease manifesting severe ocular involvement.
Journal of AAPOS
Volume 16 Number 4 / August 2012
Literature Search PubMed was used to search MEDLINE without date restriction for the following terms: cobalamin C type deficiency, methylmalonic aciduria AND homocystinuria, retinal degeneration, retina, and ocular.
References 1. Lerner-Ellis JP, Tirone JC, Pawelek PD, et al. Identification of the gene responsible for methylmalonic aciduria and homocystinuria, cb1C type. Nat Genet 2006;38:93-100. 2. Rosenblatt DS, Aspler AL, Shevell MI, Pletcher BA, Fenton WA, Seashore MR. Clinical heterogeneity and prognosis in combined methylmalonic aciduria and homocystinuria (cb1C). J Inherit Metab Dis 1997;20:528-38. 3. Gerth C, Morel CF, Feigenbaum AV, Levin A. Ocular phenotype in patients with methylmalonic aciduria and homocystinuria, cobalamin C type. J AAPOS 2008;12:591-6. 4. Ben-Omran TI, Wong H, Blaser S, Feigenbaum A. Late-onset cobalamin-C disorder: A challenging diagnosis. Am J Med Genet 2007;143A:979-84.
Journal of AAPOS
Fuchs et al
375
5. Tsai AC, Morel CF, Scharer G, et al. Late-onset combined homocystinuria and methylmalonic aciduria (cb1C) and neuropsychiatric disturbances. Am J Med Genet 2007;143A:2430-34. 6. Schimel AM, Mets MB. The natural history of retinal degeneration in association with cobalamin C (cbl C) disease. Ophthalmic Genet 2006;27:9-14. 7. Tsina EK, Marsden DL, Hansen RM, Fulton AB. Maculopathy and retinal degeneration in cobalamin c methylmalonic aciduria and homocystinuria. Arch Ophthalmol 2005;123:1143-6. 8. Robb RM, Dowton SB, Fulton AB, Levy HL. Retinal degeneration in vitamin B12 disorder associated with methylmalonic aciduria and sulfur amino acid abnormalities. Arch J Ophthalmol 1984;97:691-6. 9. Traboulsi EI, Silva JC, Geraghty MT, Maumenee IH, Valle D, Green WR. Ocular histopathologic characteristics of cobalamin c type vitamin B12 defect with methylmalonic aciduria and homocystinuria. Am J Ophthalmol 1992;113:269-80. 10. Ricci D, Pane M, Deodato F, et al. Assessment of visual function in children with methylmalonic aciduria and homocystinuria. Neuropediatrics 2005;35:181-5. 11. Patton N, Beatty S, Lloyd IC, Wraith JE. Optic atrophy in association with cobalamin C (cbl C) disease. Ophthalmic Genet 2000;21:151-4. 12. Soueid EH, Benhamou N, Sterkers M, et al. Retinal degeneration associated with congenital transcobalamin II deficiency. Arch Ophthalmol 2001;119:1076-7.
To report the ocular complications of cobalamin-C type methylmalonic aciduria with homocystinuria (cblC) in a large consecutive series of patients.
METHODS
Medical records of patients with genetically diagnosed cblC disease from Mount Sinai Medical Center, New York, and H^ opital Necker, Paris, France, were reviewed. All patients with the diagnosis of cblC seen after January 2008 at Mount Sinai and January 1998 at H^ opital Necker were included.
RESULTS
A total of 9 cases are reported. Age at initial ocular examination ranged from 3.5 months to 10 years of age. All 9 patients had early-onset disease, with manifestation of disease presenting prior to 1 year of age. Two patients had definitive optic nerve pallor. All patients had retinal findings ranging from peripheral pigmentary retinal changes to central macular atrophy with Bull’s eye lesions. Optical coherence tomography was performed on one child and showed retinal thinning in the area of the bull’s eye lesions. Electroretinography was performed in 6 of the 9 patients, three of whom showed decreased scotopic and photopic responses. The other three patients had normal responses on electroretinography.
CONCLUSIONS
Ocular findings in patients with cblC are variable. All patients in the study exhibited earlyonset disease and had noteworthy ophthalmic findings. To the best of our knowledge, this is the first study in the literature correlating optical coherence tomography findings with fundus findings in cblC. ( J AAPOS 2012;16:370-375)
C
obalamin-C type methylmalonic aciduria with homocystinuria (cblC) is a rare autosomal-recessive inborn error of intracellular cobalamin metabolism caused by mutation in the MMACHC gene.1 The conversion of dietary vitamin B12 or cobalamin into an active form is dysfunctional. Systemic findings of the disease include failure to thrive, megaloblastic anemia, and neurologic dysfunction.2 Reported ocular findings include nystagmus, optic atrophy, pigmentary retinopathy, and retinal degeneration with maculopathy.3 Age at onset of disease has been correlated with extent of ocular disease.3-5 Patients with early-onset disease, defined as manifestation of disease within the first 12 months of age, often exhibit both neurological deterioration and progressive retinopathy. Patients with late-onset disease, in which symptoms become manifest after the age of 5 years, have not been shown to develop retinopathy. Author affiliations: aOphthalmology, Mount Sinai School of Medicine, New York, New York; bService d’ophtalmologie, H^opital Necker, Paris, France Presented at the 2011 Annual Meeting of the Association for Research in Vision and Ophthalmology, May 1-5, 2011, Fort Lauderdale, Florida. Submitted July 4, 2011. Revision accepted February 11, 2012. Correspondence: Leah R. Fuchs, MD, Department of Ophthalmology, The Mount Sinai School of Medicine, One Gustave L. Levy Place, Box 1183, New York, NY 10029 (email: [email protected]). Copyright Ó 2012 by the American Association for Pediatric Ophthalmology and Strabismus. 1091-8531/$36.00 http://dx.doi.org/10.1016/j.jaapos.2012.02.019
370
Because both metabolic and biochemical abnormalities are present, the diagnosis of cblC can be made on newborn screening, hopefully allowing for initiation of treatment prior to the development of notable pathology. A total of 22 cases have been reported in the literature of ocular findings of the disease.3,6-11 The purpose of this study is to report the largest series of patients with ocular abnormalities due to cblC.
Subjects and Methods Medical records of patients with the genetic diagnosis of cblC cared for by the senior authors (SEB at Mount Sinai Medical Center, New York, and IIM at H^ opital Necker, Paris, France) were reviewed. All patients with the diagnosis of cblC seen after January 2008, at Mount Sinai, and after January 1998, at H^ opital Necker were included. All patients had genetically confirmed cblC disease. Four of the patients were known to have undergone testing using DNA extraction of peripheral blood leukocytes. The Invader Assay (Third Wave Technologies, Madison, WI) was used to detect the MTHFR C677T and MTHFR A1298C mutations. One patient had genetic sequencing identifying the exact amino acid mutation. The details of the methods of genetic testing of the remaining patients are unavailable, but in each case a notation in the medical record indicated that genetic testing had confirmed the diagnosis. Patients were referred to the ophthalmology departments from the hospital genetics service. Age and sex were recorded, as was visual acuity, when possible. The
Journal of AAPOS
Volume 16 Number 4 / August 2012
Fuchs et al
371
FIG 1. Fundus photographs. A-B, Patient 2 at 9 years of age. Vision at that time was counting fingers at 5 feet in the right eye and 20/70 in the left eye. Retinal examination revealed bilateral bull’s eye macular atrophy. C-D, Patient 3, left eye, a sibling of patient 2, at 10 years of age, with visual acuity of counting fingers at 6 feet in both eyes. Retinal examination revealed retinal pigment epithelial clumping and atrophy. E-F, Patient 9 at 2 years of age: foveal abnormalities are present in both eyes. presence or absence of nystagmus and strabismus was noted. The appearance of the optic nerves and fundi was documented. Electroretinogram (ERG) and visually evoked potentials were recorded for some of the patients. Optical coherence tomography (OCT) was performed if possible. Of the 9 patients, 7 had follow-up examinations (mean, 22 months; range, 3-58 months).
Results The medical records of nine patients (seven boys) were reviewed; no patient diagnosed with cb1C was excluded (see
Journal of AAPOS
e-Supplement 1, available at jaapos.org). Age at initial ophthalmologic examination ranged from 3.5 months to 10 years of age. All children in the study had early-onset disease. As most patients were preverbal at the time of examination, visual acuity was difficult to obtain. Two children had central, steady, and maintained vision in each eye, and 3 children seemed to fix and follow in each eye. Two children had questionable no light perception in both eyes. Visual acuity in a pair of siblings was counting fingers at 6 feet in each eye in one child (aged 10 at presentation) and 20/
372
Fuchs et al
Volume 16 Number 4 / August 2012 Table 1. Results of electroretinogram (ERG) and visual-evoked potential (VEP) testing Patient 1 5 6 7 8 9
ERG
VEP
Reduced scotopic and photopic responses Normal Normal No discernible scotopic responses; decreased photopic responses Decreased photopic and scotopic responses Normal
Primitive, undifferentiated waveforms NA Normal No discernible responses Increased P2 wave culmination latencies NA
NA, not available.
FIG 2. A-B, Macular OCT of Patient 2. The OCT of the right and left eyes in patient at age 9 showed significant retinal thinning is present through the bull’s eye maculopathy.
125 in the right eye and 20/30 in the left eye in the other child (aged 6). Three children had strabismus at presentation, all of whom exhibited an esotropia. Six children had nystagmus. The optic nerves of 6 of the children appeared normal; 2 patients’ optic nerves had definitive pallor, while one had questionable pallor. All patients had retinal findings (Figure 1). Mild changes included peripheral pigmentary changes and mottling, while the most severe findings included central macular atrophy with Bull’s eye lesions (Figure 1A and B). One child showed small abnormalities at the bottom of the foveal depressions in both eyes (Figure 1E and F). The macular OCT from the patient with fundus findings in Figure 1A and B shows retinal thinning (Figure 2).
Electroretinogram and Visually Evoked Potentials Six of the children underwent ERG testing according to International Society for Clinical Electrophysiology of Vision (ISCEV) standards (Table 1). Three children exhibited normal responses (see, for example, Figure 3); 3 children had decreased scotopic and photopic responses. One of these children, examined at 3.5 months of age, exhibited normal photopic and flicker responses but scotopic responses of about 50% of normal (Figure 4A). On repeat ERG at 19 months of age, photopic responses were normal in latency, but reduced in amplitude to about 33% of normal for both single flash and 30-Hz flicker stimulation.
Responses following dark adaptation to the standard ISCEV full-strength flash were greatly attenuated to approximately 20% of normal (Figure 4B). Four children underwent visual-evoked potential testing (Table 1): 1 had normal responses; 1 had no discernable responses; 1 child had primitive, undifferentiated waveforms; and 1 had increased P2 wave culmination latencies. Of the 9 patients, 4 of the children were known to be heterozygous for MTHFR C677T (methylenetetrahydrofolate reductase), and wild type for the MTHFR A1298C mutation. One child was found to have the following mutations: c.dup271A (p.Arg91Lys fsh13X) heterozygous and c.615C . G (p.Tyr205X) heterozygous. The remaining 4 children were known to have MMHAC mutations, but the exact mutations and details of their genetic testing are not available.
Discussion Numerous ocular complications are found in patients with cblC. Findings are variable and can include nystagmus, strabismus, optic nerve pallor, pigmentary retinopathy, and decreased ERG responses. Such ocular manifestations are present very early in life in children with early-onset disease. Maculopathy described in patients with cblC occurs very early and likely develops prior to birth, whereas most other maculopathies do not present until a later age. Similar ocular pathology is found in both transcobalamin II deficiency, which involves defective intestinal absorption of vitamin B12, and cblC. Soueid and colleagues12 describe a case of transcobalamin II deficiency in a 7-month-old patient. Fundus examination remained normal until age 16, when there was a decrease in visual acuity with accompanying pigmentary retinopathy. Fluorescein angiography revealed central hypofluorescence in the macula surrounded by hyperfluorescence. Retinal degeneration did not progress with the administration of high-dose supplementation of hydroxocobalamin in the patient described in the study. In this study, follow-up was not long enough to determine whether or not high-dose supplementation altered progression of ocular disease.
Journal of AAPOS
Volume 16 Number 4 / August 2012
Fuchs et al
373
FIG 3. Normal ERG findings in Patient 5.
The mechanism of retinal degeneration in congenital cblC is not fully elucidated. Although supplementation with hydroxocobalamin and L-methionine improves anemia, it does not stop the progression of retinopathy, especially in children with early onset of the condition7,8; however, two of the children in the series are brothers, with the child diagnosed and treated at an earlier
Journal of AAPOS
developing less retinopathy than the sibling started on treatment later. Accumulation of neither methylmalonic acid nor homocysteine is likely the cause of retinal degeneration. Once the factors responsible for such degeneration are identified, treatment to prevent the onset of macular degeneration can be developed.
374
Fuchs et al
Volume 16 Number 4 / August 2012
FIG 4. Patient 1 ERG findings. A, At 3 months of age, showing normal responses to photopic single flash and 30-Hz flicker stimulation. Responses following dark adaptation to the standard ISCEV full-strength flash were about 50% of normal in amplitude. B, At 19 months of age, showing reduced scotopic and photopic responses.
This study corroborates previously reported ocular findings in cases of cblC. To date, this is the largest series of patients with ocular abnormalities due to cblC. In addition to ERG and visual-evoked potential information, this is the
first study in the literature correlating OCT findings with fundus findings. The study also supports previous reports of patients with early-onset disease manifesting severe ocular involvement.
Journal of AAPOS
Volume 16 Number 4 / August 2012
Literature Search PubMed was used to search MEDLINE without date restriction for the following terms: cobalamin C type deficiency, methylmalonic aciduria AND homocystinuria, retinal degeneration, retina, and ocular.
References 1. Lerner-Ellis JP, Tirone JC, Pawelek PD, et al. Identification of the gene responsible for methylmalonic aciduria and homocystinuria, cb1C type. Nat Genet 2006;38:93-100. 2. Rosenblatt DS, Aspler AL, Shevell MI, Pletcher BA, Fenton WA, Seashore MR. Clinical heterogeneity and prognosis in combined methylmalonic aciduria and homocystinuria (cb1C). J Inherit Metab Dis 1997;20:528-38. 3. Gerth C, Morel CF, Feigenbaum AV, Levin A. Ocular phenotype in patients with methylmalonic aciduria and homocystinuria, cobalamin C type. J AAPOS 2008;12:591-6. 4. Ben-Omran TI, Wong H, Blaser S, Feigenbaum A. Late-onset cobalamin-C disorder: A challenging diagnosis. Am J Med Genet 2007;143A:979-84.
Journal of AAPOS
Fuchs et al
375
5. Tsai AC, Morel CF, Scharer G, et al. Late-onset combined homocystinuria and methylmalonic aciduria (cb1C) and neuropsychiatric disturbances. Am J Med Genet 2007;143A:2430-34. 6. Schimel AM, Mets MB. The natural history of retinal degeneration in association with cobalamin C (cbl C) disease. Ophthalmic Genet 2006;27:9-14. 7. Tsina EK, Marsden DL, Hansen RM, Fulton AB. Maculopathy and retinal degeneration in cobalamin c methylmalonic aciduria and homocystinuria. Arch Ophthalmol 2005;123:1143-6. 8. Robb RM, Dowton SB, Fulton AB, Levy HL. Retinal degeneration in vitamin B12 disorder associated with methylmalonic aciduria and sulfur amino acid abnormalities. Arch J Ophthalmol 1984;97:691-6. 9. Traboulsi EI, Silva JC, Geraghty MT, Maumenee IH, Valle D, Green WR. Ocular histopathologic characteristics of cobalamin c type vitamin B12 defect with methylmalonic aciduria and homocystinuria. Am J Ophthalmol 1992;113:269-80. 10. Ricci D, Pane M, Deodato F, et al. Assessment of visual function in children with methylmalonic aciduria and homocystinuria. Neuropediatrics 2005;35:181-5. 11. Patton N, Beatty S, Lloyd IC, Wraith JE. Optic atrophy in association with cobalamin C (cbl C) disease. Ophthalmic Genet 2000;21:151-4. 12. Soueid EH, Benhamou N, Sterkers M, et al. Retinal degeneration associated with congenital transcobalamin II deficiency. Arch Ophthalmol 2001;119:1076-7.