Maculopathy and Retinal Degeneration in Cobalamin C

A B

C D

Figure 2. Fluorescein angiograms. Superotemporal ischemia is seen in both eyes. A, In the right eye, the macula shows mild cystoid macular edema. Perivascular leakage is seen mainly in the superotemporal region, affecting both venules and arterioles. B, The left eye shows normal macula. C and D, Fluorescein angiograms of the superotemporal periphery of the right (C) and left (D) eyes, showing microaneurysmal dilation of small vessels, capillary permeability, preretinal neovascularization in the left eye, and major peripheral vascular closure.

retinopathy, nephropathy, and F-13385, Marseille, France (John stroke,5 but it is distinct in that the [email protected]). Maculopathy and Retinal digestive tract is not involved in Degeneration in Cobalamin those 2 syndromes, which have been 1. George F, Brisson C, Poncelet P, et al. Rapid iso- C Methylmalonic Aciduria mapped to 19q124 and 3p21,5 re- lation of human endothelial cells from whole blood using S-Endo1 monoclonal antibody and Homocystinuria spectively. In our patient, genetic coupled with immunomagnetic beads: demon- study showed a normal karyotype stration of endothelial injury after angioplasty. The cobalamin C form of methyl- (standard metaphase spread). Be- Thromb Haemost. 1992;67:147-153. 2. Rambaud JC, Galian A, Touchard G, et al. Di- malonic aciduria and homocystin- cause the patient is the only mem- gestive tract and renal small vessel hyalinosis, uria (Cc-CMAH) is an inherited de- idiopathic nonarteriosclerotic intracerebral cal- ber of his family to manifest the syn- ficiency of the 2 coezymatically drome, no linkage mapping has been cifications, retinal ischemic syndrome, and phenotypic abnormalities: a new family syndrome. active vitamin B12 derivatives, meth- performed to date. Gastroenterology. 1986;90:930-938. 3. van Effenterre G, Haut J, Brezin A, et al. Retinal ylcobalamin and deoxyadenosylco- John Conrath, MD and choroidal ischemic syndrome, digestive tract balamin (Figure 1). Its heterog- and renal small vessel hyalinosis, intracerebral eneous clinical manifestations Bertrand Roquelaure, MD calcifications and phenotypic abnormalities: a Marie Chrestian, MD new family syndrome. Graefes Arch Clin Exp include feeding difficulties, neural Laurence Camoin-Jau, MD Ophthalmol. 1989;227:315-322. dysfunction, and ophthalmic abnor- 4. Tournier-Lasserve E, Joutel A, Melki J, et al. malities.1 The ophthalmic features Elisabeth Tournier-Lasserve, MD Cerebral autosomal dominant arteriopathy with Bernard Ridings, MD subcortical infarcts and leukoencephalopathy are visual impairment, nystagmus, maps to chromosome 19q12. Nat Genet. 1993; and retinopathy with conspicuous 3:256-259. 1,2 5. Ophoff RA, DeYoung J, Service SK, et al. He- maculopathy. The mechanism by Financial Disclosure: None. reditary vascular retinopathy, cerebroretinal vas- which the biochemical abnormali- Correspondence: Dr Conrath, Oph- culopathy, and hereditary endotheliopathy with ties cause retinal disease has not retinopathy, nephropathy, and stroke map to a thalmology Department, Timone single locus on chromosome 3p21.1-p21.3. Am been defined. We analyzed photo- Hospital, 264 rue Saint Pierre J Hum Genet. 2001;69:447-453. receptor cell and postreceptoral

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OH-Cbl Reductase/ Homocysteine Methionine β-Ligand Transferase

TC II/OH-Cbl OH-Cbl GSCbl CblII CbII MeCbl

(Lysosomal Release of Cobalamin) MS Reductase

GSCbl

Reductase

CblI

Adenosyltransferase

AdoCbl

L-Methylmalonyl CoA Succinyl CoA

Methylmalonyl-CoA Mitochondrion Mutase

Figure 1. Schematic diagram of the 2 vitamin B12 derivatives. The defective derivatives deoxyadenosylcobalamin (AdoCbl) and methylcobalamin (MeCbl) act as coenzymes. The site of the defect in the cobalamin C form of methylmalonic aciduria and homocystinuria is circled. TC II indicates transcobalamin II; GSCbl, glutathionylcobalamin; CblII and CblI, cobalamins with cobalt valences of 2ϩ and 1ϩ, respectively; OH-Cbl, hydroxycobalamin; MS, methionine synthase; and CoA, coenzyme A.

9 mo 22 mo 27 mo

34 mo 45 mo

Figure 2. Progression of maculopathy in the left eye. The macular appearance in the right eye was similar.

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©2005 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 10/01/2021 tation studies secured the diagno- 120 sis of Cc-CMAH. Hydroxycobalamin Saturated Amplitude injections and betaine and protein 100 restriction were started and main- tained, with consequent improve- 80 ment of biochemical measures, in- cluding modest decreases in total 60 homocysteine level and increases in

40 methionine level. % of Normal for Age Before and after treatment, pro-

20 cesses in rod photoreceptor and Photoreceptor (Rmp3) Postreceptor (Vmax) postreceptoral cells and cone- mediated responses were investi- 0 1234gated. The variables of the activa- tion of rod phototransduction and 120 postreceptoral function were de- Sensitivity 100 rived from the full-field electroretinogram.3 Rod photoresponse sensi- Photoreceptor (S) 80 Postreceptor (1/σ) tivity and saturated amplitude were calculated from the a-wave. The 60 b-wave sensitivity and saturated amplitude represented postreceptoral 40 activity. Each variable was com- % of Normal for Age pared with normal values for age.4 20 The saturated amplitudes were, on average, approximately 50% of the

0 1234normal means. Except for normal rod cell sensitivity at age 3 years 10 0.60 months, when methionine was at the highest level, all photoreceptor and postreceptoral sensitivities were sig- 0.45 nificantly attenuated (Figure 3). Cone-mediated b-wave amplitudes remained at 50% of the normal 0.30 mean.5 Despite improving or stable full-field retinal function, the macu-

Methionine, mg/dL lopathy progressed to large, atro- 0.15 phic patches (Figure 2).

Comment. The Cc-CMAH is one of

0 1234the few causes of infantile macu- Age, y lopathy. Treatment did not rescue the macula or postreceptoral reti- Figure 3. Rod photoreceptor and postreceptoral saturated amplitudes and sensitivities of the left eye nal responses represented by the b- expressed as percentages of the normal means for age. Results from the right eye were similar. Also wave. However, in this patient, nor- shown are the methionine levels at the time of the electroretinograms. Metabolic supplement therapy was mal rod photoreceptor sensitivity started 1 month after the first electroretinogram. Rod photoresponse sensitivity (S ) and saturated was restored in conjunction with in- amplitude (Rmp3) were calculated from the a-wave. The b-wave sensitivity (1/␴) and saturated amplitude (Vmax) represented postreceptoral activity. To convert methionine to micromoles per liter, multiply by creased levels of the essential amino 67.02. acid methionine. This implies methionine rescue of transduction pro- processes represented by electro- and maculopathy (Figure 2). Grat- cesses that involve rhodopsin and retinographic responses in a child ing acuities measured by preferen- other transduction cascade pro- with Cc-CMAH. tial looking were near the lower lim- teins in the rod cell membranes. its of normal for age, and by 4 years Thus, low methionine level may, in- Report of a Case. A 7-month-old in- of age, her visual acuity with bin- deed, have a role in the pathogen- fant girl, born at term, was first ex- ocular viewing of the Lea symbols esis of retinopathy in Cc-CMAH.2 amined because of crossed eyes af- was 20/200 OU. Although develop- ter an unremarkable perinatal ment was delayed, the patient be- course. Ophthalmic examination came ambulatory and verbal. El- Efthymia K. Tsina, MD, PhD demonstrated esotropia, horizon- evated plasma homocysteine levels, Deborah L. Marsden, MD tal nystagmus of small amplitude, a large peak of urine methylmalo- Ronald M. Hansen, PhD mildly attenuated retinal arteries, nic acid level, and cell complemen- Anne B. Fulton, MD

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©2005 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 10/01/2021 Financial Disclosure: None. etal extension of areas of choroidal normal-appearing optic discs, reti- Correspondence: Dr Fulton, De- and outer retinal atrophy. Exten- nal vasculature, and maculae partment of Ophthalmology, Chil- sive rod and cone system dysfunc- (Figure 2A-C). Bone spicule for- dren’s Hospital Boston, 300 Long- tion characteristically occurs within mation and choroidal atrophy were wood Ave, Boston, MA 02115 (anne the first years of life. Eventually, the absent. His maternal grandfather had [email protected]). rod electroretinogram (ERG) be- advanced choroideremia (Figure 2D). comes undetectable and cone re- Electroretinograms (Figure 3A) 1. Rosenblatt DS, Aspler AL, Shevell MI, Fenton WA, Seashore MR. Clinical heterogeneity and sponses are recordable only with performed to standards from the In- prognosis in combined methylmalonic acid- computer averaging.1 Nyctalopia and ternational Society for Clinical Elec- uria and homocystinuria (cblC). J Inherit Metab Dis. 1997;20:528-538. progressive field constriction typi- trophysiology of Vision demon- 2. Robb RM, Dowton SB, Fulton AB, Levy HL. cally become evident in the second strated, at age 10 years, mildly Retinal degeneration in B12 disorder associ- decade with acuity loss eventually subnormal responses of rods (67% of ated with methylmalonic aciduria and sulfur amino acid abnormalities. Am J Ophthalmol. 1984; occurring because of macula involve- normal mean; lower limit, 83% of 97:691-696. ment. Female carriers often exhibit mean) and, to a greater degree, dark- 3. Cooper LL, Hansen RM, Darras BT, et al. Rod photoreceptor function in children with mito- “moth-eaten,” patchy pigmenta- adapted cones (44% of normal mean; chondrial disorders. Arch Ophthalmol. 2002; tion at the level of the RPE compat- normal lower limit, 76%) with nor- 120:1055-1062. ible with lyonization.2 mal amplitudes of light-adapted 4. Fulton AB, Hansen RM. The development of scotopic sensitivity. Invest Ophthalmol Vis Sci. 2000; We describe the finding of nor- cones consistent with mild rod and 41:1588-1596. mal or mildly subnormal ERGs in 3 scotopic cone dysfunction. Rod and 5. Fulton AB, Hansen R, Westall CA. Develop- young affected males (aged 8, 9, and cone implicit times were normal. Re- ment of ERG responses: the ISCEV rod, maxi- mal and cone responses in normal subjects. Doc 10 years) from 2 unrelated families peat ERGs at 12 years of age showed Ophthalmol. 2003;107:235-241. with choroideremia (Figure 1). Di- minimal further rod loss. Karyotyp- rect sequencing of the choroider- ing was normal. Direct sequencing of emia gene (CHM) identified a dif- CHM identified a nonsense muta- ferent nonsense (stop) mutation in tion (R239X, CGA→CTA), also iden- Stop Mutations in Exon 6 each family. The mutations were tified in the patient’s maternal grand- of the Choroideremia only 14 codons apart in exon 6, sug- father.2,3 Gene, CHM, Associated gesting that a common mechanism The patient representing case 2, With Preservation of underlying these mutations may lead who is from an unrelated family with the Electroretinogram to a milder clinical and electrophysi- choroideremia, was first evaluated at ological phenotype. 9 years of age. He was asymptom- Choroideremia (Mendelian Inher- The patient representing case 1 atic with visual acuities of 20/20 OU. itance in Man [MIM] #303100) is an was asymptomatic when evaluated at The results of color vision testing uncommon X-linked chorioretinal age 6 years. Visual acuity was 20/ and Goldmann perimetry testing degeneration characterized by mot- 20-2 OD and 20/20 OS. Fundus ex- were normal. Fundus examination tling of the retinal pigment epithe- amination disclosed fine, peppery identified fine, peppery RPE mot- lium (RPE) and inexorable centrip- RPE mottling in the midperiphery but tling in the midperiphery but nor-

A B I

II 2 2

III 3 2

IV 2 3 3 2

Case 1 Case 2 Case 3

Figure 1. Pedigrees for case 1 (A) and cases 2 and 3 (B). Black squares indicate affected males; circles with black dots, known carrier females; gray squares, males affected by history.

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