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Retinal Degeneration in Vitamin B12 Disorder Associated with Methylmalonic Aciduria and Sulfur Amino Acid Abnormalities
RETINAL DEGENERATION IN VITAMIN B l2 DISORDER ASSOCIATED WITH METHYLMALONIC ACIDURIA AND SULFUR AMINO ACID ABNORMALITIES RICHARD M. ROBB, M.D., S. BRUCE DOWTON, M.B., ANNE B. FULTON, M.D., AND HARVEY
L.
LEVY,
M.D.
Boston, Massachusetts
A 33-month-old boy with an inborn error of vitamin B12 metabolism characterized by methylmalonic aciduria, homocystinuria, cystathioninuria, and hypomethioninemia had poor vision and a progressive retinal pigmentary degeneration. The child had early growth retardation with microcephaly, developmental delay, and a megaloblastic anemia. The retinal lesions were first noted when he was 1 year of age and, by ophthalmoscopy and by electroretinographic testing, have progressed. Treatment with hydroxocobalamin and L-methionine improved the anemia and the biochemical abnormalities but apparently did not halt the retinal degeneration. We believe the retinopathy is a feature of this disease, particularly in patients with infantile involvement. The retinal lesion may be caused by an unidentified abnormality of sulfur amino acid metabolism.
Among the disorders of vitamin Bl2 metabolism is an inborn error that results in deficiencies of methylcobalamin and deoxyadenosylcobalamin, the two coenzymatically active vitamin Bl2 derivatives.! The methylcobalamin deficiency causes sulfur amino acid abnormalities
Accepted for publication April 4, 1984. From the Department of Ophthalmology (Drs. Robb and Fulton) and the IEM-PKU Program of the Developmental Evaluation Clinic (Drs. Dowton and Levy), Children's Hospital; the Joseph P. Kennedy Jr. Laboratories of the Neurology Service, Massachusetts General Hospital (Dr. Levy); and the Departments of Ophthalmology (Drs. Robb and Fulton), Neurology (Dr. Levy), and Pediatrics (Dr. Dowton), Harvard Medical School, Boston Massachusetts. This study was supported by a grant from the Massachusetts Lions Eye Research Fund, Inc. (Dr. Robb), grant EY 05325 from the National Eye Institute (Dr. FUlton), and grant NS 05096 from the National Institute of Neurological and Communicative Disorders and Stroke (Dr. Levy). Reprint requests to Richard M. Robb, M.D., Chief, Department of Ophthalmology, Children's Hospital, 300 Longwood Ave., Boston, MA 02115.
including homocystinuria, cystathioninuria, and hypomethioninemia, while the deoxyadenosylcobalamin deficiency causes methylmalonic aciduria (Fig. 1). The clinical characteristics of this disorder are megaloblastic anemia with normal serum vitamin Bl2 concentration, poor growth and development, and mental retardation.2-8 Several patients have died during infancy.2,3,&-7 Ophthalmologic abnormalities are not considered to be among the major consequences of this disorder. Two patients, however, with such problems have been described. One was an 8-year-old mentally retarded girl who had fluttering, epileptiform ocular movements'' and the other was an 8-month-old infant with poor vision and peripheral "salt and pepper" retinopathy. 6 We examined a child with this disease who has reduced vision and progressive retinal abnormalities. We believe that these retinal lesions may be similar to the
©AMERICAN JOURNAL OF OPHTHALMOLOGY 97:691--696, 1984
691
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AMERICAN JOURNAL OF OPHTHALMOLOGY
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Fig. I (Robb and associates). Metabolic pathway of cobalamin (vitamin B12) conversion to coenzymatically active derivatives methylcobalamin (MeCbl; CHaCbl) and deoxyadenosylcobalmin (AdoCbI). The vitamin B12 disorder results in the reduced synthesis of both derivatives. The consequences of this are impaired methionine remethylation (from homocysteine) and deficient methylmalonyl-CoA degradation.
"salt and pepper" changes in the infant described by Carmel and associates" and that they are a feature of this vitamin B12 disorder, particularly in patients with infantile involvement. CASE REPORT The patient was born to a primigravida after a full-term pregnancy and an uncomplicated vaginal delivery. Intrauterine growth retardation was evident at birth. The boy's birthweight was 2,160 g «3rd percentile), his crown-heel length was 48.2 cm (25th percentile), and his head circumference was 31 em «3rd percentile). Poor growth persisted after birth. When he was 4 weeks old routine urine screening for metabolic disorders disclosed the presence of methylmalonic aciduria. 10 Repeat urine testing at the age of 10 weeks showed homocystinuria as well as methylmalonic aciduria. Retrospective testing of the initial urine specimen also indicated the presence of homocystine. When he was 3 months old the patient was hospitalized for testing. Growth retardation with microcephaly and developmental delay were present. He was found to have megaloblastic anemia with normal serum concentrations of vitamin B12 and folic acid. Plasma amino acid analysis disclosed the presence of homocystine (10 fLmol!liter) and cystathionine (2 umol/liter) with a reduced level of methionine (6 umol/liter). All other plasma amino acid concentrations, included taurine, were normal. The urine contained homocystine and cystathionine. Serum and urine contained methylmalonic acid. Complementation analysis of cultured skin fibroblasts disclosed a cobalamin C mutation." Therapy with hydroxocobalamin, 1 mg given intramuscularly, was initiated. Within the first week the child's reticulocyte count increased from 0.5% to 9.4%, homocystine disappeared from his blood and
JUNE, 1984
urine, and the levels of cystathionine and methylmalonic acid decreased. Hydroxocobalamin therapy was continued on a weekly or biweekly basis until he was 11 months old when, because of persistent hypomethioninemia, 0.5 mg of methylcobalamin, given intramuscularly once a week, was substituted. Later oral methylcobalamin replaced the intramuscular medication. Continuing low blood levels of methionine required therapy with L-methionine when he was 20 months old and, later, the introduction of betaine. Because of increasing methylmalonic aciduria, hydroxocobalamin replaced methylcobalamin when the boy was 22 months old. These measures resulted in normal to slightly increased blood levels of methionine and partial control of the other biochemical abnormalities. Ophthalrrwlogic findings-An ophthalmologic examination was performed when he was 8 months of age because of wandering eye movements and an apparent inability to fix on visual stimuli. Optokinetic nystagmus could not be elicited, and vision testing by preferential looking was indeterminate. Pupillary reactions to light were present, however, and visualevoked responses to Hashed stimuli were interpreted as normal. Ophthalmoscopy disclosed optic disks of normal size and color and prominent red-brown foveal areas. Abnormalities of the ocular fundus were first apparent at the age of 1 year. There was a granular disruption of foveal pigmentation in each eye, and the retinal arteries were slightly narrowed. The
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Fig. 2 (Robb and associates). Electroretinography. The amplitudes (circles) and latencies (triangles) of b-waves at the ages of 12, 21, and 33 months are shown for scotopic (upper panel; stimuli, Grass, blue 8) and photopic (lower panel; stimuli, Grass, red 8) responses. The mean amplitudes and latencies (± 2 S.D.) are indicated at the extreme left and right of each panel.
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RETINAL DEGENERATION AND VITAMIN B12
results of electroretinography indicated that b-wave amplitudes were attenuated and time from stimulus onset to b-wave peak was prolonged in both photopic and scotopic conditions (Fig. 2). At 18 months of age the patient seemed to be aware of visual stimuli and at times would reach for them, but his visual fixation remained imprecise and following movements were not apparent. The foveal granularity was more marked in both eyes, and in the center of the left fovea there was a small area in which the pigment epithelium was missing. FUndus photographs taken at 21 months of age showed pigmentary changes in the posterior pole of each eye (Fig. 3). Six months later the dark-adapted threshold obtained by a preferential-looking procedure was 1.6 log units above the normal for that age. 12 At 33 months of age the patient turned his head and eyes toward brightly colored objects and reached for them, but his visual fixation was unsteady with occasional beats of nystagmus. Ophthalmoscopy disclosed enlargement of the pigment epithelial defect in the left eye and the new appearance of a similar lesion in the foveal area of the right eye (Fig. 4). A visual acuity estimate by preferential looking was 20/500 with both eyes (normal for age, 20/30).13 There was no evidence of dislocation of the lenses. Slight pallor of the optic disks had become evident during the second year of life, but remained less prominent than the progressive pigmentary changes in the posterior retina. There were no clinically apparent pigmentary changes in the peripheral retina. DISCUSSION
This boy with a vitamin B12 defect (cobalamin group C mutation) characterized
693
by methylmalonic aciduria, homocystinuria, cystathioninuria, and hypomethioninemia has had poor vision and a progressive macular pigmentary disturbance. The retinal lesions were first noted when he was 1 year of age and repeated ophthalmoscopy has indicated progression. His early electroretinographic responses were attenuated. His poor vision was probably secondary to a combination of the retinal degeneration and retarded psychomotor development. Ocular lesions have been recorded in other children with this vitamin B12 defect. Cogan and associates" described epileptiform episodes of blinking of the eyelids with upward deviation of the eyes associated with electroencephalographic abnormalities in an 8-year-old mentally retarded girl with normal ophthalmoscopic findings. Our patient does not have this sort of abnormal eye movement. Carmel and associates" mentioned "peripheral salt and pepper retinal degeneration" in a blind female infant. This patient died without further evaluation of this finding (A. A. Bedros, oral communication,
Fig. 3 (Robb and associates). Ocular fundi when the boy was 21 months of age. Left, Mild pigmentary disturbance in the foveal area of the right eye. Right, Focaldefect in the parafoveal pigment epithelium of the left eye.
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AMERICAN JOURNAL OF OPHTHALMOLOGY
JUNE, 1984
Fig. 4 (Robb and associates). Ocular fundi when the boy was 33 months of age. Left, Granularity of pigmentation and focal defect in the pigment epithelium of the right eye. Right, An enlarging lesion in the parafoveal pigment epithelium of the left eye.
March 1983) but it may have been similar to the lesion we found. This infant had a severe clinical course with failure to thrive and developmental delay similar to our patient. She also had severe visual impairment thought to be "cortical blindness," but details were insufficient to distinguish between an ocular and a cerebral origin for the visual disability. We believe that retinal degeneration may be characteristic of the severe infantile form of this vitamin B12 disorder and that it has not been noted in other infants because of early death or lack of careful ophthalmologic examination. The retinal degeneration in our patient was similar in some respects to the condition known as Leber's congenital amaurosis, although the location of pigmentary changes in the fovea and rapid progression of the degeneration would be unusual for Leber's disease. 14 The latter condition is not known to be associated with a systemic metabolic disease, although there is sufficient variation in reported cases to suggest that several disease entities may now be included in this diagnostic category.
Progressive hypopigmentation of the ocular fundus, brown discoloration of the macula, and optic atrophy have been described in the infantile (Santavuori) type of neuronal ceroid lipofuscinosis.P The clinical pattern of this disease, however, is dominated by a rapidly progressive encephalopathy starting at about 1 year of age, characterized by ataxia and myoclonic jerks and leaving the patients grossly retarded and motionless by the age of 3 years. Fundus changes similar to those in our patient have been reported in Zellweger's syndrome'v" and electroretinographic amplitudes have been reduced or absent in some patients with this disease. 16-18 The rest of the clinical pattern and the metabolic abnormalities in our patient, however, differed from those in the cerebrohepatorenal syndrome. If retinal degeneration is part of this vitamin B12 disorder and is related to the metabolic defect, which of the biochemical or hematologic aberrations is the culprit? The methylmalonic acid accumulation is an unlikely candidate. Children with severe methylmalonic acidemia as a
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RETINAL DEGENERATION AND VITAMIN BIz
specific disorder do not have retinal lesions" and the vitamin B12 defect we describe is associated with only the mild degree of methylmalonic aciduria thought to be clinically benign when present as a singular finding (F. D. Ledley, H. L. Levy, and V. E. Shih, unpublished data). Homocystine is also unlikely to be the toxic agent. Individuals with homocystinuria caused by cystathionine B-synthase deficiency, a disorder in which ectopia lentis is prominent, rarely develop retinal lesions and then only later in life. 20 Homocystine accumulation caused by 5,lO-methylene tetrahydrofolate reductase deficiency is also unassociated with retinal changes." Cystathioninuria has not been associated with ophthalmologic findings and is probably a benign biochemical entity. 20 Perhaps a better candidate is the reduced level of methionine. Hypomethioninemia could limit protein synthesis with adverse effects in particularly vulnerable tissues such as the retina. Alternatively, the integrity of the human retina could depend upon the level of free methionine per se or on one or more sulfur amino acid products of methionine metabolism. In the cat, for instance, a deficiency of the sulfur amino acid taurine results in retinal degeneration with ophthalmoscopic findings similar to those in our patient. 22,23 Our patient and others with this vitamin B12 defect have neither reduced levels of taurine nor a metabolic block in the pathway of taurine production. The association of retinal degeneration and a sulfur amino acid deficiency in both cat and humans is intriguing, however, and suggests that the causative factor may be similar in both species. Further, hypomethioninemia has been invoked as the causative agent in the neuropathology of pernicious anemia." If this is so, methionine deficiency might also produce retinal lesions in another setting. If methionine deficiency is responsible
695
for the retinal degeneration in this vitamin B12 defect, treatment that normalizes the blood methionine level might be effective in preventing or ameliorating the complication. We have not seen such amelioration in our patient but earlier treatment might be beneficial in other cases. REFERENCES 1. Rosenberg, L. E.: Disorders of propionate and methylmalonate metabolism. In Stanbury, J. B., Wyngaarden, ]. B., Fredrickson, D. S., Goldstein, ]. L., and Brown, M. S. (eds.): The Metabolic Basis ofInherited Disease. New York, McGraw-Hill, 1983, pp. 474-497. 2. Levy, H. L., Mudd, S. H., Schulman, ]. D., Dreyfus, P. M., and Abeles, R. H.: A derangement in B12 metabolism associated with homocystinemia, cystathioninemia, hypomethioninemia, and methylmalonic acidura. Am. ]. Med. 48:390, 1970. 3. Dillon, M. ]., England, ]. M., Gompertz, D., Goodey, P. A., Grant, D. B., Hussein, H. A.-A., Linnell,]. C., Matthews, D. M., Mudd, S. H., Seakins, ]. W. T., Uhlendorf, B. W., and Wise, I. j.. Mental retardation, megaloblastic anaemia, methylmalonic aciduria, and abnormal homocysteine metabolism due to an error in BI2 metabolism. Clin. Sci. Mol. Med. 47:43, 1974. 4. Anthony, M., and McLeay, A. C.: A unique case of derangement ofvitamin B12 metabolism. Proc. Aust. Assoc. Neurol. 13:61, 1976. 5. Baumgartner, E. R., Wick, H., Maurer, R., Egli, N., and Steinmann, B.: Congenital defect in intracellular cobalamin metabolism resulting in homocystinuria and methylmalonic aciduria. Helv. Paediatr. Acta 34:465, 1979. 6. Carmel, R., Bedros, A. A., Mace, ]. W., and Goodman, S. I.: Congenital methylmalonic aciduriahomocystinuria with megaloblastic anemia. Observations on response to hydroxocobalamin and the effect of homocysteine and methionine on the deoxyuridine suppression test. Blood 55:570, 1980. 7. Matalon, R., and Michals, K.: Methylmalonic acidemia with homocystinuria. Lack of clinical improvement to treatment with hydroxycobalamin and choline despite biochemical improvement. Pediatr. Res. 17:293A, 1983. 8. Wilcken, B., Hammond, j., and Silink, M.: A defect in cobalamin (vit B12) metabolism associated with homocystinuria and methylmalonic aciduria. Pathology 5:112, 1983. 9. Cogan, D. G., Schulman, ]., Porter, R. ]., and Mudd, S. H.: Epileptiform ocular movements with methylmalonic aciduria and homocystinuria. Am. J. Ophthalmol. 90:251, 1980. 10. Coulombe, J. T., Levy, H. L., and Shih, V. E.: Massachusetts Metabolic Disorders Screening Program. II. Methylmalonic aciduria. Pediatrics 67:26, 1981. 11. Willard, H. F., Mellman, I. S., and Rosen-
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berg, L. E.: Genetic complementation among inherited deficiencies of methylmalonyl-CoA mutase activity. Evidence for a new class of human cobalamin mutant. Am. J. Hum. Genet. 30:1, 1978. 12. Mayer, D. L., Fulton, A. B., and Hansen, R. M.: Preferential looking acuity obtained with staircase procedure in pediatric patients. Invest. Ophthalmol. Vis. Sci. 23:538, 1982. 13. Hansen, R. M., and Fulton, A. B.: Behavioral measurement of background adaption in infants. Invest. Ophthalmo!. Vis. Sci. 21:625, 1981. 14. Noble, K. G., and Carr, R. E.: Leber's congenital amaurosis. A retrospective study of 33 cases and a histopathological study of one case. Arch. Ophthalmol. 96:818, 1978. 15. Santavuori, P., Haltia, M., and Juhani, R.: Infantile type of so-called neuronal ceroidlipofuscinosis. Med. Child. Neurol. 16:644, 1974. 16. Stanescu, B., and Dralands, L.: Cerebrohepato-renal (Zellweger's) syndrome. Ocular involvement. Arch. Ophthalmol. 87:590, 1972. 17. Haddad, R., Font, R. L., and Friendly, D. S.: Cerebro-hepato-renal syndrome of Zellweger. Ocular histopathological findings. Arch. Ophthalmo!. 94:1927, 1976. 18. Hittner, H. M., Kretzer, F. L., and Mehta, R. S.: Zellweger syndrome. Lenticular opacities indicating carrier status and lens abnormalities charac-
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teristics of homozygotes. Arch. Ophthalmol. 99:1977, 1981. 19. Matsui, S. M., Mahoney, M. J., and Rosenberg, L. E.: The natural history of the inherited methylmalonic acidemias. N. Eng!. J. Med. 308:857, 1983. 20. Mudd, S. H., and Levy, H. L.: Disorders of transsulfuration. In Stanbury, J. B., Wyngaarden, J. B., Fredrickson, D. S., Goldstein, J. L., and Brown, M. S. (eds.): The Metabolic Basis of Inherited Disease. New York, McGraw-Hill, 1983, pp. 522-559. 21. Erbe, R. W.: Genetic aspects of folate metabolism. In Harris, H., and Hirschhorn, K. (eds.): Advances in Human Genetics. New York, Plenum Press, 1979, pp. 293-354. 22. Schmidt, S. Y., Berson, E. L., and Hayes, K. C.: Retinal degeneration in cats fed casein. I. Taurine deficiency. Invest. Ophthalmol. 15:47, 1976. 23. Berson, E. L., Hayes, K. C., Rabin, A. R., Schmidt, S. Y., and Watson, G.: Retinal degeneration in cats fed casein. II. Supplementation with methionine, cysteine, or taurine. Invest. Ophthalmol. 15:52, 1976. 24. Scott, J. M., Wilson, P., Dinn, J. J.; and Wein, D. G.: Pathogenesis of subacute combined degeneration. A result in methyl group deficiency. Lancet 2:334, 1981.
L.
LEVY,
M.D.
Boston, Massachusetts
A 33-month-old boy with an inborn error of vitamin B12 metabolism characterized by methylmalonic aciduria, homocystinuria, cystathioninuria, and hypomethioninemia had poor vision and a progressive retinal pigmentary degeneration. The child had early growth retardation with microcephaly, developmental delay, and a megaloblastic anemia. The retinal lesions were first noted when he was 1 year of age and, by ophthalmoscopy and by electroretinographic testing, have progressed. Treatment with hydroxocobalamin and L-methionine improved the anemia and the biochemical abnormalities but apparently did not halt the retinal degeneration. We believe the retinopathy is a feature of this disease, particularly in patients with infantile involvement. The retinal lesion may be caused by an unidentified abnormality of sulfur amino acid metabolism.
Among the disorders of vitamin Bl2 metabolism is an inborn error that results in deficiencies of methylcobalamin and deoxyadenosylcobalamin, the two coenzymatically active vitamin Bl2 derivatives.! The methylcobalamin deficiency causes sulfur amino acid abnormalities
Accepted for publication April 4, 1984. From the Department of Ophthalmology (Drs. Robb and Fulton) and the IEM-PKU Program of the Developmental Evaluation Clinic (Drs. Dowton and Levy), Children's Hospital; the Joseph P. Kennedy Jr. Laboratories of the Neurology Service, Massachusetts General Hospital (Dr. Levy); and the Departments of Ophthalmology (Drs. Robb and Fulton), Neurology (Dr. Levy), and Pediatrics (Dr. Dowton), Harvard Medical School, Boston Massachusetts. This study was supported by a grant from the Massachusetts Lions Eye Research Fund, Inc. (Dr. Robb), grant EY 05325 from the National Eye Institute (Dr. FUlton), and grant NS 05096 from the National Institute of Neurological and Communicative Disorders and Stroke (Dr. Levy). Reprint requests to Richard M. Robb, M.D., Chief, Department of Ophthalmology, Children's Hospital, 300 Longwood Ave., Boston, MA 02115.
including homocystinuria, cystathioninuria, and hypomethioninemia, while the deoxyadenosylcobalamin deficiency causes methylmalonic aciduria (Fig. 1). The clinical characteristics of this disorder are megaloblastic anemia with normal serum vitamin Bl2 concentration, poor growth and development, and mental retardation.2-8 Several patients have died during infancy.2,3,&-7 Ophthalmologic abnormalities are not considered to be among the major consequences of this disorder. Two patients, however, with such problems have been described. One was an 8-year-old mentally retarded girl who had fluttering, epileptiform ocular movements'' and the other was an 8-month-old infant with poor vision and peripheral "salt and pepper" retinopathy. 6 We examined a child with this disease who has reduced vision and progressive retinal abnormalities. We believe that these retinal lesions may be similar to the
©AMERICAN JOURNAL OF OPHTHALMOLOGY 97:691--696, 1984
691
692
AMERICAN JOURNAL OF OPHTHALMOLOGY
~br ~
THF~r.Aethionine ""'.,.-.;'\
' CH3THF
,-
I
~~~J
Homocystetne
~Cystothionine
Ado-Cbl Propionyl GoA ---.Methyl Malonyl GoA MelltylMok¥lyr Succinyl CoA CoAMl./fase
+
I
Fig. I (Robb and associates). Metabolic pathway of cobalamin (vitamin B12) conversion to coenzymatically active derivatives methylcobalamin (MeCbl; CHaCbl) and deoxyadenosylcobalmin (AdoCbI). The vitamin B12 disorder results in the reduced synthesis of both derivatives. The consequences of this are impaired methionine remethylation (from homocysteine) and deficient methylmalonyl-CoA degradation.
"salt and pepper" changes in the infant described by Carmel and associates" and that they are a feature of this vitamin B12 disorder, particularly in patients with infantile involvement. CASE REPORT The patient was born to a primigravida after a full-term pregnancy and an uncomplicated vaginal delivery. Intrauterine growth retardation was evident at birth. The boy's birthweight was 2,160 g «3rd percentile), his crown-heel length was 48.2 cm (25th percentile), and his head circumference was 31 em «3rd percentile). Poor growth persisted after birth. When he was 4 weeks old routine urine screening for metabolic disorders disclosed the presence of methylmalonic aciduria. 10 Repeat urine testing at the age of 10 weeks showed homocystinuria as well as methylmalonic aciduria. Retrospective testing of the initial urine specimen also indicated the presence of homocystine. When he was 3 months old the patient was hospitalized for testing. Growth retardation with microcephaly and developmental delay were present. He was found to have megaloblastic anemia with normal serum concentrations of vitamin B12 and folic acid. Plasma amino acid analysis disclosed the presence of homocystine (10 fLmol!liter) and cystathionine (2 umol/liter) with a reduced level of methionine (6 umol/liter). All other plasma amino acid concentrations, included taurine, were normal. The urine contained homocystine and cystathionine. Serum and urine contained methylmalonic acid. Complementation analysis of cultured skin fibroblasts disclosed a cobalamin C mutation." Therapy with hydroxocobalamin, 1 mg given intramuscularly, was initiated. Within the first week the child's reticulocyte count increased from 0.5% to 9.4%, homocystine disappeared from his blood and
JUNE, 1984
urine, and the levels of cystathionine and methylmalonic acid decreased. Hydroxocobalamin therapy was continued on a weekly or biweekly basis until he was 11 months old when, because of persistent hypomethioninemia, 0.5 mg of methylcobalamin, given intramuscularly once a week, was substituted. Later oral methylcobalamin replaced the intramuscular medication. Continuing low blood levels of methionine required therapy with L-methionine when he was 20 months old and, later, the introduction of betaine. Because of increasing methylmalonic aciduria, hydroxocobalamin replaced methylcobalamin when the boy was 22 months old. These measures resulted in normal to slightly increased blood levels of methionine and partial control of the other biochemical abnormalities. Ophthalrrwlogic findings-An ophthalmologic examination was performed when he was 8 months of age because of wandering eye movements and an apparent inability to fix on visual stimuli. Optokinetic nystagmus could not be elicited, and vision testing by preferential looking was indeterminate. Pupillary reactions to light were present, however, and visualevoked responses to Hashed stimuli were interpreted as normal. Ophthalmoscopy disclosed optic disks of normal size and color and prominent red-brown foveal areas. Abnormalities of the ocular fundus were first apparent at the age of 1 year. There was a granular disruption of foveal pigmentation in each eye, and the retinal arteries were slightly narrowed. The
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Fig. 2 (Robb and associates). Electroretinography. The amplitudes (circles) and latencies (triangles) of b-waves at the ages of 12, 21, and 33 months are shown for scotopic (upper panel; stimuli, Grass, blue 8) and photopic (lower panel; stimuli, Grass, red 8) responses. The mean amplitudes and latencies (± 2 S.D.) are indicated at the extreme left and right of each panel.
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results of electroretinography indicated that b-wave amplitudes were attenuated and time from stimulus onset to b-wave peak was prolonged in both photopic and scotopic conditions (Fig. 2). At 18 months of age the patient seemed to be aware of visual stimuli and at times would reach for them, but his visual fixation remained imprecise and following movements were not apparent. The foveal granularity was more marked in both eyes, and in the center of the left fovea there was a small area in which the pigment epithelium was missing. FUndus photographs taken at 21 months of age showed pigmentary changes in the posterior pole of each eye (Fig. 3). Six months later the dark-adapted threshold obtained by a preferential-looking procedure was 1.6 log units above the normal for that age. 12 At 33 months of age the patient turned his head and eyes toward brightly colored objects and reached for them, but his visual fixation was unsteady with occasional beats of nystagmus. Ophthalmoscopy disclosed enlargement of the pigment epithelial defect in the left eye and the new appearance of a similar lesion in the foveal area of the right eye (Fig. 4). A visual acuity estimate by preferential looking was 20/500 with both eyes (normal for age, 20/30).13 There was no evidence of dislocation of the lenses. Slight pallor of the optic disks had become evident during the second year of life, but remained less prominent than the progressive pigmentary changes in the posterior retina. There were no clinically apparent pigmentary changes in the peripheral retina. DISCUSSION
This boy with a vitamin B12 defect (cobalamin group C mutation) characterized
693
by methylmalonic aciduria, homocystinuria, cystathioninuria, and hypomethioninemia has had poor vision and a progressive macular pigmentary disturbance. The retinal lesions were first noted when he was 1 year of age and repeated ophthalmoscopy has indicated progression. His early electroretinographic responses were attenuated. His poor vision was probably secondary to a combination of the retinal degeneration and retarded psychomotor development. Ocular lesions have been recorded in other children with this vitamin B12 defect. Cogan and associates" described epileptiform episodes of blinking of the eyelids with upward deviation of the eyes associated with electroencephalographic abnormalities in an 8-year-old mentally retarded girl with normal ophthalmoscopic findings. Our patient does not have this sort of abnormal eye movement. Carmel and associates" mentioned "peripheral salt and pepper retinal degeneration" in a blind female infant. This patient died without further evaluation of this finding (A. A. Bedros, oral communication,
Fig. 3 (Robb and associates). Ocular fundi when the boy was 21 months of age. Left, Mild pigmentary disturbance in the foveal area of the right eye. Right, Focaldefect in the parafoveal pigment epithelium of the left eye.
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AMERICAN JOURNAL OF OPHTHALMOLOGY
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Fig. 4 (Robb and associates). Ocular fundi when the boy was 33 months of age. Left, Granularity of pigmentation and focal defect in the pigment epithelium of the right eye. Right, An enlarging lesion in the parafoveal pigment epithelium of the left eye.
March 1983) but it may have been similar to the lesion we found. This infant had a severe clinical course with failure to thrive and developmental delay similar to our patient. She also had severe visual impairment thought to be "cortical blindness," but details were insufficient to distinguish between an ocular and a cerebral origin for the visual disability. We believe that retinal degeneration may be characteristic of the severe infantile form of this vitamin B12 disorder and that it has not been noted in other infants because of early death or lack of careful ophthalmologic examination. The retinal degeneration in our patient was similar in some respects to the condition known as Leber's congenital amaurosis, although the location of pigmentary changes in the fovea and rapid progression of the degeneration would be unusual for Leber's disease. 14 The latter condition is not known to be associated with a systemic metabolic disease, although there is sufficient variation in reported cases to suggest that several disease entities may now be included in this diagnostic category.
Progressive hypopigmentation of the ocular fundus, brown discoloration of the macula, and optic atrophy have been described in the infantile (Santavuori) type of neuronal ceroid lipofuscinosis.P The clinical pattern of this disease, however, is dominated by a rapidly progressive encephalopathy starting at about 1 year of age, characterized by ataxia and myoclonic jerks and leaving the patients grossly retarded and motionless by the age of 3 years. Fundus changes similar to those in our patient have been reported in Zellweger's syndrome'v" and electroretinographic amplitudes have been reduced or absent in some patients with this disease. 16-18 The rest of the clinical pattern and the metabolic abnormalities in our patient, however, differed from those in the cerebrohepatorenal syndrome. If retinal degeneration is part of this vitamin B12 disorder and is related to the metabolic defect, which of the biochemical or hematologic aberrations is the culprit? The methylmalonic acid accumulation is an unlikely candidate. Children with severe methylmalonic acidemia as a
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RETINAL DEGENERATION AND VITAMIN BIz
specific disorder do not have retinal lesions" and the vitamin B12 defect we describe is associated with only the mild degree of methylmalonic aciduria thought to be clinically benign when present as a singular finding (F. D. Ledley, H. L. Levy, and V. E. Shih, unpublished data). Homocystine is also unlikely to be the toxic agent. Individuals with homocystinuria caused by cystathionine B-synthase deficiency, a disorder in which ectopia lentis is prominent, rarely develop retinal lesions and then only later in life. 20 Homocystine accumulation caused by 5,lO-methylene tetrahydrofolate reductase deficiency is also unassociated with retinal changes." Cystathioninuria has not been associated with ophthalmologic findings and is probably a benign biochemical entity. 20 Perhaps a better candidate is the reduced level of methionine. Hypomethioninemia could limit protein synthesis with adverse effects in particularly vulnerable tissues such as the retina. Alternatively, the integrity of the human retina could depend upon the level of free methionine per se or on one or more sulfur amino acid products of methionine metabolism. In the cat, for instance, a deficiency of the sulfur amino acid taurine results in retinal degeneration with ophthalmoscopic findings similar to those in our patient. 22,23 Our patient and others with this vitamin B12 defect have neither reduced levels of taurine nor a metabolic block in the pathway of taurine production. The association of retinal degeneration and a sulfur amino acid deficiency in both cat and humans is intriguing, however, and suggests that the causative factor may be similar in both species. Further, hypomethioninemia has been invoked as the causative agent in the neuropathology of pernicious anemia." If this is so, methionine deficiency might also produce retinal lesions in another setting. If methionine deficiency is responsible
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for the retinal degeneration in this vitamin B12 defect, treatment that normalizes the blood methionine level might be effective in preventing or ameliorating the complication. We have not seen such amelioration in our patient but earlier treatment might be beneficial in other cases. REFERENCES 1. Rosenberg, L. E.: Disorders of propionate and methylmalonate metabolism. In Stanbury, J. B., Wyngaarden, ]. B., Fredrickson, D. S., Goldstein, ]. L., and Brown, M. S. (eds.): The Metabolic Basis ofInherited Disease. New York, McGraw-Hill, 1983, pp. 474-497. 2. Levy, H. L., Mudd, S. H., Schulman, ]. D., Dreyfus, P. M., and Abeles, R. H.: A derangement in B12 metabolism associated with homocystinemia, cystathioninemia, hypomethioninemia, and methylmalonic acidura. Am. ]. Med. 48:390, 1970. 3. Dillon, M. ]., England, ]. M., Gompertz, D., Goodey, P. A., Grant, D. B., Hussein, H. A.-A., Linnell,]. C., Matthews, D. M., Mudd, S. H., Seakins, ]. W. T., Uhlendorf, B. W., and Wise, I. j.. Mental retardation, megaloblastic anaemia, methylmalonic aciduria, and abnormal homocysteine metabolism due to an error in BI2 metabolism. Clin. Sci. Mol. Med. 47:43, 1974. 4. Anthony, M., and McLeay, A. C.: A unique case of derangement ofvitamin B12 metabolism. Proc. Aust. Assoc. Neurol. 13:61, 1976. 5. Baumgartner, E. R., Wick, H., Maurer, R., Egli, N., and Steinmann, B.: Congenital defect in intracellular cobalamin metabolism resulting in homocystinuria and methylmalonic aciduria. Helv. Paediatr. Acta 34:465, 1979. 6. Carmel, R., Bedros, A. A., Mace, ]. W., and Goodman, S. I.: Congenital methylmalonic aciduriahomocystinuria with megaloblastic anemia. Observations on response to hydroxocobalamin and the effect of homocysteine and methionine on the deoxyuridine suppression test. Blood 55:570, 1980. 7. Matalon, R., and Michals, K.: Methylmalonic acidemia with homocystinuria. Lack of clinical improvement to treatment with hydroxycobalamin and choline despite biochemical improvement. Pediatr. Res. 17:293A, 1983. 8. Wilcken, B., Hammond, j., and Silink, M.: A defect in cobalamin (vit B12) metabolism associated with homocystinuria and methylmalonic aciduria. Pathology 5:112, 1983. 9. Cogan, D. G., Schulman, ]., Porter, R. ]., and Mudd, S. H.: Epileptiform ocular movements with methylmalonic aciduria and homocystinuria. Am. J. Ophthalmol. 90:251, 1980. 10. Coulombe, J. T., Levy, H. L., and Shih, V. E.: Massachusetts Metabolic Disorders Screening Program. II. Methylmalonic aciduria. Pediatrics 67:26, 1981. 11. Willard, H. F., Mellman, I. S., and Rosen-
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berg, L. E.: Genetic complementation among inherited deficiencies of methylmalonyl-CoA mutase activity. Evidence for a new class of human cobalamin mutant. Am. J. Hum. Genet. 30:1, 1978. 12. Mayer, D. L., Fulton, A. B., and Hansen, R. M.: Preferential looking acuity obtained with staircase procedure in pediatric patients. Invest. Ophthalmol. Vis. Sci. 23:538, 1982. 13. Hansen, R. M., and Fulton, A. B.: Behavioral measurement of background adaption in infants. Invest. Ophthalmo!. Vis. Sci. 21:625, 1981. 14. Noble, K. G., and Carr, R. E.: Leber's congenital amaurosis. A retrospective study of 33 cases and a histopathological study of one case. Arch. Ophthalmol. 96:818, 1978. 15. Santavuori, P., Haltia, M., and Juhani, R.: Infantile type of so-called neuronal ceroidlipofuscinosis. Med. Child. Neurol. 16:644, 1974. 16. Stanescu, B., and Dralands, L.: Cerebrohepato-renal (Zellweger's) syndrome. Ocular involvement. Arch. Ophthalmol. 87:590, 1972. 17. Haddad, R., Font, R. L., and Friendly, D. S.: Cerebro-hepato-renal syndrome of Zellweger. Ocular histopathological findings. Arch. Ophthalmo!. 94:1927, 1976. 18. Hittner, H. M., Kretzer, F. L., and Mehta, R. S.: Zellweger syndrome. Lenticular opacities indicating carrier status and lens abnormalities charac-
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teristics of homozygotes. Arch. Ophthalmol. 99:1977, 1981. 19. Matsui, S. M., Mahoney, M. J., and Rosenberg, L. E.: The natural history of the inherited methylmalonic acidemias. N. Eng!. J. Med. 308:857, 1983. 20. Mudd, S. H., and Levy, H. L.: Disorders of transsulfuration. In Stanbury, J. B., Wyngaarden, J. B., Fredrickson, D. S., Goldstein, J. L., and Brown, M. S. (eds.): The Metabolic Basis of Inherited Disease. New York, McGraw-Hill, 1983, pp. 522-559. 21. Erbe, R. W.: Genetic aspects of folate metabolism. In Harris, H., and Hirschhorn, K. (eds.): Advances in Human Genetics. New York, Plenum Press, 1979, pp. 293-354. 22. Schmidt, S. Y., Berson, E. L., and Hayes, K. C.: Retinal degeneration in cats fed casein. I. Taurine deficiency. Invest. Ophthalmol. 15:47, 1976. 23. Berson, E. L., Hayes, K. C., Rabin, A. R., Schmidt, S. Y., and Watson, G.: Retinal degeneration in cats fed casein. II. Supplementation with methionine, cysteine, or taurine. Invest. Ophthalmol. 15:52, 1976. 24. Scott, J. M., Wilson, P., Dinn, J. J.; and Wein, D. G.: Pathogenesis of subacute combined degeneration. A result in methyl group deficiency. Lancet 2:334, 1981.