@ Aeolus Press Ophthalmic Paediatrics and Genetics 0167-6784/92/US$ 3.50
(Accepted 22, June 1992)
Mucolipidosis type IV Presentation of a mild variant
Ophthalmic Genet Downloaded from informahealthcare.com by University of Toronto on 11/21/14 For personal use only.
I. CASTEELS', D. S. I. TAYLOR', B. D. LAKE2*, D. J. SPALTON3 and G. BACH4 Departments of 10phthalmology and 2Histopathology, Hospital for Sick Children, 3Department of Ophthalmology, St. Thomas' Hospital, London, UK and 4Department of Human Genetics, Hadassah University Hospital, Jerusalem, Israel
ABSTRACT. The authors report a 16-year-old girl with rnucolipidosis type IV. She was referred because of deteriorating vision over the past three years. Corneal clouding with the appearance of cornea verticillata and retinal dystrophy were the main ophthalmological findings. Except for clumsiness no psychomotor retardation was present. Ultrastructural analysis of a conjunctival biopsy and cultured fibroblasts suggested a diagnosis of mucolipidosis type IV which was confirmed by biochemical studies. This patient represents the mildest described presentation of mucolipidosis type IV. Key words: mucolipidosis IV ; cornea verticillata ; conjunctival biopsy
life, and retinal dystrophy are the main ophthalmological findings ; strabismus, cataracts and Mucolipidosis type IV is a lysosomal storage optic atrophy have also been described. The cordisorder first described by Berman and her col- neal opacification is most often static in nature, leagues in 1974l and has been reviewed by Amir may vary with age in the same patient and may et aL2 and by Chitayat et The condition is become less dense with time2. Most patients with inherited as an autosomal recessive trait and is mucolipidosis IV have some degree of retinal found with a relatively high incidence among the dystrophy and the deterioration of vision is Ashkenazi Jews. Mucolipidosis type IV is char- more often related to a progressive retinal acterized by ophthalmological problems and degeneration than to the corneal clouding. Othsevere but slowly progressive psychomotor er inherited systemic storage disorders having retardation, but without mucopolysacchari- corneal clouding are the mucopolysaccharidoses, duria, skeletal deformity or organomegaly. Cor- fucosidosis, oligosaccharidoses and mucolipineal clouding usually apparent in the first year of doses I, I1 and 111. For the ophthalmologist, mucolipidosis IV is especially important because the corneal clouding can be the presenting symp* Correspondence to: Professor B. D. Lake, Department of Histopathology, Hospital for Sick Children, Great tom. The enzyme defect in ML IV has not yet been Ormond Street, London WClN 3JH, UK INTRODUCTION
Ophthalmic Paediatrics and Genetics - I992, Vol. 13, No. 4, pp. 205-210 0Aeolus Press Buren (The Netherlands) I992
205
I. Casteels et al. identified and the gene has not been cloned. The stored materials have been identified as gangliosides and phospholipids, and the extent and pattern of storage has been shown to be characteristic of ML IV49 5 .
Ophthalmic Genet Downloaded from informahealthcare.com by University of Toronto on 11/21/14 For personal use only.
CASE REPORT A 16-year-old girl was referred to us because of deteriorating vision for three years. She had been prescribed glasses but her vision failed to improve. The girl was born to unrelated parents of Jewish Ashkenazi origin and there was no family history of eye problems. Her gait was unsteady for the first three years and she tended to fall frequently, and at seven years she appeared to fatigue easily and showed some incoordination. She has had mild psychological difficulties and learning problems at school. Her scholastic achievements are lower than average for the normal highschool she attends. Her vision began to deteriorate at the age of 13 and has been much worse over the last year, especially during the night. She was not photophobic. Apart from the ocular problem the girl appeared to be rather clumsy but neurological examination was otherwise normal. There were no skin lesions. On examination, vision was 6/36 in the right eye and 6/60 in the left eye. She had very defective colour vision and was unable to name even the demonstration plate of the Ishihara colour vision test. Pupil reactions were normal to light and accommodation. On visual field examination bilateral central scotomas were detected. Slit-lamp examination showed whorls of corneal epithelial changes around the axial area of both eyes with the appearances of the so-called cornea verticillata sometimes seen in fucosidosis6 (Fig. I) . Flash stimulation gave smaller than average ERGS to white flash ; ERGS to blue and green flash under scotopic conditions were also just within normal levels, however those to red flash were degraded and markedly attenuated. Pattern stimulation gave markedly abnormal VEP’s and ERG’S. VEP’s to large check stimulation had a scotomatous character as did those to flash. All those findings suggested marked dysfunction of the macular path-
206
Fig. 1. Slit-lamp examination showed whorls of corneat epithelial changes around the axial area of both eyes (cornea verticillata).
way. Examination of the fundi and fluorescein angiography revealed macular pigmentary changes and wrinkled internal limiting membrane (Fig. 2). She was admitted to the Hospital for Sick Children, London, UK, with a provisional diagnosis of fucosidosis for further investigation. Routine lab-
Fig. 2. A fluorescein angiogram revealed mottled hyperfluorescence secondary to retinal pigment epithelial atrophy.
Ophthalmic Genet Downloaded from informahealthcare.com by University of Toronto on 11/21/14 For personal use only.
Mild mucolipidosis IV
Fig. 3. Electron micrographs of a conjunctival biopsy showing in (a) The presence of vacuolated epithelial cells which are more evident towards the surface. The basal cells do not contain membranous cytoplasmic bodies. Basement membrane is at the bottom right corner (~4250).(b) One of the vacuolated cells which contain some loose membranous material (~6400). (c) Occasional cells contain, apart from the loose membranous material, some angular profiles of paracrystalline material ( ~ 1 3 , 2 0 0 ) (d) . One of the larger vessels which contain membranous cytoplasmic bodies (arrow) in some endothelial cells. L=lumen (~13,000).
207
I. Casteels et al.
Ophthalmic Genet Downloaded from informahealthcare.com by University of Toronto on 11/21/14 For personal use only.
oratory testing was normal. There was no lactic acidosis, and no abnormal oligosaccharides nor excess glycosaminoglycans were detected in urine. Lysosomal enzyme determination of plasma, white blood cells and cultured fibroblasts, performed in the Department of Clinical Biochemistry, Institute of Child Health, London, UK, and in the Department of Human Genetics, Hadassah University Hospital Jerusalem, excluded fucosidosis and other lysosomal enzyme defects.
ated GM3 ganglioside on the cultured fibroblasts performed as previously described' showed increased retention of GM3 ganglioside. In addition, storage of lysobisphosphatidic acid, lysophosphatidylcholine, phosphatidylcholine and phosphatidylethanolamine was found after incubation of cultured fibroblasts with radiolabelled phosphate and oleic acid. These results are characteristic of ML IVs.
MATERIALS AND METHODS
DISCUSSION
A conjunctival biopsy was fixed in 2.5% glutaraldehyde and processed into Araldite for electron microscopy using standard techniques. A skin biopsy was taken for culture of fibroblasts for electron microscopy and for biochemical studies.
The patient showed a very similar ophthalmological picture t o that previously described for mucolipidosis IV. However, the corneal clouding did not present until the age of 13 while corneal opacification in the 20 patients described by Amir et a1.2 appeared before the age of five. The corneal clouding in the brothers described by Zwaan and Kenyon8 and Riedel et aL9 was not noted until the teenage years but may have been present earlier. The corneal surface was regular and she did not suffer from the corneal erosions described by Newman et a/.lO,or from the episode of conjunctival injection found in some of the patients reviewed by Amir et a1.2. Severe psychomotor retardation has been present in all patients described and generally none develop beyond the 12-15 month level in either motor or language function. Growth deceleration has been noticed by two to three years of age in many patients although birth weight is normal. There is only one report of a less severe case by Lake et a/.". Except for the clumsiness in our patient there was no evidence of psychomotor retardation. She attended a normal school and her problems were due to the visual deterioration. Growth was normal. Mucopolysaccharidosis, other lysosomal enzyme disorders and disorders known to produce corneal clouding were clini-
RESULTS Ultrastructural examination of the conjunctival biopsy showed vacuolation of the epithelial cells which was patchy and more evident towards the surface (Fig. 3a). The vacuolation was irregular within the cell, and the vacuoles were either empty, contained a fine fibrillogranular material or loose lipid lamellae (Fig. 3b). In some vacuolated cells angulated paracrystalline inclusions were present (Fig. 3c). The basal cells appeared normal and contained no inclusions. Many blood vessels showed no abnormality but in the endothelial cells of some of the larger capillaries and venules collections of membranous cytoplasmic bodies were found (Fig. 3d). Fibroblasts and Schwann cells were normal. The fibroblast culture contained intracytoplasmic inclusions 0.5-1 pm in diameter which ranged from finely granular, coarsely granular to empty with some lamellae at the periphery. Biochemical studies of loading tests with triti-
208
Ophthalmic Genet Downloaded from informahealthcare.com by University of Toronto on 11/21/14 For personal use only.
Mild mucolipidosis I V cally and biochemically excluded. Because of the lack of pathognomonic clinical signs and negative laboratory findings, a conjunctival biopsy was performed to confirm or exclude the clinical suspicion of a storage disorder. The diagnosis of mucolipidosis IV was suggested from the appearance of the conjunctival biopsy at electron microscopy and was confirmed by biochemical studies on cultured fibroblasts. The ultrastructural changes were less prominent than is usually seen in the conjunctiva and were patchy. In contrast with classical cases, no basal epithelial cell changes were present. The fibroblasts, although containing inclusions were not diagnostic. The mildness of the changes may well reflect the mild clinical presentation. Various treatments of the corneal opacification have been described. Penetrating keratoplasty was performed in a five-year-old boy with poor vision due to corneal cloudiness". Due to the lack of obvious mental retardation the diagnosis of mucolipidosis IV was not considered. After reepithelialization the graft became cloudy again. Ultrastructural analysis of the corneal and conjunctival epithelium confirmed
the diagnosis of mucolipidosis IV. A more successful treatment consists of a conjunctival transplantation as described by Dangel et al. I 2 and limbal transplantation has been reported to be a useful treatmenti3. Electron microscopy of cultured cells obtained by amniocentesis has helped in parental counselling in pregnancies where mucolipidosis IV is suspectedI4. It would be important to have examined cultured fibroblasts from the affected child before prenatal diagnosis is attempted. The presenting symptoms in our patient's deterioration of vision due to corneal clouding and some degree of retinal dystrophy at the age of 13 years are certainly much milder than previously reported for mucolipidosis IV. Mucolipidosis IV should be considered in the differential diagnosis in an apparently healthy patient with corneal clouding. ACKNOWLEDGEMENT We thank Mrs V. Smith, FIMLS, for technical assistance.
REFERENCES 1. Berman ER, Livni N , Shapira E, Merin S, Levij IS. Congenital corneal clouding with abnormal systemic storage bodies: A new variant of rnucolipidosis. J Pediatr 1974; 84:519-526. 2. Amir N , Zlotogora J, Bach G. Mucolipidosis type IV: Clinical spectrum and natural history. Pediatrics 1986; 79: 953-959. 3. Chitayat D, Meunier CM, Hodgkinson KA, Silver K , Flanders M, Anderson 1J el a/. Mucolipidosis type IV. Clinical manifestations and natural history. Am J Med Genet 1991 ; 41 :313-318. 4. Bach G, Cohen MM, Kohn G. Abnormal ganglioside accumulation in cultured fibroblasts from patients with mucolipidosis IV. Biochem Biophys Res Commun 1975; 66: 1583. 5. Bargal R, Bach G. Phospholipids accumulation in mucolipidosis I V cultured fibroblasts. J Inher Metab Dis 1988; 11 144-150. 6. Buncic JR, Lloyd LA. Pediatric neuro-ophthalmology. I n : The Eye in Childhood. Crawford JS, Morin JD, editors. New York : Grune & Stratton, 1983 ; p 452. 7. Zeigler M, Bach G. Internalization of exogenous gangliosides in cultured skin fibroblasts for the diagnosis of mucolipidosis IV. Clin Chim Acta 1986; 157: 183-189. 8. Zwaan J , Kenyon KR. Two brothers with presumed mucolipidosis IV. I n : Genetic Eye Disease. Cotlier E, Maumenee IH, Berman ER, editors. New York: AR Liss, 1982; 381-390. 9. Riedel KG, Zwaan J, Kenyon KR, Kolodny EH, Hanninen L, Albert DM. Ocular abnormalities in mucolipidosis 1V. Am J Ophthalmol 1985; 99: 125-136.
209
I . Casteels et al.
Ophthalmic Genet Downloaded from informahealthcare.com by University of Toronto on 11/21/14 For personal use only.
10. Newman NJ, Starck T, Kenyon KR, Lessell S, Fish 1, Kolodny EH. Corneal surface irregularities and episodic pain in a patient with mucolipidosis 1V. Arch Ophthalmol 1990; 108:251-254. 1 1 . Lake BD, Milla PJ, Taylor DSI, Young EP. A mild variant of mucolipidosis type IV (ML4). In: Genetic Eye Disease. Cotlier E, Maumenee IH, Berman ER, editors. New York: AR Liss, 1982; 391-404. 12. Dangel ME, Bremer DL, Rogers GL. Treatment of corneal opacification in mucolipidosis IV with conjunctival transplantation. Am J Ophthalmol 1985; 99: 137-141. 13. Kenyon KR, Tseng SCG. Lirnbal autograft transplantation for ocular surface disorders. Ophthalmology 1989; 96: 709723. 14. Kohn G, Sekeles E, Arnon J, Ornoy A. Mucolipidosis IV: Prenatal diagnosis by electron microscopy. Prenatal Diagnosis 1982; 2:301-307.
210
(Accepted 22, June 1992)
Mucolipidosis type IV Presentation of a mild variant
Ophthalmic Genet Downloaded from informahealthcare.com by University of Toronto on 11/21/14 For personal use only.
I. CASTEELS', D. S. I. TAYLOR', B. D. LAKE2*, D. J. SPALTON3 and G. BACH4 Departments of 10phthalmology and 2Histopathology, Hospital for Sick Children, 3Department of Ophthalmology, St. Thomas' Hospital, London, UK and 4Department of Human Genetics, Hadassah University Hospital, Jerusalem, Israel
ABSTRACT. The authors report a 16-year-old girl with rnucolipidosis type IV. She was referred because of deteriorating vision over the past three years. Corneal clouding with the appearance of cornea verticillata and retinal dystrophy were the main ophthalmological findings. Except for clumsiness no psychomotor retardation was present. Ultrastructural analysis of a conjunctival biopsy and cultured fibroblasts suggested a diagnosis of mucolipidosis type IV which was confirmed by biochemical studies. This patient represents the mildest described presentation of mucolipidosis type IV. Key words: mucolipidosis IV ; cornea verticillata ; conjunctival biopsy
life, and retinal dystrophy are the main ophthalmological findings ; strabismus, cataracts and Mucolipidosis type IV is a lysosomal storage optic atrophy have also been described. The cordisorder first described by Berman and her col- neal opacification is most often static in nature, leagues in 1974l and has been reviewed by Amir may vary with age in the same patient and may et aL2 and by Chitayat et The condition is become less dense with time2. Most patients with inherited as an autosomal recessive trait and is mucolipidosis IV have some degree of retinal found with a relatively high incidence among the dystrophy and the deterioration of vision is Ashkenazi Jews. Mucolipidosis type IV is char- more often related to a progressive retinal acterized by ophthalmological problems and degeneration than to the corneal clouding. Othsevere but slowly progressive psychomotor er inherited systemic storage disorders having retardation, but without mucopolysacchari- corneal clouding are the mucopolysaccharidoses, duria, skeletal deformity or organomegaly. Cor- fucosidosis, oligosaccharidoses and mucolipineal clouding usually apparent in the first year of doses I, I1 and 111. For the ophthalmologist, mucolipidosis IV is especially important because the corneal clouding can be the presenting symp* Correspondence to: Professor B. D. Lake, Department of Histopathology, Hospital for Sick Children, Great tom. The enzyme defect in ML IV has not yet been Ormond Street, London WClN 3JH, UK INTRODUCTION
Ophthalmic Paediatrics and Genetics - I992, Vol. 13, No. 4, pp. 205-210 0Aeolus Press Buren (The Netherlands) I992
205
I. Casteels et al. identified and the gene has not been cloned. The stored materials have been identified as gangliosides and phospholipids, and the extent and pattern of storage has been shown to be characteristic of ML IV49 5 .
Ophthalmic Genet Downloaded from informahealthcare.com by University of Toronto on 11/21/14 For personal use only.
CASE REPORT A 16-year-old girl was referred to us because of deteriorating vision for three years. She had been prescribed glasses but her vision failed to improve. The girl was born to unrelated parents of Jewish Ashkenazi origin and there was no family history of eye problems. Her gait was unsteady for the first three years and she tended to fall frequently, and at seven years she appeared to fatigue easily and showed some incoordination. She has had mild psychological difficulties and learning problems at school. Her scholastic achievements are lower than average for the normal highschool she attends. Her vision began to deteriorate at the age of 13 and has been much worse over the last year, especially during the night. She was not photophobic. Apart from the ocular problem the girl appeared to be rather clumsy but neurological examination was otherwise normal. There were no skin lesions. On examination, vision was 6/36 in the right eye and 6/60 in the left eye. She had very defective colour vision and was unable to name even the demonstration plate of the Ishihara colour vision test. Pupil reactions were normal to light and accommodation. On visual field examination bilateral central scotomas were detected. Slit-lamp examination showed whorls of corneal epithelial changes around the axial area of both eyes with the appearances of the so-called cornea verticillata sometimes seen in fucosidosis6 (Fig. I) . Flash stimulation gave smaller than average ERGS to white flash ; ERGS to blue and green flash under scotopic conditions were also just within normal levels, however those to red flash were degraded and markedly attenuated. Pattern stimulation gave markedly abnormal VEP’s and ERG’S. VEP’s to large check stimulation had a scotomatous character as did those to flash. All those findings suggested marked dysfunction of the macular path-
206
Fig. 1. Slit-lamp examination showed whorls of corneat epithelial changes around the axial area of both eyes (cornea verticillata).
way. Examination of the fundi and fluorescein angiography revealed macular pigmentary changes and wrinkled internal limiting membrane (Fig. 2). She was admitted to the Hospital for Sick Children, London, UK, with a provisional diagnosis of fucosidosis for further investigation. Routine lab-
Fig. 2. A fluorescein angiogram revealed mottled hyperfluorescence secondary to retinal pigment epithelial atrophy.
Ophthalmic Genet Downloaded from informahealthcare.com by University of Toronto on 11/21/14 For personal use only.
Mild mucolipidosis IV
Fig. 3. Electron micrographs of a conjunctival biopsy showing in (a) The presence of vacuolated epithelial cells which are more evident towards the surface. The basal cells do not contain membranous cytoplasmic bodies. Basement membrane is at the bottom right corner (~4250).(b) One of the vacuolated cells which contain some loose membranous material (~6400). (c) Occasional cells contain, apart from the loose membranous material, some angular profiles of paracrystalline material ( ~ 1 3 , 2 0 0 ) (d) . One of the larger vessels which contain membranous cytoplasmic bodies (arrow) in some endothelial cells. L=lumen (~13,000).
207
I. Casteels et al.
Ophthalmic Genet Downloaded from informahealthcare.com by University of Toronto on 11/21/14 For personal use only.
oratory testing was normal. There was no lactic acidosis, and no abnormal oligosaccharides nor excess glycosaminoglycans were detected in urine. Lysosomal enzyme determination of plasma, white blood cells and cultured fibroblasts, performed in the Department of Clinical Biochemistry, Institute of Child Health, London, UK, and in the Department of Human Genetics, Hadassah University Hospital Jerusalem, excluded fucosidosis and other lysosomal enzyme defects.
ated GM3 ganglioside on the cultured fibroblasts performed as previously described' showed increased retention of GM3 ganglioside. In addition, storage of lysobisphosphatidic acid, lysophosphatidylcholine, phosphatidylcholine and phosphatidylethanolamine was found after incubation of cultured fibroblasts with radiolabelled phosphate and oleic acid. These results are characteristic of ML IVs.
MATERIALS AND METHODS
DISCUSSION
A conjunctival biopsy was fixed in 2.5% glutaraldehyde and processed into Araldite for electron microscopy using standard techniques. A skin biopsy was taken for culture of fibroblasts for electron microscopy and for biochemical studies.
The patient showed a very similar ophthalmological picture t o that previously described for mucolipidosis IV. However, the corneal clouding did not present until the age of 13 while corneal opacification in the 20 patients described by Amir et a1.2 appeared before the age of five. The corneal clouding in the brothers described by Zwaan and Kenyon8 and Riedel et aL9 was not noted until the teenage years but may have been present earlier. The corneal surface was regular and she did not suffer from the corneal erosions described by Newman et a/.lO,or from the episode of conjunctival injection found in some of the patients reviewed by Amir et a1.2. Severe psychomotor retardation has been present in all patients described and generally none develop beyond the 12-15 month level in either motor or language function. Growth deceleration has been noticed by two to three years of age in many patients although birth weight is normal. There is only one report of a less severe case by Lake et a/.". Except for the clumsiness in our patient there was no evidence of psychomotor retardation. She attended a normal school and her problems were due to the visual deterioration. Growth was normal. Mucopolysaccharidosis, other lysosomal enzyme disorders and disorders known to produce corneal clouding were clini-
RESULTS Ultrastructural examination of the conjunctival biopsy showed vacuolation of the epithelial cells which was patchy and more evident towards the surface (Fig. 3a). The vacuolation was irregular within the cell, and the vacuoles were either empty, contained a fine fibrillogranular material or loose lipid lamellae (Fig. 3b). In some vacuolated cells angulated paracrystalline inclusions were present (Fig. 3c). The basal cells appeared normal and contained no inclusions. Many blood vessels showed no abnormality but in the endothelial cells of some of the larger capillaries and venules collections of membranous cytoplasmic bodies were found (Fig. 3d). Fibroblasts and Schwann cells were normal. The fibroblast culture contained intracytoplasmic inclusions 0.5-1 pm in diameter which ranged from finely granular, coarsely granular to empty with some lamellae at the periphery. Biochemical studies of loading tests with triti-
208
Ophthalmic Genet Downloaded from informahealthcare.com by University of Toronto on 11/21/14 For personal use only.
Mild mucolipidosis I V cally and biochemically excluded. Because of the lack of pathognomonic clinical signs and negative laboratory findings, a conjunctival biopsy was performed to confirm or exclude the clinical suspicion of a storage disorder. The diagnosis of mucolipidosis IV was suggested from the appearance of the conjunctival biopsy at electron microscopy and was confirmed by biochemical studies on cultured fibroblasts. The ultrastructural changes were less prominent than is usually seen in the conjunctiva and were patchy. In contrast with classical cases, no basal epithelial cell changes were present. The fibroblasts, although containing inclusions were not diagnostic. The mildness of the changes may well reflect the mild clinical presentation. Various treatments of the corneal opacification have been described. Penetrating keratoplasty was performed in a five-year-old boy with poor vision due to corneal cloudiness". Due to the lack of obvious mental retardation the diagnosis of mucolipidosis IV was not considered. After reepithelialization the graft became cloudy again. Ultrastructural analysis of the corneal and conjunctival epithelium confirmed
the diagnosis of mucolipidosis IV. A more successful treatment consists of a conjunctival transplantation as described by Dangel et al. I 2 and limbal transplantation has been reported to be a useful treatmenti3. Electron microscopy of cultured cells obtained by amniocentesis has helped in parental counselling in pregnancies where mucolipidosis IV is suspectedI4. It would be important to have examined cultured fibroblasts from the affected child before prenatal diagnosis is attempted. The presenting symptoms in our patient's deterioration of vision due to corneal clouding and some degree of retinal dystrophy at the age of 13 years are certainly much milder than previously reported for mucolipidosis IV. Mucolipidosis IV should be considered in the differential diagnosis in an apparently healthy patient with corneal clouding. ACKNOWLEDGEMENT We thank Mrs V. Smith, FIMLS, for technical assistance.
REFERENCES 1. Berman ER, Livni N , Shapira E, Merin S, Levij IS. Congenital corneal clouding with abnormal systemic storage bodies: A new variant of rnucolipidosis. J Pediatr 1974; 84:519-526. 2. Amir N , Zlotogora J, Bach G. Mucolipidosis type IV: Clinical spectrum and natural history. Pediatrics 1986; 79: 953-959. 3. Chitayat D, Meunier CM, Hodgkinson KA, Silver K , Flanders M, Anderson 1J el a/. Mucolipidosis type IV. Clinical manifestations and natural history. Am J Med Genet 1991 ; 41 :313-318. 4. Bach G, Cohen MM, Kohn G. Abnormal ganglioside accumulation in cultured fibroblasts from patients with mucolipidosis IV. Biochem Biophys Res Commun 1975; 66: 1583. 5. Bargal R, Bach G. Phospholipids accumulation in mucolipidosis I V cultured fibroblasts. J Inher Metab Dis 1988; 11 144-150. 6. Buncic JR, Lloyd LA. Pediatric neuro-ophthalmology. I n : The Eye in Childhood. Crawford JS, Morin JD, editors. New York : Grune & Stratton, 1983 ; p 452. 7. Zeigler M, Bach G. Internalization of exogenous gangliosides in cultured skin fibroblasts for the diagnosis of mucolipidosis IV. Clin Chim Acta 1986; 157: 183-189. 8. Zwaan J , Kenyon KR. Two brothers with presumed mucolipidosis IV. I n : Genetic Eye Disease. Cotlier E, Maumenee IH, Berman ER, editors. New York: AR Liss, 1982; 381-390. 9. Riedel KG, Zwaan J, Kenyon KR, Kolodny EH, Hanninen L, Albert DM. Ocular abnormalities in mucolipidosis 1V. Am J Ophthalmol 1985; 99: 125-136.
209
I . Casteels et al.
Ophthalmic Genet Downloaded from informahealthcare.com by University of Toronto on 11/21/14 For personal use only.
10. Newman NJ, Starck T, Kenyon KR, Lessell S, Fish 1, Kolodny EH. Corneal surface irregularities and episodic pain in a patient with mucolipidosis 1V. Arch Ophthalmol 1990; 108:251-254. 1 1 . Lake BD, Milla PJ, Taylor DSI, Young EP. A mild variant of mucolipidosis type IV (ML4). In: Genetic Eye Disease. Cotlier E, Maumenee IH, Berman ER, editors. New York: AR Liss, 1982; 391-404. 12. Dangel ME, Bremer DL, Rogers GL. Treatment of corneal opacification in mucolipidosis IV with conjunctival transplantation. Am J Ophthalmol 1985; 99: 137-141. 13. Kenyon KR, Tseng SCG. Lirnbal autograft transplantation for ocular surface disorders. Ophthalmology 1989; 96: 709723. 14. Kohn G, Sekeles E, Arnon J, Ornoy A. Mucolipidosis IV: Prenatal diagnosis by electron microscopy. Prenatal Diagnosis 1982; 2:301-307.
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