Correspondence CONGENITAL
CEROID - LIPOFUSCINOSIS
To rhe Editor: We would like to add some remarks to the report entitled Congenirul Ceroid-lipofuscinosis by Barohn et al. [ 11. The neuronal ceroid-lipofuscinoses (NCLs) represent a heterogenous group of disorders. The basic biochemical lesion(s) responsible for the accumulation of the storage material remains unknown. The clinical picture in each of the different forms of NCL may vary greatly [2]; therefore, what should be emphasized is that it is generally accepted that the most reliable if not prerequisite means for diagnosing NCL is ultrastructural examination of the tissues and the finding of characteristic lysosomal inclusion bodies, which include granular, osmiophilic, curvilinear, and fingerprint profiles. The type of predominating inclusion bodies, together with the clinical picture, allows us to distinguish four main forms of that disease: infantile, late infantile, juvenile, and adult. Even if the occurrence of the congenital form of NCL cannot be ruled out at present, two previous ultrastructural studies [3,4] described predominantly granular osmiophilic inclusions that are typical of the infantile form of NCL [5]. Barohn et al. also reported granular osmiophilic inclusions [I], but these inclusions were not documented on electron micrographs. The only inclusions documented were lamellar. Moreover, in both of these reports [3,4]. the pattern of CNS damage was similar to that observed in infantile NCL [5]. In the report presented by Barohn et al. [I], there were also no convincing data to diagnose congenital neuronal ceroid-lipofuscinosis as a separate clinico-pathologic entity. In addition to evident methodologic faults (unusually high concentration of fixatives used, scarcity of histologic staining methods applied, and lack of details concerning autofluorescent and ultrastructural pattern), there is no mention of any lysosomal enzyme studies having been done to eliminate the other known and wellcharacterized storage disorders. The imprecise term used for describing cortical damage (“some degree of neuronal loss”) suggests relatively good preservation of the cortical mantle, which distinguishes this case from both the above-mentioned cases as well as the other infantile NCL cases. Moreover, the artifactual changes visible on the electron micrograph included in the report render it practically useless for precise analysis of ultmstructural changes; therefore, we believe that in this otherwise very interesting case, diagnosis of congenital NCL is not based on solid, substantial data and as so remains highly controversial. Krystyna E. Wisniewski, MD, PhD Elzbieia Kida, MD, PhD Institute for Basic Research in Developmental Staten Island, New York
References [I] Bar&n RJ, Dowd DC, Kagan-Hallet fuscinosis. Pediatr Neurol 1992;8:54-9.
[2] Wisniewski KJZ, Kida E. Patxot OF, Connell F. Variability in the clinical and pathological findings in the neuronal ceroid lipofuscinoses: Review of data and observations. Am J Med Genet 1992;42:525-32. [3] Humphreys S, Lake BD, Schotz CL. Congenital amaurotic idiocy -A pathological, histcchemical, biochemical and ultrastructuraJ study. Neuropathol Appl Neurobiol 1985; I I :475-84. [4] Garborg 1. Torvik A, Hals J, Tangsrud SE, Lindemann R. Congenital neuronal ceroid lipofuscinosis. Acta Pathol Microbial Immunol Stand A 1987;95: I 19-25. [S] Haltia M, Rapola J. Santavuouri P. Infantile type of so-called neuronal ceroid lipofuscinosis. Histological and electron microscopic studies. Acta Neuropathol 1973;26: 157-70. To the Ediror: The aim of our report, Congenital Ceroid-lipofuscinosis [I], was to emphasize the unusual presentation of this condition in a severely microcephalic neonate. Because this autopsy tissue was referred to us, and the diagnosis could not have been suspected clinically, its preparation for electron microscopic study was not optimal. Lamellated inclusions were identified, however, as seen in the article. Material prepared for light microscopy, however, was technically very good; the finding of striking autofluorescence as shown on page 56 effectively excludes other kinds of stored neuronal material [I]. An algorithm showing how each of the other storage diseases was excluded would not have been appropriate in the article or in this letter. The infant had no visceral storage of material, no dysostosis, and no comeal clouding. We all look forward to the elucidation of the enzymatic defect(s) of the ceroid-lipofuscinoses. Any subclassification of NCL based on the ultrastructural morphology of inclusion bodies must be viewed as a temporary one. No other subtypes of any lysosomal storage disease are so based (e.g., the inclusion bodies in Tay-Sachs disease versus its [chemical and age-based] variants do not sufficiently differ morphologically as to be useful in separating one disorder from another, likewise the [age-based] variants of Gaucher disease, and so on). Whereas the electron microscopic findings of the NCLs are often distinctive, other reports have discussed the overlap that these inclusions exhibit throughout the clinical subtypes [2,3]. We appreciate the wealth of expertise Dr. Wisniewski and her colleagues have regarding NCL; however, we believe that the pathologic findings in our case are sufficiently distinctive to include them with the NCL disorders. Because the patient was a neonate, it must be a rare congenital example. Kathleen S. Kagan-Hallet, MD Richard J. Barohn, MD University of Texas Health Science San Antonio, Texas
Center
Disabilities
KS. Congenital
ceroid-lipo-
References [l] Barohn RJ, Dowd DC, Kagan-Hallet KS. Congenital ceroidlipofuscinosis. Pediatr Neural 1992;8:54-9. [2] Dyken PR. Reconsideration of the classification of the neuronal ceroid-lipofuscinoses. Am J Med Genet 1988;5:69-84. [3] Dyken PR. Review article. Tbe neuronal ceroid lipofuscinoses. J Child Neurol 1989;4:165-74.
PEDIATRIC
NEUROLOGY
Vol.‘8
No. 4
315
CEROID - LIPOFUSCINOSIS
To rhe Editor: We would like to add some remarks to the report entitled Congenirul Ceroid-lipofuscinosis by Barohn et al. [ 11. The neuronal ceroid-lipofuscinoses (NCLs) represent a heterogenous group of disorders. The basic biochemical lesion(s) responsible for the accumulation of the storage material remains unknown. The clinical picture in each of the different forms of NCL may vary greatly [2]; therefore, what should be emphasized is that it is generally accepted that the most reliable if not prerequisite means for diagnosing NCL is ultrastructural examination of the tissues and the finding of characteristic lysosomal inclusion bodies, which include granular, osmiophilic, curvilinear, and fingerprint profiles. The type of predominating inclusion bodies, together with the clinical picture, allows us to distinguish four main forms of that disease: infantile, late infantile, juvenile, and adult. Even if the occurrence of the congenital form of NCL cannot be ruled out at present, two previous ultrastructural studies [3,4] described predominantly granular osmiophilic inclusions that are typical of the infantile form of NCL [5]. Barohn et al. also reported granular osmiophilic inclusions [I], but these inclusions were not documented on electron micrographs. The only inclusions documented were lamellar. Moreover, in both of these reports [3,4]. the pattern of CNS damage was similar to that observed in infantile NCL [5]. In the report presented by Barohn et al. [I], there were also no convincing data to diagnose congenital neuronal ceroid-lipofuscinosis as a separate clinico-pathologic entity. In addition to evident methodologic faults (unusually high concentration of fixatives used, scarcity of histologic staining methods applied, and lack of details concerning autofluorescent and ultrastructural pattern), there is no mention of any lysosomal enzyme studies having been done to eliminate the other known and wellcharacterized storage disorders. The imprecise term used for describing cortical damage (“some degree of neuronal loss”) suggests relatively good preservation of the cortical mantle, which distinguishes this case from both the above-mentioned cases as well as the other infantile NCL cases. Moreover, the artifactual changes visible on the electron micrograph included in the report render it practically useless for precise analysis of ultmstructural changes; therefore, we believe that in this otherwise very interesting case, diagnosis of congenital NCL is not based on solid, substantial data and as so remains highly controversial. Krystyna E. Wisniewski, MD, PhD Elzbieia Kida, MD, PhD Institute for Basic Research in Developmental Staten Island, New York
References [I] Bar&n RJ, Dowd DC, Kagan-Hallet fuscinosis. Pediatr Neurol 1992;8:54-9.
[2] Wisniewski KJZ, Kida E. Patxot OF, Connell F. Variability in the clinical and pathological findings in the neuronal ceroid lipofuscinoses: Review of data and observations. Am J Med Genet 1992;42:525-32. [3] Humphreys S, Lake BD, Schotz CL. Congenital amaurotic idiocy -A pathological, histcchemical, biochemical and ultrastructuraJ study. Neuropathol Appl Neurobiol 1985; I I :475-84. [4] Garborg 1. Torvik A, Hals J, Tangsrud SE, Lindemann R. Congenital neuronal ceroid lipofuscinosis. Acta Pathol Microbial Immunol Stand A 1987;95: I 19-25. [S] Haltia M, Rapola J. Santavuouri P. Infantile type of so-called neuronal ceroid lipofuscinosis. Histological and electron microscopic studies. Acta Neuropathol 1973;26: 157-70. To the Ediror: The aim of our report, Congenital Ceroid-lipofuscinosis [I], was to emphasize the unusual presentation of this condition in a severely microcephalic neonate. Because this autopsy tissue was referred to us, and the diagnosis could not have been suspected clinically, its preparation for electron microscopic study was not optimal. Lamellated inclusions were identified, however, as seen in the article. Material prepared for light microscopy, however, was technically very good; the finding of striking autofluorescence as shown on page 56 effectively excludes other kinds of stored neuronal material [I]. An algorithm showing how each of the other storage diseases was excluded would not have been appropriate in the article or in this letter. The infant had no visceral storage of material, no dysostosis, and no comeal clouding. We all look forward to the elucidation of the enzymatic defect(s) of the ceroid-lipofuscinoses. Any subclassification of NCL based on the ultrastructural morphology of inclusion bodies must be viewed as a temporary one. No other subtypes of any lysosomal storage disease are so based (e.g., the inclusion bodies in Tay-Sachs disease versus its [chemical and age-based] variants do not sufficiently differ morphologically as to be useful in separating one disorder from another, likewise the [age-based] variants of Gaucher disease, and so on). Whereas the electron microscopic findings of the NCLs are often distinctive, other reports have discussed the overlap that these inclusions exhibit throughout the clinical subtypes [2,3]. We appreciate the wealth of expertise Dr. Wisniewski and her colleagues have regarding NCL; however, we believe that the pathologic findings in our case are sufficiently distinctive to include them with the NCL disorders. Because the patient was a neonate, it must be a rare congenital example. Kathleen S. Kagan-Hallet, MD Richard J. Barohn, MD University of Texas Health Science San Antonio, Texas
Center
Disabilities
KS. Congenital
ceroid-lipo-
References [l] Barohn RJ, Dowd DC, Kagan-Hallet KS. Congenital ceroidlipofuscinosis. Pediatr Neural 1992;8:54-9. [2] Dyken PR. Reconsideration of the classification of the neuronal ceroid-lipofuscinoses. Am J Med Genet 1988;5:69-84. [3] Dyken PR. Review article. Tbe neuronal ceroid lipofuscinoses. J Child Neurol 1989;4:165-74.
PEDIATRIC
NEUROLOGY
Vol.‘8
No. 4
315
