Demyelinating Peripheral Neuropathy in Cockayne Syndrome: A Histopathologic and Morphometric Study Kimio Sasaki, MD, Nobutada Tachi, MD, Minoru Shinoda, MD, Norihiro Satoh, MD, Ryoji Minami, MD and Akio Ohnishi, MD
The clinical and histopathological features of Cockayne syndrome in a 2-year-old girl are reported. Sural nerve biopsy revealed segmental demyelination and remyelination. The density of myelinated fibers, especially small ones, was decreased in comparison with an age-matched control. Although the total number of unmyelinated fibers showed no difference from that in the control, the number of small unmyelinated fibers was slightly increased. A study of teased fibers from the patient's nerve revealed that 1% of the fibers had segmental demyelination, and 7% showed remyelination. Ultrastructurally, demyelinated fibers were present sporadically. No degeneration ofaxons was evident. Our pathological and morphometric data for the sural nerve suggest the presence of primary demyelination in early childhood. Key words: Cockayne syndrome, peripheral neuropathy, ultrastructure, morphometric study. Sasaki K, Tachi N, Shinoda M, Satoh N, Minami R, Ohnishi A. Demyelinating peripheral neuropathy in Cockayne syndrome: a histopathologic and morphometric study. Brain Dev 1992; 14:114-7
Cockayne syndrome (CS) is a rare autosomal recessive disorder [1], with characteristic features such as cachectic dwarfism, microcephaly, mental retardation, pigmentary retinal degeneration, sunken eyes, gait disturbance, neural deafness and intracranial calcifications [2-5]. Involvement of the peripheral nervous system in CS was first reported by Moosa and Dubowitz [6], who observed diminished tendon reflexes and slowed nerve conduction, with demyelination in sural nerve biopsy specimens. Thereafter, some studies have revealed the presence of demyelinating peripheral neuropathy electrophysiologically andj or pathologically [7-14]. However, no morpho-
From the Department of Pediatrics, Sapporo Medical College, Sapporo (KS, NT); Hakodate Municipal Public Health Center, Hakodate (MS); Department of Pediatrics, Hokkaido Prefectural Rehabilitation Center for Physically Handicapped Children, Sapporo (NS); National Sanatorium Yakumo Hospital, Yakumo (RM); and Department of Neurology, University of Occupational and Environmental Health, Kitakyushu (AD). Received for publication: October 14, 1991. Accepted for publication: February 9, 1992. Correspondence address: Dr. Kimio Sasaki, Department of Pediatrics, Hokkaido Prefectural Rehabilitation Center for Physically Handicapped Children, 2-2 Kanayama I-jo l-chome, Teine-ku, Sapporo 006, Japan.
metric studies of the peripheral nerves in CS of early childhood have yet been reported. Recently we studied the sural nerve of a 2-year-old girl with CS by electron microscopy and morphometric analysis. CASE REPORT The patient was born after an uncomplicated 41-week gestation. Her birth weight was 2,670 g. Head circumference was 31.0 cm. Weight gain was poor from infancy and head control was acquired at 2.5 months. Her mother noticed hypertonus of the lower limbs from the age of about 4 months. Acquisition of motor milestones was retarded: the patient became able to roll over at 7 months, sit unassisted at one year, and stand assisted at 2 years and 3 months. She was unable to walk with or without aid. She was able to speak one word before the age of one year, but thereafter her language acquisition and mental development were poor. She developed mild photosensitivity at one year. On examination at the age of 2 years and 4 months, she showed lower than average height and weight for age (76.3 cm, 7.7 kg), and microcephaly (head circumference 41.5 cm). Her facial appearance was peculiar, with sunken eyes. When she was standing with aid, anterior inclination of the trunk, equinovarus deformity of the right foot and
Fig 1 Cross-section of the sural nerve showing slightly diminished densi· ty of myelinated fibers. Arrow indicates a thinly myelinated fiber, showing remyelination (a: control; b: patient). Toluidine blue, x 840.
planovalgus of the left foot were noted. Muscle tonus of the lower limbs was increased (spastic diplegia). Patellar tendon reflexes were exaggerated, and pathological reflexes could not be elicited. Limited abduction of both hip joints was present. There was no hearing loss, and also no seizure disorder. Laboratory fmdings including CBC, results of liver function tests and serum protein levels were normal. The cerebrospinal fluid (CSF) contained 5 leukocytes/mm 3 , and CSF protein was 35 mg/dl. Analysis of serum and urinary amino acids showed normal fmdings. Funduscopic examination revealed pigmentary retinal degeneration and optic atrophy. Electroencephalography showed sporadic sharp waves in the left temporal area. The auditory brainstem responses (ABR) revealed prolongation of the latencies of waves III, IV and V without slowing of the 0-1 and I-II interpeak latencies. Motor and sensory nerve conduction velocities of the right median nerve were 33.6 mls and 45.5 mIs, respectively. X-ray examination of the hip joints showed subluxation of the femoral head on the right. CT scan revealed calcifications of the bilateral basal ganglia and mild ventricular enlargement with mild cerebellar atrophy. Cranial magnetic resonance imaging (MRI) revealed delayed myelination. An ultraviolet sensitivity test on cultured skin fibroblasts showed colony formation intermediate between that of normal controls and group A xeroderma pigmentosum (XP). Sural nerve biopsy fmdings The left sural nerve was biopsied under local anesthesia behind the external malleolus. The specimen was fixed in 2.5% glutaraldehyde in phosphate buffer, and then post-
Fig 2 A teased fiber showing segmental demyelination.
fixed with 1% OS04. One large part of the specimen was embedded in Epon. Semithin sections were stained with toluidine blue, and ultrathin sections, stained with uranyl acetate and lead citrate, were observed with a NipponDenshi 1200EX Electron Microscope. The rest of the specimen was immersed in glycerin for teased fiber preparation. In semithin sections of the nerve, the number of myelinated fibers appeared to be slightly decreased compared with an age-matched control (Fig 1). In addition, axons with thin myelination relative to axon size and demyelinated axons were occasionally observed. Teased fiber analysis revealed segmental demyelination and remyelination of myelinated fibers (Fig 2). One percent of teased fibers showed segmental demyelination, and 7% showed remyelinated internodes. On the other hand, teased fiber analysis of control nerves showed that 1% of fibers had thinly remyelinated internodes, and no segmental demyelination. On electron microscopy, demyelinated axons were occasionally found. They were usually surrounded by Schwann cells associated with, or without, macrophages containing lamellar structures which seemed to be myelin debris (Fig 3). Moreover, a few thinly myelinated fibers,
Sasaki e tal: Cockayne syndrome
115
which seemed to have been remyelinated, were observed. Onion bulb formations were not disclosed. The density of myelinated and unmyelinated fibers and their size distribution were evaluated. A size-frequency histogram showed that the density of myelinated fibers was slightly lower (12,167/mm 2 ) than that of the control (l9,337/mm 2 ). However, the density of large myelinated fibers was not different from that of the control. The decrease in the density was due to the reduction in density of small fibers « 4 pm) (Fig 4). The mean diameter of myelinated fibers was 4.4 pm, which was slightly larger than the control (3.3 pm). This was due to the relative decrease of small fibers. The density of unmyelinated fibers was 74,456/mm2 , and similar to that of the control (82,189/
Fig 3 Electron micrograph of the sural nerve shOWing a demye/ina ted axon surrounded by a Schwann cell associated with a phagocyte containing myelin debris. xII ,000.
mm 2 ). However, the relative density of small unmyelinated fibers was slightly greater (Fig 5). The mean diameter of unmyelinated fibers was 0.41 pm, which was slightly smaller than the control (0.52 pm).
DISCUSSION The present patient showed cachectic dwarfism, microcephaly, a typical facial appearance with sunken eyes, retinitis pigmentosa, mental retardation, gait disturbance (spastic diplegia), photosensitive dermatitis, limited abduction of both hip joints and slowed nerve conduction velocities. In addition to these clinical features, CT and MRI fmdings and the results of an ultraviolet hypersensitivity test of cultured skin fibroblasts were consistent with a diagnosis of CS. In our patient, hearing loss could not be proved. However, ABR revealed prolongation of the latencies of waves III to V, suggesting lesions in the pons and/or midbrain. It is known that CS is often associated with peripheral neuropathy [6,7,9-13], and that nerve conduction velocity is frequently reduced [6, 9-13, 15-19]. Sural nerve biopsies have been done in about 20 cases so far, 17 of which showed chronic demyelinating neuropathy [613, 20], and only a few showed no demyelination with or without a decrease in the density of myelinated fibers [14, 18]. The present patient is one of the youngest to have shown demyelination of the sural nerve. In previous studies of CS, morphometric analysis of the sural nerve has shown a decrease in the density of both large and small myelinated fibers [13,20], or only large myelinated fibers [9, 10, 12]. Ohnishi et al [13] reported decreased densities of both large and small myelinated fibers, and suggested the presence of primary segmental de- and remyelination in the sural nerve. In the present case, however, the density of small myelinated fibers was decreased. With regard to examination of biopsied sural
6,000
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12,167 MF/mm'
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4,000
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o
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20,000
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IX: 10,000
10.000
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en
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Z
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4
6
8
10
2
4
6
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FIBER DIAMETER (/lm)
Fig 4 Myelinated fiber size-frequency histogram showing a mild loss of small fibers.
116 Brain & Development, Vol 14, No 2,1992
0.2
0.4
0.6
0.8
1.0
1.2
1.4
1.6
1.8
0.2
0.4
0.6
0.8
1.0
1.2
14
1.6
1.8
FIBER DIAMETER (/lm)
Fig 5 Unmyelinated fiber size-frequency histogram showing a slightly greater number of small fibers with a normal density of total fibers.
nerves from infants and young children, the following data have been reported. In a study on 2- and 3-year-olds by Vos et al [11], no morphometry was done. In a study by Goto and Ogawa [14] involving a 2-year-old, the total density of myelinated fibers was decreased and the histogram was not shown. In our present case, from the fact that relatively more demyelination was observed in small myelinated fibers, and also from the results of the morphometric study, it is suggested that the demyelination may have occurred first in small myelinated fibers. Concerning MRI of the brain in CS, primary hypomyelination or secondary demyelination has been suggested [21, 22]. These MRI findings are consistent with reported neuropathologic observations, which include atrophy of the white matter and patchy loss of myelinated fibers [5, 23,24]. Our observations and previous fmdings oflesions of the peripheral nerves in CS suggest the presence of primary segmental demyelination in the peripheral nervous system as well as in the central nervous system. Recently, molecular and cytological studies of CS have been carried out. In cells from CS patients, hypersensitivity to UV light [25], and a specific deficiency in the ability to repair damage in actively transcribed regions of DNA have been shown [26,27]. However, these results do not account for the mechanisms of demyelination and the difference in susceptibility to sunlight-induced skin cancer between CS and XP patients. Further studies will be needed to clarify the underlying biochemical and cytogenetic abnormalities. REFERENCES 1. McKusick VA. Mendelian inheritance in man. 7th ed. Baltimore·London: The Johns Hopkins University Press, 1986; 895-7. 2. Cockayne EA. Dwarfism with retinal atrophy and deafness. Arch Dis Child 1936;11:1-8. 3. Cockayne EA. Case reports: dwarfism with retinal atrophy and deafness. Arch Dis Child 1946;21: 52-4. 4. Neill CA, Dingwall MM. A syndrome resembling progeria: a review of two cases. Arch Dis Child 1950;25:213-21. 5. Sugarman GI, Landing BH, Reed WB. Cockayne syndrome: clinical study of two patients and neuropathologic findings in one. Clin Pediatr 1977;16:225-32. 6. Moosa A, Dubowitz V. Peripheral neuropathy in Cockayne's syndrome. Arch Dis Child 1970;45:674-7. 7. Roy S, Srivastava RN, Gupta PC, Mayekar G. Ultrastructure of peripheral nerve in Cockayne's syndrome. Acta Neuro· pathol (Berl) 1973;24:345-9. 8. Inoue N, Hanyu N, Takatsu M, Yanagisawa N, Tsukagoshi H. The Cockayne's syndrome with benign clinical course. A study of four cases from two families (in Japanese). Rinsho Shinkeigaku (Tokyo) 1978;18:477-85.
9. Smits MG, Gabreels FJM, Renier WO et al. Peripheral and central myelinopathy in Cockayne's syndrome. Report of 3 siblings. Neuropediatrics 1982;13:161-7. 10. Grunnet ML, Zimmerman AW, Lewis RA. Ultrastructure and electrodiagnosis of peripheral neuropathy in Cockayne's syndrome. Neurology 1983;33: 1606-9. 11. Vos A, Gabreels-Festen A, Joosten E, Gabreels F, RenierW, Mullaart R. The neuropathy of Cockayne syndrome. Acta Neuropathol (Berl) 1983;61:153-6. 12. Schenone A, Rolando S, Ferrari M, Romagnoli P, Tabaton M, Mancardi GL. Peripheral neuropathy in Cockayne syndrome. Ital J Neurol Sci 1986;7:447-52. 13. Ohnishi A, Mitsudome A, Murai Y. Primary segmental demyelination in the sural nerve in Cockayne's syndrome. Muscle Nerve 1987;10:163-7. 14. Goto K, Ogawa T. A case of Cockayne's syndrome appearing clinical symptoms in neonatal period (in Japanese). No To Hattatsu (Tokyo) 1989;21:491-4. 15. Alton DJ, McDonald P, Reilly BJ. Cockayne's syndrome. A report of three cases. Radiology 1972; 102:403-6. 16. Brumback RA, Yoder FW, Andrew AD, Peck GL, Robbins JH. Normal pressure hydrocephalus. Recognition and relationship to neurological abnormalities in Cockayne's syndrome. Arch Neurol 1978;35: 337-45. 17. Gamstorp I. Donohue's syndrome-Leprechaunism-Cockayne's syndrome. Eur Neurol 1972;7:26-33. 18. Jin K, Handa T, Ishihara T, Yoshii F. Cockayne syndrome: report of two siblings and review of literature in Japan. Brain Dev (Tokyo) 1979;1:305-12. 19. See G, Dayras J-CI, Brodin M, Llewellyn D. Syndrome de Cockayne et encephalopathie evolutive. Ann Pediat 1974; 21 :215-21. 20. Sakashita Y, Kuzuhara S, Honda S, Ohkawa Y, Yamanouchi H. Ultraviolet hypersensitivity of cultured fibroblasts of a case of Cockayne's syndrome without clinical photosensitivity (in Japanese). Rinsho Shinkeigaku (Tokyo) 1987;27: 741-4. 21. Dabbagh 0, Swaiman KF. Cockayne syndrome: MRI correlates of hypomyelination. Pediatr Neurol 1988;4: 113-6. 22. Boltshauser E, Yalcinkaya C, Wichmann W, Reutter F, Prader A, Valavanis A. MRI in Cockayne syndrome type I. Neuroradiology 1989;31:276-7. 23. Moossy J. The neuropathology of Cockayne's syndrome. J Neuropathol Exp Neural 1967;26: 654-60. 24. Soffer D, Grotsky HW, Rapin I, Suzuki K. Cockayne syndrome: unusual neuropathological findings and review of the literature. Ann Neurol 1979;6: 340-8. 25. Lehmann AR. Xeroderma pigmentosum, Cockayne syndrome and ataxia-telangiectasia: disorders relating DNA repair to carcinogenesis. Cancer Surveys 1982; 1:93-118. 26. Mayne LV, Lehmann AR. Failure of RNA synthesis to recover after UV irradiation: an early defect in cells from individuals with Cockayne's syndrome and xeroderma pigmentosum. Cancer Res 1982;42:1473-8. 27. Venema J, Mullenders LHF, Natarajan AT, van Zeeland AA, Mayne LV. The genetic defect in Cockayne syndrome is associated with a defect in repair of UV-induced DNA damage in transcriptionally active DNA. Proc Natl Acad Sci USA 1990;87:4707-11.
Sasaki et af: Cockayne syndrome
117
The clinical and histopathological features of Cockayne syndrome in a 2-year-old girl are reported. Sural nerve biopsy revealed segmental demyelination and remyelination. The density of myelinated fibers, especially small ones, was decreased in comparison with an age-matched control. Although the total number of unmyelinated fibers showed no difference from that in the control, the number of small unmyelinated fibers was slightly increased. A study of teased fibers from the patient's nerve revealed that 1% of the fibers had segmental demyelination, and 7% showed remyelination. Ultrastructurally, demyelinated fibers were present sporadically. No degeneration ofaxons was evident. Our pathological and morphometric data for the sural nerve suggest the presence of primary demyelination in early childhood. Key words: Cockayne syndrome, peripheral neuropathy, ultrastructure, morphometric study. Sasaki K, Tachi N, Shinoda M, Satoh N, Minami R, Ohnishi A. Demyelinating peripheral neuropathy in Cockayne syndrome: a histopathologic and morphometric study. Brain Dev 1992; 14:114-7
Cockayne syndrome (CS) is a rare autosomal recessive disorder [1], with characteristic features such as cachectic dwarfism, microcephaly, mental retardation, pigmentary retinal degeneration, sunken eyes, gait disturbance, neural deafness and intracranial calcifications [2-5]. Involvement of the peripheral nervous system in CS was first reported by Moosa and Dubowitz [6], who observed diminished tendon reflexes and slowed nerve conduction, with demyelination in sural nerve biopsy specimens. Thereafter, some studies have revealed the presence of demyelinating peripheral neuropathy electrophysiologically andj or pathologically [7-14]. However, no morpho-
From the Department of Pediatrics, Sapporo Medical College, Sapporo (KS, NT); Hakodate Municipal Public Health Center, Hakodate (MS); Department of Pediatrics, Hokkaido Prefectural Rehabilitation Center for Physically Handicapped Children, Sapporo (NS); National Sanatorium Yakumo Hospital, Yakumo (RM); and Department of Neurology, University of Occupational and Environmental Health, Kitakyushu (AD). Received for publication: October 14, 1991. Accepted for publication: February 9, 1992. Correspondence address: Dr. Kimio Sasaki, Department of Pediatrics, Hokkaido Prefectural Rehabilitation Center for Physically Handicapped Children, 2-2 Kanayama I-jo l-chome, Teine-ku, Sapporo 006, Japan.
metric studies of the peripheral nerves in CS of early childhood have yet been reported. Recently we studied the sural nerve of a 2-year-old girl with CS by electron microscopy and morphometric analysis. CASE REPORT The patient was born after an uncomplicated 41-week gestation. Her birth weight was 2,670 g. Head circumference was 31.0 cm. Weight gain was poor from infancy and head control was acquired at 2.5 months. Her mother noticed hypertonus of the lower limbs from the age of about 4 months. Acquisition of motor milestones was retarded: the patient became able to roll over at 7 months, sit unassisted at one year, and stand assisted at 2 years and 3 months. She was unable to walk with or without aid. She was able to speak one word before the age of one year, but thereafter her language acquisition and mental development were poor. She developed mild photosensitivity at one year. On examination at the age of 2 years and 4 months, she showed lower than average height and weight for age (76.3 cm, 7.7 kg), and microcephaly (head circumference 41.5 cm). Her facial appearance was peculiar, with sunken eyes. When she was standing with aid, anterior inclination of the trunk, equinovarus deformity of the right foot and
Fig 1 Cross-section of the sural nerve showing slightly diminished densi· ty of myelinated fibers. Arrow indicates a thinly myelinated fiber, showing remyelination (a: control; b: patient). Toluidine blue, x 840.
planovalgus of the left foot were noted. Muscle tonus of the lower limbs was increased (spastic diplegia). Patellar tendon reflexes were exaggerated, and pathological reflexes could not be elicited. Limited abduction of both hip joints was present. There was no hearing loss, and also no seizure disorder. Laboratory fmdings including CBC, results of liver function tests and serum protein levels were normal. The cerebrospinal fluid (CSF) contained 5 leukocytes/mm 3 , and CSF protein was 35 mg/dl. Analysis of serum and urinary amino acids showed normal fmdings. Funduscopic examination revealed pigmentary retinal degeneration and optic atrophy. Electroencephalography showed sporadic sharp waves in the left temporal area. The auditory brainstem responses (ABR) revealed prolongation of the latencies of waves III, IV and V without slowing of the 0-1 and I-II interpeak latencies. Motor and sensory nerve conduction velocities of the right median nerve were 33.6 mls and 45.5 mIs, respectively. X-ray examination of the hip joints showed subluxation of the femoral head on the right. CT scan revealed calcifications of the bilateral basal ganglia and mild ventricular enlargement with mild cerebellar atrophy. Cranial magnetic resonance imaging (MRI) revealed delayed myelination. An ultraviolet sensitivity test on cultured skin fibroblasts showed colony formation intermediate between that of normal controls and group A xeroderma pigmentosum (XP). Sural nerve biopsy fmdings The left sural nerve was biopsied under local anesthesia behind the external malleolus. The specimen was fixed in 2.5% glutaraldehyde in phosphate buffer, and then post-
Fig 2 A teased fiber showing segmental demyelination.
fixed with 1% OS04. One large part of the specimen was embedded in Epon. Semithin sections were stained with toluidine blue, and ultrathin sections, stained with uranyl acetate and lead citrate, were observed with a NipponDenshi 1200EX Electron Microscope. The rest of the specimen was immersed in glycerin for teased fiber preparation. In semithin sections of the nerve, the number of myelinated fibers appeared to be slightly decreased compared with an age-matched control (Fig 1). In addition, axons with thin myelination relative to axon size and demyelinated axons were occasionally observed. Teased fiber analysis revealed segmental demyelination and remyelination of myelinated fibers (Fig 2). One percent of teased fibers showed segmental demyelination, and 7% showed remyelinated internodes. On the other hand, teased fiber analysis of control nerves showed that 1% of fibers had thinly remyelinated internodes, and no segmental demyelination. On electron microscopy, demyelinated axons were occasionally found. They were usually surrounded by Schwann cells associated with, or without, macrophages containing lamellar structures which seemed to be myelin debris (Fig 3). Moreover, a few thinly myelinated fibers,
Sasaki e tal: Cockayne syndrome
115
which seemed to have been remyelinated, were observed. Onion bulb formations were not disclosed. The density of myelinated and unmyelinated fibers and their size distribution were evaluated. A size-frequency histogram showed that the density of myelinated fibers was slightly lower (12,167/mm 2 ) than that of the control (l9,337/mm 2 ). However, the density of large myelinated fibers was not different from that of the control. The decrease in the density was due to the reduction in density of small fibers « 4 pm) (Fig 4). The mean diameter of myelinated fibers was 4.4 pm, which was slightly larger than the control (3.3 pm). This was due to the relative decrease of small fibers. The density of unmyelinated fibers was 74,456/mm2 , and similar to that of the control (82,189/
Fig 3 Electron micrograph of the sural nerve shOWing a demye/ina ted axon surrounded by a Schwann cell associated with a phagocyte containing myelin debris. xII ,000.
mm 2 ). However, the relative density of small unmyelinated fibers was slightly greater (Fig 5). The mean diameter of unmyelinated fibers was 0.41 pm, which was slightly smaller than the control (0.52 pm).
DISCUSSION The present patient showed cachectic dwarfism, microcephaly, a typical facial appearance with sunken eyes, retinitis pigmentosa, mental retardation, gait disturbance (spastic diplegia), photosensitive dermatitis, limited abduction of both hip joints and slowed nerve conduction velocities. In addition to these clinical features, CT and MRI fmdings and the results of an ultraviolet hypersensitivity test of cultured skin fibroblasts were consistent with a diagnosis of CS. In our patient, hearing loss could not be proved. However, ABR revealed prolongation of the latencies of waves III to V, suggesting lesions in the pons and/or midbrain. It is known that CS is often associated with peripheral neuropathy [6,7,9-13], and that nerve conduction velocity is frequently reduced [6, 9-13, 15-19]. Sural nerve biopsies have been done in about 20 cases so far, 17 of which showed chronic demyelinating neuropathy [613, 20], and only a few showed no demyelination with or without a decrease in the density of myelinated fibers [14, 18]. The present patient is one of the youngest to have shown demyelination of the sural nerve. In previous studies of CS, morphometric analysis of the sural nerve has shown a decrease in the density of both large and small myelinated fibers [13,20], or only large myelinated fibers [9, 10, 12]. Ohnishi et al [13] reported decreased densities of both large and small myelinated fibers, and suggested the presence of primary segmental de- and remyelination in the sural nerve. In the present case, however, the density of small myelinated fibers was decreased. With regard to examination of biopsied sural
6,000
E 5,000
Patient
19,337 MF/mm'
12,167 MF/mm'
E
ffi 4,000
4,000
3,000
3.000
2,000
2,000
o
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20,000
IX: W
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o
IX:
~ :2
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82,189 UF/mml
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(i)
en u. u.
Patient
Control (2y)
Control (2y)
IX: 10,000
10.000
W
en
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:2
Z 1.000
:;)
Z
500 2
4
6
8
10
2
4
6
B
10
FIBER DIAMETER (/lm)
Fig 4 Myelinated fiber size-frequency histogram showing a mild loss of small fibers.
116 Brain & Development, Vol 14, No 2,1992
0.2
0.4
0.6
0.8
1.0
1.2
1.4
1.6
1.8
0.2
0.4
0.6
0.8
1.0
1.2
14
1.6
1.8
FIBER DIAMETER (/lm)
Fig 5 Unmyelinated fiber size-frequency histogram showing a slightly greater number of small fibers with a normal density of total fibers.
nerves from infants and young children, the following data have been reported. In a study on 2- and 3-year-olds by Vos et al [11], no morphometry was done. In a study by Goto and Ogawa [14] involving a 2-year-old, the total density of myelinated fibers was decreased and the histogram was not shown. In our present case, from the fact that relatively more demyelination was observed in small myelinated fibers, and also from the results of the morphometric study, it is suggested that the demyelination may have occurred first in small myelinated fibers. Concerning MRI of the brain in CS, primary hypomyelination or secondary demyelination has been suggested [21, 22]. These MRI findings are consistent with reported neuropathologic observations, which include atrophy of the white matter and patchy loss of myelinated fibers [5, 23,24]. Our observations and previous fmdings oflesions of the peripheral nerves in CS suggest the presence of primary segmental demyelination in the peripheral nervous system as well as in the central nervous system. Recently, molecular and cytological studies of CS have been carried out. In cells from CS patients, hypersensitivity to UV light [25], and a specific deficiency in the ability to repair damage in actively transcribed regions of DNA have been shown [26,27]. However, these results do not account for the mechanisms of demyelination and the difference in susceptibility to sunlight-induced skin cancer between CS and XP patients. Further studies will be needed to clarify the underlying biochemical and cytogenetic abnormalities. REFERENCES 1. McKusick VA. Mendelian inheritance in man. 7th ed. Baltimore·London: The Johns Hopkins University Press, 1986; 895-7. 2. Cockayne EA. Dwarfism with retinal atrophy and deafness. Arch Dis Child 1936;11:1-8. 3. Cockayne EA. Case reports: dwarfism with retinal atrophy and deafness. Arch Dis Child 1946;21: 52-4. 4. Neill CA, Dingwall MM. A syndrome resembling progeria: a review of two cases. Arch Dis Child 1950;25:213-21. 5. Sugarman GI, Landing BH, Reed WB. Cockayne syndrome: clinical study of two patients and neuropathologic findings in one. Clin Pediatr 1977;16:225-32. 6. Moosa A, Dubowitz V. Peripheral neuropathy in Cockayne's syndrome. Arch Dis Child 1970;45:674-7. 7. Roy S, Srivastava RN, Gupta PC, Mayekar G. Ultrastructure of peripheral nerve in Cockayne's syndrome. Acta Neuro· pathol (Berl) 1973;24:345-9. 8. Inoue N, Hanyu N, Takatsu M, Yanagisawa N, Tsukagoshi H. The Cockayne's syndrome with benign clinical course. A study of four cases from two families (in Japanese). Rinsho Shinkeigaku (Tokyo) 1978;18:477-85.
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