the neuropathy of cockayne syndrome

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Acta Neuropathol (Berl) (1983) 61:153 - 156 Acta Neuropathologica Springer-Verlag 1983 The Neuropathy of Cockayne Syndrome A. Vos 1, A. Gabre~ls-Festen t, E. Joosten 1'2, F. Gabre~ls, W. Renier 1, and R. Mullaart 3 1 Institute of Neurology, 2 Department of Submicroscopic Morphology, and 3 Institute of Pediatrics, Radboud University Hospital, Box 9101, NL-6500 HB Nijmegen, The Netherlands Summary. We studied three unrelated infants and three adolescent siblings with Cockayne syndrome. The infants showed severe psychomotor retardation. Neurologic manifestations in the siblings were less severe and only slowly progressive. All patients had slowed peripheral nerve conduction. Nerve biopsies demonstrated segmental demyelination and remyelin- ation in each case. In the infantile cases this process was severe and rapidly progressive; in the juvenile cases it was mild and chronic. Distinctive membrane-bound polymorphous inclusions were found in occasional Schwann cells. Key words: Cockayne syndrome - Neuropathy - Segmental demyelination - Schwann cell inclusions Introduction Involvement of the peripheral nervous system (PNS) in Cockayne syndrome (CS) was first reported by Moosa and Dubowitz [11]. Their patient had sluggish tendon reflexes, slowed nerve conduction and segmental de- myelination on sural nerve biopsy. Nerve conduction studies of other cases [1 -7, 9, 12, 13, 16] revealed that PNS involvement, with few exceptions [6, 8, 17], is common in CS. The histopathology of the PNS lesion, however, is still open for discussion because segmental demylination, as in the case of Moosa and Dubowitz [11], was reported in only three other cases [6, 12, 16]; nerve biopsies in five other patients with slowed nerve conduction revealed only nonspecific alterations [9] or none at all [4, 7, 13]. Offprint requests to : Dr. F. Gabreals (address see above) Material and Methods The criteria for diagnosis in these patients are presented in Table 1 ; all or nearly all of the principal features [14] were present. The patients had healthy and unrelated parents. Birth weights were normal or low normal. The three infants (cases 1 - 3) developed slowly from the first months of life and, at the time of study, they showed severe psychomotor retardation. The three adolescent patients (cases 4- 6) were siblings with a mild illness; neurologic manifestations appeared late (approximately at age 3 years) and progressed slowly. Late onset and mild course probably explain why the characteristic feature of microcephaly was not seen. In the youngest sibling (case 4) neurologic disability was still slight. A detailed report of these siblings has been presented elsewhere [14]. Reduced tendon jerks and distal amyotrophy were present in the eldest sibling. In the other patients there were no clinical signs of neuropathy. Nerve conduction, however, was slowed in all six cases (for motor fibers in the median nerve this is shown in Fig. 1 ; slowing in other motor nerves was in the same range). Digital nerve action potentials were low or unobtainable. Electromyography (EMG) revealed a chronic neurogenic lesion in the eldest sibling; in the other patients EMG was normal. Sural nerve biopsies were performed at the midcalf level. In case 3, only the obturator nerve (biopsied at adductor tenotomy oper- ation) was examined. Cryostat sections of the nerves were stained with hematoxylin-eosin, toluidine blue, Sudan Black B, periodic acid Schiff and cresyl violet (yon Hirsch-Pfeiffer), and were also used for demonstration of various enzyme activities, including acid phos- Table 1. Diagnostic criteria Patient no. l 2 3 4 5 6 Age (yr) 2 2 Dwarfism + + Mental retardation + + Senile appearance + + Microcephaly + + Central motor disturbances + + Photosensitive dermatitis + § Retina pigmentation + - Intracerebral calcifications + + 3 13 16 19 + § + + + & + + + + + + + + + + + + + + + + § +

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Page 1: The neuropathy of Cockayne syndrome

Acta Neuropathol (Berl) (1983) 61:153 - 156 Acta Neuropathologica �9 Springer-Verlag 1983

The Neuropathy of Cockayne Syndrome

A. Vos 1, A. Gabre~ls-Festen t, E. Joosten 1'2, F. Gabre~ls, W. Renier 1, and R. Mullaart 3

1 Institute of Neurology, 2 Department of Submicroscopic Morphology, and 3 Institute of Pediatrics, Radboud University Hospital, Box 9101, NL-6500 HB Nijmegen, The Netherlands

Summary. We studied three unrelated infants and three adolescent siblings with Cockayne syndrome. The infants showed severe psychomotor retardation. Neurologic manifestations in the siblings were less severe and only slowly progressive. All patients had slowed peripheral nerve conduction. Nerve biopsies demonstrated segmental demyelination and remyelin- ation in each case. In the infantile cases this process was severe and rapidly progressive; in the juvenile cases it was mild and chronic. Distinctive membrane-bound polymorphous inclusions were found in occasional Schwann cells.

Key words: Cockayne syndrome - Neuropathy - Segmental demyelination - Schwann cell inclusions

Introduction

Involvement of the peripheral nervous system (PNS) in Cockayne syndrome (CS) was first reported by Moosa and Dubowitz [11]. Their patient had sluggish tendon reflexes, slowed nerve conduction and segmental de- myelination on sural nerve biopsy. Nerve conduction studies of other cases [1 - 7 , 9, 12, 13, 16] revealed that PNS involvement, with few exceptions [6, 8, 17], is common in CS. The histopathology of the PNS lesion, however, is still open for discussion because segmental demylination, as in the case of Moosa and Dubowitz [11], was reported in only three other cases [6, 12, 16]; nerve biopsies in five other patients with slowed nerve conduction revealed only nonspecific alterations [9] or none at all [4, 7, 13].

Offprint requests to : Dr. F. Gabreals (address see above)

Material and Methods

The criteria for diagnosis in these patients are presented in Table 1 ; all or nearly all of the principal features [14] were present. The patients had healthy and unrelated parents. Birth weights were normal or low normal. The three infants (cases 1 - 3) developed slowly from the first months of life and, at the time of study, they showed severe psychomotor retardation. The three adolescent patients (cases 4 - 6) were siblings with a mild illness; neurologic manifestations appeared late (approximately at age 3 years) and progressed slowly. Late onset and mild course probably explain why the characteristic feature of microcephaly was not seen. In the youngest sibling (case 4) neurologic disability was still slight. A detailed report of these siblings has been presented elsewhere [14].

Reduced tendon jerks and distal amyotrophy were present in the eldest sibling. In the other patients there were no clinical signs of neuropathy. Nerve conduction, however, was slowed in all six cases (for motor fibers in the median nerve this is shown in Fig. 1 ; slowing in other motor nerves was in the same range). Digital nerve action potentials were low or unobtainable. Electromyography (EMG) revealed a chronic neurogenic lesion in the eldest sibling; in the other patients EMG was normal.

Sural nerve biopsies were performed at the midcalf level. In case 3, only the obturator nerve (biopsied at adductor tenotomy oper- ation) was examined. Cryostat sections of the nerves were stained with hematoxylin-eosin, toluidine blue, Sudan Black B, periodic acid Schiff and cresyl violet (yon Hirsch-Pfeiffer), and were also used for demonstration of various enzyme activities, including acid phos-

Table 1. Diagnostic criteria

Patient no.

l 2 3 4 5 6

Age (yr) 2 2

Dwarfism + + Mental retardation + + Senile appearance + + Microcephaly + + Central motor disturbances + + Photosensitive dermatitis + § Retina pigmentation + - Intracerebral calcifications + +

3 13 16 19

+ § + + + & + + + + + + + + + + + + + + +

- - + § +

Page 2: The neuropathy of Cockayne syndrome

154 A. Vos et al. : Neuropathy of Cockayne Syndrome

phatase. Part of the specimen was fixed in 2 ~ glutaraldehyde buffered with sodium cacodylate pH 7.4, postfixed in 2 % OsO4 in Palade buffer pH 7.4 and after dehydration in aicohoI embedded in Epon 812. Semi-thin sections of this block, stained with uranyl acetate and lead citrate, were examined under the light microscope. Ultra-thin sections of the same block were similarly stained and examined in a Philips EM 300. From each sural nerve approximately 40 single myelinated fibers, each with a minimum of 4 internodes, were teased from one fascicle fixed in 2 % calcium chloride and 4 formaldehyde and postfixed in 1 ~ OsO4 in 0.1 M phosphate buffer pH 7.4.

Velocity m/s

8O

60.

40

20

. . . . . . . . . . . . +2 SD

~ ' ' ' - - m e a n " c o n t r o l

- . - 2 S D

I . . . . . . . . . . . .

5 1~0 1~5 20~ "' Age (years I

Fig. 1. Conduction velocity in motor fibers of left median nerve in forearm

Results

In the three infants (cases 1 - 3) cross-sections of the nerves revealed several demyelinated axons and many recently remyelinated axons, but virtually no onion bulbs (Fig. 2). There was no evidence of axonal de- generation. Teased fiber study (cases 1 and 2) im- pressively confirmed the severity of the myelinopathy (Table 2). In the youngest sibling (case 4), myelinated fibers in cross-sections showed no abnormalities except occasional evidence of recent remyelination. Segmental de- and remyelination was convincingly demonstrated in this nerve, however, on teased fiber study. In the eldest sibling (case 6) cross-sections revealed only a few demyelinated axons, many recently remyelinated axons and a large number of onion bulbs (Fig. 3). Small clusters were observed sporadically. Teased fibers also provided an impressive view of the lesion. In the remaining sibling (case 5) mild segmental de- and remyelination with some formation of onion bulbs was found. Abnormalities in this nerve were less pro- nounced than in the eldest sibling.

In a small number of Schwann cells, associated with myelinated as well as unmyelinated axons, a large amount of membrane-bound polymorphous inclusion material was evident (Fig. 4). These large inclusions did not contain lamellar material derived from myelin, nor were they comparable with later stages of myelin degeneration. They displayed an electron-dense ground substance in which were embedded vacuoles with a

Fig. 2, Cross-section of sural nerve (case 2). Several axons are completeiy demyelinated (closed arrows) or recently remyelinated (open arrows). No significant formation of onion bulb structures

Page 3: The neuropathy of Cockayne syndrome

A. Vos et al. : Neuropathy of Cockayne Syndrome 155

granular or membraneous content. They were seen in the infantile and juvenile cases.

Discussion

Our study provides further histopathologic data of the PNS lesion in CS. On physical examination, PNS involvement was inapparent in all but case 6. Slow nerve conduction, however, was constant (Fig. 1). The biopsies revealed that the neuropathy is characterized by segmental demyelination and remyelination. In the severely retarded infants (cases 1 - 3) this process was severe and rapidly progressive, with widespread de- myelinated and recently remyelinated segments but virtually no onion bulbs. A less severe and much slower

Table 2. Summary of neuropathic findings

process of de- and remyelination was observed in the slowly deteriorating siblings (cases 4-6) , where PNS abnormalities gradually developed from a very mild lesion in the early years of the disease (case 4) to a moderately severe neuropathy with prominent onion bulbs seen later (case 6). In most of our patients de- and remyelination was conspicuous in teased fiber prepara- tions; the lesion in the very mildly disabled youngest sibling (case 4) could have been overlooked if only cross-sections of the nerve had been studied. Therefore the lesion may have been missed in the negative biopsy studies of these patients with slow nerve conduction [4, 7, 9, 13] but no teased fiber studies.

Our data leave little doubt that, in CS, the de- myelination, which is one of the hallmarks of CNS

Case Age Cross-sections (yrs)

Demyelination Recent remyelination

Onion bulbs

Teased fiber preparations

Fibers with Fibers with demyelinated remyelinated segments (%)" segments (%)"

1 2 + + +_ 2 2 + + • 3 b 3 + + _+

4 13 - _+ - 5 16 + + 6 19 • + + +

9 24 24 31

3 17 2 20 6 24

" Control values: fibers with demyelinated segments: 0 %; fibers with remyelinated segments: < 4 % b Obturator nerve: no teased fibers obtained

Fig.3. Cross-section of sural nerve (case 6). Many myelinated fibers are surrounded by one or more layers of Schwann cell processes (onion bulbs). Several fibers show evidence of recent remyelination. Myelinated fiber density is clearly decreased

Page 4: The neuropathy of Cockayne syndrome

156 A. Vos et al.: Neuropathy of Cockayne Syndrome

Fig. 4. Membrane-bound inclusions with small vacuoles closely arranged together in an electron-dense homogenous ground substance are visible in a Schwann cell. This Schwann cell is part of an unmyelinated fiber containing a number of tmmyelinated axons (A)

pathology [15], usually involves the PNS as well. We confirm previous suggestions [11] that CS presents features of a generalized progressive leukodystrophy. A distinctive additional feature in our cases was the membrane-bound polymorphous inclusions in oc- casional Schwann cells (Fig. 4). They could be evidence of a lysosomal storage disease, but other interpretations are possible. They occurred in both myelinated and unmyelinated fibers and the ultrastructural characteris- tics do not suggest an origin in degenerated myelin. Similar material has probably been seen in another infantile case, described as coarsely granular electron- dense material [I0]. Acknowledgement. The authors are grateful to Dr. S. Notermans for nerve conduction studies.

References 1. Bensman A, Brauner M, Teboul-Faur~ L, Faur~ C (1978) Le

syndrome de Cockayne. Une entit~ radiologique. Apropos de deux observations familiales. J Radiol Electrol 59:375-380

2. Brumback RA, Yoder FW, Andrews AD, Peck GI, Robbins JH (1978) Normal pressure hydrocephalus. Recognition and re- lationship to neurological abnormalities in Cockayne's syn- drome. Arch Neurol 35 : 337 - 345

3. Cunningham M, Godfrey S, Moffat WMV (1978) Cockayne's syndrome and emphysema. Arch Dis Child 53:722-725

4. Gamstorp I (1972) Donohue's syndrome - Leprechaunism - Cockayne's syndrome. Eur Neurol 7: 26-- 33

5. Hashimoto T, Hiura K, Kobayashi Y (1978) Cockayne's syn- drome: report of two sisters and review of literature in Japan. Brain Dev (Tokyo) 10:465- 472

6. Inone K, Hanyu N, Takatsu M, Yanagisawa N, Tsukagoshi H (1979) The Cockayne's syndrome with benign clinical course. A

study of four cases from two families. Rinisho Shinkeigaku 18 : 477 - 485

7. Jin KH, Handa T, Ishihara T, Yoshii F (1979) Cockayue syndrome: report of two siblings and review of literature in Japan. Brain Dev (Tokyo) 4: 305- 312

8. Kennedy RM, Rowe VD, Kepes JJ (1980) Cockayne syndrome: an atypical case. Neurology (Minneap) 30:1268-1272

9. Lanzi G, Calligaro A, Danesino C, Rosano Burgio F, Verri AP (1976) La sindrome di Cockayne (studio di due casi). Min Ped 28:1597-1608

10. Lewis RA, Grunnet ML, Zimmerman AW (1982) Peripheral nerve demyelination in Cockayne's syndrome (abstract). Muscle Nerve 5 : 557

11. Moosa A, Dubowitz V (1970) Peripheral neuropathy in Cockayne's syndrome. Arch Dis Child 45:674-677

12. Roy S, Srivastava RN, Gupta PC, Mayekar G (1973) Ultrastructure of periperal nerve in Cockayne's syndrome. Acta Neuropathol (Berl) 24: 345- 349

13. See G, Dayras J-C1, Brodin M, Llewellyn D (1974) Syndrome de Cockayne et encrphalopathie 6volutive. Ann Pediatr 21:215- 221

14. Smits MG, Gabre~ls FJM, Renier WO, Joosten EMG, Gabre~ls- Festen AAWM, ter Laak HJ, Pinckers AJL, Hombergen GCJ, Notermans SLH, Thijssen HOM (1982) Peripheral and central myelinopathy in Cockayne's syndrome. Report of 3 siblings. Neuropediatrics 13:161 - 167

15. Softer D, Grotsky HW, Rapin I, Suzuki K (1979) Cockayne syndrome. Unusual neuropathological findings and review of the literature. Ann Neurol 6: 340 -- 348

16. Srivastava RN, Gupta PC, Mayekar G, Roy S (1974) Cockayne's syndrome in two sisters. Acta Paediatr Scand 63:461-464

17. Sugarman GI, Landing BH, Reed WB (1977) Cockayne syn- drome: clinical study of two patients and neuropathologic findings in one. Clin Pediatr 16 : 225- 232

Received March 24, 1983/Accepted May 27, 1983