Peripheral nerve involvement in familial chorea-acanthocytosis

Journal of the Neurological Sciences, 1986, 76:347-356 Elsevier

347

JNS 2743

Peripheral Nerve Involvement in Familial Chorea-Acanthocytosis Gen Sobue, Eiichiro Mukai, Katsuro Fujii, Terunori Mitsuma and Akira Takahashi Fourth Department of Internal Medicine, Aichi Medical University,Nagakute, Aichi 480-11 and Department of Neurology, Nagoya University School of Medicine, Tsurumai, Nagoya 466 (Japan) (Received 2 April, 1986) (Revised, received 25 June, 1986) (Accepted 27 June, 1986)

SUMMARY

Myelinated fibers and neuronal cell bodies of the ventral spinal outflow and primary sensory neurons were histopathologically examined in a patient with familial chorea-acanthocytosis and age-matched controls. The patient exhibited a marked loss of large myelinated axons and their neuronal cell bodies in the ventral spinal outflow, while there was frequent occurrence of axonal sprouts. Large myelinated fibers in sensory afferents were also decreased in number. Segmental de- and remyelination was markedly increased in teased fiber preparations of both motor and sensory peripheral nerves.

Key words: Familial chorea-acanthocytosis- Motor neuron loss - Peripheral neuropathy

INTRODUCTION

More than 40 patients (Levine et al. 1960, 1968; Cdtchley et al. 1967, 1968; Estes et al. 1967; Aminoff 1972; Toyokura et al. 1981; Gross et al. 1985; Spitz et al. 1985) including at least 5 autopsied patients (Bird et al. 1978; Iwata et al. 1984; Sato et al. 1984; Namba et al. 1985; Yamada et al. 1985) with familial chorea-acanthocytosis without fl-lipoproteinemia have been reported. Also, the pathological characteristics of the central nervous system in the caudate nucleus, putamen and pallidum were documented (Bird et al. 1978; Iwata et al. 1984; Sato et al. 1984; Namba et al. 1985; Yamada et al. 1985). Accumulating evidence suggests peripheral nerve involvement in 0022-510X/86/$03.50 © 1986 Elsevier Science Publishers B.V. (Biomedical Division)

348 this disease: systemic neurogenic amyotrophy, sensory disturbances particularly in vibration sense (Toyokura et al. 1981; Spitz et al. 1985), electromyographic abnormalities (Massey et al. 1986), and some abnormal findings in muscle and sural nerve biopsies (Lantos and Aminoff 1972; Ohnishi et al. 1981; Limos et al. 1982). In this study, we demonstrate the remarkable involvement of peripheral nerves particularly in spinal motor neurons in one autopsied case. CASE REPORT

A 57-year-old man complained of progressive choreatic involuntary movements, epileptic seizures, and muscular weakness in limbs. Since about the age of 40 years, he had generalized tonic-clonic seizures that could not be controlled by anticonvulsant drugs. At the age of 50 years, he noticed weakness in the proximal portion of the lower limbs as well as upper limbs. At that time, dysarthric speech and oro-lingual involuntary movement deteriorated and extended to the upper and lower limbs. There was no consanguinity between his parents. Two of his brothers were similarly affected. Orientation and understanding were well preserved and his I.Q. was 84 (WAIS). There was choreatic involuntary movement in peri-oral region and tongue, and in the proximal portion of the upper and lower limbs. He spoke in slurred dysarthric manner and was unable to retain saliva in his mouth. He was barely able to walk due to muscular weakness and involuntary movement in legs. Muscular weakness and atrophy was severe in all muscles in the upper limbs, but was mild to moderate in the lower limbs. Muscle-stretch reflexes were generally absent without Babinski's sign. Sensation of vibration was moderately impaired in the lower limbs, but other sensations were intact. Acanthocytes eiectron-microscopically confa'med, comprised 28 ~o of total red blood cells. Serum CPK was 1704 mU/ml (normal: 21-107 mU/ml). Serum lipid levels including fl-lipoprotein were within normal range. Results of CSF examination were normal. CT scan showed moderate dilatation of lateral ventricles and caudate atrophy. In EEG, sporadic wave discharge and the burst of sharp and spike waves were noted. The electromyographic examination showed a typical chronic neurogenic pattern with abundant giant spikes. Maximal motor conduction velocities in median and posterior tibial nerves were 47.7 and 41.3 m/s, respectively, and sensory conduction in the median nerve was 37.1 m/s. In December 1984, he died of septicemia secondary to pneumonia. Postmortem pathological f'mdings of the central nervous system were as follows: caudate nucleus was atrophic bilaterally with almost complete depletion of neurons and marked astrogliosis; giobus pallidus and putamen were also slightly atrophic with moderate neuronal loss and reactive mild astrogliosis. Other structures including the cerebral cortex, white matter, cerebellum, nuclei of brain stem, tracts of spinal cord appeared normal under light microscopy.

349 METHODS

At autopsy, specimens were collected from the ventral and dorsal spinal roots, dorsal column at T7, sciatic nerve and sural nerve, and fixed in 2~o giutaraldehyde in 0.1 M phosphate buffer pH 7.4, at room temperature. Finally, they were cut into 1 #m-thick transverse sections, embedded in epoxy resin and stained with toluidine blue. Fiber size distribution and density ofmyelinated fibers were estimated as described previously (Sobue et al. 198 la, b). One portion of each nerve was processed for teased fiber preparations and was morphologically evaluated by the criteria as described before (Sobue et al. 198 la, b). Ventral horn cells in the lateral nuclear group larger than 25 #m in diameter were numerically evaluated (Sobue et al. 1983, 1986), and expressed as the number per 10 sections. Five patients (age from 37 to 68 years), who died of nonneurological disorders, served as controls. RESULTS

Motor neuron cell bodies in the ventral spinal horn of the present case were severely depleted and only small neuronal cells were occasionally present (Fig. 1). However, there was considerable topographical variation in the population of the remaining ventral horn ceUs in the spinal segments; cervical spinal segments were most severely involved (11, 10, 8, 85 and 166 large neurons per 10 sections in C6, T6, TT, IA and L5, respectively, in the patient; 113 _+ 23, 14 _ 3, 155 _ 30 and 158 _ 27 in C6, T6, IA and L5, respectively, in controls). Myelinated axons in the ventral roots were also decreased, but clusters of small or thin myelinated fibers, occasionaUy surrounding large myelinated fibers, were frequently observed (Fig. 1). Histograms of the fiber size distribution of myelinated fibers in ventral spinal roots confLrmed that large myelinated fibers were predominantly diminished in number, while the population of small myelinated fibers was well preserved or even increased in IA ventral roots (Fig. 2A). Dorsal root ganglion cell bodies were apparently well preserved though somewhat atrophic, and the incidence of nodules of Nageotte was indistinguishable from that observed in controls (Fig. 1). No remarkable peaks of large myelinated fibers were noted in histograms of the posterior spinal roots, or sciatic and sural nerves (Figs. 2A and B). Particularly in the patient's L4 dorsal spinal root, the peak of large myelinated fibers shifted to the left and small myelinated fiber population was apparently increased (Figs. 2A and B). In teased fiber preparations, the frequency of segmental de- and remyelination was significantly increased in aLlthe nerves examined (31.4 7o at C6 ventral roots, 26.7 7O at IA ventral root, 35.77o at posterior root and 11.87o at sural nerve in the patient; 7.3 _+ 3.0, 4.9 _ 0.7, 8.5, 3.6 _+ 2.3 in controls, respectively). The percentages of fibers showing active axonal degeneration with linear-rows of myelin ovoids in the patient were 2.9~o at C6 ventral root, 10.07o at LA ventral root, 07o at L4 posterior root and 07o in sural nerves compared with 0.5_ 0.8, 0.4 _+ 0.8, 0.4_ 0.8, respectively, in the controls.

350

Fig. 1. Transverse section of C6 ventral spinal root (A and B), ventral horn of C6 spinal cord (C and D) and IA dorsal root ganglia (E and F ) from the patient and controls. A: C6 ventral spinal root of the patient. Note the decrease in fiber density and multiple clusters of small myelinated fibers. Toluidine blue, x 490. B: C6 ventral spinal root of a control case. x 490. C: Ventral horn of C6 spinal cord from the patient. K - B staining, x 75. D: Ventral horn of C6 spinal cord from a control case, x 75. E and F: IA dorsal root ganglia from the patient and a control case. H - E , x 300.

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353 DISCUSSION Values of fiber populations and pattern of fiber size distribution obtained in control specimens were fairly consistent with those reported previously (Kawamura and Dyck 1977; Dyck et al. 1981, 1985; Ohnishi et al. 1979, 1981; Sobue et al. 1981a, b, 1983). The most prominent change in the peripheral motor and sensory systems of our patient was loss in ventral horn cells and their axons, especially in large motor neurons and large axons. The degree of severity in neuronal and axonal loss, however, varied considerably with the spinal segments. More severe reduction in cells and axons in cervical segments than lumbar segments well corresponded to muscular wasting, which was more severe in the upper limbs than lower legs. Some studies reported no significant pathological changes in the spinal cord

A

PATIENT

CONTROL

C6V 2000

Large MF 6494±1006

Larle MF 897 Small MF 1479

Small MF 1950±341

1000

5

10

15

5

10

15

T7V 2000

1000 x z

~ "

5

Larle MF 1676± 320

1274 3758

10

1'5

5

10

15

L4V 2000

Large MF 3536 Smell MF 2349

Larse MF 6308±402 Small MF 1127+-493

1000

5

10

15

5

10

15

FIBER DIAMETER (pro)

Figs. 2.4 and B. Frequencydistribution of diameters ofmyelinatedfibers of ventral spinal outflow,fasciculus gracilis, dorsal spinal root, sciatic nerve and sural nerve in patient and controls. Columns of histogram and bars for controls represent mean values and 1 standard deviation for 3-5 control cases. Population of large and smallmyelinatedfibers per root in the ventral spinal outflowand densityof myelinatedfibers in sensory afferents and sciatic nerve are indicated in each panel.

354 B

CONTROL

PATIENT

4000 Fasciculus gracilis

3000 Total

2000

MF 20100

L,

1000

10

F 24196-+3647

1~5

10

1!5

4000 -

L4P

3000 -

MF 2826 Small MF 13899

Lari[e MF 4808-+370

Large

2000 -

8±2195

1000 E E 10

115

5

10

i

15

x Sciatic

2000

nerve

MF 3500 Smalr MF 7450

Larae MF 4699±597 Small MF 0171-+612

Large

1000

i

L

~

i 10

a_ 15

5

10

1~5

Sural

2000

nerve

~

7

Large MF 2425 0 0

4 L a r gMF e 3043± 696

1000

5

10

15

5

10

15

FIBER DIAMETER(pm)

though muscle wasting was obvious (Bird et al. 1978; Iwata et al. 1984; Sato et al. 1984). Individual differences or more possibly remarkable segmental variation in spinal myotome in motoneuron involvement, as observed in this patient, may be the reason for this discrepancy. Large myelinated fibers in sural nerve and posterior spinal roots were slightly decreased in the patient. The findings in the sural nerve were in agreement with a report on morphometry of sural nerve biopsy from the patients with similar diseases (Olmishi et al. 1981). Sensory afferent system was, however, significantly less involved than the motor system.

355 Another feature in this patient was abundant clusters o f thin myelinated fibers occasionally surrounding the large myelinated fibers, suggesting the occurrence o f sprouting process ofmyelinated fibers. Increased fiber populations in the small diameter range, particularly in the patient's ventral spinal outflow might partly consist of atrophic fibers originating from larger ones, but we speculate that the frequent occurrence of sprouting is also responsible for the increased number o f these small fibers. The high incidence o f segmental de- and remyelination was one of the major pathological changes throughout m o t o r and sensory axons in our patient. However, our findings were not direct to satisfy the criteria of axonal atrophy leading to secondary segmental demyelination (Dyck et al. 1981). The high incidence o f fibers with segmental de- and remyelination with moderate to severe axonal loss, particularly in ventral roots, the slight but definite increase in fibers undergoing active axonal degeneration, the leftward shift o f large myelinated fiber peaks, especially in sensory afferents, and the negligible decrease in motor and sensory conduction velocity despite such copious segmental demyelination suggest that the segmental de- and remyelination observed in the present patient are secondary in nature to axonal changes (Dyck et al. 1981). REFERENCES Aminoff, M.J. (1972) Acanthocytosis and neurological disease, Brain, 95: 749-760. Bird, T. D., S. Cederbaum, R.W. Volpeyand W. L. Srache (1978) Familial degeneration of the basal ganglia with acanthocytosis - - A clinical, neuropathological, and neurochemical study, Ann. Neurol., 3: 253-258. Critchley, E.M.R., D.B. Clark and A. Wilder (1967) An adult form of acanthocytosis, Trans. Amer. Neurol. Ass., 92: 132-137. Critchley, E.M.R., D.B. Clark and A. Wilder (1968) Acanthocytosis and neurological disorder without betalipoproteinemia, Arch. Neurol. (Chic.), 18: 134-140. Dyck, P.J., A.C. Lais, J.L. Karnes et al. (1981) Permanent axotomy, a model of axonal atrophy and secondary segmental demyelination and remyelination, Ann. Neurol., 9: 575-585. Dyck, P. J., J. Karnes, A. Lals, E. P. Lofgren and J.C. Stevens (1985) Pathologic alterations of the peripheral nervous system of human. In: P.J. Dyck, P.K. Thomas, E. Lambert and R. Bunge (Eds.), Peripheral Neuropathy, W.B. Saunders, pp. 760-870. Estes, J. W., T. J. Morley, I. M. Levine and C. P. Emerson (1967) A new hereditary acanthocytosis syndrome, Amer. J. Med., 42: 868-881. Gross, K.B., J.A. Skrivanek, K.C. Carlson and D.M. Kaufman (1985) Familial amyotrophic chorea with acanthocytosis. New clinical and laboratory investigations, Arch. Neurol. (Chic.), 42: 753-756. Iwata, M., S. Fuse, M. Sakuta and Y. Toyokura (1984) Neuropathological study of chorea-acanthocytosis, Jap. J. Med., 23: 118-132. Kawamura, Y. and P.J. Dyck (1977) The morphometric myelinated fiber composition of D11 as compared to L3, L4 and L5 ventral spinal roots of man, J. Neuropath. Exp. Neurol., 36: 846-852. Lantos, P.L. and M.J. Aminoff (1972) Fine structural changes in the sural nerve of patients with acanthocytosis, Acta Neuropath. (Berl.), 22: 257-263. Levine, I.M., M. Yettra and M. Stefanini (1960) A hereditary neurological disorder with acanthocytosis (Abstract), Neurology (Minneap.), 10: 425. Levine, I. M., J. W. Estes and J. M. Looney (1968) Hereditary neurological disease with acanthocytosis,Arch. Neurol. (Chic.), 19: 403-409. Limos, L., A. Ohnishi, T. Sakal, N. Fujii, I. Goto and Y. Kuroiwa (1982) "Myopathic" changes in chorea-acanthocytosis, J. Neurol. Sci., 55: 49-58. Massey, J., E. Massey and M. Bowmann (1986) Electromyographic characterization of neuropathy in choreo-acanthocytosis, Neurology (Minneap.), 36 (Suppl. 1): 116. Namba, M., T. Tamura, M. Uematsu, K. Morita, Y. Kaiya, T. Ogasawara and M. Kakezawa (1985) One autopsied case of chorea-acanthocytosis, Procs. 26th Meeting Jap. Soc. Neuropathology.

356 Ohnishi, A., M. Ikeda and J. Tateishi (1979) Morphometry of myelinated fibers of sural nerve, L5 spinal roots and faseiculus graeilis and of cytons of L5 spinal ganglion of man, Neurol. Med. (Tokyo), 11: 160-168. Ohnishi, A., Y. Sato, H. Nagara, T. Sakal, H. Iwashita, Y. Kuroiwa, T. Nakamura and K. Shida (1981) Neurogenic muscular atrophy and low density of large myelinated fibers of sural nerve in ehoreaacanthocytosis, J. Neurol. Neurosurg. Psychiat., 44: 645-648. Sato, Y., A. Ohnishi, J. Tateishi, Y. Onizuka, S. Ishimoto, H. Iwashita, Y. Kuroiwa and I. Kanazawa (1984) An autopsy case of ehorea-aeanthoeytosis, special reference to the histopathologieal and biochemical findings of basal ganglia, Brain and Nerve (Tokyo), 36:105-111. Sobue, G., Y. Matsuoka, E. Mukai, T. Takayanagl, I. Sobue and Y. Hashizume (1981a) Spinal and cranial motor nerve roots in amyotrophic lateral sclerosis and X-linked recessive bulbospinal muscular atrophy, Acta Neuropath. (Berl.), 55: 227-235. Sobue, G., Y. Matsuoka, E. Mukai, T. Takayanagi and I. Sobue (1981b) Pathology of myelinated fibers in cervical and lumbar ventral spinal roots in amyotrophic lateral sclerosis, J. Neurol. Sci., 50: 413-421. Sobue, G., K. Sahashi, A. Takahashi, Y. Matsuoka, T. Muroga and I. Sobue (1983) Degenerating compartment and functioning compartment of motor neuron in ALS - - Possible process of motor neuron loss, Neurology (Cleveland), 33: 654-657. Sobue, G., Y. Hashizurne, M. Ohya and A. Takahashi (1986) Shy-Drager syndrome - - Size, function and topography dependent neuronal loss in ventral spinal outflow, Neurology (Cleveland), 36: 404-407. Spitz, M. K., J. Jankovic and J. M. Killian (1985) Familial tie disorder, parkinsonism, motor neuron disease, and acanthocytosis m A new syndrome, Neurology (Cleveland), 35: 366-370. Toyokura, Y., K. Kamakura and Y. Shimada (1981) Familial chorea-acanthocytosis (The Levine-Critchley syndrome) - - A review of the reported cases in Japan. In: Annual Report Ministry of Welfare and Health of Japan, Report on the Research for Neurodegenerative Disorder, pp. 335-351. Yamada, T., K. Hirayama and J. Akai (1985) One autopsied case of chorea-acanthocytosis, Procs. 26th Meeting Neuropathology.