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Congenital hypomyelination neuropathy Glial bundles in cranial and spinal nerve roots.

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BRIEF COMMUNICATIONS AND CASE REPORTS
Congenital
Hypomy elination
Neuropathy: Glial Bundles
in Cranial and Stinal
Nerve Roots
A
Javad Towfighi, MD
Autopsy examination of a 3%-year-old child w i t h a severe congenital hypomyelination neuropathy showed
the anterior spinal nerve roots and motor cranial
nerves to be almost devoid o f myelin i n t h e i r subarachnoid course. The posterior spinal nerve roots a n d
peripheral nerves were less severely affected. O n i o n
b u l b formation was minimal and was present only i n
the sural nerve. There was extensive glial o v e r g r o w t h
i n cranial nerves a n d spinal nerve roots adjacent to the
brainstem a n d spinal cord. The extent a n d severity of
glial overgrowth were similar to that described i n
Werdnig-Hoffmann disease and morphologically appeared as glial bundles. These glial bundles are most
likely secondary to chronic myelin and axonal damage.
Towfighi J: Congenital hypomyelination
neuropathy : glial bundles in cranial and spinal
nerve roots. Ann Neurol 10:570-573, 1981
Extensive formation of glial b u n d l e s has b e e n d e scribed i n spinal and cranial n e r v e r o o t s of patients
with Werdnig-Hoffmann disease [2-51 and has b e e n
p r o p o s e d as the primary pathogenetic m e c h a n i s m for
the axonal and neuronal d e g e n e r a t i o n that occurs i n
t h e disorder [7]. This r e p o r t describes similar glial
bundles i n t h e spinal and cranial nerve r o o t s i n a patient with congenital hypomyelination of peripheral
nerves.
Case Report
The patient was initially seen in March, 1977, at the age of
3 months. H e was born after a full-term, uncomplicated
pregnancy, and there were no problems during delivery and
the neonatal period. His mother’s first pregnancy had produced a female child who died at 22 months of pneumonia
after an unknown neurological disorder characterized by
weakness, slow development, and elevated cerebrospinal
fluid (CSF) protein.
T h e patient fed poorly from the neonatal period onward
and gained weight poorly. At the age of 3 months he was
From the Department of Pathology, Milton S. Hershey Medical
Center of the Pennsylvania State University, Hershey, PA 17033.
Received Dec 8, 1980, and in revised form Mar 19, 1981. Accepted for publication May 2, 1981.
Address reprint requests to Dr Towfighi.
570
observed to be weak and hypotonic with diminished deep
tendon reflexes. Cranial nerves and sensation appeared intact, and the child seemed alert. T h e CSF was normal except for an elevation of total protein (344 and 484 pgldl)
due to an increase in CSF albumin. Electromyography
(EMG) showed only fibrillation upon insertion. Nerve
conduction velocity was slowed (right ulnar, 23 m/sec; right
median, 13 mfsec; right posterior tibial, 14 m/sec; right
peroneal, 13 d s e c ) . The parents did not show any EMG or
nerve conduction abnormalities. Various blood and urine
laboratory tests, including serum electrolytes, ammonia,
lactate, lipid panel, urine and blood amino acids, two urine
metabolic screens, serum protein electrophoresis, and
urine arylsulfatase, were within normal limits.
T h e boy sat at age 4 months, but lost this ability at 9
months and never regained it. H e could only roll from
prone to supine. At the age of 13 months he developed
swallowing difficulty necessitating a feeding gastrostomy.
Later he developed adynamic ileus, seizures, and pneumonia, and he died at age 39 months.
Materials and Methods
Biopsies of the left quadriceps muscle and left sural nerve
obtained at the age of 4 months and complete autopsy material at age 39 months were available for study. The sural
nerve biopsy was processed for routine paraffin sectioning
and staining and for 1 p thick epon embedding and electron microscopic sectioning. T h e quadriceps biopsy was
processed for paraffin sectioning and routine enzyme histoc hemistry.
Samples for paraffin sectioning were taken from all the
organs at autopsy, including various areas of cerebrum,
cerebellum, brainstem, spinal cord, optic nerves and retina,
and multiple cranial and spinal nerve roots with particular
emphasis o n their zone of exit from brainstem and cord. All
the sections were stained with hematoxylin and eosin.
Other stains such as lux01 fast blue and Bielschowsky’s
silver method were used when indicated. T h e peroxidaseantiperoxidase (PAP) method for demonstration of glial
fibrillary acidic protein [21] was used on paraffin sections
of nerve roots in order to determine the degree of astrocytosis. Various skeletal muscles including right quadriceps, psoas, and diaphragm were sampled and processed
for paraffin sectioning and routine muscle histochemistry .
For 1 p thick plastic sectioning and electron microscopy,
samples were taken from oculomotor nerves, vagus nerves
in the cervical region, spinal nerve roots and dorsal root
ganglia, right sural nerve at ankle level, and right obturator
nerve in the pelvis.
Results
T h e sural n e r v e biopsy s h o w e d thinly myelinated
a x o n s scattered t h r o u g h o u t the fascicles. O n l y occasional small o n i o n bulb formations made of a few
flattened Schwann cell processes a n d r e d u n d a n t
b a s e m e n t m e m b r a n e a r o u n d a myelinated axon w e r e
present. There was no a p p a r e n t loss of a x o n s w h e n
c o m p a r e d with a normal sural n e r v e from a 4m o n t h - o l d baby. The quadriceps biopsy did n o t show
abnormalities i n muscle fibers or in muscle spindles.
0364-5134/81/120570-04$01.25 @ 1981 by the American Neurological Association
B
Fig 1. Lumbar spinal roots, 2 cm away from cord. (A)Anterior root axons are virtually devoid of myelin (Toluidine blue,
x360). (B) Posterior root axons are less severely affected (Toluidine blue, X350).
Aside from pneumonia, the major findings at autopsy were limited to the nervous system. O n gross
examination there was no enlargement of peripheral
nerves. The spinal nerve roots and cranial nerves
(excluding optic and olfactory nerves) were thin and
had a dark gray appearance in most of their subarachnoid course except for a short, chalky white
segment (about 0.5 cm) near their exit from the central nervous system (CNS).
Light and electron microscopic examination of
sural and obturator nerves revealed many thinly
myelinated axons and a mild increase in endoneurial
connective tissue. Myelinated axons otherwise appeared normal, and no onion bulb formations were
seen. Vagus nerves in the neck contained small axons
not exceeding 5 p in diameter, and almost all the
axons were thinly myelinated or lacked myelin. A
mild to moderate increase in endoneurial connective
tissue was present. The cranial nerves (I11 through
VIII) in their subarachnoid course and the spinal
nerve roots showed axons of normal diameter but
F i g 2. Anterior lumbar spinal root 0.5 cm away from cord.
Many glial bundles are present (arrows).Most contain a
hypomyelinated axon (arrowheads). (Toluidine blue, X360
before 50% enlargement.)
devoid of myelin o r with very thin myelin (Fig 1).
Myelin of normal thickness resumed as these axons
entered the CNS. The motor cranial nerves and ventral spinal roots were more severely involved than
the sensory cranial nerves and dorsal spinal roots.
The Schwann cells investing the axons appeared
normal and were surrounded by a normal-appearing basement membrane.
Extensive formation of astrocytic fibers in the
nerve entry zone to the spinal cord and brainstem
was demonstrated by PAP stain for glial fibrillary
acidic protein. This glial overgrowth primarily involved the subpial region of the root entry zone to
the CNS and then extended into the nerve roots for a
distance of 0.5 to 1 cm. These fibers were arranged
into bundles (“glial bundles”) as the root emerged
from the CNS (Fig 2). The glial bundles were
oriented parallel to the nerve fibers and on cross section were seen to be made up of tongues of astrocytes
surrounded by a common basement membrane (Fig
3). The cell bodies of astrocytes were mostly located
Brief Communication: Towfighi: Glial Bundles in Nerve Roots
571
casional foci of group atrophy. Otherwise the muscle
fibers and muscle spindles were unremarkable.
F i g 3. Electron micrograph of anterior lumbar spinal root 0.5
cm away from cord, showing part of a glial bundle and enclosed
axon (AX) devoid of myelin. Arrowheads indicate basement
membrane surrounding the glial bundle; arrows, focal thirkenings of apposing membranes of astroglial processes. (GF =
glialfilaments.) ( ~ 2 0 , 0 0before
0
25 96 reduction.)
in the CNS. However, occasional astrocytic cell
bodies were found in sections 0.3 to 0.5 cm away
from the root entry zone. Frequently, an axon without myelin or with a very thin myelin sheath was
present in the center of each glial bundle. The
dorsal root ganglia showed many thinly myelinated
axons. However, the ganglion cells were unremarkable. No glial bundles or inflammatory cells were
present in the dorsal root ganglia.
The fasciculus gracilis and spinal trigeminal tract
showed mild loss of axons; the remaining axons appeared well myelinated. The anterior horn cells in
the lumbar and cervical prominence and neurons in
the cranial motor nerve nuclei, including hypoglossal,
vagus, and oculomotor nerves, showed mild atrophy
and appeared slightly decreased in number compared
with an age-matched normal control.
No other neuropathological alterations were found
except for mild hypoxic changes in the cerebral white
matter and basis pontis. Skeletal muscle showed oc-
572
Annals of Neurology
Vol 10 No 6
Discussion
Cases of congenital hypomyelination of peripheral
nerves and nerve roots similar to that in this patient
have been reported using various terms, such as congenital hypomyelination neuropathy [ 153, infantile
polyneuropathy with defective myelination [ 131,
hypertrophic interstitial polyneuropathy in infancy
[I], early infantile chronic neuropathy [ 171, and
Dejerine-Sottas disease [ 14, 201. Most patients have
had evidence of both sensory and motor neuropathy,
but in a few cases sensory abnormalities predominated [15, 161. The reported patients have shown
extensive onion bulb formations. The latter were
present only in the sural nerve in our patient. It is
clear that some clinical and pathological differences
exist among patients with congenital hypomyelination neuropathy and also between these cases and
patients with classic Dejerine-Sottas disease [ 8 ] .
Our patient showed extensive outgrowth of glial
fibers in the form of large bundles growing into the
cranial and spinal roots. Such outgrowths in nerve
roots have been described in a few pathological conditions in humans and experimental animals. These
include chronic P$’-iminodipropionitrile toxicity in
rats [9, 101, prenatal intoxication of mice with a
polychlorinated biphenyl [6], regeneration of nerve
roots following their transection in pigs [18, 191, late
stages of paralytic poliomyelitis in humans [ 121,
Kearns-Sayre syndrome [ 111, and Werdnig-Hoffmann disease [2-51. Some authors have even proposed that glial overgrowth plays a primary role
in the pathogenesis of Werdnig-Hoffmann disease
[7].The presence of numerous glial bundles in nerve
root entry zones in our patient makes this suggestion
doubtful. It would be difficult to explain hypomyelination of peripheral nervous system remote from
areas of astrogliosis by focal glial overgrowth in nerve
roots. But hypomyelination, or rather, demyelination, can readily be held responsible for astroglial
reaction and its overgrowth. It is likely that in
Werdnig-Hoffmann disease, the glial bundles in the
root exit zones from cord and brainstem also represent a secondary phenomenon, namely, a reaction to
axonal and neiironal degeneration.
The author wishes to thank Alan Parker for his technical assistance and Peggy Siegfried and Jeanne Vozzella for their help in
preparation of this manuscript.
References
1. Anderson RM, Dennett X, Hopkins IJ, Shield L K Hypertrophic interstitial polyneuropathy in infancy: clinical and
December 1981
pathologic features in two cases. J Pediatr 82:619-624,
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2. Chou SM: Infantile spinal muscular atrophy: correlation between alteration in anterior spinal roots and muscle fiber atrophy. In Kakulas BA (ed): Clinical Studies in Myology.
Amsterdam and New York, Excerpta Medica/American
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3. Chou SM: Myeloradiculopathology of Werdnig-Hoffmann
disease (WHD): a review of 43 cases. J Neuropathol Exp
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4. Chou SM: Glial bundles of nerve roots in Werdnig-Hoffmann
disease. Ann Neurol 8:79-81, 1980
5. Chou SM, Miike T, Eng LF: Studies of glial bundles in
Werdnig-Hoffmann disease (WHD) by the immunoperoxidase method. J Neuropathol Exp Neurol 38:307, 1979
6. Chou SM, Miike T , Payne WM, Davis GJ: Neuropathology of
“spinning syndrome” induced by prenatal intoxication with a
PCB in mice. Ann N Y Acad Sci 320:373-395, 1979
7. Chou SM, Nonaka 1: Werdnig-Hoffmann disease: proposal of
a pathogenetic mechanism. Actd Neuropathol (Berl) 4 1:
45-54, 1978
8. Dyck PJ: Inherited neuronal degeneration and atrophy affecting peripheral motor, sensory, and autonomic neurons. In
Dyck PJ, Thomas PK, Lambert E H (eds): Peripheral Neuropathy. Philadelphia, London, and Toronto, Saunders, 1975 , pp
825-867
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Williams & Wilkins, 1980, pp 161-178
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local axonal disease. J Neuropathol Exp Neurol 39:357, 1980
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Demyelinating radiculopathy in the Kearns-Sayre syndrome: a
clinicopathological study. Ann Neurol 8:373-380, 1980
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after paralytic anterior poliomyelitis. Ann Neurol4:562-563,
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13. Karch SB, Urich H : Infantile polyneuropathy with defective
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incidence. Neurology (Minneap) 26:565-573, 1976
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hypomyelination neuropathy: clinical, morphological, and
chemical studies. Arch Neurol 34:337-345, 1977
16. Koto A, Horoupian DS, Spiro A, Suzuki K, Torch WC: Sensory neuropathy with onion-bulb formation: a report of a
case with onset in infancy. Am J Dis Child 132:379-381,
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17. Lyon G : Ultrastructural study of a nerve biopsy from a case of
early infantile chronic neuropathy. Acta Neuropathol (Berl)
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18. Meier C , Sollmann H : Regeneration of cauda equina fibers
after transection and end-to-end suture. J Neurol2 15:81-90,
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19. Meier C, Sollmann H: Glial outgrowth and central-type
myelination of regenerating axons in spinal nerve roots following transection and suture. Neuropathol Appl Neurobiol
4:21-35, 1978
20. Moss RB, Sriram S , Kelts KA, Forno LS, Lewisron NJ:
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2 1. Sternberger LA: The unlabelled antibody peroxidase-antiperoxidase (PAP) method. In Sternberger LA (ed): Immunocyrochemistry. New York, Wiley, 1979, pp 104-169
Human Leukocyte
Antigen in Toriicollis
and Other Idiopathic
Dystonic Syndromes
Julius Korein, MD,* Ernest Willoughby, MD,t
Marilyn S. Pollack, PhD,t Lucie Levidow,”
and Bo D u p o n t , M D t
Two groups totaling 67 patients with idiopathic focal,
segmental, and generalized dystonia, including torticollis, were compared with normal controls to determine whether there was a difference in the frequency of A, B, and C locus human leukocyte (HLA)
antigens. The results indicated no statistically significant deviations in HLA antigen frequencies between the patients and the normal controls. Thirteen
of the patients with idiopathic torsion dystonia were
compared with normal controls for DR locus antigens.
A trend of increased DR3 antigens observed in the patients may be significant. HLA genotyping of parents
and children in nine families was also studied to determine if an HLA-linked factor could be related to the
dystonic syndrome in the children. The results were
indeterminate, suggesting that further family studies
are required to resolve this issue.
Korein J, Willoughby E, Pollack MS, Levidow L,
D u p o n t B: H u m a n leukocyte antigen in torticollis
and o t h e r idiopathic dystonic syndromes.
A n n Neurol 10:573-575, 1981
Hereditary factors have been implicated in idiopathic torsion dystonia (ITD), including torticollis
and other segmental and focal dystonias [5-71. Since
deviations in human leukocyte antigen (HLA) frequencies have been found in relation to other
neurological disorders [2], we decided to test
whether a specific HLA factor might be related to
these dystonic syndromes. T h e first approach was to
compare the frequencies of HLA in a group of patients with dystonic syndromes against those of a
normal population. The second approach was to
perform family studies to detect the possible presence of HLA linkage [4, 111.
From the “Department of Neurology, New York University
Medical Center (and BelIevue Hospital Center), 550 First Ave,
New York, N Y 10016, and the +Tissue Typing Laboratory,
Sloan-Kettering Institute for Cancer Research, New York, N Y
10021.
Received Apr 2, 1981, and in revised form Apr 30. Accepted for
publication May 11, 1981.
Address reprint requests to D r Korein
0364-5 134/81/120573-03$01.25@ 1981 by t h e American Neurological Association
573
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